HK1195245B - 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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Description
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, called neuropathic pain. Treatment of chronic pain is a major medical challenge because while some of the drugs on the market are highly effective in acute pain, in many cases they do not provide satisfactory pain management for chronic and particularly 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., 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, PNAS 76-7686, pNAS 9806).
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 by some significant adverse reactions, such as gastrointestinal ulcers or toxic kidney damage. In severe to very severe inflammatory pain (e.g. in the context of chronic pancreatitis), NSAIDs may only slightly reduce pain, but may therefore lead to a high risk due to increased blood pressure. The next step is to reduce the potential for treatment with μ-Opioids, with a greater potential for 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 diverse. 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 opioids. These drugs usually provide only some pain relief, while pain relief is often not achieved. The frequent side effects often prevent drug dosage increases from providing adequate pain relief. In fact, satisfactory treatment of neuropathic pain often requires a higher dose of a μ-opioid than for acute pain, making the side effects even more significant.
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 opioids, therefore, any pain sensation of the patient is suppressed, which can be quite detrimental.
Other
Spirocyclic cyclohexane derivatives acting on the nociceptin/ ORL-1 and μ-opioid receptor systems are known at the state of the art.These compounds are characterised by, among other things, an exceptional degree of structural variability and are suitable for the treatment of inflammatory and neuropathic pain, among other things.
Other
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.
Other
The purpose of the invention is to provide new compounds,The Commission has already made a number of proposals to improve the quality of the information it provides.
Other
This task is solved by the subject matter of the claims.
The invention relates to compounds of general formula (III),
In which
R1 and-H or CH3is R2 and-H or -halogen is;R3-H or -halogen is;R4-H, -Halogen or -OC1 to 3-Alkyl is andR5-H, -Halogen or -OC1 to 3- is an alkyl; and
where the compound is present as hydrochloride, citrate or hemicitrate salt.
Surprisingly, the compounds of the generic formula (III) were found to act on the nociceptin/ORL-1 and μ-opioid receptor systems and to be particularly effective in treating chronic pain, particularly neuropathic pain, without simultaneously suppressing the sensation of acute pain.
The compounds of the general formula (III) show very high analgesic efficacy in the treatment of chronic pain, particularly 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 condition (allodynia or hyperalgesia) while at the same time, if at all, only slightly affecting normal pain sensation.
The compounds according to the general formula (III) thus allow selective efficacy against chronic pain, preferably against neuropathic pain, preferably against mononeuropathic/neuralgic or polyneuropathic pain, even preferable against pain in post-herpetic neuralgia or diabetic polyneuropathy, preferably with negligible antinociceptive efficacy in acute pain.
The compounds of general formula (III) 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 of the invention show an excellent effect against chronic, preferential neuropathic pain, preferential pain in diabetic polyneuropathy in the animal model, without showing a significant effect against acute pain at the required therapeutic dose.
The compounds according to the general formula (III) are preferably achiral; the basic body of the general formula (III) contains no chirality element (center, axis or plane).
Err1:Expecting ',' delimiter: line 1 column 304 (char 303)
In the case of compounds according to the general formula (III), the two nitrogen atoms of the spiroamine are respectively syn, cis and cationic:
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%.
Other
The expert is familiar with suitable methods for the separation of isomers (diastereomers), such as column chromatography, preparative HPLC and crystallization.
Other
The advantages of the cis-isomer are also particularly surprising in that the structurally related spiroeters usually do not have pharmacologically advantageous properties (which may differ from the advantages of the cis-spiroamins of the invention) from the cis-isomer to the trans-isomer:
Err1:Expecting ',' delimiter: line 1 column 80 (char 79)
Err1:Expecting ',' delimiter: line 1 column 75 (char 74)1 to 3Err1:Expecting ',' delimiter: line 1 column 50 (char 49)1 to 3Err1:Expecting ',' delimiter: line 1 column 50 (char 49)1 to 3- Alkanyl, C1 to 3- Alkenyl and C1 to 3- It's an alkynyl.
Preferably, the prevention of the general formula (III):
Other
where the compound is present as hydrochloride, citrate or hemicitrate salt.
R is preferred2 and-H and/or R3- F.
R is preferred4and R5either both -H or both -OCH3- I 'm not .
In a particularly preferred embodiment, the invention relates to the compound of the general formula (VI)
where the compound is present as hydrochloride, citrate or hemicitrate salt.
The free base of the compound of general formula (VI) can be systematically designated as (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) or also as (E)-1-(((1s,4s)-4-dimethylamino)-4-(3-fluorophenyl)-3'-4'-dihydrospiro[cyclohexan'pyrido-[3,4-b]indol]-2'(9'H) -phenyl)-3-phenyl-2-en-1-propyr. This compound is present as a hydrochloride, or as a hemicrate.
In particular, the compounds of the invention are selected from the group consisting of:
Other
Other
in the form of hydrochloride, citrate or hemicitrate salt.
| (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 |
| (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'-dihydro-spiro[cyclohexan-1,1'-pyrido[3.4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| (E)-2',3',4',9'-Tetrahydro-N,N-dimethyl-6'-fluor-4-(3-fluorphenyl)-2'-(2-phenyl-vinyl)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'-3',4'-dihydrospiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| (E)-2',3',4',9'-Tetrahydro-N,N-dimethyl-6'-fluor-4-phenyl-2'-(2-phenylvinyl)carbonyl-bonyl-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-phenyl-3',4'-dihydrospiro-[cyclohexan-1,1'-pyrido[3,4-b]indol]-2'(9'H)-yl)-3-phenylprop-2-en-1-on |
| (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-fluorophenyl)-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 (III) are used twice daily, once daily or less frequently, preferably no more than once daily.
In another embodiment, compounds according to the general formula (III) are used in the treatment of chronic pain. Preferably, chronic pain is selected from the group consisting of inflammatory pain, visceral pain, tumor pain and neuropathic pain.
In another preferred embodiment, the compounds of general formula (III) are used to treat pain in diabetic polyneuropathy.
In another preferred embodiment, the compounds of general formula (III) are used to treat pain resulting from post-herpetic neuralgia.
The compounds of general formula (III) are suitable for use in the treatment of neuropathic pain, preferably mononeuropathic/neuralgic or polyneuropathic pain, preferably peripheral polyneuropathic pain or central polyneuropathic pain.
Other
Preferably, polyneuropathy or polyneuropathic pain is acute (up to four weeks), subacute (four to eight weeks) or chronic (more than eight weeks).
The neuropathy is characterised by a high degree of pain, which is usually caused by a combination of neurological and neurological factors, such as the presence of a neurological disorder (e.g. a neurological disorder), a neurological disorder (e.g. a neurological disorder), or a neurological disorder (e.g. a neurological disorder).
Examples of causes of peripheral neuropathic pain include diabetic polyneuropathy, post-herpetic neuralgia, radioculopathy, post-traumatic neuralgia, chemical-induced neuralgia, 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 compressional myelopathy due to narrowed canine artery stenosis, post-stress spinal pain, stroke, post-stroke myelopathy, myelopathy induced by myelopathy, multiple sclerosis induced by myelopathy 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, Aspartic acid}, hydrocarbons due to chemotherapy with cytostatins], porphyria, infectious disease, post-traumatic diseases [e. g. Amyloidosis, leukaemia, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloid, amyloidosis, amyloid, amyloidosis, amyloid, amyloid, amyloid, amyloid, amytic acid, amyloid, amyloid, amy, amyloid, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy, amy,
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 dysfunctions, cardiovascular disease, hypotension, hypertension, tinnitus, pruritus, migraine, severe hearing loss, intestinal motility, impaired appetite, anorexia, fatty liver disease, locomotive dialysis, anti-inflammatory drugs, anti-coagulants, anti-anxiety drugs, anti-muscle antibodies, and/or anti-anxiety drugs, for the treatment of mood disorders or neurological disorders, for the treatment of narcolepsy, and/or for the treatment of narcolepsy, and/or for the treatment of narcolepsy with a drug or other drug, for the treatment of narcolepsy, or for the treatment of narcolepsy, and/or for the treatment of narcolepsy.
Another subject matter of the invention concerns the use of compounds of the invention for the treatment, in particular in one of the above indications, of a non-human mammal or human being who requires the treatment of chronic pain, preferential neuropathic pain, preferential pain in diabetic polyneuropathy or post-herpetic neuralgia by administering an individually therapeutically required daily dose of a compound of the invention, or a dosage form of the invention, preferably without significant simultaneous suppression of the sensation of acute nociceptive pain and/or significant opioid-related side effects, in particular no significant sedation/epileptic shock or epileptic seizures and no excessive sedation/epileptic shock or depression and/or no/obesity and/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/or/
Another subject matter of the invention concerns the compounds of the invention for use in the treatment, in particular in one of the above indications, of a non-human mammal or human being who requires the 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 the perception of nociceptor pain and/or significant opioid-typical side effects, in the absence of significant side effects in the other group, and without significant pain/discomfort or sedation, and without any excess weight, no obesity, no depression, no dependence, no acute or acute, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no pain or discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no discomfort, no, no discomfort, no, no discomfort, no, no discomfort, no, no discomfort, no, no, no discomfort, 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 invention also relates to the compounds of general formula (III) with affinity for the μ-opioid receptor and the ORL-1 receptor, for use in the
in the treatment of neuropathic pain, preferred in the rat, preferred over mononeuropathic pain in the Chung model, significantly effective at half the maximum effective dose of ED50 nIn the case of the use of the drug in the treatment of acute pain, the dose of ED is 5 times higher than the dose of ED in the rat.50 nThe use of the drug in the treatment of patients with severe allergies is not significantly effective.
