WO2005110970A1 - Oxosubstituierte cyclohexyl-1,4-diamin-derivate - Google Patents
Oxosubstituierte cyclohexyl-1,4-diamin-derivate Download PDFInfo
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- WO2005110970A1 WO2005110970A1 PCT/EP2005/004907 EP2005004907W WO2005110970A1 WO 2005110970 A1 WO2005110970 A1 WO 2005110970A1 EP 2005004907 W EP2005004907 W EP 2005004907W WO 2005110970 A1 WO2005110970 A1 WO 2005110970A1
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- cyclohexyl
- dimethylamino
- benzyl
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- C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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Definitions
- the present invention relates to substituted cyclohexyl-1,4-diamine derivatives, processes for their preparation, medicaments containing these compounds and the use of substituted cyclohexyl-1,4-diamine derivative derivatives for the production of medicaments.
- Classic ⁇ -opioids such as morphine are effective in the treatment of severe to severe pain and are of the greatest importance for pain therapy.
- other opioid receptors in particular the ORL-1 receptor
- the pure ⁇ -opioids also have undesirable side effects such as constipation and respiratory depression, but also to Can cause dependency.
- the opioid receptors ⁇ , K and ORL-1 are also involved in the pain process (Opioids: Introduction, pp. 127-150, Further Opioid Receptors, 455-476 in: Analgesics - From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002 ).
- the ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes. These include learning and memory formation (Manabe et al., Nature, 394, 1997, pp. 577-581), hearing ability (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864) and numerous others processes. In a review by Calo et al. (Br.J. Pharmacol., 129, 2000, 1261 - 1283) gives an overview of the indications or biological processes in which the ORL1 receptor plays a role or could play with high probability.
- analgesia stimulation and regulation of food intake, influence on ⁇ -agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of opioids, anxiolysis, modulation of movement activity, memory disorders, epilepsy; Modulation of the neurotransmitter release, in particular of glutamate, serotonin and dopamine, and thus neurodegenerative diseases; Influencing the cardiovascular system, triggering an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, water storage diseases, intestinal motility (diarrhea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence).
- agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is also discussed.
- the object of the present invention was to provide medicinal products which act on the opioid receptor system and thus for medicinal products, in particular for the treatment of the various diseases associated with this system according to the prior art or for use there indicated indications are suitable.
- the compounds should also affect noradrenaline and serotonin reuptake.
- the invention therefore relates to substituted cyclohexyl-1,4-diamine derivative derivatives of the general formula I
- R1 and R 2 independently of one another for H; C ⁇
- R 1 ⁇ H; C ⁇ _5-alkyl, each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C.s-Cycloalkyl, in each case mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or via Ci.
- R 4 for each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C .g-cycloalkyl, in each case mono- or polysubstituted or unsubstituted; Aryl- or heteroaryl, each mono- or polysubstituted or unsubstituted; or aryl, C .g-cycloalkyl or heteroaryl bonded via C- ⁇ -alkyl, in each case mono- or polysubstituted or unsubstituted, in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids or cations.
- the compounds according to the invention show good binding to the ⁇ receptor and the ORL-1 receptor, but also to other opioid receptors. Surprisingly, it was found that the compounds are also good inhibitors of noradrenaline and serotonin reuptake. They are therefore also suitable for the treatment of depression and / or bulimia and / or anorexia and / or catalepsy and / or for anxiolysis and / or for increasing vigilance and / or libido.
- _3-alkyl” encompass acyclic saturated or unsaturated hydrocarbon radicals which can be branched or straight-chain and unsubstituted or mono- or polysubstituted, with 1, 2, 3, 4 or 5 carbon atoms or 1, 2 or 3 carbon atoms, ie C - ⁇ - alkanyls, C 2 _5-alkenyls and C2_5-alkynyls or C-
- Alkenyls have at least one CC double bond and alkynyls have at least one CC triple bond.
- cycloalkyl or "C 3 _3-cycloalkyl” for purposes of this invention, 6, means cyclic hydrocarbons having 3, 4, 5, 7 or 8 carbon atoms, wherein the hydrocarbons may be saturated or unsaturated (but not aromatic), unsubstituted or - Or can be substituted several times.
- cycloalkyl the term also includes saturated or unsaturated (but not aromatic) cycloalkyls in which one or two carbon atoms have been replaced by a heteroatom S, N or O.
