WO2020120606A1 - Nouveaux dérivés d'acide pyrrolidine-2-carboxylique pour le traitement de la douleur et d'états pathologiques associés à la douleur - Google Patents

Nouveaux dérivés d'acide pyrrolidine-2-carboxylique pour le traitement de la douleur et d'états pathologiques associés à la douleur Download PDF

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WO2020120606A1
WO2020120606A1 PCT/EP2019/084717 EP2019084717W WO2020120606A1 WO 2020120606 A1 WO2020120606 A1 WO 2020120606A1 EP 2019084717 W EP2019084717 W EP 2019084717W WO 2020120606 A1 WO2020120606 A1 WO 2020120606A1
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pyrrolidine
dimethylamino
amino
methyl
carboxylic acid
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PCT/EP2019/084717
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English (en)
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Anita Wegert
Menno-Cornelis-Franciscus MONNEE
Wouter DE GRAAF
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Esteve Pharmaceuticals, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to new compounds that show pharmacological activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d- 1 subunit of voltage-gated calcium channels or dual activity towards the subunit a2d of voltage-gated calcium channels (VGCC), especially the a2d-1 subunit of voltage-gated calcium channels, and the m-opiod receptor (MOR or mu-opioid).
  • VGCC voltage-gated calcium channels
  • MOR or mu-opioid m-opiod receptor
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioid agonists opioid agonists
  • calcium channel blockers and antidepressants
  • antidepressants but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.
  • Voltage-gated calcium channels are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et al.; Pharmacol. Rev.; 2015; 67; 821-870).
  • the VGCC are assembled through interactions of different subunits, namely a1 (Caval), b (CavP) a2d (Cava25) and g (Ca v y).
  • the a1 subunits are the key porous forming units of the channel complex, being responsible for Ca 2+ conduction and generation of Ca 2+ influx.
  • VGCC can be subdivided into low voltage-activated T-type (Ca v 3.1 , Ca v 3.2, and Ca v 3.3), and high voltage-activated L- (Ca v 1.1 through Ca v 1.4), N- (Ca v 2.2), P/Q-(Ca v 2.1), and R-(Ca v 2.3) types, depending on the channel forming Cava subunits.
  • Current therapeutic agents include drugs targeting L-type Cav1.2 calcium channels, particularly 1 ,4-dihydropyridines, which are widely used in the treatment of hypertension.
  • T-type (Cav3) channels are the target of ethosuximide, widely used in absence epilepsy.
  • Ziconotide a peptide blocker of N-type (Cav2.2) calcium channels, has been approved as a treatment of intractable pain.
  • the Ca v 1 and Ca v 2 subfamilies contain an auxiliary a2d subunit which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain (Perret and Luo, 2009; Vink and Alewood; British J. Pharmacol.; 2012; 167; 970- 989).
  • a2d subunits each encoded by a unique gene and all possessing splice variants.
  • Each a2d protein is encoded by a single messenger RNA and is post-translationally cleaved and then linked by disulfide bonds.
  • Four genes encoding a2d subunits have now been cloned.
  • the a2d-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution.
  • the a2d-2 and a2d-3 subunits were subsequently cloned from brain.
  • the most recently identified subunit, a2d-4 is largely non-neuronal.
  • the human a2d-4 protein sequence shares 30, 32 and 61 % identity with the human a2d-1 , a2d-2 and a2d-3 subunits, respectively.
  • the gene structure of all a2d subunits is similar. All a2d subunits show several splice variants (Davies et al.; Trends Pharmacol. Sci.; 2007; 28; 220-228; Dolphin, A. C.; Nat. Rev. Neurosci.; 2012; 13; 542-555; Dolphin, A.C.; Biochim. Biophys. Acta; 2013; 1828; 1541- 1549).
  • the Ca v a23-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009; Vink and Alewood, 2012).
  • Biochemical data have indicated a significant Ca v ⁇ x25-1, but not Ca v ⁇ x25-2, subunit upregulation in the spinal dorsal horn, and DRG (dorsal root ganglia) after nerve injury that correlates with neuropathic pain development.
  • DRG dio root ganglia
  • blocking axonal transport of injury-induced DRG Ca v ⁇ x 2 5-1 subunit to the central presynaptic terminals diminishes tactile allodynia in nerve injured animals, suggesting that elevated DRG Ca v ⁇ x25-1 subunit contributes to neuropathic allodynia.
  • the Ca v ⁇ x25-1 subunit (and the Ca v ⁇ x25-2, but not Ca v ⁇ x25-3 and Ca v ⁇ x25-4, subunits) is the binding site for gabapentin which has anti-allodynic/hyperalgesic properties in patients and animal models.
  • injury-induced Ca v ⁇ x25-1 expression correlates with neuropathic pain, development and maintenance, and various calcium channels are known to contribute to spinal synaptic neurotransmission and DRG neuron excitability
  • injury-induced Ca v ⁇ x25-1 subunit upregulation may contribute to the initiation and maintenance of neuropathic pain by altering the properties and/or distribution of VGCC in the subpopulation of DRG neurons and their central terminals, therefore modulating excitability and/or synaptic neuroplasticity in the dorsal horn.
