HK1195245A - Cis-tetrahydro-spiro(cyclohexan-1,1'-pyrido[3,4-b]indol)-4-amine derivatives - Google Patents
Cis-tetrahydro-spiro(cyclohexan-1,1'-pyrido[3,4-b]indol)-4-amine derivatives Download PDFInfo
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The invention uses compounds that act on the nociceptin/ORL-1 receptor system and on the μ-opioid receptor system and are particularly effective in the treatment of chronic pain (including inflammatory pain, visceral pain, tumour pain, preferably neuropathic pain) but do not have a pronounced effect on acute nociceptive pain.
Chronic pain can be divided into two broad groups: pathophysiological nociceptor pain, caused by the excitation of intact nociceptors after tissue trauma, and chronic inflammatory pain, caused by mechanical, metabolic or inflammatory damage to nerves themselves, which is called neuropathic pain.
The typical inflammatory pain is triggered by the release of bradykinin, histamine and prostaglandins with acidification of the tissue and pressure of the exudate on the nociceptors, which often results in sensitization phenomena in the central nervous system, expressed in increased neuronal spontaneity and stronger central neuron response (Coderre et al., Pain 1993, 52, 259-285). These changes in central neuron response behavior may contribute to spinal pain and hyperalgesia (increased pain sensation is a noxious stimulus) which is typically inflammatory for the nervous system (Yakash et al., 1999, PN 766, 968-786).
In particular, non-steroidal anti-inflammatory drugs (NSAIDs), which have an anti-inflammatory component in addition to their analgesic effect, have been proven to treat inflammatory pain (Dickensen, A., International Congress and Symposium Series - Royal Society of Medicine (2000), 246, 47-54). However, their use in the long-term treatment of chronic pain is limited in part by significant adverse reactions such as gastrointestinal ulcers or toxic kidney damage. In severe to very severe inflammatory pain (e.g. in chronic pityriasis), NSAIDs may reduce pain only slightly, but may lead to an increased blood pressure, which is a risk of acute and chronic inflammation. The next step is to reduce the risk of treatment with μ-Opioid, with the potential for greater efficacy among affected individuals.
Neuropathic pain occurs when peripheral nerves are damaged in a mechanical, metabolic or inflammatory manner. The pain patterns that occur are predominantly characterized by the occurrence of spontaneous pain, hyperalgesia and allodynia (pain is already triggered by non-noxious stimuli). (see Baron, Clin. J. Pain 2000; 16 (2 Suppl), 12-20). The causes and manifestations and therefore the treatment effects of neuropathic pain are varied. They occur as a result of injury or disease of the brain, spinal cord or peripheral nerves.
The pharmacological basis of neuropathic pain includes tricyclic antidepressants and anticonvulsants, which are used alone or in combination with oploids. These drugs usually provide only some pain relief, while pain relief is often not achieved. The frequently occurring side effects often prevent drug dosage increases from achieving adequate pain relief. In fact, a higher dose of a μ-opioid is often needed to satisfactorily treat neuropathic pain than to treat acute pain, making the side effects even more important.
Opioids used to treat neuropathic pain usually also act against acute pain at the same time. It is not possible to separate the treatment of neuropathic pain from acute pain. Depending on the dosage of the opioids, therefore, any pain sensation of the patient is suppressed, which can be quite detrimental.
Spirocyclic cyclohexane derivatives acting on the nociceptin/ORL-1 and μ-opioid receptor systems are known at the present stage of the technique. These compounds are characterised by, inter alia, exceptional structural variability and are suitable for, inter alia, the treatment of inflammatory and neuropathic pain.
There is a need for medicinal products which are effective in treating chronic, particularly neuropathic, pain while minimising the sensation of acute pain and which, where possible, should contain a low dose of the active substance to ensure satisfactory pain management without intolerable side effects.
The purpose of the invention is to provide new compounds which are suitable as medicinal products and which have advantages over the state of the art.
This task is solved by the subject matter of the claims.
The invention relates to compounds of general formula (I) for use in the treatment of neuropathic and/or chronic pain,
In which
R1 is -H or CH3;R2 is -H or -halogen;R3 is -H or -halogen;R4 is -H, -halogen or -OC1-3-alkyl;R5 is -H, -halogen or -OC1-3-alkyl;Q1-Q2- forms the group -CH2- or -CR6=CH;andR6 and R7 are either both simultaneously -H or together form a five-membered ring over the bridge -S;
in the form of free bases or physiologically compatible salts.
Surprisingly, the compounds of the general formula (I) were found to act on the nociceptin/ORL-1 and μ-opioid receptor systems and to be particularly effective in the treatment of chronic pain, particularly neuropathic pain, without simultaneously suppressing the sensation of acute pain.
The compounds according to the general formula (I) show very high analgesic efficacy in the treatment of chronic pain, in particular neuropathic pain, preferably due to poly or mononeuropathic diseases.
Surprisingly, the compounds at doses that result in almost complete remission of neuropathic pain in mono- and polyneuropathy models were found to have no effect on normal nociception in healthy animals or in healthy tissues of mononeuropathic animals, meaning that they reverse the pathological state (allodynia or hyperalgesia) but at the same time, at least slightly, if at all, impair normal pain sensation.
The compounds according to the general formula (I) thus allow selective efficacy against chronic pain, preferably neuropathic pain, preferably mononeuropathic/neuralgic or polyneuropathic pain, and even preferably post-herpetic neuralgia or diabetic polyneuropathy, preferably with negligible antinociceptive activity in acute pain.
If in the general formula (I) the group -Q1-Q2- is a group -CH2-, then the compounds of the general formula (I) are phenylacetic acid amide derivatives.
If -Q1-Q2- forms the group -CR6=CH- then the carbon atom of this group to which the remainder R6 is bound is bound to the carbon atom of the carbonyl group of the compound of general formula (I). In this case R6 can be either -H or ≠ -H. If R6-H is, then R7 is also -H. If R6 ≠ -H, then R6 and R7 together form a five-membered ring over the bridge -S- so that the compound of general formula (I) is then a benzothiophene derivative.
The compounds according to the general formula (I) represent a selection of the compounds disclosed in WO2004/043967, WO2005/066183 and WO2006/108565. Surprisingly, the spiroamines of the invention, which have the cis configuration (cis-tetrahydro-spiro ((cyclohexan-1,1'-pyrido[3,4-b]indol) -amin-4 derivatives) on the cyclohexane ring with respect to the two nitrogen elements, were found to have advantages over the other heterocycles.
Thus, unlike the other compounds described in WO2004/ 043967, WO2005/066183 and WO2006/108565, cis-spiroamides used in the present invention exhibit an excellent effect against chronic, preferably neuropathic pain, preferably pain in diabetic polyneuropathy in the animal model, without showing a significant effect against acute pain at the therapeutic dose required.
The compounds according to the general formula (I) are preferably achiral; the basic body of the general formula (I) contains no chirality element (center, axis or plane).
Err1:Expecting ',' delimiter: line 1 column 302 (char 301)
In the case of compounds of general formula (I), the two nitrogen atoms of the spiroamine are respectively syn and cis:
Other
In a preferred embodiment of the invention, the excess of the so-called cis isomer is at least 50%, preferred at least 75%, still preferred at least 90% and most preferably at least 95% and in particular at least 99%.
The expert is familiar with suitable methods for the separation of isomers (diastereomers), such as column chromatography, preparative HPLC and crystallization.
The advantages of the cis-isomer are also particularly surprising in that, in the case of structurally related spiroethems, the cis-isomer but the trans-isomer usually have pharmacologically advantageous properties (which may differ from the advantages of the cis-spiroamins of the invention):
In a preferred embodiment of the use of the invention, the compounds of general formula (I) are in the form of free bases.
In another preferred embodiment of the use of the invention, the compounds of general formula (I) are in the form of the physiologically compatible salts.
Err1:Expecting ',' delimiter: line 1 column 87 (char 86)
Physiologically compatible salts with anions or acids are salts of the respective compound with inorganic or organic acids which are physiologically compatible, especially when used in humans and/or mammals.Examples of physiologically compatible salts of certain acids are: hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulfonic acid, formic acid, acetic acid, hemicellulose, amber acid, apple acid, tartaric acid, amniotic acid, fumaric acid, lactic acid, sulfuric acid, glutamic acid, saccharic acid, monethylsalicylic acid, 5-oxoxanide, 1-heptylpropanoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid, 2-benzoic acid
Err1:Expecting ',' delimiter: line 1 column 347 (char 346)
Err1:Expecting ',' delimiter: line 1 column 75 (char 74)
For the purposes of the present invention, compounds of general formula (I) are preferred.
Other
in the form of free bases or physiologically compatible salts.
The test chemical is a chemical that is used to produce a specific chemical.
Preferably, R4 and R5 are either both -H or both -OCH3.
In a particularly preferred embodiment of the use of the invention, the compounds are selected from the group consisting of compounds of general formulae (V), (VI) and (VII),
In the form of free bases or physiologically compatible salts.
The free base of the compound of the general formula (V) can be systematically designated as 2',3',4',9'-tetrahydro-N,N-dimethyl-4- ((3-fluorphenyl) - 2'- ((3,4-dimethoxybenzyl) - carbonyl-spiro[cyclohexan-1,1'(1'H) pyrldo[3,4-b]indol]-4-amin (Cis-diastereomer) or also as 2-3,4-dimethoxyphenyl) - 1-((1s,4s) - 4-dimethylamino) - 4- ((3-fluorphenyl) - 3',4'-dihydro-spiro[cyclohexan-1,1'-pyrido[3,4-b]indratol]-2' ((9'H) - hydrochloride) - ethanolamine. This compound is preferred as a free base, or as a hemicloride.
The free base of the compound of general formula (VI) may be systematically designated as (E)-2',3',4',9'-tetrahydro-N,N-dimethyl-4-(3-fluorphenyl)-2'-(2-phenylvinyl) carbonyl-spiro[cyclohexane-1,1'(1'H) pyrido[3,4-b]indol]-4-amine (cis-diastereomer) or also as (E)-1-((1s,4s)-4-dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexane-1,1'-pyrido-[3,4-b]indol]-2'(9'H) -3-phenyl-2-en-1-propyl. This compound is preferably found as a free base, as a hydrochloric acid, as a citrate, or as a hemicloroid.
The free base of the compound of the general formula (VII) can be systematically designated as 2',3',4',9'-tetrahydro-N,N-dimethyl-4-(3-fluorphenyl) -2-'-(3,4-dimethoxybenzyl) carbonyl-spiro[cyclohexane-1,1'(1'H) pyrido[3,4-b]indol]-4-amines (cis-diastereomers) or also as benzo[b]thiophen-2-yl (((1s,4s) -4-dimethylamino) -4-3-fluorophenyl) -3-',4'-dihydrosploro[dimethyl-1,1'-pyr[3,4-bindole]-2'(9'H) hydroxybenzyl).
In particular, the compounds of the invention are selected from the group consisting of:
Other
Other
and their physiologically compatible salts and/or solvates, in particular the free bases, hydrochlorides, citrates or hemicitrate.
| (E)-2',3',4',9'-tetrahydro-N,N-dimethyl-4-phenyl-2'-(2-phenylvinyl)carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder (E)-1-((1s,4s)-4-(Dimethylamino)-4-phenyl-3',4'-dihydrospiro[cyclohexan-1,1-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| 2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluor-phenyl)-2'-(4-chlorbenzyl)-carbonyl-spiro[cyclohexan-1,1'(1'H)-pyndo[3,4-b]indol]-4-amin(Cis-Diastereomer) oder 2-(4-Chlorophenyl)-1-((1s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H) yl)ethanon |
| 2',3,4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluorphenyl)-2'-(benzothlophen-2-yl)-carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder Benzo[b]thiophen-2-yl((1s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)methanon |
| 2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluor-phenyl)-2'-(4-fluorbenzyl)-carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin(Cis-Diastereomer) oder 1-((1s,4s)-4-(Dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-2-(4-fluorophenyl)ethanon |
| (E)-2',3',4',9'-tetrahydro-N,N-dimethyl-4-(3-fluorphenyl)-2'-(2-phenylvinyl)-carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder (E)-1-((1s,4s)-4-(Dimethylamino)-4-(3-fluorophenyl)-3,4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| 2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluorphenyl)-2'-(3,4-dimethoxybenzyl)-carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder 2-(3,4-Dimethoxyphenyl)-1-((1s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)ethanon |
| (E)-2',3',4',9'-Tetrahydro-N,N-dimethyl-6'-fluor-4-(3-fluorphenyl)-2'-(2-phenylvinyl)carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder (E)-1-((1s,4s)-4-(Dimethylamino)-6'-fluoro-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| 2,3',4',9'-Tetrahydro-N,N-dimethyl-6'-fluor-4-(3-fluorphenyl)-2'-(benzyl)carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder 1-((1s,4s)-4-(Dimethylamino)-6'-fluoro-4-(3-fluorophenyl)-3',4'-dihydro-spiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-2-phenylethanon |
| (E)-2',3',4',9'-Tetrahydro-N,N-dimethyl-6'-fluor-4-phenyl-2'-(2-phenylvinyl)carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder (E)-1-((1s,4s)-4-(Dimethylemino)-6'-fluoro-4-phenyl-3',4'-dihydrospiro-[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| 2,3',4,9'-Tetrahydro-N,N-dimethyl-4-(3-fluorphenyl)-2'-benzylcarbonyl-spiro-[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer)) oder 1-((1s,4s)-4-(Dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-2-phenylethanon |
| (E)-2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(4-fluorphenyl)-2'-(2-phenylvinyl)carbonyl-spiro[cyclohexan-1,1'(1'H)-pyrido[3,4-b]indol]-4-amin (Cis-Diastereomer) oder (E)-1-((1s,4s)-4-(Dimethylamino)-4-(4-dluorophenyl)-3',4'-dihydrospiro-[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
In a preferred embodiment of the invention, the compounds of general formula (I) are used twice daily, once daily or less frequently, preferably no more than once daily.
