Patent Application
20100105722
The invention relates to substituted tetrahydrothienopyridines, to processes for their preparation, to medicaments comprising these compounds and to the use of these compounds in the preparation of medicaments.
The treatment of pain, in particular of neuropathic pain, is of great importance in medicine. There is a worldwide need for effective pain therapies. The urgent need for action for a target-orientated treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood the successful and satisfactory treatment of pain for the patient, is also documented in the large number of scientific works which have recently been published in the field of applied analgesics and of fundamental research into nociception.
A pathophysiological feature of chronic pain is the overexcitability of neurons. Neuronal excitability is influenced decisively by the activity of K+ channels, since these determine decisively the resting membrane potential of the cell and therefore the excitability threshold. Heteromeric K+ channels of the molecular subtype KCNQ2/3 (Kv7.2/7.3) are expressed in neurons of various regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate the excitability thereof. Activation of KCNQ2/3 K+ channels leads to a hyperpolarization of the cell membrane and, accompanying this, to a decrease in the electrical excitability of these neurons. KCNQ2/3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive stimuli from the periphery into the spinal marrow (Passmore et al., J. Neurosci. 2003; 23(18): 7227-36).
It has accordingly been possible to detect an analgesic activity in preclinical neuropathy and inflammatory pain models for the KCNQ2/3 agonist retigabine (Blackburn-Munro and Jensen, Eur J Pharmacol. 2003; 460(2-3); 109-16; Dost et al., Naunyn Schmiedebergs Arch Pharmacol 2004; 369(4): 382-390).
The KCNQ2/3 K+ channel thus represents a suitable starting point for the treatment of pain; in particular of pain selected from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., Eur J Pharmacol. 2004; 487(1-3): 93-103), especially neuropathic or inflammatory pain.
Moreover, the KCNQ2/3 K+ channel is a suitable target for therapy of a large number of further diseases, such as, for example, migraine (US2002/0128277), cognitive diseases (Gribkoff, Expert Opin Ther Targets 2003; 7(6): 737-748), anxiety (Korsgaard et al., J Pharmacol Exp Ther. 2005, 14(1): 282-92), epilepsy (Wickenden et al., Expert Opin Ther Pat 2004; 14(4): 457-469; Gribkoff, Expert Opin Ther Targets 2008, 12(5): 565-81; Miceli et al., Curr Opin Pharmacol 2008, 8(1): 65-74), urinary incontinence (Streng et al., J Urol 2004; 172: 2054-2058), dependency (Hansen et al., Eur J Pharmacol 2007, 570(1-3): 77-88), mania/bipolar disorders (Dencker et al., Epilepsy Behav 2008, 12(1): 49-53), dystonia-associated dyskinesias (Richter et al., Br J Pharmacol 2006, 149(6): 747-53).
It was therefore an object of the present invention to provide novel compounds which have advantages over the compounds of the prior art.
Another object of the invention was to provide compounds which are suitable in particular as pharmacological active ingredients in pharmaceutical compositions.
A further object of the invention was to provide compounds which are useful in the treatment of disorders or diseases that are mediated at least in part by KCNQ2/3 K+ channels.
Another object of the invention was to provide a new method of treating o inhibiting pain.
These and other objects have been achieved by the invention as described and claimed hereinafter.
It has been found, surprisingly, that substituted tetrahydrothienopyridines of the general formula (1) given below are suitable for the treatment of pain. It has also been found, surprisingly, that substituted tetrahydrothienopyridines of formula (1) given below also have an excellent affinity for the KCNQ2/3 K+ channel and are therefore suitable for the treatment of disorders or diseases that are mediated at least in part by KCNQ2/3 K+ channels. The substituted tetrahydrothienopyridines thereby act as modulators, that is to say agonists or antagonists, of the KCNQ2/3 K+ channel.
Substituted tetrahydropyrrolopyrazines that have an affinity for the KCNQ2/3 K+ channel are known from the prior art (WO 2008/046582).
Substituted tetrahydrothienopyridines and their use in medicaments are described in WO 96/34870. Further tetrahydrothienopyridines are also known, but the use thereof in medicaments is not described (e.g. CA 940806-85-9; CA 931614-62-9; CA 930990-23-1).
The invention provides substituted tetrahydrothienopyridines corresponding to formula (1)
“alkyl substituted”, “heterocyclyl substituted” and “cycloalkyl substituted” denote the replacement of one or more hydrogen atoms, in each case each independently, by F; Cl; Br; I; CN; CF3; ═O; ═NH; ═C(NH2)2; NO2; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(C1-8-alkyl)-O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH—S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; S(═O)2N(R0)2; and
“aryl substituted” and “heteroaryl substituted” denote the substitution of one or more hydrogen atoms, in each case each independently, by F; Cl; Br; I; NO; NO2; CF3; CN; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(C1-8-alkyl)-O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH—S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; S(═O)2N(R0)2;
with the exception of the following compounds:
According to the general formula (1), the five-membered aromatic ring fused with the tetrahydropyridine ring always contains a sulfur atom and accordingly represents a thienyl group which is disubstituted by the substituents R13 and/or R14 and/or R15, each of which can optionally denote H.
Within the scope of this invention the terms “C1-2-alkyl”, “C1-8-alkyl”, “C1-4-alkyl”, “C2-8-alkyl”, “C2-16-alkyl”, “C4-16-alkyl” include acyclic saturated or unsaturated hydrocarbon radicals, which can be branched or unbranched as well as unsubstituted or mono- or poly-substituted, having from 1 to 2 or from 1 to 4 or from 1 to 8 or from 2 to 8 or from 2 to 16 or from 4 to 16 carbon atoms, respectively, that is to say C1-2-alkanyls and C1-2-alkenyls or C1-4-alkanyls, C1-4-alkenyls and C2-4-alkynyls or C1-8-alkanyls, C1-8-alkenyls and C2-8-alkynyls or C2-8-alkanyls, C2-8-alkenyls and C2-8-alkynyls or C2-16-alkanyls, C2-16-alkenyls and C2-16-alkynyls or C4-16-alkanyls, C4-16-alkenyls and C4-16-alkynyls. Alkenyls contain at least one C—C double bond and alkynyls contain at least one C—C triple bond. Alkyl is preferably selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, ethylenyl (vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propynyl (—CH—C≡CH, —C≡C—CH3), butenyl, butynyl, pentenyl, pentynyl, hexenyl and hexynyl, heptenyl, heptynyl, octenyl, octynyl, nonenyl, nonynyl, decenyl, decynyl, undecenyl, undecynyl, dodecenyl, dodecynyl, tridecenyl, tridecynyl, tetradecenyl, tetradecynyl, pentadecenyl, pentadecynyl, hexadecenyl and hexadecynyl.
For the purposes of this invention the expression “cycloalkyl” or “C3-7-cyclo-alkyl” denotes cyclic hydrocarbons having 3, 4, 5, 6 or 7 carbon atoms, wherein the hydrocarbons can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or poly-substituted. The cycloalkyl can be bonded to the general structure of higher order via any desired and possible ring member of the cycloalkyl radical. The cycloalkyl radicals can also be fused with further saturated, (partially) unsaturated, heterocyclic, aromatic or heteroaromatic ring systems, which in turn can be unsubstituted or mono- or poly-substituted. The cycloalkyl radicals can further be bridged one or more times, as in the case of adamantyl or dicyclopentadienyl, for example. C3-7-Cycloalkyl is preferably selected from the group containing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
The term “heterocyclyl” includes saturated or unsaturated (but not aromatic) cycloalkyls having from three to seven ring members, in which one, two or three carbon atoms have been replaced by a hetero atom in each case selected each independently from the group S, N and O, it being possible for the ring members to be unsubstituted or mono- or poly-substituted. The heterocyclyl can be bonded to the general structure of higher order via any desired and possible ring member of the heterocyclyl radical. The heterocyclyl radicals can also be fused with further saturated, (partially) unsaturated or aromatic or heteroaromatic ring systems, which in turn can be unsubstituted or mono- or poly-substituted. Heterocyclyl radicals from the group azetidinyl, aziridinyl, azepanyl, quinolinyl, dioxanyl, dioxolanyl, furanyl, imidazolidinyl, isoxazolidinyl, isoquinolinyl, indolinyl, morpholinyl, pyranyl, pyrrolyl, pyridinyl, pyrrolyl, pyrrolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrazolinonyl and thiomorpholinyl are preferred. Heterocyclyl radicals from the group morpholinyl, piperazinyl and piperidinyl are particularly preferred.
Within the scope of this invention the term “aryl” denotes aromatic hydrocarbons having up to 14 ring members, inter alia phenyls and naphthyls. Each aryl radical can be unsubstituted or mono- or poly-substituted, it being possible for the aryl substituents to be identical or different and to be in any desired and possible position of the aryl. The aryl can be bonded to the general structure of higher order via any desired and possible ring member of the aryl radical. The aryl radicals can also be fused with further saturated, (partially) unsaturated, heterocyclic, aromatic or heteroaromatic ring systems, which in turn can be unsubstituted or mono- or poly-substituted. Aryl is preferably selected from the group containing phenyl, 1-naphthyl and 2-naphthyl, each of which can be unsubstituted or mono- or poly-substituted. A particularly preferred aryl is phenyl, unsubstituted or mono- or poly-substituted.
The term “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1 heteroatom, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are in each case selected independently of the others from the group S, N and O and the heteroaryl radical can be unsubstituted or mono- or poly-substituted; in the case of substitution on the heteroaryl, the substituents can be identical or different and can be in any desired and possible position of the heteroaryl. Preferred heteroatoms are S, N and O. S and N are particularly preferred. Bonding to the general structure of higher order can take place via any desired and possible ring member of the heteroaryl radical. The heteroaryl can also be part of a bi- or poly-cyclic system having up to 14 ring members, wherein the ring system can be formed with further saturated, (partially) unsaturated, heterocyclic or aromatic or heteroaromatic rings, which in turn can be unsubstituted or mono- or poly-substituted. Within the scope of this invention, the thienyl ring of formula (1) fused with the tetrahydropyridine ring accordingly represents a heteroaryl and any substituents present are accordingly preferably defined as the substituents of heteroaryl defined hereinbefore. It is preferable for the heteroaryl radical to be selected from the group comprising benzofuranyl, benzimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, quinazolinyl, carbazolyl, quinolinyl, furyl (furanyl), imidazolyl, indazolyl, indolizinyl, isoquinolinyl, isoxazolyl, isothiazolyl, indolyl, oxadiazolyl, phthalazinyl, pyrazolyl, pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl, triazolyl, thiazolyl, thiadiazolyl and triazinyl. Pyridyl and thienyl are particularly preferred.
Within the scope of the invention, the terms “C1-2-alkyl- or C1-4-alkyl- or C1-8-alkyl- or C2-8-alkyl-bridged aryl, heteroaryl, heterocyclyl or cycloalkyl” mean that C1-2-alkyl or C1-4-alkyl or C1-8-alkyl or C2-8-alkyl and aryl or heteroaryl or heterocyclyl or cycloalkyl have the meanings defined above and the aryl or heteroaryl or heterocyclyl or cycloalkyl radical is bonded to the structure of higher order via a C1-2-alkyl or C1-4-alkyl or C1-8-alkyl or C2-8-alkyl group. The alkyl chain can in all cases be saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted.
