WO1993013100A1 - Method for producing bis-pyridinic derivatives with acetylcholinesterase inhibiting properties - Google Patents

Method for producing bis-pyridinic derivatives with acetylcholinesterase inhibiting properties Download PDF

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Publication number
WO1993013100A1
WO1993013100A1 PCT/ES1992/000086 ES9200086W WO9313100A1 WO 1993013100 A1 WO1993013100 A1 WO 1993013100A1 ES 9200086 W ES9200086 W ES 9200086W WO 9313100 A1 WO9313100 A1 WO 9313100A1
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Prior art keywords
hydrogen
process according
tetrahydro
nmr
diquinoline
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PCT/ES1992/000086
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Spanish (es)
French (fr)
Inventor
Pelayo Camps Garcia
Mª Dolores PUJOL DILME
Joan Contrepas Lascorz
Diana Marina GÖRBIG ROMEU
Diego MUÑOZ-TORRERO LOPEZ-IBARRA
Montserrat Simon Fornell
Albert Badia Sancho
Josep E. BANOS DIEZ
Félix BOSCH LLONCH
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Boehringer Ingelheim España S.A.
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Publication of WO1993013100A1 publication Critical patent/WO1993013100A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • This invention describes a process for obtaining bis-pyridine derivatives and their pharmaceutically acceptable acid addition salts having therapeutic applications.
  • a process for obtaining bis-pyridine compounds that produce an increase in acetylcholine at the central level either by inhibition of the action of acetylcholinesterase or by other mechanisms of action and which are useful for treating various dysfunctions of memory characterized by decreased function, such as Alzheimer's disease or senile dementia of the Alzheimer type.
  • tacrine (9-amino- 1,2,3,4-tetrahydroacridine) which is an acetyl cholinesterase inhibitor and administered in combination with lecithin (intravenously) is useful in the treatment of Alzheimer's disease has the disadvantage of its high toxicity [WK Summers, KR Kaufman, F. Altman, Jr. and JM Fischer, Clin. Toxicol., 16, 269 (1980)].
  • the present invention describes a process for obtaining bis-pyridine compounds, designed by molecular duplication of tricyclic anticholinesterics structurally related to tacrine, and their pharmaceutically acceptable acid addition salts, represented by general structures I and II
  • R is hydrogen, alkyl or aralkyl
  • m, n, p, q can take the values 0, 1, 2, 3, .. so that m + n --- p + q ⁇ 9.
  • X and Y represent "connection bridges" that can be independent or linked together, directly through a link, and / or through one or more "suitable moieties".
  • R x hydrogen, halogen, lower alkoxy or lower alkyl.
  • alkyl represents a hydrocarbon moiety of one to six carbon atoms with straight, branched, cyclic, substituted cyclic or cycloalkyl chains. alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, etc.).
  • aralkyl means phenylalkyl or phenylalkyl substituted on phenyl, containing 7 to 13 carbon atoms.
  • alkyl in “phenylalkyl” or “phenylalkyl. Substituted in phenyl 11" means a straight chain alkylene group containing one to four carbon atoms (eg, methylene, ethylene, trimethylene, tetramethylene).
  • phenylalkyl substituted on phenyl is a phenyl group containing a substituent selected from the group consisting of halogen (for example fluorine, chlorine, bromine and iodine), lower alkyl which includes alkyl groups containing one to four carbon atoms with chains linear or branched (for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl), and lower alkoxy which includes a linear or branched chain alkoxy group containing one to four carbon atoms (for example methoxy , ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy)
  • aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4- phenylbutyl 2- (4-methoxyphenyl) ethyl, 2- (2-methylphenyl) ethyl, 2 - (4-fluor
  • connection bridges means a bond, an atom (for example: oxygen, sulfur, ...) or a substituted atom (for example: NR 2 or CH-R 2 , where R 2 can be hydrogen, alkyl or aralkyl with the same meanings given previously for R).
  • suitable residues that can connect the “connection bridges” means a grouping of the type (CH 2 ) rZ- (CH 2 ) s, where rys can take the values zero, one, two, three or four, and Z represents a bond, a vinyl, ortho-phenylene, ortho-phenylene group substituted with an R 3 group, an oxygen atom, sulfur or the NR 4 or CH-R 4 groupings.
  • the substituent R 3 can adopt the same values given previously to Rj ..
  • R 4 in NR 4 and in CH-R 4 can adopt the same values given above to R.
  • Examples of -X-, -Y- are set out in the following:
  • halogen represents a fluorine, chlorine, bromine and iodine atom.
  • lower alkoxy means a straight or branched chain alkoxy group containing one to four carbon atoms (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy).
  • lower alkyl means an alkyl group containing straight or branched chains of one to four carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl).
  • pharmaceutically acceptable inorganic or organic acid addition salts means salts formed with inorganic acids such as: hydrochloric, hydrobromic, sulfuric and nitric acids and organic acids such as: tartaric, succinic, maleic, aric and citric.
  • the process object of this patent involves the reaction of dicarbonyl compounds of general structure III with aminonitriles of general structure IV in the presence of a suitable solvent and an acid of Le is as a catalyst, a reaction that leads directly to compounds with the general structure I and / or II, with the values defined above for A, -X- and -Y, m, n, p, q, with R equal to hydrogen.
  • the compounds of general structure V derived from the reaction of III with a single equivalent of IV, are also obtained as by-products. Compounds V can become important, if the reaction conditions are conveniently chosen.
  • the compounds of general structure I, II and V obtained in these reactions are separable by conventional procedures, for example: column chromatography, or selective dissolution with different solvents and subsequent crystallization, either in the form of free bases or their addition salts of organic or inorganic acids.
  • dicarbonyl compounds of general structure III -X-, -Y-, m, n, p, q, they have the same meanings given above for I and II, being essential that in the pairs m / n, p / q, one of the values is equal to or greater than one, that is, that there is always at least one methylene group in alpha-carbonyl position with respect to each ketone grouping.
  • compounds of general structure IV A has the meaning given above in relation to I and II.
  • the Lewis acid used as a catalyst in the condensation of the diketones III with the aminonitriles IV to give the derivatives of general structure I and / or II and V, with R equal to hydrogen can be, among others, aluminum trichloride, dichloride Zinc, titanium tetrachloride, etc. All of them anhydrous.
  • aprotic solvents should be used, for example: nitrobenzene, 1,2-dichloroethane, dichloromethane, dimethylformamide, among others.
  • the reaction is carried out at temperatures between 0 and 150 [ deg.] C. with reaction times ranging from 1 to 48 hours, depending on the type of catalyst and solvent used.
  • the pharmaceutically acceptable salt formation reactions of the compounds of general structure I, II and V are carried out by conventional methods, by reacting the organic compound with an organic or inorganic acid in an appropriate solvent, such as water, alcohols (for example, methanol, ethanol, isopropanol, etc.) or ethers (ethyl ether, tetrahydrofuran, dioxane, etc.).
  • an appropriate solvent such as water, alcohols (for example, methanol, ethanol, isopropanol, etc.) or ethers (ethyl ether, tetrahydrofuran, dioxane, etc.).
  • Derivatives I, II and V and their acid addition salts may be administered orally or parenterally in the form of conventional pharmaceutical preparations, such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally in the form of solutions or emulsions, etc. They can be applied directly to the rectum, in the form of suppositories.
  • the preparations may contain physiologically acceptable carriers, excipients, activators, chelating agents, stabilizers. etc. In the case of injectables, physiologically acceptable buffers, solubilizing or isotonic agents may be incorporated.
  • the daily dose may vary depending on the symptoms of the disease, age, body weight of patients, mode of administration, etc., and the normal dose of an adult varies between 1 and 500 mg divided into several doses. up to date.
  • the mono and bis-pyridine derivatives were tested at the following concentrations ( ⁇ M): 0.1; 0.3; one; 3; 10; 30. The results are expressed as the average of at least six experiments considering the corresponding standard deviation.
  • the compound 6,7,8,15-Tetrahydro-7,15-methane-cyclooctene [1,2-b: 5,4-b '] diquinoline-14,16-diamine has the following antagonism indices: at concentration 3 ⁇ M, 19.7 + 5.8; at 10 ⁇ M, 52.7 + 1 and at 30 ⁇ M, • 68.1 + 5.1.
  • the ability to inhibit acetylcholinestera from mono- and bis-pyridine derivatives was determined by the colorimetric method of Ellman et al.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Method for obtaining bis-pyridinic derivatives having formulae (I) and (II) wherein R is hydrogen, alkyl or aralkyl, m, n, p, q may have the values 0, 1, 2, 3... providing that m + n + p + q < 9. X and Y may represent 'connection bridges' which may be independent or joined to each other, directly through a bond, and/or through one or a plurality of 'appropriate residues'. (a) is (b) or (c), R1 being hydrogen, halogen, alkoxy or alkyl. The pharmacological tests of mono and bis-pyridinic derivatives of the invention have been initiated with the study of the reversion of the blocking effect of tubocurarine, with the valuation of the anticholinesterase activity.

Description

PROCEDIMIENTO PARA LA OBTENCIÓN DE DERIVADOS BIS-PIRIDINICOS CON PROPIEDAD INHIBIDORAS DE LA ACETILCOLINESTERASA Esta invención describe un procedimiento para la obtención de derivados bis-piridínicos y sus sales de adición de ácidos farmacéuticamente aceptables que tienen aplicacio¬ nes terapéuticas. En particular, un procedimiento de obten¬ ción de compuestos bis-piridínicos que producen un aumento de la acetilcolina a nivel central, ya sea por inhibición de la acción de la acetilcolinesterasa o por otros mecanismos de acción y que son útiles para tratar varias disfunciones de la memoria caracterizadas por una función disminuida, tales como la enfermedad de Alzheimer o la demencia senil de tipo Alzheimer.PROCEDURE FOR OBTAINING BIS-PYRIDINIC DERIVATIVES WITH INHIBITING PROPERTY OF ACETILCOLINESTERASE This invention describes a process for obtaining bis-pyridine derivatives and their pharmaceutically acceptable acid addition salts having therapeutic applications. In particular, a process for obtaining bis-pyridine compounds that produce an increase in acetylcholine at the central level, either by inhibition of the action of acetylcholinesterase or by other mechanisms of action and which are useful for treating various dysfunctions of memory characterized by decreased function, such as Alzheimer's disease or senile dementia of the Alzheimer type.
Es bien conocido que el nivel de acetilcolina en el cerebro de pacientes que padecen la enfermedad de Alzheimer está disminuido, habiéndose estudiado si la fisostig ina, que es un inhibidor de la acetilcolinesterasa, es útil en el tratamiento de la demencia senil [F. M. Hershenson y W. H. Moos, J. Med. Chem. 29, 1125-1130 (1986)]. También, se ha descritoque derivados del 9-amino-l,2,3,4-tetrahidroaσridin- -l-ol [G. M. Shutske, F. A. Pierrat, K. J. Kapples, M. L. Cornfeldt, M. R. Szewczak, F. P. Huger, G. M. Bores, V. Haroutunian y K. L. Davis, J. Med. Chem. 32, 1805-1813 (1989)] y otros compuestos relacionados [J. B. Campbell, Jr. , M. T. M. Bare, Patente US 4.546.104 (1985); H. Kawaka i, R. Ohuchi, M. Kitano, K. Ono, Patente EP 268.871 (1987); E. F. Lavretskaya, A. V. Upadysheva, P. Znamenskaya, S. A. Sukhano- va, N. D. Grigorieva, I. K. Penke y A. K. Timofeeva, Patente US 4.735.953 (1988); G. M. Shutske y K. J. Kapples, Patente US 4.753.950 (1988); G. M. Shutske, Patente US 4.762.841 (1988); M. Kitano, R. Ohuchi, K. Ono, Patente EP 394.950 (1990)], tienen también acción inhibidora de la acetilcoli- nesterasa.It is well known that the level of acetylcholine in the brain of patients suffering from Alzheimer's disease is decreased, having studied whether fisostig ina, which is an acetylcholinesterase inhibitor, is useful in the treatment of senile dementia [F. M. Hershenson and W. H. Moos, J. Med. Chem. 29, 1125-1130 (1986)]. Also, it has been described that derivatives of 9-amino-l, 2,3,4-tetrahydroaσridin- -l-ol [G. M. Shutske, FA Pierrat, KJ Kapples, ML Cornfeldt, MR Szewczak, FP Huger, GM Bores, V. Haroutunian and KL Davis, J. Med. Chem. 32, 1805-1813 (1989)] and other related compounds [J . B. Campbell, Jr., M. T. M. Bare, US Patent 4,546,104 (1985); H. Kawaka i, R. Ohuchi, M. Kitano, K. Ono, EP 268,871 (1987); E. F. Lavretskaya, A. V. Upadysheva, P. Znamenskaya, S. A. Sukhanova, N. D. Grigorieva, I. K. Penke and A. K. Timofeeva, US Patent 4,735,953 (1988); G. M. Shutske and K. J. Kapples, US Patent 4,753,950 (1988); G. M. Shutske, US Patent 4,762,841 (1988); M. Kitano, R. Ohuchi, K. Ono, EP 394,950 (1990)], also have an acetylcholinesterase inhibitory action.
Por otro lado, es conocido que la tacrina (9-amino- 1,2,3,4-tetrahidroacridina) que es un inhibidor de la acetil¬ colinesterasa y que administrada en combinación con lecitina (por vía intravenosa) es útil en el tratamiento de la enfermedad de Alzheimer presenta el inconveniente de su elevada toxicidad [W. K. Summers, K. R. Kaufman, F. Altman, Jr. y J. M. Fischer, Clin. Toxicol., 16, 269 (1980)].On the other hand, it is known that tacrine (9-amino- 1,2,3,4-tetrahydroacridine) which is an acetyl cholinesterase inhibitor and administered in combination with lecithin (intravenously) is useful in the treatment of Alzheimer's disease has the disadvantage of its high toxicity [WK Summers, KR Kaufman, F. Altman, Jr. and JM Fischer, Clin. Toxicol., 16, 269 (1980)].
