Patent Application
20090215758
The present invention relates to 2,5-disubstituted thiazol-4-one derivatives and to the use thereof for producing medicaments, to processes for their preparation and to medicaments comprising these compounds.
The treatment of pain, especially of neuropathic pain, has great significance in medicine. There is a global demand for effective pain therapies. The urgent need for research into patient-oriented and targeted treatment of chronic and non-chronic states of pain, which is understood to mean the successful and satisfactory treatment of pain for the patient, is also documented in a large number of scientific studies which have recently appeared in the field of applied analgesics and fundamental research into nociception.
A suitable starting point for the treatment of pain, especially of neuropathic pain, is the vanilloid receptor of subtype 1 (VR1/TRPV1), which is frequently also referred to as the capsaicin receptor. This receptor is stimulated, inter alia, by vanilloids, for example capsaicin, heat and protons, and plays a central role in the development of pain. Furthermore, it is of significance for a multitude of further physiological and pathophysiological processes, for example migraines; depressions; neurodegenerative disorders; cognitive disorders; states of anxiety; epilepsy; coughing; diarrhea; pruritus; disorders of the cardiovascular system; disorders of food intake; medicament dependence; medicament abuse and especially urine incontinence.
It was therefore an object of the present invention to provide novel compounds which are suitable especially as active pharmaceutical ingredients in medicaments, preferably in medicaments for the treatment of disorders or diseases which are mediated at least partly by vanilloid receptors 1 (VR1/TRPV1 receptors).
It has now been found that, surprisingly, 2,5-disubstituted thiazol-4-one derivatives of the general formula I specified below are suitable for controlling pain and have an excellent affinity for the vanilloid receptor of subtype 1 (VR1/TRPV1 receptor), and are therefore suitable especially for prophylaxis and/or treatment of disorders or diseases which are mediated at least partly by vanilloid receptors 1 (VR1/TRPV1).
The present invention therefore provides for the use of at least one 2,5-disubstituted thiazol-4-one derivative of the general formula I
in which
Aliphatic radicals in the context of this invention include acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and also unsubstituted or monosubstituted or polysubstituted identically or differently, having preferably from 1 to 20 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20), more preferably from 1 to 12 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12), most preferably from 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) carbon atoms, i.e. C1-20-, C1-12-, C1-6-alkyls, C2-20-, C2-12-, C2-6-alkenyls and C2-20-, C2-12-, C2-6-alkynyls. Alkenyls have at least one C—C double bond and alkynyls have at least one C—C triple bond. Advantageously, aliphatic radicals may be selected from the group which comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-eicosanyl, ethenyl(vinyl), ethynyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), 2-methylpropenyl, propynyl (—CH2—C≡H, —C≡C—CH3), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, octenyl and octynyl.
The aforementioned aliphatic radicals may preferably have 1, 2 or 3 heteroatoms selected from the group comprising oxygen, sulfur and nitrogen, i.e. —N(H)— and —N(C1-6-alkyl).
Examples of aliphatic radicals which have 1, 2 or 3 heteroatoms include —(CH2)—(CH2)—O—CH3, —(CH2)—(CH2)—(CH2)—O—CH3, —(CH2)—(CH2)—(CH2)—N(C2H5)—(C2H5), —(CH2)—(CH2)—S—CH3, —(CH2)—(CH2)—(CH2)—S—CH3, —(CH2)—(CH2)—(CH2)—N(CH3)—(CH3) and —(CH2)—O—CH3.
In connection with aliphatic radicals, the term “substituted”—unless defined differently elsewhere in the description or in the claims—in the context of this invention is understood to mean single or multiple substitution, preferably mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa- or nonasubstitution, of one or more hydrogen atoms by, for example, F, Cl, Br, I, —CN, —NO2, —OH, —SH and —NH2, where the multiple substitution is multiple, for example double or triple, either on different or on the same atoms, for example triple on the same carbon atom as in the case of —CF3 or —CH2CF3, or on different positions as in the case of —CH(OH)—CH═CCl—CH2Cl. Multiple substitution can be effected with the same or different substituents. Particularly preferred substituted aliphatic radicals are —CF3, —C2F5, —CH2F, —CHF2, —CF2—CF2—CF3, —CH2—Cl, —CH2—Br, —CH2—CH2—Cl, —CH2—CH2—Br, —CH2—CH2—CH2—Br and —CH2—CH2—CH2—Cl.
Cycloaliphatic radicals in the context of this invention are cyclic saturated or unsaturated hydrocarbon radicals having preferably 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, more preferably 3, 4, 5, 6, 7 or 8 carbon atoms, where each radical may be unsubstituted or monosubstituted or polysubstituted identically or differently. Cycloaliphatic radicals may preferably have 1, 2, 3, 4 or 5 heteroatoms selected independently from the group consisting of oxygen, nitrogen (NH) and sulfur.
Examples of cycloaliphatic radicals which may be fused to a monocyclic or polycyclic ring system include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, [6,6]-dimethyl-[3.1.1]-bicycloheptyl, adamantyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, azepanyl, diazepanyl, dithiolanyl, indanyl, indenyl, (1,4)-benzodioxanyl, (1,2,3,4)-tetrahydronaphthyl, (1,2,3,4)-tetrahydroquinolinyl, (1,2,3,4)-tetrahydroisoquinolinyl, (1,2,3,4)-tetrahydroquinazolinyl, (1,3,4,5)-tetrahydropyrido[4,3-b]indolyl, (3,4)-dihydro-1H-isoquinolinyl, (1,3,4,9)-tetrahydro-[b]-carbolinyl, imidazolidinyl, [3,4]-dihydro-2H-1,4-benzoxazinyl, (2,3)-dihydro-1H-isoindolyl, (2,3)-dihydroindolyl and (1,3)-thiazolidinyl.
A mono- or polycyclic ring system is understood in the context of the present invention to mean mono-polycyclic hydrocarbon radicals which may be saturated or unsaturated and optionally have 1, 2, 3, 4 or 5 heteroatom(s) as ring member(s), which are each independently selected from the group consisting of oxygen, nitrogen and sulfur. Such a mono- or polycyclic ring system may, for example, be fused to an aryl radical or a heteroaryl radical.
When a polycyclic ring system, for example a bicyclic ring system, is present, the different rings may each independently have a different degree of saturation, i.e. be saturated or unsaturated. A polycyclic ring system is preferably a bicyclic ring system.
Examples of aryl radicals which are fused to a mono- or polycyclic ring system include [1,3]-benzodioxolyl, [1,4]-benzodioxanyl, [1,2,3,4]-tetrahydronaphthyl, [1,2,3,4]-tetrahydroquinolinyl, [1,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-1,4-benzoxazinyl.
In connection with cycloaliphatic radicals and mono- or polycyclic ring systems, the term “substituted”—unless defined differently elsewhere in the description or in the claims—in the context of this invention is understood to mean the single or multiple substitution, preferably the mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, octa- or nonasubstitution, of one or more hydrogen atoms by, for example, oxo (═O), thioxo (═S), F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-5-alkyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—OH, —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —NH-phenyl, —NH-pyridinyl, —N(C1-5-alkyl)-phenyl, —N(C1-5-alkyl)-pyridinyl, —NH—C(═O)—O—C1-5-alkyl, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, C(═O)—N—(C1-5-alkyl)2, —S(═O)2—C1-5-alkyl, —S(═O)2-phenyl, —NH—S(═O)2—C1-5-alkyl, —S(═O)2—NH—C1-5-alkyl, cyclohexyl, cyclopentyl, pyridinyl, [1,2,5]-thiadiazolyl, pyridazinyl, —(CH2)-benzo[b]furanyl, —O-phenyl, —O-benzyl, phenyl and benzyl, where the cyclic moiety of the —NH-phenyl, —NH-pyridinyl, —N(C1-5-alkyl)-phenyl, —N(C1-5-alkyl)-pyridinyl, pyridinyl, cyclopentyl, [1,2,5]-thiadiazolyl, cyclohexyl, pyridazinyl, —S(═O)2-phenyl, —O-phenyl, —O-benzyl, phenyl, —(CH2)-benzo[b]furanyl and benzyl radicals may in each case be substituted by 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5-alkyl, —O—C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl.