In connection with “alkyl”, “heterocyclyl” and “cycloalkyl”, the expression “mono- or poly-substituted” is understood as meaning within the scope of this invention the substitution of one or more hydrogen atoms, in each case each independently, one or more times, for example two, three or four times, by substituents selected from the group comprising F; Cl; Br; I; CN; CF3; ═O; ═NH; ═C(NH2)2; NO2; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(O1-8-alkyl)—O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—O(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH—S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; S(═O)2N(R0)2; wherein polysubstituted radicals are to be understood as being radicals that are substituted several times, for example two, three or four times, either on different atoms or on the same atom, for example three times on the same carbon atom, as in the case of CF3 or CH2CF3, or at different places, as in the case of CH(OH)—CH═CH—CHCl2. A substituent can itself optionally be mono- or poly-substituted. Polysubstitution can take place with the same substituent or with different substituents.
Preferred “alkyl”, “heterocyclyl” and “cycloalkyl” substituents are F; Cl; Br; I; CN; ═O; ═NH; ═C(NH2)2; NO2; benzyl; C1-8-alkyl; CF3; C(═O)H; C(═O)OH; C(═O)C1-8-alkyl; C(═O)aryl; C(═O)heteroaryl; C(═O)O—O1-8-alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; C(═O)NH2; C(═O)NH—O1-8-alkyl; C(═O)N(C1-8-alkyl)2; C(═O)NH-aryl; C(═O)N(aryl)2; C(═O)NH-heteroaryl; C(═O)N(heteroaryl)2; C(═O)N(C1-8-alkyl)(aryl); C(═O)N(C1-8-alkyl)(heteroaryl); C(═O)N(aryl)(heteroaryl); OH; O—C1-8-alkyl; O—C1-8-alkyl-OH; O—(C1-8-alkyl)-O; O—(C1-8-alkyl)—O—C1-8-alkyl; OCF3; O-aryl; O-heteroaryl; O-benzyl; O—C(═O)—C1-8-alkyl; O—C(═O)-aryl; O—C(═O)-heteroaryl; O—S(═O)2OH; O—S(═O)2—OC1-8-alkyl; O—S(═O)2—O-aryl; O—S(═O)2—O-heteroaryl; O—S(═O)2C1-8-alkyl; O—S(═O)2aryl, O—S(═O)2heteroaryl; O—S(═O)2NH2; O—S(═O)2NH—C1-8-alkyl; O—S(═O)2N(C1-8-alkyl)2; O—S(═O)2NH-aryl; O—S(═O)2N(aryl)2; O—S(═O)2NH-heteroaryl; O—S(═O)2N(heteroaryl)2; O—S(═O)2N(C1-8-alkyl)(aryl); O—S(═O)2N(heteroaryl)(aryl); O—S(═O)2N(C1-8-alkyl)(heteroaryl); NH2; NH(OH); N═C(NH2)2; NH—C1-8-alkyl; NH—C1-8-alkyl-OH; N(C1-8-alkyl)2; N(C1-8-alkyl-OH)2; NH-aryl; N(aryl)2; NH-heteroaryl; N(heteroaryl)2; N(C1-8-alkyl)(aryl); N(C1-8-alkyl)(heteroaryl); N(aryl)(heteroaryl); NH—C(═O)C1-8-alkyl; NH—C(═O)-aryl; NH—C(═O)-heteroaryl; N(C1-8-alkyl)-C(═O)C1-8-alkyl; N(C1-8-alkyl)-C(═O)aryl; N(C1-8-alkyl)-C(═O)heteroaryl; N(aryl)-C(═O)C1-8-alkyl; N(aryl)-C(═O)aryl; N(aryl)-C(═O)heteroaryl; N(heteroaryl)-C(═O)C1-8-alkyl; N(heteroaryl)-C(═O)aryl; N(heteroaryl)-C(═O)heteroaryl; NH—S(═O)2OH; NH—S(═O)2C1-8-alkyl; NH—S(═O)2aryl; NH—S(═O)2heteroaryl; NH—S(═O)2OC1-8-alkyl; NH—S(═O)2O-aryl; NH—S(═O)2O-heteroaryl; NH—S(═O)2NH2; NH—S(═O)2NH(C1-8-alkyl); NH—S(═O)2NH(aryl); NH—S(═O)2NH(heteroaryl); NH—S(═O)2N(C1-8-alkyl)2; NH—S(═O)2N(aryl)2; NH—S(═O)2N(heteroaryl)2; NH—S(═O)2N(C1-8-alkyl)(aryl); NH—S(═O)2N(C1-8-alkyl)(heteroaryl); NH—S(═O)2N(aryl)(heteroaryl); N(C1-8-alkyl)-S(═O)2OH; N(aryl)-S(═O)2OH; N(heteroaryl)-S(═O)2OH; N(C1-8-alkyl)-S(═O)2—C1-8-alkyl; N(C1-8-alkyl)-S(═O)2-aryl; N(C1-8-alkyl)-S(═O)2-heteroaryl; N(aryl)-S(═O)2—C1-8-alkyl; N(aryl)-S(═O)2-aryl; N(aryl)-S(═O)2-heteroaryl; N(heteroaryl)-S(═O)2—C1-8-alkyl; N(heteroaryl)-S(═O)2-aryl; N(heteroaryl)-S(═O)2-heteroaryl; N(C1-8-alkyl)-S(═O)2—OC1-8-alkyl; N(C1-8-alkyl)-S(═O)2—O-aryl; N(C1-8-alkyl)-S(═O)2—O-heteroaryl; N(aryl)-S(═O)2—OC1-8-alkyl; N(aryl)-S(═O)2—O-aryl; N(aryl)-S(═O)2—O-heteroaryl; N(heteroaryl)-S(═O)2—OC1-8-alkyl; N(heteroaryl)-S(═O)2—O-aryl; N(heteroaryl)-S(═O)2—O-heteroaryl; N(C1-8-alkyl)-S(═O)2NH2; N(aryl)-S(═O)2NH2; N(heteroaryl)-S(═O)2NH2; N(C1-8-alkyl)-S(═O)2NH(C1-8-alkyl); N(C1-8-alkyl)-S(═O)2NH(aryl); N(C1-8-alkyl)-S(═O)2NH(heteroaryl); N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)2; N(C1-8-alkyl)-S(═O)2N(aryl)2; N(C1-8-alkyl)-S(═O)2N(heteroaryl)2; N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)(aryl); N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(C1-8-alkyl)-S(═O)2N(aryl)(heteroaryl); N(aryl)-S(═O)2NH(C1-8-alkyl); N(aryl)-S(═O)2NH(aryl); N(aryl)-S(═O)2NH(heteroaryl); N(aryl)-S(═O)2N(C1-8-alkyl)2; N(aryl)-S(═O)2N(aryl)2; N(aryl)-S(═O)2N(heteroaryl)2; N(aryl)-S(═O)2N(C1-8-alkyl)(aryl); N(aryl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(aryl)-S(═O)2N(aryl)(heteroaryl); N(heteroaryl)-S(═O)2NH(C1-8-alkyl); N(heteroaryl)-S(═O)2NH(aryl); N(heteroaryl)-S(═O)2NH(heteroaryl); N(heteroaryl)-S(═O)2N(C1-8-alkyl)2; N(heteroaryl)-S(═O)2N(aryl)2; N(heteroaryl)-S(═O)2N(heteroaryl)2; N(heteroaryl)-S(═O)2N(C1-8-alkyl)(aryl); N(heteroaryl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(heteroaryl)-S(═O)2N(aryl)(heteroaryl); SH; SCF3; S—C1-8-alkyl; S-benzyl; S-aryl; S-heteroaryl; S(═O)2OH; S(═O)2—OC1-8-alkyl; S(═O)2—O-aryl; S(═O)2—O-heteroaryl; S(═O)C1-8-alkyl; S(═O)aryl, S(═O)heteroaryl; S(═O)2C1-8-alkyl; S(═O)2aryl; S(═O)2heteroaryl; S(═O)2NH2; S(═O)2NH—C1-8-alkyl; S(═O)2N(C1-8-alkyl)2; S(═O)2NH-aryl; S(═O)2N(aryl)2; S(═O)2NH-heteroaryl; S(═O)2N(heteroaryl)2; S(═O)2N(C1-8-alkyl)(aryl); S(═O)2N(heteroaryl)(aryl); S(═O)2N(C1-8-alkyl)(heteroaryl); aryl, heteroaryl, C3-7-cycloalkyl, heterocyclyl or C1-8-alkyl-bridged aryl, heteroaryl, C3-7-cycloalkyl or heterocyclyl. A substituent can itself optionally be mono- or poly-substituted. Polysubstitution is carried out with the same or with different substituents.
In connection with “aryl” and “heteroaryl”, “mono- or poly-substituted” is understood as meaning within the scope of this invention the substitution of one of more hydrogen atoms, in each case each independently, one or more times, for example two, three or four times, by substituents selected from the group comprising F; Cl; Br; I; NO; NO2; CF3; CN; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; O—(C1-8-alkyl)-O; OR0; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH—S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; S(═O)2N(R0)2 on one atom or optionally on different atoms, wherein a substituent can itself optionally be mono- or poly-substituted. Polysubstitution takes place with the same substituent or with different substituents.