La presente invención describe un procedimiento para la obtención de compuestos bis-piridínicos, diseñados por duplicaciónmolecular de anticolinesterásicos tricíclicos relacionados estructuralmente con la tacrina, y sus sales de adición de ácidos farmacéuticamente aceptables, representados por las estructuras generales I y IIThe present invention describes a process for obtaining bis-pyridine compounds, designed by molecular duplication of tricyclic anticholinesterics structurally related to tacrine, and their pharmaceutically acceptable acid addition salts, represented by general structures I and II
Figure imgf000004_0001
Figure imgf000004_0001
en donde R es hidrógeno, alquilo o aralquilo, m, n, p, q pueden adoptar los valores 0, 1, 2, 3,.. de modo que m + n --- p + q < 9.where R is hydrogen, alkyl or aralkyl, m, n, p, q can take the values 0, 1, 2, 3, .. so that m + n --- p + q <9.
X e Y representan "puentes de conexión" que pueden ser independientes o estar unidos entre sí, directamente por medio de un enlace, y/o a través de uno o más "restos adecuados".X and Y represent "connection bridges" that can be independent or linked together, directly through a link, and / or through one or more "suitable moieties".
Figure imgf000004_0002
Figure imgf000004_0002
siendo Rx hidrógeno, halógeno, alcoxi inferior o alquilo inferior.R x hydrogen, halogen, lower alkoxy or lower alkyl.
En las definiciones anteriores:In the previous definitions:
El término "alquilo" representa un resto hidrocar- bonado de uno a seis átomos de carbono con cadenas lineales, ramificadas, cíclicas, cíclicas sustituidas o cicloalquil- alquílicas (por ejemplo: metilo, etilo, propilo, isopropilo, butilo, sec-butilo, pentilo, ciclopentilo, ciclopentilmeti- lo, ciclohexilo, etc.).The term "alkyl" represents a hydrocarbon moiety of one to six carbon atoms with straight, branched, cyclic, substituted cyclic or cycloalkyl chains. alkyl (for example: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, etc.).
El término "aralquilo" significa fenilalquilo o fenilalquilo sustituido en el fenilo, conteniendo de 7 a 13 átomos de carbono. El término "alquilo" en "fenilalquilo" o "fenilalquilo. sustituido en el fenilo11 significa un grupo alquileno de cadena lineal conteniendo de uno a cuatro átomos de carbono (por ejemplo, metileno, etileno, trimetileno, tetrametileno) . El fenilo sustituido en "fenilalquilo susti¬ tuido en el fenilo" es un grupo fenilo conteniendo un sustituyente seleccionado del grupo consistente en halógeno (por ejemplo flúor, cloro, bromo y yodo), alquilo inferior que incluye grupos alquilo conteniendo de uno a cuatro átomos de carbono con cadenas lineales o ramificadas (por ejemplo metilo, etilo, propilo, isopropilo, butilo, sec-butilo y tere-butilo), y alcoxi inferior que incluye un grupo alcoxi de cadena lineal o ramificada conteniendo de uno a cuatro átomos de carbono (por ejemplo metoxi, etoxi, propoxi, isopropoxi, butoxi y sec-butoxi). Ejemplos de tales grupos aralquilo incluyen bencilo, fenetilo, 3-fenilpropilo, 4- fenilbutilo 2-(4-metoxifenil)etilo,2-(2-metilfenil)etilo,2- (4-fluorofenil)etilo, 4-(4-clorofenil)butilo.The term "aralkyl" means phenylalkyl or phenylalkyl substituted on phenyl, containing 7 to 13 carbon atoms. The term "alkyl" in "phenylalkyl" or "phenylalkyl. Substituted in phenyl 11" means a straight chain alkylene group containing one to four carbon atoms (eg, methylene, ethylene, trimethylene, tetramethylene). "phenylalkyl substituted on phenyl" is a phenyl group containing a substituent selected from the group consisting of halogen (for example fluorine, chlorine, bromine and iodine), lower alkyl which includes alkyl groups containing one to four carbon atoms with chains linear or branched (for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl), and lower alkoxy which includes a linear or branched chain alkoxy group containing one to four carbon atoms (for example methoxy , ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy) Examples of such aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4- phenylbutyl 2- (4-methoxyphenyl) ethyl, 2- (2-methylphenyl) ethyl, 2 - (4-fluorof enyl) ethyl, 4- (4-chlorophenyl) butyl.
La expresión "puentes de conexión" significa un enlace, un átomo (por ejemplo: oxígeno, azufre,...) o un átomo sustituido (por ejemplo: N-R2 ó CH-R2, en donde R2 puede ser hidrógeno, alquilo o aralquilo con los mismos significa¬ dos dados anteriormente para R) .The term "connection bridges" means a bond, an atom (for example: oxygen, sulfur, ...) or a substituted atom (for example: NR 2 or CH-R 2 , where R 2 can be hydrogen, alkyl or aralkyl with the same meanings given previously for R).
La expresión "restos adecuados" que pueden unir los "puentes de conexión" significa una agrupación del tipo (CH2)r-Z-(CH2)s, en donde r y s pueden adoptar los valores cero, uno, dos, tres o cuatro, y Z representa un enlace, un grupo vinileno, orto-fenileno, orto-fenileno sustituido con un grupo R3, un átomo de oxígeno, azufre o las agrupaciones N-R4 ó CH-R4.The expression "suitable residues" that can connect the "connection bridges" means a grouping of the type (CH 2 ) rZ- (CH 2 ) s, where rys can take the values zero, one, two, three or four, and Z represents a bond, a vinyl, ortho-phenylene, ortho-phenylene group substituted with an R 3 group, an oxygen atom, sulfur or the NR 4 or CH-R 4 groupings.
El sustituyante R3 puede adoptar los mismos valores dados anteriormente a Rj..The substituent R 3 can adopt the same values given previously to Rj ..
El sustituyente R4 en N-R4 y en CH-R4, puede adoptar los mismos valores dados anteriormente a R. Ejemplos de -X-, -Y- se recogen en lo que sigue:The substituent R 4 in NR 4 and in CH-R 4 , can adopt the same values given above to R. Examples of -X-, -Y- are set out in the following:
—CH-CH2-CH- I I
Figure imgf000006_0002
—CH-CH 2 -CH- II
Figure imgf000006_0002
Figure imgf000006_0001
Figure imgf000006_0001
En el contexto de Rx: El término halógeno representa un átomo de flúor, cloro, bromo y yodo.In the context of R x : The term halogen represents a fluorine, chlorine, bromine and iodine atom.
El término alcoxi inferior significa un grupo alcoxi de cadena lineal o ramificada conteniendo de uno a cuatro átomos de carbono (por ejemplo metoxi, etoxi, propoxi, isopropoxi, butoxi y sec-butoxi).The term "lower alkoxy" means a straight or branched chain alkoxy group containing one to four carbon atoms (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy).
El término alquilo inferior significa un grupo alquilo conteniendo cadenas lineales o ramificadas de uno a cuatro átomos de carbono (por ejemplo metilo, etilo, propilo, isopropilo, butilo, sec-butilo y tere-butilo). El término sales de adición de ácidos orgánicos o inorgánicos farmacéuticamente aceptables significa sales formadas con ácidos inorgánicos como: clorhídrico, bromhídri- co, sulfúrico y nítrico y ácidos orgánicos como: tartárico, succínico, maleico, fu árico y cítrico. El procedimiento objeto de esta patente implica la reacción de compuestos dicarbonílieos de estructura general III con aminonitrilos de estructura general IV en presencia de un disolvente adecuado y de un ácido de Le is como catali¬ zador, reacción que conduce directamente a compuestos con la estructura general I y/o II, con los valores definidos anteriormente para A, -X- e -Y, m, n, p, q, con R igual a hidrógeno. En esta reacción se obtienen además como subpro¬ ductos, los compuestos de estructura general V, procedentes de la reacción de III con un sólo equivalente de IV. Los compuestos V pueden llegar a ser importantes, si se eligen convenientemente las condiciones de reacción. Los compuestos de estructura general I, II y V obtenidos en estas reacciones son separables por procedimientos convencionales, por ejemplo: cromatografía en columna, o disolución selectiva con diferentes disolventes y posterior cristalización, bien en forma de bases libres o de sus sales de adición de ácidos orgánicos o inorgánicos.The term "lower alkyl" means an alkyl group containing straight or branched chains of one to four carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tere-butyl). The term pharmaceutically acceptable inorganic or organic acid addition salts means salts formed with inorganic acids such as: hydrochloric, hydrobromic, sulfuric and nitric acids and organic acids such as: tartaric, succinic, maleic, aric and citric. The process object of this patent involves the reaction of dicarbonyl compounds of general structure III with aminonitriles of general structure IV in the presence of a suitable solvent and an acid of Le is as a catalyst, a reaction that leads directly to compounds with the general structure I and / or II, with the values defined above for A, -X- and -Y, m, n, p, q, with R equal to hydrogen. In this reaction, the compounds of general structure V, derived from the reaction of III with a single equivalent of IV, are also obtained as by-products. Compounds V can become important, if the reaction conditions are conveniently chosen. The compounds of general structure I, II and V obtained in these reactions are separable by conventional procedures, for example: column chromatography, or selective dissolution with different solvents and subsequent crystallization, either in the form of free bases or their addition salts of organic or inorganic acids.
(CH2)-X-(CH2)n NH, do de Le is o 0 QΓ Aci(CH 2 ) -X- (CH 2 ) n NH, do Le or 0 QΓ Aci
CNCN
(CH^-Y-ÍCH^q m IV(CH ^ -Y-ÍCH ^ q m IV
Figure imgf000007_0001
Figure imgf000007_0001
II
Figure imgf000007_0002
Figure imgf000007_0002
En los compuestos dicarbonílicos de estructura general III, -X-, -Y-, m, n, p, q, tienen los mismos signifi¬ cados dados anteriormente para I y II, siendo imprescindible que en las parejas m/n, p/q, uno de los valores sea igual o superior a uno, es decir, que siempre exista al menos un grupo metileno en posición alfa-carbonílica respecto de cada agrupación cetónica. En los compuestos de estructura general IV, A tiene el significado dado anteriormente en relación con I y II.In the dicarbonyl compounds of general structure III, -X-, -Y-, m, n, p, q, they have the same meanings given above for I and II, being essential that in the pairs m / n, p / q, one of the values is equal to or greater than one, that is, that there is always at least one methylene group in alpha-carbonyl position with respect to each ketone grouping. In compounds of general structure IV, A has the meaning given above in relation to I and II.
Los compuestos de estructura general I o II y V en los que R es diferente de hidrógeno se obtienen por alquilación o aralquilación de los compuestos de estructura general I o II en los que R es hidrógeno de acuerdo con métodos descritos [G. M. Shutske y K.J. Kapples, patente US 4.753.950 (1988)].Compounds of general structure I or II and V in which R is different from hydrogen are obtained by alkylation or aralkylation of compounds of general structure I or II in which R is hydrogen according to methods described [G. M. Shutske and K.J. Kapples, US Patent 4,753,950 (1988)].
El ácido de Lewis utilizado como catalizador en la condensación de las dicetonas III con los aminonitrilos IV para dar los derivados de estructura general I y/o II y V, con R igual a hidrógeno, puede ser, entre otros, tricloruro de aluminio, dicloruro de zinc, tetracloruro de titanio, etc. todos ellos anhidros. Como disolvente en estas reacciones deben utilizarse disolventes apróticos, por ejemplo: nitrobenceno, 1,2-dicloroetano , diclorometano, dimetilforma- mida, entre otros. La reacción se efectúa a temperaturas comprendidas entre 0 y 150βC con tiempos de reacción que varían entre 1 y 48 horas, dependiendo del tipo de cataliza- dor y disolvente utilizados.The Lewis acid used as a catalyst in the condensation of the diketones III with the aminonitriles IV to give the derivatives of general structure I and / or II and V, with R equal to hydrogen, can be, among others, aluminum trichloride, dichloride Zinc, titanium tetrachloride, etc. All of them anhydrous. As solvent in these reactions, aprotic solvents should be used, for example: nitrobenzene, 1,2-dichloroethane, dichloromethane, dimethylformamide, among others. The reaction is carried out at temperatures between 0 and 150 [ deg.] C. with reaction times ranging from 1 to 48 hours, depending on the type of catalyst and solvent used.
Las reacciones de formación de sales farmacéutica¬ mente aceptables de los compuestos de estructura general I, II y V, se efectúa por métodos convencionales, haciendo reaccionar el compuesto orgánico con un ácido orgánico o inorgánico en un disolvente apropiado, tales como agua, alcoholes (por ejemplo, metanol, etanol, isopropanol, etc.) o éteres (éter etílico, tetrahidrofurano, dioxano, etc.).The pharmaceutically acceptable salt formation reactions of the compounds of general structure I, II and V are carried out by conventional methods, by reacting the organic compound with an organic or inorganic acid in an appropriate solvent, such as water, alcohols ( for example, methanol, ethanol, isopropanol, etc.) or ethers (ethyl ether, tetrahydrofuran, dioxane, etc.).
Los derivados I, II y V y sus sales de adición de ácidos pueden administrarse por vía oral o parenteral en forma de preparados farmacéuticos convencionales, tales como tabletas, cápsulas, jarabes y suspensiones. Alternativamen¬ te, pueden administrarse por vía parenteral en forma de soluciones o emulsiones, etc. Pueden aplicarse directamente al recto, en forma de supositorios. Las preparaciones pueden contener transportadores aceptables fisiológicamente, exci¬ pientes, activadores, agentes quelantes, estabilizadores. etc. En el caso de inyectables pueden incorporarse tampones fisiológicamente aceptables, agentes solubilizantes o isotónicos. La dosis diaria puede variar dependiendo de los síntomas de la enfermedad, de la edad, del peso corporal de los pacientes, del modo de administración, etc., y la dosis normal de una persona adulta varía entre 1 y 500 mg dividido en varias tomas al día.Derivatives I, II and V and their acid addition salts may be administered orally or parenterally in the form of conventional pharmaceutical preparations, such as tablets, capsules, syrups and suspensions. Alternatively, they can be administered parenterally in the form of solutions or emulsions, etc. They can be applied directly to the rectum, in the form of suppositories. The preparations may contain physiologically acceptable carriers, excipients, activators, chelating agents, stabilizers. etc. In the case of injectables, physiologically acceptable buffers, solubilizing or isotonic agents may be incorporated. The daily dose may vary depending on the symptoms of the disease, age, body weight of patients, mode of administration, etc., and the normal dose of an adult varies between 1 and 500 mg divided into several doses. up to date.
