DE10259933A1 - Substituted 4-aryl pyridines - Google Patents

Abstract

The invention relates to new 4-aryl pyridines and processes for their preparation, their use for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of pain conditions.

Description

The invention relates to new 4-aryl pyridines and processes for their preparation, their use for treatment and / or prophylaxis of diseases, in particular for treatment and / or prophylaxis of painful conditions.

G protein coupled receptors (GPCR) represent a great Family of membrane receptors A member of this family is the KiSS-1 receptor (metastatin Receptor). The KiSS-1 receptor is related to the galanin receptor (45% identity of the protein sequences), but galanin does not bind to the KiSS-1 Receptor. The KiSS-1 receptor is mainly found in the dorsal spinal cord, expressed in sensory neurons in spinal root ganglia and in the brain. A reinforced one Expression of the KiSS-1 receptor takes place in inflammatory (CFA) and in neuropathic (CCI) rat pain models.

In 2001 it was reported (Ohtaki et al., 2001, Nature, 411: 613-617), that the gene product of KiSS-1, a carboxy-terminal amidated Peptide, the ligand for the KiSS-1 receptor / metastatin receptor). Furthermore, in CHOK1 cells transfected with the KiSS-1 receptor demonstrated that the KiSS-1 peptide inhibited the phosphorylation of ERK1 / 2 and p38 MAP Triggers kinases (Kotani M et al., 2001, J. Bio. Chem., 276: 34631-34636). The activation of these kinases plays an important role in pain. WO 01/64882 describes KiSS-1 inter alia in connection with the treatment of pain.

An object of the present invention is therefore new modulators of the KiSS-1 receptor for treatment of pain in humans and animals.

Surprisingly it has been found that those described in the present invention substituted 4-aryl-pyridines potent KiSS-1 antagonists are.

Describe WO 02/24679 and WO 02/44153 substituted pyridines for the treatment of inflammatory diseases such as B. Asthma.

WO 01/62233 describes pyridinamides as adenosine receptor modulators for the treatment of diseases the central nervous system, such as. B. Depression or Parkinson's.

in welcher
R¹ für Amino oder -NHC(=O)R⁵ steht,
R² für 5- oder 6-gliedriges Heteroaryl steht, wobei Heteroaryl gegebenenfalls mit bis zu 3 Resten unabhängig voneinander ausgewählt aus der Gruppe Halogen, Hydroxy, Amino, Nitro, Cyano, Hydroxycarbonyl, Alkyl, Alkoxy, Alkylamino, Alkoxycarbonyl, Aminocarbonyl und Alkylaminocarbonyl substituiert ist,
R³ für Wasserstoff, Halogen, Hydroxy, Amino, Nitro, Cyano, Hydroxycarbonyl, Alkyl, Alkoxy, Alkylamino, Alkoxycarbonyl, Aminocarbonyl oder Alkylaminocarbonyl steht,
R⁴ für Wasserstoff, Halogen, Hydroxy, Amino, Nitro, Cyano, Hydroxycarbonyl, Alkyl, Alkoxy, Alkylamino, Alkoxycarbonyl, Aminocarbonyl oder Alkylaminocarbonyl steht, und
R⁵ für Alkyl, Alkoxy, Alkylamino, Alkoxycarbonyl oder einer Gruppe der Formel

steht,
wobei Alkyl gegebenenfalls mit bis zu 3 Resten unabhängig voneinander ausgewählt aus der Gruppe Amino, Hydroxy, Alkoxy, Alkylamino, Alkoxycarbonyl, Aminocarbonyl und Alkylaminocarbonyl substituiert ist und
wobei * für die Anknüpfstelle an die Carbonylgruppe steht.The present invention relates to compounds of the formula

in which
R ^{1 represents} amino or -NHC (= O) R ⁵ ,
R ^{2 represents} 5- or 6-membered heteroaryl, heteroaryl optionally being substituted with up to 3 radicals independently of one another from the group halogen, hydroxy, amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl is
R ^{3 represents} hydrogen, halogen, hydroxy, amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl,
R ^{4 represents} hydrogen, halogen, hydroxy, amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl, and
R ^{5 represents} alkyl, alkoxy, alkylamino, alkoxycarbonyl or a group of the formula

stands,
where alkyl is optionally substituted with up to 3 radicals selected independently of one another from the group amino, hydroxy, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl and
where * stands for the point of attachment to the carbonyl group.

The compounds of the invention can also in the form of their salts, solvates and solvates of their salts.

The compounds of the invention can in dependence their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or Diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomers isolate uniform components in a known manner.

Salts are within the scope of the invention physiologically acceptable salts of the compounds according to the invention prefers.