Preferred “aryl” and “heteroaryl” substituents are F; Cl; Br; I; CN; NH2; OCF3; SCF3; S(═O)CF3; S(═O)2CF3; NH(OH); NO; NO2; CF2H; OCF2H; SCF2H; benzyl; C1-8-alkyl; CF3; C(═O)H; C(═O)OH; C(═O)C1-8-alkyl; C(═O)aryl; C(═O)heteroaryl; C(═O)O—C1-8-alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; C(═O)NH2; C(═O)NH—C1-8-alkyl; C(═O)N(C1-8-alkyl)2; C(═O)NH-aryl; C(═O)N(aryl)2; C(═O)NH-heteroaryl; C(═O)N(heteroaryl)2; C(═O)N(C1-8-alkyl)(aryl); C(═O)N(C1-8-alkyl)(heteroaryl); C(═O)N(aryl)(heteroaryl); OH; O—C1-8-alkyl; O—C1-8-alkyl-OH; O—(C1-8-alkyl)-O; O-(C1-8-alkyl)—O—C1-8-alkyl; O-aryl; O-heteroaryl; O-benzyl; O—C(═O)—C1-8-alkyl; O—C(═O)-aryl; O—C(═O)-heteroaryl; O—S(═O)2OH; O—S(═O)2—OC1-8-alkyl; O—S(═O)2—O-aryl; O—S(═O)2—O-heteroaryl; O—S(═O)2C1-8-alkyl; O—S(═O)2aryl; O—S(═O)2heteroaryl; O—S(═O)2NH2; O—S(═O)2NH—C1-8-alkyl; O—S(═O)2N(C1-8-alkyl)2; O—S(═O)2NH-aryl; O—S(═O)2N(aryl)2; O—S(═O)2NH-heteroaryl; O—S(═O)2N(heteroaryl)2; O—S(═O)2N(C1-8-alkyl)(aryl); O—S(═O)2N(heteroaryl)(aryl); O—S(═O)2N(C1-8-alkyl)(heteroaryl); NH2; NH(OH); N═C(NH2)2; NH—C1-8-alkyl; NH—C1-8-alkyl-OH; N(C1-8-alkyl)2; N(C1-8-alkyl-OH)2; NH-aryl; N(aryl)2; NH-heteroaryl; N(heteroaryl)2; N(C1-8-alkyl)(aryl); N(C1-8-alkyl)(heteroaryl); N(aryl)(heteroaryl); NH—C(═O)C1-8-alkyl; NH—C(═O)-aryl; NH—C(═O)-heteroaryl; N(C1-8-alkyl)-C(═O)C1-8-alkyl; N(C1-8-alkyl)-C(═O)aryl; N(C1-8-alkyl)-C(═O)heteroaryl; N(aryl)-C(═O)C1-8-alkyl; N(aryl)-C(═O)aryl; N(aryl)-C(═O)heteroaryl; N(heteroaryl)-C(═O)C1-8-alkyl; N(heteroaryl)-C(═O)aryl; N(heteroaryl)-C(═O)heteroaryl; NH—S(═O)2OH; NH—S(═O)2C1-8-alkyl; NH—S(═O)2aryl; NH—S(═O)2heteroaryl; NH—S(═O)2OC1-8-alkyl; NH—S(═O)2O-aryl; NH—S(═O)2O-heteroaryl; NH—S(═O)2NH2; NH—S(═O)2NH(C1-8-alkyl); NH—S(═O)2NH(aryl); NH—S(═O)2NH(heteroaryl); NH—S(═O)2N(C1-8-alkyl)2; NH—S(═O)2N(aryl)2; NH—S(═O)2N(heteroaryl)2; NH—S(═O)2N(C1-8-alkyl)(aryl); NH—S(═O)2N(C1-8-alkyl)(heteroaryl); NH—S(═O)2N(aryl)(heteroaryl); N(C1-8-alkyl)-S(═O)2OH; N(aryl)-S(═O)2OH; N(heteroaryl)-S(═O)2OH; N(C1-8-alkyl)-S(═O)2—C1-8-alkyl; N(C1-8-alkyl)-S(═O)2-aryl; N(C1-8-alkyl)-S(═O)2-heteroaryl; N(aryl)-S(═O)2—C1-8-alkyl; N(aryl)-S(═O)2-aryl; N(aryl)-S(═O)2-heteroaryl; N(heteroaryl)-S(═O)2—C1-8-alkyl; N(heteroaryl)-S(═O)2-aryl; N(heteroaryl)-S(═O)2-heteroaryl; N(C1-8-alkyl)-S(═O)2—OC1-8-alkyl; N(C1-8-alkyl)-S(═O)2—O-aryl; N(C1-8-alkyl)-S(═O)2—O-heteroaryl; N(aryl)-S(═O)2—OC1-8-alkyl; N(aryl)-S(═O)2—O-aryl; N(aryl)-S(═O)2—O-heteroaryl; N(heteroaryl)-S(═O)2—OC1-8-alkyl; N(heteroaryl)-S(═O)2—O-aryl; N(heteroaryl)-S(═O)2—O-heteroaryl; N(C1-8-alkyl)-S(═O)2NH2; N(aryl)-S(═O)2NH2; N(heteroaryl)-S(═O)2NH2; N(C1-8-alkyl)-S(═O)2NH(C1-8-alkyl); N(C1-8-alkyl)-S(═O)2NH(aryl); N(C1-8-alkyl)-S(═O)2NH(heteroaryl); N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)2; N(C1-8-alkyl)-S(═O)2N(aryl)2; N(C1-8-alkyl)-S(═O)2N(heteroaryl)2; N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)(aryl); N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(C1-8-alkyl)-S(═O)2N(aryl)(heteroaryl); N(aryl)-S(═O)2NH(C1-8-alkyl); N(aryl)-S(═O)2NH(aryl); N(aryl)-S(═O)2NH(heteroaryl); N(aryl)-S(═O)2N(C1-8-alkyl)2; N(aryl)-S(═O)2N(aryl)2; N(aryl)-S(═O)2N(heteroaryl)2; N(aryl)-S(═O)2N(C1-8-alkyl)(aryl); N(aryl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(aryl)-S(═O)2N(aryl)(heteroaryl); N(heteroaryl)-S(═O)2NH(C1-8-alkyl); N(heteroaryl)-S(═O)2NH(aryl); N(heteroaryl)-S(═O)2NH(heteroaryl); N(heteroaryl)-S(═O)2N(C1-8-alkyl)2; N(heteroaryl)-S(═O)2N(aryl)2; N(heteroaryl)-S(═O)2N(heteroaryl)2; N(heteroaryl)-S(═O)2N(C1-8-alkyl)(aryl); N(heteroaryl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(heteroaryl)-S(═O)2N(aryl)(heteroaryl); SH; S—C1-8-alkyl; S-benzyl; S-aryl; S-heteroaryl; S(═O)2OH; S(═O)2—OC1-8-alkyl; S(═O)2—O-aryl; S(═O)2—O-heteroaryl; S(═O)2C1-8-alkyl; S(═O)2aryl, S(═O)2heteroaryl; S(═O)C1-8-alkyl; S(═O)aryl; S(═O)heteroaryl; S(═O)2NH2; S(═O)2NH—C1-8-alkyl; S(═O)2N(C1-8-alkyl)2; S(═O)2NH-aryl; S(═O)2N(aryl)2; S(═O)2NH-heteroaryl; S(═O)2N(heteroaryl)2; S(═O)2N(C1-8-alkyl)(aryl); S(═O)2N(heteroaryl)(aryl); S(═O)2N(C1-8-alkyl)(heteroaryl); aryl, heteroaryl, C3-7-cycloalkyl, heterocyclyl or C1-8-alkyl-bridged aryl, heteroaryl, C3-7-cycloalkyl or heterocyclyl. A substituent can itself optionally be mono- or poly-substituted. Polysubstitution takes place with the same substituent or with different substituents. Particularly preferred substituents are F, Cl, OCH3, CF3, OCF3, SCF3 and CH3.
The compounds according to the invention are defined by substituents, for example by R1, R2 and R3 (1st generation substituents), which are themselves optionally substituted (2nd generation substituents). Depending on the definition, these substituents of the substituents can in turn themselves be substituted (3rd generation substituents). If, for example, R1═R0, wherein R0=aryl (1st generation substituent), aryl can itself be substituted, for example by NHR0, wherein R0═C1-8-alkyl (2nd generation substituent). This yields the functional group aryl-NHC1-8-alkyl. C1-8-Alkyl can then in turn itself be substituted, for example by Cl (3rd generation substituent). Overall, this then yields the functional group aryl-NHC1-8-alkyl-Cl.
In one preferred embodiment, however, the 3rd generation substituents cannot themselves be substituted, that is to say there are no 4th generation substituents.
In another preferred embodiment, the 2nd generation substituents cannot themselves be substituted, that is to say there are not even any 3rd generation substituents. In other words, the functional groups for R0 to R35 in each case can optionally be substituted in this embodiment, but the substituents cannot themselves be substituted.
If a substituent occurs more than once within a molecule, such as, for example, the substituent R0, that substituent can have different meanings for different substituents: if, for example, both R1═R0 and R7═R0, R0 can denote for R1 and C1-8-alkyl for R7.
In some cases, the compounds according to the invention are defined by substituents which, together with the carbon atom(s) or heteroatom(s) joining them as ring member or members, form a ring, for example a C3-7-cycloalkyl or a heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted. The ring systems so formed can optionally be fused with (hetero)aryl, that is to say with an aryl such as phenyl or with a heteroaryl such as pyridyl, it being possible for the (hetero)aryl radical to be unsubstituted or mono- or poly-substituted. The ring systems so formed are preferably fused with an aryl, particularly preferably with phenyl. If the substituents R11 and R12, for example, with the nitrogen atom joining them, form a piperidine ring, that piperidine ring can be fused with phenyl to give tetrahydroisoquinolinyl.
The expression “salt formed with a physiologically acceptable acid” is understood within the scope of this invention as meaning salts of the active ingredient in question with inorganic or organic acids that are physiologically acceptable—in particular when used in humans and/or mammals. The hydrochloride is particularly preferred. Examples of physiologically acceptable acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid, saccharinic acid, monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, α-liponic acid, acetylglycine, hippuric acid, phosphoric acid and/or aspartic acid. Citric acid and hydrochloric acid are particularly preferred.
Physiologically acceptable salts with cations or bases are salts of the compound in question—in the form of the anion with at least one, preferably inorganic cation—that are physiologically acceptable—in particular when used in humans and/or mammals. Particular preference is given to the salts of the alkali and alkaline earth metals but also to ammonium salts, but in particular to (mono-) or (di-)sodium, (mono-) or (di-)potassium, magnesium or calcium salts.
Preferred embodiments of the compounds according to the invention of formula (1) have the formula (1a), (1b) or (1c):
wherein R13, R14 and R15 each independently of the others denotes H; F; Cl; Br; I; NO; NO2; CF3; CN; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(C1-8-alkyl)-O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH—S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; or S(═O)2N(R0)2.
Compounds of formulas (1a) and (1c) are particularly preferred. Compounds of formula (1a) are most particularly preferred.
Further preferred embodiments of the compounds according to the invention of formula (1) and of formulas (1a), (1b) and (1c) have the formula (2a), (2b) or (2c):
wherein R13, R14 and R15 each independently of the others denotes H; F; Cl; Br; I; NO; NO2; CF3; CN; R0; C(═O)H; C(═O)R0; CO2H; C(═O)OR0; CONH2; C(═O)NHR0; C(═O)N(R0)2; OH; OR0; O—(C1-8-alkyl)-O; O—C(═O)—R0; O—C(═O)—O—R0; O—(C═O)—NH—R0; O—C(═O)—N(R0)2; O—S(═O)2—R0; O—S(═O)2OH; O—S(═O)2OR0; O—S(═O)2NH2; O—S(═O)2NHR0; O—S(═O)2N(R0)2; NH2; NH—R0; N(R0)2; NH—C(═O)—R0; NH—C(═O)—O—R0; NH—C(═O)—NH—R0; NH—C(═O)—N(R0)2; NR0—C(═O)—R0; NR0—C(═O)—O—R0; NR0—C(═O)—NH2; NR0—C(═O)—NH—R0; NR0—C(═O)—N(R0)2; NH—S(═O)2OH; NH—S(═O)2R0; NH—S(═O)2OR0; NH—S(═O)2NH2; NH—S(═O)2NHR0; NH—S(═O)2N(R0)2; NR0—S(═O)2OH; NR0—S(═O)2R0; NR0—S(═O)2OR0; NR0—S(═O)2NH2; NR0—S(═O)2NHR0; NR0—S(═O)2N(R0)2; SH; SR0; S(═O)R0; S(═O)2R0; S(═O)2OH; S(═O)2OR0; S(═O)2NH2; S(═O)2NHR0; or S(═O)2N(R0)2.
Compounds of formulas (2a) and (2c) are particularly preferred. Compounds of formula (2a) are most particularly preferred.
In a further preferred embodiment of the compounds according to the invention, R13, R14 and R15 according to one of the formulas (1), (1a), (1b), (1c), (2a), (2b) or (2c) are in each case selected each independently from the group consisting of H; F; Cl; Br; I; NO; NO2; CN; NH2; NH—C1-8-alkyl; N(C1-8-alkyl)2; NH—C(═O)C1-8-alkyl; NH—C(═O)-aryl; NH—C(═O)-heteroaryl; C1-8-alkyl; CF3; CHO; C(═O)C1-8-alkyl; C(═O)aryl; C(═O)heteroaryl; CO2H; C(═O)O—C1-8-alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; CONH2; C(═O)NH—C1-8-alkyl; C(═O)N(C1-8-alkyl)2; C(═O)NH-aryl; C(═O)N(aryl)2; C(═O)NH-heteroaryl; C(═O)N(heteroaryl)2; C(═O)N(C1-8-alkyl)(aryl); C(═O)N(C1-8-alkyl)(heteroaryl); C(═O)N(heteroaryl)(aryl); OH; O—C1-8-alkyl; OCF3; O—(C1-8-alkyl)-O; O-(C1-8-alkyl)-O—C1-8alkyl; O-benzyl; O-aryl; O-heteroaryl; O—C(═O)C1-8-alkyl; O—C(═O)aryl; O—C(═O)heteroaryl; SH; S—C1-8-alkyl; SCF3; S-benzyl; S-aryl; S-heteroaryl; aryl; heteroaryl; C3-7-cycloalkyl; heterocyclyl or C1-8-alkyl-bridged aryl, heteroaryl, C3-7-cycloalkyl or heterocyclyl.