Los siguientes son ejemplos de compuestos obtenidos de acuerdo con el procedimiento objeto de la presente inven¬ ción:The following are examples of compounds obtained according to the process object of the present invention:
Figure imgf000009_0001
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000010_0001
Acontinuación se dan algunos ejemplos ilustrativos del procedimiento para, obtener derivados bis-piridínicos, objeto de la presente patente de invención, que no deben considerarse como limitativos del alcance de la misma.Below are some illustrative examples of the process for obtaining bis-pyridine derivatives, object of the present invention patent, which should not be considered as limiting the scope thereof.
Ejemplo 1Example 1
Preparaciónde 12-amino-6H-7,8,10,ll-tetrahidro-7,11-metano- ciclo-octeno[b]quinolin-9-ona; 6,7,8,15-tetrahidro-7,15-meta- nocicloocteno [l,2-b:5,4-b']diquinolina-14,16-diamina;6,7, 14,15-tetrahidro-7,15-metanocicloocteno[1,2-b:5,6-b']diqui- nolina-8,16-diaminaPreparation of 12-amino-6H-7,8,10, ll-tetrahydro-7,11-methane-cyclo-octene [b] quinolin-9-one; 6,7,8,15-tetrahydro-7,15-methanocyclooctene [1, 2-b: 5,4-b '] diquinoline-14,16-diamine; 6.7, 14,15-tetrahydro-7 , 15-methanocyclooctene [1,2-b: 5,6-b '] diquinoline-8,16-diamine
Figure imgf000010_0002
Figure imgf000010_0002
Figure imgf000010_0003
Una mezcla de 1,0 de biciclo [3,3,l]nonano-3,7-diona, 3,6 g de cloruro de zinc anhidro, 1,5 g de 2-aminobenzonitrilo y 20 mi de nitrobenceno se calentó a 130-140BC durante 2 horas. Se dejo enfriar, se añadieron 80 mi de disolución de hidróxi- do sódico 2N, se destiló el nitrobenceno azeotrópicamente con agua, reponiendo el agua para evitar que la mezcla de reacción quedara seca, se dejó enfriar y el sólido formado (mezcla de los productos de monorreacción y dirreacción) se aisló por filtración y se lavó con agua. Por cromatografía en columna de gel de sílice, eluyendo con mezclas de acetato de etilo y metanol en diferentes proporciones, se separaron los siguientes compues¬ tos de la mezcla anterior, en orden de elución: a) 12-amino-6H-7,8,10,ll-tetrahidro-7,11-metanoci- cloocteno[b]quinolin-9-ona:
Figure imgf000010_0003
A mixture of 1.0 of bicyclo [3,3, l] nonano-3,7-dione, 3.6 g of anhydrous zinc chloride, 1.5 g of 2-aminobenzonitrile and 20 ml of nitrobenzene was heated to 130 -140 B C for 2 hours. It was allowed to cool, 80 ml of 2N sodium hydroxide solution was added, the nitrobenzene was distilled azeotropically with water, replenishing the water to prevent the reaction mixture from becoming dry, allowed to cool and the solid formed (product mixture monoreaction and redirection) was isolated by filtration and washed with water. By silica gel column chromatography, eluting with mixtures of ethyl acetate and methanol in different proportions, the following compounds were separated from the previous mixture, in order of elution: a) 12-amino-6H-7.8 , 10, ll-tetrahydro-7,11-methanocyclochlorte [b] quinolin-9-one:
Punto de fusión: 243SC (metanol)(con descomposición) 200 MHz H RMN(CDC13, CD30D) 6(ppm): 2,1-3,5(absorción comple¬ ja, C6-H2, C7-H, C8-H2, C10-H2, C13-H2) , 3,74(s ancho, Cll-H) , 4,14(S, NH2 + H20), 7,55 (dt, J= 8,0 Hz, J'= 4,0 Hz, C3-H) , 7,80(d, J= 4,0 Hz, Cl-H y C2-H) , 8,30(d, J= 8,0 Hz, C4-H) . 50,4 MHZ "C RMN(CDC13, CD30D) ¿(ppitt): 29,2 (CH) y 29,3(CH)(C7 y CU), 29,7 (CH2, C13) 36,1(CH2, C6) 44,9(CH2, CÍO), 47,8- (CH2, C8), 111,4(C) y 115,9(C) (Clla y C12a) , 121,8(CH), 122,3(CH), 125,0(CH) y 131,3(CH) (Cl, C2, C3 y C4), 141,7(C), 151,3(C) y 151,4(C) (C4a, C5a y C12), 211,5(C, C9) .Melting point: 243 S C (methanol) (with decomposition) 200 MHz H NMR (CDC1 3 , CD 3 0D) 6 (ppm): 2.1-3.5 (complex absorption, C6-H 2 , C7 -H, C8-H 2 , C10-H 2 , C13-H 2 ), 3.74 (s wide, Cll-H), 4.14 (S, NH 2 + H 2 0), 7.55 (dt , J = 8.0 Hz, J '= 4.0 Hz, C3-H), 7.80 (d, J = 4.0 Hz, Cl-H and C2-H), 8.30 (d, J = 8.0 Hz, C4-H). 50.4 MHZ "C NMR (CDC1 3 , CD 3 0D) ¿(ppitt): 29.2 (CH) and 29.3 (CH) (C7 and CU), 29.7 (CH 2 , C13) 36, 1 (CH 2 , C6) 44.9 (CH 2 , CIO), 47.8- (CH 2 , C8), 111.4 (C) and 115.9 (C) (Clla and C12a), 121.8 (CH), 122.3 (CH), 125.0 (CH) and 131.3 (CH) (Cl, C2, C3 and C4), 141.7 (C), 151.3 (C) and 151, 4 (C) (C4a, C5a and C12), 211.5 (C, C9).
12-amino-6H-7,8,10,ll-tetrahidro-7,11-metanocicloocteno[b] quinolin-9-ona. Hidrocloruro:12-amino-6H-7,8,10, ll-tetrahydro-7,11-methanocyclooctene [b] quinolin-9-one. Hydrochloride:
Punto de fusión: 236BC(metanol) (con descomposición)Melting point: 236 B C (methanol) (with decomposition)
200 MHz XH RMN(CD3θD) 5(ppm): 2,2-3,6(absorción compleja, C6- H2, C7-H, C8-H2, C10-H2, C13-H2) , 3,79(s ancho,. Cll-H), 5,01(s, NH2 + NH+ + H20), 7,71(ddd, J= 8,3 Hz, J'= 6,8 Hz, J"= 1,2 HZ, C2-H O C3-H), 7,82(d ancho, J= 8,3 Hz, Cl-H), 7,97- (ddd, J= 8,3 Hz, J'= 6,8 HZ, J"= 1,2 Hz, C3-H o C2-H) , 8,43(d, J= 8,3 Hz, J'= 1,2 Hz, C4-H) . 50,4 MHZ 13C RMN(CD3OD) 5(ppm): 30,5(CH2, C13), 30,6(CH) y 30,8(CH) (C7 y CU), 35,5(CH2, C6) 45,9(CH2, CÍO), 49,0(CH2, C8), 113,1(0) y 116,7(0) (Olla y C12a) , 120,4(CH), 124,5(CH), 127,6(CH) y 135,1(CH) (Cl, 02, 03 y 04), 139,5(0), 151,1(0) y 156,9(0) (C4a, C5a y 012), 213,0(0, 09). b) 6,7,8,15-Tetrahidro-7,15-metanocicloocteno[1,2- b:5,4-b' ]diquinolina-14,16-diamina:200 MHz X H NMR (CD 3 )D) 5 (ppm): 2.2-3.6 (complex absorption, C6-H 2 , C7-H, C8-H 2 , C10-H 2 , C13-H 2 ) , 3.79 (wide s., Cll-H), 5.01 (s, NH 2 + NH + + H 2 0), 7.71 (ddd, J = 8.3 Hz, J '= 6.8 Hz, J "= 1.2 HZ, C2-H or C3-H), 7.82 (broad d, J = 8.3 Hz, Cl-H), 7.97- (ddd, J = 8.3 Hz, J '= 6.8 HZ, J "= 1.2 Hz, C3-H or C2-H), 8.43 (d, J = 8.3 Hz, J' = 1.2 Hz, C4- H). 50.4 MHZ 13 C NMR (CD 3 OD) 5 (ppm): 30.5 (CH 2 , C13), 30.6 (CH) and 30.8 (CH) (C7 and CU), 35.5 ( CH 2 , C6) 45.9 (CH 2 , CIO), 49.0 (CH2, C8), 113.1 (0) and 116.7 (0) (Pot and C12a), 120.4 (CH), 124.5 (CH), 127.6 (CH) and 135.1 (CH) ( Cl, 02, 03 and 04), 139.5 (0), 151.1 (0) and 156.9 (0) (C4a, C5a and 012), 213.0 (0.09). b) 6,7,8,15-Tetrahydro-7,15-methanocyclooctene [1,2- b: 5,4-b '] diquinoline-14,16-diamine:
Punto de fusión: 303aC(agua) (con descomposición) 200 MHz XH RMN(DMSO-d6) 5(ppm): 2,ll(s ancho, C17-H2) , 2,77(absorción ancha, C7-H) , 2,82[d, J= 18,0 Hz, 06(8)- Hendo], 3,25[m, C6(8)-Hexo], 4,59(s ancho, C15-H) , 6,75(s, NH2), 7,27[m, C2(12)-H], 7,47[m, C3(ll)-H], 7,59[d, J= 8,3 HZ, Cl(13)-H], 8,ll[d, J~~~ 8,3 Hz, C4(10)-H].Melting point: 303 a C (water) (with decomposition) 200 MHz X H NMR (DMSO-d 6 ) 5 (ppm): 2, ll (s wide, C17-H 2 ), 2.77 (wide absorption, C7-H), 2.82 [d, J = 18.0 Hz, 06 (8) - Hendo], 3.25 [m, C6 (8) -Hexo], 4.59 (wide s, C15-H ), 6.75 (s, NH 2 ), 7.27 [m, C2 (12) -H], 7.47 [m, C3 (ll) -H], 7.59 [d, J = 8, 3 HZ, Cl (13) -H], 8, ll [d, J ~~~ 8.3 Hz, C4 (10) -H].
50,4 MHz i3C RMN(DMS0-d6) δ(ppm): 24,4(CH, C7) , 26,9(CH, 015), 30,8(CH2, C17) 40,2[CH2/. 06(8)], 114,7(0) y 117,6(0) [C13a- (16a) y C14a(15a)], 121,9(CH), 122,9(CH), 127,2(CH) y 128,1(CH) [(01(13), 02(12), 03(11) y 04(10)], 145,7(C), 146,7(C) [C4a(9a) y C5a(8a)], 156,9[C, 014(16)]. 6,7,8,15-Tetrahidro-7,15-metanocicloocteno[1,2-b:5,4-b' ] diquinolina-14,16-diamina. Dihidrocloruro: Punto de fusión: 302aC(metanol) (con descomposición) 200 MHz XH RMN(CD30D) <S(ppm) : 2,53(s ancho, C17-H , 3,20(ab- sorción ancha, C7-H) , 3,28[d, J= 19,0 Hz, 06(8)-Hendo] , 3,70[dd, J= 19,0 Hz, J'= 6,9 Hz, C6(8)-Hexo], 4,99(s ancho, C15-H), 5,01(S, NH2 + NH+) , 7,74[m, C3(ll)-H], 7,86[d, J= 8,4 HZ, Cl(13)-H], 7,99[m, C2(12)-H], 8,43[d, J= 8,6 Hz, 04(10)- H].50.4 MHz i3 C NMR (DMS0-d 6 ) δ (ppm): 24.4 (CH, C7), 26.9 (CH, 015), 30.8 (CH 2 , C17) 40.2 [CH 2 / . 06 (8)], 114.7 (0) and 117.6 (0) [C13a- (16a) and C14a (15a)], 121.9 (CH), 122.9 (CH), 127.2 ( CH) and 128.1 (CH) [(01 (13), 02 (12), 03 (11) and 04 (10)], 145.7 (C), 146.7 (C) [C4a (9a) and C5a (8a)], 156.9 [C, 014 (16)] 6,7,8,15-Tetrahydro-7,15-methanocyclooctene [1,2-b: 5,4-b '] diquinoline- 14,16-diamine Dihydrochloride: Melting point: 302 a C (methanol) (with decomposition) 200 MHz X H NMR (CD 3 0D) <S (ppm): 2.53 (broad s, C17-H, 3 , 20 (wide absorption, C7-H), 3.28 [d, J = 19.0 Hz, 06 (8) -Hendo], 3.70 [dd, J = 19.0 Hz, J '= 6.9 Hz, C6 (8) -Hex], 4.99 (wide s, C15-H), 5.01 (S, NH 2 + NH + ), 7.74 [m, C3 (ll) -H ], 7.86 [d, J = 8.4 HZ, Cl (13) -H], 7.99 [m, C2 (12) -H], 8.43 [d, J = 8.6 Hz, 04 (10) - H].