Physiologically acceptable salts of the compounds of the invention can Acid addition salts the connections with mineral acids, carboxylic acids or sulfonic acids his. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or Benzoic acid.

However, salts with customary salts can also be used Bases are mentioned, such as alkali metal salts (e.g. Sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl-piperidine.

Solvates of the compounds according to the invention are stoichiometric in the context of the invention Compositions of the compounds or their salts with solvents.

In the context of the present invention, the substituents generally have the following meaning:
Alkyl per se and "alk" and "alkyl" in alkoxy, alkylamino, alkylcarbonyl, alkylaminocarbonyl and alkoxycarbonyl stand for a linear or branched alkyl radical with usually 1 to 6 (“C ₁ -C ₆ alkyl”), preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably for methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is exemplary and preferred for methoxy, Ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino stands for one Alkylamino radical with one or two (independently selected) alkyl substituents, exemplary and preferably for Methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

Alkoxycarbonyl stands for one straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxycarbonyl radical is preferred with 1 to 4, particularly preferably with 1 to 3 carbon atoms. Examples and preferably mentioned are: methoxycarbonyl, Ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert.butoxycarbonyl.

Alkylaminocarbonyl stands for one Alkylaminocarbonylrest with one or two (independently of one another selected) Alkyl substituents, by way of example and preferably for methylaminocarbonyl, Ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino-carbonyl and N-n-hexyl-N-methylaminocarbonyl.

5- or 6-membered heteroaryl for one aromatic monocyclic radical with 5 or 6 ring atoms and bis to 3 heteroatoms from the series S, O and / or N. The heteroaryl residue is over bound a carbon atom. For example, and preferably called: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, Imidazolyl, pyridyl, pyrimidyl, pyridazinyl.

Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred. Fluorine is particularly preferred and chlorine.

If radicals in the compounds according to the invention are optionally substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A sub substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.

steht,
wobei Alkyl gegebenenfalls mit bis zu 3 Resten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Amino, Hydroxy, Alkoxy, Alkylamino, Alkoxycarbonyl, Aminocarbonyl und Alkylaminocarbonyl substituiert ist und
wobei * für die Anknüpfstelle an die Carbonylgruppe steht.Compounds of the formula (I) in which
R ^{1 represents} amino or -NHC (= O) R ⁵ ,
R ^{2 represents} 5-membered heteroaryl,
where heteroaryl is optionally substituted with up to 3 radicals independently of one another from the group halogen, hydroxy, amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl,
R ^{3 represents} hydrogen, halogen, alkyl or alkoxy,
R ^{4 represents} hydrogen, halogen, alkyl or alkoxy, and
R ^{5 represents} alkyl, alkoxycarbonyl or a group of the formula

stands,
wherein alkyl optionally substituted with up to 3 radicals independently of one another from the group consisting of amino, hydroxy, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl and
where * stands for the point of attachment to the carbonyl group.

steht,
wobei Alkyl gegebenenfalls mit Methoxy substituiert ist, und
wobei * für die Anknüpfstelle an die Carbonylgruppe steht.Preference is also given to compounds of the formula (I) in which
R ^{1 represents} amino or -NHC (= O) R ⁵ ,
R ^{2 represents} thienyl, furyl or isoxazolyl,
R ^{3 represents} hydrogen,
R ^{4 represents} hydrogen, and
R ^{5 represents} alkyl, alkoxycarbonyl or a group of the formula

stands,
where alkyl is optionally substituted with methoxy, and
where * stands for the point of attachment to the carbonyl group.

Compounds of the formula (I) in which R ^{1 represents} amino are also preferred.

Compounds of the formula (I) in which R ^{2 represents} thienyl, furyl or isoxazolyl are also preferred.

Compounds of the formula (I) in which R ³ and R ^{4 are} hydrogen are also preferred.

steht, wobei * für die Anknüpfstelle an die Carbonylgruppe steht.Preference is also given to compounds of the formula (I) in which R ^{5 represents} a group of the formula

stands, where * stands for the connection point to the carbonyl group.

in welcher
R², R³ und R⁴ die oben angegebenen Bedeutunen haben,
mit Verbindungen der Formel

in welcher
R⁵ die oben angegebenen Bedeutungen hat, und
X¹ für Halogen, bevorzugt Brom oder Chlor, steht,
umgesetzt werden und die resultierenden Verbindungen der Formel (I) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Basen oder Säuren zu ihren Solvaten, Salzen und/oder Solvaten der Salze umsetzt.The invention further relates to processes for the preparation of the compounds according to the invention, compounds of the formula

in which
R ² , R ³ and R ^{4 have} the meanings given above,
with compounds of the formula

in which
R ^{5 has} the meanings given above, and
X ^{1 represents} halogen, preferably bromine or chlorine,
are reacted and the resulting compounds of the formula (I) are reacted, if appropriate, with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

The implementation takes place in general in inert solvents, optionally in the presence of a base, preferably in a temperature range from room temperature to 40 ° C at normal pressure.