For the purposes of the present invention, the term “aryl radical” should be understood to mean a radical which is preferably selected from the group which comprises phenyl, naphthyl, phenanthrenyl and anthracenyl, and is unsubstituted or mono- or polysubstituted identically or differently. Aryl is more preferably an unsubstituted or monosubstituted or identically or differently polysubstituted, for example bi-, tri-, tetra- or pentasubstituted, phenyl, 1-naphthyl or 2-naphthyl.
In the context of the present invention, heteroaryl radicals are those heterocycles which are heteroaromatic. Heteroaryl radicals are preferably 5- to 14-membered, i.e. 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered, and have preferably 1, 2, 3, 4 or 5 heteroatoms selected independently from the group comprising oxygen, nitrogen and sulfur. Each heteroaryl radical may be present unsubstituted or monosubstituted or polysubstituted for example bi-, tri-, tetra- or pentasubstituted, identically or differently.
Examples of heteroaryl radicals in the context of the invention include thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyranyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinazolinyl, quinolinyl, isoquinolinyl, benzimidazolinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzo[2,1,3]thiadiazolyl, [1,2,3]-benzothiadiazolyl, [2,1,3]-benzoxadiazolyl and [1,2,3]-benzoxadiazolyl.
In relation to aryl and heteroaryl radicals, “substituted” in the context of this invention is understood to mean the single or multiple substitution, for example mono-, di-, tri-, tetra- or pentasubstitution, of one or more hydrogen atoms of the ring system by suitable substituents. When the definition of these suitable substituents in connection with aryl or heteroaryl radicals is not defined elsewhere in the description or in the claims, suitable substituents are F, Cl, Br, I, —CN, —CF3, —SF5, —OH, —O—C1-10-alkyl, —O—C1-10-alkenyl, —NH2, —NO2, —O—CF3, —S—CF3, —SH, —S—C1-5-alkyl, —C1-5-alkyl, —C(═O)—OH, —C(═O)—O—C1-5-alkyl, —O—C(═O)—C1-5-alkyl, —NH—C1-5-alkyl, —N(C1-5-alkyl)2, —NH—C(═O)—O—C1-5-alkyl, —C(═O)—H, —C(═O)—C1-5-alkyl, —C(═O)—NH2, —C(═O)—NH—C1-5-alkyl, C(═O)—N—(C1-5-alkyl)2, —S(═O)2—C1-5-alkyl, —S(═O)2-phenyl, —O—S—(═O)2-phenyl, —NH—S(═O)2—C1-5-alkyl, —S(═O)2—NH—C1-5-alkyl, cyclohexyl, cyclopentyl, pyridinyl, pyridazinyl, —(CH2)— benzo[b]furanyl, —O-phenyl, —O-benzyl, phenyl and benzyl, where the cyclic moiety of the pyridinyl, cyclopentyl, cyclohexyl, pyridazinyl, —S(═O)2-phenyl, —O—S—(═O)2-phenyl, —O-phenyl, —O-benzyl, phenyl, —(CH2)-benzo[b]furanyl and benzyl radicals may in each case preferably be substituted by 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of F, Cl, Br, —OH, —CF3, —SF5, —CN, —NO2, —C1-5-alkyl, —O—C1-5-alkyl, —O—CF3, —S—CF3, phenyl and —O-benzyl. The multiple substitution is effected with the same or with different substituents.
The aforementioned linear or branched alkylene, alkenylene or alkynylene groups preferably have from 1 to 5 carbon atoms, i.e. they are C1-5-alkylene, C2-5-alkenylene or C2-5-alkynylene groups, each of which may be unsubstituted or substituted by preferably 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of F, Cl, Br, —OH, —SH, —NH9, —CN, —NO9 and phenyl, where the phenyl radical may preferably be substituted by 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and neopentyl.
Alkylene groups may more preferably be selected from the group consisting of —(CH2)—, —(CH2)2—, —C(H)(CH3)—, —C(CH3)2—, —(CH2)3—, —(CH2)4—, —(CH2)5—, —C(H)(CH3)—(CH2)—, —C(H)(C2H5)—(CH2)—, —C(phenyl)2- and —C(H)(phenyl).
Alkenylene groups may more preferably be selected from the group consisting of —CH═CH—, —C(CH3)═CH—, —C(C2H5)═CH—, —CH═C(CH3)—, —CH═C(C2H5)—, —CH═C(phenyl)-, —CH═C(p-tolyl), —C(phenyl)=CH— and —C(p-tolyl)=CH—.
An alkynylene group is more preferably a —C≡C— group.
Particular preference is given to the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I in which
is CH—CH2—Y, CH—CH(CH3)—Y, CH—CHCl—Y, CH—CHBr—Y, CH—CHF—Y or CH—CH(OH)—Y;
or is CH—CH═C(CH3)-Z, CH—CH═CH-Z, CH—CH═CH—S-Z, CH—CH═CH—O-Z, CH—CH═CH—N(CH3)-Z, CH—C(CH3)═CH-Z, CH—C(phenyl)=CH-Z, CH—CBr═CH-Z, CH—CCl═CH-Z, CH—CF═CH-Z, CH—C(OH)═CH-Z, CH—CH2—CH2-Z, CH—CH2—CH(CH3)-Z or CH—CH(CH3)—CH2-Z;
Very particular preference is given to the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I in which
Even more preferred is the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I selected from the group consisting of:
Furthermore, preference may be given to the use of inventive compounds which, in the FLIPR assay, in a concentration of 10 μM, have an inhibition of the Ca2+ ion current in dorsal root ganglia of rats of at least 10%, preferably of at least 30%, more preferably of at least 50%, even more preferably of at least 70%, even more preferably of at least 90%, compared to the maximum achievable inhibition of the Ca2+ ion current with capsaicin in a concentration of 10 μM.
In the FLIPR assay, the Ca2+ current is quantified with the aid of a Ca2+-sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described below.
The present invention further provides for the use of at least one inventive 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case, as appropriate, in the form of one of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and also, as appropriate, one or more pharmaceutically acceptable excipients, for producing a medicament for vanilloid receptor 1 (VR1/TRPV1) regulation, preferably for vanilloid receptor 1 (VR1/TRPV1) inhibition or for vanilloid receptor 1 (VR1/TRPV1) stimulation.
Preference is given to the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case, as appropriate, in the form of one of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients, for producing a medicament for prophylaxis and/or treatment of disorders or diseases which are mediated at least partly by vanilloid receptors 1.
Particular preference is given to the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case, as appropriate, in the form of one of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients, for producing a medicament for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; for prophylaxis and/or treatment of one or more disorders selected from the group consisting of migraine; depression; urine incontinence; coughing; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease; Alzheimer's disease and multiple sclerosis; disorders of food uptake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; states of anxiety; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; diarrhea and pruritus; for prophylaxis and/or treatment of alcohol and/or drug and/or medicament abuse and alcohol and/or drug and/or medicament dependence, preferably for prophylaxis and/or reduction of withdrawal symptoms in the case of alcohol and/or drug and/or medicament dependence; for prophylaxis and/or reduction of evolution of tolerance to medicaments, especially medicaments based on opioids; for regulating food uptake; for modulating movement activity; for regulating the cardiovascular system; for local anesthesia; for enhancing vigilance; for enhancing libido; for diuresis and/or for antinatriuresis.
