NITROGEN CONTAINING BICYCLIC DERIVATIVES FOR TREATING PAIN AND PAIN RELATED CONDITIONS

Abstract

The present invention relates to new compounds of formula (I):

##STR00001##

showing great affinity and activity towards the subunit 2 of voltage-gated calcium channels (VGCC), especially the 2-1 subunit of voltage-gated calcium channels or dual activity towards the subunit 2 of voltage-gated calcium channels (VGCC), especially the 2-1 subunit of voltage-gated calcium channels, and the noradrenaline transporter (NET).

Claims

1-15. (canceled)

16. A compound of general formula (I): ##STR00082## wherein n is 0 or 1; Z is one of the following moieties: ##STR00083## wherein the dotted line represents an optional double bond; R.sub.4 and R.sub.4 independently represent a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl; or a branched or unbranched C.sub.1-6 haloalkyl; A, B, D and E independently from one another represent N; NH; CH; CH.sub.2 or C(O); with the proviso that at least one of A, B, D or E is N or NH; and with the proviso that when n is 0, Z does not represent a quinoline or isoquinoline; R.sub.1 is an optionally substituted 5 to 9 membered aryl group; an optionally substituted 5 to 9 membered heteroaryl group having at least one heteroatom selected from the group consisting of N, O or S; or an optionally substituted C.sub.3-9 heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, O or S; R.sub.2 and R.sub.3 independently represent a hydrogen atom or a branched or unbranched C.sub.1-6 alkyl; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

17. The compound according to claim 16, wherein R.sub.1 represents a benzene, a thiophene, a thiazole, a pyridine or a tetrahydropyran all of which are optionally substituted by at least one substituent selected from the group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl and hydroxy.

18. The compound according to claim 16, wherein R.sub.1 represents a benzene or a thiophene.

19. The compound according to claim 16, wherein Z is selected from the group consisting of: ##STR00084## wherein R.sub.4 and R.sub.4 independently represent a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl; or a branched or unbranched C.sub.1-6 haloalkyl.

20. The compound according to claim 16, which is a compound of formula (Ia), (Ib), (Ia1), (Ia2), (Ib1) or (Ib2): ##STR00085##

21. The compound according to claim 16, which is selected from the group consisting of: N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; 3-((2-(2,2-difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; (R)N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (S)N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; 3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; 3-methyl-8-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; 2-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)isoquinolin-1(2H)-one; N-methyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; N-ethyl-3-phenyl-3-(phthalazin-5-yloxy)propan-1-amine; N-ethyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (R)N-ethyl-3-phenyl-3-(phthalazin-5-yloxy)propan-1-amine; (R)N-ethyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (S)-3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; (R)-3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; 3-(Isoquinolin-5-ylmethoxy)-N-methyl-3-phenylpropan-1-amine; 3-(Isoquinolin-8-ylmethoxy)-N-methyl-3-phenylpropan-1-amine; N-methyl-3-phenyl-3-(quinolin-5-ylmethoxy)propan-1-amine; 3-(Isoquinolin-8-ylmethoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; 3-(Isoquinolin-5-ylmethoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; N-methyl-3-(quinolin-5-ylmethoxy)-3-(thiophen-2-yl)propan-1-amine; (S)N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; (R)N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; (S)N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; (R)N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; N-ethyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; (S)-1-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinolin-2(1H)-one; (R)-1-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinolin-2(1H)-one; (R)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one;(R)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-2-methylisoquinolin-1(2H)-one; (R)-8-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one; (S)N-methyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (S)-8-(3-(ethylamino)-1-(thiophen-2.sub.11)propoxy)-3-methylquinazolin-4(3H)-one; (S)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-2-methylisoquinolin-1(2H)-one; (S)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one; (R)N-methyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (S)N-ethyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (R)N-ethyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; (R)N-ethyl-3-(quinazolin-5-yloxy)-3-(thiophen-3-yl)propan-1-amine; (R)-8-(3-(ethylamino)-1-(thiophen-3-yl)propoxy)-3-methylquinazolin-4(3H)-one; (R)-5-(3-(ethylamino)-1-(thiophen-3-yl)propoxy)-2-methylisoquinolin-1(2H)-one; (R)-3-methyl-5-(3-(methylamino)-1-(thiophen-3-yl)propoxy)quinazolin-4(3H)-one; (R)-8-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3,6-dimethylquinazolin-4(3H)-one and (R)-7-fluoro-3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; or a pharmaceutically acceptable salt, prodrug or solvate thereof.

22. The compound according to claim 16, which is a compound of formula (Ic): ##STR00086## wherein R.sub.1, R.sub.2, R.sub.3, A, B and n are as defined in claim 16, with the proviso that at least one of A or B represents N(R) wherein R is hydrogen; a branched or unbranched C.sub.1-6 alkyl; or a branched or unbranched C.sub.1-6haloalkyl.

23. The compound according to claim 22, which is selected from the group consisting of: N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine and 3-((2-(2,2-difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; or a pharmaceutically acceptable salt, prodrug or solvate thereof.

24. A process for the preparation of a compound of formula (Ia): ##STR00087## comprising: A) reaction of a compound of formula (II): ##STR00088## with a compound of formula (IIIa) or (IIIb):
ZOH or ZX (IIIa) (IIIb) wherein Z is one of the following moieties: ##STR00089## wherein the dotted line represents an optional double bond; R.sub.4 and R.sub.4 independently represent a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl; or a branched or unbranched C.sub.1-6 haloalkyl; A, B, D and E independently from one another represents N; NH; CH; CH.sub.2 or C(O); with the proviso that at least one of A, B, D or E is N or NH; and with the proviso that when n is 0, Z does not represent a quinoline or isoquinoline; R.sub.1 is an optionally substituted 5 to 9 membered aryl group; an optionally substituted 5 to 9 membered heteroaryl group having at least one heteroatom selected from the group consisting of N, O or S; or an optionally substituted C.sub.3-9 heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, O or S; R.sub.2 and R.sub.3 independently represent a hydrogen atom or a branched or unbranched C.sub.1-6 alkyl radical; and X represents a halogen, or B) reaction of a compound of formula (Va): ##STR00090## with a compound of formula (VI):
HNR.sub.2R.sub.3 (VI) wherein R.sub.1, R.sub.2, R.sub.3 and Z are as defined above, and LG represents a leaving group, including chloro, bromo, iodo, mesylate, tosylate, nosylate and triflate.

25. A process for the preparation of a compound of general formula (Ib): ##STR00091## comprising reaction between a compound of formula (II): ##STR00092## and a compound of formula (IIIc): ##STR00093## wherein Z is one of the following moieties: ##STR00094## wherein the dotted line represents an optional double bond; R.sub.4 and R.sub.4 independently represent a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl; or a branched or unbranched C.sub.1-6 haloalkyl; A, B, D and E independently from one another represents N; NH; CH; CH.sub.2 or C(O); with the proviso that at least one of A, B, D or E is Nor NH; and with the proviso that when n is 0, Z does not represent a quinoline or isoquinoline; R.sub.1 is an optionally substituted 5 to 9 membered aryl group; an optionally substituted 5 to 9 membered heteroaryl group having at least one heteroatom selected from the group consisting of N, O or S; or an optionally substituted C.sub.3-9 heterocycloalkyl group having at least one heteroatom selected from the group consisting of N, O or S; R.sub.2 and R.sub.3 independently represent a hydrogen atom or a branched or unbranched C.sub.1-6 alkyl radical; and LG represents a leaving group, including chloro, bromo, iodo, mesylate, tosylate, nosylate and triflate.

26. A method of treating and/or preventing diseases and/or disorders mediated by the subunit 2, including 2-1 subunit of voltage-gated calcium channels and/or noradrenaline transporter (NET), in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 16.

27. The method according to claim 26, wherein the disease or disorder is selected from the group consisting of pain, depression, anxiety and attention-deficit-/hyperactivity disorder (ADHD).

28. The method according to claim 27, wherein the pain is selected from the group consisting of medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain neuropathic pain, allodynia and hyperalgesia, including mechanical allodynia and thermal hyperalgesia.