50,4 MHz 13C RMN(DMS0-d6) 5(ppm): 22,5(CH, 07), 25,1(CH, 015), 28,4(CH2, C17) 35,2[CH2, 06(8)], 113,6(0) y 116,0(0) [C13a- (16a) y C14a(15a)], 119,3(CH), 124,2(CH), 126,2(CH) y 133,7(CH) [(Cl(13), 02(12), 03(11) y 04(10)], 137,4(0), 153,0(0) [C4a(9a) y C5a(8a)], 155,6[C, 014(16)]. c) 6,7,14,15-Tetrahidro-7,15-metanocicloocte- no[1,2-b:5,6-b' ] diquinolina-8,16-diamina50.4 MHz 13 C NMR (DMS0-d 6 ) 5 (ppm): 22.5 (CH, 07), 25.1 (CH, 015), 28.4 (CH 2 , C17) 35.2 [CH 2 , 06 (8)], 113.6 (0) and 116.0 (0) [C13a- (16a) and C14a (15a)], 119.3 (CH), 124.2 (CH), 126, 2 (CH) and 133.7 (CH) [(Cl (13), 02 (12), 03 (11) and 04 (10)], 137.4 (0), 153.0 (0) [C4a ( 9a) and C5a (8a)], 155.6 [C, 014 (16)]. C) 6,7,14,15-Tetrahydro-7,15-methanocyclooctene [1,2-b: 5,6 -b '] diquinoline-8,16-diamine
Punto de fusión: 320aC(agua) (con descomposición) 20Q MHz Η RMN(DMS0-d6) 5(ppm) : 2,22(s ancho, C17-H2) , 2,98[d, J= 18,0 Hz, C6(14)-Hendo], 3,16[dd, J= 18,0 Hz, J'= 2,5 Hz, C6(14)-Hexo], 3,58[s ancho, C7(15)-H], 6,72(s ancho, NH2) , - U -Melting point: 320 a C (water) (with decomposition) 20Q MHz Η NMR (DMS0-d 6 ) 5 (ppm): 2.22 (wide s, C17-H 2 ), 2.98 [d, J = 18.0 Hz, C6 (14) -Hendo], 3.16 [dd, J = 18.0 Hz, J '= 2.5 Hz, C6 (14) -Hexo], 3.58 [s wide, C7 (15) -H], 6.72 (broad s, NH 2 ), - OR -
7,24[m, C2(9)-H], 7,46[m, Cl(8)-H y C3(10)-H], 8,14[d, J= 8,1 Hz, C4(ll)-H].7.24 [m, C2 (9) -H], 7.46 [m, Cl (8) -H and C3 (10) -H], 8.14 [d, J = 8.1 Hz, C4 ( ll) -H].
50,4 MHz 13C RMN(DMS0-d6) cS(pp ): 26,3[CH, 07(15)], 29,6(CH2, C17) 37,9[CH2, 06(14)], 112,2(0) y 117,2(C) [C7a(15a) y C8a(16a)], 122,9(CH), 123,9(CH), 126,4(CH) y 130,0(CH) [ (Cl- (9), C2(10), 03(11) y 04(12)], 144,9(0), 149 ,9(C) [C4a(12a) y C5a(13a)], 155,2[C, 08(16)].50.4 MHz 13 C NMR (DMS0-d 6 ) cS (pp): 26.3 [CH, 07 (15)], 29.6 (CH 2 , C17) 37.9 [CH 2 , 06 (14) ], 112.2 (0) and 117.2 (C) [C7a (15a) and C8a (16a)], 122.9 (CH), 123.9 (CH), 126.4 (CH) and 130, 0 (CH) [(Cl- (9), C2 (10), 03 (11) and 04 (12)], 144.9 (0), 149, 9 (C) [C4a (12a) and C5a (13a )], 155.2 [C, 08 (16)].
6,7,14,15-Tetrahidro-7,15-metanocicloocteno[1 ,2-b:5,6-b' ] diquinolina-8,16-diamina. Dihicloruro: Punto de fusión: 330aC(metanol) (con descomposición)6,7,14,15-Tetrahydro-7,15-methanocyclooctene [1,2-b: 5,6-b '] diquinoline-8,16-diamine. Dihydrochloride: Melting point: 330 to C (methanol) (with decomposition)
200 MHZ XH RMN(CD30D) 6(ppm): 2,55(s ancho, C17-H2), 3,30[d, J= 18,0 Hz, 06(14)-Hendo], 3,65[dd, J= 18,0 Hz, J'= 6,9 Hz, C6(14)-Hexo], 3,86[d ancho, J= 6,9 Hz, C7(15)-H], 5,00(s ancho, NH2 + NH+) , 7,72[m, C3(10)-H], 7,79[d, J= 8,1 Hz, Cl(8)-H], 7,95 [m, C2(9)-H], 8,47[d, J= 8,4 Hz, C4(ll)-H]. 50,4 MHz 13C RMN(CD30D) 6(ppm): 24,4[CH, 07(15)], 27,5(CH2, 017) 33,5[CH2, 06(14)], 111,3(0) y 115,7(0) [C7a(15a) y C8a(16a)], 119,5(CH), 124,1(CH), 126,2(CH) Y 133,7(CH) [(01(9), 02(10), 03(11) y 04(12) ], .138,0(0) , 150,7(0) [C4a(12a) y C5a(13a)], 155,5[C, 08(16)].200 MHZ X H NMR (CD 3 0D) 6 (ppm): 2.55 (wide s, C17-H 2 ), 3.30 [d, J = 18.0 Hz, 06 (14) -Hand], 3 , 65 [dd, J = 18.0 Hz, J '= 6.9 Hz, C6 (14) -Hex], 3.86 [broad d, J = 6.9 Hz, C7 (15) -H], 5.00 (broad s, NH 2 + NH + ), 7.72 [m, C3 (10) -H], 7.79 [d, J = 8.1 Hz, Cl (8) -H], 7 , 95 [m, C2 (9) -H], 8.47 [d, J = 8.4 Hz, C4 (ll) -H]. 50.4 MHz 13 C NMR (CD 3 0D) 6 (ppm): 24.4 [CH, 07 (15)], 27.5 (CH 2 , 017) 33.5 [CH 2 , 06 (14)] , 111.3 (0) and 115.7 (0) [C7a (15a) and C8a (16a)], 119.5 (CH), 124.1 (CH), 126.2 (CH) and 133.7 (CH) [(01 (9), 02 (10), 03 (11) and 04 (12)], .138.0 (0), 150.7 (0) [C4a (12a) and C5a (13a) ], 155.5 [C, 08 (16)].
Ejemplo 2Example 2
Preparación de 12-amino-l-fluoro-6H-7 , 8 , 10 , ll-tetrahidro- 7 , 11-metanocicloocteno [ b ] quinolin-9-ona ; 1 , 13-Dif luoro-6 , 7 , 8 , 15-tetrahidro-7 , 15-metanocicloocteno [ 1 , 2-b : 5 , 4-b ' ] diquinolina-14 , 16-diamina ; 1-9-Dif luoro-6 , 7 , 14 , 15-tetrahidro- 7 , 15-metanocicloocteno [ 1 , 2-b: 5 , 6-b' ]diquinolina-8 , 16-diamina Preparation of 12-amino-l-fluoro-6H-7, 8, 10, ll-tetrahydro-7, 11-methanocyclooctene [b] quinolin-9-one; 1, 13-Dif luoro-6, 7, 8, 15-tetrahydro-7, 15-methanocyclooctene [1,2-b: 5, 4-b '] diquinoline-14, 16-diamine; 1-9-Dif luoro-6, 7, 14, 15-tetrahydro- 7, 15-methanocyclooctene [1,2-b: 5, 6-b '] diquinoline-8, 16-diamine
Figure imgf000014_0001
Figure imgf000014_0001
A una mezcla de 0,88 g de tricloruro de aluminio anhidro, 0,9 g de 2-amino-6-fluorobenzonitrilo y 60 mi de 1,2-dicloroetano se le añadió gota a gota a 0BC una disolución de 0,5 g de biciclo[3.3.1]nonano-3,7-diona en 10 mi del mismo disolvente. Finalizada la adición, la mezcla de reacción se calentó a reflujo durante 1 hora. Se dejó enfriar, se añadió una mezcla de 60 mi de tetrahidrofurano y 30 mi de agua y se basificó por adición de disolución de hidróxido sódico 2N y se agitó a temperatura ambiente durante 30 min. Se elimina¬ ron los disolventes orgánicos al vacío, y el sólido formado (mezcla de los productos de monorreacción y dirreacción) se separó de la disolución acuosa alcalina por filtración y se lavó con agua.To a mixture of 0.88 g of anhydrous aluminum trichloride, 0.9 g of 2-amino-6-fluorobenzonitrile and 60 ml of 1,2-dichloroethane was added dropwise at 0 B C a solution of 0, 5 g of bicyclo [3.3.1] nonano-3,7-dione in 10 ml of the same solvent. After the addition, the reaction mixture was heated at reflux for 1 hour. It was allowed to cool, a mixture of 60 ml of tetrahydrofuran and 30 ml of water was added and made basic by the addition of 2N sodium hydroxide solution and stirred at room temperature for 30 min. The organic solvents were removed in vacuo, and the solid formed (mixture of the monoreaction and redirection products) was separated from the alkaline aqueous solution by filtration and washed with water.
Por cromatografía en columna de gel de sílice, eluyendo con mezclas de acetato de etilo y metanol en diferentes propor¬ ciones, se separaron los siguientes compuestos de la mezcla anterior, en orden de elución: a) 12-amino-l-fluoro-6H-7,8,10,ll-tetrahidro-7,ll- metano-cicloocteno[6]quinolin-9-ona. Hidrocloruro: Punto de fusión: 90-92aC (acetato de etilo/metanol) (con descomposición)By silica gel column chromatography, eluting with mixtures of ethyl acetate and methanol in different proportions, the following compounds were separated from the previous mixture, in order of elution: a) 12-amino-l-fluoro-6H -7,8,10, ll-tetrahydro-7, ll-methane-cyclooctene [6] quinolin-9-one. Hydrochloride: Melting point: 90-92 a C (ethyl acetate / methanol) (with decomposition)
200 MHz XH RMN (DMS0-d6) <S(ppm) :2,0-3,5 (absorción comple-ja, C6-H2, C7-H, C8-H2, C10-H2, C13-H2) , 3,75 (s ancho, Cll-H), 7,40 (m, C2-H), 7,84 ( , C3-H y C4-H) , 8,40 (absorción ancha, NH2 y NH+)200 MHz X H NMR (DMS0-d 6 ) <S (ppm): 2.0-3.5 (complete absorption, C6-H 2 , C7-H, C8-H 2 , C10-H 2 , C13 -H 2 ), 3.75 (wide s, Cll-H), 7.40 (m, C2-H), 7.84 (, C3-H and C4-H), 8.40 (wide absorption, NH 2 and NH + )
50,4 NHZ 13C RMN (DMS0-d6) S(ppm) :28,7 (CH, C7 y Cll), 29,1 (CH2, C13), 34,4 (CH2/ 06), 45,2 (CH22, CÍO), 47,9 (CH2, 08), 105,8 (C, d, J= 11,7 HZ, C12a), 111,6 (CH, d, J= 22,7 Hz, C2), 113,2 (C, Clla), 115,7 (CH, C4), 134,4 (CH, d, J= 10,1 HZ, C3) 139,7 (C), 150,5 (C) (C4a y C5a) , 153,3 (C, 012), 159,5 (C, d, J= 255,5 Hz, Cl) , 211,3 (C, 09) b) 1,13-difluoro-6,7,8,15-tetrahidro-7,15-metano- cicloocteno [l,2-b:5,4-b' ]diquinolina-14,16-diamina. Dihidro- cloruro:50.4 NHZ 13 C NMR (DMS0-d 6) S (ppm): 28.7 (CH, C7 and Cll), 29.1 (CH 2, C13), 34.4 (CH 2/06), 45 , 2 (CH 2 2, CIO), 47.9 (CH 2 , 08), 105.8 (C, d, J = 11.7 HZ, C12a), 111.6 (CH, d, J = 22, 7 Hz, C2), 113.2 (C, Clla), 115.7 (CH, C4), 134.4 (CH, d, J = 10.1 HZ, C3) 139.7 (C), 150, 5 (C) (C4a and C5a), 153.3 (C, 012), 159.5 (C, d, J = 255.5 Hz, Cl), 211.3 (C, 09) b) 1.13 -difluoro-6,7,8,15-tetrahydro-7,15-methane-cyclooctene [1, 2-b: 5,4-b '] diquinoline-14,16-diamine. Dihydrochloride:
Punto de fusión: 270aC(metanol) (con descomposición) 200 MHz H RMN (DMS0-d6) ¿(ppm) :2,25 (s ancho, C17-H2) , 2,90 (s ancho, C7-H) , 3,10 [d, J= 18 Hz, C6(8)-Hendo] , 3,46[dd, J= = 18 HZ, J'= 7 HZ, C6(8)-Hexo], 5,45 (s ancho, C15-H), 7,40[dd, J= 13,5 Hz, J'= 6,5 Hz, C2(12)-H], 7,75 [m, C3(ll)- H y C4(10)-H], 8,66 (s ancho, NH2)Melting point: 270 a C (methanol) (with decomposition) 200 MHz H NMR (DMS0-d 6 ) ¿(ppm): 2.25 (wide s, C17-H 2 ), 2.90 (wide s, C7 -H), 3.10 [d, J = 18 Hz, C6 (8) -Hendo], 3.46 [dd, J = = 18 HZ, J '= 7 HZ, C6 (8) -Hexo], 5 , 45 (wide s, C15-H), 7.40 [dd, J = 13.5 Hz, J '= 6.5 Hz, C2 (12) -H], 7.75 [m, C3 (ll) - H and C4 (10) -H], 8.66 (wide s, NH 2 )