More preferably, the substituents R13, R14 and R15 according to one of the formulas (1), (1a), (1b), (1c), (2a), (2b) or (2c) are in each case selected each independently from the group consisting of H; F; Cl; Br; CN; NH2; NH—C(═O)C1-8-alkyl; NH—C(═O)-aryl; NH—C(═O)-heteroaryl; C1-8-alkyl; CF3; CONH2; C(═O)NH—C1-8-alkyl; C(═O)N(C1-8-alkyl)2; C(═O)NH-aryl; C(═O)N(aryl)2; C(═O)NH-heteroaryl; C(═O)N(heteroaryl)2; C(═O)N(C1-8-alkyl)(aryl); C(═O)N(C1-8-alkyl)(heteroaryl); C(═O)N(heteroaryl)(aryl); OH; O—C1-8-alkyl; OCF3; O-benzyl; O-aryl; O-heteroaryl; SH; S—C1-8-alkyl; SCF3; S-benzyl; S-aryl; S-heteroaryl; aryl; heteroaryl; C3-7-cycloalkyl; heterocyclyl or C1-8-alkyl-bridged aryl, heteroaryl, C3-7-cycloalkyl or heterocyclyl.
Yet more preferably, the substituents R13, R14 and R15 according to one of the formulas (1), (1a), (1b), (1c), (2a), (2b) or (2c) are in each case selected each independently from the group consisting of H; F; Cl; Br; CN; CF3; OCF3; SCF3; C1-8-alkyl; O—C1-8-alkyl; CONH2; C(═O)NH—O1-8-alkyl; NH2; NH—C(═O)C1-8-alkyl.
Particularly preferably, the substituents R13, R14 and R15 are in each case selected each independently from the group consisting of H; F, Cl; Br; CN; OCH3; OCF3; CF3 and C1-8-alkyl.
Most particularly preferably, the substituents R13, R14 and R15 according to one of the formulas (1), (1a), (1b), (1c), (2a), (2b) or (2c) each independently of the others denotes H or CH3.
Compounds in which one of R13 and R14; or R13 and R15; or R14 and R15 according to one of the formulas (1), (1a), (1b), (1c), (2a), (2b) or (2c) represents CH3 and the other denotes H are particularly preferred.
In a further preferred embodiment, the substituent R1 is selected from the group consisting of H; F; Cl; Br; CN; C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; C1-8-alkyl-bridged C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or poly-substituted; or C1-8-alkyl-bridged aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or poly-substituted; and the substituent R2 is selected from the group consisting of H and C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or
R1 and R2, together with the carbon atom joining them as ring member, form a C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted, in each case optionally fused with (hetero)aryl, unsubstituted or mono- or poly-substituted.
In a further preferred embodiment, the substituent R1 is selected from the group consisting of H; C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; C1-8-alkyl-bridged C3-7-cycloalkyl, saturated or unsaturated; or C1-8-alkyl-bridged aryl or heteroaryl, unsubstituted or mono- or poly-substituted; and the substituent R2 is selected from the group consisting of H and C1-8-alkyl, saturated or unsaturated, branched or unbranched; or
R1 and R2, together with the carbon atom joining them as ring member, form a C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted, optionally fused with (hetero)aryl, unsubstituted or mono- or poly-substituted.
In a further preferred embodiment, the substituent R1 is selected from the group consisting of H; C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; phenyl, pyridyl or thienyl, in each case unsubstituted or mono- or poly-substituted; C1-8-alkyl-bridged C3-7-cycloalkyl, saturated or unsaturated; or C1-8-alkyl-bridged phenyl, pyridyl or thienyl, in each case unsubstituted or mono- or poly-substituted; and the substituent R2 is selected from the group consisting of H and C1-8-alkyl, saturated or unsaturated, branched or unbranched.
In a further preferred embodiment, the substituent R1 is selected from the group consisting of H; C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; phenyl or thienyl, in each case unsubstituted or mono- or poly-substituted; C1-8-alkyl-bridged C3-7-cycloalkyl, saturated or unsaturated; or C1-8-alkyl-bridged phenyl or thienyl; in each case unsubstituted or mono- or poly-substituted; and the substituent R2 represents H.
In a further preferred embodiment, the substituent R1 is selected from the group consisting of H; C1-8-alkyl, saturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl, saturated, unsubstituted or mono- or poly-substituted; phenyl or thienyl, in each case unsubstituted or mono- or poly-substituted; or C1-8-alkyl-bridged phenyl, unsubstituted; and the substituent R2 represents H.
In a further preferred embodiment, the substituent R1 is selected from the group consisting of C1-8-alkyl, saturated, branched or unbranched, unsubstituted; and C1-8-alkyl-bridged phenyl, unsubstituted; or
denotes (CH2)e-bridged phenyl according to one of the following general formulas (3a) or (4a):
mono- or di-substituted by R16a and/or R16b; or
denotes according to one of the following formulas (3b) or (4b) (CH2)e-bridged thienyl
mono- or di-substituted by R16c and/or R16d; or
denotes (CH2)e-bridged C3-7-cycloalkyl according to one of the following formulas (3c) or (4c):
mono- or di-substituted by R17a and/or R17b;
and the substituent R2 represents H;
wherein e is 0, 1, 2, 3 or 4, preferably 0;
R16a and R16b are selected each independently from the group consisting of H, F, Cl, Br, CN, NH2, OCF3, SCF3, CF3, C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; aryl, heteroaryl, in each case unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted;
R16c and R16d are selected each independently from the group consisting of H, F, Cl, Br, CN, NH2, OCF3, SCF3, CF3, C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; aryl, heteroaryl, in each case unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted;
h is 0, 1, 2, 3 or 4;
R17a and R17b are selected each independently from the group consisting of H, F, Cl, Br, CN, NH2, OCF3, SCF3, CF3, C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; aryl, heteroaryl, in each case unsubstituted or mono- or poly-substituted.
R16a and R16b are preferably selected each independently from the group consisting of H, F, Cl, Br, CH3, C2N5, isopropyl, OCH3 and CF3.
R16c and R16d are preferably selected each independently from the group consisting of H, F, Cl, Br, CH3, OCH3 and CF3. Particularly preferably R16c and R16d each independently represent H or CH3.
h preferably represents 2 or 3, particularly preferably 3.
R17a and R17b are preferably selected each independently from the group consisting of H, F, Cl, Br, CH3, OCH3 and CF3. Particularly preferably R17a and R17b each represent H.
Compounds of formulas (3a), (4a), (3b) and (4b) are most particularly preferred. Compounds of formulas (4a) and (4b) are especially preferred.
In another preferred embodiment, R1 and R2 each represents H, or R2 denotes H and R1 is not H.
In a further preferred embodiment, the substituents R3, R4, R5 and R6 are selected each independently from the group consisting of H, C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl, unsubstituted or mono- or poly-substituted. Preferably, R3, R4, R5 and R6 each independently of the others represents H; CH3; or phenyl. Particularly preferably, R3, R4, R5 each denotes H and R6 is selected from H and phenyl.
In a further preferred embodiment, the substituent R7 is selected from the group consisting of H; F; Cl; Br; CN; OH; NH2; C1-8-alkyl, O—C1-8-alkyl, NH—C1-8-alkyl, N(C1-8-alkyl)2, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; C1-2-alkyl-bridged phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or poly-substituted, and R9 is selected from the group consisting of H; F; Cl; Br; CN; OH; NH2; C1-8-alkyl, O—C1-8-alkyl, NH—C1-8-alkyl, N(C1-8-alkyl)2, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; C2-alkyl-bridged phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or poly-substituted.
Preferably, R7 is selected from the group consisting of H; C1-8-alkyl, NH—C1-8-alkyl, N(C1-8-alkyl)2, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; C1-2-alkyl-bridged phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or poly-substituted, and R9 is selected from the group consisting of H; C1-8-alkyl, NH—C1-8-alkyl, N(C1-8-alkyl)2, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted; C2-alkyl-bridged phenyl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted or mono- or poly-substituted.
More preferably, R7 is selected from the group consisting of H; C1-8-alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl, unsubstituted or mono- or poly-substituted; C1-2-alkyl-bridged phenyl, unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, and R9 is selected from the group consisting of H; C1-8-alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; phenyl, unsubstituted or mono- or poly-substituted; C2-alkyl-bridged phenyl, unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated.
Yet more preferably, R7 is selected from the group consisting of H; C1-8-alkyl, in each case saturated or unsaturated, branched or unbranched; phenyl or benzyl, in each case unsubstituted or mono- or poly-substituted, and R9 is selected from the group consisting of H; C1-8-alkyl, in each case saturated or unsaturated, branched or unbranched; phenyl, unsubstituted or mono- or poly-substituted. Particularly preferably, one of R7 and R9 is selected from the group consisting of H; CH3; phenyl, unsubstituted or mono- or poly-substituted; and the other represents H. Especially preferably, one of R7 and R9 is selected from the group consisting of H; CH3; phenyl, unsubstituted; and the other represents H.
In another preferred embodiment, R7 and R9, together with carbon atoms joining them as ring members, form a C3-7-cycloalkyl or piperidinyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted, optionally fused with (hetero)aryl, unsubstituted or mono- or poly-substituted. R7 and R9, together with the carbon atoms joining them as ring members, preferably form a C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted, optionally fused with aryl, unsubstituted or mono- or poly-substituted. R7 and R9, together with the carbon atoms joining them as ring members, particularly preferably form a C3-7-cycloalkyl, saturated or unsaturated, optionally fused with phenyl.
In a further preferred embodiment, R8 is selected from the group consisting of H; and C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted. R8 is preferably selected from H and C1-8-alkyl, saturated. More preferably, R8 represents H or CH3. R8 particularly preferably denotes H.
In a further preferred embodiment, R10 is selected from the group consisting of H; and C1-8-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted. R10 is preferably selected from H and C1-8-alkyl, saturated. More preferably, R10 represents H or CH3. R10 particularly preferably denotes H.
In a further preferred embodiment, R7 and R8; or R9 and R10; together with the carbon atoms joining them as ring members, form a C3-7-cycloalkyl or piperidinyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted, optionally fused with (hetero)aryl, unsubstituted or mono- or poly-substituted. R7 and R8; or R9 and R10; together with the carbon atoms joining them as ring members, preferably form a C3-7-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted, optionally fused with aryl, unsubstituted or mono- or poly-substituted. Particularly preferably, R7 and R8; or R9 and R10; together with the carbon atoms joining them as ring members, form a C3-7-cycloalkyl, saturated or unsaturated, optionally fused with phenyl.
In a further preferred embodiment, the substituent R11 is selected from the group consisting of H; C1-8-alkyl, saturated or unsaturated, branched or unbranched, C3-7-cycloalkyl, saturated or unsaturated; and benzyl, unsubstituted or mono- or poly-substituted. R11 preferably represents H; C1-8-alkyl, saturated or unsaturated, branched or unbranched; or benzyl. More preferably, R11 denotes H or CH3. R11 particularly preferably represents H.
In a further preferred embodiment, R12 is selected from the group consisting of C4-16-alkyl, saturated or unsaturated; branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; C1-8-alkyl-bridged C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or poly-substituted; C1-8-alkyl-bridged aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or poly-substituted. More preferably, R12 is selected from the group consisting of C4-16-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; C1-8-alkyl-bridged C3-7-cycloalkyl or heterocyclyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or poly-substituted; C1-8-alkyl-bridged aryl or heteroaryl, in each case unsubstituted or mono- or poly-substituted, wherein the alkyl chain in each case can be branched or unbranched, saturated or unsaturated, unsubstituted, mono- or poly-substituted; with the proviso that when R12 denotes heterocyclyl or heteroaryl, bonding of the heterocyclyl or heteroaryl takes place via a carbon atom of the heterocyclyl or heteroaryl.