29. A pharmaceutical composition comprising the compound according to claim 16, or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0038] The invention first relates to compounds of general formula (I)

##STR00004##

[0039] wherein

[0040] n is 0 or 1;

[0041] Z is one of the following moieties:

##STR00005## [0042] where [0043] the dotted line represents an optional double bond; [0044] R.sub.4 and R.sub.4 independently represent a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl radical; or a branched or unbranched C.sub.1-6haloalkyl; [0045] A, B, D and E independently from one another represents N; NH; CH; CH.sub.2 or C(O); [0046] with the proviso that at least one of A, B, D or E is Nor NH; and [0047] with the proviso that when n is 0, Z does not represent a quinoline or isoquinoline;

[0048] R.sub.1 is selected from an optionally substituted 5 to 9 membered aryl group, an optionally substituted 5 to 9 membered heteroaryl group having at least one heteroatom selected from the group of N, O or S; or an optionally substituted C.sub.3-9 heterocycoalkyl group having at least one heteroatom selected from the group of N, O or S;

[0049] R.sub.2 and R.sub.3 independently represent a hydrogen atom or a branched or unbranched C.sub.1-6 alkyl radical;

[0050] or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

[0051] Unless otherwise stated, the compounds of the invention are also meant to include isotopically-labelled forms i.e. compounds which differ only in the presence of one or more isotopically-enriched atoms. For example, compounds having the present structures except for the replacement of at least one hydrogen atom by a deuterium or tritium, or the replacement of at least one carbon by .sup.13C- or .sup.14C-enriched carbon, or the replacement of at least one nitrogen by .sup.15N-enriched nitrogen are within the scope of this invention.

[0052] The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.

[0053] Halogen or halo as referred in the present invention represent fluorine, chlorine, bromine or iodine. When the term halo is combined with other substituents, such as for instance C.sub.1-6 haloalkyl or C.sub.1-6 haloalkoxy it means that the alkyl or alkoxy radical can respectively contain at least one halogen atom.

[0054] A leaving group is a group that in a heterolytic bond cleavage keeps the electron pair of the bond. Suitable leaving groups are well known in the art and include Cl, Br, I and OSO.sub.2R, wherein R is F, C.sub.1-4-alkyl, C.sub.1-4-haloalkyl, or optionally substituted phenyl. The preferred leaving groups are Cl, Br, I, tosylate, mesylate, nosylate, triflate, nonaflate and fluorosulphonate.

[0055] C.sub.1-6 alkyl, as referred to in the present invention, are saturated aliphatic radicals. They may be linear or branched and are optionally substituted. C.sub.1-6-alkyl as expressed in the present invention means an alkyl radical of 1, 2, 3, 4, 5 or 6 carbon atoms. Preferred alkyl radicals according to the present invention include but are not restricted to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl. The most preferred alkyl radical are C.sub.1-4 alkyl, such as methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, tert-butyl, isobutyl, sec-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. Alkyl radicals, as defined in the present invention, are optionally mono-or polysubstituted by substitutents independently selected from a halogen, C.sub.1-6-alkoxy, C.sub.1-6-alkyl, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group.

[0056] C.sub.3-6 Cycloalkyl as referred to in the present invention, is understood as meaning saturated and unsaturated (but not aromatic), cyclic hydrocarbons having from 3 to 6 carbon atoms which can optionally be unsubstituted, mono- or polysubstituted. Examples for cycloalkyl radical preferably include but are not restricted to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Cycloalkyl radicals, as defined in the present invention, are optionally mono-or polysubstituted by substitutents independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group.

[0057] A cycloalkylalkyl group/radical C.sub.1-6, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 atoms which is bonded to a cycloalklyl group, as defined above. The cycloalkylalkyl radical is bonded to the molecule through the alkyl chain. A preferred cycloalkylalkyl group/radical is a cyclopropylmethyl group or a cyclopentylpropyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for cycloalkylalkyl group/radical, according to the present invention, are independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group.

[0058] Heterocycloalkyl as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), generally 5 or 6 membered cyclic hydrocarbons which can optionally be unsubstituted, mono- or polysubstituted and which have at least one heteroatom in their structure selected from N, O or S. Examples for heterocycloalkyl radical preferably include but are not restricted to pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyran, tetrahydrofuran, dioxane, dioxolane, oxazolidine, piperidine, piperazine, morpholine, azepane or diazepane. Heterocycloalkyl radicals, as defined in the present invention, are optionally mono-or polysubstituted by substitutents independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group. More preferably heterocycloalkyl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.

[0059] A heterocycloalkylalkyl group/radical C.sub.1-6, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 atoms which is bonded to a cycloalklyl group, as defined above. The heterocycloalkylalkyl radical is bonded to the molecule through the alkyl chain. A preferred heterocycloalkylalkyl group/radical is a piperidinethyl group or a piperazinylmethyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for cycloalkylalkyl group/radical, according to the present invention, are independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group.

[0060] Aryl as referred to in the present invention, is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. These aryl radicals may optionally be mono-or polysubstituted by substitutents independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, nitro or a hydroxyl group. Preferred examples of aryl radicals include but are not restricted to phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl, indanyl or anthracenyl radicals, which may optionally be mono- or polysubstituted, if not defined otherwise. More preferably aryl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.

[0061] An arylalkyl radical C.sub.1-6, as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 carbon atoms which is bonded to an aryl group, as defined above. The arylalkyl radical is bonded to the molecule through the alkyl chain. A preferred arylalkyl radical is a benzyl group or a phenetyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for arylalkyl radicals, according to the present invention, are independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group.

[0062] Heteroaryl as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and may optionally contain one or more heteroatoms from the group consisting of N, O or S and may optionally be mono-or polysubstituted by substituents independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl trihaloalkyl or a hydroxyl group. Preferred examples of heteroaryls include but are not restricted to furan, benzofuran, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, tiophene, quinoline, isoquinoline, phthalazine, triazole, pyrazole, isoxazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole and quinazoline. More preferably heteroaryl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.

[0063] Heteroarylalkyl group/radical C.sub.1-6 as defined in the present invention, comprises a linear or branched, optionally at least mono-substituted alkyl chain of 1 to 6 carbon atoms which is bonded to an heteroaryl group, as defined above. The heteroarylalkyl radical is bonded to the molecule through the alkyl chain. A preferred heteroarylalkyl radical is a piridinylmethyl group, wherein the alkyl chain is optionally branched or substituted. Preferred substituents for heteroarylalkyl radicals, according to the present invention, are independently selected from a halogen, C.sub.1-6-alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl, trihaloalkyl or a hydroxyl group.

[0064] Heterocyclic ring or heterocyclic system, as defined in the present invention, comprise any saturated, unsaturated or aromatic carbocyclic ring systems which are optionally at least mono-substituted and which contain at least one heteroatom as ring member. Preferred heteroatoms for these heterocyclyl groups are N, S or O. Preferred substituents for heterocyclyl radicals, according to the present invention, are F, Cl, Br, I, NH.sub.2, SH, OH, SO.sub.2, CF.sub.3, carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, SO.sub.2NH.sub.2, C.sub.1-6 alkyl and/or C.sub.1-6-alkoxy.

[0065] The term C.sub.1-3 alkylene is understood as meaning a divalent alkyl group like CH.sub.2 or CH.sub.2CH.sub.2 or CH.sub.2CH.sub.2CH.sub.2. An alkylene may also be unsaturated

[0066] The term condensed according to the present invention means that a ring or ring-system is attached to another ring or ring-system, whereby the terms annulated or annelated are also used by those skilled in the art to designate this kind of attachment.

[0067] The term ring system according to the present invention refers to ring systems comprising saturated, unsaturated or aromatic carbocyclic ring systems which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted. Said ring systems may be condensed to other carbocyclic ring systems such as aryl groups, heteroaryl groups, cycloalkyl groups, etc.

[0068] The term salt is to be understood as meaning any form of the active compound according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions. The definition particularly includes physiologically acceptable salts, this term must be understood as equivalent to pharmacologically acceptable salts.

[0069] The term pharmaceutically acceptable salts in the context of this invention means any salt that is tolerated physiologically (normally meaning that it is not toxic, particularly as a result of the counter-ion) when used in an appropriate manner for a treatment, particularly applied or used in humans and/or mammals. These physiologically acceptable salts may be formed with cations or bases and, in the context of this invention, are understood to be salts formed by at least one compound used in accordance with the inventionnormally an acid (deprotonated)such as an anion and at least one physiologically tolerated cation, preferably inorganic, particularly when used on humans and/or mammals. Salts with alkali and alkali earth metals are particularly preferred, as well as those formed with ammonium cations (NH.sub.4.sup.+). Preferred salts are those formed with (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium. These physiologically acceptable salts may also be formed with anions or acids and, in the context of this invention, are understood as being salts formed by at least one compound used in accordance with the inventionnormally protonated, for example in nitrogensuch as a cation and at least one physiologically tolerated anion, particularly when used on humans and/or mammals. This definition specifically includes in the context of this invention a salt formed by a physiologically tolerated acid, i.e. salts of a specific active compound with physiologically tolerated organic or inorganic acidsparticularly when used on humans and/or mammals. Examples of this type of salts are those formed with hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

[0070] The term solvate is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.