  • Intrathecal antisense oligonucleotides against the Ca v ⁇ x25-1 subunit can block nerve injury-induced Ca v ⁇ x25-1 upregulation and prevent the onset of allodynia and reserve established allodynia.
  • the a2d subunits of VGCC form the binding site for gabapentin and pregabalin which are structural derivatives of the inhibitory neurotransmitter GABA although they do not bind to GABAA, GABAB, or benzodiazepine receptors, or alter GABA regulation in animal brain preparations.
  • the binding of gabapentin and pregabalin to the Ca v ⁇ x25-1 subunit results in a reduction in the calcium-dependent release of multiple neurotransmitters, leading to efficacy and tolerability for neuropathic pain management.
  • Gabapentinoids may also reduce excitability by inhibiting synaptogenesis (Perret and Luo, 2009; Vink and Alewood, 2012, Zamponi et al., 2015).
  • the present invention relates to compounds with inhibitory effect towards a2d subunits of voltage-gated calcium channels, preferably towards the a2d-1 subunit of voltage-gated calcium channels.
  • MOR m-opioid receptor
  • MOR agonists are not optimal for the treatment of chronic pain as indicated by the diminished effectiveness of morphine against chronic pain conditions. This is especially proven for the chronic pain conditions of neuropathic or inflammatory origin, in comparison to its high potency against acute pain.
  • the finding that chronic pain can lead to MOR down-regulation may offer a molecular basis for the relative lack of efficacy of morphine in long-term treatment settings [Dickenson, A.H., Suzuki, R. Opioids in neuropathic pain: Clues from animal studies. Eur J Pain 9, 113-6 (2005)].
  • prolonged treatment with morphine may result in tolerance to its analgesic effects, most likely due to treatment-induced MOR down-regulation, internalization and other regulatory mechanisms. Consequently, long-term treatment can result in substantial increases in dosing in order to maintain a clinically satisfactory pain relief, but the narrow therapeutic window of MOR agonists finally results in unacceptable side effects and poor patient compliance.
  • Polypharmacology is a phenomenon in which a drug binds multiple rather than a single target with significant affinity.
  • the effect of polypharmacology on therapy can be positive (effective therapy) and/or negative (side effects). Positive and/or negative effects can be caused by binding to the same or different subsets of targets; binding to some targets may have no effect.
  • Multi-component drugs or multi-targeting drugs can overcome toxicity and other side effects associated with high doses of single drugs by countering biological compensation, allowing reduced dosage of each compound or accessing context-specific multitarget mechanisms. Because multitarget mechanisms require their targets to be available for coordinated action, one would expect synergies to occur in a narrower range of cellular phenotypes given differential expression of the drug targets than would the activities of single agents.
  • multi-targeting drugs may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive pain. Because they actually make use of biological complexity, multi- targeting (or multi-component drugs) approaches are among the most promising avenues toward treating multifactorial diseases such as pain (Gilron et al.; Lancet Neurol.; 2013; 12(1 1); 1084-1095). In fact, positive synergistic interaction for several compounds, including analgesics, has been described (Schroder et al; J. Pharmacol. Exp. Ther.; 201 1 ; 337; 312-320; Zhang et al.; Cell Death Dis.; 2014; 5; e1 138; Gilron et al., 2013).
  • An alternative strategy for multitarget therapy is to design a single compound with selective polypharmacology (multi-targeting drug). It has been shown that many approved drugs act on multiple targets. Dosing with a single compound may have advantages over a drug combination in terms of equitable pharmacokinetics and biodistribution. Indeed, troughs in drug exposure due to incompatible pharmacokinetics between components of a combination therapy may create a low-dose window of opportunity where a reduced selection pressure can lead to drug resistance. In terms of drug registration, approval of a single compound acting on multiple targets faces significantly lower regulatory barriers than approval of a combination of new drugs (Hopkins, 2008).
  • the compounds of the present invention having affinity for the a2d subunits of voltage-gated calcium channels, preferably towards the a2d-1 subunit of voltage-gated calcium channels additionally have affinity towards the m- receptor and are, thus, more effective to treat chronic pain.
  • the present invention relates to compounds having a complementary dual mechanism of action (m-receptor agonist and blocker of the a2d subunit, in particular the a2d-1 subunit, of voltage-gated calcium channels) which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin).
  • m-receptor agonist and blocker of the a2d subunit, in particular the a2d-1 subunit, of voltage-gated calcium channels which implies a better profile of tolerability than the strong opioids (morphine, oxycodone, fentanyl etc) and/or better efficacy and tolerability than gabapentinoids (pregabalin and gabapentin).
  • the present invention discloses novel compounds with pharmacological activity to the a2d subunit of voltage-gated calcium channels, more specifically to the a2d-1 subunit, and which in preferred embodiments have also affinity towards the m-receptor, thus resulting in a dual activity for treating pain and pain related disorders.
