EP1968958A1 - Thiazoles substitues et leur utilisation pour produire des medicaments - Google Patents

Thiazoles substitues et leur utilisation pour produire des medicaments

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Publication number
EP1968958A1
EP1968958A1 EP06829856A EP06829856A EP1968958A1 EP 1968958 A1 EP1968958 A1 EP 1968958A1 EP 06829856 A EP06829856 A EP 06829856A EP 06829856 A EP06829856 A EP 06829856A EP 1968958 A1 EP1968958 A1 EP 1968958A1
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EP
European Patent Office
Prior art keywords
group
unsubstituted
butyl
phenyl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06829856A
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German (de)
English (en)
Inventor
Michael Haurand
Klaus Schiene
Sven KÜHNERT
Melanie Reich
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Gruenenthal GmbH
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Gruenenthal GmbH
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Publication of EP1968958A1 publication Critical patent/EP1968958A1/fr
Withdrawn legal-status Critical Current

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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted thiazoles, processes for their preparation, medicaments containing these compounds and their use for the preparation of medicaments.
  • Classic opioids such as morphine
  • Classic opioids are effective in the treatment of severe to very severe pain, but often lead to undesirable side effects such as respiratory depression, vomiting, sedation, constipation or tolerance development. Furthermore, they are often not sufficiently effective in neuropathic pain, which particularly affects cancer patients.
  • An object of the present invention was therefore to provide novel compounds which are particularly suitable as pharmaceutical active ingredients in medicaments, preferably in medicaments for the treatment of pain.
  • substituted thiazoles of the general formula I given below are suitable for mGluR ⁇ receptor regulation and therefore in particular as pharmaceutical active ingredients in medicaments for the prophylaxis and / or treatment of disorders associated with these receptors or processes Diseases can be used.
  • An object of the present invention are therefore substituted thiazoles of general formula I,
  • R 1 and R 2 together with the carbon atoms connecting them form an unsubstituted or at least monosubstituted phenylene radical
  • n 2, 3, 4, 5 or 6;
  • R 6 and R 10 together with the linking -CR 7 -CR 8 R 9 -N- group is a radical of the general formula D,
  • p and q are each 1, 2, 3, 4 or 5;
  • each of r and s is 2, 3 or 4;
  • R 4 and R 8 together with their linking -CR 5 -CR 6 R 7 -CR 9 group is a radical of the general formula G,
  • t is 1, 2, 3, 4 or 5;
  • R 3 and R 10 together with their linking -N-CR 4 R 5 -CR 6 R 7 -CR 8 R 9 - group is a radical of the general formula H,
  • u 3 or 4;
  • v and w independently of one another, are each 1, 2 or 3;
  • R 11 is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl; stands;
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are each unsubstituted or substituted alkyl, alkenyl or alkynyl; unsubstituted or substituted heteroalkyl, heteroalkenyl or heteroalkynyl; unsubstituted or substituted cycloalkyl or cycloalkenyl; unsubstituted or substituted heterocycloalkyl or heterocycloalkenyl; unsubstituted or substituted - (alkylene) cycloalkyl, - (alkenylene) cycloalkyl, - (alkynylene) cycloalkyl, - (alkylene) cycloalkyl, independently of one another
  • alkyl embraces in the sense of the present invention acyclic saturated hydrocarbon residues which may be branched or straight chained and unsubstituted or at least monosubstituted with as in the case of Ci- 12 alkyl 1 to 12 (ie, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) C-atoms or with as in the case of Ci -6 - alkyl is 1 to 6 (ie, 1, 2, 3, 4, 5 or 6) C- If one or more of the substituents are an alkyl radical or have an alkyl radical which is monosubstituted or polysubstituted, this may preferably have 1, 2, 3, 4 or 5, more preferably 1, 2, if appropriate or 3, substituents independently of one another selected from the group consisting of F, Cl, Br, I, -NO 2 , -CN 1 -OH, -SH, -NH 2 , - N (C 1-5 -alkyl) 2 , - N (C 1-5 alkyl) (
  • substituents can be independently selected from the group consisting of F, Cl, Br, I, -NO 2, -CN, -OH, -SH, -NH 2, - N (CHa) 2, -N (C 2 Hs) 2 and -N (CH 3 ) (C 2 H 5 ).
  • Suitable C- ⁇ -i 2 alkyl radicals which may be unsubstituted or mono- or polysubstituted are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n -Pentyl, 2-pentyl, 3-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, n-octyl, -C (H) (C 2 H 5 ) 2 , -C (H) (nC 3 H 7 ) 2 and -CH 2 - CH 2 -C (H) (CH 3 ) - (CH 2 ) 3 -CH 3 .
  • Ci -6 alkyl radicals include, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl , neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl.
  • multiply substituted alkyl radicals are meant those alkyl radicals which are monosubstituted, preferably triply or twice, at different or identical carbon atoms, for example, three times at the same carbon atom as in the case of -CF 3 or in different places as in the case of - (CHCI) - (CH 2 F). Multiple substitution can be with the same or different substituents.
  • substituted alkyl radicals for example -CF 3 , -CF 2 H, - CFH 2 , - (CH 2 J-OH, - (CH 2 J-NH 2 , - (CH 2 J-CN, - (CH 2 HCF 3 ), - (CH 2 HCHF 2 ), - (CH 2 ) - (CH 2 F), - (CH 2 ) - (CH 2 ) -OH, - (CH 2 ) - (CH 2 ) -NH 2 , - (CH 2 ) - (CH 2 ) -CN, - (CF 2 HCF 3 ), - (CH 2 ) - (CH 2 HCF 3 ) and - (CH 2 ) - (CH 2 ) - (CH 2 ) Called -OH.
  • alkenyl in the context of the present invention comprises acyclic unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or at least monosubstituted and have at least one double bond, preferably 1, 2 or 3 double bonds, as in the case of C 2 i 2 alkenyl 2 to 12 (ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms or with as in the case of C 2-6 alkenyl 2 to 6 (ie 2, 3, 4, 5 or 6) C atoms
  • substituents are an alkenyl radical or have an alkenyl radical which is monosubstituted or polysubstituted, this may preferably be substituted by 1, if appropriate, 2, 3, 4 or 5, more preferably 1, 2 or 3, substituents independently selected from the group consisting of F, Cl, Br, I, -NO 2 , -CN, -OH, -SH, -NH 2 , -N (C 1-5 alky
  • substituents may be independently selected from the group consisting of F, Cl, Br, I, -NO 2 , -CN, -OH, -SH, -NH 2 , -N (CH 3 ) 2 , -N (C 2 Hs) 2 and -N (CH 3 ) (C 2 H 5 ).
  • the multiple substitution can be made with the same or different substituents
  • alkynyl in the context of the present invention comprises acyclic unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or at least monosubstituted and have at least one triple bond, preferably 1 or 2 triple bonds, as in the case of C 2 -i 2 Alkynyl 2 to 12 (ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms or with as in the case of C 2-6 alkynyl 2 to 6 (ie 2, 3, 4, 5 or 6) carbon atoms
  • this radical may preferably have 1, 2, 3, 4 or 5, particularly preferably with optionally 1 or 2, substituents independently of one another selected from the group consisting of F, Cl, Br, I, -NO 2 , -CN, -OH, -SH, -NH 2 , - N (C
  • substituents can be independently selected from the group consisting of F, Cl, Br 1 1 1 -NO 2 , -CN, -OH, -SH, -NH 2 , -N (CH 3 ) 2 , -N (C 2 Hs) 2 and -N (CH 3 ) (C 2 H 5 ).
  • Suitable C 2 i 2 alkynyl radicals include for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and called hexynyl.
  • multiply substituted alkynyl radicals are meant those alkynyl radicals which are either multiply substituted on different C atoms, for example twice on different C atoms as in the case of -CHCl-C ⁇ CCI.
  • suitable substituted alkynyl radicals are -C ⁇ C-F, -C ⁇ C-Cl and -C ⁇ C-I.
  • heteroalkyl refers to an alkyl radical as described above in which one or more C atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH).
  • Heteroalkyl radicals may preferably have 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain member (s).
  • Heteroalkyl radicals may preferably be 2- to 12-membered, particularly preferably 2- to 6-membered.
