WO2004041815A1

WO2004041815A1 - Indole derivative with 5ht1a affinity

Info

Publication number: WO2004041815A1
Application number: PCT/EP2003/011132
Authority: WO
Inventors: Kai Schiemann; Henning Böttcher; Timo Heinrich; Günter Hölzemann; Christoph Van Amsterdam; Gerd Bartoszyk; Joachim Leibrock; Christoph Seyfried
Original assignee: Merck Patent Gmbh
Priority date: 2002-11-08
Filing date: 2003-10-08
Publication date: 2004-05-21
Also published as: DE10252102A1; AU2003278057A1

Abstract

Novel indole derivatives of formula (I), where A , X, R1, R1' and m have the meanings given in claim 1, have a strong affinity for the 5-HT1A and partial affinity for the 5-HT1D receptors. The compounds inhibit serotonin reuptake, display serotonin agonist and antagonist properties and are suitable as antidepressants, anxiolytics and for the treatment of neurodegenerative diseases.

Description

INDOLDΞRIVATE WITH 5HT1A AFFINITY

The invention relates to indole derivatives of the formula I.

where X is N or CH,

R ¹ , R ^{1 '} each independently of one another H, A, OH, OA, CN, shark, GOR ⁴ or CH ₂ R ⁴ ,

RH, A, Hai, OH, OA, SA, COOH, COOA ', CHO, COA \ S02A', NH ₂₎ NHA, NA ₂₎ CH ₂ NA ₂ , NHCOA, NHCOAr, NHCOOA, NHS0 ₂ A, NHS0 ₂ Ar , CH ₂ NHS0 ₂ A, NHCONH ₂ , NHGONHA, NHCONAs, NHCONHAr, CONH ₂₎ CONHA, CONA ₂ , S0 ₂ NH _2> S0 ₂ NHA, SO ₂ NA ₂ , CH ₂ S0 ₂ NH ₂ , CH ₂ S0 ₂ NHA , CH2S0 ₂ NA _2> [C (R ⁴ R ^{4 '} )] _P CN, [C (R ⁴ R ^4' )] _P CF _3! [C (R ⁴ R ⁴ ') 3 _P COR ⁴ , [C (R ⁴ R ⁴ ') 3 _P Ar, [C (R ⁴ R ⁴ ')] _P A, or [C (R ⁴ R ^{4 '} )] _p Het,

R ³ H, A, [C (R ⁴ R ^{4 '} )] _p Ar or [C (RR ⁴ ')] _p Het,

R ² and R ³ together also -CH = CH-CH = CH- or -CH ₂ -CH ₂ -CH = CH- wherein 1 or 2 CH and / or CH ₂ units can be replaced by N and / or 1 , 2, 3 or 4 H atoms due to shark, A,

OH, OA, NH _2> N0 ₂ , CN, COOH, COOA, CONH _2l NHCOA, NHCONH ₂ , NHS0 ₂ A, CHO, COA, S0 ₂ NH ₂ or S (0) ₀ A can be substituted,

R ⁴ , R ^{4 '} each independently of one another H, A, OH, OA, NH ₂ , NHA, NA ₂ or NHCOOA \

Ar unsubstituted or single, double or triple by shark, A,

OH, OA, NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH _2l NHSO ₂ A, CHO, COA, S0 ₂ NH ₂ or S (0) ₀ A, substituted phenyl, naphthyl or biphenyl, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by carbonyl oxygen, = S, = NH, Hai, A , - (CH ₂ ) ₀ -Ar, - (CHjzJo-cycloalkyl, - (CH ₂ ) ₀ -OH, - (CH ₂ ) o-NH ₂₎ N0 _2l CN, - (CH ₂ ) ₀ -COOH, - ( CH ₂ ) ₀ -COOA, - (CH ₂ ) ₀ -CONH ₂ ,

- (CH ₂ ) ₀ -NHCOA, NHCONH ₂ , - (CH ₂ ) o -NHS0 ₂ A, CHO, COA ', SO ₂ NH ₂ and / or S (0) ₀ A may be substituted,

A unbranched or branched alkyl having 1-10 C atoms, in which one or two CH ₂ groups can be replaced by -CH = CH groups and / or 1 -7 H atoms by F and / or Cl,

A 'alkyl having 1 to 6 carbon atoms or benzyl,

Shark F, Cl, Br or I and m 2, 3, 4, 5 or 6 n 1, 2, 3 or 4, o 0, 1 or 2, p 0, 1, 2, 3, 4, 5 or 6, mean, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions.

The object of the invention was to find new compounds with valuable properties, in particular those which are used for the production of medicaments.

Piperazine and piperidine derivatives as 5-HT- _A receptor agonists are known, for example, from WO 96/16056. Piperidine derivatives other than 5HT receptor agonists are disclosed in WO 96/17842, WO 97/18202 and WO 97/18203.

It has been found that the compounds of the formula I according to the invention and their physiologically acceptable acid addition salts, with good tolerability, have valuable pharmacological properties, since they have effects on the central nervous system, in particular 5-HT reuptake inhibitory effects, by influencing the serotoninergic transmission. In particular, they have a strong affinity for the 5-HTι _A - and partially for the 5-HTι _D - receptors.

Since the compounds also inhibit serotonin reuptake, they are particularly suitable as antidepressants and anxiolytics. The compounds show characteristic properties of serotonin agonism and antagonism. They inhibit the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140 (1987), 143-155) and inhibit synaptosomal serotonin reuptake (Sherman et al., Life Sei. 23 (1978) , 1863-1870). For ex vivo detection of serotonin reuptake inhibition, synaptosomal reuptake inhibition (Wong et al., Neuropsychopharmacol. 8 (1993), 23-33) and p-chloroamphetamine antagonism (Füller et al., J. Pharmacol. Exp.Ther. 212 (1980 ), 115-119). The 5-HTι _D - Affinity can be determined, for example, by the method described by Pauwels and Palmier in Neuropharmacology, 33, 67 (1994).