In another embodiment of the use of the invention, compounds according to the general formula (I) are used in the treatment of chronic pain. Preferably, chronic pain is selected from the group consisting of inflammatory pain, visceral pain, tumour pain and neuropathic pain. Neuropathic pain may be of mononeuropathic/neuralgic or polyneuropathic origin.
In another preferred embodiment of the use of the invention, the compounds of general formula (I) are used in the treatment of pain in diabetic polyneuropathy.
In another preferred embodiment of the use of the invention, the compounds of general formula (I) are used in the treatment of pain resulting from post-herpetic neuralgia.
The compounds according to the general formula (I) are suitable for use in the treatment of neuropathic pain, preferably mononeuropathic/neuralgic or polyneuropathic pain, preferably peripheral polyneuropathic pain or central polyneuropathic pain.
Preferably, the polyneuropathy or polyneuropathic pain is acute (up to four weeks), sub-acute (four to eight weeks) or chronic (more than eight weeks). Preferably, the motor, sensory, autonomic, sensorimotor or central nervous system is affected in polyneuropathy. Preferably, the symptoms are symmetrically or asymmetrically distributed. The pain can be mild, moderate, moderate, severe or very severe. The neuropathic pain scale (NPS) can be used as a measure (see B.S. Galer et al., Neurology 1997, 48, 332-8).
Examples of causes of peripheral neuropathic pain include diabetic polyneuropathy, post-herpetic neuralgia, radioculopathy, post-traumatic neuralgia, chemical-induced such as chemotherapy-induced polyneuropathy, phantom limb pain, complex regional syndrome, HIV-induced sensory polyneuropathy and alcoholic polyneuropathy. Examples of causes of central polyneuropathic pain include compressive myelopathy due to narrowed canstral stenosis, post-stomach spinal stenosis, stroke, post-chemotherapy myelopathy, myelopathy induced by multiple sclerosis and HIV-induced myelopathy.
In a preferred embodiment, the neuropathy causing the neuropathic pain is associated with a disease selected from the group consisting of diabetes mellitus, vasculitis, uremia, hypothyroidism, alcohol abuse, post-herpetic neuralgia, idiopathic neuropathy, chronic inflammatory demyelinating neuropathy, multifocal motor neuropathy, hereditary polyneuropathy, Guillain-Barré syndrome, intoxication [e. g. by alcohol, heavy metals {especially Pb, Hg, As}, hydrocarbon, as a result of a group with cytotherapy chemotherapy], porphyria, infectious disease, diarrhoea [e. g. leukemia, amyloidosis, p.
Preferably, polyneuropathic pain is pain caused by a polyneuropathy as defined in ICD-10 (International Statistical Classification of Diseases and Related Health Problems, WHO edition, preferably 2008).
Another subject matter of the invention concerns the compounds of the invention for use in the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, dementia, general cognitive dysfunction, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug abuse and/or drug dependence, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tinnitus, pruritus, migraine, hearing loss, impaired intestinal motility, food intake, anorexia, fatty liver disease, locomotive dialysis, anti-inflammatory drugs, anti-coagulants, anti-anxiety drugs, anti-muscle antibodies, and/or anti-oxidants, for the treatment of mood disorders or symptoms of narcolepsy, and/or for the treatment of narcolepsy, and/or narcolepsy, and for the treatment of narcolepsy with a drug or opioid, for the treatment of narcolepsy or narcolepsy, and/or for the treatment of narcolepsy.
Another subject matter of the invention relates to a treatment, in particular in one of the above indications, of a non-human mammal or human that requires treatment of chronic pain, preferably neuropathic pain, preferably diabetic polyneuropathy or post-herpetic neuralgia, by administration of an individually therapeutically required daily dose of a compound or dosage form of the invention, preferably without significant simultaneous suppression of sensation of acute or nociceptor pain and/or significant opioid-typical side effects, in particular no significant depression and/or sedation and/or addiction and/or no addiction and/or dependence.
Another subject matter of the invention concerns a method for the treatment, in particular in one of the above indications, of a non-human mammal or human that requires treatment of chronic pain, preferably neuropathic pain, preferably diabetic polyneuropathy or post-herpetic neuralgia, by administration of a daily dose X of a compound of the invention, or a dosage form of the invention, preferably without significant simultaneous suppression of sensation of acute nociceptor damage and/or significant opioid-typical side effects, in particular with no significant respiratory and/or stiffness and/or hypotension, no abnormalities and no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no abnormalities, no, no abnormalities, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no
The present invention also relates to the use of compounds of the alligamy formula (I) with affinity for the μ-opioid receptor and the ORL-1 receptor, which
The results of the studies were significantly ineffective in the treatment of neuropathic pain, preferably in the rat, preferable to mononeuropathic pain in the Chung model, and characterised by a half-maximum effective dose of ED50n, and in the treatment of acute pain, preferably in the rat, preferable to the tail flick test, at a dose which is 5 times higher than ED50n, but not significantly effective.
Thus, when administered at this half-maximum effective dose ED50n, defined in terms of the efficacy of the compound against neuropathic pain, and even at a dose 5 times higher than ED50n, the compounds according to the general formula (I) exhibit at best a negligible antinociceptive effect in acute pain, preferably in the rat, preferably in the tail flick test.
One preferred embodiment of neuropathic pain is mononeuropathic or neuralgic pain, preferably pain due to post-herpetic neuralgia; another preferred embodiment of pain is polyneuropathic pain, preferably pain due to diabetic polyneuropathy.
The compounds according to the general formula (I) are preferably used at a dose which is substantially not significantly effective in treating acute or nociceptive pain by a factor of 10, 20, 30, 40 or 50, preferably by a factor of 75, 100, 125, 150 or 175, preferably by a factor of 200, 300, 400 or 500, preferably by a factor of 600, 700, 800 or 900, and in particular by a factor of 1000 above the half-maximum effective dose ED50n.
The semi-maximum effective dose ED50n is known to the practitioner. It is preferably defined as the dose at which 50% of the maximum therapeutic effect is achieved for the treatment of neuropathic pain. Accordingly, a semi-maximum effective dose ED50a may be defined as the dose at which 50% of the maximum therapeutic effect is achieved for the treatment of acute pain. The compounds of the invention are, however, defined as ED50n, but not ED50a.
The expert is aware of appropriate methods for the study of the efficacy of an active substance in the treatment of neuropathic pain and for the determination of the half-maximum effective dose ED50n in the treatment of neuropathic pain, as well as for the study of the efficacy of an active substance in acute pain.
For example, the determination can be done in the animal model (e.g. mouse or rat) where
The following are the most common types of pain in the treatment of diabetic polyneuropathy: mononeuropathic pain according to Chung (S.H. Kim, J.M. Chung, Pain. 1992, 50(3), 355-63) or Bennett (G.J. Bennett, Y.K. Xie, Pain. 1988, 33(1), 87-107), pain in diabetic polyneuropathy after streptococcal (STD) induced diabetes (E.K. Joseph, J.D. Levine, Neuroscience. 2003;120(4):907-13) and acute pain in the so-called tail-flick test (D'Amour and Smith, J. Pharm. Exp. Ther. 72, 1941, 74-9)
The results of the study were published in the Journal of the European Communities.
Preferably, the determination shall be in the animal model, with respect to efficacy against neuropathic pain as efficacy against mononeuropathic pain in the rat in the Chung model and with respect to efficacy against acute pain in the rat in the tail-flick test, preferably as described in the experimental part.
Thus, the compounds of the invention show preferential affinity for the μ-opioid receptor and the ORL-1 receptor, which are present in the rat.
The results of the studies were presented in the following table:
The evaluation of experimental results for statistically significant differences between the respective dose groups and the vehicle controls is preferably done by repeated measures ANOVA and post hoc Bonferroni analysis, preferably as described in the experimental part, where the significance level is set to p < 0.05.
In principle, the comparative determination of analgesic efficacy against neuropathic pain and acute nociceptive pain can also be done in humans, but this is less preferred for ethical reasons, among others. The study of efficacy against neuropathic pain, i.e. in patients suffering from neuropathic pain, can then be done according to Hansson P, Backonja M, Bouhassira D. (2007). Use and limitations of quantitative sensory testing: clinical and research application in neuropathic pain states. 129.(3): 256-9.
Surprisingly, the compounds of the general formula (I) were found to have a very favourable side effect profile compared to common Stage 3 opioids, so that even at therapeutically effective doses, such as those needed in particular to treat neuropathic pain, no or at most only minor opioid-typical adverse reactions such as respiratory depression, constipation, ham retention, nausea, vomiting, hypotension, bradycardia, addiction, dependence, euphoria, depression, sedation and dizziness were observed.
In a preferred embodiment of use, the compounds of general formula (I) do not show significant respiratory depression as an adverse reaction, preferably in the rat, preferred in the blood gas analysis model, when administered at the half-maximum effective dose ED50n, which is defined in terms of the compound's efficacy against neuropathic pain, and preferably even at a dose slightly higher than ED60n by a factor of 5.
The experimental results are evaluated for statistically significant differences between the respective dose groups and the vehicle control groups, preferably by one-way ANOVA and post hoc Dunnett analysis, preferably as described in the experimental part, where the significance level is set at p < 0.05 pupp. The group sizes are usually n=6. For further details of this experimental part, reference is also made to the experimental part.
In a preferred embodiment of the use of the invention, compounds according to the general formula (I) do not show significant constipation as an adverse reaction, preferably in the mouse, preferred in the coal passage test, when administered at the half-maximum effective dose ED60n, defined with respect to the efficacy of the compound against neuropathic pain, and preferably even at a dose 5 times higher than ED50n.
The experimental results are evaluated for statistically significant differences between the respective dose groups and the vehicle control groups, preferably by one-way ANOVA and post hoc Dunnett analysis, preferably as described in the experimental part. Significance is set at p < 0.05 p. The group sizes are usually n=10. For further details of this model, reference is also made to the experimental part.
In a preferred embodiment of use, the compounds of the general formula (I) do not show significant hypotension as an adverse reaction, preferably in the waking rabbit, preferred in the circulatory model to waking telemetrated rabbits, when administered at the half-maximum effective dose ED50n, which is defined with respect to the efficacy of the compound against neuropathic pain, and preferably even at a dose which is 5 times higher than ED50n.
The experimental results are evaluated for statistically significant differences between the respective dose groups and the poultry control groups, preferably by one-way ANOVA and post hoc Dunnett analysis, preferably as described in the experimental part, with the significance level being set at p < 0.05; the group size is n=6. For further details of this part, reference is made to the experimental model.
In a preferred embodiment of use, the compounds of the general formula (I) when administered at the half-maximum effective dose ED50n, defined with respect to the efficacy of the compound against neuropathic pain, and preferably even at a dose 5 times higher than ED60n, do not show significant bradycardia as an adverse reaction, preferably in waking rabbits, preferably in the circulatory model of waking telemetric rabbits.
The experimental results are evaluated for statistically significant differences between the respective dose groups and the vehicle control groups, preferably by one-way ANOVA and post hoc Dunnett analysis, preferably as described in the experimental part, where the significance level is set at p < 0.05 pupp. The group sizes are usually n=6. For further details of this model, reference is also made to the experimental part.
In a preferred embodiment of use, the compounds of the general formula (I) when administered at the half-maximum effective dose ED50n, defined with respect to the efficacy of the compound against neuropathic pain, and preferably even at a dose of 5 times the ED50n, do not exhibit significant impairment of motor coordination (as a measure of central nervous system effects) as an adverse reaction, preferably in the mouse, preferred in the RotaRod test. The compounds exhibit preference even at a dose that is 10, 20, 30, 40 or 50 times the preferred dose ED50n, preferably 75, 100, 125, 150 or 175, preferably even at a dose of 200, 300 or 500, 800 or 900, preferably even at a factor of 600, and preferably at a dose that is no more than half the maximum effective side-effect of central coordination (preferably 600 or 1000, and preferably, no more than 500, 600 or 900, in particular, and preferably at a factor of 50 or 1000, preferably, the drug is not significantly associated with central coordination (as a factor of central nervous system effects).
The evaluation of experimental results for statistically significant differences between the respective dose groups and the vehicle control groups is preferably done by means of ANZAN-one-way OVA and a post hoc Dunnett analysis, described in Part One of the experiment. Significance is determined by comparing the experimental results with the p < 0.05 in the experimental group. Furthermore, the experimental model is described in greater detail in Part One.
In a preferred embodiment of the method of the invention, the compounds of general formula (I) when administered at the half-maximum effective dose ED50n, defined with respect to the efficacy of the compound against neuropathic pain, and preferably even at a dose 5 times higher than ED50n, do not exhibit significant physical dependence or withdrawal symptoms as an adverse reaction, preferably in the mouse, preferred in the jumping test. Preferably, the compounds even at a dose 10, 20, 30, 40 or 50, preferably 75, 100, 125, 150 or 175, preferably 200, 400 or 500, preferably by a factor 600, 800 or 900, and preferably even at a half-maximum effective dose ED50 do not exhibit significant physical dependence or withdrawal symptoms as the preferred side-effect.