[0071] The term prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the compounds of the invention: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. Textbook of Drug design and Discovery Taylor & Francis (April 2002).

[0072] Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

[0073] In a particular and preferred embodiment of the invention, R.sub.1 represents a benzene, a thiophene, a thiazole, a pyridine or a tetrahydropyran. These groups may optionally be substituted by at least one substituent selected from halogen, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl or a hydroxyl group. The benzene, thiophene, thiazole, pyridine or tetrahydropyran group can be attached to the main structure through different points of attachment. For instance, when R.sub.1 represents thiophene this might be a 2-thiophene or 3-thiophene, when it represents thiazole it may represent a 2-thiazole, a 4-thiazole or a 5-thiazole, when it represents a pyridine it may represent a 2-pyridine, 3-pyridine or 4-pyridine or when it represents tetrahydropyran it may represent 2-tetrahydropyran, 3-tetrahydropyran or 4-tetrahydropyran.

[0074] In a particularly prefered embodiment R.sub.1 represents a benzene or a thiophene, preferably unsubstituted although optionally substituted by at least one substituent selected from halogen, C.sub.1-6 alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl or a hydroxyl group.

[0075] In another particular and preferred embodiment of the invention, Z is selected from:

##STR00006##

[0076] which can be optionally substituted by at least one substituent selected from a halogen, a branched or unbranched C.sub.1-6 alkyl radical or by a branched or unbranched C.sub.1-6 haloalkyl.

[0077] In a still more particularly preferred embodiment Z is selected from:

##STR00007##

[0078] where R.sub.4 represents a branched or unbranched C.sub.1-6 alkyl radical or a branched or unbranched C.sub.1-6 haloalkyl, and R.sub.4 represents a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl radical; or a branched or unbranched C.sub.1-6 haloalkyl.

[0079] Another particular embodiment of the invention is that where Z is represented by:

##STR00008##

[0080] where A, B, D, E and R.sub.4 are as defined before.

[0081] A preferred embodiment of the invention is represented by compounds of formula (I):

##STR00009##

[0082] wherein

[0083] n is 0 or 1;

[0084] Z is selected from:

##STR00010## [0085] wherein R.sub.4 represents a hydrogen atom; a branched or unbranched C.sub.1-6 alkyl radical; or a branched or unbranched C.sub.1-6 haloalkyl and R.sub.4 represents a hydrogen atom; a halogen, a branched or unbranched C.sub.1-6 alkyl radical; or a branched or unbranched C.sub.1-6 haloalkyl.

[0086] R.sub.1 represents a benzene; a thiophene; a thiazole; a pyridine or a tetrahydropyran, preferably a benzene or a thiophene, all of them optionally substituted by at least one substituent selected from selected from halogen, C.sub.1-6 alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl or a hydroxyl group, and

[0087] R.sub.2 and R.sub.3 independently represent a hydrogen atom or a branched or unbranched C.sub.1-6 alkyl radical;

[0088] or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

[0089] Another preferred embodiment of the invention is represented by compounds of formula (I):

##STR00011##

[0090] wherein

[0091] n is 0 or 1;

[0092] Z is selected from:

##STR00012## [0093] wherein R.sub.4 represents a hydrogen atom; a branched or unbranched C.sub.1-6 alkyl radical; or a branched or unbranched C.sub.1-6 haloalkyl and R.sub.4 represents a hydrogen atom;

[0094] R.sub.1 represents a benzene; a thiophene; a thiazole; a pyridine or a tetrahydropyran, preferably a benzene or a thiophene, all of them optionally substituted by at least one substituent selected from selected from halogen, C.sub.1-6 alkyl, C.sub.1-6-alkoxy, C.sub.1-6-haloalkoxy, C.sub.1-6-haloalkyl or a hydroxyl group, and

[0095] R.sub.2 and R.sub.3 independently represent a hydrogen atom or a branched or unbranched C.sub.1-6 alkyl radical;

[0096] or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

[0097] Another particular embodiment of compounds of general formula (I) is represented by compounds of general formula (Ia):

##STR00013##

[0098] wherein R.sub.1, R.sub.2, R.sub.3 and Z have the same meaning as defined before.

[0099] Another particular embodiment of of compounds of general formula (I) is represented by compounds of general formula (Ib):

##STR00014##

[0100] wherein R.sub.1, R.sub.2, R.sub.3 and Z have the same meaning as defined before.

[0101] Still more particular embodiments falling within general formula (Ia) and (Ib) respectively are compounds of formula (Ia1), (Ia2), (Ib1) or (Ib2):

##STR00015##

[0102] wherein R.sub.1, R.sub.2, R.sub.3 and Z have the same meaning as defined before.

[0103] The compounds of the present invention represented by the above described formula (I), (Ia), (Ib), (Ia1), (Ia2), (Ib1) or (Ib2) may include enantiomers depending on the presence of chiral centers or isomers depending on the presence of double bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.

[0104] Among all the compounds described in the general formula (I), the following compounds are preferred for showing an intense inhibitory effect towards subunit 2-1 of voltage-gated calcium channels (VGCC): [0105] [1] N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0106] [2] N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0107] [3] 3-((2-(2,2-Difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; [0108] [4] (R)N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0109] [5] (S)N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0110] [6] N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0111] [7] 3-Methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; [0112] [8] 3-Methyl-8-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; [0113] [9] 2-Methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)isoquinolin-1(2H)-one; [0114] [10] N-methyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0115] [11] N-ethyl-3-phenyl-3-(phthalazin-5-yloxy)propan-1-amine; [0116] [12] N-ethyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0117] [13] (R)N-ethyl-3-phenyl-3-(phthalazin-5-yloxy)propan-1-amine; [0118] [14] (R)N-ethyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0119] [15] (S)-3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; [0120] [16] (R)-3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one; [0121] [17] 3-(Isoquinolin-5-ylmethoxy)-N-methyl-3-phenylpropan-1-amine; [0122] [18] 3-(Isoquinolin-8-ylmethoxy)-N-methyl-3-phenylpropan-1-amine; [0123] [19] N-methyl-3-phenyl-3-(quinolin-5-ylmethoxy)propan-1-amine; [0124] [20] 3-(Isoquinolin-8-ylmethoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; [0125] [21] 3-(Isoquinolin-5-ylmethoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine; [0126] [22] N-methyl-3-(quinolin-5-ylmethoxy)-3-(thiophen-2-yl)propan-1-amine; [0127] [23] (S)N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0128] [24] (R)N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0129] [25] (S)N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0130] [26] (R)N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0131] [27] N-ethyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine; [0132] [28] (S)-1-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinolin-2(1H)-one; [0133] [29] (R)-1-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinolin-2(1H)-one; [0134] [30] (R)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one; [0135] [31] (R)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-2-methylisoquinolin-1(2H)-one; [0136] [32] (R)-8-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one; [0137] [33] (S)N-methyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0138] [34] (S)-8-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one; [0139] [35] (S)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-2-methylisoquinolin-1(2H)-one; [0140] [36] (S)-5-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3-methylquinazolin-4(3H)-one; [0141] [37] (R)N-methyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0142] [38] (S)N-ethyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0143] [39] (R)N-ethyl-3-(quinazolin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine; [0144] [40] (R)N-ethyl-3-(quinazolin-5-yloxy)-3-(thiophen-3-yl)propan-1-amine; [0145] [41] (R)-8-(3-(ethylamino)-1-(thiophen-3-yl)propoxy)-3-methylquinazolin-4(3H)-one; [0146] [42] (R)-5-(3-(ethylamino)-1-(thiophen-3-yl)propoxy)-2-methylisoquinolin-1(2H)-one; [0147] [43] (R)-3-methyl-5-(3-(methylamino)-1-(thiophen-3-yl)propoxy)quinazolin-4(3H)-one; [0148] [44] (R)-8-(3-(ethylamino)-1-(thiophen-2-yl)propoxy)-3,6-dimethylquinazolin-4(3H)-one and [0149] [45] (R)-7-fluoro-3-methyl-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)quinazolin-4(3H)-one;

[0150] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0151] Among compounds of general formula (I) some subgroups of compounds have shown in addition a dual affinity towards subunit 2-1 of voltage-gated calcium channels (VGCC) and the noradrenaline transporter (NET). These compounds having dual affinity represent the preferred embodiments of the invention and are represented by formula (Ic):

##STR00016##

[0152] wherein R.sub.1, R.sub.2, R.sub.3, A, B and n are as defined before with the proviso that at least one of A or B represents a N(R) where R can be a hydrogen or a branched or unbranched C.sub.1-6 alkyl radical; or a branched or unbranched C.sub.1-6 haloalkyl.