  • Suitable heteroalkyl radicals which may be unsubstituted or monosubstituted or polysubstituted are, for example, -CH 2 -O-CH 3 , -CH 2 -OC 2 H 5 , -CH 2 -O- CH (CH 3 ) 2 , - CH 2 -OC (CH 3 ) 3 , -CH 2 -S-CH 3 , -CH 2 -SC 2 H 5 , -CH 2 -S-CH (CH 3 ) 2) -CH 2 -SC (CHa ) 3 , -CH 2 -NH-CH 3 , -CH 2 -NH-C 2 H 5 , -CH 2 -NH-CH (CH 3 ) 2 , -CH 2 -NH-C (CH 3 ) 3 , - CH 2 - CH 2 -O-CH 3 , -CH 2 -CH 2 -OC 2 H 5 , -CH 2 -CH 2 -O-CH (CH 3
  • Suitable substituted heteroalkyl radicals are - (CH 2 ) -O- (CF 3 ), - (CH 2 JO- (CHF 2 ), - (CH 2 ) -O- (CH 2 F), - (CH 2 ) -S- (CF 3 ), - (CH 2 JS- (CHF 2 ), - (CH 2 JS- (CH 2 F) 1 - (CH 2 ) - (CH 2 ) -O- (CF 3 ), - (CF 2 ) -O- (CF 3 ), - (CH 2 ) - (CH 2 ) -S- (CF 3 ) and - (CH 2 ) - (CH 2 ) - (CH 2 ) -O- ( CF 3 ) called.
  • heteroalkenyl refers to an alkenyl radical as described above in which one or more carbon atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH).
  • Heteroalkenyl radicals may preferably have 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain link (s).
  • Heteroalkenyl radicals may preferably be 2- to 12-membered, more preferably 2- to 6-membered.
  • heteroalkynyl denotes an alkynyl radical as described above in which one or more C atoms have each been replaced by a heteroatom selected independently of one another from the group consisting of oxygen, sulfur and nitrogen (NH).
  • Heteroalkynyl radicals can preferably have 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain link (s).
  • Heteroalkynyl radicals can preferably be 2- to 12-membered, particularly preferably 2- to 6-membered, be.
  • heteroalkynyl radicals are -CH 2 -OC ⁇ CH, -CH 2 -CH 2 -O-C ⁇ CH, -CH 2 -OC ⁇ C-CH 3 , -CH 2 -CH 2 -OC ⁇ C- CH 3 , -CH 2 -SC ⁇ CH, -CH 2 -CH 2 -SC ⁇ CH, -CH 2 -SC ⁇ C-CH 3 , -CH 2 -CH 2 -SC ⁇ C-CH 3 called.
  • Suitable substituted heteroalkynyl radicals are -CH 2 -OC ⁇ C-Cl, -CH 2 -CH 2 -OC ⁇ Cl, -CHF-OC ⁇ C-CHs, -CHF-CH 2 -OC ⁇ C-CH 3 , -CH 2 -SC ⁇ C-CI, - CH 2 -CH 2 -SC ⁇ C-CI, -CHF-SC ⁇ C-CH 3 , -CHF-CH 2 -SC ⁇ C-CH 3 called.
  • cycloalkyl in the context of the present invention means a cyclic saturated hydrocarbon radical having preferably 3, 4, 5, 6, 7, 8 or 9 C atoms, particularly preferably 3, 4, 5, 6 or 7 C atoms. Atoms, most preferably having 5 or 6 carbon atoms, where the radical may be unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • C 3-9 -cycloalkyl radicals which may be unsubstituted or monosubstituted or polysubstituted are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
  • Suitable C 3-7 cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkenyl in the context of the present invention means a cyclic unsaturated hydrocarbon radical having preferably 3, 4, 5, 6, 7, 8 or 9 C atoms, particularly preferably 3, 4, 5, 6 or 7 C atoms. Atoms, most preferably having 5 or 6 carbon atoms, which has at least one double bond, preferably a double bond, and unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • Suitable C 3-9 -cycloalkenyl radicals which may be unsubstituted or monosubstituted or polysubstituted are cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclononenyl and cyclooctenyl.
  • Suitable Cs- ⁇ -cycloalkenyl radicals are cyclopentenyl and cyclohexenyl.
  • heterocycloalkyl in the context of the present invention means a cyclic saturated hydrocarbon radical having preferably 3, 4, 5, 6, 7, 8 or 9 C atoms, particularly preferably 3, 4, 5, 6 or 7 C atoms.
  • Atoms very particularly preferably having 5 or 6 C atoms, in which one or more C atoms have in each case been replaced by a heteroatom independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH)
  • Heterocycloalkyl radicals may preferably be 1 , 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as ring member (s)
  • a heterocycloalkyl radical may be unsubstituted or monosubstituted or polysubstituted by identical or different heterocycloalkyl
  • Residues may preferably be 3- to 9-membered, particularly preferably 3- to 7-membered, very particularly preferably 5- to 7-membered.
  • Suitable 3- to 9-membered heterocycloalkyl radicals which may be unsubstituted or mono- or polysubstituted are imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, azepanyl, azocanyl, diazepanyl, Dithiolanyl, (1, 3) -dioxolan-2-yl, isoxazolidinyl, isothioazolidinyl, pyrazolidinyl, oxazolidinyl, (1, 2,4) -oxadiazolidinyl, (1, 2,4) -thiadiazolidinyl, (1, 2,4) - Triazolidin-3-yl, (1, 3,4) -thiadiazolidin
  • Suitable 5- to 7-membered heterocycloalkyl radicals are imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, azepanyl, diazepanyl and (1,3) -dioxolan-2-yl.
  • heterocycloalkenyl in the context of the present invention means a cyclic unsaturated hydrocarbon radical having preferably 4, 5, 6, 7, 8 or 9 C atoms, more preferably having 4, 5, 6 or 7 C atoms, very particularly preferably having 5 or 6 C atoms, which has at least one double bond, preferably a double bond, and in which one or more C atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH)
  • Heterocycloalkenyl radicals may preferably 1, 2 or 3 heteroatom (s) independently selected from the group consisting of oxygen, sulfur and nitrogen (NH) as a ring member (s).
  • a heterocycloalkenyl radical can be unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • Heterocycloalkenyl radicals may preferably be 4- to 9-membered, more preferably 4-7-membered, most preferably 5-7-membered.
  • heterocycloalkenyl radicals or of suitable 5- to 7-membered heterocycloalkenyl radicals which may be unsubstituted or monosubstituted or polysubstituted are (2,3) -dihydrofuranyl, (2,5) -dihydrofuranyl, (2, 3) - dihydrothienyl, (2,5) -dihydrothienyl, (2,3) -dihydropyrrolyl, (2,5) -dihydropyrrolyl, (2,3) -dihydroisoxazolyl, (4,5) -dihydroisoxazolyl, (2,5) Dihydroisothiazolyl, (2,3) -dihydropyrazolyl, (4,5) -dihydropyrazolyl, (2,5) -dihydropyrazolyl, (2,3) -dihydrooxazolyl, (4,5) -dihydrooxazolyl, (2,3)
  • the cycloalkyl radicals, heterocycloalkyl radicals, cycloalkenyl radicals or heterocycloalkenyl radicals may be condensed (fused) with an unsubstituted or at least monosubstituted monocyclic or bicyclic ring system.
  • a monocyclic or bicyclic ring system is understood as meaning monocyclic or bicyclic hydrocarbon radicals which may be saturated, unsaturated or aromatic and may optionally have one or more heteroatoms as ring members.
  • the rings of the abovementioned monocyclic or bicyclic ring systems are each 4-, 5- or 6-membered and may each preferably preferably be 0, 1, 2, 3, 4 or 5 heteroatom (s), particularly preferably 0, Have 1 or 2 heteroatom (s) as a ring member (s) independently selected from the group consisting of oxygen, nitrogen and sulfur. If a bicyclic ring system is present, the different rings, each independently of one another, can have a different degree of saturation, ie be saturated, unsaturated or aromatic.
  • Suitable cycloalkyl radicals, heterocycloalkyl radicals, cycloalkenyl radicals or heterocyclalkenyl radicals which may be unsubstituted or monosubstituted or polysubstituted and which are condensed with a monocyclic or bicyclic ring system are exemplified by (1,2,3,4 ) -Tetrahydroquinolinyl, (1, 2,3,4) -tetrahydroisoquinolinyl, (2,3) -dihydro-1H-isoindolyl, (1,2,3,4) -tetrahydronaphthyl, (2,3) -dihydrobenzo [1.4] dioxinyl, benzo [1.3] dioxolyl, (3,4) -dihydro-2H-benzo [1,4] oxazinyl and octahydro-pyrrolo [3,4-c] pyrrolyl.