Very particular preference is given to the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case, as appropriate, in the form of one of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients, for producing a medicament for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; for prophylaxis and/or treatment of one or more disorders selected from the group consisting of migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease Alzheimer's disease and multiple sclerosis; states of anxiety; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; for prophylaxis and/or treatment of alcohol and/or drug and/or medicament abuse and alcohol and/or drug and/or medicament dependence, preferably for prophylaxis and/or reduction of withdrawal symptoms in the case of alcohol and/or drug and/or medicament dependence; for prophylaxis and/or reduction of evolution of tolerance to medicaments, especially medicaments based on opioids.
Even more particular preference is given to the use of at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case, as appropriate, in the form of one of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically acceptable excipients, for producing a medicament for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
The present invention further provides 2,5-disubstituted thiazol-4-one derivatives of the general formula Ia
in which
Particular preference is given to 2,5-disubstituted thiazol-4-one derivatives of the above-specified general formula Ia in which
Very particular preference is given to 2,5-disubstituted thiazol-4-one derivatives of the above-specified general formula Ia in which
Even more preferred are 2,5-disubstituted thiazol-4-one derivatives of the above-specified general formula Ia selected from the group consisting of
In addition, preference may be given to inventive compounds which, in the FLIPR assay, in a concentration of 10 μM, have an inhibition of the Ca2+ ion current in dorsal root ganglia of rats of at least 10%, preferably of at least 30%, more preferably of at least 50%, even more preferably of at least 70%, even more preferably of at least 90%, compared to the maximum achievable inhibition of the Ca2+ ion current with capsaicin in a concentration of 10 μM.
In the FLIPR assay, the Ca2+ current is quantified with the aid of a Ca2+-sensitive dye (Fluo-4, Molecular Probes Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA), as described below.
The present invention further provides a process for preparing inventive compounds of the above-specified general formula I, according to which 2-aminothiazol-4-one is reacted in acetic acid in the presence of at least one salt selected from the group consisting of sodium acetate and potassium acetate or in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol and n-butanol in the presence of at least one organic base selected from the group consisting of triethylamine, pyridine, diisopropylamine and N-methylmorpholine with at least one compound of the general formula R—C(═O)—H, in which R is —CH═C(CH3)—Wa-Za, —CH═CH_Wa-Za, —C(CH3)═CH—Wa-Za, —C(phenyl)=CH—Wa-Za, —CBr═CH—Wa-Za, —CCl═CH_Wa-Za, —CF═CH—Wa-Za, —C(OH)═CH_Wa-Za, —CH2—CH2—Wa-Za, —CH2—CH(CH3)_Wa-Za or —CH(CH3)—CH2—Wa-Za, where Wa and Za are each as defined above, to give at least one compound of the general formula IIa,
where R2a is as defined above, and the latter is optionally purified and/or isolated,
and at least one compound of medium in the presence of at least one base, preferably in the presence of at least one metal hydride salt or of a metal alkoxide salt, more preferably in the presence of a metal hydride salt or of a metal alkoxide salt selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, sodium ethoxide and potassium ethoxide, with at least one compound of the general formula LG-R3a or of the general formula LG-R7a or of the general formula LG-R5a, in which LG is in each case a leaving group, preferably a halogen atom, more preferably a chlorine atom, and R3a, R5a and R7a are each as defined above to give at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NHR3a—, NHR5a— or NHR7a group, and the latter is optionally purified and/or isolated,
and optionally at least one compound of the general formula IIa in which R2a is as defined above and R1a is an NHR7a group is reacted in a reaction medium with at least one isocyanate of the general formula R8a—N═C═O, in which R8a is as defined above, optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of triethylamine, 4,4-dimethylaminopyridine and diisopropylethylamine, to give at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NR7a—C(═O)_NHR8a group, and the latter is optionally purified and/or isolated;
and optionally at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NR7a—C(═O)—NHR8a group is reacted in a reaction medium in the presence of at least one base, preferably in the presence of at least one metal hydride salt or of a metal alkoxide salt, more preferably in the presence of a metal hydride salt or of a metal alkoxide salt selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, sodium ethoxide and potassium ethoxide, with at least one compound of the general formula LG-R9a in which LG is a leaving group, preferably a halogen atom, more preferably a chlorine atom, and R9a is as defined above to give at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NR7a—C(═O)—NR8aR9a group, and the latter is optionally purified and/or isolated; or
optionally at least one compound of the general formula IIa in which R2a is as defined above and R1a is an NHR5a group is reacted in a reaction medium, optionally in the presence of at least one base, with at least one compound of the general formula R6a—C(═O)-LG in which R6a is as defined above and LG is a leaving group, preferably a halogen radical, or in a reaction medium in the presence of at least one coupling reagent, optionally in the presence of at least one base, with a compound of the general formula R6a—C(═O)—OH in which R6a is as defined above, to give at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NR5a—C(═O)—R6a group, and the latter is optionally purified and/or isolated or
optionally at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NHR3a group is reacted in a reaction medium in the presence of at least one base, preferably in the presence of at least one metal hydride salt or of a metal alkoxide salt, more preferably in the presence of a metal hydride salt or of a metal alkoxide salt selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, sodium ethoxide and potassium ethoxide, with at least one compound of the general formula LG-R4a in which LG is a leaving group, preferably a halogen atom, more preferably a chlorine atom, and R4a is as defined above to give at least one compound of the general formula Ia in which R2a is as defined above and R1a is an NR3aR4a group, and the latter is optionally purified and/or isolated.
The reaction of compounds of the general formula IIa in which R1a is an —NHR5a group with compounds of the general formula R6a—C(═O)—OH is effected preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of an organic base, preferably selected from the group consisting of triethylamine, 4,4-dimethylaminopyridine, pyridine and diisopropylethylamine, or of an inorganic base, at temperatures of preferably from −70° C. to 100° C.
The reaction of compounds of the general formula IIa in which R1a is an —NHR5a group with compounds of the general formula R6a—C(═O)—OH is effected preferably in a reaction medium selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, methanol, ethanol, dimethylformamide, dichloromethane and corresponding mixtures, optionally in the presence of at least one coupling reagent, preferably selected from the group consisting of 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), O-(benzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt), optionally in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and cesium carbonate, or of an organic base, preferably selected from the group consisting of triethylamine, 4-methylmorpholine, pyridine, N,N-dimethylaminopyridine and diisopropylethylamine, preferably at temperatures of from −70° C. to 100° C.