  • the main aspect of the present invention is related to compounds of general formula (I):
  • Wi is -O- or -NR a ;
  • R a is a hydrogen atom or a branched or unbranched Ci-e alkyl radical; n and m are independently from one another 0 or 1 ;
  • Ri and R ⁇ are independently from one another a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a halogen atom; a branched or unbranched Ci-e alkoxy radical; a -CN radical; a hydroxyl radical; or a Ci- 6 haloalkyl radical;
  • Rs is W 2 is -O- or -NR 3CI ; p and q are independently from one another 0 or 1 ; v’ and v” are independently 1 or 2;
  • R3 a and R 3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or
  • R3 a and R3 b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched Ci-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;
  • R3 C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a - CN radical; a Ci-e haloalkyl radical; or a -NR b R c radical;
  • R b and R c are a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • R 3d is a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • R 4 is a hydrogen atom or a -C(0)R 4a radical
  • R 4a is a hydrogen atom; a branched or unbranched C 1-6 alkyl radical; a branched or unbranched C 1-6 alkoxy radical; a -(CH 2 ) r -NR 4b R 4c radical; a - 0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 4g -(CH 2 )s-CH(R 4f )-NR 4e R4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
  • R 4 , R 4C , R 4d , R 4e , R 4g are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • R 4f is a hydrogen atom or a -COR 4h radical
  • R 4h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical
  • Re is a -C(0)R 5a radical or an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
  • Re a is a hydroxyl radical, a branched or unbranched Ci- 6 alkoxy radical; a -(ChhX- NRsbRsc radical; a -0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 5g -(CH2)v-CH(R 5f )- NR5eR5d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
  • Re b , Re c , Re d , Re e , Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • Re f is a hydrogen atom or a -CORs h radical
  • Re h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical
  • Another aspect of the invention refers to the use of such compounds of general formula (I) for the treatment and/or prophylaxis of a2d-1 mediated disorders and more preferably for the treatment and/or prophylaxis of disorders mediated by the a2d-1 subunit of voltage-gated calcium channels and/or the m-receptor.
  • the compounds of the present invention are particularly suited for the treatment of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain and pain related or pain derived conditions.
  • a further aspect of the invention refers to pharmaceutical compositions comprising one or more compounds of general formula (I) with at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions in accordance with the invention can be adapted in order to be administered by any route of administration, be it orally or parenterally, such as pulmonarily, nasally, rectally and/or intravenously. Therefore, the formulation in accordance with the invention may be adapted for topical or systemic application, particularly for dermal, subcutaneous, intramuscular, intra-articular, intraperitoneal, pulmonary, buccal, sublingual, nasal, percutaneous, vaginal, oral or parenteral application.
  • the invention first relates to compounds of general formula (I)
  • Wi is -O- or -NR a ;
  • R a is a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • n and m are independently from one another 0 or 1
  • Ri and R ⁇ are independently from one another a hydrogen atom; a branched or unbranched Ci-e alkyl radical; a halogen atom; a branched or unbranched Ci-e alkoxy radical; a -CN radical; a hydroxyl radical; or a Ci- 6 haloalkyl radical;
  • W ⁇ is -O- or -NR 3d ; p and q are independently from one another 0 or 1 ; v’ and v” are independently 1 or 2;
  • R 3a and R 3b are independently from one another a hydrogen atom or a branched or unbranched Ci-e alkyl radical; or
  • R 3a and R 3b together with the bridging nitrogen form a 4, 5 or 6-membered heterocycloalkyl radical optionally containing an additional heteroatom selected from N, O and S and optionally substituted by a branched or unbranched Ci-e alkyl radical or a branched or unbranched Ci-e alkoxy radical;
  • R 3C is a hydrogen atom; a halogen atom; a hydroxyl radical; a branched or unbranched Ci-e alkyl radical; a branched or unbranched Ci-e alkoxy radical; a - -CN radical; a Ci-e haloalkyl radical; or a -NR b R c radical;
  • R b and R c are a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • R 3d is a hydrogen atom or a branched or unbranched Ci-e alkyl radical
  • R 4 is a hydrogen atom or a -C(0)R 4a radical
  • R 4a is a hydrogen atom; a branched or unbranched Ci- 6 alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(CH2) r -NR4 b R4 c radical; a - 0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 4g -(CH 2 )s-CH(R 4f )-NR 4e R4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
  • R 4b , R 4c ,R 4d , R 4e , R 4g are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • R 4f is a hydrogen atom or a -COR 4h radical
  • R 4h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical
  • Re is a -C(0)R 5a radical or an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
  • Re a is a hydroxyl radical, a branched or unbranched Ci-e alkoxy radical; a -(CH 2 ) t - NRsbRsc radical; a -0CH(CH 3 )0C(0)CH(CH 3 ) 2 radical; or a -NR 5g -(CH 2 ) v. CH(R 5f )- NR5eR5d radical; t is 1 , 2, 3, 4, 5 or 6; v is 1 , 2, 3, 4, 5 or 6;
  • Re b , Re c , Re d , Re e , Reg are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • Re f is a hydrogen atom or a -CORs h radical
  • Halogen or“halo” as referred in the present invention represents fluorine, chlorine, bromine or iodine.