  • substituents are a cycloalkyl radical, heterocycloalkyl radical, cycloalkenyl radical or heterocyclalkenyl radical or have such a radical which is monosubstituted or polysubstituted, this may preferably have 1, 2, 3, 4, if appropriate or 5, particularly preferably with optionally 1, 2 or 3, substituents independently of one another selected from the group consisting of F, Cl, Br, I 1 -CN, -CF 3 , -OH, -NH 2 , -O-CF 3 , -SH, -O-C 1-5 alkyl, -O-phenyl, -0-CH 2 - phenyl, - (CH 2) -OC 1-5 alkyl, -SC 1-5 alkyl, -S-phenyl , -S-CH 2 -phenyl, -C 1-5 -alkyl, -C 2- s -alkenyl, -C 2-5 -alkynyl
  • Ci -5 alkyl radicals may be linear or branched and each of the phenyl radicals each unsubstituted or with 1, 2, 3, 4 or 5, preferably with 1, 2, 3 or 4, substituents independently selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -OH , -NH 2 , -O-CF 3 , -SH, -O-Ci -5- alkyl, -O-phenyl, -O-CH 2 - phenyl, - (CH 2 JOC 1 -5- alkyl, -SC 1
  • the substituents in each case independently of one another, can be selected from the group consisting of F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl Butyl, ethenyl, allyl, ethynyl, propynyl, -C ⁇ C-Si (CH 3 ) 3 , -C ⁇ C-Si (C 2 H 5 ) 3 , -OH, oxo, thioxo, -O-CH 3 , - 0-C 2 H 5 , -O-C 3 H 7 , - (CH 2 JO-CH 3 , - (CH 2 ) OC 2 H 5 , -NH 2 , -N (CH 3 ) 2 , -N (C 2 H 5 ) 2 , -NH-CH 3
  • phenylene refers to a bivalent 6-membered aromatic hydrocarbon radical of the following structure:
  • R 1 and R 2 together with the carbon atoms connecting them form an unsubstituted or at least monosubstituted phenylene radical
  • an unsubstituted or at least monosubstituted benzothiazolyl radical of the following structure is formed together with the thiazolyl radical of the general formula I:
  • aryl means a monocyclic or polycyclic, preferably a monocyclic or bicyclic, aromatic hydrocarbon radical having preferably 6, 10 or 14 carbon atoms
  • An aryl radical may be unsubstituted or monosubstituted or polysubstituted Examples of suitable aryl radicals which may be mentioned are phenyl, 1-naphthyl, 2-naphthyl and anthracenyl, and particularly preferably an aryl radical is a phenyl radical.
  • heteroaryl in the context of the present invention means a monocyclic or polycyclic, preferably a mono-, bi- or tricyclic, aromatic hydrocarbon radical with preferably 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 C atoms, particularly preferably with 5, 6, 9, 10, 13 or 14 C atoms, very particularly preferably with 5 or 6 C atoms, in which one or more C atoms in each case independently selected by a heteroatom Heteroaryl radicals may be preferably 1, 2, 3, 4 or 5, more preferably 1, 2 or 3, heteroatom (s) independently selected from the group consisting of Oxygen, sulfur and nitrogen (NH) as ring member (s) A heteroaryl radical can be unsubstituted or monosubstituted or polysubstituted by identical or different substituents.
  • heteroaryl radicals examples include thienyl, furyl, pyrrolyl, pyrazolyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, benzo [d] thiazolyl, benzodiazolyl, benzotriazolyl, benzoxazolyl , Benzisoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinazolinyl, quinolinyl, naphthtridinyl and isoquinolinyl.
  • aryl or heteroaryl radicals may be condensed (fused) with a monocyclic or bicyclic ring system.
  • aryl radicals which are condensed with a monocyclic or bicyclic ring system
  • substituents is a phenylene, aryl or heteroaryl radical or have an aryl or heteroaryl radical which is monosubstituted or polysubstituted, this may preferably have 1, 2, 3, 4 or 5, if appropriate , particularly preferably having optionally 1, 2 or 3, substituents independently of one another selected from the group consisting of F, Cl, Br, I 1 -CN, -NO 2 , -OH, -SH, -NH 2 , -C (O ) -OH, -Ci-5-alkyl, - (CH 2 ) -OC 1-5 -alkyl, -C 2-5 -alkenyl, -C 2-5 -alkynyl, -C ⁇ C-Si (CH 3 ) 3 , -C ⁇ C-Si (C 2 H 5 ) 3 , -Sds-alkyl, -S-phenyl, -S-CH 2 -phenyl, -OC
  • the substituents each independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl tert-butyl, n-pentyl, neo-pentyl, ethenyl, allyl, ethynyl, propynyl, -C ⁇ C-Si (CH 3 ) 3 , -C ⁇ C-Si (C 2 H 5 ) 3 , -CH 2 -O-CH 3 , -CH 2 - O-C 2 H 5 , -OH, -SH, -NH 2 , -C (O) -OH, -S-CH 3 , -SC 2 H 5 , -S ( O) -CH 3, -S (O) 2 -CH 3, - S (O)
  • a substituted aryl radical from the group consisting of 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl, 2-amino-phenyl, 3-amino-phenyl, 4- Amino-phenyl, 2-dimethylamino-phenyl, 3-dimethylamino-phenyl, 4-dimethyl-amino-phenyl, 2-methyl-amino-phenyl, 3-methyl-amino-phenyl, 4-methyl-amino-phenyl, 2-acetyl-phenyl, 3-acetyl phenyl, 4-acetylphenyl, 2-methylsulfinylphenyl, 3-methylsulfinylphen
  • a substituted heteroaryl radical selected from the group consisting of 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyridine 2-yl, 2-methylpyrid-3-yl, 4-methylpyrid-3-yl, 5-methylpyrid-3-yl, 6-methylpyrid-3-yl, 2-methylpyridine 4-yl, 3-methylpyrid-4-yl, 3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyridine 2-yl, 3-chloropyrid-2-yl, 4-chloropyrid-2-yl, 5-chloropyrid-2-yl, 6-chloropyrid-2-yl, 3-trifluoromethylpyridine 2-yl, 4-trifluoromethyl-pyrid-2-yl, 5-trifluoromethyl-pyrid-2-yl, 6-trifluor
  • alkylene in the context of the present invention comprises acyclic saturated hydrocarbon chains which have an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical with the substituted thiazole of the general formula I or with another substituent
  • Alkylene chains may be branched or straight-chained and unsubstituted or at least monosubstituted with as in the case of Ci- 12- alkylene 1 to 12 (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11 or 12) carbon atoms, with as in the case of d -6- alkylene 1 to 6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms or with as in the case of Ci -3 - Alkylene 1 to 3 (ie 1, 2 or 3) C atoms
  • d- ⁇ -alkylene groups such as - (CH 2 ) -, - (CH 2 ) 2 -, -C (
  • alkenylene in the context of the present invention comprises acyclic unsaturated hydrocarbon chains which have an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical with the substituted thiazole of the general formula I or with another substituent connect.
  • alkynylene in the context of the present invention comprises acyclic unsaturated hydrocarbon chains which connect an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical with the substituted thiazole of the general formula I or with another substituent
  • Alkynylene chains have at least one triple bond, preferably 1 or 2 triple bonds, and can be branched or straight-chained and unsubstituted be at least or monosubstituted with as in the case of C 2 - 12 alkynylene 2 (ie, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) to 12 C-atoms, with as in the Case of C 2-6 alkynylene 2 to 6 (ie 2, 3, 4, 5 or 6) carbon atoms or with as in the case of C 2-3 alkynylene 2 to 3 (ie 2 or 3) carbon atoms atoms.
  • C 2-3 -alkyl acyclic unsaturated
  • heteroalkylene refers to an alkylene chain as described above in which one or more C atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH).
  • Heteroalkylene groups may preferably have 1, 2 or 3 heteroatom (s), more preferably a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen (NH) as a chain member (s).
  • Heteroalkylene groups may preferably be 2- to 12-membered, particularly preferably 2- to 6-membered, very particularly preferably 2- or 3-membered.