Bases are, for example, alkali carbonates like cesium carbonate, Sodium or potassium carbonate, or potassium tert-butoxide, or hydrides such as sodium hydride, organic amines such as DBU, triethylamine or diisopropylethylamine, diisopropylethylamine and triethylamine are preferred.

Inert solvents are, for example Halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, Ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or esters such as ethyl acetate, ketones such as acetone or 2-butanone, amides such as Dimethylformamide or dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, Nitriles such as acetonitrile or heteroaromatics such as pyridine are preferred is tetrahydrofuran.

The compounds of formula (II) are known or can be obtained from the corresponding processes by known processes Synthesize starting materials.

in welcher
R², R³ und R⁴ die oben angegebenen Bedeutungen haben,
mit Reduktionsmitteln umgesetzt werden.The compounds of formula (Ia) are known or can be prepared by using compounds of formula

in which
R ² , R ³ and R ^{4 have} the meanings given above,
be implemented with reducing agents.

The implementation takes place in general in inert solvents, preferably in a temperature range from room temperature to backflow the solvent at normal pressure up to 3 bar.

Reducing agents are, for example Palladium on activated carbon and hydrogen, tin dichloride, titanium trichloride or a mixture of sodium borohydride and bismuth trichloride is preferred is palladium on activated carbon and hydrogen or a mixture from sodium borohydride and bismuth (III) chloride.

Inert solvents are, for example Ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, Dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, Amides such as dimethylformamide or dimethylacetamide, nitriles such as acetonitrile or heteroaromatics such as pyridine, the preferred solvent is methanol, Ethanol or iso-propanol.

in welcher
R³ und R⁴ die oben angegebenen Bedeutungen haben,
mit 3 bis 4 Äquivalenten der Verbindungen der Formel

in welcher
R² die oben angegebenen Bedeutungen hat, und
X² für Halogen, bevorzugt Brom oder Chlor, steht,
in einer zweistufigen Synthese umgesetzt werden.The compounds of formula (III) are known or can be prepared by using compounds of formula

in which
R ³ and R ^{4 have} the meanings given above,
with 3 to 4 equivalents of the compounds of the formula

in which
R ^{2 has} the meanings given above, and
X ^{2 represents} halogen, preferably bromine or chlorine,
can be implemented in a two-stage synthesis.

The implementation takes place in the first stage generally in inert solvents, optionally in the presence of a base, preferably in a temperature range from room temperature to 40 ° C at normal pressure.

Bases are, for example, alkali carbonates like cesium carbonate, Sodium or potassium carbonate, or alcoholates such as potassium tert-butoxide, or hydrides such as sodium hydride or organic amines such as DBU, triethylamine, Diisopropylethylamine or heteroaromatics such as pyridine are preferred is pyridine.

Inert solvents are, for example Halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, Ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, Tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or esters such as ethyl acetate, ketones such as acetone or 2-butanone, amides such as Dimethylformamide or dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, Nitriles such as acetonitrile or heteroaromatics such as pyridine are preferred is tetrahydrofuran or pyridine

In the second stage, the Reaction with ammonia in an alcohol, preferably methanol, ethanol or iso-propanol, preferably in a temperature range from room temperature up to 40 ° C at normal pressure.

For selected Examples can be the implementation of an alternative method Compounds of formula (IV) with one equivalent of the compounds of formula (V) also in one step to compounds of formula (III) respectively.

The compounds of formula (IV) can be determined by a method from Manna, F., et al., Eur. J. Med. Chem. 1999, 34, 245-254 synthesize.

The compounds of formula (V) are known or can be made according to known methods from the corresponding Synthesize starting materials.

The methods described above can be illustrated by the following formula scheme: Scheme 1:

The compounds according to the invention are suitable for use as medication for treatment and / or prophylaxis of diseases in humans and animals.

The compounds of the invention show a unpredictable, valuable pharmacological spectrum of action.

