Patent EA-003391-B1 (EA)
Title: New substituted dimeric compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: DEPREUX PATRICK
IPC: A61P3/00
Filed: 2000-05-18
Abstract: 1. A compound selected from those of formula (I): A-G1-Cy-G2-Cy'-G3-B (I) wherein: - A represents -NHC(Q)R<2>, wherein Q represents sulphur or oxygen, and R<2> represents (C1-C6)alkyl; - B represents -NHC(Q)R<2>, C(Q)OR<2>, wherein Q and R<2> are as defined hereinbefore; - G1 and G3 represent an optionally alkylene group; - Cy and Cy' represent naphthyl, 1,4-benzodioxine, tetrahydronaphthyl, benzothienyl, dihydrobenzothienyl, benzofuryl, dihydrobenzofuryl, pyrrolo[3,2-b]pyridinyl, indolyl, indolynylpyridinyl, indolyl, indolynyl; G2 represents oxy(C1-C6)alkoxy group; enantiomers and diastereoisomers thereof and addition salts thereof with a pharmaceutically-acceptable acid or base. 2. A compound of formula (I) according to claim 1, which is N-(2-{7-[2-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)ethoxy]-1-naphthyl}ethyl)acetamide, N-(2-{5-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy-1-benzofuran-3-yl}ethyl)-2-furamide, N-(2-{5-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]-1H-pyrrolo[2, 3-b]pyridin-3-yl}ethyl)cyclopropanecarboxamide, N-(2-{7-[3-({3-[2-(acetylamino)-ethyl]-1-benzothiophen-5-yl}oxy)propoxy]-1-naphthyl}ethyl)acetamide, N-[2-(5-{[6-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)hexyl]oxy}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-acetamide, N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)butoxy]-1H-indol-3-yl}ethyl)acetamide, N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}-oxy)butoxy]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acetamide, N-(2-{5-[4-({3-[2-acetyl-amino)ethyl]-1-benzofuran-5-yl}oxy)butoxy]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-acetamide, N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}oxy)butoxy]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acetamide, and addition salts of any of the foregoing with a pharmaceutically foregoing acceptable acid or base. 3. A compound of formula (I) according to claim 1, which is N-(2-{7-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)butoxy]-1-naphthyl}ethyl)acetamide, N-{2-[5-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-(phenylsulphonyl)-1H-indol-3-yl]ethyl}acetamide, N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1,2,3,4-tetra hydro1-naphthalenyl}ethyl)acetamide, N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}oxy)butoxy]-1H-indol-3-yl}ethyl)acetamide, N-(2-{7-[4-({3-[2-(acetyl-amino)ethyl]-1-benzothien-5-yl}oxy)butoxy]-1-naphthyl}ethyl)acetamide, and addition salts of any of the foregoing with a pharmaceutically acceptable acid or base. 4. A compound of formula (I) according to claim 1, which is N-[2-(7-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-1-naphthyl)ethyl]acetamide, N-[3-(5-{8-[2-(acetylamino)ethyl]-2-naphthyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)propyl]heptanamide, N-[2-(7-{3[-2-(acetylamino)ethyl]-1-benzothien-5-yl}-1-naphthyl)ethyl]acetamide, N-[2-(5-{8-[2-(acetylamino)ethyl]-2-naphthyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide, N-[2-(5-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-1-benzothien-3-yl)ethyl]acetamide, N-[2-(5-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl }-1H-indol-3-yl)ethyl]acetamide, N-[2-(5-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-acetamide, N-[2-(5-{3-[2-(acetylamino)ethyl]-1H-indol-5-yl}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide, N-[2-(5-{3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}-1H-pyrrolo-[2,3-b]pyridin-3-yl)ethyl]acetamide, and addition salts of any of the foregoing with a pharmaceutically acceptable acid or base. 5. A process for the preparation of compounds of formula (I) according to claim 1, characterized in that there is used as starting material a compound of formula (V): A-G1-Cy-Ome  (V) wherein A, G1 and Cy are as defined for formula (I), which is subjected to demethylation using conventional agents, such as HBr, AlCl3, AlBr3, BBr3 or Lewis acid/ nucleophile binary systems, such as, for example, AlCl3/PhCH2SH or BBr3/Me2S, to obtain a compound of formula (VI): A-G1-Cy-OH  (VI) wherein A, G1 and Cy are as defined hereinbefore, - which is converted, in conventional manner, - by the action of, for example, sodium N,N-dimethylthiocarbamate, to the corresponding thiol of formula (VII): A-G1-Cy-SH  (VII) wherein A, G1 and Cy are as defined hereinbefore, - or to the corresponding amine compound of formula (VIII): A-G1-Cy-NHR'a  (VIII) wherein A, G1 and Cy are as defined hereinbefore and R'a can have any of the meanings of Ra as defined for