EP1326826A1 - Verwendung von aminosäuren zur behandlung von schmerz - Google Patents

Verwendung von aminosäuren zur behandlung von schmerz

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Publication number
EP1326826A1
EP1326826A1 EP01969790A EP01969790A EP1326826A1 EP 1326826 A1 EP1326826 A1 EP 1326826A1 EP 01969790 A EP01969790 A EP 01969790A EP 01969790 A EP01969790 A EP 01969790A EP 1326826 A1 EP1326826 A1 EP 1326826A1
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EP
European Patent Office
Prior art keywords
unsubstituted
acid
amino
propyl
butyl
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EP01969790A
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German (de)
English (en)
French (fr)
Inventor
Boris Chizh
Claudia Katharina PÜTZ
Michael Haurand
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Gruenenthal GmbH
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Gruenenthal GmbH
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Publication of EP1326826A1 publication Critical patent/EP1326826A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to amino acids, processes for their preparation, medicaments containing these compounds and the use of amino acids for the production of medicaments for the treatment of pain.
  • Cyclic GABA analog gabapentin is a clinically proven antiepileptic. Gabapentin also shows other interesting, medically relevant properties, especially as an analgesic. Interesting are therefore new structural classes that have affinity for the gabapentin binding site. For the indications mentioned, there is a further need for substances which have properties in common with gabapentin, for example in the analgesic effect.
  • Classic opioids such as morphine are effective in treating severe to severe pain. However, their use is limited by the known side effects such as respiratory depression, vomiting, sedation, constipation and tolerance development. In addition, they are less effective in neuropathic or incidental pain, which particularly affects tumor patients.
  • the object of the invention was therefore to find structures, preferably new structures, which have affinity for the gabapentin binding site and / or corresponding physiological activity, for example with regard to analgesia, but also have other GBP indications.
  • the invention therefore relates to the use of an amino acid of the general formula I,
  • F and R ⁇ are each independently selected from H; C 1-4 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl, C 1-6 -cycloalkyl or heteroaryl, each unsubstituted or substituted one or more times; or
  • R1 and R2 together form a (CH2) 3_6 ring, saturated or unsaturated, substituted or unsubstituted, in which 0-2 C atoms can be replaced by S, O or NR 4 ,
  • R 4 selected from: H; C 1-6 -alky !, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • a medicament for the treatment of pain in particular neuropathic, chronic or acute pain, epilepsy and / or migraine
  • hyperalgesia and allodynia for the manufacture of a medicament for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia, or of inflammatory or postoperative pain
  • a medicament for the treatment of hot flashes postmenopausal complaints, amyotropic lateral sclerosis (ALS), reflex sympasthetic dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders, such as bipolar disorders, anxiety, panic attacks, mood changes, manic behavior, depression, manic-depressive behavior; painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy; gastrointestinal damage; erythromelalgic or post-poliomyelitic pain, trigeminal or post-herpetic neuralgia; or as an anticonvulsant, analgesic or anxiolytic.
  • ALS amyotropic lateral sclerosis
  • RSD reflex sympasthetic dystrophy
  • spastic paralysis restless leg syndrome
  • acquired nystagmus psychiatric or neuro
  • the amino acids used according to formula I R ⁇ and R ⁇ are each independently selected from H; C 1 -C 4 -alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; is preferably one of the radicals R ⁇ and R ⁇ C-
  • R1 and R2 together form cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • R ⁇ and R ⁇ are each independently selected from C ⁇ g-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl, C 1 -C 4 -cycloalkyl or heteroaryl, in each case unsubstituted or substituted one or more times;
  • R1 and R2 together form a ring and mean substituted or unsubstituted, in which 0-2 C atoms can be replaced by S, O or NR 4 ,
  • R 4 selected from: H; C ⁇ g-Alky !, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted.
  • alkyl or cycloalkyl radicals are taken to mean saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
  • d- 2 alkyl is C1- or C2-alkyl, C-.
  • C 3 - 4 cycloalkyl stands for C3 or C4 cycloalkyl, C 3 - 5 cycloalkyl for C3, C4 or C5 cycloalkyl, C 3 - 6 cycloalkyl for C3, C4, C5 or C6 cycloalkyl, C 3-7 cycloalkyl for C3, C4, C5, C6 or C7 cycloalkyl, C 3-8 cycloalkyl for C3, C4, C5, C6, C7 or C8 Cycloalkyl, C 4 .
