HK1136828B - Spirocyclic cyclohexane derivatives - Google Patents
Spirocyclic cyclohexane derivatives Download PDFInfo
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- HK1136828B HK1136828B HK10103564.8A HK10103564A HK1136828B HK 1136828 B HK1136828 B HK 1136828B HK 10103564 A HK10103564 A HK 10103564A HK 1136828 B HK1136828 B HK 1136828B
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Description
The present invention relates to spirocyclic cyclohexane derivatives, methods of their manufacture, medicinal products containing these compounds and the use of spirocyclic cyclohexane derivatives in the manufacture of medicinal products.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 ((opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, p. 532-535)), which belongs to the family of opioid receptors and is found in many regions of the brain and spinal cord and has a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors and the amino acid sequence of the nociceptin peptide is very similar to that of the known opioid peptides. Activation of the receptor induced by the nociceptin via the injection of Gi/o-proteins leads to a copulatory union of the A and A proteins (Meunier et al., Nature 372, 1995, p. 535).
The nociceptin peptide has been shown to exhibit pronociceptive and hyperalgesic activity in various animal models after intercerebroventicular application (Reinscheid et al., Science 270, 1995, pp. 792-794). These findings can be explained by inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, pp. 333-337). An anxiolytic activity of nociceptin has also been demonstrated in this context (Jenck et al., Proc.
On the other hand, an antinociceptive effect of nociceptin has also been demonstrated in various animal models, particularly after intrathecal application, where nociceptin is antinociceptive in various pain models, for example in the tail flick test in the mouse (King et al., Neurosci. Lett., 223, 1997, 113-116).
The ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes, including learning and memory formation (Manabe et al., Nature, 394, 1997, p. 577-581), hearing (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and many others. An overview article by Calo et al. (Br.J. Pharmacol., 129, 2000, 1261-1283), provides an overview of the indications or biological processes in which the ORL1 receptor plays a role or is likely to play a role. These include analgesia, stimulation and regulation of the absorption of dopamine, the influence of μ-aminotransferase on the administration of morphine, the treatment of neurotoxic effects such as blood disorders, the excretion of neurotransmitters, the use of anticoagulants (especially anticoagulants), the use of anticoagulants (antimicrobials), the reduction of blood pressure, and in particular the use of anticoagulants (antimicrobials), anticoagulants (antimicrobials), anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants, anticoagulants,
The potential applications of compounds that bind to the ORL1 receptor and activate or inhibit it are therefore varied. In addition, however, opioid receptors such as the μ-receptor and the other subtypes of these opioid receptors, namely δ and κ, play a major role in pain management, and it is therefore advantageous if the compound also has an effect on these opioid receptors.
WO 2004043967 reveals spirocyclic cyclohexane derivatives that have a high affinity for the ORL1 receptor, but also for the μ-opioid receptor. WO 2004043967 also generically describes a group where R3 stands for alkyl or cycloalkyl. However, no example compounds are revealed that are part of this subgroup.
Solubility is an important property of bioavailability and a decisive factor in terms of efficacy and thus also in the success of drug development.In order to increase solubility, complex processes are used, such as the production of micro- or nanoparticles (e.g. Exp. Op. Dug Disc. 2007, 2, 145), but it is simpler and more predictable to develop compounds that have a higher solubility at the same efficacy.
A disadvantage of the sample compounds disclosed in WO 2004043967 is the low solubility of the compounds.
The purpose of the present invention was to provide medicinal products that act on the nociceptin/ORL1 receptor system and have a higher solubility than the compounds disclosed in WO 2004043967.
Surprisingly, it has now been found that certain compounds, although described generically in WO 2004043967 but not revealed by sample compounds, have a higher solubility than the sample compounds revealed there.