Likewise provided by the present invention is a process for preparing 2,5-disubstituted thiazol-4-one derivatives of the general formula Ia, according to which at least one compound of the general formula R1a—CN in which R1a is as defined above with the exception of an NR3aR4a group, of an NR5a—C(═O)—R6a group and of an NR7a—C(═O)—NR8aR9a group, is reacted in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol and n-butanol, in the presence of at least one organic base selected from the group consisting of triethylamine, pyridine, diisopropylamine and N-methylmorpholine or in pyridine as a reaction medium, with thioglycolic acid to give at least one compound of the general formula IIIa
in which R1a is as defined above with the exception of an NR3aR4a group, of an NR5a—C(═O)—R6a group and of an NR7a—C(═O)—NR8aR9a group, and the latter is optionally purified and/or isolated;
or at least one compound of the general formula H2N—C(═S)—NHR1a in which R1a is as defined above with the exception of an NR3aR4a group, of an NR5a—C(═O)—R6a group and of an NR7a—C(═O)—NR8aR9a group, is reacted in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol and n-butanol, optionally in the presence of at least one organic base selected from the group consisting of triethylamine, pyridine, diisopropylamine and N-methylmorpholine, with chloroacetic acid to give at least one compound of the general formula IIIa in which R1a is as defined above with the exception of an NR3aR4a group, of an NR5a—C(═O)—R6a group and of an NR7a—C(═O)—NR8aR9a group, and the latter is optionally purified and/or isolated;
and at least one compound of the general formula IIIa is reacted in acetic acid in the presence of at least one salt selected from the group consisting of sodium acetate and potassium acetate or in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol and n-butanol in the presence of at least one organic base selected from the group consisting of triethylamine, pyridine, diisopropylamine and N-methylmorpholine with at least one compound of the general formula R—C(═O)—H in which R is —CH═C(CH3)—Wa-Za, —CH═CH—Wa-Za, —C(CH3)═CH—Wa-Za, —C(phenyl)=CH—Wa-Za, —CBr═CH—Wa-Za, —CCl═CH_Wa-Za, —CF═CH_Wa-Za, C(OH)═CH_Wa-Za, —CH2—CH2—Wa-Za, —CH2—CH(CH3)—Wa-Za or —CH(CH3)—CH2—Wa-Za, where Wa and Za are each as defined above, to give at least one compound of the general formula Ia in which R1a is as defined above with the exception of an NR3aR4a group, of an NR5a—C(═O)—R6a group and of an NR7a—C(═O)—NR8aR9a group and R2a is as defined above.
The compounds of the above-specified general formulae R1a—CN, R—C(═O)—H, R3a-LG, R4a-LG, R5a-LG, R7a-LG, R9a-LG, H2N—C(═S)—NHR1a, R6a—C(═O)-LG, R6a—C(═O)—OH and R8a—N═C═O are each commercially available on the market and can also be prepared by customary processes known to those skilled in the art.
Compounds of the above-specified general formula H2N—C(═S)—NHR1a can preferably be obtained by reacting 1,1′-thiocarbonyldiimidazole with compounds of the general formula R1aNH2 in tetrahydrofuran.
The above-described reactions may each be carried out under the customary conditions familiar to those skilled in the art, for example with regard to pressure or sequence of addition of the components. Optionally, the process regime which is optimal under the particular conditions can be determined by the person skilled in the art by simple preliminary experiments. The intermediates and end products obtained by the above-described reactions may in each case, if desired and/or necessary, be purified and/or isolated by customary methods known to those skilled in the art. Suitable purification processes are, for example, extraction processes and chromatographic processes such as column chromatography or preparative chromatography. All of the aforementioned process steps, and in each case also the purification and/or isolation of intermediates or end products, can be performed partly or completely under an inert gas atmosphere, preferably under a nitrogen atmosphere.
The inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formulae I and Ia, referred to hereinafter only as 2,5-disubstituted thiazol-4-one derivatives of the general formula I, and corresponding stereoisomers, may be obtained in the form of their free bases, of their free acids or else in the form of corresponding salts, especially physiologically compatible salts. The free bases of the particular inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers may, for example, be converted to the corresponding salts, preferably physiologically compatible salts, by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. The free bases of the particular 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers can likewise be converted to the corresponding physiologically compatible salts with the free acid or a salt of a sugar substitute, for example saccharin, cyclamate or acesulfame.
Accordingly, the free acids of the 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers can be converted to the corresponding physiologically compatible salts by reaction with a suitable base. Examples include the alkali metal salts, alkaline earth metal salts or ammonium salts [NHxR4-x]+ in which x=0, 1, 2, 3 or 4 and R is a linear or branched C1-4-alkyl radical.
The inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers may optionally, just like the corresponding acids, the corresponding bases or salts of these compounds, also be obtained in the form of their solvates, preferably in the form of their hydrates, by customary methods known to those skilled in the art.
When the inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I, after they have been prepared, are obtained in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their different enantiomers and/or diastereomers, they can be separated and optionally isolated by customary processes known to those skilled in the art. Examples include chromatographic separation processes, especially liquid chromatography processes under standard pressure or under elevated pressure, preferably MPLC and HPLC processes, and processes for fractional crystallization. It is possible especially to separate individual enantiomers from one another, for example by means of HPLC on a chiral stationary phase, or, by means of crystallization of diastereomeric salts formed with chiral acids, for instance (+)-tartaric acid, (−)-tartaric acid or (+)-10-camphorsulfonic acid.
The inventive 2,5-disubstituted thiazol-4-one derivatives of the aforementioned general formula I and corresponding stereoisomers, and also in each case the corresponding acids, bases, salts and solvates, are toxicologically safe and are therefore suitable as active pharmaceutical ingredients in medicaments.
The present invention therefore further provides a medicament comprising at least one inventive 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, in each case optionally in the form of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of a mixture of stereoisomers, especially of the enantiomers and/or diastereomers, in any mixing ratio, or in each case in the form of a corresponding salt, or in each case in the form of a corresponding solvate, and optionally one or more pharmaceutically compatible excipients.
These inventive medicaments are suitable especially for vanilloid receptor 1 (VR1/TRPV1) regulation, especially for vanilloid receptor 1 (VR1/TRPV1) inhibition or for vanilloid receptor 1 stimulation.
The inventive medicaments are likewise suitable with preference for prophylaxis and/or treatment of disorders or diseases which are mediated at least partly by vanilloid receptors 1.
The inventive medicament is therefore particularly suitable for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; for prophylaxis and/or treatment of one or more disorders selected from the group consisting of migraine; depression; urine incontinence; coughing; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease; Alzheimer's disease and multiple sclerosis; disorders of food uptake, preferably selected from the group consisting of bulimia, anorexia, obesity and cachexia; states of anxiety; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; diarrhea and pruritus; for prophylaxis and/or treatment of alcohol and/or drug and/or medicament abuse and alcohol and/or drug and/or medicament dependence, preferably for prophylaxis and/or reduction of withdrawal symptoms in the case of alcohol and/or drug and/or medicament dependence; for prophylaxis and/or reduction of evolution of tolerance to medicaments, especially medicaments based on opioids; for regulating food uptake; for modulating movement activity; for regulating the cardiovascular system; for local anesthesia; for enhancing vigilance, for enhancing libido; for diuresis and/or for antinatriuresis.
The inventive medicament is therefore particularly preferably suitable for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain; for prophylaxis and/or treatment of one or more disorders selected from the group consisting of migraine; depression; neurodegenerative disorders, preferably selected from the group consisting of Parkinson's disease, Huntington's disease, Alzheimer's disease and multiple sclerosis; states of anxiety; cognitive dysfunctions, preferably memory impairments; cognitive deficiencies (attention deficit syndrome, ADS); epilepsy; for prophylaxis and/or treatment of alcohol and/or drug and/or medicament abuse and alcohol and/or drug and/or medicament dependence, preferably for prophylaxis and/or reduction of withdrawal symptoms in the case of alcohol and/or drug and/or medicament dependence; for prophylaxis and/or reduction of evolution of tolerance to medicaments, especially medicaments based on opioids.
The inventive medicament is very particularly suitable for treatment and/or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, visceral pain and neuropathic pain.
The inventive medicament is suitable for administration to adults and children, including infants and babies. The inventive medicament may be present as a liquid, semisolid or solid medicament form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed to tablets, filled into capsules or suspended in a liquid, and may also be administered as such.