  • 5 - cycloalkyl means C4 or C5 cycloalkyl, C5 cycloalkyl for C4, C5 or C6 cycloalkyl, C7 cycloalkyl for C4, C5, C6 or C7 -cycloalkyl, C 5 - 6 cycloalkyl of C5 or C6 cycloalkyl, and C 5-7 cycloalkyl for C5, C6 or C7 cycloalkyl.
  • cycloalkyl the term also includes saturated cycloalkyls in which one or two carbon atoms have been replaced by a hetero atom, S, N or O.
  • cycloalkyl also includes, in particular, one or more, preferably mono-, unsaturated cycloalkyls without a hetero atom in the ring, as long as the cycloalkyl is not an aromatic system.
  • the alkyl or cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propynyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-di methylethyl , Pentyl, 1, 1-Dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-Dimethylpropyl, Hexyl, 1-Methylpentyl, Cyclopropyl, 2-Methylcyclopropyl, Cyclopropylmethyl, Cyclobutyl, Cyclopentyl, Cyclopentylmethyl, Cyclohexyl, Cycloheptyl
  • Particularly preferred substituents here are F, Cl and OH.
  • the hydrogen radical can also be substituted by OC 1-3 alkyl or C ⁇ -3 alkyl (each one or more times substituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy, to be replaced.
  • (CH 2 ) 3 -6 is -CH 2 -CH 2 -CH 2 -, -CH2-CH2-CH2-, -CH 2 -CH 2 -CH2-CH2- and CH2-CH2 -CH2-CH2-CH2-CH2- to understand, under (CH 2 ) ⁇ - is -CH 2 -, - CH2-CH2-, -CH2-CH2-CH2- and -CH2-CH 2 -CH 2 - to understand, under (CH 2 ) -5 is to be understood - CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-CH2-CH2-CH2-, etc.
  • An aryl radical is understood to mean ring systems with at least one aromatic ring but without heteroatoms in even one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or mono- or polysubstituted.
  • a heteroaryl radical is understood to mean heterocyclic ring systems with at least one unsaturated ring which contain one or more heteroatoms from the group consisting of nitrogen, oxygen and / or sulfur and can also be mono- or polysubstituted.
  • heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo [1,2,5] thiadiazole, benzothiazole, indole, benzothazole, benzodioxolane and benzodioxane , Carbazole, indole and quinazoline.
  • aryl and heteroaryl this is understood to mean the substitution of aryl or heteroaryl with R 23 , OR 23, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2 or an NR 24 R 25 , a C. - j .g- alkyl (saturated), a C ⁇ .g-alkoxy, a C3_3-cycloalkoxy, a C3_3-cycloal yl or a C2_6-alkylene.
  • R 23 OR 23, a halogen, preferably F and / or Cl, a CF3, a CN, a NO2 or an NR 24 R 25 , a C. - j .g- alkyl (saturated), a C ⁇ .g-alkoxy, a C3_3-cycloalkoxy, a C3_3-cycloal yl or a C2_6-alkylene.
  • the radical R 2 ⁇ stands for H, a C j .- j Q alkyl, preferably a C-
  • radicals R 24 and R 25 the same or different, for H, a C 1-6 -alky! -, preferably one Alkyl, saturated or unsaturated, or an aryl or heteroaryl radical bonded to a C 1-4 alkylene group, these aryl and heteroaryl radicals themselves not being substituted by aryl or heteroaryl radicals,
  • radicals R 24 and R 25 together mean CH2CH2OCH2CH2, CH 2 CH2NR 26 CH 2 CH2 or (CH 2 ) 3 .g, and
  • salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution.
  • a counterion a cation or anion
  • This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salt with cations or bases means salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation, which is physiologically - in particular when used in humans and / or mammal - are compatible.
  • the salts of the alkali and alkaline earth metals are also particularly preferred NH 4 + , but especially (mono-) or (di-) sodium, (mono-) or (di-) potassium, magnesium or calcium salts.
  • physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are compatible.
  • this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
  • physiologically compatible salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1, 1-dioxo-1, 2-dihydro1 6 - benzo [d] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid , ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
  • the hydrochloride salt is particularly preferred.