The invention is therefore concerned with spirocyclic cyclohexane derivatives of general formula I,
In which
R1 and R2 independently of each other for H; C1-5 alkyl, either saturated or unsaturated, branched or unbranched, simply or multiple substituted or unsubstituted; C3-8 cycloalkyl, either saturated or unsaturated, simply or multiple substituted or unsubstituted; aryl, unsubstituted or simply or multiple substituted; or aryl bound to C1-3 alkyl, C3-8 cycloalkyl or heteroaryl, either simply or multiple substituted or unsubstituted; or R1 and R2 together for CH2CH2OCH2CH2, CH2CH2CH2NR11CH2 or (CH2CH2CH2CH2) or (CH3CH2-6CH2)
R11H; C1-5 alkyl, whether or not saturated, branched or unbranched, simply or in multiple substitutions or unsubstituted; C3-8 cycloalkyl, whether or not saturated, simply or in multiple substitutions or unsubstituted; aryl,'R3' means C1-8 alkyl, whether saturated or unsaturated, branched or unbranched, simply or multiple substituted or unsubstituted;R5 means =O;H;C1-5 alkyl, saturated or unsaturated, branched or unbranched, substituted or simply or multiple substituted;C1-8 alkyl, unsaturated or unsaturated, branched or unsaturated;C1-8 alkyl, unsaturated or unsaturated, substituted or simply or multiple substituted;C1-8 alkyl, unsaturated or unsaturated, substituted or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or simple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted;C1-8 alkyl, unsatured or simple substituted;C1-8 alkyl, unsatured or simple substituted;C1 or simple substituted;C1-8 alkyl, unsatured or simple substituted;C1 alkyl, unsatured or simple substituted;C1 or simple substituted;C1-8 alkyl, unsatured;C1 or simple substituted;C1 or C1-8 alkyl, unsatured;C1 or C13, unsatured;C1-8 alkyl, unsatured;C1 or simple substitutSR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or simply or multiple substituted; C3-8 cycloalkyl, saturated or unsaturated, unsubstituted or simply or multiple substituted; aryl or heteroaryl, unsubstituted or simply or multiple substituted; or aryl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or multiple substituted, bound to C1-3 alkyl; or R5 and R6 (CHn2) together with NO = 2, 3, 4, 5 or 6 may also be substituted for each other by single hydrogen atoms, CF1, CF2, I3, C13, R18, or R97, and may be substituted for R10 or R98,
The following substances are to be classified in the same category as the active substance:SR13, SO2R13, SO2OR13, NHC(=O)NR14R15, SO2NR14R15, CN, COOR13, NR14R15; C1-5 alkyl, C3-8 cycloalkyl, unsubstituted or simply or repeatedly substituted; aryl or heteroaryl, unsubstituted or simply or repeatedly substituted; or aryl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or repeatedly substituted, bound to C1-3 alkyl, C3-8 cycloalkyl or repeatedly substituted, where R13H; C1-5 alkyl, either saturated or unsaturated, branched or unbranched, means unsubstituted, or simply or repeatedly substituted; C3-8 cycloalkyl, unsubstituted or repeatedly substituted, or unsubstituted, or unsubstituted, or simply or repeatedly substituted, or substituted, or substituted, or simply or repeatedly substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, substituted, or substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substitutedmeans branched or unbranched, unsubstituted or simply substituted; or C3-8 cycloalkyl, whether saturated or unsaturated, unsubstituted or simply substituted; aryl or heteroaryl, unsubstituted or simply or simply substituted; or aryl bound to C1-3 alkyl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or simply substituted; or R14 and R15 together form CH2CH2OCH2CH2, CH2NR2162CH2 or (CH2) 3-6 where R16 H; C1-5 cycloalkyl means unsaturated or unsaturated, branched or simply substituted, unsubstituted or simply substituted, or NR2 means SOX, or NR2 means SOX, or simply;
R17 for H; C1-5 alkyl, saturated or unsaturated, branched or unbranched; COR12 or SO2R12, where R12 is H; C1-5 alkyl, either saturated or unsaturated, branched or unbranched,Err1:Expecting ',' delimiter: line 1 column 461 (char 460)The following is added to the list of active substances:
in the form of racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomers; the bases and/or salts of physiologically compatible acids or cations,
When summing different residues, e.g. R7, R8, R9 and R10, and summing residues on their substituents, e.g. OR13, SR13, SO2R13 or COOR13, a substituent, e.g. R13, may have different meanings for two or more residues, e.g. R7, R8, R9 and R10, within a substance.
The compounds of the invention show good binding to the ORL1 receptor, but also to other opioid receptors.
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
The term (CH2) 3-6 is understood to mean -CH2-CH2-CH2, -CH2-CH2-CH2, -CH2-CH2-CH2-CH2 and CH2-CH2-CH2-CH2.
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
Err1:Expecting ',' delimiter: line 1 column 103 (char 102)
Err1:Expecting ',' delimiter: line 1 column 63 (char 62)
Err1:Expecting ',' delimiter: line 1 column 56 (char 55)
The term salt means any form of the active substance of the invention in which it takes or is charged in an ionic form and is coupled with or in solution with a antigene (a cation or anion). It also includes complexes of the active substance with other molecules and ions, in particular complexes complexed by ionic interactions. In particular, it includes (and this is also a preferred embodiment of the invention) physiologically compatible salts, in particular salts that are physiologically compatible with cations or bases and physiologically similar to anions or acids or also with a physiologically compatible acid or a physiologically compatible salt formed by a chemical reaction.