  • halo When the term“halo” is combined with other substituents, such as for instance“Ci-e haloalkyl” or“Ci-e haloalkoxy” it means that the alkyl or alkoxy radical can respectively contain at least one halogen atom.
  • 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 -O- SO2R’, wherein R’ is F, Ci-4-alkyl, Ci-4-haloalkyl, or optionally substituted phenyl.
  • the preferred leaving groups are Cl, Br, I, tosylate, mesylate, nosylate, triflate, nonaflate and fluorosulphonate.
  • Protecting group is a group that is chemically introduced into a molecule to avoid that a certain functional group from that molecule undesirably reacts in a subsequent reaction. Protecting groups are used, among others, to obtain chemoselectivity in chemical reactions.
  • the preferred protecting group in the context of the invention are Boc (te/f-butoxycarbonyl) or Teoc (2-(trimethylsilyl)ethoxycarbonyl).
  • C1 -6 alkyl are saturated aliphatic radicals. They may be unbranched or branched and are optionally substituted. Ci- 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 -di ethyl propyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl or 1-methylpentyl.
  • the most preferred alkyl radical are C1-4 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 are optionally mono-or polysubstituted by substitutents independently selected from a halogen atom, a branched or unbranched Ci- 6 -alkoxy radical, a branched or unbranched Ci- 6 -alkyl radical, a Ci- 6 -haloalkoxy radical, a Ci- 6 -haloalkyl radical, CN, a trihaloalkyl radical, hydroxyl group and an amino radical such as -NR’R” wherein R’ and R” are independently from one another a hydrogen atom or a branched or unbranched C1-6 alkyl radical .
  • Ci- 6 alkoxy as referered to in the present invention, is understood as meaning an alkyl group as defined above attached via oxygen linkage to the rest of the molecule.
  • alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy or tert-butoxy.
  • Heterocycloalkyl as referred to in the present invention, are understood as meaning saturated and unsaturated (but not aromatic), generally 5, 6 or 7 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.
  • heterocycloalkyl radical preferably include but are not restricted to pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, oxirane, oxetane, dioxetane, tetrahydropyrane, tetrahydrofurane, dioxane, dioxolane, oxazolidine, piperidine, piperazine, homopiperazine, morpholine, azepane or diazepane.
  • Heterocycloalkyl radicals are optionally mono- or polysubstituted by substitutents independently selected from a halogen atom, a branched or unbranched Ci- 6 -alkyl radical, a branched or unbranched Ci- 6 -alkoxy radical, a Ci- 6 -haloalkoxy radical, a Ci- 6 -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group. More preferably heterocycloalkyl in the context of the present invention are 6 or 7-membered ring systems optionally at least monosubstituted.
  • 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 atom, a branched or unbranched Ci- 6 -alkyl radical; a branched or unbranched Ci- 6 -alkoxy radical, a Ci- 6 -haloalcoxy radical, a Ci- 6 -haloalkyl radical; a trihaloalkyl radical or a hydroxyl group.
  • 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 6-membered ring systems optionally at least monosubstituted.
  • Heteroaryl as referred to in the present invention, is understood as meaning heterocyclic ring systems which have at least one aromatic ring and 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 atom, a branched or unbranched Ci- 6 -alkyl radical, a branched or unbranched Ci- 6 -alkoxy radical, a Ci-e- haloalkoxy radical, a Ci- 6 -haloalkyl radical, a trihaloalkyl radical and a hydroxyl group.
  • heteroaryls include but are not restricted to furan, benzofuran, thiophene, thiazole, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, imidazole, imidazo[4,5-b]pyridine, isoxazole, oxadiazole, indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole or quinazoline. More preferably heteroaryl in the context of the present invention are 5 or 6-membered ring systems optionally at least monosubstituted.
  • Heterocyclic system comprises 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, NH2, SH, OH, SO2, CF 3 , carboxy, amido, cyano, carbamyl, nitro, phenyl, benzyl, -SO2NH2, C 1-6 alkyl and/or Ci- 6 -alkoxy.
  • ring system refers to a system consisting of at least one ring of connected atoms but including also systems in which two or more rings of connected atoms are joined with“joined” meaning that the respective rings are sharing one (like a spiro structure), two or more atoms being a member or members of both joined rings.
  • The“ring system” thus defined comprises saturated, unsaturated or aromatic carbocyclic rings which contain optionally at least one heteroatom as ring member and which are optionally at least mono-substituted and may be joined to other carbocyclic ring systems such as aryl radicals, heteroaryl radicals, cycloalkyl radicals etc.
  • the terms“condensed”,“annulated” or“annelated” are also used by those skilled in the art to designate this kind of join.