In addition to at least one 2,5-disubstituted thiazol-4-one derivative of the above-specified general formula I, optionally in the form of its pure stereoisomers, especially enantiomers or diastereomers, of its racemates or in the form of mixtures of the stereoisomers, especially of the enantiomers or diastereomers, in any mixing ratio, or optionally in the form of a corresponding salt or in each case in the form of a corresponding solvate, the inventive medicament typically comprises further physiologically compatible pharmaceutical assistants which may, for example, be selected from the group consisting of carrier materials, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, aromas and binders.
The selection of the physiologically compatible assistants and the amounts thereof to be used depends upon whether the medicament is to be administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example to infections on the skin, the mucous membranes and in the eyes. For oral application, suitable formulations are preferably those in the form of tablets, coated tablets, capsules, granules, pellets, drops, juices and syrups; suitable formulations for parenteral, topical and inhalative application are preferably solutions, suspensions, readily reconstitutable dry formulations and sprays.
The inventive 2,5-disubstituted thiazol-4-one derivatives used in the inventive medicament, in a depot, in dissolved form or in a plaster, optionally with addition of skin penetration-promoting agents, are suitable percutaneous administration formulations. Orally or percutaneously applicable formulation forms may also release the particular inventive 2,5-disubstituted thiazol-4-one derivative in a retarded manner.
The inventive medicaments are produced with the aid of conventional means, apparatus, methods and processes known from the prior art, as described, for example, in “Remington's Pharmaceutical Sciences”, editor A. R. Gennaro, 17th edition, Mack Publishing Company, Easton, Pa., 1985, more particularly in part 8, chapter 76 to 93. The corresponding description is hereby included as a reference and forms part of the disclosure.
The amount of the particular inventive 2,5-disubstituted thiazol-4-one derivatives of the above-specified general formula I to be administered to the patient may vary and is, for example, dependent on the weight or age of the patient and of the administration method, the indication and the severity of the disorder. Typically, from 0.001 to 100 mg/kg, preferably from 0.05 to 75 mg/kg, more preferably from 0.05 to 50 mg/kg, of body weight of the patient of at least one such inventive compound are administered.
The agonistic or antagonistic action of the substances to be studied on the vanilloid receptor 1 (VR1/TRPV1) of the rat species can be determined with the following assay. In this assay, the Ca2+ current through the receptor channel is quantified with the aid of a Ca2+-sensitive dye (Fluo-4 type, Molecular Probes Europe BV, Leiden the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
Complete medium: 50 ml HAMS F12 Nutrient Mixture (Gibco Invitrogen GmbH, Karlsruhe, Germany) with
10% by volume of FCS (fetal calf serum, Gibco Invitrogen GmbH, Karlsruhe, Germany, heat-inactivated);
1% by weight of AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria) and 25 ng/ml of NGF medium (2.5 S, Gibco Invitrogen GmbH, Karlsruhe, Germany)
Cell culture plate: poly-D-lysine-coated, black 96-hole plates with a clear bottom (96 well black/clear plate, BD Biosciences, Heidelberg, Germany) are additionally coated with laminin (Gibco Invitrogen GmbH, Karlsruhe, Germany) by diluting laminin to a concentration of 100 μg/ml with PBS (Ca—Mg-free PBS, Gibco Invitrogen GmbH, Karlsruhe, Germany). Aliquots having a concentration of 100 μg/ml of laminin are withdrawn and stored at −20° C. The aliquots are diluted with PBS in a ratio of 1:10 to 10 μg/ml of laminin and in each case 50 μl of the solution are pipetted into a well of the cell culture plate. The cell culture plates are incubated at 37° C. for at least two hours, the supernatant solution is removed by suction and the wells are each washed twice with PBS. The coated cell culture plates are stored with supernatant PBS which is not removed until directly before the application of the cells.
The spinal column is removed from beheaded rats and placed directly into cold HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany), i.e. placed in an ice bath, which has been admixed with 1% by volume of an AA solution (antibiotic/antimycotic solution, PAA, Pasching, Austria). The spinal column is severed longitudinally and removed from the spinal canal together with fasciae. Subsequently, the dorsal root ganglia (DRGs) are removed and in turn stored in cold HBSS buffer admixed with 1% by volume of an AA solution. The DRGs freed completely of blood residues and spinal nerves are in each case transferred to 500 μl of cold type 2 collagenase (PAA, Pasching, Austria) and incubated at 37° C. for 35 minutes. After addition of 2.5% by volume of trypsin (PAA, Pasching, Austria), incubation is continued at 37° C. for a further 10 minutes. After complete incubation, the enzyme solution is cautiously pipetted off and the remaining DRGs are each suspended with 500 μl of complete medium.
The DRGs are each suspended repeatedly, drawn through cannulas No. 1, No. 12 and No. 16 by means of a syringe and transferred to 50 ml Falcon tubes which are made up to 15 ml with complete medium. The contents of each Falcon tube are in each case filtered through a 70 μm Falcon filter insert and centrifuged at 1200 revolutions and room temperature for 10 minutes. The resulting pellet is in each case taken up in 250 μl of complete medium and the cell count is determined.
The number of cells in the suspension is adjusted to 3 times 105 per ml and in each case 150 μl of this suspension are added to one well of the cell culture plates coated as described above. In the incubator, the plates are left to stand at 37° C., 5% by volume of CO2 and 95% relative air humidity for two to three days.
Subsequently, the cells are laden with 2 μM Fluo-4 and 0.01% by volume of Pluronic F127 (Molecular Probes Europe BV, Leiden, the Netherlands) in HBSS buffer (Hank's buffered saline solution, Gibco Invitrogen GmbH, Karlsruhe, Germany) at 37° C. for 30 min, washed 3× with HBSS buffer and, after a further incubation of 15 minutes, used in the FLIPR assay at room temperature for Ca2+ measurement. The Ca2+-dependent fluorescence is measured before and after addition of substances (λex=488 nm, λem=540 nm). The quantification is effected by the measurement of the highest fluorescence intensity (FC, fluorescence counts) over the time.
The FLIPR protocol consists of 2 substance additions. First, the compounds to be tested (10 μM) are pipetted onto the cells and the Ca2+ current is compared with the control (capsaicin 10 μM). This gives rise to the result in % activation based on the Ca2+ signal after addition of 10 μM capsaicin (CP). After incubation for 5 minutes, 100 nM capsaicin is applied and the current of Ca2+ is likewise determined.
Desensitizing agonists and antagonists lead to a suppression in the Ca2+ current. % inhibition is calculated compared to the maximum achievable inhibition with 10 μM capsaicin.
Triple determinations (n=3) are performed and they are repeated in at least 3 independent experiments (N=4).
The agonistic or antagonistic action of the substances to be tested on vanilloid receptor (VR1) can also be determined with the assay which follows. In this assay, the Ca2+ current through the channel is quantified with the aid of a Ca2+-sensitive dye (Fluo-4 type, Molecular Probes, Europe BV, Leiden, the Netherlands) in a fluorescent imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, USA).