Yet more preferably, R12 represents C4-16-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or is selected from the following partial structures A, B and C
Particular preference is given to compounds in which R12 represents the partial structure A. Most particular preference is given to compounds in which R12 represents the partial structure A wherein
R18 and R19 each independently denote H; F; Cl; Br; I; CN; NH2; OCF3; SCF3; S(═O)CF3; S(═O)2CF3; NH(OH); NO; NO2; CF2H; OCF2H; SCF2H; benzyl; C1-8-alkyl; CF3; C(═O)H; C(═O)OH; C(═O)C1-8-alkyl; C(═O)aryl; C(═O)heteroaryl; C(═O)O—C1-8-alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; C(═O)NH2; C(═O)NH—C1-8-alkyl; C(═O)N(C1-8-alkyl)2; C(═O)NH-aryl; C(═O)N(aryl)2; C(═O)NH-heteroaryl; C(═O)N(heteroaryl)2; C(═O)N(C1-8-alkyl)(aryl); C(═O)N(C1-8-alkyl)(heteroaryl); C(═O)N(aryl)(heteroaryl); OH; O—C1-8-alkyl; O—C1-8-alkyl-OH; O—(C1-8-alkyl)-O; O—(C1-8-alkyl)-O—C1-8-alkyl; O-aryl; O-heteroaryl; O-benzyl; O—C(═O)—C1-8-alkyl; O—C(═O)-aryl; O—C(═O)-heteroaryl; O—S(═O)2OH; O—S(═O)2—OC1-8-alkyl; O—S(═O)2—O-aryl; O—S(═O)2—O-heteroaryl; O—S(═O)2C1-8-alkyl; O—S(═O)2aryl; O—S(═O)2heteroaryl; O—S(═O)2NH2; O—S(═O)2NH—C1-8-alkyl; O—S(═O)2N(C1-8-alkyl)2; O—S(═O)2NH-aryl; O—S(═O)2N(aryl)2; O—S(═O)2NH-heteroaryl; O—S(═O)2N(heteroaryl)2; O—S(═O)2N(C1-8-alkyl)(aryl); O—S(═O)2N(heteroaryl)(aryl); O—S(═O)2N(C1-8-alkyl)(heteroaryl); NH2; NH(OH); N═C(NH2)2; NH—C1-8-alkyl; NH—C1-8-alkyl-OH; N(C1-8-alkyl)2; N(C1-8-alkyl-OH)2; NH-aryl; N(aryl)2; NH-heteroaryl; N(heteroaryl)2; N(C1-8-alkyl)(aryl); N(C1-8-alkyl)(heteroaryl); N(aryl)(heteroaryl); NH—C(═O)C1-8-alkyl; NH—C(═O)-aryl; NH—C(═O)-heteroaryl; N(C1-8-alkyl)-C(═O)C1-8-alkyl; N(C1-8-alkyl)-C(═O)aryl; N(C1-8-alkyl)-C(═O)heteroaryl; N(aryl)-C(═O)C1-8-alkyl; N(aryl)-C(═O)aryl; N(aryl)-C(═O)heteroaryl; N(heteroaryl)-C(═O)C1-8-alkyl; N(heteroaryl)-C(═O)aryl; N(heteroaryl)-C(═O)heteroaryl; NH—S(═O)2OH; NH—S(═O)2C1-8-alkyl; NH—S(═O)2aryl; NH—S(═O)2heteroaryl; NH—S(═O)2OC1-8-alkyl; NH—S(═O)2O-aryl; NH—S(═O)2O-heteroaryl; NH—S(═O)2NH2; NH—S(═O)2NH(C1-8-alkyl); NH—S(═O)2NH(aryl); NH—S(═O)2NH(heteroaryl); NH—S(═O)2N(C1-8-alkyl)2; NH—S(═O)2N(aryl)2; NH—S(═O)2N(heteroaryl)2; NH—S(═O)2N(C1-8-alkyl)(aryl); NH—S(═O)2N(C1-8-alkyl)(heteroaryl); NH—S(═O)2N(aryl)(heteroaryl); N(C1-8-alkyl)-S(═O)2OH; N(aryl)-S(═O)2OH; N(heteroaryl)-S(═O)2OH; N(C1-8-alkyl)-S(═O)2—C1-8-alkyl; N(C1-8-alkyl)-S(═O)2-aryl; N(C1-8-alkyl)-S(═O)2-heteroaryl; N(aryl)-S(═O)2—C1-8-alkyl; N(aryl)-S(═O)2-aryl; N(aryl)-S(═O)2-heteroaryl; N(heteroaryl)-S(═O)2—C1-8-alkyl; N(heteroaryl)-S(═O)2-aryl; N(heteroaryl)-S(═O)2-heteroaryl; N(C1-8-alkyl)-S(═O)2—OC1-8-alkyl; N(C1-8-alkyl)-S(═O)2—O-aryl; N(C1-8-alkyl)-S(═O)2—O-heteroaryl; N(aryl)-S(═O)2—OC1-8-alkyl; N(aryl)-S(═O)2—O-aryl; N(aryl)-S(═O)2—O-heteroaryl; N(heteroaryl)-S(═O)2—OC1-8-alkyl; N(heteroaryl)-S(═O)2—O-aryl; N(heteroaryl)-S(═O)2—O-heteroaryl; N(C1-8-alkyl)-S(═O)2NH2; N(aryl)-S(═O)2NH2; N(heteroaryl)-S(═O)2NH2; N(C1-8-alkyl)-S(═O)2NH(C1-8-alkyl); N(C1-8-alkyl)-S(═O)2NH(aryl); N(C1-8-alkyl)-S(═O)2NH(heteroaryl); N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)2; N(C1-8-alkyl)-S(═O)2N(aryl)2; N(C1-8-alkyl)-S(═O)2N(heteroaryl)2; N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)(aryl); N(C1-8-alkyl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(C1-8-alkyl)-S(═O)2N(aryl)(heteroaryl); N(aryl)-S(═O)2NH(C1-8-alkyl); N(aryl)-S(═O)2NH(aryl); N(aryl)-S(═O)2NH(heteroaryl); N(aryl)-S(═O)2N(C1-8-alkyl)2; N(aryl)-S(═O)2N(aryl)2; N(aryl)-S(═O)2N(heteroaryl)2; N(aryl)-S(═O)2N(C1-8-alkyl)(aryl); N(aryl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(aryl)-S(═O)2N(aryl)(heteroaryl); N(heteroaryl)-S(═O)2NH(C1-8-alkyl); N(heteroaryl)-S(═O)2NH(aryl); N(heteroaryl)-S(═O)2NH(heteroaryl); N(heteroaryl)-S(═O)2N(C1-8-alkyl)2; N(heteroaryl)-S(═O)2N(aryl)2; N(heteroaryl)-S(═O)2N(heteroaryl)2; N(heteroaryl)-S(═O)2N(C1-8-alkyl)(aryl); N(heteroaryl)-S(═O)2N(C1-8-alkyl)(heteroaryl); N(heteroaryl)-S(═O)2N(aryl)(heteroaryl); SH; S—C1-8-alkyl; S-benzyl; S-aryl; S-heteroaryl; S(═O)2OH; S(═O)2—OC1-8-alkyl; S(═O)2—O-aryl; S(═O)2—O-heteroaryl; S(═O)2C1-8-alkyl; S(═O)2aryl, S(═O)2heteroaryl; S(═O)C1-8-alkyl; S(═O)aryl; S(═O)heteroaryl; S(═O)2NH2; S(═O)2NH—C1-8-alkyl; S(═O)2N(C1-8-alkyl)2; S(═O)2NH-aryl; S(═O)2N(aryl)2; S(═O)2NH-heteroaryl; S(═O)2N(heteroaryl)2; S(═O)2N(C1-8-alkyl)(aryl); S(═O)2N(heteroaryl)(aryl); S(═O)2N(C1-8-alkyl)(heteroaryl); aryl, heteroaryl, C3-7-cycloalkyl, heterocyclyl or C1-8-alkyl-bridged aryl, heteroaryl, C3-7-cycloalkyl or heterocyclyl; or
R18 and R19, together with the carbon or nitrogen atoms joining them as ring members, form an aryl or heteroaryl group fused with the phenyl ring and in each case unsubstituted or mono- or poly-substituted; or a C3-7-cycloalkyl or heterocyclyl group fused with the phenyl ring and in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted.
In a further preferred embodiment, R12 represents C4-18-alkyl, saturated or unsaturated, branched or unbranched, or is selected from the following partial structures A, B and C
Particular preference is given to compounds in which R12 represents the partial structure A. Most particular preference is given to compounds in which R12 represents the partial structure A wherein R18 and R19 each independently denote H; F; Cl; Br; CN; NH2; C1-8-alkyl; CF3; OH; O—C1-8-alkyl; OCF3; or SCF3, or R18 and R19, together with the carbon or nitrogen atoms joining them as ring members, form a C3-7-cycloalkyl fused with the phenyl ring and saturated or unsaturated, unsubstituted or mono- or poly-substituted; or a phenyl, imidazolyl or thiadiazolyl fused with the phenyl ring and in each case unsubstituted or mono- or poly-substituted; or together with the carbon atoms joining them as ring members form O—CH2—O; or O—CH2—CH2—O.
In a further preferred embodiment, R12 represents C4-16-alkyl, saturated or unsaturated, branched or unbranched, or is selected from the following partial structures A, B and C
Particular preference is given to compounds in which R12 represents the partial structure A. Most particular preference is given to compounds in which R12 represents the partial structure A wherein R18 and R19 each independently denote H; F; Cl; CN; CH3; CF3; OH; OCH3; OCF3; or SCF3.
In another preferred embodiment, R11 and R12, together with the nitrogen atom joining them as ring member, form one of the following groups
R11 and R12, together with the nitrogen atom joining them as ring member, preferably form one of the following groups:
Particularly preferably, R11 and R12, together with the nitrogen atom joining them as ring member, form one of the following groups:
Particular preference is given to compounds in which R11 and R12, together with the nitrogen atom joining them as ring member, form the group
Particular preference is given to compounds of formula (1) wherein R1 is selected from the group consisting of H; C1-8-alkyl; C3-7-cycloalkyl; C1-alkyl-bridged C3-7-cycloalkyl; phenyl, unsubstituted or mono- or di-substituted by substituents selected each independently from the group consisting of F, Cl, Br, CH3, C2H5, isopropyl, OCH3 and CF3; thienyl, unsubstituted or mono- or di-substituted by CH3; C1-3-alkyl-bridged saturated, unsubstituted phenyl;
Most particular preference is given to compounds selected from the group consisting of:
The substituted tetrahydrothienopyridines according to the invention, and in each case the corresponding acids, bases, salts and solvates, or a compound selected from the group consisting of
The present invention therefore also provides pharmaceutical compositions comprising a substituted tetrahydrothienopyridine according to the invention of formula (1) wherein R1 to R12 have the meanings given above, including compounds selected from the group consisting of
Particular preference is given to pharmaceutical compositions comprising a compound selected from the group consisting of:
In addition to at least one compound according to the invention, the pharmaceutical compositions according to the invention optionally comprise suitable additives and/or auxiliary substances, that is to say also carriers, fillers, solvents, diluents, colorings and/or binders, and can be administered as liquid medicament forms in the form of injection solutions, drops or juices, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be used are dependent on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to the skin, the mucosa or into the eyes. Preparations in the form of tablets, dragées, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, readily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalatory administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents that promote penetration through the skin, are suitable percutaneous forms of administration. Forms of preparation for administration orally or percutaneously can release the compounds according to the invention in a delayed manner. The compounds according to the invention can also be administered in parenteral long-term depot forms such as, for example, implants or implanted pumps. In principle, other further active ingredients known to persons skilled in the art can be added to the medicaments according to the invention.