  • room temperature in the context of this invention as the meaning of temperature between 20 and 25°C.
  • salt is to be understood as meaning any form of the active compound according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
  • a counter-ion a cation or anion
  • 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”.
  • 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.
  • 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 invention - normally 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 (NhV).
  • 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 invention - normally protonated, for example in nitrogen - such 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 acids particularly when used on humans and/or mammals.
  • 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.
  • 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.
  • 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).
  • 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.
  • Wi is -0-.
  • n is 0.
  • Ri and R ⁇ are independently from one another a hydrogen atom or a halogen atom, more preferable fluorine or chlorine.
  • R3 is in meta position.
  • R3 is selected from: wherein W ⁇ , p, q, R 3a , R 3b and R 3C are as defined above.
  • R 3a and R 3b are independently from one another a branched or unbranched Ci-e alkyl radical, more preferable methyl.
  • R 3C is a hydrogen atom or a halogen atom, more preferable fluorine.
  • R 4 is a hydrogen atom.
  • Rs a is a hydroxyl radical or a branched or unbranched Ci- 6 alkoxy radical, preferably a methoxy radical.
  • a particularly preferred embodiment of the invention is represented by compounds of general formula (I’a):
  • Ri, R ⁇ , R 3 , R 4 and R 5 are as defined above; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • a still more particularly preferred embodiment of the invention is represented by compounds of general formula (I’a): wherein Ri and R ⁇ are independently from one another a hydrogen atom or a halogen atom, more preferable fluorine or chlorine;
  • R 3 is selected from:
  • W ⁇ is -O- or -NR3d; p and q are independently from one another 0 or 1 ;
  • R 3a and R 3b are independently from one another a C 1-6 alkyl radical, more preferable methyl;
  • R 3C is a hydrogen atom or a halogen atom, more preferable fluorine
  • R 3d is a hydrogen atom or a branched or unbranched C 1-6 alkyl radical
  • R 4 is a hydrogen atom;
  • R 4a is a hydrogen atom; a branched or unbranched Ci- 6 alkyl radical; a branched or unbranched Ci-e alkoxy radical; a -(CH2) r -NR4 b R4c radical; a - 0CH(CH 3 )0C(0)CH(CH 3 )2 radical; or a -NR 4g -(CH 2 )s-CH(R 4f )-NR 4e R4d radical; r is 1 , 2, 3, 4, 5 or 6; s is 1 , 2, 3, 4, 5 or 6;
  • R 4b , R 4C , R 4d , R 4e , R 4g are independently from one another a hydrogen atom; or a branched or unbranched Ci- 6 alkyl radical;
  • R 4f is a hydrogen atom or a -COR 4h radical
  • R 4h is a hydroxyl radical or a branched or unbranched Ci- 6 alkyl radical
  • Re is a -C(0)R 5a radical or an optionally substituted 5 or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S;
  • Re a is a hydroxyl radical or a branched or unbranched Ci-e alkoxy radical, preferably a methoxy radical; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the compounds of the present invention represented by the above described general formula (I) 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.
  • the compounds of general formula (I) are represented by the S,S-isomers according to the following general formula (la): wherein Wi, Ri, R 2 , R 3 , R 4 and R 5 are as defined before.
  • VGCC voltage-gated calcium channels
  • the following compounds of general formula (lb) or (lc) are preferred for showing dual affinity towards the subunit a2d-1 of voltage-gated calcium channels (VGCC) and the m-opioid receptor (MOR): wherein W ⁇ , Ri, R ⁇ , R3 a , R3 b and R3 C are as defined before; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • VGCC voltage-gated calcium channels
  • MOR m-opioid receptor
  • VGCC voltage-gated calcium channels
  • the invention refers to the processes for the preparation of the compounds of general formula (I).
  • Method A represents a first process for synthesizing compounds according to general formula (I).
  • Method A allows the preparation of compounds of general formula (A1 ) that is compounds of general formula (I) where Wi is -0-, namely Method A1 , and compounds of general formula (A2) that is compounds of general formula (I) where Wi is -N-, namely Method A2.
  • Ri , R 2 , R 3 , R 4 , Rs, m and n have the meanings as defined above, can be prepared by treating a pyrrolidine derivative of general formula (lla):
  • Ri , R2, R3 and n have the meanings as defined above, under Mitsunobu conditions using a suitable coupling agent, such as cyanomethylenetributylphosphorane (CM BP) or diisopropyl azodicarboxylate in the presence of a phosphine, such as triphenylphosphine, in the presence of a suitable solvent, such as toluene or tetrahydrofuran, at a suitable temperature, between room temperature and 100 °C, preferably room temperature.