The binding properties of the compounds of the formula I can be determined by known 5-HT _1A - (serotonin) binding tests (5-HT 1 _A -

(Serotonin) binding test: Matzen et al., J. Med. Chem., 43, 1149-1157, (2000) in particular page 1156 with reference to Eur. J. Pharmacol .: 140, 143-155 (1987).

The compounds according to the invention can be used for the treatment of diseases which are connected to the serotonin neurotransmitter system and in which high-affinity serotonin receptors (5-HT _1A receptors) and / or 5-HTι _D receptors are involved.

The compounds of the formula I are therefore suitable both in veterinary medicine and in human medicine for the treatment of functional disorders of the central nervous system and of inflammation. They can be used for prophylaxis and to combat the consequences of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia, as well as for the treatment of extrapyramidal-motor side effects of neuroleptics and Parkinson's disease, for the acute and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis , They are also suitable as therapeutic agents for the treatment of brain and spinal cord trauma. In particular, however, they are suitable as active pharmaceutical ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and / or for positively influencing obsessive-compulsive disorder (OCD), anxiety states, panic attacks, psychoses, anorexia, delusional obsessive-compulsive illnesses, migraines, migraines , Sleep disorders, tardive dyskinesias, learning disorders, age-related memory disorders, eating disorders such as bulimia, substance abuse and / or sexual dysfunction. An important indication for the administration of the compound of the general formula I are psychoses of all types, in particular also mental illnesses from the schizophrenia group. In addition, the compounds can also reduce cognitive

Performance disorders, i.e. to improve learning ability and memory. The compounds of the general formula I are also suitable for combating the symptoms of Alzheimer's disease. In addition, the substances of general formula I according to the invention are suitable for the prophylaxis and control of cerebral infarcts (apoplexia cerebri), such as stroke and cerebral ischemia. The substances are also used to treat diseases such as pathological anxiety, overexcitation, hyperactivity and attention disorders in children and adolescents, profound developmental disorders and disorders in social behavior with mental retardation, depression, OCD and other senses (OCSD) certain sexual dysfunctions, sleep disorders and disorders in food intake, as well as such psychiatric symptoms in the context of age dementia and dementia of the Alzheimer type, that is, diseases of the central nervous system in the broadest sense, into question.

The compounds of the formula I are also suitable for the treatment of extrapyramidal movement disorders, for the treatment of side effects which occur in the treatment of extrapyramidal movement disorders with conventional anti-Parkinson medications or for the treatment of extrapyramidal symptoms (EPS) which are induced by neuroleptics.

Extrapyramidal movement disorders are, for example, idiopathic Parkinson's disease, Parkinson's syndrome, dyskinetic choreatic or dystonic syndromes, tremors, Gilles de la Torette Syndrome, ballism, muscle spasm, restless legs syndrome, Wilson's disease, Lewy bodies dementia, Huntington and Tourette syndrome.

The compounds according to the invention are also particularly suitable for the treatment of neurodegenerative diseases, such as e.g. lathyrism,

Alzheimer's, Parkinson's, and Huntington's.

The compounds of the formula I are particularly suitable for the treatment of side effects which occur in the treatment of idiopathic Parkinson's disease with conventional Parkinson's medication. Therefore, they can also be used as add-on therapy in the treatment of Parkinson's disease. Known Parkinson's drugs are drugs such as L-dopa (levodopa) and L-dopa combined with benserazide or carbidopa, dopamine agonists such as bromocriptine, apomorphine, cabergoline,

Pramipexole, ropinirole, pergolide, dihydro-α-ergocriptin or lisuride and all drugs that stimulate the dopamine receptor, inhibitors of catechol-O-methyl-transferase (COMT) such as entacapone or tolcapone, inhibitors of monoamine oxidase (MAO) such as selegiline and antagonists of N-methyl-D-aspartate (NMDA) receptors such as amantadine or budipine.

The compounds of the general formula I and their compatible salts and solvates can thus be used as active ingredients for medicaments such as anxiolytics, antidepressants, neuroleptics and / or antihypertensives.

A measure of the absorption of an active pharmaceutical ingredient into an organism is its bioavailability. If the active pharmaceutical ingredient is in the form of a solution for injection

Added organism intravenously, so its absolute bioavailability, ie the proportion of the drug that reaches unchanged in the systemic blood, ie in the large circulation, at 100%.

When a therapeutic active ingredient is administered orally, the active ingredient is usually present as a solid in the formulation and must therefore first dissolve so that it blocks the entry barriers, for example the gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum, can overcome or be absorbed by the body. Pharmacokinetic data, i.e. bioavailability can be obtained analogously to the method of J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318.

Another measure of the resorbability of a therapeutic agent is the logD value, because this value is a measure of the lipophilicity of a molecule.

Insofar as the compounds of the general formula I are optically active, the formula I comprises both each isolated optical antipode and the corresponding optionally racemic mixtures in any conceivable composition.

Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or addition compounds with alcohols, such as e.g. with methanol or ethanol.

The invention relates to the compounds of formula I and their salts and solvates according to claim 1 and a process for the preparation of compounds of formula I and their salts and solvates, characterized in that

a compound of formula II

wherein A) and X have the meanings given in claim 1, with a compound of formula III

wherein

L denotes Cl, Br or I and R ¹ , R ^{1 '} and m have the meanings given in Claim 1,

and or

converts a remainder (A into another remainder (A,

by converting an ester to an aminocarbonyl group, or by cleaving an amino protecting group.

and / or converts a basic or acidic compound of the formula I into one of its salts or solvates by treatment with an acid or base.

Pharmaceutically usable derivatives are taken to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds. Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention. This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 115. 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.

A means alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1, 2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1 - or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferably for example Trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or 1, 1, 1-trifluoroethyl. A also means cycloalkyl.

Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A ¹ preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl or benzyl.

-COA or -COA '(acyl) preferably means acetyl, propionyl, further also butyryl, pentanoyl, hexanoyl or e.g. Benzoyl. Shark preferably means F, Cl or Br, but also I.