  • the object of the invention is the use of the named and defined amino acids in the above-mentioned indications in which gabapentin acts, that is to say in particular in pain therapy, in the case of epilepsy or migraine, but especially also in neuropathic pain including hyperalgesia and allodynia and the other gabapentin indications.
  • Gabapentin is a well-known antiepileptic with an anticonvulsant effect.
  • gabapentin is also used in various other indications, among others by doctors treating migraines and bipolar disorders as well as hot flashes (e.g. in postmenopause) (M. Schrope, Modern Drug Discovery, September 2000, p. 11).
  • Other indications in which gabapentin shows therapeutic potential have been identified during human studies and clinical use (JS Bryans, D. Wustrow; "3-Substituted GABA Analogs with Central Nervous System Activity: A Review" in Med. Res. Rev. (1999), pp.
  • Gabapentin is effective in the treatment of chronic pain and behavioral disorders.
  • anticonvulsive and antiepileptic effects the use against chronic, neuropathic pain , in particular thermal hyperalgesia, mechanical allodynia, cold allodynia. It is also effective against neuropathy caused by nerve damage, especially neuropathic pain, as well as inflammatory and postoperative pain.
  • Gabapentin is also successful in antipsychotic effects, especially as an anxiolytic Include: Amyotropic Lateral Sclerosis (ALS), Reflex Sympasthetic Dystrophy (RSD), Spastic Paralysis, Restless Leg Syndrome, Treatment of Symptoms and Pain due to Multiple Sclerosis, Acquired Nystagmus, Treatment of Symptoms of Parkinson's Disease, Painful Diabetic Neuropathy and Psychiatric Disorders , eg bipolar disorders, mood swings, manic behavior.
  • ALS Amyotropic Lateral Sclerosis
  • RSD Reflex Sympasthetic Dystrophy
  • Spastic Paralysis Restless Leg Syndrome
  • Restless Leg Syndrome Treatment of Symptoms and Pain due to Multiple Sclerosis
  • Acquired Nystagmus Treatment of Symptoms of Parkinson's Disease
  • Painful Diabetic Neuropathy and Psychiatric Disorders eg bipolar disorders, mood swings, manic behavior.
  • neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy.
  • the effectiveness of gabapentin in gastrointestinal damage is also known.
  • amino acids according to formula I are used for which
  • R ⁇ and R 2 are each independently selected from C- ⁇ Q alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; aryl, or heteroaryl, each unsubstituted or mono- or polysubstituted;
  • R1 and R2 together form a ring and are ( ⁇ 2) 5, substituted or unsubstituted, so that a substituted or unsubstituted cyclohexyl is formed.
  • amino acids of the formula I are used, for which:
  • radicals R ⁇ and R 2 C- ⁇ -alkyl in particular methyl, ethyl n-propyl or i-propyl, each unsubstituted or substituted one or more times; means and the other of the radicals R ⁇ and R 2 C3_-
  • Q- alkyl especially n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, branched or unbranched, saturated or unsaturated, unsubstituted or one - or substituted several times; or aryl or heteroaryl, in particular phenyl, naphthyl, furanyl, thiphenyl, pirimidinyl or piridinyl, in each case unsubstituted or simply (preferably substituted with OCH 3 , CH 3 , OH, SH,
  • radicals R 1 and R 2 C- j - ⁇ - alkyl in particular methyl, ethyl n-propyl or i-propyl, each unsubstituted or one or more times substituted; means and the other of the radicals R ⁇ and R 2 C3_-
  • 0-alkyl especially n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, branched or unbranched, saturated or unsaturated, unsubstituted or a - or substituted several times; or C4_7-cycloalkyl, preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular cyclobutyl, cyclopentyl or cyclohexyl, in
  • radicals R ⁇ and R 2 C - ⁇ - alkyl especially methyl, ethyl n-propyl or i-propyl, each unsubstituted or mono- or polysubstituted; means and the other of the radicals R ⁇ and R 2 C3_-
  • o-alkyl especially n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, branched or unbranched, saturated or unsaturated, unsubstituted or a - or substituted several times; means.
  • R1 and R2 together form a ring and are (CH2) g, substituted or unsubstituted, so that a substituted or unsubstituted cyclohexyl is formed,
  • R1 and R2 together form a ring and are (CH 2 ) s, substituted or unsubstituted, so that a monosubstituted or unsubstituted cyclohexyl is formed, in particular an unsubstituted or methyl-substituted cyclohexyl.