  • heteroalkylene groups such as - (CH 2 ) O-, - (CH 2 J 2 -O-, - (CH 2 ) 3 -O-, - (CHz) 4 -O-, -O- (CH 2 ) -, -O- (CHz) 2 -, -O- (CHz) 3 -, -O- (CHz) 4 -, -C (C 2 H 5 ) (H) -O-, -O-C (C 2 H 5 ) (H) -, -CH 2 -O-CH 2 -, -CH 2 -S-CH 2 -, -CH 2 -NH-CH 2 -, -CH 2 -NH- and -CH 2 - CH 2 - called NH-CH 2 -CH 2 .
  • heteroalkenylene refers to an alkenylene chain as described above in which one or more C atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur and nitrogen (NH).
  • Heteroalkenylene groups may preferably have 1, 2 or 3 heteroatom (s), more preferably 1 heteroatom, selected from the group consisting of oxygen, sulfur and nitrogen (NH) as a chain member (s).
  • substituents is an alkylene, alkenylene, alkynylene, heteroalkylene or heteroalkenylene group or have such a group which is monosubstituted or polysubstituted, this may preferably have 1, if appropriate, 2, 3, 4 or 5, particularly preferably with optionally 1, 2 or 3, substituents independently selected from the group consisting of phenyl, F, Cl 1 Br, I, -NO 2 , - CN, -OH, -O -Phenyl, -O-CH 2 -phenyl, -SH, -S-phenyl, -S-CH 2 -phenyl, -NH 2 , -N (C 1-5 -alkyl) 2 , -NH-phenyl, (phenyl) -N (C 1-5 alkyl) (phenyl), -N (C 1-5 alkyl) (CH 2 -phenyl), - N (Ci -5 alkyl) (CH 2 -phenyl
  • alkylene, alkenylene, alkynylene, heteroalkylene or heteroalkenylene groups having 1, 2 or 3 substituents can be selected independently of one another from the group consisting of phenyl, F, Cl, Br, I, -NO 2 , -CN , - OH, -O-phenyl, -SH, -S-phenyl, -NH 2 , -N (CH 3 ) 2 , -N (C 2 Hs) 2 and -N (CH 3 ) (C 2 H 5 ) be substituted, wherein the phenyl radical having 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, I, - OH, -SH, -NO 2 , -CN, -O -CH 3 , -O-CF 3 and -O-C 2 H 5 may be substituted.
  • each of these substituents may each be independently selected from other substituents having the same name of the substituent.
  • R 1 and R 2 together with the carbon atoms connecting them form an unsubstituted or at least monosubstituted phenylene radical
  • R 3 and R 4 together with the -N-CR 5 group connecting them, have a radical of the general formula A,
  • R and R together with the linking -CR-N- group is a radical of the general formula B,
  • n 2, 3, 4, 5 or 6;
  • R 6 and R 10 together with the linking -CR 7 -CR 8 R 9 -N- group is a radical of the general formula D,
  • each of r and s is 2, 3 or 4; or R and R together with their linking -CR-CR R -CR group have a radical of the general formula G,
  • t is 1, 2, 3, 4 or 5;
  • u 3 or 4;
  • v and w independently of one another, are each 1, 2 or 3;
  • R 11 is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are each unsubstituted or substituted alkyl, alkenyl or alkynyl; unsubstituted or substituted heteroalkyl, heteroalkenyl or heteroalkynyl; unsubstituted or substituted cycloalkyl or cycloalkenyl; unsubstituted or substituted heterocycloalkyl or heterocycloalkenyl; unsubstituted or substituted - (alkylene) cycloalkyl, - (alkenylene) cycloalkyl, - (alkynylene) cycloalkyl, - (alkylene) cycloalkyl, independently of one another
  • alkyl radicals are each branched or straight-chain and have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms as chain members;
  • alkenyl radicals are each branched or straight-chain and have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms as chain members;
  • alkynyl radicals are each branched or straight-chain and have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms as chain members;
  • heteroalkyl radicals, heteroalkenyl radicals and heteroalkynyl radicals are each 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered;
  • heteroalkyl radicals each optionally having 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen as chain link (s);
  • alkyl radicals alkenyl radicals, alkynyl radicals, heteroalkyl radicals, heteroalkenyl radicals and heteroalkynyl radicals each having optionally 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, -NO 2 , -CN, -OH, -SH, -NH 2 , -N (C 1-5 -alkyl) 2 , -N (C 1-5 -alkyl) (phenyl), N (C 1.
  • cycloalkyl radicals each have 3, 4, 5, 6, 7, 8 or 9 carbon atoms as ring members;
  • the aforementioned cycloalkenyl radicals each have 3, 4, 5, 6, 7, 8 or 9 carbon atoms as ring members;
  • the above-mentioned heterocycloalkyl radicals are each 3-, 4-, 5-, 6-, 7-, 8- or 9-membered;
  • heterocycloalkenyl radicals are each 4-, 5-, 6-, 7-, 8- or 9-membered;
  • heterocycloalkyl radicals and heterocycloalkenyl radicals each optionally having 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as ring member (s);
  • cycloalkyl radicals heterocycloalkyl radicals, cycloalkenyl radicals or heterocycloalkenyl radicals each having optionally 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, CN, -CF 3 , -OH, -NH 2 , -O-CF 3 , -SH, -O-C 1 -C 5 -alkyl, -O-phenyl, -O-CH 2 -phenyl, - (CH 2 ) - OC 1-5 -alkyl, -SC 1-5 -alkyl, -S-phenyl, -S-CH 2 -phenyl, -C 1-5 -alkyl, -C 2-5 -alkenyl, -C 2-5 - Alkynyl, -C ⁇ C-Si (CH 3 ) 3 , -C ⁇ C-Si (C 2
  • alkylene radicals are each branched or straight-chain and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms as chain members;
  • alkenylene radicals are each branched or straight-chain and have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms as chain members;
  • alkynylene radicals mentioned above are each branched or straight-chain and have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms as chain members;
  • heteroalkylene heteroalkenylene radicals and heteroalkynylene radicals are each 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered;
  • heteroalkylene, heteroalkenylene and heteroalkynylene groups each optionally having 1, 2 or 3 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as chain member (s);
  • alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene groups are each unsubstituted or optionally substituted by 1,
  • aryl radicals are monocyclic or bicyclic and have 6, 10 or 14 carbon atoms;
  • heteroaryl radicals are mono-, bi- or tricyclic and 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered;
  • the abovementioned 5- to 14-membered heteroaryl radicals optionally have 1, 2, 3, 4 or 5 heteroatom (s) independently of one another selected from the group consisting of oxygen, sulfur and nitrogen (NH) as ring member (s);
  • substituted thiazoles of the general formula I given above wherein R 8 and R 10 together with the linking -N-CR 9 - group is a radical selected from the group consisting of
  • R 3 and R 6 together with the linking -N-CR 4 R 5 -CR 7 - group is a radical selected from the group consisting of
  • R 6 and R 10 together with their linking -CR 7 -CR 8 CR 9 -N- group is a radical selected from the group consisting of
  • R 3 and R 8 together with the linking -N-CR 4 R 5 -CR 6 R 7 -CR 9 - group a radical selected from the group consisting of
  • R 4 and R 10 together with the linking -N-CR 8 R 9 -CR 6 R 7 -CR 5 - group a radical selected from the group consisting of
  • substituted thiazoles of the above general formula I wherein R 4 and R 8 together with the linking -CR 5 -CR 6 R 7 -CR 9 - group a radical selected from the group consisting of
  • R 3 and R 10 together with their linking -N-CR 4 R 5 -CR 6 R 7 -CR 8 R 9 -N- group is a radical selected from the group consisting of
  • R 3 and R 10 together with their linking -N-CR 4 R 5 -CR 6 R 7 -CR 8 R 9 -N- group has a bicyclic radical selected from the group consisting of
  • R 11 is a radical selected from the group consisting of phenyl, naphthyl, anthracenyl, furyl, thienyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, imidazolyl, indolyl, benz [b] thiophenyl, benzo [d] thiazolyl, benzo [b] furanyl, quinolinyl, isoquinolinyl and quinazolinyl, each of which is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl 1 Br, I, -CN, methyl, ethyl, n-propyl, isopropyl
  • R 51 , R 52 and R 53 are each d- ⁇ -alkyl which is unsubstituted or optionally having 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of F, Cl, Br, I, -NO 2 , -CN, -OH, -SH and -NH 2 ; C 3-7 -cycloalkyl, C 5-6 -cycloalkenyl, 5- to 7-membered heterocycloalkyl and 5- to 7-membered heterocycloalkenyl, each via a C 1-3 -alkylene, C 2-3 -alkenylene- or C 2-3 alkynylene group may be bonded and / or unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, I, -CN, methyl, ethyl , n-propyl, isopropyl, n-butyl, 2-butyl, isobut
  • Substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
  • C 3-6 -cycloalkyl which is unsubstituted or optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, I, - NO 2 , -CN, -OH, - SH and -NH 2 is substituted; or for a phenyl residue, which in each case via a C- ⁇ -3 alkylene, C 2-3 - 2-3 alkenylene or alkynylene group C to be bound and / or unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, OH, -O-CH 3) -O-C 2 H 5 and -O-C 3 H 7 ;
  • R 3 and R 4 together with the -N-CR 5 group connecting them, are a radical selected from the group consisting of
  • R 8 and R 10 together with the -N-CR 9 - group linking them, are selected from the group consisting of
  • R 3 and R 6, together with the -N-CR 4 R 5 -CR 7 - group linking them, is a radical selected from the group consisting of
  • R 6 and R 10 together with their linking -CR 7 -CR 8 CR 9 -N- group is a radical selected from the group consisting of
  • R 4 and R 10 together with their linking -N-CR 8 R 9 -CR 6 R 7 -CR 5 group is a radical selected from the group consisting of
  • R 4 and R 8 together with the linking -CR 5 -CR 6 R 7 -CR 9 group are selected from the group consisting of
  • R 3 and R 10 together with their linking -N-CR 4 R 5 -CR 6 R 7 -CR 8 R 9 -N- group is a radical selected from the group consisting of
  • R 3 and R 10 together with their linking -N-CR 4 R 5 -CR 6 R 7 -CR 8 R 9 -N- group has a bicyclic radical selected from the group consisting of
  • R 11 is a radical selected from the group consisting of phenyl, naphthyl, anthracenyl, furyl, thienyl, pyrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, imidazolyl, indolyl, benz [b] thiophenyl, benzo [d] thiazolyl, benzo [b] furanyl, quinolinyl, isoquinolinyl and quinazolinyl, each unsubstituted or optionally having 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F , Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-
  • R 33, R 34, R 35, R 36, R 37, R 42, R 43, R 44, R 45, R 46, R 47 and R 48 independently of one another each represent unsubstituted Ci -6 alkyl; unsubstituted C 3-7 cycloalkyl; unsubstituted C 5-6 cycloalkenyl; unsubstituted 5- to 7-membered heterocycloalkyl and unsubstituted 5- to 7-membered heterocycloalkenyl; or is a radical selected from the group consisting of phenyl, benzyl, naphthyl, anthracenyl, pyrrolyl, indolyl, furanyl, benzo [b] furanyl, thiophenyl, benz [b] thiophenyl, benzo [d] thiazolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, Triazolyl, oxazoly
  • R 1 for H; F; Cl; Br; I; -CF 3 ; NO 2 ; -CN; -C (O) -OH; -C (O) -OR 37 ; -C (O) -NH 2 ; C (O) -NH-R 42 ; -C (O) -NR 43 R 44 ; -OR 45 ; -SR 46 ; -S (O) -R 47 ; -S (O) 2 -R 48 ; an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl and tert-butyl; or is selected from the group consisting of (1, 3) -dioxolan-2-yl, phenyl, benzyl, phenethyl, oxadiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridy
  • R 2 for H; F; Cl; Br; I; -CF 3 ; NO 2 ; -CN; -C (O) -OH; -C (O) -OR 37 ; -C (O) -NH 2 ; C (O) -NH-R 42 ; -C (O) -NR 43 R 44 ; -OR 45 ; -SR 46 ; -S (O) -R 47 ; -S (O) 2 -R 48 ; an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl and tert-butyl; or selected for a rest from the group consisting of (1, 3) -dioxolan-2-yl, phenyl, benzyl, phenethyl, oxadiazolyl, 2-pyridyl, 3-pyridyl, 4-pyr
  • Substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
  • R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 are each H; F; Cl; Br; I; NO 2 ; -CN; -NH 2 ; -OH; SH; -NH-R 33 ; -NR 34 R 35 ; -OR 45 ; -SR 46 ; -CF 3 ; -C 2 F 5 ; or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl;
  • R 3 and R 4 together with the -N-CR 5 group connecting them, are a radical selected from the group consisting of
  • R 8 and R 10 together with the -N-CR 9 - group linking them, are selected from the group consisting of
  • R 3 and R 6, together with the -N-CR 4 R 5 -CR 7 - group linking them, is a radical selected from the group consisting of
  • R 6 and R 10 together with their linking -CR 7 -CR 8 CR 9 -N- group is a radical selected from the group consisting of form;
  • R 4 and R 8 together with the linking -CR 5 -CR 6 R 7 -CR 9 group, are selected from the group consisting of
  • R 3 and R 10 together with their linking -N-CR 4 R 5 -CR 6 R 7 -CR 8 R 9 -N- group has a bicyclic selected from the group consisting of
  • R 11 is a radical selected from the group consisting of phenyl, naphthyl, anthracenyl, furyl, thienyl, pyrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, imidazolyl, indolyl, benz [b] thiophenyl, benzo [d] thiazolyl, benzo [b] furanyl, quinolinyl, isoquinolinyl and quinazolinyl, each unsubstituted or optionally having 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F , Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 and R 48 are each an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl; or represents a phenyl, benzyl or phenethyl radical which is unsubstituted or has 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, Isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, -OH, -O-CH 3 , -O-C 2
  • Substituents independently of one another selected from the group consisting of F, Cl 1 Br, I 1 -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
  • R 11 is a radical selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyrrolyl, Oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, imidazolyl, indolyl, benz [b] thiophenyl, benzo [d] thiazolyl, benzo [b] furanyl, quinolinyl, isoquinolinyl and quinazolinyl, each of which is unsubstituted or optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, I 1 -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 and R 48 are each an alkyl radical selected from the group consisting of methyl, ethyl, n -propyl, isopropyl, n -butyl, 2-butyl, isobutyl, tert -butyl, n -pentyl and n -hexyl; or represents a phenyl, benzyl or phenethyl radical which is unsubstituted or has 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, Isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, -OH, -O-CH 3 ,
  • R 11 is a radical selected from the group consisting of phenyl, furyl, thienyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, triazolyl and imidazolyl, each unsubstituted or with optionally 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, ethenyl, allyl, ethynyl, propynyl, -O-CH 3 , -O-C 2 H 5 , -NO 2
  • R 33 , R 34 , R 35 , R 36 , R 37 , R 45 and R 46 are each an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl , 2-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl; in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, their racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any mixing ratio, or in each case in the form of corresponding salts, or in each case in the form of corresponding solvates.
  • R 3 and R 10 independently of each other, are each H; an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl and tert-butyl; or for cyclopropyl; stand;
  • R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each H;
  • R 11 is a radical selected from the group consisting of 3,4-dimethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-fluoro-4-methylphenyl, pyrid-2-yl, pyridine 3-yl, pyrid-4-yl, phenyl, 3-methyl-phenyl, 3-fluoro-phenyl, 3-cyano-phenyl, 3-chloro-phenyl, 3-trifluoromethyl-phenyl, 3-difluoromethyl-phenyl, 3 Fluoromethylphenyl, 3-nitro-phenyl, 3-ethenylphenyl, 3-ethynylphenyl, 3-allyl-phenyl, 3-bromophen
  • R 11a is a radical selected from the group consisting of 2-trifluoromethylphenyl, 3,4-dimethylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-methylphenyl, 4-methylphenyl, 2-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethylphenyl, 3-fluoro-4-methylphenyl, pyrid-2-yl, pyridine 3-yl, pyrid-4-yl, phenyl, 3-methyl-phenyl, 3-fluoro-phenyl, 3-cyano-phenyl, 3-chloro-phenyl, 3-trifluoromethyl-phenyl, 3-difluoromethyl-phenyl, 3 Fluoromethylphenyl, 3-nitro-phenyl, 3-ethenylphenyl, 3-ethynylphenyl, 3-allyl-phenyl, 3-bromoph
  • substituted thiazoles of the above general formula I which after 60 minutes incubation in 450 ug protein from Schweinehimhomogenat at a temperature between 20 0 C and 25 0 C in a concentration less than 2000 nM, preferably less than 1000 nM, particularly preferably smaller 700 nM, most preferably less than 100 nM, even more preferably less than 30 nM, a 50 percent displacement of [ 3 H] -2-methyl-6- (3-methoxyphenyl) ethynylpyridine cause in a concentration of 5 nM is present.