OA preferably means e.g. Methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy.

R ¹ is preferably, for example, CN or F, very particularly preferably CN.

R ^{1 '} is preferably H. m is preferably 4.

R ² preferably denotes H, OH, COOA ', CONH ₂ , [C (RR ^4' )] _P CF ₃₎

[C (R ⁴ R ^{4 '} )] _p COR ⁴ , [C (R ⁴ R ^4' )] _p Ar, [C (R ⁴ R ^{4 '} )] _P A or [C (R ⁴ R ^4' )] _p Het.

R ² particularly preferably denotes H, OH, COOA ', CONH ₂ , Het, CF ₃ ,

[C (R ⁴ R ^{4 '} )] pCOOA', [C (R ⁴ R ')] _P A or [C (R ⁴ R ^4' )] _p Ar, where Het is preferably unsubstituted or simply substituted by shark or COOA '

Chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl, pyrrolyl,

Isoxazolyl imidazolyl, thiazolyl, triazolyl, tetrazolyl or isoquinolyl and Ar preferably denotes phenyl.

R ³ preferably denotes H or A, very particularly preferably H or methyl, ethyl, propyl or butyl.

R ⁴ is preferably H or A.

R ^{4 '} is preferably H, A, NHCOOA' or NH ₂ .

Ar means, for example, unsubstituted phenyl, naphthyl or biphenyl, further preferably, for example, by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, Ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyan, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamidamidamidamamido, dimylsulfonamido, dimethylsulfonamido, butyl methoxycarbonyl,

Ethoxycarbonyl, aminocarbonyl mono-, di- or tri-substituted phenyl, naphthyl or biphenyl. Ar very particularly preferably denotes phenyl. Het means apart from the possible substituents, e.g. 2- or 3- furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazoM-, -3- or 5-yl , 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3 ~ or -5-yl, 1, 2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5- , 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6 - or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4 -, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalin-yl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1, 3-benzothiadiazol-4- or -5-yl, 2,1, 3-benzoxadiazol-5-yl or chromenyl.

The heterocyclic radicals can also be partially or completely hydrogenated. Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrroli- dinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, - 4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or - 4-pyranyl, 1 , 4-dioxanyl, 1, 3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7 - or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2 -, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo [1, 4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3- Ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) phenyl or also 3,4 - Dihydro-2H-1,5-benzodioxepin-6- or -7-yl, more preferably 2,3-dih ydro-benzofuranyl or 2,3-dihydro-2-oxo-furanyI.

Het very particularly preferably means unsubstituted or simply substituted by shark or COOA 'chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazolyl, thiazolyl, triazolyl, tetrazolyl or isoquinolyl.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to If, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in la R ¹ CN or F, RR ¹¹ 'HH; in Ib R ² H, OH, COOA ', CONH ₂ , [C (R ⁴ R ^4' )] pCF ₃ , [C (R ⁴ R ⁴ ')] _p COR ⁴ , [C (RR ^' )] _p Ar , [C (R ⁴ R ^{4 '} )] _PA or [C (R ⁴ R ^4' )] _p Het, R ^{3 is} H or A;

in Ic Het is unsubstituted or simply substituted by shark or COOA 'chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazoiyl, thiazolyl, triazolyl, tetrazolyl or isoquinolyl;

in Id Ar represents phenyl;

R ² H, OH, COOA ', CONH ₂ , Het, [C (R ⁴ R')] _P CF ₃ ,

[C (R ⁴ R ^{4 '} )] _p COOA', [C (R ⁴ R ^{4 '} )] _P A or [C (R ⁴ R ^4' )] _p Ar, R ³ H or A,

Het unsubstituted or simply substituted by shark or COOA 'chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazoiyl, thiazolyl, triazolyl, tetrazolyl or isoquinolyl, ar phenyl,

R ⁴ H or A,

R ^{4 'is} H, A, NHCOOA' or NH ₂ , p 0, 1, 2 or 3;

R ² H, OH, COOA ', CONH ₂ , Het, CF ₃ , [C (R ⁴ R ⁴ )] _p COOA',

[C (R ⁴ R ⁴ ')] _PA or [C (R ⁴ R ⁴ ')] _p Ar, R ³ H or A, het unsubstituted or simply substituted by shark or COOA ', chromen-2-one-yl, Thienyl, pyridinyl, pyrimidinyl,

Indolyl, furyl, pyrrolyl, isoxazolyl imidazoiyl, thiazolyl,

Triazolyl, tetrazolyl or isoquinolyl, Ar phenyl, R ⁴ H or A,

R ^{4 'is} H, A, NHCOOA' or NH ₂ , p 0, 1, 2 or 3, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

The compounds of formula I according to claim 1 and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag) , Stuttgart) are described, namely under reaction conditions known for the reactions mentioned and are suitable. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I according to claim 1.

The starting compounds of the formula II and III are generally known. If they are new, they can be manufactured according to methods known per se.

Compounds of the formula I can be prepared by nucleophilic substitution of the leaving group L of the compounds of the formula III, where L is Cl, Br or I, by the piperazine nitrogen of the compound of the formula II under standard conditions.

The reaction conditions for nucleophilic substitutions, as described above, are well known to the person skilled in the art, see also Organikum, 17th edition, Deutscher Verlag für Wissenschaften, Berlin 1988.

The reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. The addition of an organic base such as ethyldiisopropylamine, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the component of the formula II or the alkylation derivative of the formula III can also be favorable. Depending on the conditions used, the reaction time is between a few minutes and 14 days. temperature between about 0 ° and 150 °, usually between 20 ° and 130 °.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as

Trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol),

Ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, N-methylpyrrolidone, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

Compounds of formula I can also be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group and / or those which have one instead of the H atom Hydroxy group carry a hydroxyl protecting group, for example those of the formula I. correspond, but instead of a group -COOH carry a group -COOR ", in which R" denotes a hydroxy protective group. Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.