50,4 MHZ 13C RMN (DMS0-d6) 5(ppm): 22,2 (CH, C7), 23,8 (CH, C15), 28,1 (CH2, C17), 35,1 [CH2, C6(8)], 106,4 (C, d, J= 12,5 HZ, C13a(16a)], 111,3 [CH, d, J= 22,9 Hz, C2(12)], 114,0 [C, C14a(15a)], 115,6 [CH, C4(10)], 134,5 [CH, d, J= 10,8 Hz, C3(ll)], 139,3 (C), 153,6 (C) y 154,3 (C) [C4a(9a), C5a(8a) y C14(16)], 159,3 [C, d, J=255,6 Hz, Cl(13)] c) 1,9-difluoro-6,7,14,15-tetrahidro-7,15-metano- cicloocteno [l,2-b:5,6-b' ]diquinolina-8,16-diamina. Dihidro- cloruro:50.4 MHZ 13 C NMR (DMS0-d 6 ) 5 (ppm): 22.2 (CH, C7), 23.8 (CH, C15), 28.1 (CH 2 , C17), 35.1 [ CH 2 , C6 (8)], 106.4 (C, d, J = 12.5 HZ, C13a (16a)], 111.3 [CH, d, J = 22.9 Hz, C2 (12)] , 114.0 [C, C14a (15a)], 115.6 [CH, C4 (10)], 134.5 [CH, d, J = 10.8 Hz, C3 (ll)], 139.3 ( C), 153.6 (C) and 154.3 (C) [C4a (9a), C5a (8a) and C14 (16)], 159.3 [C, d, J = 255.6 Hz, Cl ( 13)] c) 1,9-Difluoro-6,7,14,15-tetrahydro-7,15-methane-cyclooctene [1,2-b: 5,6-b '] diquinoline-8,16-diamine. Dihydrochloride:
Punto de fusión: 290aC(metanol) (con descomposición) 200 MHZ 1H RMN (D20) fi(ppm): 2,29 (s ancho, C17-H2) , 3,05 [d, J= 18,2 Hz, C6(14)-Hendo], 3,38 [dd, J= 18,2 Hz, J= 5,4 Hz, C6(14)-Hexo], 3,59 [s ancho, C7(15)-H], 7,11 [dd, J= 7,8 Hz, J'= 14,0 Hz, C2(10)-H], 7,30 [d, J= 8,8 Hz, C4(12)-H], 7,60 [m, C3(ll)-H] 50,4 MHz 13C RMN (DMSO-ds) ¿(ppra): 23,7 [CH, C7(15)], 27,2 (CH2, C17), 33,2 [CH2, C6(14)], 106,2 [C, d, J= 12,2 H2, C8a(16a)], 111,3 [CH, d, J= 22,9 Hz, C2(10)], 112,3 [C, C7a(15a)], 115,7 [CH, C4(12)], 134,0 [CH, d, J= 11,0 Hz, C3(ll)], 139,8 (C) y 151,1 (C) [C4a(12a) y C5a(13a)], 153,9 [C, C8(16)], 159,5 [C, d, J= 255 Hz, 01(9)]Melting point: 290 a C (methanol) (with decomposition) 200 MHZ 1 H NMR (D 2 0) fi (ppm): 2.29 (wide s, C17-H 2 ), 3.05 [d, J = 18 , 2 Hz, C6 (14) -Hendo], 3.38 [dd, J = 18.2 Hz, J = 5.4 Hz, C6 (14) -Hexo], 3.59 [s wide, C7 (15 ) -H], 7.11 [dd, J = 7.8 Hz, J '= 14.0 Hz, C2 (10) -H], 7.30 [d, J = 8.8 Hz, C4 (12 ) -H], 7.60 [m, C3 (ll) -H] 50.4 MHz 13 C NMR (DMSO-d s ) ¿(ppra): 23.7 [CH, C7 (15)], 27.2 (CH 2 , C17), 33.2 [CH 2 , C6 (14 )], 106.2 [C, d, J = 12.2 H2, C8a (16a)], 111.3 [CH, d, J = 22.9 Hz, C2 (10)], 112.3 [C , C7a (15a)], 115.7 [CH, C4 (12)], 134.0 [CH, d, J = 11.0 Hz, C3 (ll)], 139.8 (C) and 151.1 (C) [C4a (12a) and C5a (13a)], 153.9 [C, C8 (16)], 159.5 [C, d, J = 255 Hz, 01 (9)]
De manera análoga se han obtenido también los compuestos siguientes:Similarly, the following compounds have also been obtained:
Cis-6,6a,7,13b-tetrahidropentaleno[2,1-b:5,6-b']diquinolina- 13,14-diamina:Cis-6,6a, 7,13b-tetrahydropentalene [2,1-b: 5,6-b '] diquinoline- 13,14-diamine:
Punto de fusión: 330aC(metanol) (con descomposición). 200 MHz XH RMN(DMS0-d6) 5(ppm):2,80 [dd, J= 16,5 Hz, J'= 5,0 HZ, C6(7)-Hendθ], 3,20.[dd, J= 16,5 Hz, J'= 7,3 Hz, C6(7)- Hexo], 3,37 (m, C6a-H), 4,87 (d, J= 6,4 Hz, C13b-H), 6,76 (s ancho, NH2) , 7,36 [m, C2(ll)-H], 7,53 [m, C3(10)-H], 7,70 [d, J= 8,3 HZ, Cl(12)-H], 8,15 [d, J= 8,3 Hz, C4(9)-H]. 50,4 MHZ 13C RMN(DMSO-dβ+CDaOD) S(ppm): 39,8 [CH2, C6(7)], 41,4 CH, C6a) 47,4 (CH, C13b), 114,6 (C) y 118,7 (C)[C12a(14a) y C13a(13c)], 122,8 (CH), 124,2 (CH) , 128,2 (CH) y 129,3 (CH)[(C1(12), C2(ll), C3(10) y 04(9)], 147,3 (C), 148,4 (C) [C4a(8a) y C5a(7a)]# 166,7 [C, 013(14)].Melting point: 330 to C (methanol) (with decomposition). 200 MHz X H NMR (DMS0-d 6 ) 5 (ppm): 2.80 [dd, J = 16.5 Hz, J '= 5.0 HZ, C6 (7) -Hendθ], 3.20. [ dd, J = 16.5 Hz, J '= 7.3 Hz, C6 (7) - Hex], 3.37 (m, C6a-H), 4.87 (d, J = 6.4 Hz, C13b -H), 6.76 (broad s, NH 2 ), 7.36 [m, C2 (ll) -H], 7.53 [m, C3 (10) -H], 7.70 [d, J = 8.3 HZ, Cl (12) -H], 8.15 [d, J = 8.3 Hz, C4 (9) -H]. 50.4 MHZ 13 C NMR (DMSO-dβ + CD to OD) S (ppm): 39.8 [CH 2 , C6 (7)], 41.4 CH, C6a) 47.4 (CH, C13b), 114.6 (C) and 118.7 (C) [C12a (14a) and C13a (13c)], 122.8 (CH), 124.2 (CH), 128.2 (CH) and 129.3 ( CH) [(C1 (12), C2 (ll), C3 (10) and 04 (9)], 147.3 (C), 148.4 (C) [C4a (8a) and C5a (7a)] # 166.7 [C, 013 (14)].
Cis-6,6a,7,13b-tetrahidropentaleno[2,1-b:5,6-b']diquinolina- 13,14-diamina. Dihidrocloruro:Cis-6,6a, 7,13b-tetrahydropentalene [2,1-b: 5,6-b '] diquinoline- 13,14-diamine. Dihydrochloride:
Punto de fusión 330aC(metanol) (con descomposición). 200 MHz *H RMN(D20) í(ppm) : 3,07 [dd, J= 18,0 Hz, J'~~~ 5,2 Hz, C6(7)-Hendθ], 3,38 [dd, J= 18,0 Hz, J'= 8,0 Hz, C6(7)-Hexo], 3,70 (m, C6a-H) , 4,63 (s ancho, NH2 + NH+), 4,82 (d, J= 6,6 HZ, C13b-H), 7,46 [m, C2(ll)-H], 7,57 [d, J= 7,8 Hz, Cl(12)- H], 7,68 [m, C3(10)-H], 8,00 [d, J= 8,4 Hz, C4(9)-H]. 50,4 MHz 13C RMN(DMSO-de) «S(ppm): 36,2 [CH2, C6(7)], 42,3 (CH, C6a) 48,0 (CH, C13b), 114,2 (C) y 116,9 (C) [C12a(14a) y C13a(13c)], 120,2 (CH), 124,3 (CH), 126,7 (CH) y 133,7 (CH) [(Cl(12), C2(ll), C3(10) y C4(9)], 138,6 (C), 154,3 (C) [C4a(8a) y C5a(7a)], 160,4 [C, 013(14)]. Cis-6,6a,7,13a-tetrahidropentaleno[2,l-b:5,4-b']diquinolina- 7,14-diamina. Dihidrόcloruro: Punto de fusión 364aC(agua) (con descomposición). 200 MHz XE RMN(DMSO-d6) S(ppm): 3,05 [d, J= 17,0 Hz , 06(13)- Hendo], 3,75 [d ancho, J= 17,0 Hz, C6(13)-Hexo] , 4,25 [s ancho, C6a(13a)-H], 7,50 [m, C2(9)-H y C3(10)-H], 7,3-7,8 (absorción ancha, NH2 + NH+) , 7,70 [d, J= 8,0 Hz, Cl(8)-H], 8,35 [d, J= 8,0 HZ, C4(ll)-H].Melting point 330 to C (methanol) (with decomposition). 200 MHz * H NMR (D 2 0) í (ppm): 3.07 [dd, J = 18.0 Hz, J ' ~~~ 5.2 Hz, C6 (7) -Hendθ], 3.38 [ dd, J = 18.0 Hz, J '= 8.0 Hz, C6 (7) -Hex], 3.70 (m, C6a-H), 4.63 (wide s, NH 2 + NH + ), 4.82 (d, J = 6.6 HZ, C13b-H), 7.46 [m, C2 (ll) -H], 7.57 [d, J = 7.8 Hz, Cl (12) - H], 7.68 [m, C3 (10) -H], 8.00 [d, J = 8.4 Hz, C4 (9) -H]. 50.4 MHz 13 C NMR (DMSO-d e ) «S (ppm): 36.2 [CH 2 , C6 (7)], 42.3 (CH, C6a) 48.0 (CH, C13b), 114 , 2 (C) and 116.9 (C) [C12a (14a) and C13a (13c)], 120.2 (CH), 124.3 (CH), 126.7 (CH) and 133.7 (CH ) [(Cl (12), C2 (ll), C3 (10) and C4 (9)], 138.6 (C), 154.3 (C) [C4a (8a) and C5a (7a)], 160 , 4 [C, 013 (14)]. Cis-6,6a, 7,13a-tetrahydropentalene [2, lb: 5,4-b '] diquinoline- 7,14-diamine. Dihydrochloride: Melting point 364 a C (water) (with decomposition). 200 MHz X E NMR (DMSO-d 6 ) S (ppm): 3.05 [d, J = 17.0 Hz, 06 (13) - Hendo], 3.75 [d wide, J = 17.0 Hz , C6 (13) -Hexo], 4.25 [s wide, C6a (13a) -H], 7.50 [m, C2 (9) -H and C3 (10) -H], 7.3-7 , 8 (wide absorption, NH 2 + NH + ), 7.70 [d, J = 8.0 Hz, Cl (8) -H], 8.35 [d, J = 8.0 HZ, C4 (ll ) -H].
Cis-10-amino-3a,10b-dimetil-lH-3,3a,4,lOb-tetrahidropentale- no[2,1-b]quinolin-2-ona: Punto de fusión: 123-127BC (agua) 200 MHZ H RMN (CD30D) á(ppm): 1,40 (s, C3a-CH3) , 1,51 (s, C10b-CH3), 2,34 (d, J= 19,0 Hz) y 2,36 (d, J= 19,0 Hz) (03- H2), 2,60 (d, J= 19,0 Hz, Cl-Hexo), 3,05 (d, J= 16,4 Hz) y 3,14 (d, J= 16,4 Hz) (C4-H2) , 3,27 (d, J= 19,0 Hz, Cl-Hendo) , 5,01 (S, NH2), 7,47 (m, C8-H) , 7,67 (m, C7-H) , 7,82 (dd, J= 8,4 HZ, J'= 1,4 HZ, C9-H) , 8,18 (dd, J= 8,6 Hz, J'= 1,4 Hz, C6-H) .Cis-10-amino-3a, 10b-dimethyl-lH-3,3a, 4, lOb-tetrahydropentalene [2,1-b] quinolin-2-one: Melting point: 123-127 B C (water) 200 MHZ H NMR (CD 3 0D) á (ppm): 1.40 (s, C3a-CH 3 ), 1.51 (s, C10b-CH 3 ), 2.34 (d, J = 19.0 Hz ) and 2.36 (d, J = 19.0 Hz) (03- H 2 ), 2.60 (d, J = 19.0 Hz, Cl-Hexo), 3.05 (d, J = 16, 4 Hz) and 3.14 (d, J = 16.4 Hz) (C4-H 2 ), 3.27 (d, J = 19.0 Hz, Cl-Hendo), 5.01 (S, NH 2 ), 7.47 (m, C8-H), 7.67 (m, C7-H), 7.82 (dd, J = 8.4 HZ, J '= 1.4 HZ, C9-H), 8.18 (dd, J = 8.6 Hz, J '= 1.4 Hz, C6-H).
50,4 MHZ 13C RMN (CD30D) á(ppm): 19,5 (CH3, C10b-CH3) , 21,3 (CH3, C3a-CH3), 46,5 (CH2) y 47,2 (CH2) (C4 y Cl), 48,4 (C, C3a), 52,4 (C, ClOb), 52,9 (CH2, C3), 118,9 (C) y 120,1 (C) (C9a y C10a), 122,7 (CH), 125,2 (CH) , 128,4 (CH) , y 130,4 (CH) (C6, 07, 08 y C9), 149,3 (C) Y 149,4 (C) (C4a y C5a) , 165,2 (C, CÍO), 220,0 (C, 02).50.4 MHZ 13 C NMR (CD 3 0D) á (ppm): 19.5 (CH 3 , C10b-CH 3 ), 21.3 (CH 3 , C3a-CH 3 ), 46.5 (CH 2 ) and 47.2 (CH 2 ) (C4 and Cl), 48.4 (C, C3a), 52.4 (C, ClOb), 52.9 (CH 2 , C3), 118.9 (C) and 120 , 1 (C) (C9a and C10a), 122.7 (CH), 125.2 (CH), 128.4 (CH), and 130.4 (CH) (C6, 07, 08 and C9), 149 , 3 (C) and 149.4 (C) (C4a and C5a), 165.2 (C, CIO), 220.0 (C, 02).