Err1:Expecting ',' delimiter: line 1 column 548 (char 547)
In a preferred embodiment of use, the compounds of the general formula (I) when administered at the half-maximum effective dose ED50n, defined with respect to the efficacy of the compound against neuropathic pain, and preferably even at a dose factor 5 higher than ED50n, do not exhibit significant psychoactive dependence or addiction as a side effect, preferably in the rat, preferred by conditioned site preference. Preferably, the compounds even at a dose factor 10, 20, 30, 40 or 50, preferred by 100, 75, 125, 150 or 175, still preferred by 200, 300 or 500, preferred by 600, 800 or 900, and in particular, preferably at a factor 600 or 1000, do not exhibit significant psychoactive dependence or addiction as a side effect factor.
Neuroscience Letters 329, 25-28 The evaluation of the pre-clinical findings for statistically significant differences in the preference of the animals for the active substance or vehicle is preferably done by means of a paired t-test, with the level of significance set at p 0.05. The group group group n= n. For further details on this, reference is made to the experimental method in T. W. F. W. and F. Neuroscience Letters 329, 25-28 and the animal T-test, which is referred to in the Neuroscience Letters 329, 25-28 and the animal T-test, which is referred to in the Neuroscience Letters F. W. F. and F. Neuroscience Letters 329, 28-22.
The compounds of general formula (I) are indicated for use in the treatment of chronic pain, preferably neuropathic pain, preferably mononeuropathic/ neuralgic or polyneuropathic pain, and preferably post-herpetic neuralgia or diabetic polyneuropathy.
The expert is familiar with the definitions of the different forms of chronic pain. In this context, reference may be made, for example, to Merskey H., Bogduk N. Classification of chronic pain.
For the purpose of description, chronic pain is preferably defined as a pain symptom that persists over a long period of time (usually at least 3, 4, 5 or 6 months) and lasts beyond the normal healing time. Preferably, neuropathic pain is defined as pain or sensory phenomenon caused by injury, disease, or dysfunction of the central or peripheral nervous system. For the purpose of description, acute pain is preferably defined as an unpleasant sensory and emotional experience that is accompanied by or is described in the form of acute or potential tissue damage (see International Association for the Study of Pain® (IASP) definition).
The compounds of the invention, according to the general formula (1), have a Kl value at the μ-opioid receptor of preferably not more than 1000 nM, preferably not more than 500 nM, still more preferably not more than 100 nM, preferably not more than 50 nM and in particular not more than 25 nM.
Methods for determining the Kl value at the μ-opioid receptor are known to the professional. Preferably, the determination is carried out in a homogeneous approach in microtiter plates. This is done by dilution series of the test substances with a receptor membrane preparation (15-40 μg protein per 250 μl incubation approach) of CHO-K1 cells expressing the human μ-opioid receptor (RB-HOM receptor membrane preparation from NEN, Amerentem, Belgium) in the presence of 1 n/mol of the radioactive ligand [3H] naloxone (NET719, Amerentem, Belgium) and 1 mg of WGA-SPA (WGA-SPA agglomerate agglomerate SPA agglomerate SPA agglomerate SPA agglomerate SPA agglomerate is preferred for incubation in a room with a total temperature of 250 μm/L, preferably at 90 μm/L.The preferable dose is 25 μmol/l naloxone to determine the non-specific binding. After the 90 minute incubation period, the microtiter plates are preferably decentrifuged for 20 minutes at 1000 g and the radioactivity is measured in a β-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage of displacement of the radioactive ligand from its binding to human μ-opiate is determined at a concentration of the test substance of preferably 1 μmol/l and is expressed as a percentage (inhibition) of the different specific binding concentrations.The results of the conversion using the Cheng-Prusoff relation allow the Ki values for the test substances to be calculated.
The compounds used according to the invention according to the general formula (I) have a Ki value at the ORL1 receptor of preferably not more than 500 nM, preferably not more than 100 nM, preferably not more than 50 nM and in particular not more than 10 nM.
The method for determining the Ki value at the ORL1 receptor is known to the practitioner. Preferably, the determination is performed in a receptor binding assay with 3H-nociceptin/orphanin FQ with membranes of recombinant CHO-ORL1 cells. This test system is preferably performed according to the method presented by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824). The concentration of 3H-nociceptin/orphanin FQ in these assays is preferably 0.5 nM. The binding assays are preferably performed with 20 μg of membrane protein 200 μl each in 50 mM heaps, pH 7.4, 10 mMCl2 and 1 mM Mg. The measurement of the BRL1 is performed using the ORL1 receptor prior to use by the EDP (Stimulatory Inhibition of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation (Stimulation of Stimulation of Stimulation of Stimulation of Stimulation) by the Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation) by the Stimulation of Stimulation (Stimulation of Stimulation of Stimulation of Stimulation) by the Stimulation of Stimulation of Stimulation) by the Stimulation of Stimulation of Stimulation (Stimulation) by the Stimulation of Stimulation of Stimulation of Stimulation of Stimulation) by the Stimulation of Stimulation of Stimulation (Stimulation) by the Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stimulation of Stim
The invention also relates to a method for the production of the compounds of the invention.
The following are the preferred synthesis routes:
Structures of formula B can be produced by reaction of ketones A with amines and acid reactants Z-H. Suitable reactants Z-H are e.g. hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazol. A particularly preferred route to compounds of structure B is the conversion of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of -40 to 60 °C, preferably at room temperature with alkali metal cyanides in methanol. Another particularly preferred route to compounds of structure B is the conversion of ketones with 1,2,3-triazole and corresponding amine in the presence of water-absorbing conditions, preferably using a water-boosting agent or using a dry solvent in a pyrazol or other analogous to B-methanol.
The production of imines of general formula Q from ketones A is a result of the general state of the art.
In general, acetals C can be obtained by substitution of suitable derivatives Z in structures of formula B. Suitable derivatives are preferably cyanogroups; 1,2,3-triazole-1-yl groups. Other suitable derivatives are 1H-benzo[d][1,2,3]triazole-1-yl groups and pyrazol-1-yl groups (Katritzky et al., Synthesis 1989, 66-69). A particularly preferred route to compounds of structure C is the conversion of aminonitryl B (Z=CN) with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably in RT. The organometallic compounds are either available commercially or are widely manufactured by organometric techniques.
Amino acetals C with no more than one substituent on the nitrogen atom can be obtained by methods known to the expert by adding carbon nucleophiles to imine Q, preferably organometallic compounds in inert solvents, especially preferably with Grignard reagents or organolithium compounds, preferably in ethers, preferably at temperatures from 100 to RT.
Compounds of formula E can be released from corresponding acetals C or their salts D by acid clearance, according to the state of the art, where X is selected from the group of alkyl, alkyl/alkylide/ with aryl or alkyl (saturated/unsaturated) substituted alkylids
Manufacture of C (R1 ≠ -H) from Ca (R1 = -H)
Other
Amino acetals Ca with a maximum of one substituent on the nitrogen atom can be converted by methods known to the skilled person in principle, e.g. by reductive amination, into corresponding amino acetals C with one or two additional substituents on the nitrogen.
For example, the necessary ketone intermediate E can be produced by the following three different routes: (1) aminonitrile route, (2) imine route and (3) triazole route.
The aminonitrile route, as described in the following synthesis scheme, synthesizes aminonitrile Ba from a ketone precursor A, which is transferred to the C and D and further to E using a nucleophile MR3 as described and applied in WO 2004/043967.
The imine route synthesizes imine Q from a ketone precursor A, which is transferred to the building blocks C and D and further to E using a nucleophile MR3, as described in the following diagram. The required imine building blocks Q can be produced by a method known to the expert (Layer, Chem. Rev., 1963, 8, 489-510).
Other
In the triazole route, triazole Bb was synthesised from a ketone precursor A, as described in the following diagram, and transferred to the C and D building blocks and further to E using a nucleophile MR3.
Other
Tryptamines of type H may be reacted in reactions of the Pictet-Spengler reaction type with ketones E by addition of at least one reagent from the group of acids, acid anhydrides, esters, weakly acidic salts or leucic acids to form products of formula AMN.
Preferably, a reagent from the group of carbonic, phosphoric or sulphonic acids or their respective anhydrides, carbonic tri-alkyl esters, acidic salts, mineral acids or leucic acids selected from the group consisting of boron trifluoride, indium (III) chloride, titan tetrachloride, aluminium (III) chloride, or with the addition of at least one transition metal salt, preferably with the addition of at least one transition metal trifluoride (transition metal trifluoride sulphur sulphate), preferably with the addition of a transition metal trifluoride sulphur sulphur, in particular with the addition of a transition metal trifluoride sulphur polyethylene, is obtained from the group consisting of boron trifluoride, indium (III) chloride, titan tetrachloride, aluminium (III) chloride, or titan trifluoride sulphur, then obtained in combination with a solvent such as Tritritol or Tritol, or in the case of methanol, trifluoride sulphur, or in the presence of a solvent, in solution with a solvent, such as Tritol, or in the case of methanol, trifluoride sulphur, or in solution with a solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution, in solution
Once again, the conditions given in the following examples are preferred.
The following citations are particularly relevant: Jirkovsky et al., J. Heterocycl. Chem., 12, 1975, 937-940; Lett et al., J. Chem. Soc. Perkin 1, 1992, 813-822; Shinada et al., Tetrahedron Lett., 39, 1996, 7099-7102; Garden et al., Tetrahedron, 58, 2002, 8399-8412; Lednicer et al., J. Med., 23, 1980, 424-430; Bandini et al., J. Org. Chem., 67, 15; 5386-5389; Davis et al., J. Med., 31, 31, 27, 27, 27, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29,
Compounds of the general formula AMN may be added to carbon acids in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethylformamide, diethyl ether, dioxane and tetrahydrofuran, with the addition of at least one coupling agent, preferably selected from the group consisting of carbonyldimidazole (CDI), 2-chloro-1-methylpyridinium iodide (Mukaiyama reenz), N-(3-dimethylpropyl) -nethylcarbodiol (EDCI), O-benzotriazol-1-hydro-base-1-yl) -N,N,N,N',N'-tetrahydramethylcarbodiol (TBTBTU), N-Dicyclamethyl-N-Doxylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamy
Compounds of the general formula AMN may be added to acid anhydrides and carbonic chlorides in at least one solvent, preferably selected from the group consisting of dichloromethane, acetonitrile, dimethylformamide, diethyl ether, dioxane and tetrahydrofuran, if appropriate, in the presence of at least one inorganic base, preferably selected from the group consisting of potassium carbonate and caesium carbonate, or an organic base, preferably selected from the group consisting of triethylamine, diisopropylethylamine and pyridine and, where appropriate, with the addition of 4-dimethylamino) pyridine or 1-hydroxyzole at temperatures between 150°C and 25°C. If necessary, organic compounds preferably selected from the group consisting of triethylamine, diisopylethylamine and pyridine and, where appropriate, with the addition of 4-dimethylamino) pyridine or 1-hydroxyzole at temperatures between 150°C and 25°C.
For further details on the synthesis of the compounds used in accordance with the invention, in particular with regard to the synthesis of suitable edible building blocks, full reference is also made to WO2004/043967, WO2005/063769, WO2005/066183, WO2006/018184, WO2006/108565, WO2007/124903 and WO2008/009416.
The compounds used in accordance with the invention act, for example, on the ORL1 and μ-opioid receptors relevant for various diseases, making them suitable as active substances (drugs) in a pharmaceutical composition.
The invention also relates to the use of a pharmaceutical composition for use in the treatment of neuropathic and/or chronic pain, where the composition contains a physiologically compatible carrier and at least one compound according to the general formula (I).
Preferably, a composition is used which
is solid, liquid or paste-like; and/or contains the compound of the invention in an amount between 0,001 and 99 weight per cent, preferably between 1,0 and 70 weight per cent, by weight of the total composition.
The pharmaceutical composition used in accordance with the invention may contain suitable additives and/or excipients and/or other active substances, as appropriate.
Examples of physiologically compatible media, additives and/or excipients are fillers, solvents, diluents, dyes and/or binders, which are known to the professional (cf. H.P. Fiedler, Lexicon of Excipients for Pharmaceuticals, Cosmetics and Related Fields, Editio Cantor Aulendoff).
Preferably, the composition used according to the invention contains the compound according to the invention in a quantity of 0.001 to 99 weight per cent, preferably 0.1 to 90 weight per cent, still preferably 0.5 to 80 weight per cent, preferably 1.0 to 70 weight per cent and in particular 2.5 to 60 weight per cent, based on the total weight of the composition.
Preferably, the composition is prepared for systemic, topical or local administration, preferably for oral administration.
In another embodiment of the use of the invention, a pharmaceutical form of administration containing the pharmaceutical composition of the invention is used.
In a preferred embodiment, the dosage form used in accordance with the invention is for twice daily administration, once daily administration or less frequently than once daily administration, preferably at a maximum of once daily administration.
Preferably, this is systemic, particularly oral administration.
In a preferred embodiment, the dosage formulation of the invention contains the compound according to the general formula (I) at a dose so low that it is not significantly effective in the treatment of acute pain, preferably in the range of 1.0 μg to 10 mg based on the molecular weight of the free base.