Several - identical or different - protected amino and / or hydroxyl groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can be split off selectively in many cases.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or sequence of reactions), their type and size is otherwise not critical; however, those with 1-20, in particular 1-8, carbon atoms are preferred. The expression "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are

Alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOG (teributyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl. The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction at other points in the

Molecule has been carried out. Typical of such groups are the unsubstituted or substituted aryl, araikyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; are preferred

Groups with 1-20, especially 1-10 carbon atoms. Examples of hydroxy protecting groups include Benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - z. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or

Sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.

Hydrogenolytically removable protective groups (e.g. CBZ, benzyl or the release of the amidino group from their oxadiazole derivative) can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are the above, in particular z. B. alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Suitable inert solvents are e.g. the above.

Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, or reacted with CH ₃ -C (= NH) -OEt, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, sulfurous acid, dithionic acid,

Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as e.g. Orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, niconic acid, asonic acid, ascorbic acid

Ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexane carboxylic acid, glucose-1-phosphonic acid or naphthalenesulfonic acid, monophthalene and naphthalenesulfonic acid, naphthalenesulfonic acid or naphthalenesulfonic acid, monodisulfonic acid, or naphthalenesulfonic acid, monophosphonic acid or naphthalenesulfonic acid, or monodisulfonic acid, or naphthalenesulfonic acid, or naphthalenesulfonic acid, or naphthalenesulfonic acid, or naphthalenesulfonic acid, or monodisulfonic acid, Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I. On the other hand, compounds of the formula I with bases (for example sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal or into the corresponding ammonium salts. The invention also relates to the compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.

The invention furthermore relates to compounds of the formula I and their physiologically acceptable salts or solvates as 5HTι _A - and / or 5HTι _D - agonists and as inhibitors of 5-HT reuptake.

The invention also relates to the compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts or solvates for use in combating diseases.

Compounds of formula I according to the invention can be chiral due to their molecular structure and can accordingly occur in various enantiomeric forms. They can therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art, or can already be used as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optical active camphorsulfonic acids. Chromatographic separation of enantiomers using an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous. Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3.

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament (pharmaceutical preparation), in particular in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

The invention furthermore relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.

Another object of the invention is the use of a compound of general formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament which is suitable for the treatment of human or animal diseases, in particular diseases of the central nervous system such as pathological tension, depression and / or psychoses, to reduce side effects in the treatment of high blood pressure (e.g. with a-methyldopa), to treat endoclinological and / or gynecological diseases, e.g. to treat agromegaly, hypogonadism, secondary amenorrhea , the post-menstrual Syndrome and unwanted lactation during puberty and for the prophylaxis and therapy of cerebral diseases (e.g. migraines), especially in gereatria, in a manner similar to certain ergot alkaloids and for the control and prophylaxis of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia Treatment of extrapyramidal

Movement disorders, for the treatment of side effects that occur in the treatment of extrapyramidal movement disorders with conventional anti-Parkinson medication or for the treatment of extrapyramidal symptoms (EPS) that are induced by neuroleptics. In addition, the pharmaceutical preparations and medicaments which contain a compound of the general formula I are suitable for improving cognitive performance and for treating Alzheimer's disease symptoms. Such medicinal products are particularly suitable for the treatment of mental illnesses from the schizophrenia group and for

Combating psychotic anxiety. In the context of the invention, the term treatment includes prophylaxis and therapy of human or animal diseases. The invention furthermore relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for combating diseases which are associated with the serotonin neurotransmitter system and in which are involved in high-affinity serotonin receptors (5-HTι _A receptors) and / or 5-HT _ID receptors.

The invention furthermore relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the production of a medicament as an anxiolytic, antidepressant, neuroleptic and / or antihypertensive. The substances of the general formula I are normally administered analogously to known, commercially available pharmaceutical preparations (for example bromocriptine and dihydroergocornine), preferably in doses of between 0.2 and 500 mg, in particular between 0.2 and 15 mg per dose unit. The daily dose unit is between 0.001 and

10 mg per kg body weight. Low doses (between 0.2 and 1 mg per dose unit, 0.001 to 0.005 mg per kg body weight) are particularly suitable for pharmaceutical preparations for the treatment of migraines. A dose between 10 and 50 mg per dose unit is preferred for other indications. However, the dose to be administered depends on a variety of factors, e.g. the effectiveness of the relevant component, the age, body weight and general condition of the patient.

The invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.

The invention also relates to a set (kit) consisting of separate packs of

(a) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and

(b) an effective amount of another drug ingredient.

The set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set can contain, for example, separate ampoules, each containing an effective amount of a compound of formula I and / or its pharmaceutically usable Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient are dissolved or in lyophilized form.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel, by preparative HPLC and / or by crystallization. The purified compounds are optionally freeze-dried. Mass spectrometry (MS): El (electron impact ionization) M ⁺ FAB (Fast Atom Bombardment) (M + H) ⁺

ESI (Electrospray lonization) (M + H) ⁺ (unless stated otherwise) Example 1

The synthesis of ethyl 2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxylate is carried out analogously to the following scheme:

1.1 2.0 g (10.7 mmol) of tert-butyl piperazine-1-carboxylate is dissolved in THF (25 ml), 2.1 g (11.7 mmol) of thiocarbonyldiimidazole are added and the mixture is stirred at RT (room temperature) for 5 h touched. 10 mL ammonia solution (25% in water) are then added and the mixture is stirred at RT for 18 h. The reaction mixture is concentrated on a rotary evaporator and water is added to the residue, the product 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester precipitating.

The solid is filtered off with suction, washed with water and dried at 65 ° C. for 18 h in a vacuum drying cabinet and further reacted raw. Yield: 2.3 g of yellowish solid; [M + Hf 246, [M-55] ⁺ 190 (HPLC-MS).