  • Another object of the present invention is a process for the preparation of compounds of the above general formula I according to the at least one compound of the general formula H 1
  • radicals R 1 and R 2 have the abovementioned meaning and X is a leaving group, preferably a halogen radical or a sulfonic acid ester, particularly preferably a chlorine or bromine radical, with at least one compound of the general formula III .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the abovementioned meaning, if appropriate in a reaction medium, if appropriate in the presence of at least one base and / or at least one organometallic compound and / or at least one metal hydride reagent or in the presence of at least one copper salt and optionally in the presence of at least one metal, preferably at a temperature of - 70 0 C to 150 0 C - 70 0 C to 300 0 C, more preferably from in at least one corresponding compound of the general formula IV, if appropriate in the form of a corresponding salt,
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the abovementioned meaning and PG is a protective group, preferably a protective group selected from the group consisting of tert-butyloxy carbonyl, benzyl, benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 have the abovementioned meaning and X is a leaving group, preferably a halogen radical or a sulfonic acid ester, more preferably a chlorine - or bromine radical, optionally in a reaction medium, if appropriate in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, dimethylamine and Triethylamine, particularly preferably in the presence of diethylamine, or if appropriate in the presence of at least one organometallic compound selected from the group consisting of methyllithium and butyllithium or optionally in the presence of at least one metal hydride, more preferably in the presence of sodium hydride , preferably at a temperature of - 70 0 C to 300 0 C, more preferably from - 70 0 C to 150
  • R 1 has the abovementioned meaning
  • X is a leaving group, preferably a halogen radical, particularly preferably a bromine atom, in a reaction medium, if appropriate in the presence of at least one organic base or in the presence of at least one Acid, preferably in the presence of at least one base selected from the group consisting of triethylamine, diisopropylethylamine
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the abovementioned meaning, and this is optionally purified and / or isolated;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the abovementioned meaning, and this is optionally purified and / or isolated,
  • R 11 is as defined above and X is a leaving group, preferably a halogen radical or a sulphonic acid ester, more preferably iodine, Bromine or triflate, in a reaction medium, if appropriate in the presence of at least one catalyst, preferably in the presence of at least one palladium catalyst selected from the group consisting of palladium chloride [PdCl 2 ], palladium acetate [Pd (OAc) 2 ], tetrakistriphenylphosphinepalladium [Pd (PPh 3 ) 4 ], bistriphenylphosphinepalladium dichloride [Pd (PPh 3 ) 2 Cl 2 ] and Bistriphenylphosphinepalladium acetate [Pd (PPh 3 ) 2 (OAc) 2 ], if appropriate in the presence of at least one ligand, preferably in the presence of
  • an object of the present invention is a process for the preparation of compounds of general formula I according to the at least one compound of general formula XVI,
  • a reaction medium preferably selected from the group consisting of diethyl ether, tetrahydrofuran, methanol, ethanol, dichloromethane and toluene
  • at least one reducing agent preferably with the addition of at least one reducing agent selected from the group consisting of sodium borohydride, Natriacetoxyborhydrid, resin bound Natriumacetoxyborhydridborhydrid and sodium cyanoborohydride, at temperatures from -80 0 C to 150 0 C, preferably from -78 ° C to 100 0 C, to give compounds of the general formula I 1, if appropriate in the form of a corresponding salt, and these are optionally purified and / or isolated.
  • an object of the present invention is a process for the preparation of compounds of general formula I according to the at least one compound of general formula III,
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the abovementioned meaning
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 have the abovementioned meaning and PG is a protective group, preferably a protective group selected from the group consisting of tert-butyloxy-carbonyl , Benzyl, benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl,
  • Leaving group preferably a halogen radical or a sulfonic acid ester, particularly preferred for a chlorine or bromine radical is, in a reaction medium, optionally in the presence of at least one base and / or at least one organometallic compound and / or at least one metal hydride reagent, preferably at a temperature of - 70 0 C bis 300 0 C is converted into at least one corresponding compound of general formula I, optionally in the form of a corresponding salt, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the abovementioned meaning, and this is optionally purified and / or isolated;
  • At least one compound of general formula IX by reaction with potassium thiocyanate and ethyl chloroformate or ammonium thiocyanate or trimethylsilyl isothiocyanate or thiophosgene and ammonia or cyanogen bromide and hydrogen sulfide in a reaction medium, optionally in the presence of at least one acid, preferably in the presence of at least one acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid, more preferably in the presence of hydrochloric acid, or optionally in the presence of at least one base, preferably in the presence of at least one base selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, dimethylamine and Triethylamine, particularly preferably in the presence of diethylamine, or optionally in the presence of at least one organometallic compound, preferably in the presence of at least one organometallic compound selected from the group consist
  • step 1 are thiazoles of the above-mentioned general formula II wherein X is a leaving group, preferably a halogen radical or a sulfonic acid ester selected from the group consisting of mesylate, triflate and tosylate, particularly preferably a chlorine or bromine atom, with Compounds of the above general formula IM, if appropriate in a reaction medium, preferably selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, acetonitrile, pyridine, dioxane, ethyl acetate, dimethyl sulfoxide , Toluene and corresponding mixtures, more preferably in a reaction medium selected from the group consisting of methanol, ethanol and n-butanol, optionally in the presence of at least one organic or inorganic acid
  • step 1 are thiazoles of the above-mentioned general formula II wherein X is a leaving group, preferably a halogen radical or a sulfonic acid ester selected from the group consisting of mesylate, triflate and tosylate, particularly preferably a chlorine or bromine atom, with Compounds of the above general formula V, wherein PG is a protective group, preferably a protective group selected from the group consisting of tert-butyloxy-carbonyl, benzyloxycarbonyl, benzyl and 9-Fluorenylmethyloxycarbonyl converted into compounds of general formula VI.
  • PG is a protective group, preferably a protective group selected from the group consisting of tert-butyloxy-carbonyl, benzyloxycarbonyl, benzyl and 9-Fluorenylmethyloxycarbonyl converted into compounds of general formula VI.
  • Exact conditions can also be found in the publication Journal of Medicinal Chemistry 1972
  • step 3 compounds of general formula VI in the case where PG is a tert-butoxycarbonyl or 9-fluorenylmethyloxycarbonyl group are selected in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethyl acetate, ethanol, isopropanol , n-butanol, diethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, Dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, toluene and mixtures thereof, in the presence of at least one acid, preferably in the presence of at least one acid selected from the group consisting of hydrochloric acid and trifluoroacetic acid, preferably at a temperature between -70 0 C to 100 0 C or the case that PG is a benzyl group or benzyloxycarbonyl group, in a reaction medium, preferably in a reaction
  • X is a leaving group, preferably one Halogen radical, particularly preferably chlorine or bromine
  • step 2 are compounds of the general formula VIII given above with compounds of the general formula R 11 -X, wherein R 11 is as defined above and X is a leaving group, preferably a halogen radical or a sulfonic acid ester, more preferably iodine, bromine or triflate, in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethyl acetate, ethanol, isopropanol, n-butanol, diethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dimethylformamide, acetonitrile, pyridine, dimethyl sulfoxide, water , Toluene and corresponding mixtures, preferably in dimethylformamide, water, Ethyl acetate, tetrahydrofuran and corresponding mixtures, if appropriate in the presence of at least one catalyst, preferably in the presence of at least one palladium catalyst
  • step 2 compounds of general formula XI wherein PG is a protecting group, preferably a protecting group selected from the group consisting of tert-butyloxycarbonyl, benzyl, benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl, are described as in Scheme 2, step 3 converted into compounds of general formula IX.