  • R 1 and R 2 are simultaneously CH 3 ,
  • R 1 and R 2 are CH 3 and the other is C 2 H 5 ,
  • amino acids used are selected from the following group:
  • the invention furthermore relates to the amino acids of the general formula I,
  • R1 and R 2 are each independently selected from H; C ⁇ _ 1 Q-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; Aryl, C 1 -C 4 -cycloalkyl or heteroaryl, in each case unsubstituted or substituted one or more times; or
  • R1 and R2 together form a (CH2) 3_g- ing, saturated or unsaturated, substituted or unsubstituted, in which 0-2 C atoms can be replaced by S, O or NR 4 ,
  • R 4 selected from: H; C ⁇ Q alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • R ⁇ and R 2 are each independently selected from H; C- j .
  • IQ-alkyl branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; preferably one of the radicals R1 and R 2 is C ⁇ _ 2 alkyl and the other C2_ ⁇ o-alkyl, preferably unsubstituted, unbranched and saturated, or
  • R1 and R2 together form cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • one of the radicals R ⁇ and R 2 C ⁇ alkyl in particular methyl, ethyl n-propyl or i-propyl, each unsubstituted or substituted one or more times; means and the other of the remnants in particular n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted ; or aryl or heteroaryl, in particular phenyl, naphthyl, furanyl, thiphenyl, pirimidinyl or piridinyl, in each case unsubstituted or simply (preferably substituted with OCH 3 , CH 3 , OH, SH, CF 3 , F, Cl, Br or I); or C
  • one of the radicals R 1 and R 2 is C 1 -C 4 -alkyl, in particular methyl, ethyl n-propyl or i-propyl, in each case unsubstituted or mono- or polysubstituted; means and the other of the remnants Q-yl, in particular n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, branched or unbranched, saturated or unsaturated, unsubstituted or substituted one or more times; or C 1 -C 6 -cycloalkyl, preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular cyclobuty
  • radicals R1 and R2 C1-3-alkyl in particular methyl, ethyl n-propyl or i-propyl, in each case unsubstituted or mono- or polysubstituted; means and the other of the radicals R1 and R2 C3-10-alkyl, in particular n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted; means.
  • amino acids according to the invention are selected from the following group:
  • the amino acids according to the invention are toxicologically harmless, so that they are suitable as active pharmaceutical ingredients in pharmaceuticals.
  • the invention therefore furthermore relates to medicaments comprising at least one amino acid according to the invention, and, if appropriate, suitable additives and / or auxiliaries and / or optionally further active compounds.
  • the invention therefore furthermore relates to medicaments comprising at least one of the amino acids used according to the invention, and, if appropriate, suitable additives and / or auxiliaries and / or optionally further active compounds.
  • the medicaments according to the invention optionally contain suitable additives and / or auxiliaries, including carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be used as liquid medicament forms in the form of injection solutions, drops or juices semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols can be administered.
  • suitable additives and / or auxiliaries including carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be used as liquid medicament forms in the form of injection solutions, drops or juices semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols can be administered.
  • suitable additives and / or auxiliaries including carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be used as liquid medicament forms in the form of injection solutions, drops or juices semi
  • parenterally intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on the skin, the mucous membranes or in the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
  • invention Amino acids in a depot, in dissolved form or in a plaster, optionally with the addition of agents that promote skin penetration, are suitable percutaneous application preparations. Formulations which can be used orally or percutaneously can release the amino acids according to the invention with a delay. In principle, other active substances known to the person skilled in the art can be added to the medicaments according to the invention.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. Usually 0.005 to 1000 mg / kg, preferably 0.05 to 5 mg / kg, of at least one amino acid according to the invention are applied.
  • an amino acid according to the invention is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
  • Another object of the invention is the use of an amino acid of the formula I according to the invention for the manufacture of a medicament for the treatment of pain, in particular neuropathic, chronic or acute pain, epilepsy and / or migraine
  • hyperalgesia and allodynia for the manufacture of a medicament for the treatment of hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia, or of inflammatory or postoperative pain
  • psychiatric or neuropathological disorders such as bipolar disorders, anxiety, panic attacks, mood swings, manic behavior, depression, manic depressive behavior; painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and epilepsy; gastrointestinal damage; erythromelalgic or post-poliomyelitic pain, trigeminal or post-herpetic neuralgia; or as an anticonvulsant, analgesic or anxiolytic.