Chinese hamster ovary cells (CHO K1 cells, European Collection of Cell Cultures (ECACC) Great Britain) are transfected stably with the VR1 gene. For functional studies, these cells are plated out onto poly-D-lysine-coated black 96-well plates with a clear bottom (BD Biosciences, Heidelberg, Germany) in a density of 25 000 cells/well. The cells are incubated overnight at 37° C. and 5% CO2 in a culture medium (Ham's Nutrient Mixture F12, 10% by volume of FCS (fetal calf serum), 18 μg/ml of L-proline). The next day, the cells are incubated with Fluo-4 (Fluo-4 2 μM, Pluronic F127 0.01% by volume, Molecular Probes in HBSS (Hank's buffered saline solution), Gibco Invitrogen GmbH, Karlsruhe, Germany) at 37° C. for 30 minutes. Subsequently, the plates are washed 3 times with HBSS buffer and, after a further incubation of 15 minutes at room temperature, used for Ca2+ measurement in FLIPR. The Ca2+-dependent fluorescence is measured before and after addition of the substances to be studied (wavelength λex=488 nm, λem=540 nm). The quantification is effected by measuring the highest fluorescence intensity (FC, fluorescence counts) over the time.
The FLIPR protocol consists of 2 substance additions. First, the substances to be tested (10 μM) are pipetted onto the cells and the Ca current is compared with the control (capsaicin 10 μM) (% activation based on the Ca2+ signal after addition of 10 μM capsaicin). After incubation for 5 minutes, 100 nM capsaicin is applied and the current of Ca2+ is likewise determined.
The test to determine the antinociceptive action of the inventive 2,5-disubstituted thiazol-4-one derivatives is carried out in the formalin test on male mice (NMRI, body weight from 20 to 30 g, Iffa, Credo, Belgium).
In the formalin test, according to D. Dubuisson et al., Pain 1977, 4, 161-174, a distinction is drawn between the first (early) phase (from 0 to 15 minutes after the formalin injection) and the second (late) phase (from 15 to 60 minutes after the formalin injection). The early phase, as a direct reaction to the formalin injection, constitutes a model for acute pain, while the late phase is considered to be a model for persistent (chronic) pain (T. J. Coderre et al., Pain 1993, 52, 259-285). The corresponding literature descriptions are hereby included as a reference and form part of the disclosure.
The inventive 2,5-disubstituted thiazol-4-one derivatives are tested in the second phase of the formalin test in order to obtain statements regarding substance effects on chronic/inflammatory pain.
According to the administration type of the inventive compounds, the administration time of the inventive 2,5-disubstituted thiazol-4-one derivatives before the formalin injection is selected. The intravenous administration of 10 mg/kg of body weight of the test substances is effected 5 minutes before the formalin injection. This is done by a single subcutaneous formalin injection (20 μl, 1% aqueous solution) into the dorsal side of the right hind paw, such that a nociceptive reaction is induced in freely mobile test animals, which is manifested in obvious licking and biting of the paw affected.
Subsequently, for a test period of three minutes in the second (late) phase of the formalin test (from 21 to 24 minutes after the formalin injection), the nociceptive behavior is registered continuously by observing the animals. The pain behavior is quantified by summation of the seconds in which the animals exhibit licking and biting of the paw affected within the test period.
The comparison is in each case with control animals which, instead of the inventive compounds, receive vehicle (0.9% aqueous sodium chloride solution) before formalin administration. Based on the quantification of the pain behavior, the substance action in the formalin test is determined as the change relative to the corresponding control in percent.
After injection of substances which have antinociceptive activity in the formalin test, the behavior of the animals described, i.e. licking and biting, is reduced or eliminated.
The test of the inventive compounds of the general formula I for analgesic activity was carried out in phenylquinone-induced writhing in mice, modified according to I. C. Hendershot and J. Forsaith (1959), J. Pharmacol. Exp. Ther. 125, 237-240. The corresponding literature description is hereby included as a reference and forms part of the disclosure.
To this end, male NMRI mice with a weight of from 25 to 30 g were used. Groups of 10 animals per compound dose received, 10 minutes after intravenous administration of the compounds to be tested, 0.3 ml/mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, from Sigma, Deisenhofen, Germany; preparation of the solution with addition of 5% by weight of ethanol and storage in a water bath at 45° C.) which was applied intraperitoneally. The animals were placed individually into observation cages. With the aid of a push-button counter, the number of pain-induced stretching motions (so-called writhing reactions=arching of the back with stretching out of the rear extremities) was counted for from 5 to 20 minutes after the phenylquinone administration. The control employed was animals which had received only physiological saline. All compounds were tested in the standard dosage of 10 mg/kg.
The invention will be illustrated hereinafter with reference to examples. These illustrations are merely by way of example and do not restrict the general concept of the invention.
The yields of the compounds prepared are not optimized.
All temperatures are uncorrected.
The chemicals and solvents used were purchased commercially from the conventional suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized by methods known to those skilled in the art.
The stationary phase used for the column chromatography was silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt.
The thin layer chromatography analyses were carried out with ready-to-use HPTLC plates, silica gel 60 F 254, from E. Merck, Darmstadt.
The mixing ratios of solvents, eluents or for chromatographic analyses are always reported in volume/volume.
The analysis was effected by mass spectroscopy and NMR.
4-Hydroxy-3-methoxybenzonitrile (25 g, 167.7 mmol) was dissolved in EtOH (355 ml) and admixed with thioglycolic acid (18.8 g, 167.7 mmol) and triethylamine (12.2 g, 120.4 mmol). The solvent was reduced down to 150 ml under reduced pressure and the precipitated solid was filtered off with suction, washed with a little EtOH and diisopropyl ether and dried.
The mother liquor was reduced further down to 75 ml and cooled.
The further solid which had precipitated out was filtered off with suction, washed with a little EtOH and diisopropyl ether and dried.
The combined precipitates were heated to reflux again in EtOH (50 ml). The precipitated solid was filtered off with suction, washed with a little EtOH and diisopropyl ether and dried. The desired product was obtained in a yield of 37% of theory (13.9 g).
2-(4-Hydroxy-3-methoxyphenyl)thiazol-4-one (1.34 mmol, 300 mg) and 4-methyl-benzaldehyde (194 mg, 1.61 mmol) were dissolved in acetic acid (7 g, 117.5 mmol) and admixed with sodium acetate (408 mg, 4.972 mmol). The reaction mixture was heated to reflux overnight and admixed with water, and the resulting precipitate was washed with butanol and diisopropyl ether and dried. The desired product was obtained as a solid (323 mg, 74% of theory).
Cyanomorpholine (15.3 g, 136.3 mmol) and thioglycolic acid (12.5 g, 136.3 mmol) were introduced into a reaction vessel with pyridine (12.2 ml). The reaction vessel was heated to 10° C. in a Pyrex tube. After one hour, the reaction was ended and the mixture was cooled.
The resulting precipitate was filtered off with suction, washed with a little EtOH and diisopropyl ether and dried. The desired product was obtained as a white solid (21.5 g, 85% of theory).
2-Morpholin-4-ylthiazol-4-one (500 mg, 2.7 mmol) and n-decanal (503 mg, 3.22 mol) were dissolved in EtOH (10 ml) and admixed with triethylamine (815 mg). The reaction mixture was heated to reflux for 48 h. The precipitated solid was filtered off with suction and dried. For further purification, the precipitate was heated in a little butanol (3 ml). The further solid which had precipitated out was filtered off with suction and dried. The desired product was obtained as a solid (82 mg, 10% of theory).
2-Morpholin-4-yl-thiazol-4-one (1 g, 5.4 mmol) and 3-phenoxybenzaldehyde (1.27 g, 6.43 mmol) were dissolved in acetic acid (28 g) and admixed with sodium acetate (1.63 g, 19.9 mmol). The reaction mixture was heated to reflux overnight and stirred at RT for 24 h, and the resulting precipitate was washed with butanol and diisopropyl ether and dried. The desired product was obtained as a solid (1.37 g, 70% of theory).