Thus, the compounds of the general formula (III) when administered at this half maximum effective dose have ED of less than 0.50 nThe dose of the drug is defined in terms of the efficacy of the compound against neuropathic pain, and even at a dose that is 5 times higher than ED.50 nThe effect of the test on acute pain is, if any, at best negligible, preferably in the rat, preferably in the tail flick test.
Other
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 (III) are preferably used at a dosage which is 10, 20, 30, 40 or 50 times, preferably 75, 100, 125, 150 or 175, preferably 200, 300, 400 or 500 times, preferably 600, 700, 800 or 900 times, and in particular 1000 times higher than the half-maximum effective dose ED50 nThe use of this product in patients with severe pain is not considered to be significantly effective in the treatment of acute or nociceptive pain.
The half-maximum effective dose ED50 nIt is preferably defined as the dose at which 50% of the maximum therapeutic effect is achieved for the treatment of neuropathic pain.50 a)The compounds of the invention are defined as the dose at which 50% of the maximum therapeutic effect is achieved for the treatment of acute pain.50 nDefined but not by ED50 a)- I 'm not .
Appropriate methods for investigating the efficacy of an active substance in the treatment of neuropathic pain and determining the half-maximum effective dose ED50 nThe use of the drug in the treatment of neuropathic pain is known to the practitioner, as is the study of the effectiveness 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 (STC) 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.
significantly effective in the treatment of mononeuropathic pain in the Chung model and at a half-maximum effective dose ED50 nThe use of ED in the treatment of acute pain in the tail-flick test is at a dose of 5 times higher than ED in the treatment of acute pain in the tail-flick test.50 nThe use of the drug in patients with severe liver disease is not significantly effective.
The evaluation of experimental results for statistically significant differences between the respective dose groups and the vehicle control groups shall preferably be carried out 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.
Other
In principle, the comparative determination of analgesic efficacy against neuropathic pain and acute nociceptive pain can also be carried out in humans, but this is less favourable for ethical reasons, among others.Usefulness and limitations of quantitative sensory testing: clinical and research application in neuropathic pain states. Pain. 129(3): 256-9. The study of efficacy against acute pain can then be carried out according to Posner J, Telekes A, Crowley D, Phillipson R, Peck AW. (1985). Effects of an opiate on cold-induced pain and the CNS in healthy volunteers. Pain. 231):73-82.
Other
Surprisingly, the compounds of the generic formula (III) were found to have a very favourable side effect profile compared to common stage 3 opioids.No or at least only mild opioid-typical adverse reactions, such as respiratory depression, constipation, urinary retention, nausea, vomiting, hypotonia, bradycardia, addiction, dependence, euphoria, depression, sedation and dizziness, have been observed.50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nThe compounds according to the general formula (III) are preferred even when used at a dose of 10, 20, 30, 40 or 50, preferably by a factor of 75, 100, 125, 150 or 175, and preferably by a factor of 200 higher than the half-maximum effective dose ED.50 nThe use of this product in patients with severe respiratory distress is not recommended.
Other
The appropriate methods for the examination of drug-induced respiratory depression are known to the practitioner.2 andand CO2 andPartial pressure: the evaluation of experimental findings for statistically significant differences between the respective dose groups and the vehicle control groups is preferably done by one-way ANOVA and post hoc Dunnett analysis, preferably as described in the experimental part, where the significance level is set to p < 0.05.
Other
In a preferred embodiment of the use of the invention, the compounds of general formula (III) show ED when administered at the half maximum effective dose.50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nPreferably, compounds even in a dosage that is by a factor of 10, 20, 30, 40 or 50, preferably by a factor of 75, 100, 125, 150 or 175, still preferably by a factor of 200, 300, 400 or 500, preferably by a factor of 600 higher than the semi-maximum effective dose ED50 nThe use of this product has not been associated with any significant side effect, such as constipation.
Other
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 groups. The group sizes are usually n=10. For further details of this model, reference is also made to the experimental part.
Other
In a preferred embodiment of the use of the invention, the compounds of general formula (III) show ED when administered at the half maximum effective dose.50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nThe drug is preferred even at a dosage that is 10, 20, 30, 40 or 50, preferred by a factor of 75, 100, 125, 150 or 175, even preferred by a factor of 200 higher than the half-maximum effective dose ED50 nThe incidence of hypotension is not significant.
Other
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, as described in the experimental part, where the significance level is set at p < 0.05; the group sizes are usually n=6. Further details of this part of the experiment are referred to in the experimental part.
Other
In a preferred embodiment of the use of the invention, the compounds of general formula (III) show ED when administered at the half maximum effective dose.50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nThe drug is not considered to be a significant bradycardia as a side effect, preferably in the waking rabbit, preferable in the circulatory model in the waking, telemetrated rabbit.50 nThe incidence of bradycardia is not significant.
Other
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 experiment. The significance level is set at p < 0.05 pp. The group sizes are usually n=6. For further details of this model, reference is also made to the experimental part.
Other
In a preferred embodiment of the use of the invention, the compounds of general formula (III) show ED when administered at the half maximum effective dose.50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nThe compounds are preferred even at a dosage that is a factor of 10, 20, 30, 40 or 50, preferably a factor of 75, 100, 125, 150 or 175, or even a factor of 200, 300, 400 or 500, preferably a factor of 600, 700, 800 or 900, and in particular a factor of 1000 higher than the semi-maximum effective dose ED50 nThe incidence of motor functional disorders (as a measure of central nervous system adverse events) is not significant.
Other
The evaluation of experimental findings for statistically significant differences between the respective dose groups and the vehicle control groups is preferably done by means of ANZAN-OVA and post hoc analysis, partly described in the experiment. The significance of this experiment is defined as p < 0.05 in the experimental section. Furthermore, reference is made to the experimental group in greater detail in relation to the p < 10.05.
Other
In a preferred embodiment of the method of the invention, the compounds of general formula (III) show ED when administered at the half maximum effective dose.50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nThe test is performed on a single test tube with no significant physical dependence or withdrawal symptoms as a side effect, preferably in the mouse, preferably in the jumping test.
Preferably, the compounds themselves are in a dosage which is by a factor of 10, 20, 30, 40 or 50, preferably by a factor of 75, 100, 125, 150 or 175, still 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 higher than the half-maximum effective dose ED50 nErr1:Expecting ',' delimiter: line 1 column 650 (char 649)50 n, which is defined in terms of the efficacy of the compound against neuropathic pain and is preferred even at a dose that is 5 times higher than ED.50 nThe compounds themselves are preferred at a dose which is 10, 20, 30, 40 or 50 times, preferably 75, 100, 125, 150 or 175, and preferably 200, 300, 400 or 500 times, preferably 600, 700, 800 or 900 times, and in particular 1000 times higher than the semi-maximum effective dose ED.50 nThe use of this drug in the treatment of depression is not associated with significant psychological dependence or addiction.
Other
Neuroscience Letters 329, 25-28 The evaluation of experimental findings for statistically significant differences in the preference of animals for the active substance or vehicle is preferably done by a paired t-test, where the significance level is set at p 0.05. The group size of n=0 is described in greater detail in T-Method, W. F., T-Method, W. F., T-Method, and Neuroscience (2009, 32-28), which refers to the T-Method.
The compounds of general formula (III) 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.
Other
The expert is familiar with the definitions of the different forms of chronic pain, and can refer to Merskey H., Bogduk N., Classification of chronic pain, Seattle: IASP Press 1994, Bennett G.J., Anesth Analg. 2003, 97, 619-20, and Backonja M.M., Anesth Analg. 2003, 97, 785-90.
Other
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 lesion, 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).
Other
The compounds of the invention according to the general formula (III) have a preferential KI-Values at the μ-opioid receptor of 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.
Other
Methods for determining the KI-The values of the μ-opioid receptor are known to the expert.Preferably, the determination is carried out in a homogeneous way in microtiter plates.For this purpose, dilution series of the substances to be tested are preferably made 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, Zaventem, Belgium) in the presence of 1 n/mol of the radioactive ligand [3H]-Naloxone (NET719, company NEN, Zaventem, Belgium) and 1 mg WGA-SPA-Beads (Wheat germ agglutinin SPA Beads, Amersham/Pharmacia, Freiburg, Germany) incubated in a total volume of 250 μl for 90 minutes at room temperature. Preferably 50 mmol/l Tris-HCI supplemented with 0.05% w/w sodiumumazid and 0.06% bovine serum albumin is used as an incubation buffer. To determine the non-specific binding, an additional 25 μmol/l naloxone is preferably added. After the 90 minute incubation period, the microcubes are incubated for 20 minutes at 1000 μl and the different concentrations in a β-microburic acid concentration (CoCoT) determined as a percentage of the concentration of the radioactive substance (CoT) can be used to inhibit the release of the B-O-B in the human body.50The results of the analysis are then calculated at inhibitory concentrations which cause a 50% displacement of the radioactive ligand.I-Values for the test substances to be calculated.
The compounds used in accordance with the invention according to the general formula (III) have a K-preference.I- Value at the ORL1 receptor of 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.