Cis-10-amino-3a,10b-dimetil-lh-3,3a,4,lOb-tetrahidropentale- no[2,l-b]quinolin-2-ona. Hidrocloruro: Punto de fusión 223-230aC (metanol)Cis-10-amino-3a, 10b-dimethyl-lh-3,3a, 4, 10-tetrahydropentalene [2, lb] quinolin-2-one. Hydrochloride: Melting point 223-230 a C (methanol)
200 MHz 2H RMN (CD30D) 6(ppm): 1,45 (s, C3a-CH3) , 1,57 (s, C10b-CH3) 2,46 (d, J= 19,0 Hz) y 2,51 (d, J= 19,0 Hz) (C3-H2) , 2,66 (d, J= 19,4 HZ, Cl-Hexo), 3,23 (d, J= 19,4 Hz, 01- Hendo), 3,32 (d, J= 17,0 Hz) y 3,39 (d, J= 17,0 Hz) (C4-H2), 5,05 (NH2 + NH+), 7,75 (m, C7-H) , 7,90 (d, J= 8,4 Hz, C9-H) , 8,00 (m, C8-H), 8,50 (d, J= 8,4 Hz, C6-H) .200 MHz 2 H NMR (CD 3 0D) 6 (ppm): 1.45 (s, C3a-CH 3 ), 1.57 (s, C10b-CH 3 ) 2.46 (d, J = 19.0 Hz ) and 2.51 (d, J = 19.0 Hz) (C3-H 2 ), 2.66 (d, J = 19.4 HZ, Cl-Hexo), 3.23 (d, J = 19, 4 Hz, 01- Hendo), 3.32 (d, J = 17.0 Hz) and 3.39 (d, J = 17.0 Hz) (C4-H 2 ), 5.05 (NH 2 + NH + ), 7.75 (m, C7-H), 7.90 (d, J = 8.4 Hz, C9-H), 8.00 (m, C8-H), 8.50 (d, J = 8.4 Hz, C6-H).
50.4 MHZ "C RMN (CD30D) δ(ppm): 19,3 (CH3, C10b-CH3) , 21,2 (CH3, C3a-CH3), 43,4 (CH2, 04) , 47,7 (CH2, Cl), 48,8 (C, C3a) ,50.4 MHZ "C NMR (CD 3 0D) δ (ppm): 19.3 (CH 3 , C10b-CH 3 ), 21.2 (CH 3 , C3a-CH 3 ), 43.4 (CH 2 , 04) , 47.7 (CH 2 , Cl), 48.8 (C, C3a),
52.5 (CH2, C3), 53,3 (C, ClOb), 118,5 (C) y 119,7 (C) (C9a y ClOa), 120,9 (CH), 124,5 (CH) , 127,8 (CH) y 134,6 (CH) (C6,52.5 (CH 2 , C3), 53.3 (C, ClOb), 118.5 (C) and 119.7 (C) (C9a and ClOa), 120.9 (CH), 124.5 (CH), 127.8 (CH) and 134.6 (CH) (C6,
07, 08 y 09), 140,0 (C) , 155,7 (C) (C4a y C5a) , 158,7 (C, - 16 -07, 08 and 09), 140.0 (C), 155.7 (C) (C4a and C5a), 158.7 (C, - 16 -
CIO), 218,0 (C, C2).CIO), 218.0 (C, C2).
Cis-6,6a,7,13b-tetrahidro-6a,13b-dimetilpentaleno[2,1-b:5,6- b' ] diquinolina-13,14-diamina: Punto de fusión 203-209aC (metanol) 200 MHZ XH RMN (CD30D) 5(ppm): 1,35 (s, C6a-CH3) , 1,80 (s, C13b-CH3), 3,08 [s, C6(7)-H2], 5,02 [s, NH2] , 7,48 [m, 02(11)- H], 7,67 [m, C3(10)-H], 7,84 [dd, J= 8,4 Hz, J'= 1,4 Hz, Cl(12)-H], 8,18 [dd, J= 8,4 Hz, J'= 1,4 Hz, C4(9)-H]. 50,4 MHZ 13C RMN (CD30D) <S(ppm): 18,0 (CH3 C6a-CH3) , 20,3 (CH3, C13b-CH3), 46,0 [CH2, 06(7)], 53,2 (C, C6a) , 58,7 (C, C13b) , 118,3 (C) y 120,2 (C) [C12a(14a) y C13a(13c)], 122,7 (CH), 125,6 (CH), 128,4 (CH) Y 130,5 (CH) [Cl(12) , 02(11) , 03(10), 04(9)], 149,0 (C) Y 149,-1 (C) [C4a(8a) y C5a(7a)], 166,5 [C, 013(14)]. Cis-6,6a,7,13b-tetrahidro-6a,13b-dimetilpentaleno[2,1-b:5,6- b'] diquinolina-13,14-diamina. Dihidrocloruro: Punto de fusión 283aC (metanol) (con descomposición) 200 MHz XH RMN (CD3OD) 6(ppm):l,51 (s, C6a-CH3) , 2,00 (C13b- CH3), 3,43 (d, J= 18,3 Hz) y 3,51 (d, J= 18,3 Hz) [C6(7)-H2], 5,02 (NH2 + NH+), 7,83 [m, C3(10)-H], 7,96 [d, J= 8,4 Hz, Cl(12)-H], 8,07 [m, C2(ll)-H], 8,58 [d, J= 8,4 Hz, C4(9)-H]. 50,4 MHZ 13C RMN (CD30D) <5(ppm): 17,3 (CH3, C6a-CH3) , 19,9 (CH3, C13b-CH3) 42,2 [CH2, 06(7)], 56,2 (C, C6a) , 60,0 (C, C13b), 117,6 (C) y 118,8 (C) [C12a(14a) y C13a(13c)], 121,0 (CH), 124,7 (CH) , 128,4 (CH) , 135,1 (CH) [01(12), 02(11), C3(10)r C4(9)], 139,6 (C) y 155,9 (O) [C4a(8a) y C5a(7a)], 160,6 [C, 013(14)].Cis-6,6a, 7,13b-tetrahydro-6a, 13b-dimethylpentalene [2,1-b: 5,6- b '] diquinoline-13,14-diamine: Melting point 203-209 a C (methanol) 200 MHZ X H NMR (CD 3 0D) 5 (ppm): 1.35 (s, C6a-CH 3 ), 1.80 (s, C13b-CH 3 ), 3.08 [s, C6 (7) - H 2 ], 5.02 [s, NH 2 ], 7.48 [m, 02 (11) - H], 7.67 [m, C3 (10) -H], 7.84 [dd, J = 8.4 Hz, J '= 1.4 Hz, Cl (12) -H], 8.18 [dd, J = 8.4 Hz, J' = 1.4 Hz, C4 (9) -H]. 50.4 MHZ 13 C NMR (CD 3 0D) <S (ppm): 18.0 (CH 3 C6a-CH 3 ), 20.3 (CH 3 , C13b-CH 3 ), 46.0 [CH 2 , 06 (7)], 53.2 (C, C6a), 58.7 (C, C13b), 118.3 (C) and 120.2 (C) [C12a (14a) and C13a (13c)], 122 , 7 (CH), 125.6 (CH), 128.4 (CH) and 130.5 (CH) [Cl (12), 02 (11), 03 (10), 04 (9)], 149, 0 (C) Y 149, -1 (C) [C4a (8a) and C5a (7a)], 166.5 [C, 013 (14)]. Cis-6,6a, 7,13b-tetrahydro-6a, 13b-dimethylpentalene [2,1-b: 5,6- b '] diquinoline-13,14-diamine. Dihydrochloride: Melting point 283 a C (methanol) (with decomposition) 200 MHz X H NMR (CD 3 OD) 6 (ppm): l, 51 (s, C6a-CH 3 ), 2.00 (C13b-CH 3 ), 3.43 (d, J = 18.3 Hz) and 3.51 (d, J = 18.3 Hz) [C6 (7) -H 2 ], 5.02 (NH 2 + NH + ), 7.83 [m, C3 (10) -H], 7.96 [d, J = 8.4 Hz, Cl (12) -H], 8.07 [m, C2 (ll) -H], 8 , 58 [d, J = 8.4 Hz, C4 (9) -H]. 50.4 MHZ 13 C NMR (CD 3 0D) <5 (ppm): 17.3 (CH 3 , C6a-CH 3 ), 19.9 (CH 3 , C13b-CH 3 ) 42.2 [CH 2 , 06 (7)], 56.2 (C, C6a), 60.0 (C, C13b), 117.6 (C) and 118.8 (C) [C12a (14a) and C13a (13c)], 121 , 0 (CH), 124.7 (CH), 128.4 (CH), 135.1 (CH) [01 (12), 02 (11), C3 (10) r C4 (9)], 139, 6 (C) and 155.9 (O) [C4a (8a) and C5a (7a)], 160.6 [C, 013 (14)].
Cis-6,6a,13,13 -tetrahidro-6a,13a-dimetilpentaleno[2,1-b:5,4- b'] diquinolina-7,14-diamina: Punto de fusión 340aC(metanol) (con descomposición.)Cis-6,6a, 13,13-tetrahydro-6a, 13a-dimethylpentalene [2,1-b: 5,4- b '] diquinoline-7,14-diamine: Melting point 340 to C (methanol) (with decomposition.)
200 MHz XH RMN (DMSO-dβ δ(ppm): 1,48 [S, C6a(13a)-CH3] , 3,00 [d, J= 16,8 Hz, C6(13)-Hexθ], 3,78 [d, J= 16,8 Hz, 06(13)- Hendo], 6,53 [s, NH2] , 7,22 [m, C2(9)-H], 7,41 [m, C3(10)-H], 7,53 [d, J= 8,4 Hz, Cl(8)-H], 8,19 [d, J= 8,4 Hz, C4(ll)-H]. 50,4 MHZ 13C RMN (DMSO-d6) δ (ppm) : 18,6 [CH3, C6a(13a)-CH3] , 42,2 [CH2, C6(13)], 53,2 [C, C6a(13a) ] , 117,8(C) y 119,0 (C) [C6b(13b) y C7a(14a)], 122,4 (CH) y 123,1 (CH) , 128,3 (CH), 128,3 (CH) [Cl(8), C2(9), C3(10), 04(11)], 146,5 (C) Y 148,7 (C) [C4a(lla) y C5a(12a)], 165,2 [C, C7(14)]. Cis-6,6a,13,13a-tetrahidro-6a,13a-dimetilpentaleno[2,1-b:5,4- b' ] diquinolina-7,14-diamina. Dihidrocloruro:200 MHz X H NMR (DMSO-dβ δ (ppm): 1.48 [S, C6a (13a) -CH 3 ], 3.00 [d, J = 16.8 Hz, C6 (13) -Hexθ], 3.78 [d, J = 16.8 Hz, 06 (13) - Hendo], 6.53 [s, NH 2 ], 7.22 [m, C2 (9) -H], 7.41 [m , C3 (10) -H], 7.53 [d, J = 8.4 Hz, Cl (8) -H], 8.19 [d, J = 8.4 Hz, C4 (ll) -H] 50.4 MHZ 13 C NMR (DMSO-d 6 ) δ (ppm): 18.6 [CH 3 , C6a (13a) -CH 3 ], 42.2 [CH 2 , C6 (13)], 53, 2 [C, C6a (13a)], 117.8 (C) and 119.0 (C) [C6b (13b) and C7a (14a)], 122.4 (CH) and 123.1 (CH), 128.3 (CH), 128.3 (CH) [Cl (8), C2 (9), C3 (10), 04 (11)], 146.5 (C) and 148.7 (C) [C4a (lla) and C5a (12a)], 165.2 [C, C7 (14)]. Cis-6,6a, 13,13a-tetrahydro-6a, 13a-dimethylpentalene [2,1-b: 5,4- b '] diquinoline-7,14-diamine. Dihydrochloride:
Punto de fusión 285aC(metanol) (con descomposición) 200MHz XH RMN (CD30D) 5(ppm): 1,80 [s, C6a(13a)-CH3] , 3,61 [d, J= 18,2 Hz, C6(13)-Hendo], 4,09 [d, J=18,2 Hz, C6(13)-Hexo] , 5,00 (NH2 + NH+), 7,72 [m, C3(10)-H], 7,83 [d, 8,4 Hz, Cl(8)- H], 7,94 [m, C2(9)-H], 8,50 [d, J= 8,5 Hz, C4(ll)-H].Melting point 285 a C (methanol) (with decomposition) 200MHz X H NMR (CD 3 0D) 5 (ppm): 1.80 [s, C6a (13a) -CH 3 ], 3.61 [d, J = 18.2 Hz, C6 (13) -Hendo], 4.09 [d, J = 18.2 Hz, C6 (13) -Hexo], 5.00 (NH 2 + NH + ), 7.72 [m , C3 (10) -H], 7.83 [d, 8.4 Hz, Cl (8) - H], 7.94 [m, C2 (9) -H], 8.50 [d, J = 8.5 Hz, C4 (ll) -H].
50,4 MHZ 13C RMN (CD30D) 5(ppm): 18,4 [CH3, C6a(13a)-CH3] , 39,8 [CH2, C6(13)], 56,7 [C, C6a(13a)], 120,2 (C) y 120,4 (C) [C6b(13b) y C7a(14a)], 120,9 (CH), 124,4 (CH) , 127,7 (CH) y 134,6 (CH) [Cl(8), C2(9), C3(10) y 04(11)], 139,9 (C) y 155,3 (C) [C4a(lla) Y C5a(12a)], 158,1 [C, C7(14)].50.4 MHZ 13 C NMR (CD 3 0D) 5 (ppm): 18.4 [CH 3 , C6a (13a) -CH 3 ], 39.8 [CH 2 , C6 (13)], 56.7 [ C, C6a (13a)], 120.2 (C) and 120.4 (C) [C6b (13b) and C7a (14a)], 120.9 (CH), 124.4 (CH), 127.7 (CH) and 134.6 (CH) [Cl (8), C2 (9), C3 (10) and 04 (11)], 139.9 (C) and 155.3 (C) [C4a (lla) And C5a (12a)], 158.1 [C, C7 (14)].