1.2 1.0 g (4.1 mmol) of tert-butyl 4-thiocarbamoyl-piperazine-1-carboxylate is taken up in DMF / dioxane (20 mL, 1: 1), 0.8 g (4.1 mmol) Ethyl bromopyruvate added and stirred at 70 ° C for 18 h. The cooled solution is mixed with diethyl ether (30 mL), the product 4- (4-ethoxycarbonyl-thiazol-2-yl) -piperazine-1-carboxylic acid tert-butyl ester precipitating as HBr salt. The crude product is filtered off and taken up in dichloromethane / trifluoroacetic acid (20 mL, 1: 1) for 30 min RT stirred, the solvent removed and the residue freeze-dried in water after slurrying. A white solid (2-piperazin-1-yl-thiazol-4-carboxylic acid ethyl ester) of high purity is obtained. Yield: 1.3 g of white solid, TFA salt; [M + H] ⁺ 242 (HPLC-MS).

1.3 131 mg (0.56 mmol) of 3- (4-chlorobutyl) -1 H-indole-5-carbonitrile (the corresponding iodine compound can also be used) and 200 mg (0.56 mmol) of 2-piperazine-1 -yl-thiazole-4-carboxylic acid ethyl ester is taken up in Λ-methylpyrrolidone (4 mL) and 0.22 g (1.7 mmol) of ethyldiisopropylamine are added at RT. The solution is stirred at 100 ° C. for 18 h, the solvent is largely removed from the cooled reaction mixture and the residue is purified by column chromatography (ethyl acetate / methanol, 9: 1). The purified product (2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxylic acid ethyl ester) is added to the HCl in the usual way Salt transferred.

Yield: 120 mg of white solid, HCl salt; [M + H] ⁺ 439 (HPLC-MS).

Example 2

Preparation of 2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxamide

100 mg (0.19 mmol) of ethyl 2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxylate x HCl is dissolved in ethanol (2 mL), 2 mL ammonia solution (25% in water) added dropwise at RT and stirred at RT for 18 h.

The solvent is removed, the residue is taken up in ethyl acetate, washed once each with water and saturated NaCl solution, dried with Na2SO4 (anhydrous), filtered and the solvent of the filtrate is removed. The crude product is taken up in 0.1 M HCl solution in 2-propanol, treated in an ultrasound bath for 5 min and the solid formed is filtered off. Yield: 74 mg of 2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxamide, HCl salt; [M + H] ⁺ 410 (HPLC-MS).

Example 3

An alternative synthesis of 2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxylic acid ethyl ester is carried out analogously to the following scheme:

3.1 2.0 g (7.1 mmol) of 3- (4-piperazin-1-yl-butyl) -1 H-indole-5-carbonitrile is dissolved in THF / DMF (10 mL, 1: 1), 1, Add 4 g (7.8 mmol) of thiocarbonyldiimidazole and stir at RT for 5 h. Then 8 mL ammonia solution (25% in water) is added and the mixture is stirred at RT for 18 h. The reaction mixture is concentrated on a rotary evaporator and water is added to the residue, the product (4- [4- (5-cyan-1H-indol-3-yl) butyl] piperazin-1-carbothioamide) precipitating.

The product was filtered off with suction, washed with water and dried at 65 ° C. for 18 hours in a vacuum drying cabinet and further reacted raw.

Yield: 1.7 g of yellowish solid, [M + H] ⁺ 342 (HPLC-MS).

3.2 100 mg (0.3 mmol) 4- [4- (5-Cyan-1 H-indol-3-yl) butyl] piperazin-1 - carbothioamide is dissolved in DMF / dioxane (4 mL, 1: 1) added, 79 mg (0.3 mmol) ethyl bromopyruvate added and stirred at 70 ° C for 18 h. The cooled solution is mixed with diethyl ether (10 mL), the product (2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole -4-carboxylic acid ethyl ester) with high purity. Yield: 110 m g of yellowish solid, HBr salt; [M + H] ⁺ 439 (HPLC-MS).

Example 4

Analogously to Example 1, the following compounds are obtained by reacting 3- (4-chlorobutyl) -1 H -indole-5-carbonitrile with the corresponding piperazine derivatives

5- (2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) - isoxazol-3-carboxylic acid ethyl ester, [ M + H] ⁺ 506; 2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl-7-oxo-4,5,6,7-tetrahydro-thiazolo [4th , 5-r] quinoline-8-carbonitrile, [M + H] ⁺ 511

3- (4- {4- [4- (2-Oxo-2H-chromen-3-yl) thiazol-2-yl] piperazin-1-yl} butyl) -1 H-indole-5-carbonitrile , [M + H] ⁺ 511;

3- {4- [4. (4-Ethylthiazol-2-yl) piperazin-1-yl] butyI} -1 H-indole-5-carbonitrile, [M + H] ⁺ 395;

3- {4- [4- (5-Methyl-4-trifluoromethylthiazol-2-yl) piperazin-1-yl] butyl} - 1 H-indole-5-carbonitrile, [M + H] ⁺ 449 ;

3- (4- {4- [4- (3-Chlorothiophen-2-yl) thiazol-2-yl) piperazin-1-yl} butyl) - 1 H-indole-5-carbonitrile, [ M + H] ⁺ 483;

3- {4- [4- (4,5-Dihydro-2-oxa-6-thia-1, 3,8-triaza-as-indacen-7-yl) - piperazin-1-yl] butyl} - 1 H-indole-5-carbonitrile, [M + H] ⁺ 461

3- {4- [4- (4-pyridin-3-yl-thiazol-2-yl) piperazin-1-yl] butyl} -1 H-indole-5-carbonitrile, [M + H 444;

3- (4- {4- [4- (1- {N-Benzyloxycarbonylamino} -2-phenylethyl) thiazol-2-yl] piperazin-1-yl} butyl) -1 H-indole -5-carbonitrile, [M + H] ⁺ 620;

3- (4- {4- [4- (l H-indol-3-yl) thiazol-2-yl] piperazin-1-yl} butyl) -1 H-indole-5-carbonitrile, [M + H] ⁺ 482; 3- (2- {4- [4- (5-Cyan-1H-indol-3-yl) -butyl] -ρiperazin-1 -yl} -thiazol-4-yl) -3-methyl-butyric acid ethyl ester, [ M + H] ⁺ 495.