For the purposes of this invention, the term physiologically compatible salt with anions or acids means salts with at least one of the compounds of the invention - usually protonated, for example, to nitrogen - as a cation with at least one anion that is physiologically compatible, particularly when used in humans and/or mammals. In particular, for the purposes of this invention, it means the salt formed with a physiologically compatible acid, namely salts of the respective active substance with inorganic or organic acids that are physiologically compatible, particularly when used in humans and/or mammals. Examples of physiologically compatible salts of certain acids are: Hypoglycine, L-acetyl sulphate, 2-aminobutyric acid, 2-aminobutyric acid, 2-aminobutyric acid, 2-aminobutyric acid, 2-aminobutyric acid, 2-aminobutyric acid, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 3-methionine, 3-methionine, 2-methionine, 2-methionine, 2-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 2-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine, 3-methionine
For the purposes of this invention, the term salt formed from a physiologically compatible acid means salts of the active substance with inorganic or organic acids which are physiologically compatible, particularly when used in humans and/or mammals. Hydrochloride and citrate are particularly preferred. Examples of physiologically compatible acids are hydrochloric acid, hydrobromic acid, sulfuric acid, methanosulfonic acid, formic acid, acetic acid, oxalic acid, beryl stearic acid, tartaric acid, citric acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharomycin, monohydroxylic acid, 5-O-aminobenzene, 1-Hydroxybromoxybutyric acid, 2-Hydroxybutyric acid, 4-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutyric acid, 2-Hydroxybutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutylbutyl, 2-Hydroxybutylbutylbutylbutylbutylbutylbutylbutyl, 2-Hydrate, 2-Hydroxybutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutyl and 2-Hydrate, 2-Hydroxybutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutylbutyl and 2-
For the purposes of this invention, the term physiologically compatible salt with cations or bases means salts of at least one of the compounds of the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation that is physiologically compatible, especially when used in humans and/or mammals.
For the purposes of this invention, the term salt formed with a physiologically compatible cation means salts containing at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically viable, particularly when used in humans and/or mammals.
The preference shall be given to compounds of general formula I.
In which
R1 and R2 independently of each other for H; C1-5 alkyl, either saturated or unsaturated, branched or unbranched, simply or multiple substitution or unsubstituted; C3-8 cycloalkyl, either saturated or unsaturated, simply or multiple substitution or unsubstituted; Aryl, unsubstituted or simply or multiple substitution; or C1-3 alkyl-bound aryl, C3-8 cycloalkyl or heteroaryl, either simply or multiple substitution or unsubstituted; or R1 and R2 together for CH2OCH2CH2, CH2CH2CH2CH2 or (CH3-6CH, RCH11NR2); or C1-5 alkyl, either branched or unsaturated, unsaturated, unsaturated or simply or multiple substitution or unsaturated, or C3-8 cycloalkyl, or unsaturated, or simply or multiple substitution or unsaturated;'R3' means C1-8 alkyl, whether saturated or unsaturated, branched or unbranched, simply or multiple substituted or unsubstituted;R5 means =O;H;C1-5 alkyl, saturated or unsaturated, branched or unbranched, substituted or simply or multiple substituted;C1-8 alkyl, unsaturated or unsaturated, branched or unsaturated;C1-8 alkyl, unsaturated or unsaturated, substituted or simply or multiple substituted;C1-8 alkyl, unsaturated or unsaturated, substituted or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or simple substituted;C1-8 alkyl, unsaturated or multiple substituted;C1-8 alkyl, unsaturated or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted or simple substituted;C1-8 alkyl, unsaturated or simple substituted;C1-8 alkyl, unsatured or simple substituted;C1-8 alkyl, unsatured or simple substituted;C1 or simple substituted;C1-8 alkyl, unsatured or simple substituted;C1 alkyl, unsatured or simple substituted;C1 or simple substituted;C1-8 alkyl, unsatured;C1 or simple substituted;C1 or C1-8 alkyl, unsatured;C1 or C13, unsatured;C1-8 alkyl, unsatured;C1 or simple substitutSR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or simply or multiple substituted; C3-8 