formula (I) and can also represent a hydrogen atom, which compounds of formulae (VI), (VII) and (VIII) represent the compound of formula (IX): A-G1-Cy-W4H  (IX) wherein W4 represents an oxygen or sulphur atom, or an NH or NRa group (wherein Ra is as defined hereinbefore), which compound of formula (IX) is condensed with : - a compound of formula (X) : wherein Hal represents a bromine, chlorine or iodine atom, and n, W2 and m are as defined for formula (I), (with the proviso that it is not possible to have two consecutive hetero atoms and that the chain so defined may have one or more unsaturated bonds), - or a compound of formula (XI): wherein Hal, n, m and W2 are as defined hereinbefore and Alk represents an alkyl radical (with the proviso that it is not possible to have two consecutive hetero atoms and that the chain so defined may have one or more unsaturated bonds), followed by reduction, to yield a compound of formula (XII): A-G1-Cy-W4-(CH2)n-W2-(CH2)n-OH  (XII) wherein A, G1, Cy, W4, n, m and W2 are as defined hereinbefore (with the proviso that it is not possible to have two consecutive hetero atoms in the -W4-(CH2)n-W2-(CH2)m-OH chain and that the chain so defined may have one or more unsaturated bonds), the hydroxyl function of which is converted in conventional manner to a leaving group, such as, for example, a mesylate, a tosylate, or a halogen compound, to yield a compound of formula (XII'): A-G1-Cy-W4-(CH2)n-W2-(CH2)m-E  (XII') wherein A, G1, Cy, W4, n, W2 and m are as defined hereinbefore and E represents a mesyl or tosyl group or a halogen atom, which is subjected to the action of a compound of formula (XIII): B-G3-Cy'-W'4H  (XIII) wherein B, G3 and Cy' are as defined for formula (I) and W'4 can have the same meanings as W4 defined hereinbefore, to yield a compound of formula (I/a), a particular case of the compounds of formula (I): A-G1-Cy-W4-(CH2)n-W2-(CH2)mW'4-Cy'-G3-B  (I/a) wherein A, G1, Cy, Cy', W4, n, W2, m, W'4, G3 and B are as defined hereinbefore, - or converted using, for example, phenyl bis(trifluoromethanesulphonimide) in a basic medium to the corresponding trifluoromethanesulphonate of formula (XIV): A-G1-Cy-OSO2CF3  (XIV) wherein A, G1 and Cy are as defined hereinbefore, - which is subjected, under conditions of catalysis by a suitable palladium compound, to the action of a boric acid compound (RbB(OH)2) or of a tin compound (RbSnBu3) (wherein Rb represents a grouping of formula (XV): B-G3-Cy'-W3-(CH2)mW2-(CH2)n-CH2-  (XV) wherein B, G3, Cy', W3, m, W2 and n are as defined hereinbefore, with the proviso that it is not possible to have two consecutive hetero atoms in the -W3-(CH2)m-W2- chain and that the chain so defined may have one or more unsaturated bonds), to yield a compound of formula (I/b), a particular case of the compounds of formula (I): A-G1-Cy-CH2-(CH2)n-W2-(CH2)mW3-Cy'-G3-B  (I/b) wherein A, G1, Cy, Cy', n, W2, m, W3, G3 and B are as defined hereinbefore (with the proviso that it is not possible to have two consecutive hetero atoms in the -W2-(CH2)m-W3- chain and that the chain so defined may have one or more unsaturated bonds), which compounds of formula (I/c), a particular case of the compounds of formula (I): A-G1-Cy-W1-(CH2)n-W2-(CH2)m-CH2-Cy'-G3-B  (I/c) wherein A, G1, Cy, Cy', W1, n, W2, m, G3 and B are as defined hereinbefore (with the proviso that it is not possible to have two consecutive hetero atoms in the -W1-(CH2)n-W2- chain and that the chain so defined may have one or more unsaturated bonds), are obtained according to a similar procedure starting from a compound of formula (XIV'): B-G3-Cy'-OSO2CF3  (XIV') wherein B, G3 and Cy' are as defined hereinbefore, - or is treated, under coupling conditions using, for example, nickel or palladium compounds, with a compound of formula (XIV') to yield a compound of formula (I/d), a particular case of the compounds of formula (I): A-G1-Cy-Cy'-G3-B  (I/d) wherein A, G1, Cy, Cy', G3 and B are as defined hereinbefore, the totality of the compounds (I/a) to (I/d) constituting the compounds of formula (I) which may be purified, if desired, by a conventional purification technique, are separated, where appropriate, into their isomers according to a conventional separation technique, and converted , if necessary, into addition salts thereof with a pharmaceutically acceptable salt or base. 6. A pharmaceutical composition comprising, as active principle, at least one compound of formula (I) according to one of claims 1 to 4 or an addition salt thereof with together with one or more pharmaceutically acceptable excipient. 7. A pharmaceutical composition according to claim 6 useful for preparing a medicament for treating melatoninenergic disorders.