The dose should preferably be 0,001 mg±50%, 0,002 mg±50%, 0,003 mg±50%, 0,004 mg±50%, 0,005 mg±50%, 0,006 mg±50%, 0,007 mg±50%, 0,008 mg±50%, 0,009 mg±50%, 0,01 mg±50%, 0,02 mg±50%, 0,03 mg±50%, 0,04 mg±50%, 0,05 mg±50%, 0,06 mg±50%, 0,07 mg±50%, 0,08 mg±50%, 0,09 mg±50%, 0,1 mg±50%, 0,15 mg±50%, 0,25 mg±50%, 0,3 mg±50%, 0,35 mg±50%, 0,009 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,01 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,05 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5 mg±50%, 0,5%, 0,5 mg±50%, 0,5%, 0,5 mg±50%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5%, 0,5% or 0,5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%,
The preferred dose is 0,001 mg±25%, 0,002 mg±25%, 0,003 mg±25%, 0,004 mg±25%, 0,005 mg±25%, 0,006 mg±25%, 0,007 mg±25%, 0,008 mg±25%, 0,009 mg±25%, 0,009 mg±25%, 0,01 mg±25%, 0,02 mg±25%, 0,03 mg±25%, 0,04 mg±25%, 0,05 mg±25%, 0,06 mg±25%, 0,07 mg±25%, 0,08 mg±25%, 0,09 mg±25%, 0,1 mg±25%, 0,15 mg±25%, 0,15 mg±25%, 0,2 mg±25%, 0,25 mg±25%, 0,35 mg±25%, 0,45 mg±25%, 0,45 mg±25%, 0,5 mg±25%, 0,01 mg±25%, 0,02 mg±25%, 0,02 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,05 mg±25%, 0,25 mg±25%, 0,25 mg±25%, 0,25 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg±25%, 0,5 mg, 0,5 mg, 0,5 mg, 0,5 mg, 0,5 mg, 0,525 or 0,5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg, 5 mg,
In particular, the preferred dose is 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.25 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.5 mg, 6.5 mg, 2 mg, 2.6 mg, 3 mg, 3.5 mg, 4.5 mg, 4.5 mg, 5 mg, 6.5 mg, 6 mg, 7 mg, 8 mg, 8.5 mg, 9.5 mg, 5.5 mg, or 10 mg, based on the free molecular weight.
In a preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (I) in an amount of 10 μg±90%, preferably 10 μg±75%, still preferably 10 μg±50%, preferably 10 μg±25%, and in particular 10 μg±10%, based on the molecular weight of the free base.
In another preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (I) in an amount of 100 μg±90%, preferably 100 μg±75%, still preferably 100 μg±50%, preferably 100 μg±25%, and in particular 100 μg±10%, based on the molecular weight of the free base.
In another preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (I) in an amount of 250 μg±90%, preferably 250 μg±75%, still preferably 250 μg±50%, preferably 250 μg±25%, and in particular 250 μg±10%, based on the molecular weight of the free base.
In another preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (I) in an amount of 500 μg±90%, preferably 500 μg±75%, still preferably 500 μg±50%, preferably 500 μg±25%, and in particular 500 μg±10%, based on the molecular weight of the free base.
In another preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (I) in an amount of 750 μg±90%, preferably 750 μg±75%, still preferably 750 μg±50%, preferably 750 μg±25%, and in particular 750 μg±10%, based on the molecular weight of the free base.
In another preferred embodiment, the dosage form used according to the invention contains a compound according to the general formula (I) in an amount of 1000 μg±90%, preferably 1000 μg±75%, still preferably 1000 μg±50%, preferably 1000 μg±25%, and in particular 1000 μg±10%, based on the molecular weight of the free base.
The presentation form according to the invention may be administered, for example, as a liquid formulation in the form of solutions for injection, drops or juices, or as a semi-solid formulation in the form of granules, tablets, pellets, patches, capsules, patches/spray patches or aerosols.
For oral application, the dosage forms are tablets, dressing, capsules, granules, drops, juices and syrups, for parenteral, topical and inhaled applications solutions, suspensions, easily reconstituted dry preparations and sprays.
Oral or percutaneous dosage forms may release the compounds of the invention with delayed release. The compounds of the invention may also be used in parenteral long-term deposition forms such as implants or implanted pumps. In principle, other active substances known to the practitioner may be added to the dosage forms of the invention.
In a preferred embodiment, the compounds used in accordance with the invention are immediately released (IR) from the dosage form, i.e. preferably at least 80% of the original active substance is released after 20 minutes under in vitro conditions, preferably according to Ph. Eur.
Surprisingly, the compounds used according to the general formula (I) of the invention were found to have an unusually long half-life (t1/2) or pharmacodynamic duration of action, so that a comparatively infrequent dose is sufficient to achieve a comparatively long duration of pharmacological efficacy and thus pain relief.
The long half-life of the drug gives rise to a long-lasting effect, even with immediate release (IR). This has the added advantage that, despite long-lasting effects, the drug is rapidly introduced and thus has a rapid onset of pharmacological activity after the first administration.
Err1:Expecting ',' delimiter: line 1 column 584 (char 583)
The amount of compounds used in accordance with the invention to be administered to the patient varies according to the weight of the patient, the type of application, the indication and the severity of the disease.
For all the foregoing embodiments of the dosage forms used according to the invention, it is particularly preferable if the dosage form contains at least one compound of the general formula (I) in addition to another active substance.
The ORL1 receptor and the μ-opioid receptor are particularly associated with pain, and accordingly the compounds of the invention can be used to produce a medicinal product for the treatment of chronic pain, preferably neuropathic pain, preferably mononeuropathic/neuralgic or polyneuropathic pain, and even preferably pain in post-herpetic neuralgia or diabetic polyneuropathy.
Err1:Expecting ',' delimiter: line 1 column 253 (char 252)
Commercially available at Aldrich at the time of synthesis.
At the time of synthesis commercially available at Fluorochem.
To prepare the reaction mixture, 1,82 M phenylammagnesium chloride solution in THF (109 ml, 0,198 mol) was added to an argon-freezing solution and the aminonitril B-1 (21 g, 0,1 mol), dissolved in THF (210 ml), was added within 15 min and then stirred at room temperature for 16 h. Saturated ammonium chloride solution (150 ml) was added under ice-cooling and extracted with diethyl ether (3 x 100 ml). The organic phase was dissolved with water (100 ml) and saturated NaCl solution (100 ml) and diluted for eons. An oil-bearing oil (25,2 mol) was left. The raw product was dissolved in ethyl ketone (280 ml) and dissolved in E-SiCl (18,3 ml) with 0,158 ml of white solids, which was then dissolved in a white solution of D-hydrochloride after a reaction time of 6 to 35 minutes (10,5 mol).
The hydrochloride D-1 (10.5 g, 35.2 mmol) was dissolved in 7.5 N hydrochloric acid (36 ml) and stirred at room temperature for 96 h. After completing the hydrolysis, the reaction mixture was extracted with diethyl ether (2 x 50 ml). The aqueous phase was made alkaline by ice-cooling with 5 N sodium salt, extracted and compressed with dichloromethane (3 x 50 ml). The ketone 6 was thus isolated as a yellow solid with a melting point of 104-108 °C at a yield of 97 % (7.4 g).
To prepare the reaction mixture, saturated ammonium chloride solution (150 ml) and water (60 ml) were added under ice-cooling and extracted with diethyl ether (3 x 100 ml). The organic phase was boiled and dissolved with water (50 ml) and saturated NaCl solution (50 ml) under argon and ice-cooling for 15 min. A boiling point of oil (26.5 g) was reached, which contained, in addition to the phenyl compound, the 2 g of ketone. The reaction product was dissolved in a solid solution of ethyl isomethyl methyl ether (15.6 to 27.6 ml) with a white solution of ethyl chloride (16.6 to 27.8 mmol) at a temperature of 141 °C. The solution was dissolved in a white solution of ethyl isomethyl ether (16.6 to 27.3 ml) with a white solution of ethyl chloride (16.6 to 27.3 mmol) and a solution of hydrochloric acid (16.6 to 27.3 ml).
A solution of 1-bromo-3-fluorbenzole (5.00 g, 28.6 mmol) in abs ether (15 mL) was dripped into a suspension of magnesium (694 mg, 28.6 mmol) in abs ether (10 mL) so that the ether settled. After completion of the addition, the ether was stirred for 10 min at RT, and the magnesium was then completely dissolved. The reaction solution was cooled in the bathtub and the aminonitrile B-1 (3.00 g, 14.3 mmol) was dripped at 10 °C into abs THF (30 mL). The approach was carried out at room temperature overnight, the reaction product was soaked in ice with 20 per cent NH4Cl solution (20 mL) and water (30 mL) and the ether was soaked with 50 mL (32 mL) of ether. The product was dissolved in water with extra ether (50 mL) and dissolved in a vacuum, with a vacuum and a vacuum. The product was dissolved in water with 5 mL (50 mL) of ether (50 mL) and then dissolved in water with extra ether (50 mL) and then cooled at room temperature, with a vacuum and a vacuum.
The yield of D-2: 2.8 g (62%)
The mean value of the 1H-NMR (DMSO-d6) is 1.91 (8 H, m); 2.54 (6 H, s); 3.91 (4 H, d); 7.37 (1 H, m); 7.61 (3 H, m).
The hydrochloride D-2 (7.2 g, 22.75 mmol) was dissolved in water (9.6 ml), mixed with concentrated hydrochloric acid (14 ml, 455 mmol) and stirred for 4 days at room temperature. After completion of hydrolysis, the reaction mixture was extracted with diethyl ether (2 x 50 ml), the aqueous phase was made alkaline by ice-cooling with 5N sodium salts, with the product being eliminated. The ketone E-2 was isolated as a yellow solid with a melting point of 83-88 °C and a yield of 50% (6.05 g).
The hydrochloride D-2 (2.80 g, 8.86 mmol) was dissolved in water (3.7 mL), mixed with concentrated hydrochloric acid (5.5 mL) and stirred at RT 4 d. After completion of hydrolysis, the reaction mixture was extracted with ether (2 x 10 mL), the aqueous solution was made alkaline by 5N sodium brine ice cooling, the reaction mixture was extracted with dichloromethane (3 x 50 mL), the organic phase was dried with sodium sulphate and i. i. vacuum condensed.
E-2 yield: 676 mg (32%) of colourless solid
The melting point is 62-67 °C.
The mean value of the dose of the active substance is calculated as follows:
1M 4-fluorophenylmagnesium bromide solution in THF (3.125 ml, 125 mmol) was added to a solution of aminonitryl B-1 (10.5 g, 50 mmol) in THF (150 ml) under argon and ice cooling for 15 min and then stirred at room temperature for 16 h. To prepare the reaction mixture, saturated ammonium chloride solution (37 ml) and water (50 ml) were added under ice cooling and extracted with diethyl ether (3 x 100 ml). The organic phase was brazed and dissolved with water (50 ml) and saturated NaCl solution (50 ml). An oil (12.55 g) was returned, which contained B-148 g of phenyl compound C-34. The solid product was dissolved in ethyl methyl ether (75 ml) in a solution of white water (75 ml) and hydrochloric acid (75 ml) with a dissolved white water (75 ml).
The hydrochloride D-3 (7.2 g, 22.75 mmol) was dissolved in water (9.6 ml), mixed with concentrated hydrochloric acid (14 ml, 455 mmol) and stirred for 4 days at room temperature. After completion of hydrolysis, the reaction mixture was extracted with diethyl ether (2 x 50 ml), the aqueous phase was made alkaline by ice-cooling with 5N sodium salts, extracted with dichloromethane (3 x 50 ml) and condensed. The ketone E-3 was isolated as a yellow solid with a melting point of 128-133 °C and a yield of 76 g % (4.05).
2-thlodlophen (1.22.9 g, 109 mmol) was dissolved in THF (80 ml) under argon and transferred to THF with 2M isopropyl magnesium chloride (2.35.7 ml, 72 mmol) within 30 min at 0 °C. After a reaction time of 1 h at 3-5 °C, aminonitril B-1 (10 g, 47.6 mmol) dissolved in tetrahydrofuran (20 ml) was added and stirred at room temperature for 20 h. The method was completed by adding saturated NH4Cl solution (85 ml) and extraction with Dlethyl ether (3x100 phase). The organic ketone was dissolved in water (50 ml) and saturated NaCl solution (50 ml) and dissolved in oil. A dark gloss obtained from the extraction of ammonium (21.3 mmol) was obtained by dissolving it in a white crystalline solution of 2-methyl ether (11.74 ml) and dissolving it in a white crystalline solution of Dlethyl ether (11.74 ml) and 71.3 mmol (11.74 ml) of hydrochloride.
The hydrochloride D-4 (8.68 g, 28.6 mmol) was dissolved in 7.5 N hydrochloric acid (29 ml) and stirred at room temperature for 48 h. After completing hydrolysis, the reaction mixture was extracted with diethyl ether (2 x 50 ml). The aqueous phase was made alkaline by ice-cooling with 5 N sodium salt, extracted and compressed with dichloromethane (3 x 50 ml). The ketone E-4 was obtained as a yellow solid with a melting point of 108 to 110 °C at a yield of 89% (5.66 g).