Other
Methods for determining the KI-The values of the ORL1 receptor are known to the specialist.3This test system is preferably performed according to the method proposed by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824).3H-nociceptin/orphanine FQ is preferably 0.5 nM in these tests. The binding assays are preferably with 20 μg membrane protein per 200 μl of solution in 50 mM hepes, pH 7.4, 10 mM MgCl2 andBinding to the ORL1 receptor is determined preferably using 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by one hour incubation of the approach in RT followed by measurement in the Trilux scintillation counter (Wallac, Finland).
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 the 1,2,3-triazole and corresponding amine in the presence of water-absorbing conditions, preferably using a water-soluble solvent or using a pyrazol or other analogous solvent in a dry solution.
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 starting groups Z in structures of formula B. Suitable starting groups are preferably cyanogroups; 1,2,3-triazole-1-yl groups. Other suitable starting groups 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 aminonitryls B (Z=CN) with corresponding organometallic compounds, preferably Grignard compounds, preferably in yeasts, preferably in RT. Organometallic compounds are available either in the form of ether or in all forms of organometallic compounds.
Amino acetals C with no more than one substituent on the nitrogen atom can be obtained by methods known in principle by the addition of 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/alkylids/ with aryl or alkyl (saturated/unsaturated) substitutes
Other
Manufacture of C (R)1 and≠ -H) from Ca (R)1 and= -H)
Other
Amino acetals Ca with up to 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 required 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 or 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, which is transferred to the C and D and further to E using a nucleophile MR3 respectively.
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 acids, phosphoric acids or sulphonic acids or their respective anhydrides, carboxylic acid triethylsyl esters, acidic salts, mineral acids or leucic acids selected from the group consisting of boron trifluoride, indium (3) chloride, titanium tetrachloride, aluminium (3) chloride, or with the addition of at least one transition metal salt, preferably with the addition of at least one transition methanol methylate (transition methylate orthotrifluoric acid sulphonic acid), preferably with the addition of a transition methylate of polyethyl sulphonic acid or polyethyl sulphonic acid of the group containing a small amount of sulphuric acid, is obtained by adding a small amount of methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methylated methy
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; Beck 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. Chem., 23, 1980, 424-430; Bandini et al., J. Org., 67, 15; 5386-5389; Davis et al., J. Med., 31, 35, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 2, 1, 2, 1, 2, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 3, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 3, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 3, 2, 2, 2, 2, 2, 2, 2, 3, 2, 2, 2, 2, 2, 3, 2, 2, 2, 2, 3, 2, 2, 2, 3, 2, 2, 3, 2, 2, 3, 4, 5, 5, 5, 5, 5, 6, 6, 6, 8, 8, 8, 8, 8, 8, 8, 8, 8, 8, 9, 9, 9, 9, 9, 9, 9, 10, 10, 10, 10, 10, 10, 10, 10, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 11, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 12, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15, 15,
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 reagent), N-(3-dimethylaminopropyl) -nethylcarbodiol (EDCI), O-dimethylamino-1-benzotriazol) -N,N,N,N'-tetrahydraminoylcarbodiol tetrahydrofuran (TBTU), N-dimethylaminoxylamine, N'-dimethylaminoxylaminoxylamine, 1-dimethylaminoxylaminoxylamine (CCFC), 1-dimethylaminoxylaminoxylamine, 1-dimethylaminoxylamine, 1-dimethylaminoxylaminoxylamine, 4-dimethylaminoxylaminoxylamine, or 4-dimethylaminoxylaminoxylaminoxylamine, and may be subjected to a temperature of at least 150°C and to a minimum of 25°C, and to a minimum of 1 microprophosphosphatidylphosphenol, and to a minimum of 1 microphosphenol, and to a minimum of 1 microphosphenol.
Compounds of the general formula AMN may be added to acid anhydrides and carbonic acid 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 pyridozothiazine and, if necessary, with the addition of 4-dimethylamino) pyridine or 1-hydroxybenzoles at temperatures between 150°C and 25°C. If necessary, micro-injection of the compounds under general formula AMD is recommended.
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 components, full reference is also made to WO2004/043967, WO2005/063769, WO2005/066183, WO2006/018184, WO2006/108565, WO2007/124903 and WO2008/009416. A professional recognises that suitable edible components for the synthesis of the compounds of the invention can be produced by analogy with the synthesis schemes and examples disclosed in these documents.
Other
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.
Other
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 one physiologically compatible carrier and at least one compound according to the general formula (III).
Other
Preferably, a composition is used which
is solid, liquid or paste-like; and/or contains the compound of the invention in an amount of 0,001 to 99 weight per cent, preferably 1,0 to 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 additional active substances, if appropriate.
Other
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 Areas, Editio Cantor Aulendoff).Other
Other
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, 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.
Other
Preferably, the composition is prepared for systemic, topical or local administration, preferably for oral administration, according to the invention.
In another embodiment of the use of the invention, a pharmaceutical form of administration containing the pharmaceutical composition of the invention is used.
Other
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.
Other
Preferably, this is systemic, particularly oral administration.
Other
In a preferred embodiment, the dosage formulation used according to the invention contains the compound according to the general formula (III) 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,Relative to the molecular weight of the free base.
Other
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%, 0,006 mg±50%, 0,25 mg±50%, 0,3 mg±50%, 0,35 mg±50%, 0,45 mg±50%, 0,45 mg±50%, 0,5 mg±50%, 0,55 mg±50%, 0,6 mg±50%, 0,65 mg±50%, 0,75 mg±50%, 0,50 mg±50%, 0,50 mg±50%, 0,8 mg±50%, 0,95 mg±50%, 1,5 mg±50%, 1,5 mg±50%, 1,5 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 mg±50%, 0,5%, 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%, 0,5%, 0,5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 5%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, 6%, and so on.The concentration of the active substance in the test chemical is calculated as follows:
Other
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%, 0,01 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%, 0,006 mg±25%, 0,25 mg±25%, 0,3 mg±25%, 0,35 mg±25%, 0,4 mg±25%, 0,45 mg±25%, 0,5 mg±25%, 0,55 mg±25%, 0,6 mg±25%, 0,65 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,8 mg±25%, 0,25 mg±25%, 0,85 mg±25%, 0,65 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,85 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±25%, 0,75 mg±2%, 0,75 mg±2%, 0,75 mg±2%, 0,75 mg±2%, 0,75 mg±2%, 0,75 mg±2%, 0,75 mg±2%, 0,75 mg±2%, 0,75%, 0,75 mg±2%, 0,75%, 0,75 mg±2%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%, 0,25%,The total number of test concentrations of the active substance shall be calculated from the total number of test concentrations of the active substance.
Other
The dose of the drug that is particularly preferred 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, 0.3 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0 mg, 0.0The dose of the active substance is based on the molecular weight of the free base, which may be 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 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg.
Other
In a preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (III) 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% by the molecular weight of the free base.
Other
In another preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (III) 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.
Other
In another preferred embodiment, the dosage formulation of the invention contains a compound according to the general formula (III) 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.
Other
In another preferred embodiment, the dosage formulation of the invention contains a compound according to the general formula (III) 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.
Other
In another preferred embodiment, the dosage formulation of the invention contains a compound according to the general formula (III) 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.
Other
In another preferred embodiment, the dosage formulation used according to the invention contains a compound according to the general formula (III) 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%,Relative to the molecular weight of the free base.
Other
The presentation form according to the invention may be, for example, in liquid form, in the form of solutions for injection, drops or juices, or in semi-solid form, in the form of granules, tablets, pellets, patches, capsules, patches/spray patches or aerosols. The choice of excipients etc. and the amounts to be used depend on whether the dosage form is to be applied orally, orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example on the skin, mucous membranes or in the eyes.
Other
For oral application, the dosage forms are tablets, tablets, capsules, granules, drops, juices and syrups, for parenteral use,Topical and inhalation solutions, suspensions, easily reconstituted dry preparations and sprays. Compounds in a depot, in solution or in a patch, possibly with the addition of skin penetration enhancers, are suitable percutaneous application preparations for use in accordance with the invention.
Other
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 storage 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.
Other
In a preferred embodiment, the compounds used in accordance with the invention are immediately released (IR) from the dosage form, i.e. preferably under in vitro conditions,preferably according to Ph. Eur., at least 80% of the original active substance is released after 20 minutes.
Surprisingly, the compounds used in accordance with the invention, according to the general formula (III), were found to have an unusually long half-life (t)1/2 of the totalThe effects of the drug on the patient' s body are characterised by a relatively low dose of the drug (e.g. a very low dose of the drug) and a relatively high pharmacodynamic duration of action, so that a relatively infrequent dose is sufficient to achieve a relatively long duration of pharmacological efficacy and thus pain relief.
Other
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 the pharmacological effect is rapidly established after the first administration.Err1:Expecting ',' delimiter: line 1 column 628 (char 627)Usually 0,00005 to 50 mg/kg, preferably 0,001 to 0,5 mg/kg, preferably 1 to 10 μg/kg at least of a compound according to the general formula (III).
Other
For all the foregoing uses of the dosage forms used according to the invention, it is particularly preferable if the dosage form contains at least one compound of general formula (III) 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 258 (char 257)
Commercially available at Aldrich at the time of synthesis.
At the time of synthesis commercially available at Fluorochem.