10-amino-lH-3,3a,4,10b-tetrahidro-3a,lOb-butanopentaleno[2,1- b]quinolin-2-ona:10-amino-lH-3,3a, 4,10b-tetrahydro-3a, lOb-butanopentalene [2,1- b] quinolin-2-one:
200 MHz *H RMN (CDC13) 5(ppm): 1,4-1,8 (absorción compleja, C12-H2, C13-H2, C14-H2), 1,9-2,0 y 2,1-2,3 (Cll-H2) , 2,28 (d, J= 18,7 Hz), 2,32 [d, J= 18,7 Hz, (C3-H2)], 2,70 (dd, J= 19,0 HZ, J'= 1,5 HZ, Cl-Hexo), 2,90 (d, J= 17,7 Hz) y 3,01 (d, J= 17,7 Hz), 3,31 (d, J= 19,0 Hz, Cl-Hendo)], 4,66 (s ancho, NH2), 7,43 (m, C8-H), 7,62 (m, C7-H) , 7,74 [dd, J= 8,4 Hz, J'= 1,4 HZ, (C9-H)], 7,94 (dd, J= 8,4 Hz, J'= 1,4 Hz, C6-H) 50,4 MHz "C RMN (CDC13) 5(ppm) : 20,0 (CH2) y 21,2 (CH2) [C12 y C13], 30,9 (CH2, 31,6 (CH2, 011 y C14), 42,0 (CH2) , 42,9 (CH2) (Cl y C4), 46,5 (C, C3a) , 49,9 (C, ClOb), 51,8 (CH2, 03), 118,7 (C) y 119,8 (C) (C9a y ClOa) , 120,0 (CH) , 124,3 (CH), 128,7 (CH) y 128,9 (CH) (C6, 07, C8 y 09), 145,7 (C) y 148,3 (C) (C4a y C5a) , 164,3 (C, CIO), 217,6 (C, 02)200 MHz * H NMR (CDC1 3 ) 5 (ppm): 1.4-1.8 (complex absorption, C12-H 2 , C13-H 2 , C14-H 2 ), 1.9-2.0 and 2 , 1-2.3 (Cll-H 2 ), 2.28 (d, J = 18.7 Hz), 2.32 [d, J = 18.7 Hz, (C3-H 2 )], 2, 70 (dd, J = 19.0 HZ, J '= 1.5 HZ, Cl-Hexo), 2.90 (d, J = 17.7 Hz) and 3.01 (d, J = 17.7 Hz ), 3.31 (d, J = 19.0 Hz, Cl-Hendo)], 4.66 (broad s, NH 2 ), 7.43 (m, C8-H), 7.62 (m, C7 -H), 7.74 [dd, J = 8.4 Hz, J '= 1.4 HZ, (C9-H)], 7.94 (dd, J = 8.4 Hz, J' = 1, 4 Hz, C6-H) 50.4 MHz "C NMR (CDC1 3 ) 5 (ppm): 20.0 (CH 2 ) and 21.2 (CH 2 ) [C12 and C13], 30.9 (CH 2 , 31.6 (CH 2 , 011 and C14), 42.0 (CH 2 ), 42.9 (CH 2 ) (Cl and C4), 46.5 (C, C3a), 49.9 (C, ClOb ), 51.8 (CH 2 , 03), 118.7 (C) and 119.8 (C) (C9a and ClOa), 120.0 (CH), 124.3 (CH), 128.7 (CH ) and 128.9 (CH) (C6, 07, C8 and 09), 145.7 (C) and 148.3 (C) (C4a and C5a), 164.3 (C, CIO), 217.6 ( C, 02)
6,6a,7,13b-tetrahidro-6a,13b-butanopentaleno[2,1-b:5,6- ' ] diquinolina-13,14-diamina:6.6a, 7.13b-tetrahydro-6a, 13b-butanopentalene [2,1-b: 5,6- '] diquinoline-13,14-diamine:
Punto de fusión: 203-207aC(acetato de etilo).Melting point: 203-207 a C (ethyl acetate).
200 MHz XH RMN (DMS0-d6) <5(ppm): 1,32 (abs. ancha, 2H) y 1,58 (abs. ancha 4H) [C15-H2, C16-H2, C17-H2], 2,22 [abs. ancha, C18-H2], 2,74 [d, J= 16,2 Hz, C6(7)-Hendθ] , 2,93 [d, J= 16,2 HZ, C6(7)-Hexo], 6,32 [s, NH2] , 7,34 [m, C2(ll)-H], 7,54 [m, C3(10)-H], 7,69 [d, J= 8,3 Hz, Cl(12)-H], 8,21 [d, J= 8,1 Hz, C4(9)-H.200 MHz X H NMR (DMS0-d 6 ) <5 (ppm): 1.32 (wide abs, 2H) and 1.58 (broad abs 4H) [C15-H 2 , C16-H 2 , C17- H 2 ], 2.22 [abs. wide, C18-H 2 ], 2.74 [d, J = 16.2 Hz, C6 (7) -Hendθ], 2.93 [d, J = 16.2 H Z , C6 (7) -Hex], 6.32 [s, NH 2 ], 7.34 [m, C2 (ll) -H], 7.54 [m, C3 (10) -H], 7 , 69 [d, J = 8.3 Hz, Cl (12) -H], 8.21 [d, J = 8.1 Hz, C4 (9) -H.
50,4 MHz 13C RMN (DMSO-d6) 5(ppm): 21,0 (CH2) y 22,0 (CH2) [C16 y C17], 29,9 (CH2) y 31,2 (CH2) [C15 y 018], 43,5 [CH2, C6(7)], 50,5 [C, C6a], 58,2 [C, C13b] , 116,8 (C) y 119,2 (C) [C12a(14a) y C13a(13c)], 122,5 (CH), 123,8 (CH) , 128,6 (CH) y 128,8 (CH) [Cl(12), 02(11), 03(10) y C4(9)], 146,4 (C) y 148,4 (C) [C4a(8a) y C5a(7a)], 166,0 [C, 013(14)]. 6,6a,13,13a-tetrahidro-6a,13a-butanopentaleno[2,1-b:5,4-b'] diquinolina-7,14-diamina: Punto de fusión 270aC.50.4 MHz 13 C NMR (DMSO-d 6 ) 5 (ppm): 21.0 (CH 2 ) and 22.0 (CH 2 ) [C16 and C17], 29.9 (CH 2 ) and 31.2 (CH 2 ) [C15 and 018], 43.5 [CH 2 , C6 (7)], 50.5 [C, C6a], 58.2 [C, C13b], 116.8 (C) and 119, 2 (C) [C12a (14a) and C13a (13c)], 122.5 (CH), 123.8 (CH), 128.6 (CH) and 128.8 (CH) [Cl (12), 02 (11), 03 (10) and C4 (9)], 146.4 (C) and 148.4 (C) [C4a (8a) and C5a (7a)], 166.0 [C, 013 (14) ]. 6,6a, 13,13a-tetrahydro-6a, 13a-butanopentalene [2,1-b: 5,4-b '] diquinoline-7,14-diamine: Melting point 270 to C.
200 MHz XH RMN (DMS0-d6) í(ppm): 1,52 [absorción ancha, C15(18)-Hanti + C16(17)-H2], 2,66 [absorción ancha, 015(18)- Hsin], 3,23[d, J= 17,0 Hz, 06(13)-Hendo], 3,56 [d, J= 17,0 Hz, C6(13)-Hexθ], 6,37 [s ancho, NH2] , 7,21 [m, C2(9)-H], 7,40 [m, C3(10)-H], 7,51 [d, J= 8,3 Hz, Cl(8)-H], 8,10 [d, J= =8,4 Hz, C4(ll)-H].200 MHz X H NMR (DMS0-d 6 ) í (ppm): 1.52 [wide absorption, C15 (18) -Hanti + C16 (17) -H 2 ], 2.66 [wide absorption, 015 (18) - Hsin], 3.23 [d, J = 17.0 Hz, 06 (13) -Hendo], 3.56 [d, J = 17.0 Hz, C6 (13) -Hexθ], 6.37 [ s wide, NH 2 ], 7.21 [m, C2 (9) -H], 7.40 [m, C3 (10) -H], 7.51 [d, J = 8.3 Hz, Cl ( 8) -H], 8.10 [d, J = = 8.4 Hz, C4 (ll) -H].
50,4 MHz 13C RMN (DMS0-d6) ιS(ppm): 20,5 [CH2, C16(17)], 30,1[CH2, C15(18)], 38,8 [CH2, C6(13)], 52,3[C, C6a(13a)], 119,0 (C) y 119,4 (C) [C6b(13b) y C7a(14a) ] , 122,4 (CH) , 123,0 (CH), 128,3 (CH) y 128,4 (CH) [Cl(8), C2(9), 03(10) y C4(ll)], 146,3 (C) y 148,6 (C) [C4a(lla) y C5a(12a)], 165,2 [C, C7(14)]. 6,6a,13,13a-tetrahidro-6a,13a-butanopentaleno[2,l-b:5,4-b'] diquinolina-7,14-diamina. Dihidrocloruro:50.4 MHz 13 C NMR (DMS0-d 6 ) ιS (ppm): 20.5 [CH 2 , C16 (17)], 30.1 [CH 2 , C15 (18)], 38.8 [CH 2 , C6 (13)], 52.3 [C, C6a (13a)], 119.0 (C) and 119.4 (C) [C6b (13b) and C7a (14a)], 122.4 (CH) , 123.0 (CH), 128.3 (CH) and 128.4 (CH) [Cl (8), C2 (9), 03 (10) and C4 (ll)], 146.3 (C) and 148.6 (C) [C4a (lla) and C5a (12a)], 165.2 [C, C7 (14)]. 6,6a, 13,13a-tetrahydro-6a, 13a-butanopentalene [2, lb: 5,4-b '] diquinoline-7,14-diamine. Dihydrochloride:
Punto de fusión 260aC (metanol/acetato de etilo)(con descom¬ posición)Melting point 260 to C (methanol / ethyl acetate) (with decomposition)
200 MHz XH RMN (DMSO-dβ) £(ppm): 1,51 [absorción ancha, C16(17)-H2], 1,7 [absorción ancha, C15(18)-Hanti], 2,72 [absorción ancha, 015(18)-Hsin], 3,56 [d, J= 18,5 Hz, C6(13)- Hendo], 3,79 [d, J= 18,5 Hz, C6(13)-Hexo], 7,56 [m, C3(10)- H], 7,81 [m, C2(9)-H], 7,90 [d, J= 7,9 Hz, Cl(8)-H], 8,60 [d, J= 8,5 Hz, C4(ll)-H], 8,1-9,2 [absorción ancha, NH2], 14,81 [s, N-H4"].200 MHz X H NMR (DMSO-dβ) £ (ppm): 1.51 [wide absorption, C16 (17) -H 2 ], 1.7 [wide absorption, C15 (18) -Hanti], 2.72 [ Wide absorption, 015 (18) -Hsin], 3.56 [d, J = 18.5 Hz, C6 (13) - Hendo], 3.79 [d, J = 18.5 Hz, C6 (13) - Hexo], 7.56 [m, C3 (10) - H], 7.81 [m, C2 (9) -H], 7.90 [d, J = 7.9 Hz, Cl (8) -H ], 8.60 [d, J = 8.5 Hz, C4 (ll) -H], 8.1-9.2 [wide absorption, NH 2 ], 14.81 [s, NH 4 " ].
50,4 MHZ 13C RMN (DMS0-d6) <S(ppm): 19,0 [CH2, 016(17)], 28,5 [CH2, 015(18)], 38,4 [CH2, 06(13)], 54,2 [C, C6a(13a)], 117,0 (C) y 117,9 (C) [C6b(13b) y C7a(14a)], 120,1 (CH) , 124,1 (CH), 126,1 (CH), 133,2 (CH) [01(8), 02(9), C3(10) y 04(11)], 138,7 (C) y 153,3 (C) [C4a(lla) y C5a(12a)], 157,3 [C, 07(14)].50.4 MHZ 13 C NMR (DMS0-d 6 ) <S (ppm): 19.0 [CH 2 , 016 (17)], 28.5 [CH 2 , 015 (18)], 38.4 [CH 2 , 06 (13)], 54.2 [C, C6a (13a)], 117.0 (C) and 117.9 (C) [C6b (13b) and C7a (14a)], 120.1 (CH), 124.1 (CH), 126.1 (CH), 133.2 (CH) [01 (8), 02 (9), C3 ( 10) and 04 (11)], 138.7 (C) and 153.3 (C) [C4a (lla) and C5a (12a)], 157.3 [C, 07 (14)].
Las pruebas farmacológicas de los derivados mono- y bis-piridínicos objeto de esta patente se han iniciado con el estudio de la reversión del efecto bloqueante de la tubocurarina, dado que es la forma más sensible para objeti- var los posibles efectos de actividad anticolinesterásica. La preparación empleada fue la de frénico-hemidiafragma de rata siguiendo la metodología descrita por Bülbring (Br. J. Pharmacol. Chemother 1946; 1: 38-61).Pharmacological tests of the mono- and bis-pyridine derivatives object of this patent have begun with the study of the reversal of the blocking effect of tubocurarin, since it is the most sensitive way to objectify the possible effects of anticholinesterase activity. The preparation used was that of rat phrenic-hemidiaphragm following the methodology described by Bülbring (Br. J. Pharmacol. Chemother 1946; 1: 38-61).
El estudio de la actividad anticolinesterásica se basa en la capacidad de los compuestos que la poseen de revertir el bloqueo inducido por tubocurarina. El fundamento de tal acción se basa en el aumento de la disponibilidad de acetilcolina en la unión neuromuscular, consecuencia de la inhibición de su catabolismo por parte de los fármacos que inhiben la acetilcolinesterasa. En esta situación, la acetilcolina puede desplazar a la tubocurarina de su unión al receptor colinérgico. Este hecho se manifiesta como una recuperación de la amplitud de la contracción muscular por pérdida del efecto bloqueante de la tubocurarina. El efecto se determinó mediante el Índice de antagonismo, siguiendo el método descrito por Riesz et al. (J. Pharm. Pharmacol. 1986; 38: 156-8).The study of anticholinesterase activity is based on the ability of the compounds that possess it to reverse the blockade induced by tubocurarin. The rationale for such action is based on the increase in the availability of acetylcholine in the neuromuscular junction, a consequence of the inhibition of its catabolism by drugs that inhibit acetylcholinesterase. In this situation, acetylcholine can displace tubocurarin from its binding to the cholinergic receptor. This fact is manifested as a recovery of the extent of muscle contraction due to loss of the blocking effect of tubocurarin. The effect was determined by the Index of antagonism, following the method described by Riesz et al. (J. Pharm. Pharmacol. 1986; 38: 156-8).