  • ALS amyotropic lateral sclerosis
  • RSD reflex sympasthetic dystrophy
  • spastic paralysis restless leg Syndrome
  • restless leg Syndrome acquired nystagmus
  • psychiatric or neuropathological disorders such as bipolar disorders, anxiety, panic attacks, mood swings, manic behavior, depression, manic depressive behavior
  • painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease neurodegenerative diseases
  • an amino acid used is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
  • Another object of the invention is a method for the treatment of a non-human mammal or human being which needs treatment of medically relevant symptoms by administration of a therapeutically viable dose of an amino acid according to the invention or used according to the invention, or of a medicament according to the invention.
  • the invention relates in particular to corresponding methods for the treatment of pain, in particular neuropathic, chronic or acute pain; Migraines, hyperalgesia and allodynia, in particular thermal hyperalgesia, mechanical hyperalgesia and allodynia and cold allodynia, or of inflammatory or postoperative pain; Epilepsy, hot flashes, postmenopausal complaints, amyotropic lateral sclerosis (ALS), reflex sympasthetic dystrophy (RSD), spastic paralysis, restless leg syndrome, acquired nystagmus; psychiatric or neuropathological disorders, such as bipolar disorders, anxiety, panic attacks, mood swings, manic behavior, depression, manic-depressive behavior; painful diabetic neuropathy, symptoms and pain due to multiple sclerosis or Parkinson's disease, neurodegenerative diseases such as Alzheimer's disease, Huntington 's disease, Parkinson's disease and epilepsy; of erythromelalgic or post-poliomyelitic pain, trigeminal or post-
  • Another object of the invention is a method for producing an amino acid according to the invention in a form as described below.
  • the subject of the invention is also a process for the preparation of a compound of formula 1 according to Schemal:
  • the diastereomers are separated at a suitable stage by means of HPLC, column chromatography or crystallization.
  • the enantiomer separation is also carried out on the final stage by means of HPLC, column chromatography or crystallization.
  • the amino acids of the general formula 1 are obtained as hydrochlorides by this process. By releasing the base or reprecipitation by conventional methods, further salt forms are obtained.
  • the compounds of formula I can be combined with physiologically acceptable acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1 , 2-dihydro1 ⁇ 6 -benzo [c] isothiazol-3-one (saccharic acid), monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6 -Trimethyl-benzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid, convert into their salts in a known manner.
  • Salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetate, acetone and / or 2-butanone or else water.
  • Trimethylchlorosilane in aqueous solution is also suitable for the preparation of the hydrochlorides. It is also possible to convert them into basic salts using metal ions, for example: alkali and alkaline earth ions.
  • the analysis was carried out using ESI mass spectrometry or HPLC.
  • the indication ether means diethyl ether.
  • the residue was mixed with 300 ml of diethyl ether and 200 ml of water.
  • the organic phase was separated and the aqueous phase was washed twice with 120 ml of ether each time.
  • the combined organic phases were washed with 80 ml of 2N NaHCO 3 solution and rocked over MgSO 4 .
  • the solvent was then evaporated.
  • the crude product thus obtained was digested with 200 n-hexane.
  • the solid was filtered off, washed four times with 80 ml of hexane each time and dried in an oil pump vacuum.
  • the first fraction obtained was 2.2 g (40% of theory) of ethyl D-2-formylamino-3-methyl-nonanoate (Prod. 15) and the second fraction was 1 g (22% of theory) of L-2-formylamino -3-methyl-nonanoic acid ethyl ester (Prod. 16) 6.
  • the binding assay uses gabapentin to test the binding and affinities of the selected compounds.
  • the affinity of the compounds according to the invention is measured by the displacement of gabapentin from its binding site. If the selected compounds can displace gabapentin from its binding site, it can be expected that it will develop pharmacological properties comparable to gabapentin, for example as an agent against pain or epilepsy.
  • the compounds of the invention show good gabapentin inhibition in this assay. The examined In this biochemical assay, compounds therefore have an affinity for the previously unknown gabapentin binding site.
  • Analgesia test in the writhing test on the mouse The antinociceptive activity of the compounds according to the invention was modified in the phenylquinone-induced writhing test, modified according to IC Hendershot, J. Forsaith, J.Pharmacol. Exp. Ther. 125, 237-240 (1959) on the mouse. Male NMRI mice weighing 25-30 g were used for this.