Because of their pharmacological properties, the compounds according to the invention can be used alone or in combination with other medicaments for the prophylaxis and treatment of acute and / or chronic pain (for a classification see "Classification of Chronic Pain, De descriptions of Chronic Pain Syndromes and Definitions of Pain Terms ", 2nd ed., Meskey and Begduk, eds .; IASP-Press, Seattle, 1994), in particular for the treatment of cancer-induced pain, such as, for example, visceral or neuropathic pain Cancer or cancer treatment, and neuropathic pain, such as herpes zoster and herpes neuralgia, painful diabetic neuropathy, neuropathic back pain, post-traumatic and surgical neuralgia, neuralgia as a result of compressed nerves or other neuralgia, phantom pain, complex regional pain syndromes, infectious and para-infectious neuropathies, for example as a result of HIV infection, pain in Parkinson's or spinal cord injuries or traumatic brain injuries and pain after a stroke, and chronic neuropathic pain such as diabetic neuropathy, post-herpetic neuralgia, peripheral nerve damage, centr all pain (e.g. as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain such as lumbago, low back pain, inflammatory or rheumatic pain, and painful conditions of the musculoskeletal system such as in Osteoarthritis or rheumatic arthritis or other forms of arthritis or back pain, and visceral pain, such as pain in the internal organs, for example biliary colic, irritable colon, pelvic pain, orchilage or prostatodynia, and pain in inflammatory processes, such as the bones, skin , Muscles or nerves, and orofacial pain and headache such as migraine or tension headache.

In addition, with active ingredients that bind the KiSS-1 receptor (metastatin receptor), also processes, that contribute to pain, such as altered excitability, peripheral or central sensitization, synaptic reorganization, Phänotypmodulierung or disinhibition.

These substances are also suitable also for the therapy of primary acute pain of any origin and resultant secondary Pain, as well as for the treatment of chronic, formerly acute pain conditions.

rating the physiological effectiveness

The in vitro effect of the compounds according to the invention can be demonstrated with the following biological assays:

1. Human KiSS-1 receptor assay

To develop a biological assay, a fusion protein of the human KiSS-1 receptor (Accession # AB051065) and the human G _{α16 .} cDNA (Accession # M63904) cloned into pcDNA3.1 (Invitrogen). The construct is stably transfected into a CHO cell, which expresses the mitochondrial aequorin, using lipofectamines (according to the test description by the manufacturer Invitrogen). Clones expressing KiSS-1 receptor are selected in G418 (1 mg / ml; GIBCO). The clones are cultured in 45% Dulbecco's modified Eagle Medium, 45% F12 (DMEM / F12) and 10% fetal calf serum at 37 ° C in 5% CO ₂ at 100% humidity. For substance testing, 2000 cells / well are sown in 35 μl culture medium (DMEM / F12 with 1% FBS) in 384 well plates and cultivated for 48 hours. The culture medium is then replaced by a Tyrode solution (cafty buffer pH 7.4; PAA Laboratories GmbH). Cells are then incubated for 4 hours with Coelenteracine (1 μg / ml) in 2 mM calcium chloride Tyrode. Substances dissolved in DMSO are diluted in Tyrode with 0.1% bovine albumin and added to the cell cultures (maximum 10 μM substance). The cells are then stimulated with 5 nM of the amidated KiSS-1 peptide (H-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-amide). The maximum DMSO concentration in the test is 1%. The receptor-mediated change in luminescence is detected with a camera photomultiplier system.

2. Rat KiSS-1 receptor assay

To develop a biological assay, a fusion protein of the rat KiSS-1 receptor (Accession # AB051066) and the human G _α16. cDNA (Accession # M63904) cloned into pcDNA3.1 (Invitrogen). The construct is stably transfected into a CHO cell, which expresses the mitochondrial aequorin, using lipofectamines (according to the test description by the manufacturer Invitrogen). Clones expressing KiSS-1 receptor are selected in G418 (1 mg / ml; GIBCO). The clones are cultured in 45% Dulbecco's modified Eagle Medium, 45% F 12 (DMEM / F12) and 10% fetal calf serum at 37 ° C in 5% CO ₂ at 100% humidity. For substance testing, 2000 cells / well are sown in 35 μl culture medium (DMEM / F12 with 1% FBS) in 384-well plates and cultivated for 48 hours. The culture medium is then replaced by a Tyrode solution (cafty buffer pH7.4; PAA Laboratories GmbH). Cells are then incubated for 4 hours with Coelenteracine (1 μg / ml) in 2mM calcium chloride Tyrode. Substances dissolved in DMSO are diluted in Tyrode with 0.1% bovine albumin and added to the cell cultures (maximum 10 μM substance). The cells will then with 5 nM of the amidated KiSS-1 peptide (H-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-amide). The maximum DMSO concentration in the test is 1%. The receptor-mediated change in luminescence is detected with a camera photomultiplier system.

Representative in-vitro activity data (human KiSS-1 receptor) for the compounds according to the invention are shown in Table A: Table A

The in vivo effect of the compounds according to the invention can be demonstrated with the following biological assays:

1. Acute pain

Acute pain comes with a hot plate mainly tested on rats. Therefor are mainly 2 test procedures used. In the classic test procedure Rats on a hot surface (52 to 56 ° C) set and the time until nocifensive behavior (e.g. licking the paws, lifting the paws). The other test method the rat is placed on a non-preheated plate, which is then slowly warmed up until the rat starts licking a hind paw. The temperature at which the rat starts Licking the paws is a measure of the pain threshold.