3-lodthiophen (1.5 g, 23.8 mmol) was dissolved in argon in THF (18 ml) and transferred to THF within 8 min at 0 °C with 2M isopropylmagnesium chloride (2.7.8 ml, 15.5 mmol) after a reaction time of 1 h at 3-5 °C, aminonitril B-1 (2.16 g, 10.3 mmol) dissolved in tetrahydrofuran (20 ml) was added, then stirred at room temperature for 20 h. The treatment was completed by adding saturated NH4Cl solution (20 ml) and extraction with diethyl ether (3 x 50 ml). The organic phase was dissolved with water (20 ml) and dissolved NaCl (20 ml) and dissolved in water, resulting in a bright golden yellow solution (1.95 mmol) of ethyl chloride (15.95 to 25.5 ml) in a white crystalline solution of ethyl methanol, with a reaction time of 250 ml.
The hydrochloride D-5 (1.8 g, 5.9 mmol) was dissolved in 7.5 N hydrochloric acid (7 ml) and stirred at room temperature for 48 h. After completion of hydrolysis, the reaction mixture was extracted with diethyl ether (2 x 30 ml), the aqueous phase was made alkaline with 5 N baking soda under ice cooling, extracted and condensed with dichloromethane (3 x 30 ml). The ketone E-5 was isolated as a yellow solid with a melting point of 147 to 150 °C and a yield of 98 % (1.27 g).
Note: This rule applies mainly to the cis product AMN-1cis.
The ketone E-1 (3.26 g, 15 mmol) and tryptamine H-1 (2.4 g, 15 mmol) were dissolved in dry MeOH (100 ml) without oxygen. Sodium sulphate (3 g) was added to this mixture. After a reaction time of 17 h, the solvent was distilled in the rotary evaporator and the residue was absorbed in 1,2-dichlorethane (100 ml). The reaction mixture was dissolved with trifluoroacetic acid (15 ml) and stirred for 1 h at room temperature. The course of the reaction was followed by DC.The solid was washed and dried with H2O (3 x 5 ml), the cis product AMN-1cis, which was obtained as a white solid with a melting point of 214-218 °C at a yield of 4 g (74%). The parent sludge (aqueous phase) was extracted with 1,2-dichlorethane (3 x 25 ml). The organic phase was dried and compressed with Na2SO4. The solid brown residue was decrystallized from MeOH (10 ml) and produced a mixture of cis-AMN-1cis and trans-AMN-1 trans-spiro (1: 1). The mixture was obtained as a white solid at a yield of 940 (17 mg).
The measurement of the frequency of the measurement is based on the following equation:
The ketone E-2 (4.71 g, 20 mmol) and tryptamine H-1 (3.2 g, 20 mmol) were dissolved in dry MeOH (200 ml) under argon. After a reaction time of 24 h, MeOH was distilled and the yellow, oily residue suspended in 1,2-dichlorethane (200 ml). The reaction mixture was mixed with trifluoroacetic acid (20 ml) and stirred at room temperature for 2 h. The course of the reaction was monitored by DC. For processing, the solution was diluted with H2O (100 ml) and set to pH 11 with NaOH (5 mo/l). After adding ethylacetate (50 ml) to the solution, a white solid was removed by stirring it over a step. The solid was dried with H2O (32 ml) at room temperature and obtained by melting it in a white solid of 220-225 °C (7-223 °F) and then melting it in a cistern containing a white solid.
The measurement of the frequency of the measurement is based on the following equation:
The residue was dissolved in 1,2-dichlorethane (130 ml), rapidly added with trifluoroacetic acid (12.7 ml) and stirred for 2 h at room temperature. Under ice-cooling, water (120 ml) and 5Nron solution (40 ml) were added and stirred for 1 h. The resulting colourless solid was removed by filtration and washed with 1,2-dichlorethane (30 ml) and water (425 ml). The cis-Nron solution was removed from the solid by transpiration at 60 g of the methanol (37 g/ ml) and separated from the nitrous oxide (29 g/ ml) by a white filter at room temperature (29 g/ ml) and obtained by filtration with a nitrous oxide of methanol (29 g/ ml).
The measurement of the frequency of the measurement is based on the following equation:
The ketone E-2 (9.6 g, 41.2 mmol) and fluortryptamine H-2 (7.3 g, 41.2 mmol) were dissolved in ethanol (200 ml) and heated for 12 hours to return. The ethanol was then distilled and the raw product suspended in 1,2-dichlorethane (100 ml). The reaction mixture was added to trifluoric acid (90 ml) and stirred at room temperature for 12 h. The reaction was followed by DC. The solution was treated with 500 ml of 1 NOH NaOH solution at 0 °C basically and then extracted 3x with 500 ml of ethylene glycol acetate. The combined organic phases were dried over magnetic sulphate and reduced under concentrated pressure. The solution was obtained from a white solid (100 ml) obtained from methanol (2-3 g/ml) obtained from a white liquid obtained from a white liquid obtained from methanol (2-3 g/ml) and obtained from a white liquid obtained from methanol (2-3 g/ml).
The mean time between the onset and the end of the treatment is approximately 1 hour NMR (DMSO-d6, 400 MHz): δ 10.39 (s, 1H), 7.44-7.49 (m, 1H), 7.11-7.24 (m, 4H), 7.00-7.04 (m, 1H), 6.72-6.78 (m, 1H), 2.95-2.98 (t, 2H), 2.48-2.50 (m, 1H), 2.36-2.39 (d, 2H), 1.98-2.11 (m, 2H), 1.91 (s, 6H), 1.51-1.67 (m, 5H)
The following information shall be provided in the form of a summary of the results of the analysis:
The ketone E-1 (8.4 g, 47 mmol) and fluortryptamine H-2 (10.2 g, 47 mmol) were dissolved in ethanol (200 ml) and heated for 12 hours to return. The ethanol was then distilled and the raw product suspended in 1,2-dichlorethane (120 ml). The reaction mixture was mixed with trifluoroacetic acid (100 ml) and stirred at room temperature for 12 h. The reaction was followed by DC. The solution was treated with 1 N NaOH solution at 0 °C and then extracted 3x with 500 ml of ethyl diethyl acetate. The combined organic phases were magnetically dried and reduced to concentrated pressure. The resulting solid was obtained from a white solid (28 g/ml) of methanol (2-4 g/ml) which was obtained by treating it with a white solid (2 g/ml) of methanol (2-4 g/ml) and dissolving it in a white liquid (2 g/ml) of water.
The mean time between the onset and the end of the treatment is approximately 1 hour NMR (DMSO-d6, 400 MHz): δ 10.36 (s, 1H), 7.45 (s, 4H), 7.32 (s, 4H), 7.14 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 2.99 (s, 2H), 2.40 (s, 2H), 2.37 (s, 2H), 2.13 (s, 2H), 1.91 (s, 6H), 1.88 (s, 1H), 1.65 (s, 4H), 1.23 (s, 1H).
The reaction mixture was added with trifluoric acid (11.9 ml) and stirred at room temperature for 2 h. Then the reaction mixture was diluted with 1,2-dichloroethane (119 ml) and partially set to pH 11 by ice cooling with 1N sodium dihydroxide solution. A lighter dry phase was obtained. The mixture was stirred at room temperature. The dry phase was filtered through the water. The water was filtered through the water, and the best is nitric acid was extracted from the water. The resulting isomer of isomeric acid was removed from the water at a vacuum temperature of 0.68 °C (56 °C) and dissolved in water at a temperature of 0.6 to 0.6 °C (250 to 5.6 mg/L) and the rest was transferred to the water at a temperature of 0.68 to 0.6 °C (260 to 5.6 °C). The resulting isomer of isomeric acid was filtered at room temperature. The water was dissolved in water at a vacuum temperature of 0.68 to 0.6 °C (250 to 5.6 °C) and the resultant isomer was dissolved in water at a temperature of 0.6 to 0.6 °C (260 to 0.6 °C). The resultant isomer of isomeric acid was removed from the water at a vacuum temperature of 0.6 to 0.6 °C (250 to 0.6 °C) and the resultant isomer was dissolved in water at a temperature of 0.6 to 0.6 °C (250 to 0.6 °C).
The mean value of the measured values of the active substance (s) in the active substance (s) is calculated as follows:
The aqueous phase was extracted three times with 10 ml of ethyl acetate each. The organic phase was then dried using MgSO4 and compressed in the rotary evaporator. The raw product was dried by column sulphate-pump [60 mg; DCM/methanol (19,570 mg). The product was dried in a 50 mg (26%) tube. To further produce the product, the solid was dissolved in a 30 mg (0.5 mm) (0.5 mg) of methanol and acetone, and the product was dissolved in a 30 mg (0.5 mm) (0.5 mg) (135 mg) of methyl acetate, and dried in a vacuum at 3 °C. The product was obtained by adding 15 mg of methanol to the solution.
The value of the product used in the manufacture of the product is calculated as the value of the product obtained from the use of the product in the manufacture of the product.
The reaction solution was irradiated at 120°C for 10 min. in the microwave (Initiator Eight, Biotage). After completion of the reaction (DC control), the reaction solution was first filtered, transferred to a diethyl methanol (15 ml) and re-filtered. It was reconstituted with saturated Na2CO3 solution (8 ppm). The reconstituted phase was reconstituted with 60 mg (10.0 mg) of the product. The product was combined with a mixture of hydrogel and AMD (10.4 mg/ ml) of methanol. The product was further agglomerated with a mixture of hydrogel and methyl methanol.
The maximum value of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the
The reaction solution was irradiated at 100°C for 10 min. in the microwave (Initiator Eight, Biotage). After completion of the reaction (DC control), the reaction solution was diluted and filtered with DCM (15 ml). The mother liquor was dried with dissolved Na2CO3 (8 ml). After separating the phases, the phase was doubled with DCM: 125 mg (1,3 ml) of the product was washed with 60 mg (33 mg) of methanol and 60 mg (33 mg) of methyl methanol. The product was obtained by washing the seeds in a red washer.
The mean value of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the
The reaction solution was irradiated at 130°C for 10 min. in the microwave (Initiator Eight, Product Biotage). After completion of the reaction (DC control), the reaction solution was first filtered, the mother liquor was diluted with 50 mg DC (45 ml) of sulphuric acid and dried with Na2CO3 solution (25 mg, 3.18 mmol) and the organic phase was re-dried with Na2CO3 solution (408 mg, 3.18 mmol). The product was dissolved in a vacuum with methanol (148 mg, 1.29 mg/ ml) and obtained in a 150 mg (129 mg/ ml) DC (10.9 mg/ ml) of diethyl methanol (10.9 mg/ ml) The product was dissolved in a vacuum with a dilute solution of methanol (10.9 mg/ ml) and obtained in a vacuum with a dilute solution of methanol (10.9 mg/ ml). The product was obtained by dissolving the organic phase with a dilute solution of Na2CO3 (10.2 mg/ ml) in an air-filled vacuum.
The value of the active substance is calculated by adding the following values to the total value of the active substance:
The spiroamine (AMN-2cis; 378 mg, 1.0 mmol) was dissolved in dry aprotic solvent (6 ml), mixed with cinnamoyl chloride (183 mg, 1.1 mmol) and diisopropylethylamine (155 mg, 1.2 mmol) and stirred overnight at RT After the end of the reaction (DC control), the solvent was removed, the residue was treated with water and extracted with halogenated solvent. The combined organic phases were dried and compressed using Na2SO4. The raw product was column-natographed. During the compressing process a solid was removed, which was filtered and then dried. The product was obtained at a yield of 220 mg (43%)
The measurement of the effect of the measurement on the concentration of the substance in the sample is based on the following equation:
To produce the salt, the amide AMD-5cis (220 mg, 0.43 mmol) was dissolved in dry aprotic solvent (1.5 ml) and mixed with citric acid (83 mg, 0.43 mmol) dissolved in the least possible protic solvent.
The reaction product was irradiated at 120°C for 10 min in the microwave (Initiator Eight, Biotage). After completion of the reaction (DC control), the product was first filtered and then the mother' s bladder was mixed with NaOH solution (5 N, 10 ml). After separation of the phases, the aqueous phase was mixed three times with a polar organic solution (5 ml). The product was extracted from raw Pyrrhophenol and obtained in a 140 mg-77 mg of AMD.
The value of the product used in the manufacture of the product is calculated as the value of the product obtained from the product obtained from the use of the product.
The suspension of the spiroamine AMN-3cis (0.197 g; 0.5 mmol; 1 eq.) was presented in a microwave container in 15 ml of DCM. This suspension was given successively ethyl diisopropylamine (0.129 g; 1 mmol; 2 eq.) and cinnamic acid chloride (0.166 g; 1 mmol; 2 eq.) The microwave container was closed and heated in the microwave (Initiator Eight, Biotage) for 10 min at 120 °C. For processing, the reaction mixture was diluted with 4 ml of water and 4 ml of 1 N Natronic acid solution. This mixture was stirred at RT for 2 h. The phases were then separated and the phase 3 was extracted with DCM. The organic phases were combined with water and reduced to a 0.08% solution of sodium nitrate (3-dimethyl sulphate) and the product was obtained at a cleaning solution of 1: 0-8% (AMD).
The test chemical is used to determine the concentration of the test substance in the test medium.