To prepare the reaction mixture, saturated ammonium chloride solution (150 ml) was added under ice-cooling and extracted with diethyl ether (3 × 100 ml). The organic phase was dissolved with water (100 ml) and saturated NaCI solution (100 ml) and diluted. One crude copper (25.2 g) remained. The product was dissolved in ethyl ketone (280 ml) and dissolved in clisolic acid.3After a reaction time of 6 h, hydrochloride D-1 was isolated as a white solid at a yield of 35% (10.5 g).
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 hydrolysis, the reaction mixture was extracted with diethyl ether (2 × 50 ml). The aqueous phase was made alkaline by ice-cooling with 5 N sodium salt, extracted and compressed with dichloromethane (3 × 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 × 100 ml). The organic phase was agitated and dissolved with water (50 ml) and saturated NaCI solution (50 ml) in the organic chain. A residual oil (26.5 g) was left, which contained in addition to the phenyl compound 4Si (2. The product was dissolved in ethyl methyl ether (15 ml) and dissolved in clonidine (15 ml).3After a reaction time of 6 h, the hydrochloride D-2 was isolated at a yield of 55% (16.3 g) as a white solid with a melting point of 275-278 °C.
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 an ice bath and the aminonitril B-1 (3.00 g, 14.3 mmol) was dripped at 10 °C into abs THF (30 mL). The approach was stirred at room temperature above night, the reaction rate was reduced by 20 °C under ice-freezing conditions.4The org phase was washed with water (50 mL) and then with saturated NaCI solution (50 mL), over Na2 andSo4The raw product was dissolved in ethyl methyl ketone (25 ml) and chilled with CISiMe3The resulting precipitation was filtered and dried in a vacuum.
Other
The yield of D-2: 2.8 g (62%)
Other
Other1 andThe following information shall be provided for the purpose of the assessment:6The following are the main types of data: 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 × 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 ice-cooling with 5N sodium salts, the reaction mixture was extracted with dichloromethane (3 x 50 mL), the organic phase was dried with sodium sulphate and i. i. vacuum condensed. The raw product was obtained by flash chromatography with CHCl3/MeOH (20:1) purified
Other
The following table shows the results of the analysis:
Other
The melting point is 62-67 °C.
Other
Other1 andThe following information shall be provided for the purpose of the assessment:6The following are the main types of the test:
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 × 100 ml). The organic phase was brazed and dissolved with water (50 ml) and saturated NaCI solution (50 ml). A residual oil (12.55 g) was left, which contained the CIS-1-3 phenyl compound besides the B ketone. The product was dissolved in ethyl methyl methyl (75 ml) and dissolved in ice.3After a reaction time of 6 h, the hydrochloride D-3 was isolated as a white solid at a yield of 47% (7.48 g).
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 × 50 ml), the aqueous phase was made alkaline by ice-cooling with 5N sodium salt, extracted and condensed with dichloromethane (3 × 50 ml). 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-lodthiophen (1.22.9 g, 109 mmol) was dissolved in THF (80 ml) under argon and transferred to THF with 2M isopropylmagnesium chloride (2.35.7 ml, 72 mmol) at 0 °C for 30 min. After a reaction time of 1 h at 3-5 °C, aminonitrile B-1 (10 g, 47.6 mmol) dissolved in tetrahydrofuran (20 ml) was added and stirred at room temperature for 20 h.4Cl solution (85 ml) and extraction with diethyl ether (3×100 ml). The organic phase was agitated and compressed with water (50 ml) and saturated NaCl solution (50 ml). A dark brown oil (21.3 g) was obtained, containing in addition to the desired ketal the aminonitrile B-1 and 2-lodthiophene. The raw product was dissolved in ethyl methyl ketone (140 ml) and treated with CISiMe3After a reaction time of 6 h, the hydrochloride D-4 was isolated as a white crystalline compound at a yield of 60% (8.74 g).
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 × 50 ml). The aqueous phase was made alkaline by ice-cooling with 5 N sodium salt, extracted with dichloromethane (3 × 50 ml) and compressed. The ketone E-4 was obtained as a yellow solid with a melting point of 108-110 °C at a yield of 89 % (5.66 g).
3-lodthiophen (1.5 g, 23.8 mmol) was dissolved in THF (18 ml) under argon and mixed with 2M isopropylmagnesium chloride (2.7.8 ml, 15.5 mmol) in THF for 8 min at 0 °C. After a reaction time of 1 h at 3-5 °C, aminonitrile B-1 (2.16 g, 10.3 mmol) dissolved in tetrahydrofuran (20 ml) was added.4Cl solution (20 ml) and extraction with diethyl ether (3 × 50 ml). The organic phase was agitated and compressed with water (20 ml) and saturated NaCI solution (20 ml). A light brown oil (3.95 g) was obtained. The raw product was dissolved in ethyl methyl ketone (40 ml) and treated with ClSiMe.3After a reaction time of 3 h, the desired hydrochloride was isolated as a white crystalline compound at a yield of 60% (1.86 g) with a melting point of 250-251 °C.
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 × 30 ml), the aqueous phase was made alkaline with 5 N sodium salt, extracted and compressed with dichloromethane (3 × 30 ml) under ice cooling. The ketone E-5 was isolated as a yellow solid with a melting point of 147 °C to 150 °C and a yield of 98 % (1.27 g).
Note: This Regulation applies primarily to the cis product AMN-1.cisThe trans product AMN-1 is obtained from theTransIt is only a by-product or contaminant.
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 incorporated into 1,2-dichlorethane (100 ml). The reaction mixture was mixed with trifluoroacetic acid (15 ml) and stirred for 1 h at room temperature. The course of the reaction was monitored by DC.2 andThe resulting white solid was sucked out through a fryer and the solid was mixed with H.2 andO (3 × 5 ml) washed and dried.cisThe parent sludge (aqueous phase) was extracted with 1,2-dichlorethane (3 × 25 ml). The organic phase was extracted with Na2 andSo4The solid brown residue was decrystallized from MeOH (10 ml) to give a mixture of cis-AMN-1cisand trans- AMN-1TransSpiroamine (1: 1) The mixture was obtained as a white solid at a yield of 940 mg (17%)
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6): 1,61 (m, 2 H) 1,63 (m, 2 H) 1,92 (s, 6 H) 2,12 (m, 2 H) 2,39 (m, 2 H) 2,53 (t, J = 5,36 Hz, 2 H) 2,99 (t, J = 5,35 Hz, 2 H) 6,86 (m, 1 H) 6,91 (m, 1 H) 7,16 (d, J = 7,52 Hz, 1 H) 7,28 (d, J = 7,52 Hz, 1 H) 7,31 (m, 1 H) 7,43 (m, 4 H) 10,21 (s, 1 H)
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-dichloroethane (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.2 andThe solution was then diluted with NaOH (100 ml) and adjusted to pH 11 with NaOH (5 mol/l).2 andThe cis-diastereomer AMN-2 was washed and dried.cis, obtained as a white solid with a melting point of 220-225 °C at a yield of 5,5 g (73%).
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following is a list of the main components of the system: 1.61 (m, 2 H) 1.62 (m, 2 H) 1.93 (s, 6 H) 2.11 (m, 2 H) 2.38 (m, 2 H) 2.53 (t, J = 5.56 Hz, 2 H) 2.99 (t, J = 5.56 Hz, 2 H) 6.87 (m, 1 H) 6.92 (m, 1 H) 7.14 (m, 1 H) 7.17 (d, J = 8.34 Hz, 1 H) 7.20 (m, 1 H) 7.25 (d, J = 7.82 Hz, 1 H) 7.28 (d, J = 7.47 Hz, 1 H) 7.47 (m, 1 H) 10.26 (s, 1 H)
Tryptamine H-1 (2.03 g, 12.7 mmol) and ketone (E-2, 3.0 g, 12.7 mmol) were dissolved in methanol (130 ml) and stirred under argon for 16 h at room temperature. The reaction mixture was then compressed. The residue was dissolved in 1,2-dichloroethane (130 ml) and rapidly added to trifluoroacetic acid (12.7 ml) and stirred for 2 h at room temperature. Ice-cold water (120 ml) and 5N natron solution (40 ml) were added and stirred for 1 h. The resulting colourless solid was separated by filtration and washed with 1,2-dichloroethane (30 ml) and water (4 × 25 ml).ciswas obtained at a yield of 77 % (3.7 g) with traces of trans-spiroamine AMN-2TransThe organic phase was dried with sodium sulphate, compressed, mixed with methanol (3 ml) and stirred at room temperature for 1 h. A white solid was produced, which was separated by filtration and washed with methanol (4 × 3 ml).TransThe results of the study were positive, with a yield of 5% (250 mg) of cis-spiroamine AMN-2 in the human body.cisAfter chromatographic purification [silica gel 60 (20 g; methanol (200 ml) ] the trans-spiroamine AMN-2 was obtained from theTrans(170 mg) obtained with a melting point of 296 °C to 299 °C.