  • CM BP cyanomethylenetributylphosphorane
  • a phosphine such as triphenylphosphine
  • a suitable solvent such as toluene or tetrahydrofuran
  • Ri , R2, R3, R4, Rs, Ra, m and n have the meanings as defined above, can be prepared by treating a pyrrolidine derivative of general formula (Mb):
  • Ri , R2, R3 and n have the meanings as defined above and Z is a halogen atom under the following reaction conditions:
  • the reaction may be carried out under Buchwad-Hartwig conditions, using a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate, and a suitable ligand, preferably a phosphine ligand such as BINAP or XPhos, using a suitable base such as sodium tert- butoxide or cesium carbonate, in a suitable solvent such as toluene or 1 ,4-dioxane, at a suitable temperature, preferably 110 °C;
  • a Pd catalyst such as tris(dibenzylideneacetone)dipalladium(0) or palladium acetate
  • a suitable ligand preferably a phosphine ligand such as BINAP or XPhos
  • a suitable base such as sodium tert- butoxide or cesium carbonate
  • a suitable solvent such as toluene or 1 ,4-dioxane
  • the reaction may be carried out under alkylation conditions, in a suitable solvent, such as acetonitrile or dimethylformamide, in the presence of a base such as triethylamine, K 2 CO 3 or A/./V-diisopropylethylamine, at a suitable temperature comprised between room temperature and the reflux temperature.
  • a suitable solvent such as acetonitrile or dimethylformamide
  • a base such as triethylamine, K 2 CO 3 or A/./V-diisopropylethylamine
  • Method B represents an alternative process for synthesizing compounds according to general formula (I). Method B allows the preparation of compounds of general formula (I) from a compound of general formula (V):
  • Ri, R 2 , R 4 , Rs, Wi, m and n have the meanings as defined above and Y represents a group that can be converted into R3 under the following conditions:
  • Y is a halogen atom
  • Suitable reagents such as tris(dibenzylideneacetone)-dipalladium (0) (Pd2(dba)3), 4,5-bis(diphenyl phosphino)-9,9-dimethylxanthene (Xantphos) or 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (Ru-Phos) in the presence of a base, such as cesium carbonate, in suitable solvents, such as 1 ,4-dioxane, and with conventional heating at a suitable temperature, between 80 °C and 110 °C;
  • a base such as cesium carbonate
  • suitable solvents such as 1 ,4-dioxane
  • a reductive amination reaction by means of a reductive amination reaction, using suitable reagents, such as sodium triacetoxyborohydride or sodium borohydride, using suitable solvents mixtures such as methanol and acetonitrile, and at a suitable temperature, such as room temperature;
  • suitable reagents such as sodium triacetoxyborohydride or sodium borohydride
  • suitable solvents mixtures such as methanol and acetonitrile
  • the intermediate of general formula (V) can be prepared by reaction of a compound of general formula (lla) or (Mb):
  • Ri , R2 and n have the meanings as defined above, Z represents a hydroxyl or an halogen group and Y represents a group that can be converted into R3; under the conditions described in Method A (including Method A1 and Method A2).
  • Ri, R 2 , R 3 , R 4 , Rs, Wi, m and n have the meanings as defined above, Z represents a hydroxyl or an halogen group and Y represents a group that can be converted into R 3 .
  • an aromatic ring may be halogenated in the presence of N- chlorosuccinimide, using a suitable solvent such as acetonitrile with stirring at a convenient temperature such as room temperature.
  • protecting groups such as for example Boc (tert- butoxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) or benzyl for the protection of amino groups, ethyl or tert- buty ester for the carboxylic acid group and common silyl protecting groups for the protection of the hydroxyl group.
  • Boc tert- butoxycarbonyl
  • Teoc 2-(trimethylsilyl)ethoxycarbonyl)
  • benzyl for the protection of amino groups
  • ethyl or tert- buty ester for the carboxylic acid group
  • common silyl protecting groups for the protection of the hydroxyl group.
  • the simultaneous removal of the ethyl ester and Boc groups may be carried out in aqueous HCI, optionally in the presence of a suitable co-solvent like acetonitrile, and at a suitable reaction temperature, e.g. heating at 60 °C.
  • a compound of formula (I) can be obtained in enantiopure form by resolution of a racemic compound of general formula (I) either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal.
  • the resolution step can be carried out at a previous stage, using any suitable intermediate.
  • Compounds of general formula (I) for wich R 4 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.
  • PG Protecting Group
  • these intermediate compounds of general formula (I) are selected from:
  • the invention also relates to the therapeutic use of the compounds of general formula (I).
  • compounds of general formula (I) show a strong affinity to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels.
  • compounds of general formula (I) show a strong affinity both to the subunit a2d and more preferably to the a2d-1 subunit of voltage-gated calcium channels as well as to the m-receptor and can behave as agonists, antagonists, inverse agonists, partial antagonists or partial agonists thereof. Therefore, compounds of general formula (I) are useful as medicaments.
  • compounds of general formula (I) are suitable for the treatment and/or prophylaxis of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain, inflammatory pain, and chronic pain or other pain conditions involving allodynia and/or hyperalgesia, depression anxiety and attention-deficit-/hyperactivity disorder (ADHD).