  • Groups of 10 animals per substance dose were given 10 minutes after intravenous administration of a compound according to the invention to 0.3 ml / mouse of a 0.02% strength aqueous solution of phenylquinone (phenylbenzoquinone, from Sigma, Deisenhofen; preparation of the solution with addition of 5% ethanol and storage in Water bath at 45 ° C) applied intraperitoneally.
  • the animals were placed individually in observation cages.
  • the tracheal tube was tied in at a 2.5% halothane concentration using a syringe cylinder (20ml Ommnifix, Luer) that was shortened to approx. 20mm and placed over the mouth and nose of the animals.
  • the halothane concentration has now been reduced to approximately 1.5%.
  • Exhaled air was removed via a closed system.
  • a PE-20 (1.09 * 0.38mm) catheter was inserted into the dorsal branch of the left jugular vein to apply test substances, and a PE-50 tube (0.9569mm * 0.58mm) was inserted into the left one as a catheter for continuous monitoring of blood pressure Carotid artery introduced.
  • the actual laminectomy begins with vertebral body L2 (lumbar 2) after removal of the spinal process from vertebra L3 and extends into the area rostral from TH8 to where the large dorsal vein turns laterally and caudally.
  • the bones of each vertebral body were Carefully removed in small steps using fine bone rippers (rongeurs).
  • the muscles around TH8 / 9 and L1 / S2 were also removed so that immobilization clamps could be attached later. Exposed tissue was protected against drying out by applying 0.9% NaCl solution or thin PVC strips.
  • liquid paraffin oil pool
  • the animals spontaneously breathed additional oxygen-enriched room air (200 ml / min).
  • the blood pressure was continuously monitored via the arterial catheter, which was connected to a pressure transmitter (Elcomatic EM751A, filled with paraffin oil), and the blood pressure preamplifier NL108 (Neurolog) (Spike 2, Cambridge Electronic).
  • the systolic pressure should be close to 100 mmHg or above.
  • the local blood circulation was assessed visually, with a rosy skin color on the paws indicating normal microcirculation. An intact blood supply to the spinal cord was seen in a cherry red dorsal vein and rapid blood flow in the smaller veins.
  • Self-made multibarrel glass microelectrodes were used to derive action potentials and eject excitatory amino acids (EAA s).
  • the outer angled capillaries were temporarily fixed with shrink tubing (Shrink-KON HSB 250 6.4 to 3.2 mm; RS order no. RS 208- 9005) so that the central capillary protrudes approx. 35 mm.
  • the final fixation was now carried out using fast-curing epoxy adhesive (RS Quick Set Epoxy Adhesive RS 850-940). These electrode blanks were processed further.
  • a usable electrode has a diameter of 15-20 ⁇ m at a distance of approx. 100 ⁇ m from the tip.
  • the tips of the electrodes were checked under a microscope (Olympus BH-2 microscope; Zeiss Measuring eyepiece; magnification x 20; x 40) broken back to a diameter of 3-5 ⁇ m.
  • the electrode tips were brought into the immediate vicinity (mirror image of the electrode visible) of a glass rod and broken by carefully tapping the fine adjustment screw of the cross table.
  • the electrodes were filled with Microfil MF34G syringe capillaries (WPI) using 1 ml Ommnifix-F (B.Braun) disposable syringes and stored in a self-made holder between experiments in the refrigerator (4-6 ° C). Good electrodes can be used several times after a corresponding check.
  • the individual capillaries (barrels) were marked in color with a permanent fiber pen and filled accordingly.
  • Barrel 1 Mark: red; NMDA 100mM in 100mM NaCI; pH 7.5 - 8.0 barrel 2: marrow: green; AMPA 10mM in 200mM NaCI; pH 7.5 - 8.0 barrel 3: Mark: blue; Kainate 5mM in 200mM NaCI; pH 7.5 - 8.0 barrel 4: marrow: without; Current balance 150mM NaCI
  • the electrical resistance of the central capillary in NaCI solution against a silver-silver chloride pellet should be measured and should be between 1 and 5 Mohm (measuring device: Multimeter Voltcraft 4550B; measuring range 20MOhm). It has proven to be practical to use the resistance of the outer barrels only after inserting the electrode (depth approx. 200-400 ⁇ m) into the spinal cord of the test animal using the IP-2 microiontophoresis pumps. Usable values are around 20-100MOhm. Electrodes with too high resistances (especially the central capillary) can be broken back under microscopic control and checked again.