- C 3 _3-Cycloalkyl is advantageously selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, pyridolidoline, pyridolinyloline pyridoline, pyridololine, pyridololine, pyridolinyl pyridoline contains.
- (CH 2 ) 3-6 is -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH 2 -CH 2 - and CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - to understand.
- aryl means carbocyclic ring systems with at least one aromatic ring, but without heteroatoms in only one of the rings, including phenyls, naphthyls and phenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.
- the aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
- Each aryl radical can be unsubstituted or mono- or polysubstituted, the aryl substituents being the same or different and being in any and possible position of the aryl. Phenyl or naphthyl radicals are particularly advantageous.
- heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different and the heterocycle can be unsubstituted or mono- or polysubstituted; in the case of substitution on the heterocycle, the substituents can be identical or different and can be in any and possible position of the heteroaryl.
- the heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
- the heteroaryl radical is selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalylazidyl, pyrazolyl, pyrazole Thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, imidazolyl, thazinyl, phenazoliazyl,
- the multiple substitution can take place with the same or with different substituents. Possibly. a substituent can in turn be substituted; so includes -Oalkyl including -O-CH 2 -CH2-O-CH2-CH 2 -OH.
- aryl means one or more, for example two, three, four or five times, substitution of one or more hydrogen atoms the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (cycloalkyl) 2 , N (alkyl-OH) 2 , NO 2 , SH, S-alkyl, S-cycloalkyl, S -Aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl
- salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution.
- This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
- physiologically compatible salts in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or a physiologically compatible cation.
- physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are tolerated.
- this is understood in particular to mean the salt formed with a physiologically compatible acid, namely salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
- physiologically acceptable salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,
- the hydrochloride salt, the citrate and the hemicitrate are particularly preferred.
- salt formed with a physiologically compatible acid is understood to mean salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
- the hydrochloride and the citrate are particularly preferred.
- physiologically compatible acids are: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxo-1-sulfinic acid , Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid and / or aspartic acid.
- physiologically compatible salt with cations or bases is understood to mean salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiological, in particular when used in humans and / or mammal - are compatible.
- the salts of the alkali and alkaline earth metals but also ammonium salts are particularly preferred, but in particular (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.
- the term salt formed with a physiologically compatible cation is understood to mean salts of at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically compatible, in particular when used in humans and / or mammals.
- the salts of the alkali and alkaline earth metals but also ammonium salts are particularly preferred, but in particular (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.
- R1 and R 2 independently of one another for H; C-
- substituted cyclohexyl-1,4-diamine derivatives in which R is cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolimylyl, pyrrolimyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolimyl, pyrrolimyl, pyrrolimyl, pyrrolimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted; over a saturated, unbranched C ⁇
- R3 phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl, in each case unsubstituted or mono- or polysubstituted; over a saturated, unbranched C-
- Substituted cyclohexyl-1,4-diamine derivatives in which R 3 is phenyl, phenethyl, thiophenyl, pyridyl or benzyl, in each case substituted or unsubstituted, are particularly preferred, particularly preferably phenyl, thienyl, 4-chlorobenzyl, benzyl, 3- Chlorobenzyl, 4-methylbenzyl, 2-chlorobenzyl, 4-fluorobenzyl, 3-methylbenzyl, 2-methylbenzyl, 3-fluorobenzyl, 2-fluorobenzyl or phenethyl.
- substituted cyclohexyl-1,4-diamine derivatives are preferred, in which R 4 for C -5 alkyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl, cyclooctyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furanyl, Isothiazolyl, imidazolyl, triazolyl, triazinyl, pyrazolyl, benzofuranyl, benzodioxolanyl, isoquinolinyl, phthalazine, benzo [1, 2.5] thiadiazole, benzothiazole, benzotriazole, quinolinyl, carbazole, isoxazolyl, oxazolyl, benzazidylolyl, indanylolyl, indanylolanyl Py
- R 4 for C -5 alkyl, cyclohexyl, cyclopentyl, phenyl, benzyl, naphthyl, thiophenyl, benzothiophenyl, furanyl, isothiazolyl, imidazolyl, triazolyl, pyrazolyl, benzofuranyl, isoquinolinyl, benzothiazole, benzotriazole, quinolylol, isoxyl, isoxyl , Pyridyl, pyrimidyl or pyrazinyl, each unsubstituted or mono- or polysubstituted; Benzyl or phenethyl, each unsubstituted or mono- or polysubstituted.