Substance-treated animals are included solvent-treated Compared animals. Substance application takes place at different Times and over different routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) before the pain test.

2. Persistent pain

Persistent pain comes with the formalin or capsaicin test (mainly on Rats). A 1 to 5% formalin solution or 10–100 μg capsaicin are injected into a hind paw. After that, injection of formalin or capsaicin the animals show nocifensive behavior e.g. Lick, Biting and Twitching of the paw. The number of nocifensive reactions within 90 minutes is a measure of pain intensity.

Substance-treated animals are included solvent-treated Compared animals. Substance application takes place at different Times and over different routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) before the administration of formalin or capsaicin.

3. Neuropathic pain

Neuropathic pain can go through unilateral injury of the sciatic nerve (mainly on Rats). The operation is performed on anesthetized patients Animals. So can the damage of the sciatic nerve by a slightly constrictive ligature triggered the sciatic nerve (Bennett and Xie, Pain 33 (1988): 87-107). Alternatively, one Ligature by setting about half of the neurons tightly together (Seltzer et al., Pain 43 (1990): 205-218). In another process the L5 and L6 spinal nerves or only the L5 spinal nerve are severed or damaged by a constrictive ligature (Kim S.H .; Chung, J.M, Pain 50 (3) (1992): 355-363). The fourth variant is an axotomy model. Here 2 of the 3 terminal branches of the sciatic nerve (tibial nerve and common nerve peroneus), with the sural nerve remains unharmed. In another axotomy model, only the The tibial nerve is severed, leaving the sural nerve intact remains. Control animals are subjected to a "sham operation" without nerve damage.

After the nerve damage, chronic mechanical allodynia, cold allodynia and thermal hyperalgesia occur after the operation. The mechanical allodynia is carried out using a pressure transducer (electronic from Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA; Electronic from Frey System, Somedic Sales AB, Hörby, Sweden). Thermal hyperalgesia is examined using a heat source (Plantar Test, Ugo Basile, Comerio, Italy) or a cold plate at 5 to 10 ° C. The nocifensive reactions are counted and are a measure of the pain intensity.

Another model for cold-induced Pain is the plantar application of acetone. Here's the number and measured the duration of the nocifensive reactions.

Chronic pain can also be relieved Investigation of the circadian rhythm (Surjo and Arndt, University of Cologne, Cologne, Germany) and by examining the gait (paw prints; Klapdor et al., 1997. A low cost method to analyze footprint patterns. J. Neurosci. Methods 75, 49-54) be evaluated.

Substance-treated animals are treated with "sham-operated" and solvent-treated Compared animals. Substance application takes place at different Times and over different routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) before the pain test.

4. Flammable pain

Inflammatory pain can e.g. in rats by injection of 0.75 mg carrageenan or whole friend Adjuvant being triggered in a hind paw. The animals develop an edema, mechanical allodynia and thermal hyperalgesia. The mechanical allodynia is achieved by means of a pressure transducer (electronic by Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA; Electronic from Frey System, Somedic Sales AB, Hörby, Sweden) certainly. Thermal hyperalgesia is by means of a heat source (Plantar Test, Ugo Basile, Comerio, Italy, Paw thermal stimulator, G. Ozaki, University of California, USA). For edema determination 2 methods are used: 1. After the animal is killed the hind paw removed and weighed. 2. The paw volume increases determined with a plethysmograph (Ugo Basile, Comerio, Italy). Substance-treated animals are treated with animals without inflammation and solvent treated Compared animals. Substance application takes place at different Times and over different routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) before the pain test.

5. Diabetic neuropathic pain

Rats intraperitoneally 50 to 80 mg / kg streptozoticin administered develop within 1-3 weeks hyperglycaemia and a mechanical allodynia. The mechanical allodynia is determined by means of a Pressure transducer (electronic from Frey Anesthesiometer, IITC Inc.-Life Science Instruments, Woodland Hills, SA, USA; Electronic from Frey System, Somedic Sales AB, Hörby, Sweden).

Substance-treated animals are included diabetic and non-diabetic solvent treated animals compared. Substance treatment takes place at different times and over different routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal, transdermal) before the pain test.

The new active ingredients can be used in known manner in the usual Formulations are transferred such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, Suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvent. Here, the therapeutically active compound should be in one A concentration of about 0.5 to 90% by weight of the total mixture is present be, i.e. in amounts sufficient to give the indicated dosage range to reach.

The formulations are, for example produced by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersing agents, where e.g. in the case of using water as a diluent optionally organic solvents as auxiliary solvent can be used.