  • wound pain around an incision on the plantar side of a rat's rear paw is examined as a model for postoperative pain (Brennan, T.J., Vandermeulen, E.P., Gebhart, G.F., Pain (1996) 493-501).
  • the pull-away latency is determined after punctiform mechanical stimulation with an electronic von Frey filament.
  • a mechanical hyperalgesia develops that remains stable for several days.
  • the pull-away threshold of the paw is determined after punctiform mechanical stimulation.
  • the withdrawal threshold is measured five times per measuring point at intervals of 30 seconds and the individual median is determined, on the basis of which the mean value of the animal collective is calculated. 10 rats are tested per experimental animal group.
  • the withdrawal threshold is determined on the ipsilateral paw in the immediate vicinity of the incision and in the same position on the contralateral paw.
  • the measurements are taken twice before the surgical intervention to determine the pre-test mean, postoperatively immediately before the substance is administered and at different times after substance administration (usually 15, 30, 60, 90, 120 min per application).
  • the examinations of substances can take place within a period of 2 hours to 3 days postoperatively.
  • % MPE 100 - [(WTH SUB - WTH PRA-OP ) / (WTH POST - OP - WTH PRA . OP ) * 100]
  • the Mann-Whitney U test is used for the significance calculation (p ⁇ 0.05).
  • the ED 50 value is determined using a regression analysis.
  • Gabapentin shows a value of 66% MPE at 100 mg / kg.
  • Example 7 Parenteral application form.
  • 38.5 g of compound 7 are dissolved in 1 liter of water for injections at room temperature and then adjusted to isotonic conditions by adding anhydrous glucose for injections.

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EP01969790A 2000-09-30 2001-09-28 Verwendung von aminosäuren zur behandlung von schmerz Withdrawn EP1326826A1 (de)

Applications Claiming Priority (3)

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DE10048715 2000-09-30
DE10048715A DE10048715A1 (de) 2000-09-30 2000-09-30 Verwendung von Aminosäure zur Behandlung von Schmerz
PCT/EP2001/011230 WO2002030871A1 (de) 2000-09-30 2001-09-28 Verwendung von aminosäuren zur behandlung von schmerz

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NI200300043A (es) 2002-03-28 2003-11-05 Warner Lambert Co AMINOACIDOS CON AFINIDAD POR LA PROTEINA a2DELTA.
US7659305B2 (en) 2002-10-31 2010-02-09 Pfizer Inc. Therapeutic proline derivatives
CA2451267A1 (en) 2002-12-13 2004-06-13 Warner-Lambert Company Llc Pharmaceutical uses for alpha2delta ligands
WO2004054560A1 (en) 2002-12-13 2004-07-01 Warner-Lambert Company Llc Alpha-2-delta ligand to treat lower urinary tract symptoms
DE602004024317D1 (de) 2003-09-12 2010-01-07 Pfizer Kombinationen aus alpha-2-delta liganden und serotonin / noradrenalin-wiederaufnahmehemmern
WO2005030703A1 (en) 2003-09-25 2005-04-07 Warner-Lambert Company Llc PRODRUGS OF AMINO ACIDS WITH AFFINITY FOR THE α2δ- PROTEIN
US7354955B2 (en) 2004-01-07 2008-04-08 Abbott Laboratories (2S)-amino(phenyl)acetic acid and derivatives as α2δ voltage-gated calcium channel ligands
BRPI0609879A2 (pt) * 2005-04-28 2010-05-11 Pfizer Ltd derivados de aminoácidos
US8278355B2 (en) 2006-09-12 2012-10-02 Therexcell Pharma Inc. Isovaline for treatment of pain
DK2125021T3 (da) 2006-12-22 2011-09-19 Recordati Ireland Ltd Kombinationsterapi af sygdomme i de nedre urinveje med alfa2delta-ligander og NSAID'er

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HUP0302970A2 (hu) 2003-12-29
PL361629A1 (en) 2004-10-04
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MXPA03002740A (es) 2003-07-28
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US20030229145A1 (en) 2003-12-11
AR034265A1 (es) 2004-02-18

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