2-Morpholin-4-ylthiazol-4-one (530 mg, 2.85 mmol) and 3-p-tolylpropenal (500 mg, 3.42 mmol) were dissolved in acetic acid (15 g) and admixed with sodium acetate (865 mg, 10.5 mmol). The reaction mixture was heated to reflux for 5 h and stirred at RT for 48 h. The solvent was removed under reduced pressure and the residue was taken up in water and EtOAc. The organic phase was dried over magnesium sulfate, the solvent was removed under reduced pressure and the residue was dried. The residue was heated in butanol (20 ml) and the precipitated solid was washed with a little diisopropyl ether and dried. The desired product was obtained as a solid (224 mg, 21% of theory).
2-Morpholin-4-ylthiazol-4-one (500 mg, 2.7 mmol) and diphenylacrolein (670 mg, 3.22 mol) were dissolved in EtOH (10 ml) and admixed with triethylamine (815 mg). The reaction mixture was heated to reflux for 48 h. The precipitated solid was filtered off with suction and dried. The desired product was obtained as a solid (862 mg, 85% of theory).
1,1′-Thiocarbonyldiimidazole (45.4 g, 254 mmol) was suspended in THF (605 g). Thiomorpholine (25 g, 242.6 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (346 g) was added thereto and the reaction mixture was stirred at 40° C. overnight. The solvent was removed under reduced pressure, and the residue was washed with a little cold butanol and ether and dried. The desired product was obtained in an amount of 31.5 g.
Thiomorpholine-4-thiocarboxamide (38 g, 234 mmol) was suspended with chloroacetic acid (23 g, 243 mmol) in pyridine (87 g). The suspension was heated in a microwave vessel for 45 min and left to stand overnight. The precipitated solid was filtered off with suction, washed with a little butanol and ether and dried. The desired product was obtained as a solid (21.7 g, 46% of theory).
2-Thiomorpholin-4-ylthiazol-4-one (800 mg, 3.96 mmol) and alpha-chloro-cinnamaldehyde (789 mg, 4.752 mmol) were dissolved in acetic acid (21 g) and admixed with sodium acetate (1.2 g, 14.6 mmol). The reaction mixture was heated to reflux for 4 h and added to water (100 ml). The aqueous phase was extracted with DCM and the solvent was removed under reduced pressure. The aqueous phase was left to stand overnight. A second phase formed, which was concentrated under reduced pressure. The residue was heated in butanol (1 ml) and the precipitated solid was washed with a little diisopropyl ether and dried. The desired product was obtained as a solid (138 mg, 10% of theory).
2-Thiomorpholin-4-ylthiazol-4-one (5 g, 25 mmol) and 3-carboxybenzaldehyde (4.45 g, 29.7 mmol) were dissolved in acetic acid (130 g) and admixed with sodium acetate (7.5 g, 91.5 mmol). The reaction mixture was heated to reflux overnight. After cooling, a precipitate formed, which was filtered off with suction, washed with water, butanol and diisopropyl ether and dried. The desired product was obtained as a solid (4.91 g, 60% of theory).
piperazine (22.4 g, 260.2 mmol) was dissolved in DMSO (462 g) and admixed with 2,6-dichloropyridine (35 g, 236 mmol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was admixed with portions of sat. aq. sodium hydrogencarbonate solution (250 ml in total), and the resulting precipitate was filtered off with suction. The filtrate was extracted repeatedly with EtOAc and the combined organic phases were dried, and the solvent was removed under reduced pressure. The residue was distilled at 2.5-1 mbar. The product was obtained at top temperature 120° C. and bottom temperature 165° C. Yield: 17.7 g (38% of theory).
3-(4-Oxo-2-thiomorpholin-4-yl-4H-thiazol-5-ylidenemethyl)benzoic acid (500 mg, 1.5 mmol), 1-(6-chloropyridin-2-yl)piperazine (295 mg, 1.5 mmol), TBTU (480 mg, 1.5 mmol), HOBT (201 mg, 1.5 mmol) and diisopropylethylamine (643 mg, 4.5 mmol) were dissolved in THF (10 ml) and stirred at RT overnight. The resulting precipitate was filtered off with suction, washed with EtOAc and ether, and dried.
Yield: 579 mg (75% of theory)
3-(4-Oxo-2-thiomorpholin-4-yl-4H-thiazol-5-ylidenemethyl)benzoic acid (500 mg, 1.5 mmol), 1-(2-chloro-4-(trifluoromethyl)phenyl)hydrazine (315 mg, 1.5 mmol), TBTU (480 mg, 1.5 mmol), HOBT (201 mg, 1.5 mmol) and diisopropylethylamine (643 mg, 4.5 mmol) were dissolved in THF (10 ml) and stirred at RT for 48 h. The resulting precipitate was filtered off with suction, washed with EtOAc and ether, and dried.
Yield: 305 mg (39% of theory).
Piperazine (15 g, 174 mmol) was dissolved in DMSO (309 g) and admixed with 2,3-dichloropyridine (23.4 g, 158 mmol). The reaction mixture was stirred at 110° C. for 60 h. The reaction mixture was admixed with portions of sat. aq. sodium hydrogencarbonate solution (250 ml in total), and the resulting precipitate was filtered off with suction. The filtrate was extracted repeatedly with EtOAc (150 ml each time) and the combined organic phases were dried, and the solvent was removed under reduced pressure. The residue was distilled at 2.1-1 mbar. The product was obtained at top temperature 95° C. and bottom temperature 155° C. Yield: 9.6 g (28% of theory).
1,1′-Thiocarbonyldiimidazole (3.8 g, 21.2 mmol) was suspended in THF (23.4 g). 1-(3-Chloropyridin-2-yl)piperazine (4 g, 20.2 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (28.9 g) was added thereto and the reaction mixture was stirred at 40° C. overnight. The solvent was removed under reduced pressure, and the residue was washed with a little cold butanol and ether and dried. The desired product was obtained in an amount of 4.1 g (78% of theory).
4-(3-Chloropyridin-2-yl)piperazine-1-thiocarboxamide (8.1 g, 31.9 mmol) was suspended with chloroacetic acid (3.1 g, 33.1 mmol) in EtOH (7 g). The suspension was heated to 85° C. in a microwave vessel for 60 min and left to stand overnight. The precipitated solid was filtered off with suction, washed with a little butanol and ether and dried. The precipitate was heated in a little butanol (10 ml) and the remaining solid was filtered off with suction. The desired product was obtained as a solid (2.34 g, 25% of theory).
2-[4-(3-Chloropyridin-2-yl)piperazin-1-yl]thiazol-4-one (500 mg, 1.7 mmol) and vanillin (308 mg, 2.02 mmol) were dissolved in acetic acid (9 g) and admixed with sodium acetate (514 mg, 6.3 mmol). The reaction mixture was heated to reflux overnight. After cooling, a precipitate formed, which was filtered off with suction, washed with diisopropyl ether and dried. The precipitate was heated in a little butanol (8 ml) and hot-filtered. The precipitate was discarded and the filtrate was left to stand. The resulting precipitate was filtered off with suction and dried. The desired product was obtained as a solid (157 mg, 22% of theory).
2-[4-(3-Chloropyridin-2-yl)piperazin-1-yl]thiazol-4-one (500 mg, 1.7 mmol) and naphthalene-2-carbaldehyde (263 mg, 1.7 mmol) were dissolved in EtOH (10 ml) and admixed with triethylamine (512 mg, 5.1 mmol). The reaction mixture was heated to reflux for 72 h. After cooling, a precipitate formed, which was filtered off with suction, washed with butanol and diisopropyl ether and dried. The desired product was obtained as a solid (295 mg, 40% of theory).