The application takes place in the usual Manner, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. It can also be inhaled through the mouth or nose, for example with the help of a spray, or topically over the skin.

In general, it has proven to be beneficial proven amounts of about 0.01 to 30 mg / kg, preferably about 0.1 up to 20 mg / kg body weight, when administered orally about 0.1 to 30 mg / kg, preferably about 0.5 up to 10 mg / kg body weight to deliver effective results.

Nevertheless, it may be necessary be different from the amounts mentioned, depending on of body weight or the type of application route, the individual behavior across from the drug, the type of formulation and the time or interval at which the administration takes place. It can in some cases be sufficient with less than the aforementioned minimum amount get along while in other cases the specified upper limit was exceeded must become. In the case of application of larger quantities, it can be recommended be spread over the day in several separate doses.

A. Examples

Abbreviations:

• CDCl ₃ deuterochloroform
• DCI direct chemical ionization (for MS)
• DMSO dimethyl sulfoxide
• DMF dimethylformamide
• EDC N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide x HCl
• EE ethyl acetate (ethyl acetate)
• EI electron impact ionization (for MS)
• ESI electrospray ionization (for MS)
• Mp melting point
• HOBt 1-hydroxy-1H-benzotriazole x H ₂ O
• h hour
• HPLC high pressure, high performance liquid chromatography
• LC-MS liquid chromatography-coupled mass spectroscopy
• MS mass spectroscopy
• MeOH methanol
• N normal
• NH ₃ ammonia
• NMR nuclear magnetic resonance spectroscopy
• RT room temperature, 20 ° C
• R _t retention time (with HPLC)
• Dec. decomposition

HPLC and LCMS methods:

Method A (HPLC):

Column: Chromasil C18 60 * 2; Injection volume 1.00 μl; Flow: 0.75 ml / min; Eluent: A = 5 ml HClO ₄ / l water, B = acetonitrile; Gradient [t (min): A / B]: 0.0: 98/2; 0.5: 98/2; 4.5: 10/90; 6.5: 10/90; 6.7: 98/2; 7.5: 98: 2.

Method B (LCMS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Pillar: Grom-Sil 120 ODS-4 HE 50 × 2 mm, 3.0 µm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0min 5% B → 2.0min 40% B → 4.5min 90% B → 5.5min 90% B; Oven: 45 ° C; Flow: 0.0min 0.75ml / min → 4.5min 0.75ml / min → 5.5min 1.25ml / min; UV detection: 210 nm.

Starting Compounds:

Example 1A

2-Thiophencarbonsäure- (2- [6- [bis (2-thienylcarbonyl) amino] -5-cyano-4- (3-nitrophenyl) -2-pyridinyl]) phenyl ester

Under argon, 1000 mg (3.01 mmol) of 2-amino-6- (2-hydroxyphenyl) -4- (3-nitrophenyl) nicotinonitrile (Manna, F., et al., Eur. J. Med. Chem. 1999, 34 , 245-254) in 15 ml of pyridine and 1540 mg (10.5 mmol) of thiophene-2-carboxylic acid chloride were added dropwise with vigorous stirring. The mixture is stirred overnight at room temperature. The pyridine is evaporated in vacuo, the residue is partitioned between ethyl acetate and 1N hydrochloric acid and the aqueous phase is extracted three more times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is drawn up on silica gel and purified chromatographically in an ethyl acetate / cyclohexane mixture with an increasing proportion of ethyl acetate (1:10 - 1: 2).
This gives 808 mg (41%) of the target compound.
¹ H -NMR (400MHz, CDCl ₃ ): δ = 7.05 (t, 2H), 7.17 (t, 1H), 7.30 (d, 1H), 7.35 (t, 1H). 7.52 (t, 1H), 7.60 - 7.72 (m, 7H), 7.81 (d, 1H), 7.84 (s, 1H), 7.93 (d, 1H), 8.29 (s, br, 1H), 8.35 (s, 1H).
MS (ESIpos): m / z = 663 (M + H) ⁺
HPLC (method A): R _t = 5.32 min

Example 2A

N- [3-cyano-6- (2-hydroxyphenyl) -4- (3-nitrophenyl) -2-pyridinyl] -2-thiophenecarboxamide

790 mg (1.19 mmol) of the compound from Example 1A are mixed with 7.6 ml of a 7N solution of ammonia in methanol under argon. After 2 hours of stirring at room temperature, a further 4 ml of the ammonia solution are added, then stirring is continued overnight at room temperature. The product obtained as a precipitate in the reaction mixture is collected by filtration and washed with diethyl ether.
This gives 380 mg (72%) of the target compound.
¹ H-NMR (400MHz, DMF-d ₇ ): δ = 6.96 (t, 1H), 6.99 (d, 1H), 7.26 (t, 1H), 7.41 (t, 1H), 7.90 (d, 1H), 7.97 (t, 1H), 8.11 (d, 1H), 8.18 (s, 1H), 8.24 (d, 1H), 8.31 (d, 1H), 8.50 (d, 1H), 8.69 (s, 1H).
MS (ESIpos): m / z = 443 (M + H) ⁺
HPLC (method A): R _t = 4.97 min