Example 5

Removal of the protective group from 3- (4- {4- [4- (1- {N-benzyloxycarbonyl-amino} -2-phenyl-ethyl) -thiazol-2-yl] -piperazin-1-yl} -butyl) -1 H-indole-5-carbonitrile is carried out according to customary standard methods by hydrogenation. The compound 3- (4- {4- [4- (1-amino-2-phenyl-ethyl) -thiazol-2-yl] -piperazin-1 -yl} -butyl) -1 H-indole-5 is obtained carbonitrile.

Example 6

The synthesis of ethyl 2- {1- [4- (5-cyano-1 rV-indol-3-yl) -butyl] -piperidin-4-yl} - thiazole-4-carboxylate follows the scheme below:

6.1 1.0 g (7.8 mmol) of piperidine-4-carboxamide and 1.6 g (3.9 mmol) of Lawesson's reagent (2,4-bis (4-methoxyphenyl) - [1, 3.2.4 ] dithia diphosphetane 2,4-disulfide) are taken up in pyridine / dioxane (50 mL, 1: 1) and heated under reflux for 3 h. The solid which precipitates after cooling is filtered off and discarded. The filtrate is evaporated to dryness and reacted without further purification. Yield: 1.1 g of yellow solid substance (piperidine-4-carbothioamide)

[M + H] ⁺ 145 (HPLC-MS).

6.2 1.0 g (6.9 mmol) of piperidine-4-carbothioamide is taken up in DMF / dioxane (30 mL, 1: 1), 1.3 g (6.9 mmol) of ethyl bromopyruvate are added and the mixture is stirred at 70 ° C. for 18 h touched. The cooled solution is mixed with diethyl ether (30 mL), the product (2-piperidin-4-yl-thiazol-4-carboxylic acid ethyl ester) precipitating as a yellowish solid. Yield: 1.8 g of yellowish solid, HBr salt; [M + H] ⁺ 241 (HPLC-MS).

6.3 1.0 g (4.3 mmol) of 3- (4-chloro-butyl) -1 H-indole-5-carbonitrile is taken up in acetone (50 mL), 3.9 g (25.8 mmol) of Nal and 5 g of molecular sieve (0.3 nm bead form, 2 mm, Merck) were added and the mixture was stirred at reflux for 16 h. The cooled suspension was filtered and the filtrate evaporated to dryness. The raw material (3- (4-iodo-butyl) -1 H-indole-5-carbonitrile) is used without further purification. Yield: 1.2 g of white solid, [M + H] ⁺ 325 (HPLC-MS).

6.4 200 mg (0.62 mmol) of 3- (4-iodobutyl) -1 H-indole-5-carbonitrile and 200 mg (0.62 mmol) of 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester x HBr is taken up in Λ / methylpyrrolidone (4 mL) and 0.24 g (1.9 mmol) of ethyldiisopropylamine is added at RT. The solution is stirred at 100 ° C. for 18 h, the solvent is largely removed from the cooled reaction mixture and the residue is purified by column chromatography (ethyl acetate / methanol, 9: 1). The purified product (2- {1- [4- (5-cyano-1H-indol-3-yl) butyl] piperidin-4-yl} thiazole-4-carboxylic acid ethyl ester is added in a conventional manner to the HCl- Salt transferred. Yield: 202 mg of white solid, HCl salt; [M + H] ⁺ 438 (HPLC-MS).

Example 7

Preparation of 2- {1 - [4- (5-cyano-1H-indol-3-yl) butyl] piperidin-4-yl} thiazole-4-carboxamide

100 mg (0.23 mmol) of ethyl 2- {1- [4- (5-cyano-1H-indol-3-yl) butyl] piperidin-4-yl} - thiazole-4-carboxylate is dissolved in ethanol ( 2 mL), 2 mL ammonia solution (25% in water) were added dropwise at RT and the mixture was stirred at RT for 18 h. The solvent is removed.

The crude product is taken up in 0.1 M HCl solution (in 2-propanol), treated in an ultrasound bath for 5 min and the solid formed is filtered off. Yield: 78 mg of white solid, HCl salt; [M + H] ⁺ 409 (HPLC-MS).

Example 8

3- [4- (4-thiazol-2-yl-piperazin-1-yl) butyl] -1 H-indole-5-carbonitrile, ESI 367; 3- {4- [4- (4-Hydroxythiazol-2-yl) piperazin-1-yl] butyl} -1 H-indole-5-carbonitrile, ESI 383;

3- {4- [4- (4-pyridin-2-yl-thiazol-2-yl) piperazin-1-yl] butyl} -1 H-indole-5-carbonitrile, ESI 444;

3- {4- [4- (4-pyridin-4-yl-thiazol-2-yl) piperazin-1-yl] butyl} -1 H-indole-5-carbonitrile, ESI 444; [1 - (2- {4- [4- (5-Cyan-1 H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) -3-methylbutyl- carbamic acid te / t-butyl ester

3- (2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) -3-methyl-butyramide, ESI 466th

Example 9

Removal of the protective group from [1- (2- {4- [4- (5-cyan-1 - / - indol-3-yl) - butyl] -piperazin-1-yl} -thiazol-4-yl) - 3-methyl-butyl] -carbamic acid tert-butyl ester is carried out according to customary standard methods by hydrogenation. The compound 3- (4- {4- [4- (1-amino-3-methylbutyl) thiazol-2-yl] piperazin-1-yl} -butyl) -1 H-indole-5 is obtained -carbonitrile, ESI 452.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH ₂ P0 ₄ • 2 H ₂ 0, 28.48 g Na ₂ HP0 ₄ • 12 H ₂ 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions. Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I: Inhalation Spray

14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCl solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

claims

1. Compounds of the formula

wherein

X N or CH,

R ¹ , R ^{1 '} each independently of one another H, A, OH, OA, CN, shark, COR ⁴ or CH ₂ R ⁴ ,