  • ADHD attention-deficit-/hyperactivity disorder
  • the compounds of general formula (I) are especially suited for the treatment of pain, especially neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain, inflammatory pain or other pain conditions involving allodynia and/or hyperalgesia.
  • 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.
  • compounds of the invention are used for the treatment and/or prophylaxis of allodynia and more specifically mechanical or thermal allodynia.
  • compounds of the invention are used for the treatment and/or prophylaxis of hyperalgesia.
  • compounds of the invention are used for the treatment and/or prophylaxis of neuropathic pain, central neuropathic pain and/or peripheral neuropathic pain and more specifically for the treatment and/or prophylaxis of hyperpathia.
  • a related aspect of the invention refers to the use of compounds of general formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d-1 subunit of voltage-gated calcium channels and/or the m-receptor, as explained above.
  • Another related aspect of the invention refers to a method for the treatment and/or prophylaxis of disorders and diseases mediated by the subunit a2d, especially the a2d- 1 subunit of voltage-gated calcium channels and/or the m-receptor, as explained above comprising the administration of a therapeutically effective amount of a compound of general formula (I) to a subject in need thereof.
  • compositions 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.
  • 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 a2d, especially the a2d-1 subunit of voltage-gated calcium channels or comprising at least a compound binding to the subunit a2d, especially the a2d-1 subunit of voltage gated calcium channels and the m-receptor and optionally at least one further active substance and/or optionally at least one auxiliary substance.
  • the auxiliary substances or additives can be selected among carriers, excipients, support materials, lubricants, fillers, solvents, diluents, colorants, flavour conditioners such as sugars, antioxidants and/or agglutinants.
  • suppositories this may imply waxes or fatty acid esters or preservatives, emulsifiers and/or carriers for parenteral application.
  • auxiliary materials and/or additives and the amounts to be used will depend on the form of application of the pharmaceutical composition.
  • composition in accordance with the invention can be adapted to any form of administration, be it orally or parenterally, for example pulmonarily, nasally, rectally and/or intravenously.
  • the composition is suitable for oral or parenteral administration, more preferably for oral, intravenous, intraperitoneal, intramuscular, subcutaneous, intrathekal, rectal, transdermal, transmucosal or nasal administration.
  • 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.
  • Suitable preparations for parenteral applications are solutions, suspensions, reconstitutable dry preparations or sprays.
  • the compounds of the invention can be formulated as deposits in dissolved form or in patches, for percutaneous application.
  • 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.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
  • 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 the normal pharmaceutical practice, in particular with an enteric coating.
  • 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.
  • 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.
  • CMBP Cyanomethylenetributylphosphorane
  • DIAD Diisopropyl azodicarboxylate
  • MS parameters Source: ESI, Capillary voltage: 3000 V, Drying gas flow: 12 L/min, Nebulizer Pressure 60 psig, Drying Gas Temp: 350 °C, Fragmentor 70, MS scan: MS range 100-1000 (positive and negative mode), scan speed: 0.84 sec/cycle; Flow into MS 0.8 mL/min.
  • Intermediate 25 was obtained from intermediate 21 (189 mg, 0.435 mmol) and intermediate 22 (101 mg, 0.435 mmol), following the same synthesis and purification method as described for intermediate 24. Yield: 73 mg (28%) as a glass-like solid.
  • Intermediate 27 was obtained from intermediate 19 (540 mg, 1.291 mmol) and intermediate 23 (300 mg, 1.291 mmol), using 0.1 Eq of Ru-Phos (60.2 mg, 0.129 mmol), 0.05 Eq. of Pd2(dba)3 (59.1 mg, 0.065 mmol) and 1.5 Eq. of CS2CO3 (631 mg, 1.937 mmol) as described for intermediate 24 with heating at 80 °C for ⁇ 40 h. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 40 g, gradient DCM / (5-80% DCM/MeOH (9:1)) in 54 Min) afforded 252 mg (34%) of the title compound as a foam.
  • Intermediate 29 was obtained from intermediate 28 (268 mg, 0.716 mmol), and (is, 4s)- 4-(dimethylamino)-4-phenylcyclohexan-1-ol (157 mg, 0.716 mmol) according to the synthesis method as described for intermediate 2. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 40 g, gradient DCM to 100% DCM/MeOH (9: 1)) in 40 Min, 100% DCM/MeOH (9:1) for 15 Min) afforded 326 mg (85%) of compound 29 (stereoconfiguration: trans-isomer). LCMS (method B): Rt, 2.50 Min; ESI m/z ⁇ 539.2 [M+H] + .
  • Intermediate 32 was obtained from intermediate 19 (165 mg, 0.395 mmol) and intermediate 30 (99 mg, 0.395 mmol), according to the method described for intermediate 27 using 1.2 Eq. of Cs 2 C0 3 (155 mg, 0.475 mmol) with heating at 1 10 °C overnight.