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6): 1,55 (m, 2 H) 1,62 (m, 2 H) 1,88 (s, 6 H) 2,26 (m, 2 H) 2,43 (m, 2 H) 2,55 (t, J = 5,49 Hz, 2 H) 2,96 (t, J = 5,25 Hz, 2 H) 6,91 (m, 1 H) 6,99 (m, 1 H) 7,08 (m, 1 H) 7,14 (m, 1 H) 7,20 (d, J = 7,64 Hz, 1 H) 7,32 (m, 2 H) 7,40 (m, 1 H) 10,63 (s, 1 H)
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 1N NaOH solution at 0 °C basically and then extracted 3 times with 500 ml of diethylacetate. The combined organic phases were sulfurised over a magnetic medium and reduced under concentrated pressure. The solid was removed from the ethanol (100 ml × 3 F) by a white liquid, and the ethanol (2 ml × 3 F) was removed from the ethanol.cis, which was obtained as a white solid at a yield of 3.6 g (22%)
Other
Other1 andH NMR (DMSO-d6, 400 MHz): δ 10.39 (s, 1H), 7.44 to 7.49 (m, 1H), 7.11 to 7.24 (m, 4H), 7.00-7.04 (m, 1H), 6.72-6.78 (m, 1H), 2.95 to 2.98 (t, 2H), 2.48 to 2.50 (m, 1H), 2.36 to 2.39 (d, 2H), 1.98 to 2.11 (m, 2H), 1.91 (s, 6H), 1.51-1.67 (m, 5H)
Other
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 trifluoric acid (100 ml) and stirred at room temperature for 12 h. The reaction was followed by DC. The solution was treated with 1N NaOH solution at 0 °C and then magnetically extracted 3x with 500 ml of ethyl diethyl acetate. The combined organic phases were magnetically pulverized over cisterns and then reduced under concentrated pressure. The resulting solid was a white methanol (100 ml × 4 ml) which was removed from the liquid and then dissolved in water.cis, which was obtained as a white solid at a yield of 4 g (28%)
Other
Other1 andH NMR (DMSO-d)6The frequency range used for the calculation of the frequency bands is: δ 10.36 (s, 1H), 7.45 (s, 4H), 7.42 (s, 4H), 7.32 (s, 1H), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.14 (s), 7.40 (s), 400 (s), 400 (s), 400 (s), 400 (s), 400 (s), 400 (s), 400 (s), 400) MHz: δ 10.36 (s), 1H), 7.45 (s), 7.45 (s), 7.42 (s), 7.32 (s), 7.32 (s), 7.32 (s), 7.32 (s), 7.32 (s), 7.32 (s), 7.33 (s), 7.33 (s), 6.33 (s), 2.37 (s), 2.13 (s), 2.13 (s), 2.13 (s), 2.34 (s), 1.31 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.38 (s), 1.
The ketone E-3 (2800 mg, 11.90 mmol) and tryptamine (H-1, 1910 mg, 11.90 mmol) were dissolved in dry methanol (119 ml) under argon and stirred for 18 h. The methanol was then distilled in a vacuum and the residue was suspended in 1,2-dichlorethane (119 ml). The reaction mixture was added to trifluoric acid (11.9 ml) and stirred at room temperature for 2 h. Then the reaction mixture was diluted with 1,2-dichlorethane (119 ml) and set to pH 11 under ice cooling with 1N sodium hydroxide solution. A bright, dry precipitation was produced. The mixture was stirred at room temperature. The precipitation was distilled with water, water vapor and cis-N-5 amine dihydrate at room temperature.cisThe organic phase was dried, filtered and removed from the vacuum by sodium sulphate. The light residue (trans-diastereoisomer AMN-5) was obtained from the organic phase.TransThe precipitate was filtered and vacuum dried. The trans-diastereoisomer AMN-5 was obtained from the ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-based ammonia-ammonia-ammonia-ammonia-ammonia-ammonia-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-am-TransThe results of the analysis showed that the concentration of the active substance in the test chemical was approximately 6%.
Other
Other13C {1 andThe maximum value of the measurement shall be calculated as the sum of the values of the measurements.6The number of cells in the blood is not known, but the number of cells in the blood is not known.
Amnestic acidcisAfter the reaction was completed, the solid was filtered and the filtrate was mixed with saturated Na2 andCO3The aqueous phase was extracted three times with 10 ml of ethyl acetate each, and the organic phase was extracted via MgSO.4The product was obtained at a yield of 174 mg (26%) to produce methane sulphonate. The newly obtained spiroamide (174 mg, 0.355 mmol) was suspended in DCM (6 ml) and diluted in RT with methane sulphonic acid (23.7 μl, 0.355 mmol). Acetone (0.8 ml) was then added and enough diethyl ether was added to dissolve the resulting cloudiness by shaking. The product was stirred for another 30 minutes and the resulting solid was dried under air, washed with diethyl ether for AMD-1 at 50°C. The product was then pumped to a vacuum at 3°C.cisThe results of the analysis were obtained at a yield of 159 mg (76%).
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following are the main features of the new system: 1.65 (t, J = 13.22 Hz, 2 H) 2.20 (t, J = 12.84 Hz, 2 H) 2.51 (d, J = 4.53 Hz, 9 H) 2.87 - 3.16 (m, 4 H) 4.13 (br. s., 2 H) 6.92 (t, J = 7.55 Hz, 1 H) 6.99 (t, J = 7.55 Hz, 1 H) 7.20 (d, J = 8.31 Hz, 1 H) 7.31 (d, J = 7.55 Hz, 1 H) 7.36 - 7.51 (m, J = 7.55 Hz, 1 H) 7.56 - 7.69 (m, 3 H) 7.74 (d, J = 7.55 Hz, 2 H) 7.82 (d, J = 7.55 Hz, 2 H) 9.62 (br, s, 1 H)
The spiroamine (AMN-2) is acisThe solution was irradiated at 120°C for 10 min in the microwave (Initiator Eight, Biotage). After completion of the reaction (DC control), the solution was first filtered, then diethyl (15 ml) added and re-filtered. It was saturated with sodium nitrate.2 andCO3- the aqueous phase was washed with DCM once again after the phases had been separated.4The raw product has been column chromatographically purified [silica gel 60; DCM/methanol (19: 1) ].cisThe use of the product in the production of the test chemical was limited to the following:
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following are the main features of the new system: the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' and so-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' and 'cross-border' system, the 'cross-border' system, the 'cross-border' system
The spiroamine (AMN-2) is acisThe 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's saliva was irradiated with saturated Na2 andCO3- the aqueous phase was washed twice with DCM after the phases had been separated.4The raw product has been column chromatographically purified [silica gel 60; DCM/methanol (19: 1) ].cisThe use of the product in the production of the product concerned was limited to the following:
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following table shows the number of hours of work that a worker may be required to complete a training course in order to obtain a qualification in a particular field:
The spiroamine (AMN-2) is acis;600 mg, 1.59 mmol) was suspended in DCM (15 ml) in a microwave-equipped vessel and infused with 2- ((4-fluorophenyl) acetyl chloride (548 mg, 3.18 mmol) and diisopropylethylamine (408 mg, 3.18 mmol). The solution was irradiated at 130°C for 10 min in the microwave (Initiator Eight, Biotage Company). After completion of the reaction (DC control), the solution was first filtered, the mother's ovary diluted with DCM (45 ml) and saturated with na2 andCO3After separating the phases, the organic phase was re-stained with saturated Na2 andCO3The organic phase was washed with MgSO.4The raw product was column chromatographically purified [silica gel 60; DCM/methanol (4: 1) ]. The product was obtained at a yield of 150 mg (18 %). To produce methane sulfonate, the spiroamide (150 mg, 0.29 mmol) was dissolved in DCM (1 ml) and added to RT with methane sulfonic acid (18.9 μl, 0.29 mmol). It was diluted with diethyl ether to form a stirring substance. The solid was sucked under air extraction, washed with diethyl ether and dried at 50 °C in an oil pump vacuum. The product AMD-4cisThe use of the product in the production of the product concerned was limited to the following:
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following table shows the number of hours of work that a worker may be required to complete a training course in a given country:
The spiroamine (AMN-2) is acisAfter completion 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 obtained by using Na2 andSo4The raw product was column chromatographically cleaned. During the crushing process a solid was released, which was filtered and then dried. The product was obtained at a yield of 220 mg (43%).
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following table shows the number of hours of work that a worker may be required to complete in order to obtain a job:
For the production of the salt, the amide AMD-5 was used.cisThe product was then extracted from the solid by air extraction and dried at 50°C in an oil pump vacuum.cisThe results of the analysis were obtained at a yield of 100 mg (33%).
The spiroamine (AMN-2) is acisThe reaction solution was irradiated at 120°C for 10 min in the microwave (Initiator Eight, Biotage). After completion of the reaction (DC control), the mother's saliva was first filtered and then mixed with NaOH solution (5 N, 10 ml). After separation of the phases, the aqueous phase was combined with a polar, aprotic organic solution (5 mg/ ml).4The raw product was purified column chromatographically.cisThe use of the product in the production of the product concerned was limited to the following:
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following are the main features of the new system: the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the use of the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' and 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' system, the 'cross-border' and 'cross-border' system, the 'cross-border' system, 'cross-border' and 'c
A suspension of spiroamine AMN-3 was placed in a microwave.cisThe microwave was closed and heated in the microwave (Initiator Eight, Biotage) for 10 min to 120°C. The reaction mixture was mixed with 4 ml and 4 ml of 1Nron saline for processing. This mixture was stirred at 2h. The water phase and the aqueous phase were then separated 3x with DCM. The organic phase was washed with water and dried over sodium nitrate. The product was reduced to nitrous oxide by removal of the sodium nitrate at a pH of 1: 0.87 (RAT/DMT)cisThe number of people who have received a grant (33%)
Other
The test chemical is used to determine the concentration of the test substance in the test medium.tThe test chemical is used to determine the concentration of the active substance in the test chemical.