[0153] The preferred compounds of the invention showing dual inhibitory effect towards subunit 2-1 of voltage-gated calcium channels (VGCC) and noradrenaline transporter (NET) are selected from the following group:

[0154] [1] N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine and

[0155] [3] 3-((2-(2,2-Difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine;

[0156] or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0157] In another aspect, the invention refers to the processes for obtaining the compounds of general formula (I). Several procedures have been developed for obtaining all the compounds of the invention, and the procedures will be explained below in methods A and B.

[0158] The obtained reaction products may, if desired, be purified by conventional methods, such as crystallization and chromatography. Where the processes described below for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

Method A

[0159] Method A represents a first process for synthesizing compounds according to general formula (I). Method A allows for the preparation of compounds of general formula (Ia) that is compounds of formula (I) where n is 0.

[0160] In this sense, a process is described for the preparation of a compound of general formula (Ia):

##STR00017##

[0161] comprising:

[0162] A) the reaction of a compound of formula (II):

##STR00018##

[0163] with a compound of formula (IIIa) or (IIIb):

ZOH or ZX (IIIa) (IIIb)

[0164] wherein R.sub.1, R.sub.2, R.sub.3 and Z are as defined before and X represents a halogen, or

[0165] B) the reaction of a compound of formula (Va):

##STR00019##

[0166] with a compound of formula (VI):

HNR.sub.2R.sub.3 (VI)

[0167] wherein R.sub.1, R.sub.2, R.sub.3 and Z are as defined before and LG represents a leaving group, such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

[0168] Different reaction conditions are applied when the compounds of formula (Ia) are synthesized through the reaction of a compound of formula (II) with either a compound of formula (IIIa) or a compound of formula (IIIb): [0169] a) When a hydroxy compound of formula (IIIa) is used, the reaction is carried out under conventional Mitsunobu conditions by treating an alcohol of formula (II) with a compound of formula (IIIa) preferably in the presence of an azo compound such as 1,1-(azodicarbonyl)dipiperidine (ADDP), diisopropylazodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) and a phosphine such as tributylphosphine or triphenylphoshine. The Mitsunobu reaction is carried out in a suitable solvent, such as toluene or tetrahydrofuran; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. [0170] b) When a halo compound of formula (IIIb) is used, the reaction is carried out under conventional aromatic nucleophilic substitution conditions by treating an alcohol of formula (II) with a compound of formula (IIIb) wherein X represents halogen (preferably fluoro), in the presence of a strong base such as sodium hydride or potassium tert-butoxide. The reaction is carried out in a suitable solvent, such as a polar aprotic solvent, preferably dimethylformamide, dimethylacetamide or dimethylsulfoxide; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Alternatively, when X is bromo or iodo, the compound of formula (IIIb) can be introduced under cross-coupling conditions, using a Pd or Cu catalyst and a suitable ligand.

[0171] Alternatively and, as explained above, a compound of formula (Ia) can be obtained by reaction of a compound of formula (Va) with an amine of formula (VI). The alkylation reaction is carried out in a suitable solvent, such as ethanol, dimethylformamide, dimethylsulfoxide or acetonitrile, preferably ethanol; optionally in the presence of a base such as K.sub.2CO.sub.3 or triethylamine; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Additionally, an activating agent such as sodium iodide or potassium iodide can be used.

Method B

[0172] Method B represents a process for synthesizing compounds according to general formula (Ib), namely compounds of general formula (I) where n is 1.

[0173] In this sense, a process is described for the preparation of a compound of general formula (Ib):

##STR00020##

[0174] comprising the reaction between a compound of formula (II):

##STR00021##

[0175] and a compound of formula (IIIc):

##STR00022##

[0176] wherein R.sub.1, R.sub.2, R.sub.3 and Z are as defined before and LG represents a leaving group, such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate.

[0177] The reaction between a compound of formula (II) with an alkylating agent of formula (IIIc) is preferably carried out in the presence of a strong base such as sodium hydride or potassium tert-butoxide. The alkylation reaction is carried out in a suitable solvent, such as tetrahydrofuran or dimethylformamide, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Additionally, an activating agent such as sodium iodide or a phase transfer catalyst such as tetrabutylammonium iodide can be used.

[0178] Both methods A and B use compound (II) as starting material. The amino group can be either introduced in compound of formula (II) at an early stage, that is, before the reaction for producing compounds of formula (Ia) and (Ib) or later in the synthesis by reaction of a precursor compound of formula (II)-LG or (Va) wherein LG represents a leaving group (such as chloro, bromo, iodo, mesylate, tosylate, nosylate or triflate) with an amine of formula (VI) to render a compound of formula (II) or (Ia), respectively, as shown in Scheme 1 below. The alkylation reaction is carried out in a suitable solvent, such as ethanol, dimethylformamide, dimethylsulfoxide or acetonitrile, preferably ethanol; optionally in the presence of a base such as K.sub.2CO.sub.3 or triethylamine; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Additionally, an activating agent such as sodium iodide or potassium iodide can be used.

[0179] The different reactions of methods A and B as well as the reactions for preparing the intermediate compounds for such reactions are depicted in scheme 1:

##STR00023##

[0180] The intermediate compound (II) which is the basic reagent for producing compounds of formula (I), according to methods A and B, can be prepared, as shown in scheme 1 above by the reduction of a keto compound of formula (IV) following conventional procedures described in the literature. As a way of example, the reduction can be performed using a hydride source such as sodium borohydride in a suitable solvent such as methanol, ethanol or tetrahydrofuran or lithium aluminium hydride in a suitable solvent such as tetrahydrofuran or diethyl ether, at a suitable temperature, preferably comprised between 0 C. and room temperature.

[0181] Alternatively, the reduction can be carried out by hydrogenation under hydrogen atmosphere and metal catalysis, preferably by the use of palladium over charcoal or Nickel-Raney as catalysts, in a suitable solvent such as methanol, ethanol or ethyl acetate. In addition, the reduction can be performed under asymmetric hydrogenation conditions using a rhodium catalyst to render chiral compounds of formula II in enantiopure form, following procedures described in the literature (i.e. Angew. Chem. Int. Ed. 2004, 43, 2816; Angew. Chem. Int. Ed. 2005, 44, 1687; Angew. Chem. Int. Ed. 2015, 54, 2260)

[0182] A compound of formula (Va) can be synthesized from a compound of formula (II)-LG by reaction with a compound of formula (IIIa), following the conditions described above for the preparation of a compound of formula (Ia) from a compound of formula (II) and a compound of formula (IIIa).

[0183] The compounds of general formula (IIIa), (IIIb), (IIIc) and (VI) are commercially available or can be prepared by conventional methods described in the bibliography.

[0184] The compounds of formula (II)-LG are commercially available or can be obtained from a compound of formula (IV)-LG following the reduction conditions described above, (Step 1), preferably using a hydride source. In addition, the reduction can be performed under asymmetric conditions described in the literature to render chiral compounds of formula (II-LG) in enantiopure form. As a way of example, the chiral reduction can be performed using a hydride source such as borane-tetrahydrofuran complex or borane-dimethyl sulfide complex, in the presence of a Corey-Bakshi-Shibata oxazaborolidine catalyst, in a suitable solvent such as tetrahydrofuran or toluene, at a suitable temperature, preferably comprised between 0 C. and room temperature.

[0185] In turn, compounds of formula (IV) and (IV)-LG are commercially available or can be synthesized following procedures described in the literature. As a way of example, some routes of synthesis are described in Schemes 2 and 3 below. In addition, a compound of formula (IV) can be prepared from a compound of formula (IV)-LG and an amine of formula (VI) following the conditions described above for the synthesis of a compound of formula (Ia) from a compound of formula (Va).

[0186] The preparation of compounds of general formula (IV) can be performed following several methods described in the literature. As a way of example, two routes of synthesis are described in Scheme 2:

##STR00024##

[0187] wherein R.sub.1, R.sub.2 and R.sub.3 have the meanings as defined above for a compound of formula (I).

[0188] Following Route A, the treatment of a compound of formula (VIII) with a strong base such as butyl lithium to generate the corresponding organometallic reagent and subsequent condensation with a Weinreb amide of formula (VII), in a suitable solvent such as tetrahydrofuran, renders a compound of formula (IV).