cycloalkyl, saturated or unsaturated, unsubstituted or simply or multiple substituted; Aryl or heteroaryl, unsubstituted or simply or multiple substituted; or Aryl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or multiple substituted, bound to C1-3 alkyl; or R5 and R6 (CHn2) together with NO = 2, 3, 4, 5 or 6 or with NO = n, and may also be composed of single hydrogen atoms, CF1, CF2, CF3, CF1, CF3, CF1, CF3, R1, CF3, R1, CF3, R1, CF3, R1, CF3, R1, R1, CF3, R1, R1, R1, R1, R1, R3, R1, R1, R1, R3, R1, R1, R1, R2, R3, R3, R3, R3, R3, R3, R3, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, R4, RSR13, SO2R13, SO2OR13, NHC(=O)NR14R15, SO2NR14R15, CN, COOR13,NR14R15; C1-5 alkyl, C3-8 cycloalkyl, unsubstituted or simply or repeatedly substituted; aryl or heteroaryl, unsubstituted or simply or repeatedly substituted; or aryl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or repeatedly substituted, bound to C1-3 alkyl, C3-8 cycloalkyl or repeatedly substituted, where R13H; C1-5 alkyl, either saturated or unsaturated, branched or unbranched, means unsubstituted, or simply or repeatedly substituted; C3-8 cycloalkyl, unsubstituted or repeatedly substituted, or unsubstituted, or unsubstituted, or simply or repeatedly substituted, or substituted, or substituted, or simply or repeatedly substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, or substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted, substituted,means branched or unbranched, unsubstituted or simply substituted; or C3-8 cycloalkyl, whether saturated or unsaturated, unsubstituted or simply substituted; aryl or heteroaryl, unsubstituted or simply or simply substituted; or aryl bound to C1-3 alkyl, C3-8 cycloalkyl or heteroaryl, unsubstituted or simply or simply substituted; or R14 and R15 together form CH2CH2OCH2CH2, CH2NR2162CH2 or (CH2) 3-6, where R16 H; C1-5 cycloalkyl means unsaturated or unsaturated, branched or simply substituted, unsubstituted or unsubstituted, or S1X-5 or C1X-117 or C1X-112 or C1X-117 or C1X-112 or C1X-112 or C1X-117 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112 or C1X-112; orErr1:Expecting ',' delimiter: line 1 column 461 (char 460)Diastereomers, mixtures of the enantiomers or diastereomers or of a single enantiomer or diastereomers; bases and/or salts of physiologically compatible acids or cations, except the compound 2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(1'H) pyrido[3,4-b]indol]-4-amine.
For a preferred embodiment of the spirocyclic cyclohexane derivatives of the invention, the following shall apply:
R1 and R2 are independently of each other H, C1-8 alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or simply or repeatedly substituted, or phenyl or benzyl, unsubstituted or simply or repeatedly substituted,
or together they represent a ring and mean (CH2) 3-6,
In particular:
R1 and R2 stand independently for H, methyl, ethyl, n-propyl, or together for -CH2CH2CH2- or -CH2CH2CH2-, preferably with only one of the residues R1 and R2 meaning H.
In particular, R1 and R2 are preferably independent of each other for H, CH3 or C2H5, with not both residues R1 and R2 being H,
or R1 and R2 form a ring and stand for -CH2CH2CH2- or -CH2CH2CH2-.
In particular, R1 and R2 are preferred for H or CH3, where R1 and R2 do not mean CH3 at the same time, especially for CH3.
The preferred product is also spirocyclic cyclohexane derivatives of the general formula I, wherein
R3 stands for ethyl, n-propyl, 2-propyl, allyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, whether or not substituted or simply or multiple substituted with OH, OCH3 or OC2H5.
In particular:
R3 stands for ethyl, n-propyl, 2-propyl, allyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, each unsubstituted or simply or repeatedly substituted with OH, OCH3 or OC2H5.
In particular, preference shall be given to substituted cyclohexane derivatives of the general formula I, where R3 means ethyl, n-propyl or n-butyl, unsubstituted or simply or repeatedly substituted with OCH3, OH or OC2H5, in particular OCH3.
For a preferred embodiment of the spirocyclic cyclohexane derivatives of the invention, the following shall apply:
The remainder R5 is H, CH3, COOH, COOCH3, or CH2OH.
Particularly preferred are substituted cyclohexane derivatives, where R5 stands for H.
Preferably, substitution cyclohexanderivatives of the general formula I, where R6H may mean methyl, ethyl, CF3, benzyl or phenyl, where the benzyl or phenyl residue may be replaced by F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3) 2.
Especially preferred are spirocyclic cyclohexane derivatives, where R6 stands for H.