A suspension of spiroamine AMN-3 was placed in a microwave.cisThe microwave was closed and heated in the microwave (Initiator Eight, Biotage) for 10 min to 120°C. The reaction solution was mixed with 5 ml of water and 5 ml of 1N sodium salts for processing. This mixture was stirred at RT pressure for 2 h. The phases were then separated and the aqueous phase was extracted with 3x DCM. The organic phases were combined with water and water-soluble nitrogen. The product was reduced to sodium by reducing the sodium salts by using a nitrogenous nitrogenous nitrogenous nitrate (AMD-9145), which was then removed at the desalination stage.cisThe number of people who received a
Other
The test chemical is used to determine the concentration of the test substance in the test medium.tThe test chemical is used to determine the concentration of the active substance in the test chemical.
A solution of cinnamic acid chloride (0.198 g; 1.192 mmol; 3 eq.) in 4.5 ml of THF was obtained by spraying a solution of spiroamine AMN-4 on RT nitrogen.cisAfter 1 hour of stirring at RT, the cloudy reaction solution was first mixed with 3 ml of water and then ice-cooled with 3 ml of 1 N of baking soda. It was stirred for 1.5 h. After removing the solvent at reduced pressure, the failed solid was filtered and washed with water. The raw product was cleaned column chromatographically (chalk gel; acetic acid). 0.043 g of product AMD-10 were obtained.cisThe number of people who received a
Other
The test chemical is used to determine the concentration of the test substance in the test medium.tThe test chemical is used to determine the concentration of the active substance in the test chemical.
The cis-spiroamine AMN-2cisThe solution was dissolved in absolute tetrahydrofuran (20 ml) and absolute dichloromethane (120 ml) without oxygen, replaced with Hünig base (1,167 ml, 6,8 mmol) and replaced at room temperature with 2-phenylacetyl chloride (900 μl, 6,8 mmol). 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 × 10 ml). The combined organic phases were extracted by Na2 andSo4A raw product was isolated and chromatographically separated [silica gel 60 (100 g); EtOAc (1000 ml) ].cishas been obtained as a colourless solid at a yield of 820 mg (49%) and a melting point of 95-100 °C.
Other
Other13The following information shall be provided for each frequency band:6The following table shows the percentage of the total number of samples of the product in the sample:
For a suspension of cis-spiroamine AMN-5cisThe reaction mixture was stirred at room temperature for 1 h, then mixed with water (30 ml) and 1N sodium hydroxide solution (5 ml) and stirred for 1.5 h. The dichloromethane was then removed in the vacuum, leaving a lighter solid, which was separated by filtration and then washed with water (3 x 30 ml) to remove the tetrahydrate. The resulting product was treated with a raw material [60 g/ ml: 60 cycloacetate (70 g/ ml): cycloacetate: 1 mg: 1 mg: 500 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1 mg: 1cis(Smp. 145-155 °C) was obtained as a colourless solid at a yield of 31% (204 mg, 0.40 mmol).
Other
Other13C {1 andThe maximum value of the measurement shall be calculated as the sum of the values of the measurements.6The following table shows the number of ppm of the test chemical in the blood: δ ppm: 22.5 (1 C), 29.3 (2 C), 32.6 (2 C), 37.8 (2 C), 41.3 (1 C), 59.5 (1 C), 60.3 (1 C, br), 105.4 (1 C), 111.1 (1 C), 114.3 (2 C, d, J = 20 Hz), 117.3 (1 C), 118.4 (1 C), 120.5 (1 C), 123.1 (1 C), 126.6 (1 C), 127.9 (2 C), 128.7 (2 C), 129.3 (2 C), 129.8 (2 C, d, J = 8 Hz), 132.4 (1 C, br), 135.1 (1 C), 135.4 (1 C), 139.4 (1 C), 140.4 (1 C), 160.9 (1 C, d, J = 243 Hz), 170.3 (1 C)
Benzo[b]thiophen-2-carbonate chloride (728 mg, 3.96 mmol) was dissolved in tetrahydrofuran (30 ml) with argon and treated at room temperature with trans-spiroamine AMN-2Trans(500 mg, 1.32 mmol), dissolved in tetrahydrofuran (60 ml) for 75 min. After a reaction time of 2 h, the reaction mixture was diluted with water (15 ml), put under ice cooling with 1 N of sodium nitrate (15 ml) and stirred for 2.5 h. Tetrahydrofuran was removed in a vacuum, leaving a solid which was separated by filtration and washed with water (3 × 20 ml). The raw product (587 mg) was separated chromatographically [Cycle 60 (80 g); Ethylacetate/clohexane 1 1 (1 I), Ethylacetate/methanol 4 1 (500 ml). The trans-amino acid was obtained as a colourless solid at a melting point of 122% (89-221 mg) at a melting point of 21 °C.
Other
Other13The following information shall be provided for the purpose of the assessment:3The following table shows the percentage of the total number of samples of the test chemical in the sample:
The trans-amide (82 mg, 0.152 mmol) was suspended at 80 °C in ethanol (8 ml) 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 × 3 ml) (64 mg). After 3 days, another solid had been removed from the room at filter temperature, which was sucked out and washed with diethyl ether (2 × 2 ml) (35 mg).Transhas been obtained at a yield of 81% (89 mg) at a melting point of 175 °C to 185 °C.
Cinnamic acid chloride (1.32 g, 7.92 mmol) was dissolved in tetrahydrofuran (30 ml) with argon and treated at room temperature with impurity spiroamine AMN-2.cisThe substance was found to contain approximately 10% trans-diastereoisomers of AMN-2.TransAfter a reaction time of 1 h, the cloudy solution was mixed with water (20 ml) and ice-cooled with 1 N of sodium chloride (20 ml) and stirred for 1.5 h. Tetrahydrofuran was removed in a vacuum, leaving a solid which was separated by filtration and washed with water (3 × 25 ml). The raw product (1.16 g) was chromatographically separated [silica gel 60 (200 g); ethylacetate/cyclohexane 1 : 1 (1,3 I), ethylacetate 151.6 I). The cis-amide was obtained as a colourless solid at a yield of 40 % (540 mg) with a melting point of 155-158 °C. The amide was trans-amide at a yield of 7 mg (93-155 °C) by an isotope of 15 mg (93 mg).
The trans-amide (188 mg, 0.37 mmol) obtained was dissolved in ethanol (35 ml) at 80 °C 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 crystallizing. The mixture was kept at 5 °C for 1.5 h, the colourless solid was separated by filtration and washed with diethyl ether (3 × 3 ml) (146 mg). The filter was compressed, soaked in ethanol (1 ml) and mixed with diethyl ether (20 ml). The colourless salt was further separated and washed with diethyl ether (2 × 2 ml) (36 mg).TransIt is obtained at a yield of 71 % (182 mg) and a melting point of 161 °C to 164 °C .
Other
Other13The following information shall be provided for each frequency band:6The following is a list of the active substances which may be used in the manufacture of the active substance:
3,4-dimethoxyphenylenedioxy acid (1 g, 5.1 mmol, 2.2 eq.) is suspended in 25 ml of toluene and mixed with thionyl chloride (0.84 ml, 11.6 mmol, 5.0 eq.) It is heated for 2 h under reflux and the solvent is then removed. The residue is co-distilled with toluene (3 x 50 ml) and the raw product is dissolved in dichloromethane (37 ml) and transferred to a microwave. Spiroamine AMN-2 is transferredTransThe reaction mixture was mixed with 17 ml of water and 17 ml of 1N sodium salts, stirred for 2 h at RT, then the phases were separated and the aqueous phase extracted 3 times with dichloromethane, the combined organic phases were washed with water and dried over sodium sulphate, after removing the solvent at reduced pressure, the residual salts (exat; 0.23 g/mol/an) were cleaned.TransThe number of people who received a
Other
The test chemical is used to determine the concentration of the test substance in the test medium.tThe 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 in absolute 1,2-dichloroethane (30 ml) together with 5-fluorotriptophol (2.394.4 mg, 2 mmol). The mixture was then mixed with methanesulfonic acid (0.13 ml, 2 mmol), changing the colour of the reaction solution from red-brown to dark grey. After 5 min a light grey solid began to fall out. The solution was stirred for 20 h. Then the methanesulfonate from the cis-spirothere 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 (RTETH-145).cisThe trans-spirotheether was obtained as a colourless solid and obtained after filtration at a yield of 8 % (58.5 mg).
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6The following is a list of the most commonly used methods of measuring the frequency of the radio frequency spectrum: 1.67 (m, 2 H) 1.94 (m, 2 H) 2.24 (m, 2 H) 2.44 (s, 8 H) 2.53 (s, 3 H) 2.54 (s, 3 H) 2.66 (t, J = 5.27 Hz, 2 H) 2.72 (m, 2 H) 3.95 (t, J = 5.28 Hz, 2 H) 6.84 (m, 1 H) 7.14 (m, 1 H) 7.19 (dd, J = 4.50 / 8.70 Hz, 1 H) 7.47 (d, J = 5.10 Hz, 1 H) 7.0783 (m, 1 H) 8.