[0189] Alternatively, the compounds of formula (IV) can be prepared through a Mannich reaction by condensation of an acetyl compound of formula (IX) with an amine of formula (VI) and a formaldehyde source such as paraformaldehyde, preferably in the presence of an acid such as hydrochloric acid, in a suitable solvent such as ethanol or isopropanol, at a suitable temperature, preferably heating.

[0190] The preparation of compounds of general formula (IV)-LG can be performed following several methods described in the literature. As a way of example, a route of synthesis is described in Scheme 3:

##STR00025##

[0191] wherein R.sub.1 has the meaning as defined above for a compound of formula (I), LG represents a leaving group (preferably chloro, bromo or iodo) and X represents halogen (preferably chloro or bromo).

[0192] The Friedel-Crafts acylation of an heteroaryl compound of formula (X) with an acid halide of formula (XI) in the presence of a Lewis acid such as aluminum trichloride renders a compound of formula (IV)-LG. The reaction is carried out in a suitable solvent, such as dichloromethane or dichloroethane; at a suitable temperature comprised between 0 C. and the reflux temperature.

[0193] The compounds of general formula (VI), (VII), (VIII), (IX), (X) and (XI) are commercially available or can be prepared by conventional methods described in the bibliography.

[0194] Moreover, certain compounds of the present invention can also be obtained starting from other compounds of formula (I) by appropriate conversion reactions of functional groups, in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions.

[0195] In some of the processes described above it may be necessary to protect the reactive or labile groups present with suitable protecting groups, such as for example Boc (tert-butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups. The procedures for the introduction and removal of these protecting groups are well known in the art and can be found thoroughly described in the literature.

[0196] In addition, a compound of formula (I) that shows chirality can also be obtained by resolution of a racemic compound of formula I either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal. Alternatively, the resolution step can be carried out at a previous stage, using any suitable intermediate.

[0197] Compounds of general formula (I) for which R.sub.3 contains a Protecting Group (PG), such as Boc or 2-(trimethylsilyl)ethylcarbamate), can be used as intermediates useful for the preparation of other compounds of general formula (I) as defined above.

[0198] Another particular aspect is represented by the intermediate compounds used for the preparation of compounds of general formula (I).

[0199] In a particular embodiment, these intermediate compounds are selected from: [0200] 8-Fluoro-3-methylquinazolin-4(3H)-one; [0201] 5-Fluoro-2-methylisoquinolin-1(2H)-one; [0202] 2-(2,2-Difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-ol; [0203] (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol; [0204] (R)-3-(ethylamino)-1-(thiophen-2-yl)propan-1-ol; [0205] 3-(Ethylamino)-1-(thiophen-2-yl)propan-1-ol; [0206] 3-(Ethylamino)-1-phenylpropan-1-ol; [0207] (R)-3-(ethylamino)-1-phenylpropan-1-ol; [0208] (R)-3-(Methylamino)-1-(thiophen-3-yl)propan-1-ol; [0209] (S)-3-(ethylamino)-1-(thiophen-2-yl)propan-1-ol; [0210] (R)-3-(ethylamino)-1-(thiophen-3-yl)propan-1-ol; [0211] 8-Fluoro-3,6-dimethylquinazolin-4(3H)-one; and [0212] 5,7-Difluoro-3-methylquinazolin-4(3H)-one.

[0213] Turning to another aspect, the invention also relates to the therapeutic use of the compounds of general formula (I). As mentioned above, compounds of general formula (I) show a strong affinity to subunit an and, more preferably, to 2-1 subunit of voltage-gated calcium channels. In a more preferred embodiment of the invention compounds of general formula (I) show a strong affinity both to subunit an and, more preferably, to 2S-1 subunit of voltage-gated calcium channels, as well as to noradrenaline transporter (NET) and can behave as agonists, antagonists, inverse agonists, partial antagonists or partial agonists thereof. Therefore, compounds of general formula (I) are useful as medicaments.

[0214] They are suitable for the treatment and/or prophylaxis of diseases and/or disorders mediated by the subunit an, especially 2-1 subunit of voltage-gated calcium channels and/or noradrenaline transporter (NET). In this sense, compounds of formula (I) are suitable for the treatment and/or prophylaxis of pain, depression anxiety and attention-deficit-/hyperactivity disorder (ADHD).

[0215] The compounds of formula (I) are especially suited for the treatment of pain, especially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain neuropathic pain, allodynia or hyperalgesia, including mechanical allodynia or thermal hyperalgesia.

[0216] PAIN is defined by the International Association for the Study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.

[0217] In a preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of allodynia and more specifically mechanical or thermal allodynia.

[0218] In another preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of hyperalgesia.

[0219] In yet another preferred embodiment compounds of the invention are used for the treatment and/or prophylaxis of neuropathic pain and more specifically for the treatment and/or prophylaxis of hyperpathia.

[0220] A related aspect of the invention refers to the use of compounds of formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit an, especially 2-1 subunit of voltage-gated calcium channels and/or noradrenaline transporter (NET), as explained before.

[0221] Another related aspect of the invention refers to a method for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit an, especially 2-1 subunit of voltage-gated calcium channels and/or noradrenaline transporter (NET), as explained before comprising the administration of a therapeutically effective amount of a compound of general formula (I) to a subject in need thereof.

[0222] Another aspect of the invention is a pharmaceutical composition, which comprises at least a compound of general formula (I) or a pharmaceutically acceptable salt, prodrug, isomer or solvate thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

[0223] The pharmaceutical composition of the invention can be formulated as a medicament in different pharmaceutical forms comprising at least a compound binding to the subunit 2, especially 2-1 subunit of voltage-gated calcium channels and/or noradrenaline transporter (NET) and optionally at least one further active substance and/or optionally at least one auxiliary substance.

[0224] Preferably, the composition is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.

[0225] The composition of the invention can be formulated for oral administration in any form preferably selected from the group consisting of tablets, dragees, capsules, pills, chewing gums, powders, drops, gels, juices, syrups, solutions and suspensions. The composition of the present invention for oral administration may also be in the form of multiparticulates, preferably microparticles, microtablets, pellets or granules, optionally compressed into a tablet, filled into a capsule or suspended in a suitable liquid. Suitable liquids are known to those skilled in the art.

[0226] In a preferred embodiment, the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

[0227] The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

[0228] The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

[0229] The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.

[0230] The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.

[0231] The following examples are merely illustrative of certain embodiments of the invention and cannot be considered as restricting it in any way.

EXAMPLES

[0232] In the next preparation examples the synthesis of both intermediate derivatives as well as compounds according to the invention are disclosed.

[0233] The following abbreviations are used in the examples:

[0234] ACN: acetonitrile

[0235] ADDP: 1,1-(azodicarbonyl)dipiperidine

[0236] Anh: anhydrous

[0237] Boc: tert-butoxycarbonyl

[0238] Conc: concentrated

[0239] DCM: dichloromethane

[0240] DEA: diethylamine

[0241] DIPEA: N,N-diisopropylethylamine

[0242] DMA: dimethylacetamide

[0243] DME: 1,2-dimethoxyethane

[0244] DMF: dimethylformamide

[0245] Eq: equivalent/s

[0246] Et.sub.2O; diethyl ether

[0247] EtOAc; ethyl acetate

[0248] EtOH: ethanol

[0249] EX: example

[0250] h: hour/s

[0251] HPLC: high performance liquid chromatography

[0252] INT: intermediate

[0253] 2-Me-CBS-oxazaborolidine: 5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine

[0254] (Corey-Bakshi-Shibata oxazaborolidine catalyst)

[0255] MeOH: methanol

[0256] MS: mass spectrometry

[0257] Min.: minutes

[0258] Quant: quantitative

[0259] Ret.: retention

[0260] r.t.: room temperature

[0261] Sat: saturated

[0262] TFA: trifluoroacetic acid

[0263] THF: tetrahydrofuran

[0264] Wt: weight

[0265] The following methods were used to determine the HPLC-MS spectra:

[0266] Method A

[0267] Column Xbridge C18 XP 304.6 mm, 2.5 um

[0268] Temperature: 40 C.

[0269] Flow: 2.0 mL/min

[0270] Gradient: NH.sub.4HCO.sub.3 pH 8:ACN (95:5)0.5 min(95:5)6.5 min(0:100)1 min(0:100)

[0271] Sample dissolved approx. 1 mg/mL in NH.sub.4HCO.sub.3 pH 8/ACN

[0272] Method B

[0273] Column: Gemini-NX 304.6 mm, 3 um

[0274] Temperature: 40 C.