  • Intermediate 33 was obtained from intermediate 19 (297 mg, 0.711 mmol) and intermediate 31 ( (178 mg, 0.711 mmol) according to the method described for 32. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 40 g, gradient DCM / (3-55% DCM/MeOH (9: 1) in 54 Min) afforded 244 mg (58%) of compound 33 as a foam. LCMS (method C): Rt, 4.68 Min; ESI m/z. 588.4 [M+H] + . Purity according to LCMS: 90.4%.
  • Step 1 Intermediate 36 (268 mg, 0.653 mmol) was dissolved in dry DCM (6.5 ml_) (dried over activated MS 4A) under an atmosphere of nitrogen. TFA (1.0 ml_, 13.06 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with DCM to give 369 mg of the crude TFA-salt. The crude material was dissolved in DCM, water was added and aqueous layer was basified to ⁇ pH 10 using solid Na2CC>3. Subsequently, the layers were separated and the aqueous layer was extracted with DCM (3 x).
  • Step 2 Methanol (9 ml_) was added, followed by 10 Eq. of formaldehyde (37 wt% solution in water) (0.491 ml_, 6.53 mmol) and AcOH (0.1 13 ml_, 1.959 mmol). The reaction mixture was stirred at room temperature for a couple of Min, after which sodium triacetoxyborohydride (554 mg, 2.61 mmol) was added slowly in one portion.
  • Intermediate 39 was obtained from intermediate 19 (264 mg, 0.631 mmol) and intermediate 38 (mixture of diastereoisomers) (129 mg, 0.631 mmol) according to the method described for intermediate 32. Purification by flash column chromatography (pre packed silica cartridge GraceResolvTM 24 g, gradient DCM / 5% DCM/MeOH (9:1) in 38 Min) afforded 81 mg (23.7%) of the target compound (stereoconfiguration: cis-isomer), which slowly solidified upon standing. LCMS (method B): Rt, 2.39 Min; ESI m/z. 542.2 [M+H] + .
  • Intermediate 44 was prepared from intermediate 27 (690 mg, 1.211 mmol) and N- chlorosuccinimide (162 mg, 1.211 mmol) according to the method described for intermediate 41. Purification by flash column chromatography (pre-packed silica cartridge GraceResolvTM 120 g, gradient heptane to 50% EtOAc/heptane (+ 2% E ⁇ bN) in 3 h), followed by flash column chromatography (pre-packed silica cartridge GraceResolvTM 120 g, DCM / (30-65% DCM/MeOH (9:1) in 75 Min) and flash column chromatography (pre-packed silica cartridge GraceResolvTM 120 g, isocratic 25% (EtOAc/heptane (+ 2% TEA), 50 mL/min for 60 min) gave 203 mg (27%) of the title compound as a solid (stereoconfiguration: cis-isomer).
  • Human a2d-1 enriched membranes (2.5 pg) were incubated with 15 nM of radiolabeled [3H]-Gabapentin in assay buffer containing Hepes-KOH 10 mM, pH 7.4.
  • NSB non specific binding
  • the binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki).
  • 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-HCI, pH 7.4.
  • Transfected CHO-K1 cell membranes (20 pg) were incubated with [ 3 H]-DAMGO (1 nM) in assay buffer containing Tris-HCI 50 mM, MgCh 5 mM at pH 7.4.
  • NBS non-specific binding
  • the binding of the test compound was measured at either one concentration (% inhibition at 1 or 10 mM) or five different concentrations to determine affinity values (Ki). Plates were incubated at 27 °C for 60 min. After the incubation period, the reaction mixture was then transferred to Multiscreen HTS, FC plates (Millipore), filtered and plates were washed 3 times with ice- cold 10 mM Tris-HCI (pH 7.4).
  • K,(a 2 d-1) > 3000 nM the following scale has been adopted for representing the binding to the a 2 d-1 subunit of voltage-gated calcium channels: + K(a 2 d-1) > 3000 nM or inhibition ranges between 1 % and 50 %
  • Ki For the m-opioid receptor, the following scale has been adopted for representing the binding, expressed as Ki:
  • K (m) > 500 nM the following scale has been adopted for representing the binding to the m -receptor: + K (m) > 500 nM or inhibition ranges between 1 % and 50 %.

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Abstract

La présente invention concerne de nouveaux composés présentant une activité pharmacologique vis-à-vis de la sous-unité α2δ des canaux calciques dépendants de la tension (VGCC), en particulier, la sous-unité α2δ-1 des canaux calciques dépendants de la tension ou une double activité vis-à-vis de la sous-unité α2δ des canaux calciques dépendants de la tension (VGCC), en particulier, la sous-unité α2δ-1 des canaux calciques dépendants de la tension, et le récepteur μ-opioïde (MOR ou mu-opioïde). L'invention concerne également un procédé de préparation desdits composés ainsi que des compositions les comprenant, et leur utilisation en tant que médicaments (formule (I)).
PCT/EP2019/084717 2018-12-12 2019-12-11 Nouveaux dérivés d'acide pyrrolidine-2-carboxylique pour le traitement de la douleur et d'états pathologiques associés à la douleur WO2020120606A1 (fr)

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