Los derivados mono y bis-piridínicos se probaron a las siguientes concentraciones (μM): 0,1; 0,3; 1; 3; 10; 30. Los resultados se expresan como la media de al menos seis experimentos considerando la correspondiente desviación media extándar. El compuesto 6,7,8,15-Tetrahidro- 7,15-metano-cicloocteno[1,2-b:5,4-b' ]diquinolina-14,16- diamina presenta los siguientes índices de antagonismo: a concentración 3 μM, 19,7 + 5,8; a 10 μM, 52,7 + 1 y a 30 μM, •68,1 + 5,1. La capacidad de inhibición de la acetilcolinestera¬ sa de los derivados mono- y bis-piridínicos se determinó por el método colorimétrico de Ellman et al. (Biochem. Pharmacol. 1961; 7:88-95). El valor de CIso molar observado para 6,7,8, 15-Tetranidro-7,15-metano-cicloocteno[1,2-b:5,4-b']diquinoli- na-14,16-diamina fue 380-10"6 (frente a 156-10"6 observado para la tacrina en las mismas condiciones) . The mono and bis-pyridine derivatives were tested at the following concentrations (μM): 0.1; 0.3; one; 3; 10; 30. The results are expressed as the average of at least six experiments considering the corresponding standard deviation. The compound 6,7,8,15-Tetrahydro-7,15-methane-cyclooctene [1,2-b: 5,4-b '] diquinoline-14,16-diamine has the following antagonism indices: at concentration 3 μM, 19.7 + 5.8; at 10 μM, 52.7 + 1 and at 30 μM, • 68.1 + 5.1. The ability to inhibit acetylcholinestera from mono- and bis-pyridine derivatives was determined by the colorimetric method of Ellman et al. (Biochem. Pharmacol. 1961; 7: 88-95). The CI value so molar observed for 6,7,8, 15-Tetranidro-7,15-methano-cyclooctene [1,2-b: 5,4-b '] diquinoli- na-14,16-diamine was 380 -10 "6 (vs. 156-10" 6 observed for tacrine under the same conditions).

Claims

ReivindicacionesClaims
l4.- Procedimiento para obtener derivados bis- piridínicos de estructuras generales I y II y subproductos piridínicos de estructura general V, que se obtienen en el mismo. 4 .- Procedure for obtaining bis-pyridine derivatives of general structures I and II and pyridine by-products of general structure V, which are obtained therein.
Figure imgf000023_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0002
en donde R es hidrógeno, alquilo o aralquilo, m, n, p, q pueden adoptar los valores 0, l, 2, 3,.. de modo que m + n + p + q < 9. X e Y representan "puentes de conexión" que pueden ser independientes o estar unidos entre sí, directamente por medio de un enlace, y/o de uno o más "restos adecuados".where R is hydrogen, alkyl or aralkyl, m, n, p, q can take the values 0, l, 2, 3, .. so that m + n + p + q <9. X and Y represent "bridges of connection "which may be independent or linked together, directly by means of a link, and / or one or more" suitable moieties ".
Figure imgf000023_0003
Figure imgf000023_0003
siendo,. R^ hidrógeno, halógeno, alcoxi inferior o alquilo inferior, que consiste en hacer reaccionar un compuesto dicarbonílico de estructura general III (CH2)-X—(CH2)„being,. R ^ hydrogen, halogen, lower alkoxy or lower alkyl, which consists in reacting a dicarbonyl compound of general structure III (CH 2 ) -X— (CH 2 ) „
0=< y0 (CH2)p-Y-(CH2)q ffl 0 = <and 0 (CH 2 ) p -Y- (CH 2 ) q ffl
en donde X, Y, m, n, p, q tienen los mismos significados dados anteriormente para I, II y V donde X, Y, m, n, p, q tienen los mismos significados dados anteriormente para I, II y V con un aminonitrilo de estructura general IVwhere X, Y, m, n, p, q have the same meanings given above for I, II and V where X, Y, m, n, p, q have the same meanings given above for I, II, and V with an aminonitrile of general structure IV
Figure imgf000024_0001
Figure imgf000024_0001
IVIV
en donde GT «" X
Figure imgf000024_0002
where GT «" X
Figure imgf000024_0002
siendo Rx hidrógeno, halógeno, alcoxi inferior o alquilo inferior, en presencia de un disolvente adecuado y.de un ácido de Le is como catalizador, a temperaturas comprendidas entre 0 y 150aC durante 1 a 48 horas, seguido, en su caso, de alquilación o aralquilación de los compuestos de estructuras generales I, II y V, en los que R es hidrógeno, y transformación, cuando proceda, en las sales de ácidos farmacéuticamente aceptables, por tratamiento con ácidos orgánicos "o inorgánicos de acuerdo.where R x hydrogen, halogen, lower alkoxy or lower alkyl, in the presence of a suitable solvent and of an acid of Le is as catalyst, at temperatures between 0 and 150 at C for 1 to 48 hours, followed, where appropriate , of alkylation or aralkylation of the compounds of general structures I, II and V, in which R is hydrogen, and transformation, where appropriate, into pharmaceutically acceptable acid salts, by treatment with organic or " inorganic acids accordingly.
2a.- Un procedimiento de acuerdo con la reivindi¬ cación 1*, para producir compuestos de fórmulas generales I, II y V, partiendo de las dicetonas III siguientes:
Figure imgf000025_0001
= n = p = q = 1.; -X-, -Y- = -CH-CH-2 .- a process according to the reivindi¬ cation 1 *, to produce compounds of general formulas I, II and V, based on the following diketones III:
Figure imgf000025_0001
= n = p = q = 1 .; -X-, -Y- = -CH-CH-
Figure imgf000025_0002
Figure imgf000025_0002
m = n = p = q = l; -X-, -Y- = -C(CH3)-C(CH3)-m = n = p = q = l; -X-, -Y- = -C (CH 3 ) -C (CH 3 ) -
Figure imgf000025_0003
Figure imgf000025_0003
m = n = p = q = l; -X-, -Y- = -CH-CH2-CH-m = n = p = q = l; -X-, -Y- = -CH-CH 2 -CH-
' 0> m = n = p = q = l; -X-, -Y- =
Figure imgf000025_0004
'0> m = n = p = q = l; -X-, -Y- =
Figure imgf000025_0004
hid
Figure imgf000025_0005
hid
Figure imgf000025_0005
m = q = 0; n = p = 1; -X-, -Y- = -CH-CH2-CH-m = q = 0; n = p = 1; -X-, -Y- = -CH-CH 2 -CH-
Figure imgf000025_0006
m = q = 0; n = p = 2 ; -X- , -Y- = -CH-CH- 3 * . - Un procedimiento de acuerdo con las reivindi¬ caciones 1 * y 2 * , para producir compuestos de fórmulas generales I, II y V,
Figure imgf000025_0006
m = q = 0; n = p = 2; -X-, -Y- = -CH-CH- 3 *. - A process according to claims 1 * and 2 *, to produce compounds of general formulas I, II and V,
en donde G-C
Figure imgf000026_0001
where GC
Figure imgf000026_0001
R es hidrógeno y Rr es hidrógeno o halógeno.R is hydrogen and R r is hydrogen or halogen.
4*.- Un procedimiento de acuerdo con las reivindi- caciones 1* y 2*, para producir compuestos de fórmulas generales I, II y V,4 * .- A process according to claims 1 * and 2 *, to produce compounds of general formulas I, II and V,
en donde G-
Figure imgf000026_0002
y R y Rj. son hidrógeno.where G-
Figure imgf000026_0002
and R and Rj. They are hydrogen.
5*.- Un procedimiento de acuerdo con las reivindi¬ caciones 1» y 2*, para producir compuestos de fórmulas generales I, II y V,5 * .- A process according to claims 1 » and 2 *, to produce compounds of general formulas I, II and V,
eenn ddoonnddee (Λl|| β«
Figure imgf000026_0003
eenn ddoonnddee ( Λl || β «
Figure imgf000026_0003
R es hidrógeno y Rx es. flúor.R is hydrogen and R x is. fluorine.
6*.- Un procedimiento de acuerdo con las reivindi¬ caciones anteriores, caracterizado porque el ácido de Lewis utilizado es tricloruro de aluminio anhidro.6 * .- A process according to the preceding claims, characterized in that the Lewis acid used is anhydrous aluminum trichloride.
7*.- Un procedimiento de acuerdo con las reivindi¬ caciones anteriores, caracterizado porque el ácido de Lewis utilizado es dicloruro de zinc anhidro.7 * .- A process according to the preceding claims, characterized in that the Lewis acid used is anhydrous zinc dichloride.
8*.- Un procedimiento de acuerdo con las reivindi- caσiones anteriores, caracterizada porque el ácido, de Lewis utilizado es tetracloruro de titanio anhidro.8 * .- A process according to the preceding claims, characterized in that the Lewis acid used is anhydrous titanium tetrachloride.
' 9*.- Un procedimiento de acuerdo con las reivindi¬ caciones anteriores, caracterizado porque el disolvente empleado es 1,2-dicloroetano.9 * .- A process according to the preceding claims, characterized in that the solvent used is 1,2-dichloroethane.
10*.- Un procedimiento de acuerdo con las reivin- dicaciones anteriores, caracterizado porque el disolvente empleado es nitrobenceno.10 * .- A procedure in accordance with the claims previous instructions, characterized in that the solvent used is nitrobenzene.
11*.- Un procedimiento de acuerdo con las reivin¬ dicaciones anteriores, caracterizado porque el disolvente empleado es diclorometano.11 * .- A procedure according to the preceding claims, characterized in that the solvent used is dichloromethane.
12.- Un procedimiento de acuerdo con las reivindi¬ caciones 1* - 7» y 10* anteriores, caracterizado porque se opera a temperaturas comprendidas entre 100 y 150 aC durante un tiempo de 1 a 6 horas. 13».- Un procedimiento de acuerdo con las reivin¬ dicaciones l4 - 6*, 8a, 9a y 11a anteriores, caracterizado porque se opera a temperaturas comprendidas entre 0 aC y la temperatura de reflujo del disolvente, durante un tiempo de 1 a 24 horas. 14a.- Un procedimiento de acuerdo con las reivin¬ dicaciones anteriores, para producir los compuestos siguien¬ tes:12.- A process according to claims 1 * -7 » and 10 * above, characterized in that it is operated at temperatures between 100 and 150 to C for a time of 1 to 6 hours. 13 ».- A method according to reivin¬ in claims l 4-6 *, 8, 9 and 11 above, characterized in that one operates at temperatures between 0 C and the reflux temperature of the solvent, for a Time from 1 to 24 hours. 14 a .- A procedure according to the preceding claims, to produce the following compounds:
Figure imgf000027_0001
Figure imgf000027_0001
6,7,8,15-Tetrahidro-7,15-metanocicloocteno[1,2-b:5,4-b' ] diquinolina-14,16-diamina6,7,8,15-Tetrahydro-7,15-methanocyclooctene [1,2-b: 5,4-b '] diquinoline-14,16-diamine
Figure imgf000027_0002
Figure imgf000027_0002
1 , 13-Dif luoro-6 , 7 , 8 , 15-tetrahidro-7 , 15-metanocicloocteno [ 1 , 2-b: 5 , 4-b' ]diquinolina-14 , 16-diamina 1, 13-Dif luoro-6, 7, 8, 15-tetrahydro-7, 15-methanocyclooctene [1,2-b: 5, 4-b '] diquinoline-14, 16-diamine
Figure imgf000028_0001
Figure imgf000028_0001
Cis-6,6a,13,13a-Tetrahidro-6a,13a-dimetilpentaleno[2,1-b:5,4- b']diquinolina-7,14-diamina y/o sus sales farmacéuticamente aceptables derivadas de la adición de un ácido orgánico o inorgánico. Cis-6,6a, 13,13a-Tetrahydro-6a, 13a-dimethylpentalene [2,1-b: 5,4- b '] diquinoline-7,14-diamine and / or its pharmaceutically acceptable salts derived from the addition of an organic or inorganic acid.
PCT/ES1992/000086 1991-12-26 1992-12-24 Method for producing bis-pyridinic derivatives with acetylcholinesterase inhibiting properties WO1993013100A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013754A1 (en) * 1995-10-11 1997-04-17 Pelayo Camps Garcia Novel polycyclic aminopyridine compounds as acetylcholinesterase inhibitors, preparation process and use thereof
EP2018874A2 (en) 1998-08-07 2009-01-28 Targacept, Inc. Pharmaceutical compositions for the prevention and treatment of central nervous system disorders comprising a nicotinic compound and an acetylcholinesterase inhibitor
WO2011100373A1 (en) 2010-02-09 2011-08-18 The Johns Hopkins University Methods and compositions for improving cognitive function
WO2014090929A1 (en) 2012-12-13 2014-06-19 H. Lundbeck A/S Compositions comprising vortioxetine and donepezil
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311303A2 (en) * 1987-10-05 1989-04-12 Pfizer Inc. 4-aminopyridine derivatives

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK569087A (en) * 1986-10-31 1988-05-01 Sumitomo Pharma QUINOLINE DERIVATIVES, THEIR PREPARATION AND USE
EP0287977B1 (en) * 1987-04-23 1994-06-29 Hoechst-Roussel Pharmaceuticals Incorporated Fused heteroalkylene quinolinamines, a process and intermediates for their preparation and their use as medicaments
CA2015282A1 (en) * 1989-04-25 1990-10-25 Renzo Ohuchi Pyridine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311303A2 (en) * 1987-10-05 1989-04-12 Pfizer Inc. 4-aminopyridine derivatives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997013754A1 (en) * 1995-10-11 1997-04-17 Pelayo Camps Garcia Novel polycyclic aminopyridine compounds as acetylcholinesterase inhibitors, preparation process and use thereof
ES2100129A1 (en) * 1995-10-11 1997-06-01 Medichem Sa Novel polycyclic aminopyridine compounds as acetylcholinesterase inhibitors, preparation process and use thereof
US5965569A (en) * 1995-10-11 1999-10-12 Medichem, S.A. Polycyclic aminopyridine compounds which are acetylcholinesterase inhibitors, process for preparing them and their use
EP2018874A2 (en) 1998-08-07 2009-01-28 Targacept, Inc. Pharmaceutical compositions for the prevention and treatment of central nervous system disorders comprising a nicotinic compound and an acetylcholinesterase inhibitor
WO2011100373A1 (en) 2010-02-09 2011-08-18 The Johns Hopkins University Methods and compositions for improving cognitive function
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2014090929A1 (en) 2012-12-13 2014-06-19 H. Lundbeck A/S Compositions comprising vortioxetine and donepezil
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10925834B2 (en) 2015-05-22 2021-02-23 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam

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