[0275] Flow: 2.0 mL/min

[0276] Gradient: NH.sub.4HCO.sub.3 pH 8:ACN (95:5)0.5 min(95:5)6.5 min(0:100)1 min(0:100)

[0277] Sample dissolved approx. 1 mg/mL in NH.sub.4HCO.sub.3 pH 8/ACN

[0278] Method C

[0279] Column: Kinetex EVO 504.6 mm, 2.6 um

[0280] Temperature:40 C.

[0281] Flow: 2.0 mL/min

[0282] Gradient: NH.sub.4HCO.sub.3 pH 8:ACN (95:5)0.5 min(95:5)6.5 min(0:100)1 min(0:100)

[0283] Sample dissolved approx. 1 mg/ mL in NH.sub.4HCO.sub.3 pH 8/ACN

[0284] Method D

[0285] Column: Eclipse XDB-C18 4.6150 mm, 5 m;

[0286] Flow: 1 mL/min

[0287] Gradient: H.sub.2O (0.05% TFA): ACN (95:5)7 min(5:95)5 min(5:95)

[0288] Method E

[0289] Column: Kinetex EVO 504.6 mm, 2.6 um

[0290] Temperature:40 C.

[0291] Flow: 1.5 mL/min

[0292] Gradient: NH.sub.4HCO.sub.3 pH 8:ACN (95:5)0.5 min(95:5)6.5 min(0:100)2 min(0:100)

[0293] Sample dissolved approx. 1 mg/ mL in NH.sub.4HCO.sub.3 pH 8/ACN

Synthesis of Intermediates

[0294] Intermediate 1: 8-Fluoro-3-methylquinazolin-4(3H)-one

##STR00026##

[0295] Step1. 2-Amino-3-fluorobenzamide: To a solution of 2-amino-3-fluorobenzoic acid (1 g, 6. 5 mmol) in DMF (3 mL), 1H-benzo[d][1,2,3]triazol-1-ol (1.13 g, 8.4 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (1.2 g, 7.7 mmol), NH.sub.4Cl (1.45 g, 21.1 mmol) and DIPEA (4.7 mL, 27.1 mmol) were added. The reaction mixture was stirred at r.t. overnight. Water was then added and it was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. The crude product was slurried in DCM (6.5 mL). The solids were filtered, washed with cold DCM and dried under vacuum to afford the title compound (444 mg, 45% yield)

[0296] Step 2. Title compound: A mixture of the product obtained in Step 1 (444 mg, 2.8 mmol) and dimethylformamide dimethylacetal (1 g, 8.6 mmol) in DMF (14 mL) was heated at 150 C. in a sealed tube for 1.5 h. The solvent was distilled off and the residue (which contained a mixture of the title compound and 8-fluoroquinazolin-4(3H)-one) was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (104 mg, 20% yield).

[0297] Intermediate 2: 5-Fluoro-2-methylisoquinolin-1(2H)-one

##STR00027##

[0298] To a solution of 5-fluoroisoquinolin-1(2H)-one (60 mg, 0.37 mmol) in DMF (2 mL), NaH (60% dispersion in mineral oil, 19 mg, 0.48 mmol) was added. After stirring at r.t. for 1 h, iodomethane (0.028 mL, 0.44 mmol) was added and the reaction mixture was stirred at r.t. overnight. Water was added and it was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgSO.sub.4 and concentrated under vacuum to afford the title compound (66 mg, quant. yield).

[0299] Intermediate 3: 2-(2,2-Difluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-ol

##STR00028##

[0300] To a solution of 1,2,3,4-tetrahydroisoquinolin-5-ol (0.95 g, 2.39 mmol) and acetic acid (0.28 mL, 4.78 mmol) in DCM (16 mL), 2,2-difluoroacetaldehyde (0.16 M solution in DCM, 15 mL, 2.39 mmol) and sodium triacetoxyborohydride (1 g, 4.78 mmol) were added. After stirring at r.t. for 24 h, additional 2,2-difluoroacetaldehyde (0.16 M solution in DCM, 15 mL) and sodium triacetoxyborohydride (1 g) were added and the reaction mixture was again stirred at r.t. overnight. NaHCO.sub.3 sat. solution was added and it was extracted with DCM. The combined organic phases were dried over MgSO.sub.4 and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (371 mg, 73% yield).

[0301] Intermediate 4: (R)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol

##STR00029##

[0302] A solution of (R)-3-chloro-1-(thiophen-2-yl)propan-1-ol (4.7 g, 26.9 mmol) and methylamine (33% wt in EtOH, 33 mL, 269 mmol) in EtOH (20 mL) was heated in a sealed tube at 90 C. overnight. The solvent was evaporated to dryness and the residue was re-dissolved in DCM. The organic phase was washed with 1 N NaOH, dried over MgSO.sub.4 and concentrated to dryness. The crude product (3.9 g) was slurried in a mixture of methylcyclohexanetoluene (3:1 v/v, 22 mL) and heated at 60 C. for 1 h. Then, it was allowed to cool down and it was stirred at r.t. for 1 h. The solids were filtered, washed with methylcyclohexane and dried under vacuum to obtain the title compound (2.9 g, 62% yield).

[0303] This method was used for the preparation of Intermediates 5-8 using suitable starting materials:

TABLE-US-00001 INT Structure Chemical name 5 [00030] (R)-3-(ethylamino)-1- (thiophen-2-yl)propan-1-ol 6 [00031] 3-(ethylamino)-1-(thiophen- 2-yl)propan-1-ol.sup.(1) 7 [00032] 3-(ethylamino)-1- phenylpropan-1-ol.sup.(1) 8 [00033] (R)-3-(ethylamino)-1- phenylpropan-1-ol.sup.(1) .sup.(1)Final crystallization was not performed

[0304] Intermediate 9: (R)-3-(Methylamino)-1-(thiophen-3-yl)propan-1-ol

##STR00034##

[0305] Step 1. (R)-3-Chloro-1-(thiophen-3-yl)propan-1-ol: To a solution of (S)-2-Me-CBS-oxazaborolidine (0.635 g, 2.3 mmol) in dry THF (42 mL), borane dimethyl sulfide complex (2.17 mL, 22.9 mmol) was added dropwise at r.t. After stirring for 10 min, a solution of 3-chloro-1-(thiophen-3-yl)propan-1-one (prepared according to the procedure described in US2003/0158185 Example 74 steps a-c) (2 g, 11.45 mmol) in dry THF (80 mL) was added during 45 min. The reaction mixture was stirred at r.t. for 1 h. Then, it was concentrated to dryness. The residue was dissolved in Et.sub.2O and it was washed with NH.sub.4Cl sat. solution. The organic phase was dried over MgSO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient Cyclohexane/EtOAc 100:0 to Cyclohexane/EtOAc 0:100, to give the title compound (0.982 g, 48% yield).

[0306] Step 2. Title compound: Starting from the product obtained in Step 1 and following the experimental procedure described for the preparation of Intermediate 4, the title compound was obtained (842 mg, 88% yield).

[0307] This method was used for the preparation of Intermediates 10-11 using suitable starting materials:

TABLE-US-00002 INT Structure Chemical name 10 [00035] (S)-3-(ethylamino)-1- (thiophen-2-yl)propan-1-ol 11 [00036] (R)-3-(ethylamino)-1- (thiophen-3-yl)propan-1-ol

[0308] Intermediate 12: 8-Fluoro-3,6-dimethylquinazolin-4(3H)-one

##STR00037##

[0309] Step 1. 2-Amino-5-bromo-3-fluorobenzamide: A solution of 2-amino-5-bromo-3-fluorobenzoic acid (0.5 g, 2.14 mmol) and 1,1-carbonyldiimidazole (0.346 g, 2.14 mmol) in anhydrous THF (15 mL) was heated to reflux for 30 min. After cooling to r.t., ammonia (32 wt % aq. solution, 10 mL, 3.8 mmol) was added and the reaction was stirred at r.t. overnight. The solvent was evaporated to dryness, the residue was slurried in water and the precipitated solids were filtered, washed with water and dried under vacuum to afford the title compound (349 mg, 70% yield).

[0310] Step 2. 6-Bromo-8-fluoro-3-methylquinazolin-4(3H)-one: Following the experimental procedure described in Step 2 of Intermediate 1, starting from the product obtained in Step 1, the title compound was obtained (280 mg, 72% yield).