- substituted cyclohexyl-1,4-diamine derivatives in which X is C 1-5 alkyl, branched or unbranched, unsubstituted or mono- or polysubstituted, or one via a branched or unbranched, substituted or unsubstituted C 1 - 3- alkyl chain-bound phenyl or C 3-8 cycloalkyl radical, unsubstituted or mono- or polysubstituted.
- Substituted cyclohexyl-1,4-diamine derivatives in which n is 0 are also preferred.
- Substituted cyclohexyl-1,4-diamine derivatives from the group 5-oxo-5-phenyl-valeric acid (4-dimethylamino-4-phenyl-cyclohexyl) -amide N- (4-dimethylamino-4-thiophene) are very particularly preferred.
- the substances according to the invention act, for example, on the ⁇ -opioid receptor relevant in connection with various diseases, so that they are suitable as an active pharmaceutical ingredient in a medicament.
- the invention therefore furthermore relates to medicaments comprising at least one substituted cyclohexycarboxylic acid derivative according to the invention, and, if appropriate, suitable additives and / or auxiliaries and / or if appropriate further active compounds.
- the medicaments according to the invention optionally contain suitable additives and / or auxiliaries, including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be in the form of liquid pharmaceutical forms in the form of Injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters / spray plasters or aerosols.
- suitable additives and / or auxiliaries including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be in the form of liquid pharmaceutical forms in the form of Injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters / spray plasters or aerosols.
- suitable additives and / or auxiliaries including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be
- the amounts to be used depend on whether the medicinal product is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local, for example on the skin, mucous membranes or in the eyes to be applied.
- Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
- Substituted cyclohexyl-1,4-diamine derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous application preparations.
- Formulations which can be used orally or percutaneously can release the substituted cyclohexyl-1,4-diamine derivatives according to the invention with a delay.
- the substituted cyclohexyl-1, 4-diamine derivatives according to the invention can also in parenteral long-term depot forms such.
- B. implants or implanted pumps can be used. In principle, other active substances known to the person skilled in the art can be added to the medicaments according to the invention.
- the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, the indication and the severity of the disease. Usually 0.00005 to 50 mg / kg, preferably 0.01 to 5 mg / kg, of at least one substituted cyclohexyl-1,4-diamine derivative according to the invention are applied.
- the medicament in addition to at least one substituted cyclohexyl-1,4-diamine derivative, the medicament also preferably a further active ingredient, in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic Contains hexobarbital or halothane.
- an opioid preferably a strong opioid, in particular morphine, or an anesthetic Contains hexobarbital or halothane.
- a substituted cyclohexyl-1,4-diamine derivative according to the invention is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
- substituted cyclohexyl-1,4-diamine derivatives according to the invention can be used for the production of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain.
- Another object of the invention is therefore the use of a substituted cyclohexyl-1, 4-diamine derivative according to the invention for the manufacture of a medicament for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
- Another object of the invention is the use of a substituted cyclohexyl-1, 4-diamine derivative according to the invention for the manufacture of a medicament for the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, catalepsy, general cognitive dysfunction, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and / or drug and / or drug abuse and / or addiction, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tinitus, pruhtus, migraine, hearing loss, lack of intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhea, cachexia, urinary incontinence or as muscle incontinence , Anticonvulsant or anesthetic or for co-administration in the case of treatment with an opioid analgesic or with an anesthetic, for diuresis or antinatriuresis, anxiolysis, for modulating movement activity, for modulating neurotransmitter release and treating associated neurode
- a substituted cyclohexyl-1,4-diamine derivative used is present as a pure diastereomer and / or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
- Another object of the invention is a method for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human, which requires treatment of pain, in particular chronic pain, by administering a therapeutically viable dose of a substituted cyclohexyl-1 according to the invention , 4-diamine derivative, or a medicament according to the invention.
- Another object of the invention is a process for the preparation of the substituted cyclohexyl-1,4-diamine derivatives according to the invention as set out in the following description and examples.
- radicals R ⁇ and R ⁇ 2 have the meaning given for compounds of the formula I according to the invention for R ⁇ and R 2 and can additionally independently of one another stand for a protective group.
- the remaining radicals have the meaning given in formula I:
- the process according to the invention is preferably based on linking substituted cyclohexane-1,4-diamines (WO 02090317) with suitable carboxylic acids and / or carboxylic acid derivatives, in particular carboxylic acid chlorides or bromides, and thus converting them into compounds according to the invention.