The compounds and compositions according to the invention are suitable for influencing KCNQ2/3 channels and exert an agonistic or antagonistic action, in particular an agonistic action. The compounds and compositions according to the invention are preferably suitable for the treatment of disorders or diseases that are mediated at least in part by KCNQ2/3 channels. The compounds and compositions according to the invention thus are suitable for the treatment or inhibition of disease states or disorders selected from the group consisting of pain, especially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases, dystonia-associated dyskinesias and/or urinary incontinence. The compounds and compositions according to the invention are suitable particularly preferably for the treatment of pain, most particularly preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain. The compounds and compositions according to the invention are also preferably suitable for the treatment of epilepsy.
The invention further provides the use of at least one substituted tetrahydrothienopyridine according to the invention, including compounds selected from the group consisting of
Preference is given to the use of at least one substituted tetrahydrothienopyridine compound according to the invention, or a composition comprising a substituted tetrahydrothienopyridine compound and one or more pharmaceutically acceptable auxiliary substances, for the treatment of pain, especially pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain; epilepsy, urinary incontinence, anxiety, dependency, mania, bipolar disorders, migraine, cognitive diseases, dystonia-associated dyskinesias and/or urinary incontinence. Particular preference is given to the use of at least one substituted tetrahydrothienopyridine according to the invention, or of a composition comprising a substituted tetrahydrothienopyridine compound and one or more pharmaceutically acceptable auxiliary substances, for the treatment of pain, most particularly preferably chronic pain, neuropathic pain, inflammatory pain and muscular pain. Particular preference is given also to the use of at least one substituted tetrahydrothienopyridine according to the invention, or a composition comprising a substituted tetrahydrothienopyridine compound and one or more pharmaceutically acceptable auxiliary substances, for the treatment of epilepsy.
The effectiveness of the compounds and compositions of the invention against pain can be shown, for example, in the Bennett or Chung model (Bennett, G. J. and Xie, Y. K., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 1988, 33(1), 87-107; Kim, S. H. and Chung, J. M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363). The effectiveness against epilepsy can be demonstrated, for example, in the DBA/2 mouse model (De Sarro et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 2001, 363, 330-336).
The substituted tetrahydrothienopyridines according to the invention preferably have a EC50 value of not more than 10 μM or not more than 5 μM, more preferably not more than 3 μM or not more than 2 μM, yet more preferably not more than 1.5 μM or not more than 1 μM, most preferably not more than 0.8 μM or not more than 0.6 μM and especially not more than 0.4 μM or not more than 0.2 μM. Methods for determining the EC50 value are known to persons skilled in the art. The EC50 value is preferably determined by fluorimetry, particularly preferably as described under “Pharmacological Experiments”.
The invention further provides a process for the preparation of the substituted tetrahydrothienopyridines according to the invention.
The chemicals and reaction components used in the reactions described hereinbelow are available commercially or in each case can be prepared by conventional methods known to persons skilled in the art.
In step 1, amines of formula II are reacted with succinic anhydrides of formula III, in a reaction medium, preferably selected from the group consisting of acetone, acetonitrile, chloroform, dioxane, dichloromethane, ethanol, ethyl acetate, nitrobenzene, methanol and tetrahydrofuran, optionally in the presence of an inorganic base, preferably potassium carbonate, or of an organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine and diisopropylethylamine, preferably at temperatures of from −20° C. to 160° C., to give carboxylic acids of formula V.
In step 2, carboxylic acids of formula IV wherein PG represents a C1-6-alkyl group, preferably methyl, ethyl, isopropyl or tert-butyl, are reacted with amines of formula II by the processes described under step 4 to give compounds of formula VI.
In step 3, carboxylic acid esters of formula VI wherein PG represents a C1-6-alkyl group, preferably methyl, ethyl, isopropyl or tert-butyl, are cleaved, optionally in a reaction medium, preferably selected from the group consisting of acetone, acetonitrile, chloroform, dioxane, dichloromethane, ethanol, methanol, tetrahydrofuran and water, or in a mixture of these reaction media, optionally in the presence of an inorganic base, preferably LiOH or NaOH, or optionally in the presence of an acid, preferably formic acid, hydrochloric acid or trifluoroacetic acid, optionally in the presence of triethylsilane, triisopropylsilane or ethanediol, preferably at temperatures of from −20° C. to 80° C., to give carboxylic acids of formula V.
In step 4, carboxylic acids of formula V are reacted with amines of formula VII, in a reaction medium, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide and dichloromethane, optionally in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N′-(3-dimethylaminopropyl)-N-ethylcarbo-diimide (EDCI), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxy-7-aza-benzotriazole (HOAt), optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and caesium carbonate, or of an organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine and diisopropylethylamine, preferably at temperatures of from −70° C. to 150° C., to give compounds of formula I.
In step 5, amines of formula VII are reacted with succinic anhydrides of formula III according to the processes described under step 1 to give carboxylic acids of formula XVI.
In step 6, amines of formula VII are reacted with carboxylic acids of formula VIII according to the processes described under step 4 to give compounds of formula IX.
In step 7, carboxylic acid esters of formula IX wherein PG represents a C1-6-alkyl group, preferably methyl, ethyl, isopropyl or tert-butyl, are cleaved according to the processes described under step 3 to give carboxylic acids of formula XVI.
In step 8, amines of formula II are reacted with carboxylic acids of formula XVI according to the processes described under step 4 to give compounds of formula I.
In step 9, amines of formula X are reacted with ketones or aldehydes (R2═H) of formula XI, in a reaction medium, preferably selected from the group consisting of acetonitrile, chloroform, dichloromethane, diethyl ether, ethanol, methanol, tetrahydrofuran, toluene and xylene, optionally in the presence of an inorganic base, preferably potassium carbonate, or an organic base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine and diisopropylethylamine, preferably at temperatures of from 0° C. to 160° C., to give imines of formula XII.
In step 10, imines of formula XII are cyclized, optionally in a reaction medium, preferably selected from the group consisting of benzene, ethanol, methanol, toluene, water and xylene, with the addition of an acid, preferably selected from the group consisting of hydrochloric acid, trifluoroacetic acid and trifluoromethanesulfonic acid, preferably at temperatures of from 0° C. to 160° C., to give compounds of formula II.
In step 11, amines of formula X are reacted with carboxylic acids of formula XIII according to the processes described under step 4 to give amides of formula XIV.
In step 12, amides of formula XIV are cyclized in a reaction medium, preferably selected from the group consisting of benzene, chloroform, toluene or xylene, in the presence of a suitable cyclizing reagent, preferably phosphoryl trichloride or phosphorus pentachloride, optionally with the addition of phosphorus pentoxide, preferably at temperatures of from 20° C. to 150° C., to give compounds of formula XV.
In step 13, compounds of formula XIV are reduced in a reaction medium, preferably selected from the group consisting of diethyl ether, ethanol, acetic acid, methanol and tetrahydrofuran, in the presence of a suitable reducing agent, preferably selected from the group consisting of sodium borohydride, sodium cyano-borohydride, lithium aluminium hydride and hydrogen, optionally with the addition of a catalyst, preferably selected from the group consisting of palladium, platinum, platinum oxide and Raney nickel, optionally with the addition of an organic base selected from the group consisting of ammonia, triethylamine and diisopropylethyl-amine, preferably at temperatures of from −20° C. to 100° C., to give compounds of formula II′ (R2═H).
0.45 equiv. of NH4OAc was added to a solution of 3.78 g (30.0 mmol) of 2-methyl-thiophene-3-carbaldehyde in nitromethane (45 ml), and stirring was carried out for 2 h at 100° C. After cooling to RT, the mixture was diluted with EA and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (hexane/EA 20:1) of the residue, 4.16 g (24.6 mmol, 82%) of 2-methyl-3-(2-nitrovinyl)thiophene were obtained.
A solution of 5.08 g (30.0 mmol) of 2-methyl-3-(2-nitrovinyl)thiophene in ether (150 ml) was added dropwise at RT to a solution of 2.1 equiv. of LiAlH4 in ether (190 ml). When the addition was complete, quenching with a sat. aq. Na2SO4 sol. was carried out. The mixture was then filtered over kieselguhr and the filtrate was concentrated in vacuo. After CC (DCM/MeOH 20:1+0.1% NEt3) of the residue, 2.33 g (16.5 mmol, 55%) of intermediate TAM01 were obtained.
20.2 g (105.5 mmol) of EDC, 9.50 g (70.3 mmol) of HOBt and 47.8 ml (281.2 mmol) of DIPEA were added at 0° C. to a solution of 10.0 g (70.3 mmol) of 2-(thiophen-3-yl)-acetic acid in DCM (200 ml). After stirring for 20 min at 0° C., 3.08 g (84.4 mmol) of N,O-dimethylhydroxylamine hydrochloride were added. Stirring was then carried out for a further 16 h at RT. The mixture was then quenched with a sat. aq. NH4Cl sol. and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. After CC (hexane/EA 17:3), 9.98 g (53.9 mmol, 77%) of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide were obtained.
53.4 ml (53.4 mmol, 1M in THF) of phenylmagnesium bromide solution were added dropwise at 0° C. to a solution of 9.9 g (53.4 mmol) of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide in ether (100 ml). Stirring was then carried out for 3 h at RT, followed by quenching, while cooling with ice, with a sat. aq. NH4Cl sol. The mixture was extracted with EA and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude product (8.98 g, 44.4 mmol, 83%) 1-phenyl-2-(thiophen-3-yl)ethanone was reacted further without additional purification.
14.56 g (177.6 mmol) of sodium acetate and 6.17 g (88.8 mmol) of hydroxylamine hydrochloride were added to a solution of 8.98 g (44.4 mmol) of 1-phenyl-2-(thiophen-3-yl)ethanone in EtOH (220 ml), and the mixture was heated for 4 h at 85° C. Filtration through Celite was then carried out, and the filtrate was concentrated in vacuo. The residue was taken up in EA, dried over Na2SO4, filtered and concentrated in vacuo. There were obtained as residue 7.52 g (34.6 mmol, 78%) of 1-phenyl-2-(thiophen-3-yl)ethanone-oxime, which was reacted further without additional purification.
3.81 g of Raney nickel were added to a solution of 7.52 g (34.6 mmol) of 1-phenyl-2-(thiophen-3-yl)ethanone-oxime dissolved in EtOH (760 ml). The reaction solution was then stirred for 3 d under a hydrogen atmosphere at 4.14 bar and 30° C. Filtration over Celite was then carried out, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in 1M aq. hydrochloric acid and washed with EA. The aqueous phase was adjusted to pH 8-10 with a sat. aq. Na2CO2 sol., while cooling with ice, and extraction with EA was then carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in dioxane (40 ml), and a sat. HCl sol. in dioxane (115 ml) was added at 0° C. (ice bath). After 2 h stirring at RT, concentration in vacuo was carried out. 3.1 g (12.8 mmol, 37%) of intermediate TAMO3 were obtained.
4.8 ml (34.6 mmol) of NEt3 and 8.2 ml (78.6 mmol) of 2-fluoro-benzaldehyde were added to a solution of 9.2 ml (78.6 mmol) of 2-thiophen-2-yl-ethylamine in EtOH (80 ml), and stirring was carried out for 72 h at 50° C. The mixture was then concentrated in vacuo. The residue was taken up in TFA (300 ml), and stirring was carried out for a further 72 h at RT. After concentration in vacuo, the residue was taken up in DCM and washed with a 2M aq. NaOH sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA/hexane 3:1) of the residue, 12.2 g (52.3 mmol, 66%) of intermediate SAMN04 were obtained.