The ketone E-4 (223 mg, 1 mmol) was presented with tryptopholic acid (2,161 mg, 1 mmol) in absolute dichloromethane (40 ml) and methanosulfonic acid (0.071 ml, 1.1 mmol) was added. The solution was agitated for 16 h at RT, with the methanosulfonate of the spiroether being eliminated.cisThe organic phase was separated and the aqueous phase was extracted with dichloromethane (2 × 20 ml). The organic phases were combined, dried and compressed to obtain a mixture of substances (274 mg) which was chromatographically dissolved [silica gel g (20 g); ethylacetate/methanol 8 : 1]. The trans-spiroether was obtained at a yield of 54% (196 mg, Fp. 235-238 °C), the cis-spiroether at a yield of 10 mg (38 %).
Other
Other1 andThe measurement of the measured value shall be performed in accordance with the following equation:6(b)
Other
The following is a list of the most commonly used methods of measuring the frequency of the radio frequency spectrum:
The HPLC-MS analytical apparatus and methods: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: acetonitrile (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% + 0,2% formic acid; UV: 200 - 400 nm.
A) Comparison of analgesic efficacy (as ED)50The following data are available for the treatment of acute pain in the tail-spot, rat/mouse, mono-neuropathic (Chung, rat; Bennett, rat) and poly-neuropathic (STT, rat) models.
To describe the surprising pharmacological properties of the compounds of the invention, the results of the Chung mononeuropathic pain model in the rat and the tail-flick acute pain model in the rat are compared in the first instance, showing that the compounds of the invention can be used at a multiple of a significantly effective dose in the Chung model (e.g. ED)50 nThe findings from other models of neuropathic pain, such as the Bennett model in the rat or STD polyneuropathy in the rat, highlight the generally very good efficacy of the compounds in different forms of neuropathic pain.
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.
Methodology: 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 exposed to 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 time the lamp was switched on to the sudden flick of the tail (weglaziez) in untreated animals was 2.5-5 seconds. The animals were measured within 30 minutes prior to a second dose of the test compound (tail-flick type 50/08/1.bc, Labtec, Dr. Hess). The mean value of this was calculated as 40, 60, 20, or 180 mg/kg. The test was carried out after the injection of the drug, and the effect was measured as follows:1 and- T0(T)2 and- T0) x 100. These are:0: Control latency time before application of the substance, T1 and: Latency time after application of the substance, T2 and: maximum exposure time of the focus beam (12 seconds), MPE: maximum effect.
For antinociceptive test compounds, 3-5 logarithmically increasing doses, each including the threshold and maximum effective dose, were used to determine dose dependence.50The maximum effect was determined by semilog-
Statistical evaluation: The group sizes were usually n=10 and repeated measures ANOVA and post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE 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 (Macrolone cage type IV, Fa. Ebeco, Castrop-Rauxel, Germany) with a maximum of 5 animals each, in a light-dark rhythm of 12:12h with ad libitum feed and running water.
Methodology: The modulatory effect of the test substances on acute noxious thermal stimuli was studied in the tail-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 beam of an analgesimeter (model 2011, Rhema Labortechnik, Subheim, Germany). The intensity of the burn was set so that the time from the start of the tail-flick test to the sudden pull-up (Welaghalase) occurred at approximately 12-13 seconds. The maximum measurement time was approximately 10 minutes. The maximum effective dose of the anti-conceptive agent (Vegetable) was determined after administration of the drug or anti-conceptive agent (Vegetable) by a control agent (Vegetable) at a distance of 2 to 4 minutes (two to 10 minutes) or after administration of the drug or substance.1 and- T0(T)2 and- T0) x 100. These are:0: Control latency time before application of the substance, T1 and: Latency time after application of the substance, T2 andFor antinociceptively effective test compounds, 3-5 logarithmically increasing doses, each including the threshold and maximum dose, were applied to determine the dose dependence.50The maximum effect was determined by semilog-
Statistical evaluation: The group sizes were usually n=10 and repeated measures ANOVA and post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE 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 (veglaziez) in untreated animals was 2.5-5 seconds. The animals were measured within 30 minutes prior to the test and the mean value was calculated as 60 per cent of the dose (e.g. Veglaziez) and the mean dose was calculated as follows:1 and- T0(T)2 and- T0) x 100. These are:0: Control latency time before application of the substance, T1 and: Latency time after application of the substance, T2 andFor antinociceptively effective test compounds, 3-5 logarithmically increasing doses, each including the threshold and maximum dose, were applied to determine dose dependence.50The maximum effect was determined by semilog-
Statistical evaluation: The group sizes were usually n=10 and repeated measures ANOVA and post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE between the respective dose groups and vehicle controls.
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, Melsungen, Germany) (Kim and Chung 1992). After ligation, the muscle and adjacent tissues were stitched together and the wounds closed with metal bandages.The median of five stimulations yielded a data point. 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 elimination thresholds were expressed in grams. For analgesically effective test compounds, 3-5 logarithmically increasing doses, each including the threshold and maximum dose, were used to determine dose dependence.50The maximum effect was determined by semilog-
Statistical evaluation: The group sizes were usually n=10 and repeated measures ANOVA and post hoc Bonferroni analysis were used to test for statistically significant differences in %MPE between the respective dose groups and vehicle controls.
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, at 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 allodynia) 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 ptofo 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 the vehicle control (AUC) or baseline (individual measurement points).
Test animals: 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 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 running 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. Increasing pressure was applied to the dorsal surface of the hind legs and the pressure that eventually led to the reflective pull of the focus or vocalization was recorded. The results were obtained after three weeks.
References: Randall LO, Selitto JJ. A method for measurement of analgesic activity on inflamed tissue. Arch. Int. Pharamcodyn. 1957; 111: 409-19B) 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 first compared.50 nThe findings from other models of opioid-typical adverse reactions, such as circulatory parameters in rabbits, gastrointestinal carbon passage in mice, RotaRod test in mice, jumping test in mice and conditioned seat preference in rats, highlight the generally absent or very low opioid-typical adverse reactions of the compounds of the invention.
The respiratory depressant effect of test substances is studied after intravenous administration to instrumented, alert rats.2 andThe pressure is the pressure of the air inside the cylinder.2 andThe effects of the drug on the blood are not known.
Test animals: male Sprague-Dawley rats (CD (SD) outbred; breeder: Charles River, Sulzfeld, Germany); weight: 250-275 g; the animals are kept individually in standard cages (Type II Makrolone cages, Fa. Ebeco, Castrop-Rauxel, Germany) under a 12:12h light-dark rhythm with ad libitum feed and tap water.
Method: At least 6 days prior to application of test substance, and at defined points after application of 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 test substance or vehicle and at defined points after application of test substance or vehicle, the arterial catheter is opened and flushed with approximately 500 μl of heparin solution. Then, approximately 100 μl of blood is taken with the help of the catheter and heated glass capsule. The blood is collected with the blood of a catheter (LASAN) and can be taken immediately after a week, with the help of a catheter.
Test evaluation and statistics: The blood gas analyser automatically provides the pCO values2 andand pO2 andFor statistical evaluation, the post-dose and post-vehicle values are compared using one-way ANOVA and 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 under a 12:12h light-dark rhythm 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 (TL11 M2-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 two biopotential 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 signal is received via the RM-1 type DSI (Fa.C.Resever). Data collection, processing and processing software is used, the D-Fa-Ne-Fa (Ne-Fa-Si) data pack.
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 measurements of blood pressure (in mmHg) and heart rate (in beats per minute) 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 measurements after drug administration and the simultaneous measurements after vehicle application are compared by one-way ANOVA and post hoc Dunnett analysis. The significance level was set at p < 0.05.
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, in a 12:12h light-dark rhythm with ad libitum feed and tap water.
Description of the experiment: animals are kept sober on wire rost cage liners for 20 to 24 hours before the experiment.As a marker of the intestinal passage, an activated carbon suspension (10% activated carbon in 0.5% CMC solution; volume of application: 0.1 ml/10 g body weight) is applied orally to the animals.Then the test substance or vehicle solution is administered intravenously.Two hours after the application of the activated carbon suspension, the animals are treated with CO2 and- the intestinal tract is removed from the stomach up to and including the caecum and stretched on a glass plate moistened with 0.9% NaCl solution, the distance from the pylorus to the caecum and the passage of the carbon suspension (the widest point) are measured immediately.
For experimental evaluation: to determine the relative inhibition of gastrointestinal transit, the coal suspension's coefficient of passage (in cm) /Pylorus-Caecum distance (in cm) is expressed in % inhibition. For statistical evaluation, the measurements after administration and the measurements after vehicle application are compared by one-way ANOVA and post hoc Dunnett analysis. The significance level was set at p < 0.05.
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, at a 12:12 h light-dark rhythm with ad libitum feed and tap water.
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 measurements after vehicle application are compared by one-way ANOVA and post hoc Dunnett analysis. The significance level was set to p < 0.05.
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 12:12 h light-dark rhythm with ad libitum feed and tap water.
Err1:Expecting ',' delimiter: line 1 column 974 (char 973)
Err1:Expecting ',' delimiter: line 1 column 298 (char 297)
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 with the low abuse potential of tramadol.