R ² H, A, Shark, OH, OA, SA, COOH, COOA ', CHO, COA', S0 ₂ A ', NH ₂ , NHA, NA ₂ , CH ₂ NA ₂ , NHCOA, NHCOAr, NHCOOA, NHS0 ₂ A, NHS0 ₂ Ar, CH ₂ NHS0 ₂ A, NHCONH ₂ , NHCONHA, NHCONA ₂ , NHCONHAr, CONH ₂ , CONHA, CONA ₂ , S0 ₂ NH ₂ , S0 ₂ NHA, S0 ₂ NA ₂ , CH ₂ S0 ₂ NH ₂ , CH ₂ S0 ₂ NHA, CH ₂ S0 ₂ NA ₂ , [C (R ⁴ R ^{4 '} )] _P CN, [C (R ⁴ R ⁴ ')] _P CF ₃ , [C (R ⁴ R ')] _P C0R ⁴ ,

[C (R ₁ 4Wr-, 4 ')] _P A, or [C (R 4r> r4S)] _p Het

R ^d H, A, [C (R ⁴ R ^{4 '} )] _p Ar or [C (R ⁴ R ^4' )] _p Het, R ² and R ³ together also -CH = CH-CH = CH- or -CH ₂ -CH ₂ - CH = CH- wherein 1 or 2 CH and / or CH ₂ units can be replaced by N and / or 1 , 2, 3 or 4 H atoms through shark, A, OH, OA, NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHS0 ₂ A, CHO,

COA, S0 ₂ NH ₂ or S (O) ₀ A can be substituted, R ⁴ , R ^{4 '} each independently of one another H, A, OH, OA, NH ₂ , NHA,

NA≥or NHCOOA ', Ar unsubstituted or single, double or triple by shark, A, OH, OA, NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ , NHCOA,

NHCONH ₂ , NHSO ₂ A, CHO, COA, S0 ₂ NH ₂ or S (O) ₀ A, substituted phenyl, naphthyl or biphenyl, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O - and / or S atoms which are unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, = S, = NH, shark, A, - (CH ₂ ) ₀ -Ar, - (CH ₂ ) o-cycloalkyl, - (CH ₂ ) ₀ -OH, - (CH ₂ ) ₀ -NH ₂ , N0 ₂ , CN, - (CH ₂ ) ₀ -COOH, - (CH ₂ ) ₀ -COOA, - (CH ₂ ) o-CONH ₂ , - (CH ₂ ) ₀ -NHCOA, NHCONH ₂ , - (CH ₂ ) o -NHS0 ₂ A, CHO, COA ', S0 ₂ NH ₂ and / or S (O) ₀ A may be substituted,

A unbranched or branched alkyl having 1 -10 C atoms, in which one or two CH ₂ groups can be replaced by -CH = CH groups and / or 1-7 H atoms by F and / or Cl, A ' Alkyl with 1 to 6 carbon atoms or benzyl,

Shark F, Cl, Br or I and m 2, 3, 4, 5 or 6 n 1, 2, 3 or 4,

0 means 0, 1 or 2, p 0, 1, 2, 3, 4, 5 or 6, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

2. Compounds according to claim 1, wherein

R ¹ CN or F,

R ¹ 'H and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Conditions.

3. Compounds according to one or more of claims 1-2, wherein R ^{2 is} H, OH, COOA ', CONH ₂ , [C (R ⁴ R ^4' )] _P CF ₃ , [C (R ⁴ R ⁴ ')] _p COR ⁴ , [C (R ⁴ R ^{4 '} )] _p Ar, [C (R ⁴ R ⁴ ')] _P A, or [C (R ⁴ R ^{4 '} )] _p Het,

R ^{3 is} H or A, and their pharmaceutically usable derivatives, solvates and

Stereoisomers, including their mixtures in all proportions.

4. Compounds according to one or more of claims 1-3, wherein Het is unsubstituted or simply substituted by shark or COOA 'chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazoiyl, thiazolyl,

Triazolyl, tetrazolyl or isoquinolyl means, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions.

5. Compounds according to one or more of claims 1-4, wherein Ar is phenyl, and their pharmaceutically usable derivatives, solvates and

Stereoisomers, including their mixtures in all

Conditions.

6. Compounds according to one or more of claims 1-5, wherein

R ² H, OH, COOA ', CONH ₂ , Het, [C (R ⁴ R ^4' )] _p CF ₃ ,

[C (R ⁴ R ^{4 *} )] _p COOA ', [C (R ⁴ R ^4' )] _P A or [C (R ⁴ R ⁴ ')] _p Ar,

R ³ H or A, Het unsubstituted or simply substituted by shark or COOA 'chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl, indolyl, furyl, pyrrolyl, isoxazolyl imidazoiyl, thiazolyl, triazolyl, tetrazolyl or isoquinolyl,

Ar phenyl, R ⁴ H or A,

R ⁴ 'is H, A, NHCOOA' or NH ₂ , p 0, 1, 2 or 3, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Conditions.

7. Compounds according to one or more of claims 1-6, wherein

R ^ H, OH, COOA ', CONH ₂ , Het, CF ₃ , [C (R 4Wι-ι4'>)] _p COOA '[C (R ⁴ R ^4' )] _P A or [C (R ⁴ R ^{4 '} )] _p Ar,

R H or A, Het unsubstituted or simply substituted by shark or COOA 'chromen-2-one-yl, thienyl, pyridinyl, pyrimidinyl,

Indolyl, furyl, pyrrolyl, isoxazolyl imidazoiyl, thiazolyl,

Triazolyl, tetrazolyl or isoquinolyl,

Ar phenyl,

H or A,

4 'H, A, NHCOOA' or NH ₂ , p 0, 1, 2 or 3 mean, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

8. Compounds according to claim 1

2- {4- [4- (5-Cyan-1H-indol-3-yl) -butyl] -piperazin-1-yl} -thiazole-4-carboxamide, 2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl} thiazole-4-carboxylic acid, ethyl ester,

5- (2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) -isoxazole-3-carboxylic acid ethyl ester, 2 - {4- [4- (5-Cyan-1 H -indol-3-yl) butyl] piperazin-1 -yl} -7-oxo

4,5,6,7-tetrahydro-thiazolo [4,5-f | quinoline-8-carbonitrile,

3- (4- {4- [4- (2-Oxo-2H-chromen-3-yl) thiazoI-2-yl] piperazin-1-yl} - butyl) -1 H-indole-5-carbonitrile .