- suitable carboxylic acids and / or carboxylic acid derivatives in particular carboxylic acid chlorides or bromides, and thus converting them into compounds according to the invention.
- polar or non-polar aprotic solvents are used, to which an organic or inorganic auxiliary base, preferably tertiary amines such as triethylamine, diisopropylethylamine or DMAP, has been added.
- an organic or inorganic auxiliary base preferably tertiary amines such as triethylamine, diisopropylethylamine or DMAP, has been added.
- pyridine for example, is also suitable as a base and as a
- Acid chlorides are preferably reacted with amines at -30 to +40 ° C. in dichloromethane or chloroform in the presence of triethylamine or pyridine and, if appropriate, catalytic amounts of DMAP.
- carboxylic acids with a substituted cyclohexane-1,4-diamine (WO 02090317)
- organic or inorganic dehydrating agents such as molecular sieve, magnesium sulfate, sulfuric acid or carbodiimides such as DCC or DIC, the latter optionally in the presence of HOBt.
- These reactions are also preferably carried out in polar or non-polar aprotic solvents at temperatures between -30 and +110 ° C, preferably -10 and +40 ° C. If necessary, the protective groups are then split off. Examples
- ether means diethyl ether, "EE” ethyl acetate and “DCM” dichloromethane.
- equivalents means equivalent amounts, "mp.” Melting point or melting range, “decomp.” Decomposition, "RT” room temperature, “abs.” absolute (anhydrous),, “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol.%” volume percent, “m%” mass percent and “M” is a concentration in mol / l.
- Table 1 lists the carboxylic acids used for the last step for the examples.
- Table 1 List of examples and illustration of the carboxylic acids used in the last synthesis step
- Example 61 4- (4-Chlorophenyl) -N- (4-dimethylamino-4-phenylcyclohexyl) -4-oxobutyramide hydrochloride, non-polar diastereoisomer
- Example 62 4- (4-chlorophenyl) -N- (4-dimethylamino-4-phenylcyclohexyl) -4-oxobutyramide hydrochloride, more polar diastereoisomer
- Example 61 As described for Example 61, 350 mg of the more polar diastereoisomer of N, N-dimethyl-1-phenylcyclohexane-1, 4-diamine, 230 ⁇ l of N, N-diisopropylcarbodiimide and 200 ⁇ g of 1-hydroxybenzotriazole (HOBt) were added with stirring 0 ° C. 310 mg of 3- (4-chlorobenzoyl) propionic acid dissolved in 1.6 ml of DMF were added. After three hours at this temperature, stirring was continued overnight while warming to room temperature.
- HOBt 1-hydroxybenzotriazole
- Example 63 350 mg of the more polar diastereoisomer of N, N-dimethyl-1-phenylcyclohexane-1, 4-diamine, 230 ⁇ l of N, N-diisopropylcarbodiimide and 200 ⁇ g of 1-hydroxybenzothazole (HOBt) were added with stirring 280 mg of 5-oxo-5-phenylpentanoyl chloride dissolved in 1.6 ml of DMF are added at 5 ° C. After three hours at this temperature, stirring was continued overnight while warming to room temperature.
- HOBt 1-hydroxybenzothazole
- the cyclohexane derivatives of the general formula I were investigated in a receptor binding assay with ⁇ H-nociceptin / orphanin FQ with membranes of recombinant CHO-ORL1 cells.
- This test system was developed according to the method described by Ardati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824) performed method presented. The concentration of ⁇ H-nociceptin / orphanin FQ was 0.5 nM in these experiments.
- the binding assays were carried out with 20 ⁇ g membrane protein each with 200 ⁇ l batch in 50 mM Hepes, pH 7.4, 10 mM MgCl 2 and 1 mM EDTA.
- Binding to the ORL1 receptor was determined using 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubating the mixture at RT for one hour and then measuring in the Trilux scintillation counter (Wallac, Finland).
- the receptor affinity for the human ⁇ -opiate receptor was determined in a homogeneous approach in microtiter plates.
- the percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor at a concentration of the test substances of 1 ⁇ mol / l was determined and indicated as a percentage inhibition (% inhibition) of the specific binding.
- Partial o the compounds to be tested of formula I IC 5 inhibitory concentrations were prepared starting from the percentage displacement by different concentrations calculated which cause a 50 percent displacement of the radioactive ligand. Ki values for the test substances were obtained by conversion using the Cheng-Prusoff relationship.