Preparation Examples:

example 1

N- [4- (3-aminophenyl) -3-cyano-6- (2-hydroxyphenyl) -2-pyridinyl] -2-thiophenecarboxamide

100 mg (0.23 mmol) of the compound from Example 2A in 100 ml of isopropanol / etha nol 3: 1 submitted, 100 mg of palladium (10%) on activated carbon added under argon countercurrent and the reaction mixture hydrogenated at 3 bar hydrogen overnight in a shaker. The catalyst is separated off by filtration through diatomaceous earth, washed with isopropanol and the solvent is evaporated in vacuo. The residue is coated on silica gel and purified by chromatography using first cyclohexane, then cyclohexane / ethyl acetate in a ratio of 3: 1 as the eluent.
This gives 28.4 mg (30%) of the target compound.
¹ H -NMR (400MHz, DMF-d ₇ ): δ = 5.54 (s, 2H), 6.90 (d, 1H), 6.94 (d, 1H), 6.98 - 7.04 (m, 2H), 7.06 (s, br , 1H), 7.28 (t, 1H), 7.3 3 (t, 1H), 7.43 (t, 1H), 8.05 (d, 1H), 8.20 (s, 1H), 8.21 - 8.28 (m, 2H) .11.46 (s, 1H), 12.38 (s, 1H).
MS (ESIpos): m / z = 413 (M + H) ⁺
HPLC (method A): R _t = 4.25 min

Alternative procedure:

Under argon, 1500 mg (3.39 mmol) of the compound from Example 2A are placed in 22.5 ml of ethanol, and 1600 mg (5.09 mmol) of bismuth (III) chloride are added. 1030 mg (27.2 mmol) of sodium borohydride are then added in portions at room temperature with vigorous stirring. After the evolution of gas has subsided, 3 ml of 1N hydrochloric acid are added and stirring is continued for 1 hour. The ethanol is removed in vacuo, the aqueous residue is made alkaline with 25% aqueous ammonia solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is coated on silica gel and purified by chromatography first with cyclohexane, then with a 2: 1 cyclohexane / ethyl acetate mixture as the eluent.
This gives 145 mg (10%) of the target compound.
In addition, 85 mg (8%) of 2-amino-4- (3-aminophenyl) -6- (2-hydroxyphenyl) nicotinonitrile are isolated.

 2-amino-4- (3-aminophenyl) -6- (2-hydroxyphenyl) -nicotinsäurenitril:

¹ H -NMR (400MHz, DMF-d ₇ ): δ = 5.44 (s, 2H), 6.90 (t, 2H), 6.94 - 7.00 (m, 2H), 7.01 (s, br, 1H), 7.26 (t , 1H), 7.41 (t, 1H), 7.48 (s, 1H), 7.59 (s, br, 2H), 8.17 (d, 1H), 13.58 (s, 1H).
MS (ESIpos): m / z = 303 (M + H) ⁺
HPLC (method A): R _t = 3.81 min

Example 2

2 - [(3- {3-cyano-6- (2-hydroxyphenyl) -2 - [(2-thienylcarbonyl) amino] -4-pyridinyl} phenyl) amino] -2-oxoacetic acid ethyl ester

Under argon, 125 mg (0.30 mmol) of the compound from Example 1 are placed in 15 ml of tetrahydrofuran, and 38 μl (28 mg, 0.28 mmol) of triethylamine and 31 μl (38 mg, 0.28 mmol) of ethoxalyl chloride are added at room temperature. The mixture is stirred at room temperature overnight and the solvent is then concentrated in vacuo. The residue is stirred with water and filtered, the filter residue on the frit is slurried three more times with diethyl ether, filtered again and dried.
This gives 81.4 mg (57%) of the target compound.
(400MHz, DMF-d ₇ ): δ = 1.35 (t, 3H), 4.36 (q, 2H), 6.98 - 7.07 (m, 2H), 7.34 (t, 1H), 7.43 (t, 1H), 7.61 - 7.72 (m, 2H), 8.06 (d, 1H), 8.16 (d, 1H), 8.29 - 8.3 5 (m, 4H), 11.11 (s, 1H), 11.55 (s, 1H), 12.34 (s, 1H ).
MS (ESIpos): m / z = 513 (M + H) ⁺
HPLC (method A): R _t = 4.55 min