3- {4- [4- (4-ethylthiazol-2-yl) piperazin-1-yl] butyl} -1H-indole-5-carbonitrile,

3- {4- [4- (5-methyl-4-trifluoromethylthiazol-2-yl) piperazin-1-yl] - butyl} -1 H-indole-5-carbonitrile,

3- (4- {4- [4- (3-chlorothiophen-2-yl) thiazol-2-yl) piperazin-1-yl} - butyl) -1 H -indole-5-carbonitrile, 3 - {4- [4- (4,5-Dihydro-2-oxa-6-thia-1, 3,8-triaza-as-indacen-7-yl) - piperazin-1-yl] -butyl} -1 H-indole-5-carbonitrile,

3- {4- [4- (4-pyridin-3-yl-thiazol-2-yl) piperazin-1-yl] butyl} -1 H-indole-5-carbonitrile,

3- (4- {4- [4- (1-Amino-2-phenylethyl) thiazol-2-yl] piperazin-1-yl} - butyl) -1 H -indole-5-carbonitrile,

3- (4- {4- [4- (1- {N-Benzyloxycarbonylamino} -2-phenylethyl) thiazol-2-yl] piperazin-1-yl} butyl) -1 H-indole -5-carbonitrile,

3- (4- {4- [4- (1 H-indol-3-yl) thiazol-2-yl] piperazin-1-yl} butyl) -1 H-indole-5-carbonitrile, 3- (2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) -3-methyl-butyric acid ethyl ester,

2- {1- [4- (5-cyano-1H-indol-3-yl) butyl] piperidin-4-yl} thiazole-4-carboxamide,

2- {1- [4- (5-Cyan-1H-indol-3-yl) butyl] piperidin-4-yl} thiazole-4-carboxylic acid ethyl ester,

3- [4- (4-thiazol-2-yl-piperazin-1-yl) butyl] -1 H-indole-5-carbonitrile, 3- {4- [4- (4-Hydroxy-thiazol-2-yl) piperazin-1-yl] butyl} -1 H-indole-5-carbonitrile,

3- {4- [4- (4-pyridin-2-yl-thiazol-2-yl) piperazin-1-yl] butyl} -1H-indole-5-carbonitrile, 3- {4- [4- (4-pyridin-4-yl-thiazol-2-yl) -piperazin-1 -yl] -butyl} -1 H-indole-

5-carbonitrile,

[1 - (2- {4- [4- (5-Cyan-1H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) -3-methylbutyl- carbamic acid fe / t-butyl ester,

3- (2- {4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazin-1-yl} thiazol-4-yl) -3-methyl-butyramide,

3- (4- {4- [4- (1-amino-3-methylbutyl) thiazol-2-ylJ-piperazin-1-yl} - butyl) -1 H -indole-5-carbonitrile,

as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Conditions.

9. A process for the preparation of compounds of formula I according to claims 1-8 and their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that

a compound of formula II

wherein

(V) and X have the meanings given in claim 1,

with a compound of formula III

wherein

L denotes Cl, Br or I and R ¹ , R ¹ 'and m have the meanings given in Claim 1,

and or

converts a residue (V) into another residue (V),

by converting an ester to an aminocarbonyl group or by cleaving an amine protecting group,

and / or converts a basic or acidic compound of the formula I into one of its salts and / or solvates by treatment with an acid or base.

10. Compounds of formula I according to one or more of claims 1 to 8 and their physiologically acceptable salts or solvates as 5HT _1A - and / or 5HTID agonists and as inhibitors of 5-HT reuptake.

11. Medicament containing at least one compound of formula I according to one or more of claims 1 to 8 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.

12. Medicament containing at least one compound of formula I according to one or more of claims 1 to 8 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and at least one further active pharmaceutical ingredient.

13. Use of compounds of formula I according to one or more of claims 1 to 8 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament.

14. Use of compounds of formula I according to one or more of claims 1 to 8 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for combating diseases which are associated with the serotonin Neurotransmitter system are connected and in which high affinity serotonin receptors (5-HT- _A receptors) and / or 5-HT _D

Receptors are involved.

15. Use of compounds of formula I according to one or more of claims 1 to 8 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament as an anxiolytic, antidepressant, neuroleptic and / or antihypertensive ,

16. Use of compounds of formula I according to one or more of claims 1 to 8 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for combating psychoses, the symptoms of Alzheimer's disease, pathological anxiety, overexcitation, hyperactivity, attention problems in children and adolescents, profound developmental disorders and disorders of

Social behavior with mental retardation, depression, obsessive-compulsive illnesses in the narrower (OCD) and wider sense (OCSD), sexual dysfunction, sleep disturbances, disturbances in the food intake, as well as such psychiatric symptoms within the framework of the age dementia and the dementia of the Alzheimer type

Reduction of cognitive dysfunction or for the prophylaxis and control of cerebral infarctions (apoplexia cerebri), for the treatment of extrapyramidal movement disorders, for the treatment of side effects that occur in the treatment of extrapyramidal movement disorders with conventional anti¬

Parkinson's medications occur or to treat extrapyramidal symptoms (EPS) that are induced by neuroleptics.

17. Use of compounds of formula I according to one or more of claims 1 to 8 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for combating schizophrenia.

18. Use of compounds of formula I according to one or more of claims 1 to 8 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for combating neurodegenerative

Diseases.

19. Use according to claim 17, wherein the diseases are Lathyrismus, Alzheimer, Parkinson, and Huntington.

20. Set (kit) consisting of separate packs of (a) an effective amount of a compound of formula I according to one or more of claims 1 to 21 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all Ratios, and (b) an effective amount of another

Drug ingredient.