  • PG is a protecting group, preferably a protecting group selected from the group consisting of tert-butyloxycarbonyl, benzyl, benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl
  • X is a leaving group, preferably a halogen radical, particularly preferably chlorine or bromine
  • step 4 compounds of general formula IX are reacted with compounds of general formula II as in Scheme 1, step 1 to give compounds of general formula I.
  • the intermediate and end products obtained according to the above-described reactions can each be purified and / or isolated, if desired and / or required, by customary methods known to the person skilled in the art.
  • Suitable purification methods are, for example, extraction methods and chromatographic methods, such as column chromatography or preparative chromatography.
  • substituted thiazoles according to the invention denoted by the above-mentioned general formula I are obtained after preparation in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their various enantiomers and / or diastereomers, these can be prepared by customary methods known to the person skilled in the art separated and possibly isolated. Examples which may be mentioned are chromatographic separation processes, in particular liquid chromatography processes under atmospheric pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallization processes.
  • the respective salts of the substituted thiazoles according to the invention of the abovementioned general formula I and corresponding stereoisomers can be obtained, for example, by reaction with one or more inorganic acids and / or one or more organic acids.
  • Suitable acids may preferably be selected from the group consisting of perchloric, hydrochloric, hydrobromic, sulfuric, methanesulfonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic, succinic, cyclohexanesulfamic, aspartame, monomethylsebacic, 5 Oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-aminobenzoic acid, 3-aminobenzoic acid or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric
  • substituted thiazoles according to the invention of the abovementioned general formula I and, if appropriate, corresponding stereoisomers and in each case their physiologically tolerated salts can also be obtained in the form of their solvates, in particular in the form of their hydrates, by customary methods known to the person skilled in the art.
  • substituted thiazoles according to the invention of the abovementioned general formula I are suitable for mGluR5 receptor regulation and therefore in particular as pharmaceutical active ingredients in medicaments for the prophylaxis and / or treatment of disorders or disorders associated with these receptors or processes Diseases can be used.
  • the substituted thiazoles according to the invention of the abovementioned general formula I and, if appropriate, corresponding stereoisomers and in each case the corresponding salts and solvates appear toxicologically harmless and are therefore suitable as pharmaceutical active ingredients in medicaments.
  • Another object of the present invention is therefore a medicament containing at least one inventive substituted thiazole of the above general formula I, in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, especially 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.
  • the medicament according to the invention is suitable for mGluR ⁇ receptor regulation, in particular for inhibiting the mGluR ⁇ receptor.
  • the medicament according to the invention is preferably suitable for the prophylaxis and / or treatment of disorders and / or diseases which are at least partially mediated by mGluR ⁇ receptors.
  • the medicament according to the invention is therefore particularly preferably suitable for the treatment and / or prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive disorders, preferably cognitive deficits, most preferably attention deficit syndrome (ADD); Anxiety; Panic attacks; Epilepsy; To cough; urinary incontinence; diarrhea; pruritus; Schizophrenia; cerebral ischemia; muscle spasms; convulsions; Pulmonary diseases, preferably selected from the group consisting of Asthma and pseudo-group; Regurgitation (vomiting); Stroke; dyskinesia; retinopathy; listlessness; Laryngitis (laryngitis); Food ingestion, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity
  • the medicament according to the invention is very particularly preferably suitable for the prophylaxis of pain, preferably of pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Anxiety; Panic attacks; Alcohol dependency; Drug addiction; Food ingestion, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug dependence, preferably nicotine and / or cocaine addiction; Alcohol abuse; Drug abuse; Drug abuse; preferably nicotine and / or cocaine abuse; Withdrawal symptoms in alcohol, drug and / or drug (especially nicotine and / or cocaine) dependency; Development of tolerance to drugs and / or drugs, in particular to natural or synthetic opioids; Gastro-oesophageal reflux syndrome, gastroesophageal reflux disease and irritable bowel syndrome.
  • the pharmaceutical composition according to the invention is suitable for the prophylaxis and / or treatment of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, anxiety and Panic attacks.
  • the pharmaceutical composition of the invention is suitable for the prophylaxis and / or treatment of pain, preferably of acute pain, chronic pain, neuropathic pain or visceral pain.
  • Another object of the present invention is the use of at least one inventive substituted thiazole of the above general formula I 1 each optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, especially the enantiomers and or diastereomers, in any mixing ratio, or each 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 the preparation of a medicament for mGluR5 receptor regulation, preferably for inhibiting mGluR ⁇ receptor.
  • At least one substituted thiazole according to the invention of the abovementioned general formula I in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any Mixing ratio, or each 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 the manufacture of a medicament for the prophylaxis and / or treatment of pain, preferably pain selected from the group consisting of acute Pain, chronic pain, neuropathic pain and visceral pain; Migraine; Depressions; neurodegenerative diseases, preferably selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; cognitive disorders, preferably cognitive deficits, most preferably attention deficit syndrome (ADD);
  • ADD attention deficit syndrome
  • At least one substituted thiazole of the abovementioned general formula I in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers , in any mixing ratio, or each 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 the manufacture of a medicament for the prophylaxis and / or treatment of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain and visceral pain; Anxiety; Panic attacks; Alcohol dependency; Drug addiction; Food ingestion, preferably selected from the group consisting of bulimia, cachexia, anorexia and obesity; Drug dependence, preferably nicotine and / or cocaine addiction; Alcohol abuse; Drug abuse; Drug abuse; Drug abuse
  • At least one substituted thiazole of the general formula I given above in each case optionally in the form of one of its pure stereoisomers, in particular enantiomers or diastereomers, its racemates or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers , in any mixing ratio, or each 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 the manufacture of a medicament for the prophylaxis and / or treatment of pain, preferably pain selected from Group consisting of acute pain, chronic pain, neuropathic pain and visceral pain, anxiety and panic attacks.
  • the pharmaceutical composition of the invention is suitable for administration to adults and children, including infants and babies.
  • the medicament according to the invention can be used as a liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and as such also administered.
  • the medicament according to the invention usually contains further physiologically acceptable pharmaceutical excipients, which can preferably be selected from the group consisting of carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants Lubricants, lubricants, flavors and binders.
  • physiologically acceptable excipients depend on whether the drug is administered orally, subcutaneously, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on infections of the skin, mucous membranes and on the eyes, to be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • the substituted thiazole of the above-indicated general formula I used in the medicament according to the invention are in a depot in dissolved form or in a plaster, optionally with the addition of Skin penetration promoting agents are suitable percutaneous application preparations.
  • compositions of the invention are prepared by conventional means, devices, methods and procedures well known in the art, as described, for example, in "Remington's Pharmaceutical Sciences", published by AR Gennaro, 17th Edition, Mack Publishing Company, Easton, Pa. 1985, in particular in Part 8, Chapters 76 to 93. The corresponding description is hereby incorporated by reference and is considered part of the disclosure.
  • the amount of the respective substituted thiazole of the above-indicated general formula I to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as on the mode of administration, the indication and the severity of the disease. Usually, 0.05 to 100 mg / kg, in particular 0.05 to 10 mg / kg, body weight of the patient of at least one such compound is applied.
  • Porcine brain homogenate is prepared by homogenizing (Polytron PT 3000, Kinematica AG, 10,000 revolutions per minute for 90 seconds) of porcine brain halves without medulla, cerebellum and pons in buffer pH 8.0 (3 oMM Hepes, Sigma, Order No. H3375 + 1 tablet Complete to 100ml, Roche Diagnostics , Order No. 1836145) at a ratio of 1:20 (brain weight / volume) and differential centrifugation at 900 xg and 40,000 xg.
  • In 250 ⁇ l incubation mixtures in 96-well microtiter plates 450 ⁇ g protein from brain homogenate with 5nM 3 [H] - MPEP (Tocris, Order No. R1212) (MPEP 2-methyl-6- (3-methoxyphenyl) - ethynylpyridine) and the zu of test compounds (10 ⁇ M in assay) in buffer (as above) at room temperature for 60 min.
  • the batches are then filtered on Unifilter plates with glass fiber filter mats (Perkin Elmer, Order No. 6005177) with the aid of a Brandel Cell harvester (Brandel, TYP Robotic 9600) and subsequently washed with buffer (as above) 3 times with 250 ⁇ l per sample.
  • the filter plates are then dried for 60 min at 55 0 C.