- Parenteral solution of a substituted cyclohexyl-1,4-diamine derivative according to the invention 38 g of one of the substituted cyclohexyl-1,4-diamine derivatives according to the invention, here Example 1, is dissolved in 1 liter of water for injections at room temperature and then adjusted to isotonic conditions by adding anhydrous glucose for injections.
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Abstract
Description
Claims
Priority Applications (4)
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JP2007512027A JP4896009B2 (ja) | 2004-05-10 | 2005-05-06 | オキソ置換されたシクロヘキシル−1,4−ジアミンの酸誘導体 |
CA2566210A CA2566210C (en) | 2004-05-10 | 2005-05-06 | Oxo-substituted cyclohexyl-1,4-diamine derivatives |
EP05738450.5A EP1751088B1 (de) | 2004-05-10 | 2005-05-06 | Oxosubstituierte cyclohexyl-1,4-diamin-derivate |
US11/594,952 US7476763B2 (en) | 2004-05-10 | 2006-11-09 | Oxo-substituted cyclohexyl-1,4-diamine compounds |
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DE102004023501.5 | 2004-05-10 | ||
DE102004023501A DE102004023501A1 (de) | 2004-05-10 | 2004-05-10 | Oxosubstituierte Cyclohexyl-1,4-diamin-Derivate |
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US11/594,952 Continuation US7476763B2 (en) | 2004-05-10 | 2006-11-09 | Oxo-substituted cyclohexyl-1,4-diamine compounds |
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US (1) | US7476763B2 (de) |
EP (1) | EP1751088B1 (de) |
JP (1) | JP4896009B2 (de) |
CA (1) | CA2566210C (de) |
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WO (1) | WO2005110970A1 (de) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008110351A2 (en) * | 2007-03-15 | 2008-09-18 | Dompe' Pha.R.Ma S.P.A. | Use of (r) and (s)-2-aryl-propionic acid derivatives as antiseptic agents |
WO2009118168A1 (de) | 2008-03-27 | 2009-10-01 | Grünenthal GmbH | Substituierte 4-aminocyclohexan-derivate |
US7977370B2 (en) | 2008-03-27 | 2011-07-12 | Gruenenthal Gmbh | (Hetero)aryl cyclohexane derivatives |
US8288430B2 (en) | 2008-03-27 | 2012-10-16 | Grunenthal Gmbh | Spiro(5.5)undecane derivatives |
US8288406B2 (en) | 2008-03-27 | 2012-10-16 | Gruenenthal Gmbh | Hydroxymethylcyclohexylamines |
US8293758B2 (en) | 2008-03-27 | 2012-10-23 | Grunenthal Gmbh | Substituted spirocyclic cyclohexane derivatives |
US8357705B2 (en) | 2008-03-27 | 2013-01-22 | Gruenenthal Gmbh | Substituted cyclohexyldiamines |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5304479A (en) | 1991-12-06 | 1994-04-19 | Diagnostic Reagents, Inc. | Phencyclidine compounds and assays for its determination |
WO2002090317A1 (de) | 2001-05-09 | 2002-11-14 | Grünenthal GmbH | Substituierte cyclohexan-1,4-diaminderivate |
US20030236250A1 (en) | 2000-05-19 | 2003-12-25 | Castro Pineiro Jose Luis | Cyclohexane derivatives and their use as therapeutic agents |
WO2004043899A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | 4-aminomethyl-1-aryl-cyclohexylamin-derivate |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1200072A2 (de) * | 1999-05-12 | 2002-05-02 | Solvay Pharmaceuticals B.V. | Verfahren zur behandlung von psychotischen erkrankungen |
FR2797874B1 (fr) * | 1999-08-27 | 2002-03-29 | Adir | Nouveaux derives de la pyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
ES2188344B1 (es) * | 2000-11-29 | 2004-09-16 | Laboratorios Vita, S.A. | Compuestos derivados de benzotiofeno, su procedimiento de obtencion y utilizacion de los mismos. |
US6571525B2 (en) | 2001-08-01 | 2003-06-03 | J. David Coleman | Construction block |