Preferably, spirocyclic cyclohexane derivatives, where R7 R8, R9 and R10 are independently H; C1-8 alkyl, branched or unbranched, unsubstituted or single or multiple substituted; F, Cl, Br, I, CF3, OH, OCH3, NH2, COOH, COOCH3, NHCH3 Thienyl, pyrimidinyl, pyridinyl, NCH3) 2 or NO2
preferably
R7 R8, R9 and R10 for H; C1-8 alkyl, branched or unbranched, unsubstituted or single or multiple substituted; F, Cl, Br, I, OH, OCH3, COOH, COOCH3, NH2, NHCH3 or N(CH3) 2 or NO2, whereas the remaining residues are H,
or
two of the residues R7 R8, R9 and R10 are independently of each other for H; C1-5 alkyl, branched or unbranched, unsubstituted or single or multiple substituted; F, Cl, Br, I, OH, OCH3, COOH, COOCH3, NH2, NHCH3 or N(CH3) 2 or NO2 while the remaining residues are H.
Particularly preferred are spirocyclic cyclohexane derivatives, where R7 stands for R8, R9 and R10 for H, F, OH, Cl or OCH3.
Compounds with X for O are particularly favoured, and compounds of general formula I, where X stands for NR17, are particularly favoured.
The preferred is spirocyclic cyclohexane derivatives, wherein R17 COR12 and R12 H; C1-5 alkyl; C3-8 cycloalkyl; or C1-3 alkyl bound aryl, C3-8 cycloalkyl or heteroaryl, either simply or multiple times substituted or unsubstituted; NR14R15 means
in particular R12 H; benzyl, phenethyl, phenethenyl; whether or not substituted with OCH3; means CH3, 2,2-dimethylpropyl or cyclopentyl.
The most preferred compounds are:
The term 'methyl methacrylate' means a compound containing a compound with a high molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a high molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a low molecular weight, a high molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, a low molecular weight, etc.
where appropriate, as a mixture.
The substances of the invention, for example, act on the ORL1 receptor relevant for various diseases, making them suitable as pharmaceutical active substances in a medicinal product.
The medicinal products of the invention contain, in addition to at least one spirocyclic cyclohexane derivative of the invention, suitable additives and/or excipients, as appropriate, as well as carrier materials, fillers, solvents, diluents, dyes and/or binders, and may be administered as liquid forms in the form of solutions for injection, drops or juices, as semi-solid forms in the form of granules, tablets, pellets, patches, capsules, pills/spray sprays or aerosols. The specific characteristics of the excipients, as well as the degree of recycling of the granules, depend on whether the product is sprayed, whether or not it is intended for oral administration, or for intra-venous administration. The medicinal products of the invention, known as Cyclohexan, can be administered in the form of tablets, tablets, pellets, patches, capsules, or other preparations, such as intra-cutaneous or intra-ocular injections, or in the form of oral or intramuscular injections.
The dose to be administered to the patient will vary according to the patient' s weight, type of application, indication and severity of the disease, usually 0.00005 to 50 mg/kg, preferably 0.001 to 0.5 mg/kg, of at least one spirocyclic cyclohexane derivative of the invention.
A spirocyclic cyclohexane derivative of the invention is present in a preferred form of the medicinal product as a pure diastereomer and/ or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and/ or enantiomers.
As can be seen in the introduction to the state of the art, the ORL1 receptor has been identified in pain in particular, and therefore spirocyclic cyclohexane derivatives of the invention can be used to manufacture a medicinal product for the treatment of pain, in particular acute, neuropathic or chronic pain.
Therefore, another subject matter of the invention is the use of a spirocyclic cyclohexane derivative of the invention to manufacture a medicinal product for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
Another subject matter of the invention is the use of a spirocyclic cyclohexane derivative of the invention to manufacture a medicinal product for 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), disorders, alcohol and/ or drug and/ or drug abuse and/ or dependence, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tincture, pruritus, migraine, difficulty hearing, insufficient bowel movements, anti-inflammatory drug use, analgesic analgesics, anti-retroviral drugs, diuretics, diuretics, to treat mood disorders or neurological disorders, and/or to treat narcolepsy, narcolepsy, and/or narcolepsy, and/or to treat narcolepsy with a drug or other drug, or to treat narcolepsy, narcolepsy, and/or narcolepsy, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to reduce the sensitivity to narcotic drugs, or to narcotic drugs.
It may be preferred in one of the above uses if a spirocyclic cyclohexane derivative is used as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.
The invention also relates to a procedure for the treatment, in particular in one of the above indications, of a non-human mammal or human being requiring the treatment of pain, in particular chronic pain, by the administration of a therapeutically active dose of a spirocyclic cyclohexane derivative of the invention or of a medicinal product of the invention.
Another subject of the invention is a process for the production of the spirocyclic cyclohexane derivatives of the invention as described and illustrated below, in particular a process for the production of a spirocyclic cyclohexane derivative of the invention by translating a cyclohexane underivative of the general formula E into an inderivative of the general formula F or H.