In a microwave, a suspension of spiramine AMN-3cis (0.25 g; 0.63 mmol; 1 eq.) was presented in 19 ml of DCM. This suspension was given successively ethyl diisopropylamine (0.163 g; 1.26 mmol; 2 eq.) and 2-phenylacetyl chloride (0.195 g; 1.26 mmol; 2 eq.) in a microwave. The microwave was closed and heated in the microwave (Initiator Eight, Biotage) to 120 °C for 10 min. The reaction mixture was transferred to 5 ml of water and 5 ml of natron salts. This mixture was stirred at 2 h. The phases were then separated and the phase 3 was mixed with 0.195 g of DCM. The organic phases were reduced to sodium methanol (414-95%) and the product was removed from the water by means of a sodium nitrate solution, which was obtained by washing the food.
The test chemical is used to determine the concentration of the test substance in the test medium.
For a solution of cinnamic acid chloride (0.198 g; 1.192 mmol; 3 eq.) in 4.5 ml of THF, a solution of spiroamine AMN-4cis (0.15 g; 0.397 mmol; 1 eq.) in 9 ml of THF was administered under nitrogen at RT. After 1 hour of stirring at RT, the cloudy reaction solution was first mixed with 3 ml of water and ice-cooled with 3 ml of 1 N sodium bicarbonate. It was stirred for 1.5 h. After removing the solvent at reduced pressure, the unfiltered solid was filtered and washed with water. The raw product was cleaned with columns of chroma (silicon; silicone) obtained 0.043 g of product (21-10%) AMD.
The test chemical is used to determine the concentration of the test substance in the test medium.
The cis-spiroamine AMN-2cis (1.29 g, 3.4 mmol) was dissolved in absolute tetrahydrofuran (20 ml) and absolute dichloromethane (120 ml) without oxygen, mixed with Hünig base (1.167 ml, 6.8 mmol) and mixed with 2-phenylacetyl chloride (900 μl, 6.8 mmol) at room temperature. After a reaction time of 30 min, the solution was mixed with 5N sodium chloride solution (100 ml) and stirred for 2 h. The aqueous phase was separated and extracted with dichloromethane (3 x 10 ml). The combined organic phases were dried over Na2SO4 and then sealed. A raw product was isolated, which was chromatographically separated [60 g]; the solution of the cis-acid was obtained from 60 mg (100 mg) of ammonium chloride (1000 mg) in a solution of 8 to 120 mg of 95 °C (49 to 100 mg) in a solution of 8 to 100 mg of AMD.
The following are the active substances which may be used in the manufacture of the active substance:
The reaction mixture was stirred at room temperature for 1 hour, then with water (30 ml) and 1N sodium hydroxide solution (5 ml) and stirred 1.5 times. The dichloromethane was then removed in a vacuum. This resulted in a clear solid tetrahydrate separated by filtration and then washed with water (3 x 30 ml). The resulting product was obtained by chromatograph: this solid was dissolved in 1 mg (150 mg/ ml) of ethanol (150 mg/ ml), 1 mg (130 mg/ ml) of cyclohexane (150 mg/ ml) of ethanol (150 mg/ ml), 1 mg/ ml (130 mg/ ml) of ethanol (150 mg/ ml) of ethanol (130 mg/ ml), 1 mg/ ml (130 mg/ ml) of ethanol (150 mg/ ml) of ethanol (150 mg/ ml) of ethanol (150 mg/ ml)), which must be dissolved in a crude ethanol (130 mg/ ml) of ethanol (150 mg/ ml) of ethanol (150 mg/ ml) which must be dissolved in a crude ethanol (130 mg/ ml).
The mean value of the measured values of the active substance in the sample was calculated using the following formula:
Benzo[b]thiophen-2-carbonate chloride (728 mg, 3.96 mmol) was dissolved in abs tetrahydrofuran (30 ml) under argon and transferred to the trans-spiroamine AMN-2trans (500 mg, 1.32 mmol) dissolved in abs tetrahydrofuran (60 ml) at room temperature within 75 min. This resulted in a slight precipitation. After a reaction time of 2 h, the reaction mixture was diluted with water (15 ml), refrigerated with 1 N sodium leach (15 ml) and stirred 2.5 h. Tetrahydrofuran was removed in a vacuum. This resulted in a solid which was separated by filtration and washed with water (3 x 20 ml). The raw product (587 mg) was obtained by chromatograph: 60 g/l [60 °C: 1 mg/l] of ethyl methacrylate (121 g/l) dissolved in a 21% ethanol (180 mg/l) of 1 l (221 g/l); the solid was dissolved in a 1 l (121 mg/l) ethanol (121 mg/l) of 1 cycyl methacrylate (121 mg/l) dissolved in a 12 l (121 mg/l) ethanol).
The following are the active substances which may be used in the manufacture of the active substance:
The trans-amide (82 mg, 0.152 mmol) was suspended in ethanol (8 ml) at 80 °C and infused with an ethanol solution (3 ml) of citric acid (32 mg, 0.167 mmol). A solid was released from the clear solution when cooled to room temperature. After 1.5 h, the mixture was compressed to 2 ml, infused with diethyl ether (20 ml) and stirred for 20 min. A colourless solid was separated by filtration and washed with diethyl ether (2 x 3 ml) (64 mg). After 3 days, another solid was removed from the filtrate at room temperature, which was sucked and washed with diethyl ether (2 x 2 ml) (35 mg), resulting in a reaction of fridges. The trans-amide was removed from the filtrate at a melting point of 81 mg (85-185 mg) at a melting point of 17 °C (89 °C) with a melting yield of 81%.
Cinnamic acid chloride (1,32 g, 7.92 mmol) was dissolved in tetrahydrofuran (30 ml) under argon and transferred to tetrahydrofuran (60 ml) under 40 min at room temperature with contaminated spiroamine AMN-2cis (1,0 g, 2.64 mmol, containing almost 10% trans-diastereoisomer AMN-2trans), dissolved in tetrahydrofuran (60 ml), after a reaction time of 1 h, the cloudy solution was dissolved with water (20 ml) and ice-cooled with 1 N natron solution (20 ml) and stirred for 1.5 h. Tetrahydrofuran was removed in a vacuum. A solid was removed by filtration and washed with water (3 x 25 x 151 ml) The product was obtained by heating (1,16 g) of chromatograph g (2,5 g) at 60 °C (93 mg/ ml) of ethanol (1,5-15 g) by means of a cis-cycyl ether (1,5-15 g) of a liquid containing 15 mg (1,5-15 g) of ethanol (1,5-15 g) by means of a liquid solution of ethyl ether (1,5-15 g) dissolved in a liquid containing 15 mg (1-40 mg/ ml) of ethanol (1,5-15 g) by means of a liquid solution of ethanol (1,5 g/ ml) dissolved in a liquid.
The trans-amide (188 mg, 0.37 mmol) obtained was dissolved at 80 °C in ethanol (35 ml) and mixed with an ethanol solution (2 ml) of citric acid (77 mg, 0.4 mmol). It was stirred at room temperature for 2 h, gradually starting to crystallize. The mixture was stored at 5 °C for 1.5 h, the colourless solid was separated by filtration and washed with diethyl ether (3 x 3 ml) (146 mg). The filter was compressed, taken in ethanol (1 ml) and mixed with diethyl ether (20 ml). After 16 h, colourless salt was separated and washed with diethyl ether (2 x 2 ml) (36 mg).
The total number of samples of the active substance shall be calculated by dividing the total number of samples of the active substance by the total number of samples of the active substance.
3,4-dimethoxyphenylenedioxyclic acid (1 g, 5.1 mmol, 2.2 oz) is suspended in 25 ml of toluene and mixed with thionyl chloride (0.84 ml, 11.6 mmol, 5.0 oz). It is heated for 2 h under return flow and the solvent is then removed. The residue is co-distilled with toluene (3 x 50 ml) and the raw product in dichloromethane (37 ml) and transferred to a microwave vessel. Spiroamine AMN-2 (0.875 mg, 2.32 mmol) and Huneig Base (0.78 mmol, 5.80 mmol, 250 oz.) are added, the microwave oil is sealed and transferred to the microwave (in the Eighton, Bioxan, 20 g) for 120 min. The product is then separated by means of a hydrotransfer medium (Acromethane) and the resulting solution is added to 17 ml of sodium nitrate (1 x 17 g/ oz) and removed at a temperature of 17 °C. These products are mixed with 17 ml of sodium nitrate (1 x 17 g/ oz) and removed at a temperature of 2 °C. These products are obtained by extracting 17 ml of sodium nitrate (1 x 17 g/ oz) and adding 2 ml of sodium nitrate (1 x 17 g/ oz) to the solution.
The test chemical is used to determine the concentration of the active substance in the test chemical.
The ketone E-5 (446.6 mg, 2 mmol) was dissolved with 6-fluorotriptophol (2.394.4 mg, 2 mmol) in absolute 1,2-dichloroethane (30 ml). The mixture was then mixed with methan sulphonic acid (0.13 ml, 2 mmol), changing from red-brown to dark grey to colour the reaction solution. After 5 min a light grey solid began to fall out. The solution was stirred for 20 h. Then the methan sulphonate of cis-spiroether was soaked and washed with 1,2-dichloroethane (2 × 10 ml). The light grey solid was obtained at a yield of 76 % (733 mg) and a melting point of 143-145 °C (OH 143-145 mg). The solvent was removed from the cis-spiroether and obtained as a solid with a transition coating of RT-N (18,5 mg) and was removed from the RT-N (18,5 mg) after 8 ml of filtration and removed as a solid by a transition coating.
The measurement of the frequency of the measurement is based on the following equation:
The ketone E-4 (223 mg, 1 mmol) was presented together with tryptopholic acid (2,161 mg, 1 mmol) in absolute dichloromethane (40 ml). The solution was then added methanosulfonic acid (0,071 ml, 1,1 mmol). The solution was stirred at RT for 16 h, with the methanosulfonate of the spiroether failing. The light grey solid (ETHER-2cis) was extracted, washed with dichloromethane (2 × 10 ml) and obtained in a yield of 25% (117 mg) with a melting point of 132 °C. The substrate was translated with 1 N NaOH (20 ml) and stirred 16 h at RT. The organic phase was separated and the distilled phase was extracted with dichloromethane (20 × 20 ml) at 20 °C. The organic phase was extracted from the Phasmide (38 mg, 8 mg, 10 mg, 10 mg) and obtained in a cis-methanol filter (20 mg, 8 mg, 15 mg, 20 mg, 20 mg, 54 ml) at a temperature of 23 °C. The extract was obtained from the Phasmide (38 mg, 10 mg, 10 mg, 10 mg, and 23 mg) in a gasoline filter (20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, and 20 mg/kg) and obtained in a cis-methanol filter (20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, 20 mg, and 20 mg, 20 mg, 20 mg, 20 mg, and 20 mg, and 20 mg, respectively).
The measurement of the measured value shall be performed in accordance with the following equation:
The following is a list of the most commonly used methods of measuring the frequency of the radio frequency spectrum:
The HPLC-MS analytical instruments and methods are:HPLC: Waters Alliance 2795 with PDA Waters 996; MS: ZQ 2000 MassLynx Single Quadrupol MS Detector; Column: Waters AtlantisTM dC18, 3 μm, 2.1 x 30 mm; Column temperature: 40°C, Eluent A: purified water + 0,1% formic acid; Eluent B: Acetethyl (gradient grade) + 0,1% formic acid; Gradient: 0% B to 100% B in 8,8 min, 100% B for 0,4 min, 100% B to 0% B in 0,01 min, 0% B for 0,8 min, flow: 1,0 mL/min; Ionisation: ES 25 V; Make up: 100 μL/min 70% methanol + 0,2% formic acid; UV: 200 - 400 nm.
A) Comparison of analgesic efficacy (as ED50 or %MPE at a given test dose) in the acute pain model (tail-flick, rat/mouse) and in mono-neuropathic pain models (Chung, rat; Sennett, rat) or poly-neuropathic pain models (STZ polyneuropathy, rat).
Err1:Expecting ',' delimiter: line 1 column 497 (char 496)
Test animals: female Sprague Dawley rat (crl: CD (SD) outbred; breeder: Charles River, Sulzfeld, Germany); body weight: 130-190 g; animals are kept in standard cages (Type IV Makrolone cage, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 8 animals each, at a light-dark rhythm of 12:12h with ad libitum feed and tap water.
The analgesic effect of the test compounds was assessed in the tail-flick test on the rat according to the method of D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941)). The animals were placed individually in special test cages and the tail base was measured within 30 minutes prior to administration by a focused heat beam from a lamp (tail-flick type 50/08/1.bc, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from the start of the lamp to the sudden pulling of the tail (wavelength subtraction) was 2.5-5 seconds in untreated animals.
For antinociceptive test compounds, 3-5 logarithmically increasing doses, each including the threshold and maximum effective dose, were used to determine dose dependence.
Statistical evaluation: The group sizes were usually n=10 and repeated measures ANOVA and a post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE data between the respective dose groups and vehicle controls.
Test animals: male Sprague-Dawley rats (breeder: Janvier, Le Genest St. Isle, France): body weight: 200-250 g; animals are kept in standard cages (Type IV Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 5 animals each, at a light-dark rhythm of 12:12 h with ad libitum feed and running water.