CA2467337A1 (en) * | 2001-12-21 | 2003-07-10 | H. Lundbeck A/S | Aminoindane derivatives as serotonin and norepinephrine uptake inhibitors |
US6818772B2 (en) * | 2002-02-22 | 2004-11-16 | Abbott Laboratories | Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor |
DE10252650A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Cyclohexyl-Harnstoff-Derivate |
DE102004023522A1 (de) * | 2004-05-10 | 2005-12-01 | Grünenthal GmbH | Substituierte Cyclohexyl-1,4-diamin-Derivate |
-
2004
- 2004-05-10 DE DE102004023501A patent/DE102004023501A1/de not_active Withdrawn
-
2005
- 2005-05-06 WO PCT/EP2005/004907 patent/WO2005110970A1/de active Application Filing
- 2005-05-06 EP EP05738450.5A patent/EP1751088B1/de active Active
- 2005-05-06 CA CA2566210A patent/CA2566210C/en not_active Expired - Fee Related
- 2005-05-06 JP JP2007512027A patent/JP4896009B2/ja not_active Expired - Fee Related
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2006
- 2006-11-09 US US11/594,952 patent/US7476763B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5304479A (en) | 1991-12-06 | 1994-04-19 | Diagnostic Reagents, Inc. | Phencyclidine compounds and assays for its determination |
US20030236250A1 (en) | 2000-05-19 | 2003-12-25 | Castro Pineiro Jose Luis | Cyclohexane derivatives and their use as therapeutic agents |
WO2002090317A1 (de) | 2001-05-09 | 2002-11-14 | Grünenthal GmbH | Substituierte cyclohexan-1,4-diaminderivate |
WO2004043899A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | 4-aminomethyl-1-aryl-cyclohexylamin-derivate |
Non-Patent Citations (3)
Title |
---|
CALO ET AL., BR.J. PHARMACOL., vol. 129, 2000, pages 1261 - 1283 |
MANABE ET AL., NATURE, vol. 394, 1997, pages 577 - 581 |
NISHI ET AL., EMBO J., vol. 16, 1997, pages 1858 - 1864 |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008110351A2 (en) * | 2007-03-15 | 2008-09-18 | Dompe' Pha.R.Ma S.P.A. | Use of (r) and (s)-2-aryl-propionic acid derivatives as antiseptic agents |
WO2008110351A3 (en) * | 2007-03-15 | 2009-04-30 | Dompe Pha R Ma Spa Res & Mfg | Use of (r) and (s)-2-aryl-propionic acid derivatives as antiseptic agents |
WO2009118168A1 (de) | 2008-03-27 | 2009-10-01 | Grünenthal GmbH | Substituierte 4-aminocyclohexan-derivate |
US7977370B2 (en) | 2008-03-27 | 2011-07-12 | Gruenenthal Gmbh | (Hetero)aryl cyclohexane derivatives |
US8288430B2 (en) | 2008-03-27 | 2012-10-16 | Grunenthal Gmbh | Spiro(5.5)undecane derivatives |
US8288406B2 (en) | 2008-03-27 | 2012-10-16 | Gruenenthal Gmbh | Hydroxymethylcyclohexylamines |
US8293758B2 (en) | 2008-03-27 | 2012-10-23 | Grunenthal Gmbh | Substituted spirocyclic cyclohexane derivatives |
EP2518052A1 (de) | 2008-03-27 | 2012-10-31 | Grünenthal GmbH | Substituierte 4-Aminocyclohexan-Derivate |
US8357705B2 (en) | 2008-03-27 | 2013-01-22 | Gruenenthal Gmbh | Substituted cyclohexyldiamines |
US8835689B2 (en) | 2008-03-27 | 2014-09-16 | Grünenthal GmbH | Substituted 4-aminocyclohexane derivatives |
US9403767B2 (en) | 2008-03-27 | 2016-08-02 | Gruenenthal Gmbh | Substituted 4-aminocyclohexane derivatives |
US9580386B2 (en) | 2008-03-27 | 2017-02-28 | Grünenthal | Substituted 4-aminocyclohexane derivatives |
Also Published As
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US20070088034A1 (en) | 2007-04-19 |
JP4896009B2 (ja) | 2012-03-14 |
EP1751088A1 (de) | 2007-02-14 |
DE102004023501A1 (de) | 2005-12-01 |
EP1751088B1 (de) | 2014-10-08 |
CA2566210A1 (en) | 2005-11-24 |
JP2007536317A (ja) | 2007-12-13 |
US7476763B2 (en) | 2009-01-13 |
CA2566210C (en) | 2013-08-27 |
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