Other
Tryptopholes of type F (Y = O) may be reacted in reactions of the Oxa-Pictet Spengler type and tryptamines of type H in reactions of the Pictet Spengler type with ketones, with the addition of at least one suitable reagent from the group of acids, acid anhydrides, esters or weakly acidic salts or leucine acids, to form products of formula I. For X = SH, the reaction is carried out in an analogous manner.
Preferably, at least one reagent from the group of carbonic acids, phosphoric acids or sulphonic acids or their respective anhydrides, carbonic tri-ethylsyl esters, acid-reactive salts, mineral acids or leucic acids selected from the group consisting of boron trifluoride, indium (III) chloride, titanium tetrachloride, aluminium (III) chloride, or with the addition of at least one transition metal salt,preferably with the addition of at least one transition metal triflate (transition metal trifluoromethane sulphonate), preferably in particular with the addition of at least one transition metal trifluoromethane sulphonate selected from the group consisting of scandium ((III) trifluoromethane sulphonate, ytterbium (III)) trifluoromethane sulphonate and indium (III)) trifluoromethane sulphonate, if applicable with the addition of cellite, with fixed phase reactants or reagents, at elevated or lowered temperature, with or without microwave irradiation, if appropriate in an appropriate solvent or solvent such as chlorinated or unchlorinated, preferably in aromatic solvents, hydrophobic solvents, ethylene or nitrites; in case of diethylene, also in aqueous or aqueous solutions, preferably in acrylic acids, or in case of diethylene, suitable for use in water;
In particular, preference shall be given to pyridinium para-toluol sulphonate, phosphorus pentoxide in the presence of celite, boron trifluoride etherate, trifluoric acid, orthotitan tetrazine propyl ester together with trifluoric acid, trifluoromethan sulphonic urethyl silyl ester, trifluoromethan sulphonic acid, methan sulphonic acid, trifluoric acid, acetic acid,Phosphoric acid, polyphosphoric acid, polyphosphatesters, p-toluol sulphonic acid, hydrochloric acid HCl gas, sulphuric acid together with acetate buffer, tin tetrachloride, used.
Secondary amines of type I can be acylated, sulphonylated or carbamoylated to L/M/N compounds by known techniques, preferably at elevated temperatures, preferably under microwave irradiation.
Such a method, known to the professional, may be the implementation with an anhydride or an acid chloride with the addition of a base, e.g. triethylamine.
Compounds of formula E can be released from corresponding acetals C or their salts D by means of acid clearance methods known to the expert, X being selected from the group of alkyl, alkyl/alkylide/ with aryl or alkyl (saturated/unsaturated) substituted alkylide
Amino acetals Cb with up to one substituent at the nitrogen atom can be converted by methods known to the skilled person, e.g. by reductive amination, into corresponding amino acetals Ca with one or two additional substituents at the nitrogen.
Other
Amino acetals Cb with up to one substituent on the nitrogen atom can be obtained by adding carbon nucleophiles to imine Q by the method known to the expert, preferably organometallic compounds in inert solvents, especially preferably with Grignard reagents or organolithium compounds, preferably in ethers, preferably at temperatures from - 100 to room temperature.
Amino acetals C with two substituents on the nitrogen atom can also be obtained by adding carbon nucleophiles to salts of enamines Qa, preferably with organometallic compounds in inert solvents, by methods known to the skilled.
The production of imines is known from the literature.
Other
Acetals C can also 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 aminonitryl B with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at room temperature.
Another particularly preferred route to compounds of structure C is the conversion of aminotriazoles B with corresponding organometallic compounds, preferably Grignard compounds, preferably in ethers, preferably at room temperature.
The organometallic compounds are either available on the market or can be produced by methods known in the literature.
Other
Structures of formula B can be produced by reaction of ketones A with amines and acid reactants Z-H. Suitable reactants Z-H are e.g. hydrogen cyanide, 1,2,3-triazole, benzotriazole or pyrazol.
A particularly preferred route to compounds of structure B is the conversion of ketones with metal cyanides and the corresponding amine in the presence of acid, preferably in an alcohol, at temperatures of - 40 to 60 °C, preferably at room temperature with alkali metal cyanides in methanol.
Another particularly preferred route to compounds of structure B is the conversion of ketones with 1,2,3-triazole and the corresponding amine under water-repellent conditions, preferably using a water separator at elevated temperature in an inert solvent or using molesieb or another drying agent.