Example 3

N- (3-cyano-6- (2-hydroxyphenyl) -4- {3 - [(methoxyacetyl) amino] phenyl} -2-pyridinyl) -2-thiophenecarboxamide

50 mg (0.12 mmol) of the compound from Example 1 are placed in 5 ml of tetrahydrofuran under argon and 13.5 μl (9.8 mg, 0.10 mmol) of triethylamine and 9.1 μl (10.9 mg, 0.10 mmol) of methoxyacetyl chloride are added at room temperature. The mixture is left to stir at this temperature for 4 hours and then the solvent is concentrated in vacuo. The residue is taken up in dichloromethane, 0.5 ml of water is added, the mixture is stirred for 30 minutes, filtered through an Extrelut cartridge and washed with 3 times the amount of dichloromethane. The filtrate is concentrated, the remaining crude product is drawn up on silica gel and purified by chromatography using first cyclohexane, then cyclohexane / ethyl acetate in a ratio of 3: 1 as the eluent.
This gives 35.5 mg (61%) of the target compound.
¹ H -NMR (400MHz, DMF-d ₇ ): δ = 3.57 (s, 3H), 4.22 (s, 2H), 7.10 - 7.17 (m, 2H), 7.45 (t, 1H), 7.56 (t, 1H ), 7.66 (d, 1H), 7.72 (t, 1H), 8.17 (d, 1H), 8.21 (d, 1H), 8.34 - 8.42 (m, 4H), 10.15 (s, 1H), 11.64 (s, 1H), 12.46 (s, 1H).
MS (ESIpos): m / z = 485 (M + H) ⁺
HPLC (method A): R _t = 4.74 min

Examples 4 to 6 can be from the corresponding starting materials according to the methods described above getting produced.

Claims (9)

Compounds of the formula

in which R ^{1 stands} for amino or -NHC (= O) R ⁵ , R ^{2 stands} for 5- or 6-membered heteroaryl, heteroaryl optionally having up to 3 radicals independently selected from the group halogen, hydroxy, amino, nitro , Cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl, R ^{3 is} hydrogen, halogen, hydroxy, amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl, R ^{4 represents} hydrogen, halogen, hydroxy, amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl, R ^{5 represents} alkyl, alkoxy, alkylamino, alkoxycarbonyl or a group of the formula

where alkyl is optionally substituted with up to 3 radicals independently of one another from the group amino, hydroxy, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl, and where * stands for the point of attachment to the carbonyl group, and their salts, solvates and solvates of salts. Compounds according to claim 1, characterized in that R ^{1 is} amino or -NHC (= O) R ⁵ , R ^{2 is} 5-membered heteroaryl, where heteroaryl optionally up to 3 radicals independently selected from the group halogen, hydroxy, Amino, nitro, cyano, hydroxycarbonyl, alkyl, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl, R ^{3 represents} hydrogen, halogen, alkyl or alkoxy, R ^{4 represents} hydrogen, halogen, alkyl or alkoxy, and R ^{5 represents} Alkyl, alkoxycarbonyl or a group of the formula

where alkyl is optionally substituted with up to 3 radicals independently of one another from the group amino, hydroxy, alkoxy, alkylamino, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl, and where * stands for the point of attachment to the carbonyl group, and their salts, solvates and solvates of salts. Compounds according to claim 1 or 2, characterized in that R ^{1 is} amino or -NHC (= O) R ⁵ , R ^{2 is} thienyl, furyl or isoxazolyl, R ^{3 is} hydrogen, R ^{4 is} hydrogen, and R ^{5 is} alkyl, alkoxycarbonyl or a group of the formula

stands, where alkyl is optionally substituted with methoxy, and where * stands for the point of attachment to the carbonyl group, and their salts, solvates and solvates of the salts. A process for the preparation of compounds according to claim 1, characterized in that compounds of the formula

in which R ² , R ³ and R ^{4 have} the meanings given in claim 1, with compounds of the formula

in which R ^{5 has} the meanings given in Claim 1 and X ^{1 represents} halogen, preferably bromine or chlorine, are reacted and the resulting compounds of the formula (I) are optionally reacted with the corresponding (i) solvents and / or (ii) Converting bases or acids to their solvates, salts and / or solvates of the salts. Compounds according to one of claims 1 to 3 for treatment and / or prophylaxis of diseases. Medicaments containing at least one of the compounds according to one of the claims 1 to 3 in admixture with at least one pharmaceutical acceptable essentially non-toxic carrier or excipients. Use of compounds according to one of claims 1 to 3 for the manufacture of a medicament for treatment and / or prophylaxis of painful conditions. Medicament according to claim 6 for treatment and / or Prophylaxis of painful conditions. Process for controlling pain in humans and animals by administering a effective amount of at least one compound according to any one of claims 1 to 3.