Statistical evaluation: The evaluation of experimental findings for statistically significant differences in the preference of animals for the active substance or vehicle is preferably done by means of a paired t-test. Tabelle 1a: Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-6
Tabelle 1a: Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-6
Tabelle 1b: Zusammenfassung der pharmakologischen Daten zu Beispiel AMD-7
Tabelle 1b: 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 Schmerzes bei Mononeuropathie (Trennung von anti-allodynischer und anti-nociceptiver Wirkung) | --- | |
| Bennett, Ratte | Hemmung des neuropathischen Schmerzes bei Mononeuropathie | --- | |
| STZ, Ratte | Hemmung des neuropathischen Schmerzes 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 |
| Blutgasanalyse, Ratte | 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: ≥10 mg/kg i.v. | >2200x |
| Jumping-Test, Maus | Körperlicher Abhängigkeit / Entzugssymptome | NOEL: 10 mg/kg i.p. | 2200x |
| Platzpräferenz, Ratte | 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 / Entzugssymptome | 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 example of AMD-6 was used.cisThese are highly-affin ORL1 and μ-opioid receptor ligands with a ratio of ORL1 to μ-opioid receptor affinity of approximately 5 and approximately 6 respectively.cisThe results of the study show that the compounds used in accordance with the invention have a very high efficacy against neuropathic pain (here: ED)50 nIn contrast, no significant anti-nociceptive effects (such as respiratory depression, decreased blood pressure and heart rate, constipation, central nervous system effects, physical dependence, psychological dependence/ addiction) were observed in animal models investigating adverse reactions at doses 11 to more than 3000 times higher. Tabelle 2: Übersicht über ausgewählte pharmakologische bzw. pharmakokinetische Charakteristika weiterer Beispiele
Tabelle 2: Übersicht über ausgewählte pharmakologische bzw. pharmakokinetische Charakteristika weiterer Beispiele
| 0,030 | 0,138 | NOEL = 1000 µg/kg i.v. | NOEL = 3000 µg/kg i.v. | NOEL: ≥10000 µg/kg i.v. | 8 h // » 5 h (10 µg/kg i.v.) | |||
| 0,018 | 0,032 | 18%MPE bei 100 µg/kg i.v. | NOEL > 100 µg/kg i.v. | NOEL = 1000 µg/kg i.v. | ||||
| 0,017 | 0,05 | 35%MPE bei 100 µg/kg i.v. | NOEL > 1000 µg/kg i.v. | NOEL = 4600 µg/kg i.v. | ||||
| 0,016 | 0,059 | 42%MPE 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, in adverse reaction animal models (e.g. blood gas analysis, gastrointestinal charcoal passage and RotaRod test), no significant opioid-typical adverse effects were observed at 10 to more than 300 times higher doses.
Other Tabelle 3: Vergleich von cis- und trans-Spiroamin
Tabelle 3: 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 = 1000 µg/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 show the general formula (I) (here, for example AMD-6)cisand comparison example AMN-2cisSimilarly, in the animal models of adverse reactions (e.g. blood gas analysis) no significant opioid-typical adverse reactions are observed at many times the dose.Transand comparison example AMN-2TransIn contrast, no difference is observed between doses that are effective for neuropathic pain and those that are effective for acute pain, and no difference is observed between doses that are effective for opioid-type side effects (e.g. blood gas analysis).cisor AMD-6cisIn the overall comparison, the largest ranges for maximum analgesic effect. Tabelle 4: Vergleich von cis-Spiroaminen und cis-Spiroethern
Tabelle 4: 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.* | |
| 0,06 | 0,12 | 28%MPE bei 100 µg/kg i.v | 33%MPE bei 1000 µg/kg i.v. |
Conclusion: Surprisingly, when used in accordance with the invention, only the cis-spiroamines (here, for example, AMN-2) showcisSimilarly, in animal models of adverse reactions (e.g. blood gas analysis) no opioid-typical adverse reactions are observed at many times the dose.cisand comparison example Ether-1cisHowever, the results of the studies do not show a significant difference in dosage between the doses that are effective for neuropathic pain and acute pain.
Other Tabelle 5: Vergleich von AMD-5cis (freie Base) und AMD-6cis (Citrat-Salz)
Tabelle 5: Vergleich von AMD-5cis (freie Base) und AMD-6cis (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) showed no relevant differences in the pharmacological properties of base and salt. Tabelle 6: Vergleich der Affinitäten gegenüber einzelnen Rezeptoren
Tabelle 6: 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) 73% (10000) | 106 | |
| 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) 58% (10000) | 9,2 | |
| 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 a compound of the general formula (III),
where the compound is present as hydrochloride, citrate or hemicitrate salt.
In another preferred embodiment of the compounds of the invention, R is2 and-H and/or R3- F.
In another preferred embodiment of the compounds of the invention, R is the4and R5either both -H or both -OCH3are.
In another preferred embodiment of the compounds of the invention, these are selected from the group consisting of:
(E)-1- ((((1s,4s) -4- ((Dimethylamino) -4-dihydrospiro-phenyl-3',4'-dihydrospiro[cyclohexan-1,1'-spiro[cyclohexan-1,1'-pyrido[3,4-b]indol]-2' (((9'H) -yl) methanol; ((E)-1-(((1s,4s) -4-dimethylamino) -4-dihydrospiro[fluorophenyl) -3-dihydrospiro[fluorophenyl) -3-dihydrospiro[fluorophenyl]-1' (dihydrospyrido[3-b]indol]-2' (dihydrospyrido) -3-dihydrospyrido[3-b]indol) -2- (dihydrospyrido) -3-dihydrospyrido[3-dihydrospyrido]-2' (dihydrospyrido) -3-dihydrospyrido[3-dihydrospyrido]-4' (dihydrospyrido) -3-dihydrospyrido) -3-dihydrospyrido (dihydrospyrido) -3-dihydrospyrido) -3-dihydrospyrido (dihydrospyrido) -3-dihydrospyrido) -3-dihydrospyrido) -3-dihydrospyrido (dihydrospyrido) -3-dihydrospyrido) -3-dihydrospyrido (dihydrospyrido) -dihydrospyrido) -dihydrospyrido) -diethyl-phenyl-propyl (dihydrospyrido) -diphenyl) -4-diphenyl) -diphenyl -diphenyl -diphenyl -4-diphenyl (diphenyl) -diphenyl) -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl -diphenyl
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.
Other
In another embodiment of the invention, the above dosage form is packaged for a maximum of once daily administration.
Other
In another preferred embodiment of the invention, the presentation form is configured for systemic administration.
Other
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 in a dose range of 1,0 μg to 10 mg, based on the molecular weight of the free base.
Claims (15)
- Compound of the general formula (III), in whichR1 is -H or CH3;R2 is -H or -halogen;R3 is -H or -halogen;R4 is -H, -halogen or -OC1-3-alkyl; andR5 is -H, -halogen or -OC1-3-alkyl;wherein the compound is present as hydrochloride, citrate or hemi-citrate salt.
- Compound according to claim 1, wherein R2 is -H and/or R3 is -F.
- Compound according to claim 1 or 2, wherein R4 and R5 are either both -H or both- OCH3.
- Compound according to one of the above claims, selected from the group consisting of• (E)-1-((1s,4s)-4-(dimethylamino)-4-phenyl-3',4'-dihydrospiro[cyclohexane-1, 1'-pyrido[3,4-b]indole]-2'(9'H)-yl)-3-phenylprop-2-en-1-one;• (E)-1-((1s,4s)-4-(dimethylamino)-4-(3-fluorophenyl)-3',4'-dihydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indole]-2'(9'H)-yl)-3-phenylprop-2-en-1-one;• (E)-1-((1s,4s)-4-(dimethylamino)-6'-fluoro-4-(3-fluorophenyl)-3',4'-dihydrospiro-[cyclohexane-1,1'-pyrido[3,4-b]indole]-2'(9'H)-yl)-3-phenylprop-2-en-1-one;• (E)-1-((1s,4s)-4-(dimethylamino)-6'-fluoro-4-phenyl-3',4''-dihydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indole]-2'(9'H)-yl)-3-phenylprop-2-en-1-one;• (E)-1-((1s,4s)-4-(dimethylamino)-4-(4-fluorophenyl)-3',4'-dihydrospiro[cyclohexane-1,1'-pyrido[3,4-b]indole]-2'(9'H)-yl)-3-phenylprop-2-en-1-one,in each case in the form of hydrochloride, citrate or hemi-citrate salt.
- Compound according to one of claims 1 to 4 with the structure in the form of the hydrochloride, citrate or hemi-citrate salt.
- Compound according to one of claims 1 to 4 for use as a medicament.
- Pharmaceutical composition which contains a physiologically acceptable carrier and a compound according to one of claims 1 to 5.
- Composition according to claim 7, which- is solid, liquid or pasty; and/or- contains the compound according to one of claims 1 to 5 in an amount from 0.001 to 99 wt. % relative to the total weight of the composition.
- Pharmaceutical dosage form which contains the pharmaceutical composition according to claim 7 or 8.
- Dosage form according to claim 9, which is prepared for administration no more than once daily.
- Dosage form according to claim 9 or 10, which is prepared for systemic administration.
- Dosage form according to claim 11, which is prepared for oral administration.
- Dosage form according to claim 12, which contains the compound according to one of claims 1 to 5 in a dose within the range of 1.0 µg to 10 mg relative to the molecular weight of the free base.
- Compound according to one of claims 1 to 5 for application in the treatment of neuropathic and/or chronic pain.
- Compound for application according to claim 14, with application being effected no more than once daily.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10007822.9 | 2010-07-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1195245A HK1195245A (en) | 2014-11-07 |
| HK1195245B true HK1195245B (en) | 2019-12-20 |
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