Methodology: The modulatory effect of the test substances on acute noxious thermal stimuli was studied in the partial flick test on rats using the D'Amour and Smith method (J. Pharm. Exp. Ther. 72, 74 79 (1941)). The animals were individually placed in special test compartments and the tail base exposed to a focused focused focus of an analgesimeter (model 2011, Rhema Labortechnik, Hofheim, Germany). The intensity of the focus was set so that the time from the start of the flash to the sudden pull of the tail (latent pull) at untreated distance was approximately 12-13 seconds.The anti- or pronodceptive effect was determined as an increase or decrease in the elimination delay time according to the formula (% MPE) = [(T1 - T0) /(T2 - T0)] x 100. These are: T0: control-end time of substance application, T1: latency time after substance application, T2: maximum exposure time of the pre-inflammatory dose (30 seconds), T: maximum effective dose of the antiseptic compound was determined by 3 - 5 MPE, depending on the logarithm of the dose.The half-maximum effective dose (ED50) with 95% confidence intervals was determined by semilog-arithmic regression analysis at the time of maximum effect.
Statistical evaluation: The group sizes were usually n=10 and a repeated measures ANOVA and a post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE data between the respective dose groups and vehicle controls.
Test animals: male NMRI mice (breeder: Charles River, Sulzfeld, Germany); body weight: 20-25 g; animals are kept in standard cages (Type III Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 6 animals each, at a 12:12 h light-dark rhythm with ad libitum feed and tap water.
Methodology: The analgesic effect of the test compound was studied in the tail-flick test on mice according to the method of D'Amour and Smith (J. Pharm. Exp. Ther, 72, 74 79 (1941): the animals were placed individually in special test cages and the tail base exposed to a focused heat beam from an electric lamp (tail-flick type 55/12/10.fl, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from the lighting of the lamp to the sudden flick of the tail (weggetz) in untreated animals was 2.5-5 sec.The antinociceptive effect was determined as an increase in the elimination target latency time according to the following formula: (% MPE) = [(T1 - T0)/(T2 - T0)] x 100 where: T0: control latency time before application, T1: latency time after application, T2: maximum exposure time of the focus beam (12 seconds), MPE: maximum possible effect. For antinociceptive active test compounds, 3-5 logarithmically increasing dose doses, each including the threshold and maximum dose doses, were used to determine dose dependence. The half-life of the maximum dose (ED50), with a 95% confidence interval, was determined at the time of the regimen.
Statistical evaluation: The group sizes were usually n=10 and a repeated measures ANOVA and a post hoc Bonferroni analysis were used to test for statistically significant differences in the %MPE data between the respective dose groups and the poultry control groups.
Experimental animals: Male Sprague Dawley rats (RjHan:SD outbred; breeder: Janvier, Genest St. Isle, France) with a body weight of 140-160g were kept in standard cages (Type IV Makrolone cage, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 8 animals each, under a 12:12h light-dark rhythm with ad libitum feed and tap water.
Model description: Under pentobarbital anesthesia (Narcoren®, 60 mg/kg i.p., Merial GmbH, Hallbergmoos, Germany), the left L5, L6 spinal nerves were exposed by removing a piece of the paravertebral muscle and part of the left spinal process of the L5 lumbar spine. The L5 and L6 spinal nerves were carefully isolated and bound with a fixed ligature (NC-silk black, USP 5/0, metric 1, Braun Melsungen AG, Meinungen, Germany) (Kim and Chung 1992). After ligation, the muscles and adjacent tissues were sewn together and the wounds closed with metal fasteners.The animals were tested 30 min before and at different times after application of test substance or vehicle solution. The data were determined as % maximum possible effect (%MPE) from the single animal samples (= 0%MPE) and the test values of an independent sham control group (= 100%MPE). Alternatively, the withdrawal thresholds were expressed in grams. For analgesically effective test compounds, 3-5 logarithmically increasing doses, including the threshold and maximum dose doses, were used to determine dose dependence. The half-maximum dose (ED50) with 95% of the corresponding range of half-resolution effects was determined at the time of application of the regimen.
Statistical evaluation: The group sizes were usually n=10 and a repeated measures ANOVA and a post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE data between the respective dose groups and the vehicle control groups.
Reference:Kim, S.H. and Chung, J.M., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation In the rat, Pain, 50 (1992) 355-363.
Experimental animals: Male Sprague Dawley rats (RjHan:SD outbred; breeder: Janvier, Genest St. Isle, France) with a body weight of 140-160g were kept in standard cages (Type IV Makrolone cage, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 8 animals each, under a 12:12h light-dark rhythm with ad libitum feed and tap water.
Methodology: The study of effectiveness in neuropathic pain was conducted in the Bennett model (chronic constriction injury; Bennett and Xie, 1988, Pain 33: 87-107). The rats are given narcorenic anesthesia with four loose ligatures of the right sciatic nerve. The animals develop hypersensitivity at the toe of the affected nerve, which is quantified by a 4°C cold metal plate (cold allodyne) after a recovery period of about four weeks. The animals are observed for 2 minutes on this plate and the number of pull-up reactions of the damaged ptefo is measured.
Evaluation and statistics: Based on the pre-application value, the effect is determined over a period of one hour at four points (e.g. 15, 30, 45, 60 min. after application) and the resulting area under the curve (AUC) and inhibition of cold allodynia at each of the measurement points is expressed as a percentage of vehicle control (AUC) or baseline (individual measurement points).
Experimenter: Male Sprague-Dawley rats (breeder: Janvier, Le Genest St. Isle, France); body weight: 140-160 g; animals are kept in standard cages (Type IV Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 8 animals each, under a 12:12h light-dark rhythm with ad libitum feed and tap water.
Methodology: For the induction of diabetes, male Sprague Dawley rats were injected intraperitoneally with streptozotocin (STZ, 75 mg/kg). Diabetic rats had blood glucose levels of at least 17 mM one week after STZ injection. Control animals were injected with a vehicle solution. Mechanical nociceptive stimulus threshold (in grams) was measured with an algesiometer in the Randall & Selitto (1957) paw pressure test. Increased pressure was applied to the dorsal surface of the hind legs and the pressure that eventually led to the refractive pathway of the spots or vocalization was recorded. The results were obtained after three weeks.
The use of the drug in the treatment of inflammation is recommended for patients with severe pain.
B) Comparison of the analgesic effective dose range in mono-neuropathic pain models (Chung, rat) with the dose range in which opioid-typical adverse reactions are observed.
To describe the surprising pharmacological properties of the compounds of the invention, the results of the Chung model in the rat (as an example of analgesic efficacy against neuropathic pain) and the blood gas analysis model in the rat (as an example of respiratory depression as a very serious but well quantifiable opioid-typical side effect) are compared in the first instance to show that the compounds of the invention at multiple doses of a significantly incorrect dose (e.g. ED50n) do not resolve significantly incorrect respiratory depression in the rat.
The respiratory depressant effect of test substances is studied in instrumented, alert rats after IV administration, with the test parameter being the change in arterial blood partial pressure of carbon dioxide (pCO2) and partial pressure of oxygen (pO2) after administration.
The test animals are male Sprague-Dawley rats (CD (SD) outbred; breeder: Charles River, Sulzfeld, Germany), weighing 250-275 g; the animals are kept individually in standard cages (Type II Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) at a light-dark rhythm of 12:12 h with ad libitum feed and tap water.
Method: At least 6 days before application of the test substance, and at defined times after application of the test substance, the rats under pentobarbital anaesthesia are each implanted with a PP catheter into the femoral artery and jugular vein. The catheters are filled with heparin solution (4000 IU) and closed with a wire pin. The test substance or vehicle is administered via the venous catheter. Before application of the test substance or vehicle and at defined times after application of the test substance or vehicle, the arterial catheter is opened and approximately 500 μl of Heparin solution is injected into the vein. Approximately 100 μl of blood is injected into the catheter and heated with a glass capsule. The blood is injected with a blood sample from the blood of a catheter (LASL) and can be taken immediately after a week or so.
For statistical evaluation, the measurements after administration and the measurements after simultaneous application are compared by one-way ANOVA and a post hoc Dunnett analysis. The significance level was set at p < 0.05. The group sizes are usually n=6.
The effects of test substances on the cardiovascular system are studied after administration to telemetrically monitored, alert rabbits, with test parameters being changes in heart rate and arterial blood pressure after administration.
Test animals: female rabbits (New Zealand Whites; breeder: Charles River, Kisslegg, Germany); body weight: approximately 3 to 5.5 kg; animals are kept in special rabbit cages (B x T x H = 885 x 775 x 600 mm; Fa. Ebeco, Castrop-Rauxel, Germany) in solitary confinement with a light-dark rhythm of 12:12h with ad libitum feed and tap water.
Test preparation: At least 21 days before the start of the experiments, animals under general anaesthesia (isoflurane 2-3%) are implanted with a telemetry unit (TL11M2-D70-PCT of the Fa. DSI, St. Paul, Minnesota, USA) for measuring blood pressure and electrocardiogram (ECG). The telemetry unit's pressure catheter is inserted into the A. femoralis and the blopotential electrodes are attached subcutaneously in the sternum region or in the upper left thoracic wall. The sensor unit is sewn into a skin bag on the left side of the animals. The telemetry signals are received via the RM-1 data receiver (Fa. DSI).
Test procedure: the substance or vehicle is administered via a venous catheter (V. auricularis). Before the substance or vehicle is administered and at defined times after the substance or vehicle is administered, the heart rate and arterial pressure (systolic, diastolic and mean) are directly measured and stored electronically by the calibrated telemetry system. After a minimum washing period of one week, the animals can be returned to the test.
Test evaluation and statistics: From the measured values of blood pressure (in mmHg) and heart rate (in beats per min) at the defined time points, the mean values of 10 consecutive heartbeats are determined. Substance effects on the test parameters are calculated as percentage changes to the pre-value without substance or vehicle. For statistical evaluation, the measured values after substance administration and the measured values after vehicle application are compared by one-way ANOVA and post hoc Dunnett analysis. The significance level was set at p < 0.05. The group sizes are generally n=6.
Test animals: male NMRI mice (breeder: Charles River, Sulzfeld, Germany), body weight: 30-35 g; the animals are kept in standard cages (Type IV Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 18 animals each, under a 12:12h light-dark rhythm with ad libitum feed and tap water.
Description of the experiment: animals are kept sober on wire-resistant cage liners for 20 to 24 hours before the experiment.As a marker of the intestinal passage, animals are given an active-carbon suspension (10% activated carbon in 0.5% CMC solution; application volume: 0.1 ml/10 g body weight) orally.Then the test substance or vehicle solution is given intravenously.Two hours after the application of the active-carbon suspension, the animals are killed by CO2 gassing.Then the intestinal tract is removed from the brain including Caecum and stretched on a glass plate moistened with 0.9% NaCl solution.The Caecum is then immediately measured by the abrasive coating - Pestere, the active-carbon suspension and the passing point.
For experimental evaluation: to determine the relative inhibition of gastrointestinal transit, the coal suspension (in cm) /pylorus-caecum distance (in cm) coefficient of passage is calculated in % inhibition. For statistical evaluation, the post-administration and post-vehicle values are compared by one-way ANOVA and post-hoc Dunnett analysis. The significance level is set to p < 0.05. The group sizes are usually n=10.
Test animals: male CD-1 mice (breeder: Charles River, Sulzfeld, Germany); body weight: 18-25 g; animals are kept in standard cages (Type IV Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 18 animals each, under a 12:12h light-dark rhythm with ad libitum feed and tap water.Method description: For a description of the method see Kuribara H., Higuchi Y., Tadokoro S. (1977), Effects of central depressants on Rota-Rod and traction performance in mice.
Statistical evaluation: For statistical evaluation, the measurements after administration and the concurrent measurements after vehicle application are compared by one-way ANOVA and post hoc Dunnett analysis.
Test animals: male NMRI mice (breeder: Charles River, Sulzfeld, Germany); body weight: 20-24 g; animals are kept in standard cages (Type III Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 6 animals each, at a 12:12h light-dark rhythm with ad libitum feed and tap water.
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For the study of place preference, see Tzschentke, T.M., Bruckmann, W. and Friderichs, F. (2002) Lack of sensitization during place conditioning In rats is consistent wlth the low abuse potential of tramadol.