[0311] Step 3. Title compound: A mixture of the product obtained in Step 2 (170 mg, 0.66 mmol), K.sub.2CO.sub.3 (0.59 mg, 4.3 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.1 mL, 0.73 mmol) and dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium (II) CH.sub.2Cl.sub.2 adduct (484 mg, 0.66 mmol) in DME (3.5 mL), under an Ar atmosphere, was heated at 120 C. for 1 h in a MW oven. The reaction mixture was filtered through a pad of Celite and it was washed with EtOAc. The filtrate was concentrated to dryness and the residue was purified by by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (79 mg, 40% yield).

[0312] Intermediate 13: 5,7-Difluoro-3-methylquinazolin-4(3H)-one

##STR00038##

[0313] Following the procedure described for the synthesis of intermediate 2 but using 5,7-difluoroquinazolin-4(3H)-one as starting material, the title compound was obtained.

Synthesis of Examples

Example 1

N-Methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine

[0314] ##STR00039##

[0315] Step 1. 5-(3-Chloro-1-(thiophen-2-yl)propoxy)-1-methyl-1,2,3,4-tetrahydro quinoline: To a solution of 3-chloro-1-(thiophen-2-yl)propan-1-ol (0.39 g, 2.21 mmol), tributylphosphine (0.66 mL, 2.65 mmol) and 1-methyl-1,2,3,4-tetrahydroquinolin-5-ol (0.36 g, 2.21 mmol) in toluene (15 mL), ADDP (0.67 g, 2.65 mmol) was added. The mixture was stirred at 100 C. overnight. The suspension was filtered through a pad of Celite that was washed with toluene and the filtrate was concentrated under vacuum. The crude product was used in the next step without further purification (1.38 g, overweight, quantitative yield assumed).

[0316] Step 2. Title compound: In a sealed tube, a mixture of the product obtained in Step 1 and methylamine (33 wt % in EtOH, 5.3 mL, 42.4 mmol) was heated at 100 C. overnight. Then, it was concentrated to dryness. The residue was dissolved in DCM (10 mL) and it was washed with 1 N NaOH solution and brine. The organic phase was dried over MgSO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (22 mg, 3% yield, 2 steps).

[0317] HPLC retention time (method C): 4.21 min; MS: 317.1 (M+H).

[0318] This method was used for the preparation of Examples 2-3 using suitable starting materials:

TABLE-US-00003 Ret time Ms HPLC EX Structure Chemical name (min) (M + H) Method 2 [00040] N-methyl-3-((2-methyl- 1,2,3,4- tetrahydroisoquinolin-5- yl)oxy)-3-(thiophen-2- yl)propan-1-amine 3.19 317.1 C 3 [00041] 3-((2-(2,2-difluoroethyl)- 1,2,3,4- tetrahydroisoquinolin-5- yl)oxy)-N-methyl-3- (thiophen-2-yl)propan-1- amine 3.96 Only fragmentation m/z 214.1 observed C

Example 4

(R)N-Methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine

[0319] ##STR00042##

[0320] To a solution of Intermediate 4 (75 mg, 0.44 mmol) in anhydrous DMA (3 mL) cooled at 0 C., NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol) was added portionwise under a nitrogen atmosphere. After stirring for 30 min at 0 C., a solution of 5-fluorophthalazine (65 mg, 0.44 mmol) in anhydrous DMA (2 mL) was added and the reaction mixture was heated at 50 C. for 1.5 h. It was then cooled to 0-5 C. and then water was added. The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO.sub.4 and evaporated to dryness. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:4) to give the title compound (34 mg, 49% yield).

[0321] HPLC retention time (method A): 2.44 min; MS: 300.1 (M+H).

[0322] This method was used for the preparation of Examples 5-16 using suitable starting materials:

TABLE-US-00004 Ret time MS HPLC EX Structure Chemical name (min) (M + H) Method 5 [00043] (S)-N-methyl-3- (phthalazin-5-yloxy)-3- (thiophen-2-yl)propan-1- amine 2.48 300.1 A 6 [00044] N-methyl-3-(phthalazin-5- yloxy)-3-(thiophen-2- yl)propan-1-amine 2.46 300.1 A 7 [00045] 3-methyl-5-(3- (methylamino)-1- (thiophen-2- yl)propoxy)quinazolin- 4(3H)-one 2.67 330.1 A 8 [00046] 3-methyl-8-(3- (methylamino)-1- (thiophen-2- yl)propoxy)quinazolin- 4(3H)-one 2.82 330.1 A 9 [00047] 2-methyl-5-(3- (methylamino)-1- (thiophen-2- yl)propoxy)isoquinolin- 1(2H)-one 2.79 329.0 A 10 [00048] N-methyl-3-(quinazolin-5- yloxy)-3-(thiophen-2- yl)propan-1-amine 2.60 300.1 A 11 [00049] N-ethyl-3-phenyl-3- (phthalazin-5- yloxy)propan-1-amine 2.71 308.1 A 12 [00050] N-ethyl-3-(phthalazin-5- yloxy)-3-(thiophen-2- yl)propan-1-amine 2.57 314.1 A 13 [00051] (R)-N-ethyl-3-phenyl-3- (phthalazin-5- yloxy)propan-1-amine 2.73 308.1 A 14 [00052] (R)-N-ethyl-3-(phthalazin- 5-yloxy)-3-(thiophen-2- yl)propan-1-amine 2.57 314.1 A 15 [00053] (S)-3-methyl-5-(3- (methylamino)-1- (thiophen-2- yl)propoxy)quinazolin- 4(3H)-one 2.81 330.1 B 16 [00054] (R)-3-methyl-5-(3- (methylamino)-1- (thiophen-2- yl)propoxy)quinazolin- 4(3H)-one 2.84 330.1 B

Example 17

3-(Isoquinolin-5-ylmethoxy)-N-methyl-3-phenylpropan-1-amine

[0323] ##STR00055##

[0324] Step 1. tert-Butyl (3-(isoquinolin-5-ylmethoxy)-3-phenylpropyl)(methyl) carbamate: To a suspension of NaH (70 mg, 60% dispersion in mineral oil, 1.74 mmol) in THF (2 mL) cooled at 0 C., a solution of tert-butyl (3-hydroxy-3-phenylpropyl)(methyl)carbamate (181 mg, 0.7 mmol) in THF (9 mL) was added. The reaction mixture was stirred at r.t. for 60 min and then a solution of 5-(chloromethyl)isoquinoline (145 mg, 0.82 mmol) in THF (5 mL) and tetrabutylammonium iodide (22 mg, 0.6 mmol) were added at 0 C. The reaction mixture was heated at 45 C. for 24 h. NH.sub.4Cl sat. solution was added and it was extracted with DCM. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash chromatography, silica gel, gradient Hexane to Hexane:EtOAc 1.5:1, to afford the title compound (147 mg, 53% yield).

[0325] Step 2. Title compound: To a solution of the product obtained in Step 1 (54 mg, 0.13 mmol) in 1,4-dioxane (0.3 mL), HCl (4 M solution in 1,4-dioxane, 0.47 mL, 1.9 mmol) was added and the mixture was stirred at r.t. for 35 min. The reaction mixture was concentrated under vacuum, 10% Na.sub.2CO.sub.3 aqueous solution was added and it was extracted with DCM. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated to dryness to afford the title compound (34 mg, 84% yield).

[0326] HPLC retention time (method D): 4.35 min; MS: 307.4 (M+H).

[0327] This method was used for the preparation of Examples 18-19 using suitable starting materials:

TABLE-US-00005 Ret time MS HPLC EX Structure Chemical name (min) (M + H) Method 18 [00056] 3-(isoquinolin-8- ylmethoxy)-N-methyl- 3-phenylpropan-1- amine 4.38 307.1 D 19 [00057] N-methyl-3-phenyl-3- (quinolin-5- ylmethoxy)propan-1- amine 4.38 307.1 D

Example 20

3-(Isoquinolin-8-ylmethoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine

[0328] ##STR00058##

[0329] Step 1. tert-Butyl (3-(isoquinolin-8-ylmethoxy)-3-(thiophen-2-yl)propyl)(methyl) carbamate: tert-Butyl (3-hydroxy-3-(thiophen-2-yl)propyl)(methyl)carbamate was reacted with 8-(chloromethyl)isoquinoline following the conditions described in Example 17 Step 1, to afford the title compound (71% yield).

[0330] Step 2. Title compound: In a round bottomed flask, ZnBr.sub.2 (350 mg, 1.5 mmol) was dried under vacuum at 200 C. for 4 h and then it was allowed to cool. Once the solid reached r.t., a solution of the compound obtained in Step 1 (125 mg, 0.3 mmol) in DCM (3 mL) was added and the mixture was stirred at r.t. under an argon atmosphere for 24 h. Water was added and the mixture was stirred for 1 h. The phases were separated and the aqueous phase was extracted with DCM. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash chromatography, silica gel, gradient DCM to MeOH:DCM (1:1.5) to afford the title compound (11 mg, 12% yield).