The following citations are particularly relevant: Jirkovsky et al., J. Heterocycl. Chem., 12, 1975, 937-940; Lett et al., J. Chem. Soc. Perkin 1, 1992, 813-822; Shinada et al., Tetrahedron Lett., 39, 1996, 7099-7102; Garden et al., Tetrahedron, 58, 2002, 8399-8412; Lednicer et al., J. Med., 23, 1980, 424-430; Chemini et al., J. Org. Chem., 67, 15; 5386-5389; Davis et al., J. Med., 31, 31, 27, 27, 27, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29, 29,
The solubility studies were carried out on five compounds of the invention and five sample compounds, and data were collected on a series of compounds which, apart from the rest of R3, have a high degree of similarity to ensure comparability.
It was found that compounds that carry an alkyl residue at R3 are significantly more soluble than compounds that carry a phenyl or thienyl residue at R3. Surprisingly, this structural variation causes an increase in solubility. The introduction of an OH group at R8, a typical derivation (metabolization) performed by the living organism to increase solubility to eliminate a compound via the kidney, did not result in a comparable increase in solubility (compounds V-4 and V-5).
The following examples are intended to explain the invention in more detail but do not limit the general idea of the invention.
The yields of the compounds produced are not optimized.
All temperatures are uncorrected.
Err1:Expecting ',' delimiter: line 1 column 54 (char 53)
The stationary phase for column chromatography was silica gel 60 (0.040 - 0.063 mm) from E. Merck, Darmstadt.
The thin-film chromatographic studies were carried out with HPTLC-prepared plates, silica gel 60 F 254, by E. Merck, Darmstadt.
The mixing ratios of the reagents used for chromatographic examinations are always given in terms of volume.
A mixture of 4N hydrochloric acid (50 ml) and methanol (30 ml) was added to a mixture of dimethylamine solution (116 ml, 0.92 mol), cyclohexane-1,4-dione-monoethylene ketal (30.0 g, 0.192 mol) and potassium cyanide (30.0 g, 0.46 mol) by freezing. The mixture was stirred at room temperature for 72 h and then extracted after adding water (80 ml) with ether (4 x 100 ml). After narrowing the solution, the residue was absorbed in dichloromethane (200 ml) and dried overnight with magnesium ketone sulphate. The organic phase was closed and the B-1 white solid was obtained.
The yield is 38.9 g (96%)
The melting point is 86-88°C.
The mean value of the dose of the active substance is calculated as the following:
The maximum residue levels for the active substance are:
A mixture of 4 N hydrochloric acid (15 ml, 60 mmol) and methanol (10 ml) was first given, under freezing, ethylmethylamine (16.0 g, 23 ml, 262 mmol) and water (10 ml), followed by 1,4-Dioxaspiro[4.5]deca-8-on (9.40 g, 60 mmol) and potassium cyanide (9.20 g, 141 mmol). The reaction mixture was stirred for 5 days at room temperature.
Production: 10.8 g (80%) of yellow oil
The mean value of the measurements performed was 1.04 (t, 3H, J = 7.1 Hz); 1.50-1.59 (m, 2H); 1.68-1.77 (m, 2H); 1.89-1.95 (m, 2H); 1.98-2.06 (m, 2H); 2.23 (s, 3H); 2.42-2.48 (m, 2H, superimposed by the DMSO signal); 3.87 (s, 4H).
This component was obtained instead of the target product, and it is obvious that D-1 can also be produced specifically from erthylmagnesium bromide and B-1.
After the grinding was completed, the grey solution was transferred to THF (80 ml) at 0 °C for 15 min with aminonitrile B-1 (10.5 g, 47.6 mmol) and stirred overnight at room temperature. The reaction solution was then transferred to ice-cooled with 20 ml of ammonium chloride (50 ml) solution and water (50 ml). The reaction solution was diluted with diethyl ether (100 ml) which was separated and the org. was removed. Phase 2 was frozen with phenylethylamine (100 ml) solution at 0 °C. The reaction solution was removed with water (50 ml) and added to the air and removed with 2 ml of i-Cl and i-Cl.
The yield is 6.8 g (64%), light brown solid
The mean value of 1H (DMSO-d6) is 0.94 (3 H, t); 1.51-1.60 (2 H, m); 1.77-1.86 (8 H, m); 2.64 (6 H, 2 s); 3.83-3.89 (4 H, m).
The hydrochloride D-1 (6.67 g, 0.026 mmol) was dissolved in 6N HCl (40 ml) and stirred overnight at room temperature. The reaction mixture was extracted twice with diethylether (100 ml). The reaction mixture was then made alkaline with 5N NaOH under ice cooling and extracted again three times with Et2O (100 ml). The combined org. phases were dried using NaSO4, filtered and the solvent i.