  • add 30 ⁇ L Ultima Gold TM Scintillator Packard BioScience, P / N 6013159
  • measure the samples on the ⁇ -counter microbeta, Perkin Elmer.
  • the nonspecific binding is determined by addition of 10 ⁇ M MPEP (Tocris, Order No. 1212).
  • mGluR ⁇ receptor of the rat species with the following assay. According to this assay, the intracellular release of Ca 2+ after activation of the mGluR ⁇ receptor by means of a Ca 2+ -sensitive dye (type Fluo-4, Molecular Probes Europe BV, Leiden Netherlands) in the FlexStation (Molecular Devices, Sunnyvale, USA ). Preparation of cortical neurons:
  • Cortical neurons are prepared under sterile conditions from postnatal rats (P2-6).
  • the cortex is removed and transferred directly into collagenase solution (PAA Laboratories GmbH, Cölbe, Germany) and incubated for 45 minutes in a hot shaker (37 ° C, 300 revolutions per minute). Subsequently, the collagenase solution is removed and the tissue is mixed with culture medium.
  • collagenase solution PAA Laboratories GmbH, Cölbe, Germany
  • Neurobasal medium (Gibco Invitrogen GmbH, Düsseldorf, Germany)
  • the cells are separated by resuspension and centrifuged after addition of 15 ml of neurobasal medium through a 70 micron filter cartridge (BD Biosciences, Heidelberg, Germany). The resulting cell pellet is taken up in culture medium. Subsequently, the cells are plated on poly-D-lysine-coated black 96-well plates with clear bottom (BD Biosciences, Heidelberg, Germany), previously additionally with laminin (2 ug / cm 2 , Gibco Invitrogen GmbH, Düsseldorf, Germany ) were coated, plated. The cell density is 15,000 cells / hole. The cells are incubated at 37 0 C and 5% CO 2 and on the 2nd or 3rd day after preparation, a medium change. Depending on the cell growth, the functional examination on 3-7. Day after preparation. Description of the functional Ca 2+ -I nflux assay
  • 20,000 CHO-hmGluR5 cells / well (Euroscreen.Gosselies, Belgium) are pipetted out into 96 well plates (BD Biosciences, Heidelberg, Germany, Ref 356640, clear bottom, 96 well, poly-D-Lysine) and overnight in HBSS buffer (Gibco # 14025-050) with the following ingredients: 10% FCS (GIBCO 1 10270-106) and doxycycline (BD Biosciences Clontech 631311 600ng / ml).
  • the cells were co-infected with 2 ⁇ M Fluo-4 and 0.01% by volume Pluronic F127 (Molecular Probes Europe BV, Leiden Netherlands) in HBSS buffer (Hank 's buffered saline solution, Gibco Invitrogen GmbH, Düsseldorf, Germany) Probenicid (Sigma P8761, 0.69 mg / ml) for 30 min at 37 0 C loaded.
  • Pluronic F127 Molecular Probes Europe BV, Leiden Netherlands
  • HBSS buffer Horco Invitrogen GmbH, Düsseldorf, Germany
  • Probenicid Sigma P8761, 0.69 mg / ml
  • the cells are then washed 3 times with washing buffer (HBSS buffer, Gibco No. 14025-050, with Probenicid (Sigma P8761, 0.69 mg / ml) and then taken up with the same buffer ad 100 ⁇ l After 15 min for the determination of Ca 2+ measurements in the presence of DHPG ((S) -3,5-dihydroxyphenylglycine, Tocris Biotrend Chemikalien GmbH, Cologne, Germany, final DHPG concentration: 10 ⁇ M) and in the presence or absence of test substances in one Fuorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA).
  • washing buffer Gibco No. 14025-050, with Probenicid (Sigma P8761, 0.69 mg / ml)
  • the Ca 2+ -dependent fluorescence is measured before and after addition of test substances.
  • the quantification is done by measuring the highest fluorescence intensity over time.
  • test substance solution different test substance concentrations in HBSS buffer with 1% DMSO and 0.02% Tween 20, Sigma
  • 50 ⁇ l of test substance solution are added and the fluorescence signal is measured for 6 min.
  • 50 ⁇ l of DHPG solution ((S) -3,5-dihydroxyphenylglycine, Tocris Biotrend Chemikalien GmbH, Cologne, Germany, final DHPG concentration: 10 ⁇ M) are added and the influx of Ca 2+ is measured simultaneously for 60 sec.
  • the final DMSO concentration is 0.25% and the final Tween 20 content is 0.005%.
  • the data comes with Microsoft Excel and GraphPad Prism analyzed.
  • the dose-response curves are calculated using non-linear regression and IC 50 values are determined. Each data point is determined 3-fold and IC 5 o values are averaged from a minimum of 2 independent measurements.
  • the first phase reflects a direct stimulation of the peripheral nociceptors with high spinal nociceptive input or glutamate release (acute pain phase); Phase 2 reflects spinal and peripheral hypersensitization (chronic pain phase). In the studies presented here, the chronic pain component (phase 2) was evaluated.
  • Formalin is administered subcutaneously in the dorsal side of the right hind paw of each animal with a volume of 50 ⁇ l and a concentration of 5%.
  • the substances to be tested are administered orally (po), intravenously (iv) or intraperitoneally (ip) 30 min before the formalin injection.
  • the specific behavioral changes such as raising and shaking the paw, shifting the weight of the animal as well as biting and licking reactions are reported during the observation period of Observed and registered 21 to 27 min after formalin injection.
  • the summary of the different behaviors takes place in the so-called pain rate (PR), the, on the subintervals of 3 min, representing the calculation of a mean nociception reaction.
  • T 0 , Ti, T 2 , and T 3 each correspond to the time in seconds in which the animal shows the behaviors 0, 1, 2, or 3.
  • the chemicals and solvents used were commercially obtained from the conventional suppliers (Acros, Avocado, Aldrich, Bachern, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized by the usual methods known in the art.
  • the analysis was carried out by mass spectroscopy and / or NMR.
  • Example compound 1 N- (3 - ((thiazol-2-yl) amino) propyl) -3-phenylpropiolamid
  • Exemplary compound 2 4- (thiazol-2-ylamino) -1- (3-phenylpropiolyl) piperidine
  • Exemplary compound 4 4- (methylthiazol-2-ylamino) -1- (3-phenylpropiolyl) piperidine
  • Example Compound 2 A suspension of 132 mg (0.42 mmol) 4- (thiazol-2-ylamino) -1- (3-phenylpropiolyl) piperidine (Example Compound 2) in MeCN (4 ml) was treated with 20 mg (0.50 mmol, 60 % in mineral oil) sodium hydride and stirred for 10 min at RT. Subsequently, 53 .mu.l (0.84 mmol) of iodomethane were added and it was stirred for a further 2 h at RT. The solution was concentrated in vacuo, taken up with DCM and washed with water and sat. aq. NaCl solution. washed.
  • Example compound 7 4- (Benzothiazol-2-yl-amino) -1- (3- (3-trifluoromethyl-phenyl) -propiolyl) -piperidine
  • the example compounds 8 1 - ((3,4-dimethyl-phenyl) -propiolyl) -4- (thiazol-2-yl-amino) -piperidine (MS [MH +] 340.1) and 9 4- (benzothiazol-2-yl) amino) -1- (3,4-dimethylphenyl) propiolyl) piperidine (MS [MH +] 390.2) were prepared by the method described above for Example Compound 7.
  • the substituted thiazoles according to the invention show an excellent affinity for the mGluR ⁇ receptor.

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Abstract

La présente invention concerne des thiazoles substitués de formule générale (I), des procédés de production de ces composés, des médicaments contenant ces composés, ainsi que l'utilisation desdits composés pour produire des médicaments, de préférence des médicaments pour traiter la douleur.
EP06829856A 2005-12-28 2006-12-22 Thiazoles substitues et leur utilisation pour produire des medicaments Withdrawn EP1968958A1 (fr)

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DE102005062990A DE102005062990A1 (de) 2005-12-28 2005-12-28 Substituierte Thiazole und ihre Verwendung zur Herstellung von Arzneimitteln
PCT/EP2006/012483 WO2007079961A1 (fr) 2005-12-28 2006-12-22 Thiazoles substitues et leur utilisation pour produire des medicaments

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US8318774B2 (en) 2012-11-27
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CA2633734A1 (fr) 2007-07-19
DE102005062990A1 (de) 2007-07-05

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