[0331] HPLC retention time (method D): 4.26 min; MS: 313.1 (M+H).

[0332] This method was used for the preparation of Examples 21-22 using suitable starting materials:

TABLE-US-00006 Ret time MS HPLC EX Structure Chemical name (min) (M + H) Method 21 [00059] 3-(isoquinolin-5- ylmethoxy)-N-methyl- 3-(thiophen-2- yl)propan-1-amine 4.25 313.1 D 22 [00060] N-methyl-3-(quinolin-5- ylmethoxy)-3- (thiophen-2-yl)propan- 1-amine 4.26 313.1 D

Examples 23 and 24

(S)N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine and (R)N-methyl-3-((1-methyl-1,2,3,4-tetrahydroquinol-5yl)oxy)-3-(thiophen-2-yl)propan-1-amine

[0333] ##STR00061##

[0334] Starting from Example 1, a chiral preparative HPLC separation (column: Chiralpak IC; temperature: ambient; flow: 2.4 mL/min; eluent: n-Heptane/(EtOH+0.2% DEA) 90/10 v/v) was carried out to give the title compounds.

Examples 25 and 26

(S)N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine and (R)N-methyl-3-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-3-(thiophen-2-yl)propan-1-amine

[0335] ##STR00062##

[0336] Starting from Example 2, a chiral preparative HPLC separation (column: Chiralpak IC;

[0337] temperature: ambient; flow: 11 mL/min; eluent: n-Heptane/(IPA+0.33% DEA) 70/30 v/v) was carried out to give the title compounds.

[0338] Following the method described for the preparation of Example 1 but using suitable starting materials, Example 27 was obtained:

TABLE-US-00007 Ret time MS HPLC EX Structure Chemical name (min) (M + H) Method 27 [00063] N-ethyl-3-((2-methyl- 1,2,3,4- tetrahydroisoquinolin- 5-yl)oxy)-3-(thiophen- 2-yl)propan-1-amine 3.83 331.2 E

[0339] Following the method described for the preparation of Example 4 but using suitable starting materials, Examples 28-45 were obtained:

TABLE-US-00008 Ret time MS HPLC EX Structure Chemical name (min) (M + H) Method 28 [00064] (S)-1-methyl-5-(3- (methylamino)-1- (thiophen-2- yl)propoxy)quinolin- 2(1H)-one 3.50 329.1 E 29 [00065] (R)-1-methyl-5-(3- (methylamino)-1- (thiophen-2- yl)propoxy)quinolin- 2(1H)-one 3.57 329.1 E 30 [00066] (R)-5-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-3- methylquinazolin- 4(3H)-one 3.79 344.1 E 31 [00067] (R)-5-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-2- methylisoquinolin- 1(2H)-one.sup.(1) 3.45 342.9 E 32 [00068] (R)-8-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-3- methylquinazolin- 4(3H)-one 3.83 344.1 E 33 [00069] (S)-N-methyl-3- (quinazolin-5-yloxy)-3- (thiophen-2-yl)propan- 1-amine 3.15 301.0 E 34 [00070] (S)-8-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-3- methylquinazolin- 4(3H)-one 3.32 344.1 E 35 [00071] (S)-5-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-2- methylisoquinolin- 1(2H)-one.sup.(1) 3.45 342.9 E 36 [00072] (S)-5-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-3- methylquinazolin- 4(3H)-one 3.25 344.1 E 37 [00073] (R)-N-methyl-3- (quinazolin-5-yloxy)-3- (thiophen-2-yl)propan- 1-amine 3.14 299.9 E 38 [00074] (S)-N-ethyl-3- (quinazolin-5-yloxy)-3- (thiophen-2-yl)propan- 1-amine 3.36 313.9 E 39 [00075] (R)-N-ethyl-3- (quinazolin-5-yloxy)-3- (thiophen-2-yl)propan- 1-amine 3.34 313.9 E 40 [00076] (R)-N-ethyl-3- (quinazolin-5-yloxy)-3- (thiophen-3-yl)propan- 1-amine.sup.(1) 3.38 314.1 E 41 [00077] (R)-8-(3-(ethylamino)- 1-(thiophen-3- yl)propoxy)-3- methylquinazolin- 4(3H)-one.sup.(1) 3.52 344.1 E 42 [00078] (R)-5-(3-(ethylamino)- 1-(thiophen-3- yl)propoxy)-2- methylisoquinolin- 1(2H)-one.sup.(1) 3.49 343.1 E 43 [00079] (R)-3-methyl-5-(3- (methylamino)-1- (thiophen-3- yl)propoxyl)quinazolin- 4(3H)-one.sup.(1) 3.44 330.1 E 44 [00080] (R)-8-(3-(ethylamino)- 1-(thiophen-2- yl)propoxy)-3,6- dimethylquinazolin- 4(3H)-one.sup.(1) 3.97 358.1 E 45 [00081] (R)-7-fluoro-3-methyl- 5-(3-(methylamino)-1- (thiophen-2- yl)propoxyl)quinazolin- 4(3H)-one.sup.(1) 4.00 348.1 E .sup.(1)The reaction was carried out using .sup.tBuOK as base and DMSO as solvent.

Pharmacological Data

[0340] Binding assay to human .sub.2-1 subunit of Cav2.2 calcium channel.

[0341] Human .sub.2-1 enriched membranes (2.5 g) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10 mM, pH 7.4.

[0342] NSB (non specific binding) was measured by adding 10 M pregabalin. The binding of the test compound was measured at five different concentrations. After 60 min of incubation at 27 C., the binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5% polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCl, pH 7.4.

[0343] Filter plates were dried at 60 C. for 1 h and 30 l of scintillation cocktail were added to each well before radioactivity reading.

[0344] Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer). [0345] Binding assay to human norepinephrine transporter (NET).

[0346] Human norepinephrine transporter (NET) enriched membranes (5 g) were incubated with 5 nM of radiolabeled [3H]-Nisoxetin in assay buffer containing 50 mM Tris-HCl, 120 mM NaCl, 5 mM KCl, pH 7.4.

[0347] NSB (non specific binding) was measured by adding 10 M desipramine. The binding of the test compound was measured at five different concentrations. After 60 min incubation at 4 C., binding reaction was terminated by filtering through Multiscreen GF/C (Millipore) presoaked in 0.5% polyethyleneimine in Vacuum Manifold Station, followed by 3 washes with ice-cold filtration buffer containing 50 mM Tris-HCl, 0.9% NaCl, pH 7.4.

[0348] Filter plates were dried at 60 C. for 1 h and 30 l of scintillation cocktail were added to each well before radioactivity reading.

[0349] Readings were performed in a Trilux 1450 Microbeta radioactive counter (Perkin Elmer).

[0350] The following scale has been adopted for representing the binding to the 21 receptor expressed as Ki: [0351] + Ki-21>=3000 nM [0352] ++ 500 nM<Ki-21<3000 nM [0353] +++ 100 nM<Ki-21<500 nM [0354] ++++ Ki-21<100 nM

[0355] For the dual compounds and regarding the NET receptor, the following scale has been adopted for representing the binding expressed as Ki: [0356] + Ki-NET>=1000 nM [0357] ++ 500 nM<Ki-NET<1000 nM [0358] +++ 100 nM<Ki-NET<500 nM [0359] ++++ Ki-NET<100 nM

[0360] The results of the binding for 2 receptor are shown in Table 1:

TABLE-US-00009 TABLE 1 Ki(nM) alpha2delta EXAMPLE Hum 1 +++ 2 ++++ 3 +++ 4 +++ 5 + 6 ++++ 7 +++ 8 +++ 9 +++ 10 +++ 11 ++ 12 +++ 13 ++ 14 ++++ 15 + 16 ++++ 17 + 18 + 19 + 20 + 21 + 22 + 23 ++ 24 +++ 25 +++ 26 ++++ 27 ++++ 28 ++ 29 +++ 30 ++++ 31 ++++ 32 +++ 33 +++ 34 + 35 ++ 36 + 37 ++++ 38 ++ 39 +++ 40 ++++ 41 ++++ 42 ++++ 43 +++ 44 +++ 45 +++

[0361] The binding results for the 2 receptor and the NET receptor for the dual compounds are shown in Table 2:

TABLE-US-00010 TABLE 2 Ki(nM) Ki(nM) NET alpha2delta EXAMPLE Hum Hum 1 ++ +++ 3 ++ +++