2-[4-(3-Chloropyridin-2-yl)piperazin-1-yl]thiazol-4-one (500 mg, 1.7 mmol) and 3-quinolinecarboxaldehyde (318 mg, 2.02 mmol) were dissolved in acetic acid (9 g) and admixed with sodium acetate (514 mg, 6.3 mmol). The reaction mixture was heated to reflux overnight. After cooling, the mixture was admixed with water (100 ml). The precipitate formed was filtered off with suction and heated in a little butanol (4 ml). The precipitate formed was filtered off with suction, washed with a little butanol and ether and dried. The desired product was obtained as a solid (367 mg, 50% of theory).
1,1′-Thiocarbonyldiimidazole (18 g, 101.2 mmol) was suspended in THF (112 g). 1-Benzylpiperazine (17 g, 96.5 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (137 g) was added thereto and the reaction mixture was stirred at 40° C. overnight. The solvent was removed under reduced pressure, and the residue was heated in a little butanol (25 ml). After cooling, a precipitate was obtained, which was washed with a little cold butanol and ether and then dried. The desired product was obtained in an amount of 14.1 g.
4-Benzylpiperazine-1-thiocarboxamide (14 g, 59.5 mmol) was suspended with chloroacetic acid (5.8 g, 61.9 mmol) in pyridine (55 g). The suspension was heated to 120° C. in a microwave vessel for 45 min. The reaction mixture was concentrated fully under reduced pressure and the residue was heated in MeOH (150 ml). The precipitated solid was filtered off with suction, washed with ether and dried. The desired product was obtained as a solid (8.9 g, 55% of theory).
2-(4-Benzylpiperazin-1-yl)thiazol-4-one (500 mg, 1.8 mmol) and 4-tert-butyl-benzaldehyde (353 mg, 2.18 mmol) were dissolved in acetic acid (9.5 g) and admixed with sodium acetate (552 mg, 6.7 mmol). The reaction mixture was heated to reflux overnight. After cooling, the mixture was admixed with water (50 ml). The precipitate formed was filtered off with suction and heated in a little butanol (1 ml). The resulting precipitate was filtered off with suction, washed with a little butanol and ether and dried. The desired product was obtained as a solid (245 mg, 32% of theory).
2-(4-Benzylpiperazin-1-yl)thiazol-4-one (350 mg, 1.3 mmol) and 4-(pentafluorosulfanyl)benzaldehyde (353 mg, 1.52 mmol) were dissolved in acetic acid (6.7 g) and admixed with sodium acetate (387 mg, 4.7 mmol). The reaction mixture was heated to reflux overnight. The resulting precipitate was filtered off with suction, washed with a little butanol and ether and dried. The desired product was obtained as a solid (108 mg).
1,1′-Thiocarbonyldiimidazole (12.5 g, 70.4 mmol) was suspended in THF (167 g). 4-tert-Butylaniline (10 g, 67 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (95 g) was added thereto and the reaction mixture was stirred at 40° C. for 48 h. The solvent was removed under reduced pressure and the residue was heated in a little butanol (25 ml). After cooling, a precipitate was obtained, which was washed with a little cold butanol and ether and then dried. The desired product was obtained in an amount of 14 g.
(4-tert-Butylphenyl)thiourea (14 g, 68.7 mmol) was suspended with chloroacetic acid (6.7 g, 71.49 mmol) in EtOH (15 g). The suspension was heated to 85° C. in a microwave vessel for 60 min. The precipitated solid was filtered off with suction, washed with a little butanol and diisopropyl ether and dried. The desired product was obtained as a solid (4.9 g).
2-(4-tert-Butylphenylamino)thiazol-4-one (550 mg, 2.2 mmol) and 4-methylbenzaldehyde (319 mg, 1.02 mmol) were dissolved in acetic acid (11.6 g) and admixed with sodium acetate (673 mg, 8.2 mmol). The reaction mixture was heated to reflux for 5 h and stirred at RT for 72 h. The resulting precipitate was filtered off with suction, washed with a little water and hexane and dried. The desired product was obtained as a solid (525 mg, 67% of theory).
1,1′-Thiocarbonyldiimidazole (12.3 g, 69.5 mmol) was suspended in THF (167 g). 3,4-Methylenedioxybenzylamine (10 g, 66.2 mmol) was dissolved in a little THF and added to the suspension. The reaction mixture was stirred at RT for 1 h. 7 N ammonia solution in MeOH (94.5 g) was added thereto and the reaction mixture was stirred at 40° C. for 24 h. The solvent was removed under reduced pressure and the residue was heated in a little butanol (15 ml). After cooling, a precipitate was obtained, which was washed with a little cold butanol and ether and then dried. The desired product was obtained in an amount of 11.1 g (80% of theory).
Benzo[1.3]dioxol-5-ylmethylthiourea (11 g, 52.4 mmol) was suspended with chloroacetic acid (5.1 g, 54.4 mol) in pyridine (20 g). The suspension was heated to 110° C. in a microwave vessel for 60 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved with a little butanol (15 ml) while heating. After cooling, a precipitate formed, which was filtered off with suction, washed with a little butanol and diisopropyl ether and dried. The desired product was obtained as a solid (4.0 g, 30% of theory).
2-[(Benzo[1,3]dioxol-5-ylmethyl)amino]thiazol-4-one (350 mg, 1.4 mmol) and 4-(trifluoromethoxy)benzaldehyde (319 mg, 1.68 mmol) were dissolved in acetic acid (7.3 g) and admixed with sodium acetate (425 mg, 5.2 mmol). The reaction mixture was heated to reflux for 14 h. The reaction mixture was admixed with water (30 ml), and the resulting precipitate was filtered off with suction, washed with a little water and hexane and dried. The desired product was obtained as a solid (460 mg, 78% of theory).
Thiourea (30 g, 395 mmol) was suspended with chloroacetic acid (38.7 g, 410 mol) in pyridine (146 g). The suspension was heated in a microwave vessel for 45 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOH (250 ml) while heating. After cooling, a precipitate formed, which was filtered off with suction, washed with ether and dried. The desired product was obtained as a solid (26.9 g).
2-Aminothiazol-4-one (6 g, 51.7 mmol) and 4-(trifluoromethyl)benzaldehyde (10.8 g, 62 mmol) were dissolved in acetic acid (271 g) and admixed with sodium acetate (15.7 g, 191 mmol). The reaction mixture was heated to reflux for 5 h. The reaction mixture was admixed with water (30 ml), and the resulting precipitate was filtered off with suction, washed with EtOH and ether and dried. The desired product was obtained as a solid (8.8 g, 63% of theory).
2-Amino-5-(4-trifluoromethylbenzylidene)-4-thiazol-4-one (436 mg, 1.6 mmol) was dissolved in DMSO (28 g) and admixed with triethylamine (179 mg, 1.76 mmol) and 1-isocyanato-4-trifluoromethylbenzene (436 mg, 1.6 mmol). The reaction mixture was stirred at RT overnight and added to ice-water (50 ml). The resulting precipitate was filtered off with suction and heated to reflux in a little acetone. A little water was added thereto and the reaction mixture was left to stand. The resulting precipitate was filtered off with suction, washed with water and dried. The desired product was obtained as a white solid (553 mg, 75% of theory).
The following inventive 2,5-disubstituted thiazol-4-one derivatives were prepared as described under 1. to 8.
The affinity of the inventive 2,5-disubstituted thiazol-4-one derivatives for vanilloid receptor 1 (VR1/TRPV1 receptor) was determined as described above.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2005 024 012.7 | May 2005 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/004666 | 5/17/2006 | WO | 00 | 6/10/2008 |