Statistical evaluation: The evaluation of experimental results In view of statistically significant differences in the preference of animals for the active substance or vehicle, the paired t-test is preferred. Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-6
Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-6
: Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-7
: Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-7
| Bindung ORL1-Rezeptor | Bindungsaffinität | Ki = 0.030 µM | --- |
| Bindung µ-Opioidrezeptor | Bindungsaffinität | Ki = 0,138 µM | --- |
| Chung, Ratte | Hemmung des neuropathischen Schrnerzes bei Mononeuropathie (Trennung von anti-allodynischer und anti-nociceptiver Wirkung) | --- | |
| Bennett, Ratte | Hemmung des neuropathischen Schrnerzes bei Mononeuropathie | --- | |
| STZ, Ratte | Hemmung des neuropathischen Schrnerzes bei diabetischer Polyneuropathie | --- | |
| Tail-flick, Ratte | Hemmung von Akutschmerz (nociceptiver Schmerz) | NOEL: 1 mg/kg i.v. bzw. 4 64 mg/kg i.v. bei reduzierter Brennstrahlintensität | 220-1000x |
| NOEL: 1 mg/kg i.v. | 220x | ||
| Herz-Kreislauf, Kaninchen | Arterieller Blutdruck und Herzfrequenz | NOEL: 1 mg/kg i.v. | 220x |
| Kohlepassage, Maus | Gastrointestinaler Transit | NOEL: 3 mg/kg i.v | 660x |
| RotaRod-Test Maus | Motorkoordination | NOEL: ≥10mg/kg i.v. | >2200x |
| Jumping-Test Maus | Körperlicher Abhängigkeit/Entzugssymptome | NOEL: 10 mg/kg i.p. | 2200x |
| Psychische Abhängigkeit | NOEL: ≥13,8 mg/kg i p. | >3000x |
| Bindung ORL1-Rezeptor | Bindungsaffinität | Ki = 0,070 µM | --- |
| Bindung µ-Opioidrezeptor | Bindungsaffinität | Ki = 0,450 µM | --- |
| Chung, Ratte | Hemmung des neuropathischen Schmerzes bei Mononeuropathie (Trennung von anti-allodynischer und anti-nociceptiver Wirkung) | --- | |
| STZ, Maus | Hemmung des neuropathischen Schmerzes bei diabetischer Polyneuropathie | 68% MPE bei 100 µg/kg i p ; keine anti-nociceptive Wirkung in nicht-neuropathischen Kontrolltieren | --- |
| Tail-flick, Ratte | Hemmung von Akutschmerz (nociceptiver Schmerz) | NOEL: ≥10 mg/kg i.v. | >110x |
| Blutgasanalyse, Ratte | NOEL: 1 mg/kg i.v | 11x | |
| Herz-Kreislauf, Kaninchen | Arterieller Blutdruck und Herzfrequenz | NOEL: ≥3 mg/kg i.v. | >34x |
| Kohlepassage, Maus | Gastrointestinaler Transit | NOEL: 1 mg/kg i.v. | 11x |
| RotaRod-Test, Maus | Motorkoordination | NOEL: 10 mg/kg i.v. | 110x |
| Jumping-Test, Maus | Körperlicher Abhängigkeit / Enizugssymptome | NOEL: ≥10 mg/kg i.p. | >110x |
| Platzpräferenz, Ratte | Psychische Abhängigkeit | NOEL: ≥20 mg/kg i.p. | >220x |
Conclusion: To illustrate the surprising pharmacological properties of the compounds used in accordance with the invention, the examples AMD-6cis and AMD.7cis were selected. These are highly affinitary ORL1 and μ-opioid receptor ligands with a ratio of ORL1 to μ-opioid receptor affinity of approximately 5 and approximately 6 respectively. The examples AMD-6cis and AMD-7cis demonstrate that the compounds used in accordance with the invention have a very high efficacy against neuropathic pain (here: ED50n between 1 and 10 μg/kg i.v. and 88 μg/kg i.v. respectively). Übersicht über ausgewählte pharmakologische bzw. pharmakokinetische Charakterstika weiterer Beispiel
Übersicht über ausgewählte pharmakologische bzw. pharmakokinetische Charakterstika weiterer Beispiel
| 0,030 | 0,138 | NOEL =1000 µg/kg i.v. | NOEL = 3000 µg/kg i.v. | NOEL: ≥10000 µg/kg i.v. | 8h// >> 5 h (10 µg/kg i.v.) | |
| 0,018 | 0,032 | 18%MPE bei 100 µg/kg i.v. | NOEL > 1 00 µg/kg i.v. | NOEL=1000 µg/kg i.v. | ||
| 0,017 | 0,05 | 35%MPE bei 100 µg/kg i.v. | NOEL = 4600 µg/kg i.v. | |||
| 0,016 | 0,059 | 42%MPE bei 100 bei 100 µg/kg i.v. | NOEL > 1000 µg/kg i.v. | NOEL = 3000 µg/kg i.v. | NOEL: ≥10000 µg/kg i.v. | |
| 0,003 | 0,009 | 20%MPE bei 100 µg/kg i.v. | NOEL > 100 µg/kg i.v. | NOEL = 300 µg/kg i.v. | ||
| 0,070 | 0,450 | NOEL > 10000 µg/kg i.v. | NOEL = 1000 µg/kg i.v. | NOEL = 1000 µg/kg i.v. | NOEL = 10000 µg/kg i.v. | 3 h // ca. 3 h (100 µg/kg i.v.) |
Conclusion: The compounds used in accordance with the invention show very good efficacy against neuropathic pain. Surprisingly, however, in the acute pain model, no significant anti-nociceptive effects were observed even at doses approximately 10 to more than 100 times higher than the effective doses in the neuropathy model. Similarly, surprisingly, no significant opioid-typical adverse effects were observed in adverse animal models (e.g. blood gas analysis, gastrointestinal charcoal passage and RotaRod test) at 10 to more than 300 times higher doses.
Other Vergleich von cis- und trans-Spiroamin
Vergleich von cis- und trans-Spiroamin
| 0.030 | 0,138 | NOEL = 1000 µg/kg i.v. | |||
| 0,002 | 0,008 | NOEL ≥ 100 µg/kg i.v | NOEL = 300 µg/kg i.v. | ||
| 0,070 | 0,450 | NOEL = 1000 µg/kg i.v. | |||
| 0.001 | 0.001 | 54%MPE bei 31.6 µg/kg i.v. | |||
| 0,012 | 0,031 | NOEL = 1000µg/kg i.v. | |||
| 0,0004 | 0.0005 | 27%MPE bei 30 µg/kg i.v. | 60%MPE: bei 100 µg/kg i.v. |
Conclusion: Surprisingly, only cis-spiroamines according to the general formula (I) (e.g. AMD-6cis and AMN-2cis) show good efficacy against neuropathic pain, while not having antinociceptive effects in acute pain. Similarly, in animal models of adverse reactions (e.g. blood gas analysis) no significant opioid-typical adverse reactions are observed at many times higher doses. In contrast, the respective trans-spiroamines (e.g. AMD-6 and AMN-2) do not show a difference between doses that are effective against neuropathic pain or acute pain. Similarly, the differences between doses of acasanide and opioid-typical adverse reactions are not observed at many times higher doses (e.g. AMD-5 and AMN-6), which show the greatest possible difference in overall analgesic effect. Vergleich von cis-Spiroaminen und cis-Spiroethern
Vergleich von cis-Spiroaminen und cis-Spiroethern
| 0.012 | 0,031 | |||
| 0,031 | 0,092 | 17%MPE bei 100 µg/kg i.v | 78%MPE bei 1000 µg/kg i.v.* 1000 µg/kg i.v.* | |
| 0,06 | 0,12 | 28%MPE bei 100 µg/kg i.v | 33%MPE bei 1000 µp/kg i.v. |
Conclusion: Surprisingly, when used in a controlled manner, only cis-spiroamines (e.g. AMN-2cis) show good efficacy against neuropathic pain, with no antinociceptive effect in acute pain. Similarly, in animal models of adverse reactions (e.g. blood gas analysis) no opioid-typical adverse effects are observed at many times higher doses.
Other Vergleich von (freie Base) und (Citrat-Salz)
Vergleich von (freie Base) und (Citrat-Salz)
| 0,030 | 0,138 | |||
| 0,020 | 0.117 | NOEL > 10000 µg/kg i.v. |
Conclusion: A comparison of AMD-5cis (free base) and AMD-6cis (citrate salt) did not reveal any relevant differences in the pharmacological properties of base and salt. Vergleich der Affinitäten gegenüber einzelnen Rezeptoren
Vergleich der Affinitäten gegenüber einzelnen Rezeptoren
| Ki * | Ki | Ki | Ki | |||||||
| 16 | 102/ 92% | 59 | 1112/ 82% | 160 | 874/ 42% | 6,7 | 41/ 92% | 0% (1000) | 106 | |
| 73% (10000) | ||||||||||
| 14 | 16/ 81% | 12 | 13/ 66% | 49 | -/55% | 8 | -/ 87% | 0% (1000) | 20%(100) | |
| 30 | 76/ 106% | 138 | 300/ 63% | 768 | 1035/ 30% | 38 | 463/ 78% | 0% (1000) | 9,2 | |
| 58% (10000) | ||||||||||
| 3 | 47/ 104% | 8 | 79/ 97% | 19 | 59/ 88% | 6 | 19/ 126% | 640 | 400 | |
| 70 | 50/ 90% | 450 | 49/ 94% | 542 | 1170/ 85 % | 791 | 2684 / 106% | 0% (10000) | 88 | |
| 1 | 16/ 90% | 1 | 3/88% | 4 | 29/64 % | 1 | 5/82 % | 54 % (31.6) | nicht durchgeführt | |
| * Radio-binding assay - Ki in nM | ||||||||||
| ** GTPgammaS assay - EC50 in nM and relative efficacy in % | ||||||||||
In another respect, the invention relates to the combination of the general formula (I),
Other
In which
R1 is -H or CH3;R2 is -H or halogen;R3 is -H or halogen;R4 is -H, -halogen or -OC1-3 alkyl;R5 is -H, -halogen or -OC1-3 alkyl;Q1-Q2- forms the group -CH2- or -CR6=CH;andR6 and R7 are either simultaneously -H or together form a five-membered ring over the bridge -S;
in the form of free bases or physiologically compatible salts.
In a preferred embodiment of this aspect of the invention, the compound according to formula (I) shown above is a compound of general formula (II), (III) or (IV):
Other
in the form of free bases or physiologically compatible salts.
In another preferred embodiment of the compounds of the invention, R2 -H and/or R3 -F.
In another preferred embodiment of the compounds of the invention, R4 and R5 are either both -H or both are -OCH3.
In another preferred embodiment of the compounds of the invention, these are selected from the group consisting of:
The term 'dioxins' means compounds containing a mixture of hydrocarbons, which are not chemically defined, but which are chemically defined and which are chemically defined in accordance with the principles of the chemical composition of the compounds.
in the form of free bases or physiologically compatible salts.
In another preferred embodiment of the invention, the compounds of the invention are pharmaceutical products,
Another preferred embodiment of the invention concerns a pharmaceutical composition containing a physiologically compatible carrier and one of the compounds of the invention.
In a preferred embodiment of the pharmaceutical composition of the invention, this is:
solid, liquid or paste; and/or contains the compound of the invention in an amount between 0,001 and 99% by weight, based on the total weight of the composition.
Another preferred embodiment of the invention concerns a pharmaceutical formulation containing one of the pharmaceutical formulations described above.
In another embodiment of the invention, the above dosage form is packaged for a maximum of once daily administration.
In another preferred embodiment of the invention, the presentation form is prepared for systemic administration.
In another preferred embodiment of the invention, the presentation form is prepared for oral administration.
In another preferred embodiment of the invention, the dosage formulation of the invention contains one of the compounds of the invention at a dose so low that it is not significantly effective in the treatment of acute pain.
In another preferred embodiment of the invention, the dosage formulation of the invention contains one of the compounds of the invention in a dose range of 1.0 μg to 10 mg, based on the molecular weight of the free base.
Claims (14)
- Compound of generic formula (I) for use in the treatment of neuropathic and/ or chronic pain, Other In which OtherR1 is -H or CH3;R2 is H or halogen;R3 is H or halogen;R4 is -H, -Halogen or -OC1-3-Alkyl;R5 is -H, -Halogen or -OC1-3-Alkyl;-Q1-Q2- the group -CH2- or -CR6=CH- is formed; andRe and R7 are either both simultaneously -H or together form a five-membered ring over the bridge;Other in the form of free bases or physiologically compatible salts.
- Compound according to claim 1, which is a compound of general formula (II), (III) or (IV): Other in the form of free bases or physiologically compatible salts.
- The test chemical is a chemical that is used to produce a reaction.
- A compound according to one of the above claims, where R4 and R5 are either both -H or both -OCH3.
- Compound having one of the above claims is selected from the group consisting of Compounds are selected from the group consisting of OtherThe following substances are to be classified in the same heading as the active substance:The following substances are to be classified in the same heading as the product:The following substances are to be classified in the same heading as the active substance:The following substances are to be classified in the same heading as the product:The following substances are to be classified in the same heading as the active substance:The following substances are to be classified in the same heading as the product:The following substances are to be classified in the same heading as the active substance:The following substances are to be classified in the same heading as the product:The following substances are to be classified in the same heading as the active substance:• 1- (((1s,4s) -4- ((Dimethylamino) -4- ((3-fluorophenyl) -3,4'-dihydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indol]-2' ((9'H) -yl) --2-phenylethanoate), andThe following substances are to be classified in the same heading as the active substance:Other in the form of free bases or physiologically compatible salts.
- Compound according to one of claims 1 to 5 as a medicinal product.
- A pharmaceutical formulation for use in the treatment of neuropathic and/or chronic pain containing a physiologically compatible carrier and a compound according to claims 1 to 5.
- Composition according to claim 7, which Other- is solid, liquid or paste-like; and/or- the compound in any of claims 1 to 5 contains between 0.001 and 99% by weight of the total weight of the composition.
- Pharmaceutical formulation for use in the treatment of neuropathic and/or chronic pain containing the pharmaceutical composition as claimed by claim 7 or 8.
- The dosage formulation as claimed by claim 9, which is packed for once daily administration at most.
- Dosage formulation according to claim 9 or 10, which is packed for systemic administration.
- The formulation described in claim 11 is a soft pack for oral administration.
- A formulation according to claims 9 to 12 that contains the compound according to claims 1 to 5 at a dose so low that it is not significantly effective in the treatment of acute pain.
- The dosage formulation of claim 12 or 13, containing the compound of claim 1 to 5 in a dose range of 1,0 μg to 10 mg based on the molecular weight of the free base.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10007822.9 | 2010-07-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1195245A true HK1195245A (en) | 2014-11-07 |
| HK1195245B HK1195245B (en) | 2019-12-20 |
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