4 Å molecular sieve was added to a solution of 2.0 g (14.1 mmol) of 2-(5-methylthien-2-yl)-ethylamine and 1.42 ml (14.1 mmol) of benzaldehyde in toluene (75 ml), and the mixture was heated under reflux for 16 h with a water separator. The molecular sieve was then filtered off and washed with toluene. The filtrate was concentrated in vacuo. The residue was taken up in TFA (54 ml) and stirring was carried out for 6 d at RT. The mixture was then concentrated in vacuo. The resulting residue was taken up in EA and washed with a 2M aq. NaOH sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA/hexane 4:1) of the residue, 1.98 g (8.6 mmol, 61%) of intermediate SAMN08 were obtained.
A solution of 3.1 g (12.8 mmol) of intermediate TAM03 in a mixture of formaldehyde/-AcOH (1:1 vv, 230 ml) was heated for 1 h under reflux. The mixture was then diluted with water and neutralized with liquid ammonia. Extraction with EA was then carried out, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. After CC (hexane/EA 7:3) of the residue, 1.27 g (5.9 mmol, 46%) of intermediate SAMN10 were obtained.
4 Å molecular sieve was added to a solution of 2.5 g (19.7 mmol) of 2-thiophen-2-yl-ethylamine and 2.9 g (19.7 mmol) of 2-isopropyl-benzaldehyde in toluene (40 ml), and the mixture was heated for 16 h under reflux with a water separator. The molecular sieve was then filtered off and washed with toluene. The filtrate was concentrated in vacuo. The residue was taken up in TFA (40 ml) and stirred for 72 h at 90° C. The mixture was then concentrated in vacuo. A 2M aq. NaOH sol. was added to the resulting residue, and extraction with DCM was then carried out. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA/hexane 1:1) of the residue, 3.28 g (12.7 mmol, 64%) of intermediate SAMN13 were obtained.
A stirred solution of 4-methoxy-2-methylene-4-oxo-butyric acid (5.0 g, 34.7 mmol) in ethanol (100 ml) was deoxygenated for 15 min with N2; palladium (10% on carbon, 1.85 g, 1.74 mmol) was then added and deoxygenation with N2 was carried out again for 15 min. The reaction mixture was stirred for 16 h under a H2 atmosphere and then filtered over Celite. The solvent was removed using a rotary evaporator. The resulting crude intermediate ASP01 was used further without additional purification.
A solution of intermediate ASP01 (20.2 g, 138.0 mmol), DMAP (8.44 g, 69.0 mmol) and tert-butanol (14.45 ml, 152.0 mmol) in DCM (500 ml) was cooled to 0° C., and EDC (29.1 g, 152.0 mmol) was added. The reaction mixture was stirred for 16 h at RT. When the reaction was ended, the mixture was washed with brine (500 ml). The organic phase was then dried over Na2SO4, filtered and concentrated to dryness. The resulting crude product, 1-tert-butyl 4-methyl 2-methylsuccinate, was used further without additional purification.
LiOH.H2O (5.19 g, 124.0 mmol) was added to a solution of (25.0 g, 124.0 mmol) 1-tert-butyl 4-methyl 2-methylsuccinate in a mixture of MeOH (85 ml), THF (85 ml) and water (85 ml), and the reaction mixture was stirred for 16 h at RT. When the reaction was ended, the solvent was removed using a rotary evaporator. The residue was taken up in aq. HCl (1M, 130 ml) and extracted twice with DCM (150 ml). The combined organic phases were dried over Na2SO4, filtered and then concentrated to dryness. The resulting crude intermediate ASP02 was used further without additional purification.
A solution of 8.0 g (37.2 mmol) of 4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in MeCN (20 ml) was added to a suspension of 13.0 g (130.1 mmol) of succinic anhydride in MeCN (80 ml). 10.3 ml (74.3 mmol) of NEt3 were then added to the reaction solution, and stirring was carried out for 72 h at RT. The mixture was then concentrated in vacuo; the residue was taken up in EA, and water was added thereto. Extraction with a sat. aq. NaHCO3 sol. was then carried out several times. The combined aqueous phases were adjusted to pH 6-8 with 2N hydrochloric acid. Extraction with EA was then carried out. The organic phase was washed several times with water; activated carbon was added, and stirring was carried out for 15 min. The mixture was then filtered over kieselguhr and the filtrate was dried over MgSO4, filtered and concentrated in vacuo. 7.08 g (22.4 mmol, 60%) of intermediate SAAS01 were obtained as residue.
1.53 g (7.1 mmol) of 4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 2.46 g (6.5 mmol) of HATU and 1.7 ml (12.3 mmol) of NEt3 were added in succession to a solution of 945 mg (6.5 mmol) of (R)-4-methoxy-2-methyl-4-oxobutyric acid in THF (50 ml). After 16 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with a sat. aq. NH4Cl sol. and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 1.14 g (3.3 mmol, 51%) of (3R)-3-methyl-4-oxo-4-(4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)butyric acid methyl ester were obtained.
A solution of 1.14 g (3.3 mmol) of (3R)-3-methyl-4-oxo-4-(4-phenyl-6,7-dihydrothieno-[3,2-c]pyridin-5(4H)-yl)butyric acid methyl ester in a mixture of THF/MeOH (1:1 vv, 50 ml) was cooled to 0° C. (ice bath), and 25 ml of a 1M aq. LiOH sol. were added. Stirring was then carried out for 10 min, the ice bath was removed, and stirring was carried out for a further 150 min. The mixture was then diluted with EA (100 ml), and 1M aq. hydrochloric acid (25 ml) was added. The phases were separated and the aqueous phase was extracted with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 795 mg (2.4 mmol, 73%) of intermediate SAAS02 were obtained.
8.2 ml (59.0 mmol) of NEt3 were added to a solution of 9.82 g (39.3 mmol) of intermediate SAMN12 in DCM (250 ml). A solution of 6.50 g (43.2 mmol) of 4-chloro-4-oxobutyric acid methyl ester in DCM (100 ml) was then added dropwise. After 3 h stirring at RT, washing with 0.5 M aq. hydrochloric acid (250 ml) and with a sat. aq. NaHCO3 sol. (250 ml) was carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. After CC with the residue (heptane/EA 3:1), 13.9 g (38.2 mmol, 97%) of 4-(4-(4-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-4-oxobutyric acid methyl ester were obtained.
A 6M aq. NaOH sol. (30 ml) was added to a solution of 11.0 g (30.3 mmol) of 4-(4-(4-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-4-oxo-butyric acid methyl ester in a mixture of THF/MeOH (1:1 vv, 200 ml), and the mixture was then stirred for 2 h at RT. Most of the organic solvents were then removed in vacuo. The mixture was then neutralized with 6M aq. hydrochloric acid. Extraction with DCM (2×200 ml) was then carried out. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude intermediate SAAS07 was used further without additional purification.
9.3 g (48.5 mmol) of EDC were added to a solution of 6.95 g (32.3 mmol) of 4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 6.38 g (33.9 mmol) of intermediate ASP02, 436 mg (3.2 mmol) of HOAt and 11 ml (64.6 mmol) of DIPEA in DCM (300 ml), and the mixture was stirred for 16 h at RT. Washing with 0.5 M aq. hydrochloric acid (250 ml) and a sat. aq. NaHCO3 sol. (250 ml) was then carried out. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. After CC (heptane/EA 4:1) of the residue, 9.67 g (25.1 mmol, 78%) of 2-methyl-4-oxo-4-(4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)butyric acid tert-butyl ester were obtained.
A 6M aq. NaOH sol. (25 ml) was added to a solution of 9.64 g (25.0 mmol) of 2-methyl-4-oxo-4-(4-phenyl-6,7-dihydrothieno-[3,2-c]pyridin-5(4H)-yl)butyric acid tert-butyl ester in a mixture of THF/MeOH (1:1 vv, 165 ml), and the mixture was then stirred for 2 h at RT. Most of the organic solvents were then removed in vacuo. The mixture was then neutralized with 6M aq. hydrochloric acid. Extraction with DCM (2×200 ml) was then carried out. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. 7.82 g (23.7 mmol, 95%) of intermediate SAAS09 were obtained as residue and were used further without additional purification.
A solution of 15.0 g (85.6 mmol) of (3-(trifluoromethyl)phenyl)methylamine in ether (40 ml) was added dropwise in the course of 30 min to a suspension of 7.5 g (85.6 mmol) of succinic anhydride in ether (450 ml). Stirring was then carried out for 72 h at RT. The resulting precipitate was filtered off and dried. After CC (EA/MeOH 1:1) of the residue, 10.4 g (37.8 mmol, 44%) of intermediate PAAS01 were obtained.
A solution of 5.0 g (28.4 mmol) of (3-(trifluoromethyl)phenyl)methylamine in ether (50 ml) was added dropwise in the course of 30 min to a suspension of 5.0 g (28.4 mmol) of 3-phenyldihydrofuran-2,5-dione in ether (100 ml). The resulting precipitate was filtered off and dried. After repeated CC (TBME/hexane 4:1, then TBME/EA 1:1, then EA/MeOH 9:1) of the residue, 1.27 g (3.6 mmol, 13%) of intermediate PAAS03 and 372 mg (1.1 mmol, 4%) of intermediate PAAS04 were obtained.
1.32 g (7.5 mmol) of 3-(trifluoromethyl)phenyl)methylamine, 2.60 g (6.8 mmol) of HATU and 1.8 ml (13.0 mmol) of NEt3were added in succession to a solution of 1.0 g (6.8 mmol) of (R)-4-methoxy-2-methyl-4-oxobutyric acid in THF (50 ml). After 16 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with a sat. aq. NH4Cl sol. and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 1.30 g (4.3 mmol, 63%) of (R)-3-methyl-4-oxo-4-(3-(trifluoro-methyl)benzylamino)butyric acid methyl ester were obtained.
A solution of 1.29 g (4.3 mmol) of (R)-3-methyl-4-oxo-4-(3-(trifluoromethyl)benzyl-amino)butyric acid methyl ester in a mixture of THF/MeOH (1:1 vv, 70 ml) was cooled to 0° C. (ice bath), and 35 ml of a 1M aq. LiOH sol. were added. Stirring was then carried out for 10 min, the ice bath was removed, and stirring was carried out for a further 120 min. The mixture was then diluted with EA (100 ml), and 1M aq. hydrochloric acid (25 ml) was added. The phases were separated and the aqueous phase was extracted with EA. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 185 mg (0.6 mmol, 15%) of intermediate PAAS05 were obtained.
The synthesis of further intermediates was carried out according to the processes already described. Table 1 shows which compound was prepared by which process. It will be clear to persons skilled in the art which starting materials were used in each case.
To a solution of 275 mg (1.0 mmol) of intermediate PAAS01 in THF (8 ml) there were added in succession 236 mg (1.1 mmol) of 4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine, 380 mg (1.0 mmol) of HATU and 263 μl (1.9 mmol) of NEt3. After 48 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with 2N aq. hydrochloric acid and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 386 mg (0.8 mmol, 82%) of illustrative compound 2 were obtained. MS: m/z 473.1 [M+H]+.
To a solution of 349 mg (1.27 mmol) of intermediate PAAS01 in THF (10 ml) there were added in succession 325 mg (1.40 mmol) of intermediate SAMN05, 482 mg (1.27 mmol) of HATU and 334 μl (2.41 mmol) of NEt3. After 48 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with 2N aq. hydrochloric acid and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. 377 mg (0.77 mmol, 61%) of illustrative compound 3 were obtained as residue. MS: m/z 491.1 [M+H]+.
To a solution of 300 mg (1.09 mmol) of intermediate PAAS01 in THF (8 ml) there were added in succession 258 mg (1.20 mmol) of intermediate SAMN09, 414 mg (1.09 mmol) of HATU and 287 μl (2.07 mmol) of NEt3. After 72 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with 2N aq. hydrochloric acid and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from EA yielded 280 mg (0.59 mmol, 54%) of illustrative compound 9. MS: m/z 473.1 [M+H]+.
To a solution of 400 mg (1.27 mmol) of intermediate SAAS01 in THF (10 ml) there were added in succession 169 mg (1.40 mmol) of (4-methylphenyl)-methylamine, 482 mg (1.27 mmol) of HATU and 334 μl (2.41 mmol) of NEt3. After 24 h stirring at RT, the reaction solution was diluted with EA (30 ml), and washing was carried out twice with 2N aq. hydrochloric acid and twice with a 1N aq. NaHCO3 sol. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization of the residue from EA yielded 239 mg (0.57 mmol, 45%) of illustrative compound 11. MS: m/z 419.2 [M+H]+.
A solution of 400 mg (1.27 mmol) of intermediate SAAS01 and 216 mg (1.33 mmol) of CDI in DCM (10 ml) was stirred for 1 h at RT. A solution of 138 μl (1.27 mmol) of benzylamine in DCM (10 ml) was then added, and stirring was carried out for a further 16 h at RT. The reaction solution was then washed three times with a sat. aq. NH4Cl sol. and three times with a sat. aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Recrystallization of the residue from EA yielded 244 mg (0.60 mmol, 47%) of illustrative compound 12. MS: m/z 405.2 [M+H]+.
A solution of 400 mg (1.27 mmol) of intermediate SAAS01 and 216 mg (1.33 mmol) of CDI in THF (13 ml) was stirred for 1 h at RT. A solution of 219 μl (1.27 mmol) of N-methyl-1-(3-(trifluoromethyl)phenyl)methylamine in THF (13 ml) was then added, and stirring was carried out for a further 16 h at RT. The reaction solution was then washed three times with a sat. aq. NH4Cl sol. and three times with a sat. aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 416 mg (0.85 mmol, 67%) of illustrative compound 24 were obtained. MS: m/z 482.2 [M+H]+.
To a solution of 515 mg (1.56 mmol) of intermediate SAAS02 in THF (12 ml) there were added in succession 274 mg (1.56 mmol) of (3-trifluoromethyl)phenyl)methyl-amine, 594 mg (1.56 mmol) of HATU and 433 μl (3.13 mmol) of NEt3. After 72 h stirring at RT, the reaction solution was diluted with EA and washed three times with a sat. aq. NH4Cl sol. and three times with a sat. aq. NaHCO3 sol. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. After CC (EA) of the residue, 550 mg (1.13 mmol, 72%) of illustrative compound 34 were obtained. MS: m/z 487.2 [M+H]+.
210 mg of racemic 4-oxo-4-(4-phenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-N-(3-(trifluoromethyl)benzyl)-butanamide (for synthesis see Example 2) were separated into the two (R) and (S) enantiomers by means of chiral HPLC (column: Chiralpak AD-H, 250×4.6 mm, eluant: ethanol+0.1% diethylamine, flow rate 1 ml/min). 92 mg of illustrative compound 35, retention time 14.24 min, specific rotation: [α]
1.71 g (8.9 mmol) of EDC, 797 mg (5.9 mmol) of HOBt and 4.0 ml (23.6 mmol) of DIPEA were added at 0° C. to a solution of 1.62 g (5.9 mmol) of intermediate PAAS01 in DCM (30 ml), and the mixture was then stirred for 20 min at 0° C. 1.27 g (5.9 mmol) of intermediate SAMN10 were added at that temperature, and stirring was then carried out for 16 h at RT. The mixture was then diluted with DCM and washed in succession with a sat. aq. NH4Cl sol., brine, a sat. aq. Na2CO3 sol. and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. After CC (hexane/EA 4:1) of the residue, 2.28 g (4.8 mmol, 82%) of illustrative compound 44 were obtained. MS: m/z 473.1 [M+H]+.
In a screw-cap jar having a magnetic stirring rod and a septum cap, a 0.105 M solution of CDI (105 μmol) in DCM (1 ml) was added to a 0.05 M solution of the particular carboxylic acid used (100 μmol) in DCM (2 ml). After 1 h stirring at RT, a 0.10 M solution of the particular amine used (100 μmol) in DCM (1 ml) was added by means of a pipette. Stirring was then carried out for a further 16 h at RT. Water (3 ml) was then added and the phases were mixed thoroughly for 30 min in a spin reactor. The magnetic stirring rod was separated off and the screw-cap jar was rinsed with DCM (2×1.25 ml). The phases were separated by removing the aqueous phase from the swelling vessel (Allex system from Mettler-Toledo). Further water (3 ml) was then added, the whole was mixed thoroughly, and the phases were separated as described. This procedure was repeated with brine (2.5 ml). The organic phase was then transferred to a test tube and concentrated in vacuo (evaporator from Genevac). The resulting residue was purified by means of HPLC.
The synthesis of further illustrative compounds was carried out according to the processes already described. Table 2 indicates which compound was prepared by which process. It will be clear to persons skilled in the art which starting materials were used in each case.
Pharmacological Experiments
Fluorescence Assay using a Voltage Sensitive Dye
Human CHO-K1 cells expressing KCNQ2/3 channels are cultivated adherently at 37° C., 5% CO2 and 95% humidity in cell culture bottles (e.g. 80 cm2 TC flasks, Nunc) with DMEM-high glucose (Sigma Aldrich, D7777) including 10% FCS (PAN Biotech, e.g. 3302-P270521) or alternatively MEM Alpha Medium (1×, liquid, Invitrogen, #22571), 10% fetal calf serum (FCS) (Invitrogen, #10270-106, heat-inactivated) and the necessary selection antibiotics.
Before being sown out for the measurements, the cells are washed with a 1×DPBS buffer without Ca2+/Mg2+ (e.g. Invitrogen, #14190-094) and detached from the bottom of the culture vessel by means of Accutase (PAA Laboratories, #L11-007) (incubation with Accutase for 15 min at 37° C.). The cell count then present is determined using a CASY™ cell counter (TCC model, Schärfe System) in order subsequently to apply, depending on the density optimization for the individual cell line, 20,000-30,000 cells/well/100 μl of the described nutrient medium to 96-well measuring plates of the Corning™ CellBIND™ type (Flat Clear Bottom Black Polystyrene Microplates, #3340). Incubation is then carried out for one hour at room temperature, without gassing or adjusting the humidity, followed by incubation for 24 hours at 37° C., 5% CO2 and 95% humidity.
The voltage-sensitive fluorescent dye from the Membrane Potential Assay Kit (Red™ Bulk format part R8123 for FLIPR, MDS Analytical Technologies™) is prepared by dissolving the contents of a vessel Membrane Potential Assay Kit Red Component A in 200 ml of extracellular buffer (ES buffer, 120 mM NaCl, 1 mM KCl, 10 mM HEPES, 2 mM CaCl2, 2 mM MgCl2, 10 mM glucose; pH 7.4). After removal of the nutrient medium, the cells are washed with 200 μl of ES buffer, then covered with a layer of 100 μl of the dye solution prepared above and incubated for 45 min at room temperature with the exclusion of light.
The fluorescence measurements are carried out with a BMG Labtech FLUOstar™, BMG Labtech NOVOstar™ or BMG Labtech POLARstar™ instrument (525 nm excitation, 560 nm emission, Bottom Read mode). After incubation of the dye, 50 μl of the test substances in the desired concentrations, or 50 μl of ES buffer for control purposes, are introduced into separate cavities of the measuring plate and incubated for 30 min at room temperature while being shielded from light. The fluorescence intensity of the dye is then measured for 5 min and the fluorescence value F1 of each well is thus determined at a given, constant time. 15 μl of a 100 mM KCl solution (final concentration 92 mM) are then added to each well. The change in fluorescence is subsequently measured until all the relevant measured values have been obtained (mainly 5-30 min). At a given time after KCl application, a fluorescence value F2 is determined, in this case at the time of the fluorescence peak.
For calculation, the fluorescence intensity F2 is compared with the fluorescence intensity F1, and the agonistic activity of the target compound on the potassium channel is determined therefrom. F2 and F1 are calculated as follows:
In order to determine whether a substance has agonistic activity,
for example, can be compared with
of control cells.
is determined by adding to the reaction batch only the buffer solution instead of the test substance, determining the value F1K of the fluorescence intensity, adding the potassium ions as described above, and measuring a value F2K of the fluorescence intensity. F2K and F1K are then calculated as follows:
A substance has an agonistic activity on the potassium channel when
is greater than
Independently of the comparison of
it is possible to conclude that a target compound has agonistic activity if an increase in
is to be observed as the dosage of the target compound increases.
Calculations of EC50 and IC50 values are carried out with the aid of ‘Prism v4.0’ software (GraphPad Software™).
Voltage Clamp Measurements
In order to confirm a KCNQ2/3-agonistic action of the substances electro-physiologically, patch-clamp measurements (Hamill O P, Marty A, Neher E, Sakmann B, Sigworth F J.: Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, Pflugers Arch. 1981 August; 391(2):85-100) were carried out in voltage clamp mode on a stably transfected hKCNQ2/3 CHO-K1 cell line. After formation of the gigaseal, the cells were first clamped at a holding potential of −60 mV. Thereafter, depolarizing voltage jumps were applied up to a potential of +20 mV (increment: 20 mV, duration: 1 second) in order to confirm the functional expression of KCNQ2/3-typical currents. The testing of the substances was carried out at a potential of −40 mV. The increase in current induced by retigabine (10 μM) at −40 mV was first recorded as a positive control on each cell. After complete washing out of the retigabine effect (duration: 80 s), the test substance (10 μM) was applied. The increase in current induced by the test substance was standardized to the retigabine effect and indicated as the relative efficacy (see below).
Formalin Test in the Rat
The formalin test (Dubuisson, D. and Dennis, S. G., 1977, Pain, 4, 161-174) represents a model for both acute and chronic pain. In the studies presented here, the chronic pain component (phase II of the formalin test; time period 21-27 min after formalin administration) was evaluated. A biphase nociceptive reaction is induced in freely mobile test animals by a single formalin injection into the dorsal side of a rear paw, the reaction being detected by observation of three clearly distinguishable behavior patterns. Formalin is administered subcutaneously into the dorsal side of the right rear paw of each animal in a volume of 50 μl and a concentration of 5%. The vehicle and the test substances are administered intravenously 5 min, or orally 30 min, before the formalin injection. The specific changes in behavior, such as lifting and shaking of the paw, weight displacement of the animal and biting and licking reactions, are observed and recorded continuously up to 60 min after the formalin administration. The changes in behavior are given different weightings (score 0-3) and a pain rate (PR) is calculated using the following formula:
PR=[(T0×0)+(T1×1)+(T2×2)+(T3×3)/180,
where T0, T1, T2, T3 correspond to the time, in seconds, at which the animal exhibited behavior 0, 1, 2 or 3.
Rats of the strain Sprague Dawley (Janvier, Belgium) are used as the animal strain. The weight of the animals is 180-200 g; the size of the group was n=10.
The results from the pharmacological models described above are summarized in the following Table 3.
Comparison Experiments
The substituted tetrahydrothienopyridines according to the invention are distinguished, as compared with substituted tetrahydropyrrolopyrazines known from WO 2008/046582, by improved activity in vitro and in vivo, as is illustrated by the following comparison experiments:
Example No. 2 of WO2008/046582 compound 2 of the invention
Example No. 76 of WO2008/046582 compound 1 of the invention
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08018617.4 | Oct 2008 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| 61108180 | Oct 2008 | US |