Production: 4.16 g (92%) of brown oil
The mean value of 1H (DMSO-d6) is 0.81 (3 H, t); 1.43-1.50 (2 H, q); 1.67-1.89 (2 H, m); 1.83-1.89 (2 H, m); 1.99-2.06 (2 H, m); 2.22 (6 H, 2 s); 2.39-2.43 (4 H, m).
The following information is provided in the summary of the product characteristics and the manufacturer's specifications:
8-Dimethylamino-1,4-dioxa-spiro[4.5]decan-8-carbonitrile B-1 (10.5 g, 50 mmol) was presented in THF (150 ml) under ice and argon.
The solution was reconstituted with a 20% ammonium chloride solution (37 ml) and water (50 ml) and extracted with ether (3 x 50 ml) by freezing. The org phase was washed with water (1 x 50 ml) and saturated sodium chloride solution (1 x 50 ml), the organic phase was dried with Na2SO4 and compressed in a vacuum. The raw product (2.05 g) was dissolved in ethyl methyl ketone (75 ml), cooled in ClMe3 (9.5 ml, 75 mmol) and stirred at room temperature for 6 h. The white precipitate was sucked out and vacuum dried.
Production: 3.1 g (22%)
The mean value of the 1H-NMR (DMSO-d6) is 0.91 (3 H, t); 1.31 (4 H, m); 1.56 (2 H, m); 1.75 (8 H, m); 2.64 (6 H, s); 3.87 (4 H, s); 9.87 (1 H, s).
8-Butyl-1,4-dioxa-spiro[4.5]dec-8-yl) -dimethyl-amine hydrochloride D-2 (3.10 g, 11.1 mmol) was presented in H2O (4.7 ml) and concentrated HCl (7 ml) and stirred at room temperature for 24 h. The solution was extracted with ether (1 x 15 ml), the aqueous phase was alkalized with 5N NaOH under ice cooling and extracted with dichloromethane (3 x 20 ml).
Production: 1.96 g (89%) and oil
The mean value of the 1H-NMR (DMSO-d6) is 0.88 (3 H, t); 1.23 (4 H, m); 1.40 (2 H, m); 1.68 (2 H, m); 1.91 (2 H, m); 2.31 (2 H, m); 2.22 (6 H, s); 2.42 (2 H, m).
The following information is provided in the summary of the information provided by the Authority:
A solution of aminonitrile B-1 (38.3 g, 0.182 mol) in tetrahydrofuran (420 ml) was slowly added to a solution of aminonitrile B-1 (38.3 g, 0.182 mol) in a solution of ammonium chloride (420 ml) under an ice-cooled mixture of table salt, slowly added to a solution of 2 M n-butylmagnesium chloride in THF (228 ml, 0.456 mol) under argon, and the reaction temperature was not to rise above 10 °C. The reaction mixture was then stirred at room temperature for 16 h to produce a clear brown solution. To process the reaction mixture, saturated ammonium chloride (150 ml) was added under ice-cooled (0 to 10 °C) and a white solid was formed, which was dissolved by the addition of water (250 ml of hydrochloric acid). The reaction product was dissolved in water (42 ml) of nitrile diethyl chloride (100 ml) (42 ml) by means of a dilute solution of hydrochloric acid (225 ml) and was then removed from the mixture by extraction of water (42 ml) of hydrochloric acid (224 ml) and dissolved in a dry phase at room temperature. The product was then removed from the mixture by extraction of water (42 ml) and dissolved in a white liquid.
The hydrochloride D-2 (41.8 g, 0.15 mmol) was dissolved in water (78 ml) and stirred and iced with 37% hydrochloric acid (100 ml, 1.2 mol). The clear reaction mixture was stirred at room temperature for 7 days. After completion of hydrolysis, the reaction mixture was extracted with diethyl ether (2 × 70 ml). The organic extracts were discarded. The aqueous phase was made alkaline (about 250 ml) and stirred vigorously under ice-cooling with 5N natron ketone. The solution was extracted with diethyl ether (3 × 100 ml). The combined organic extracts were washed with water (2 × 70 ml) and dried, dried and e-ketone. The ketone was obtained as a clear green extract of 96 % (28.4%) of the ketone in a 75-24% -percent solution at the first step.
Sodium hydride (24.0 g, 1.0 mol) and lodomethane (142 g, 1.0 mol) were presented in 350 ml of THF. Under argon and ice cooling, a solution of 4-chlorobutan-1-ol (54 g, 0.5 mol) was dripped into 50 ml of THF within 1.5 h, resulting in slight gas formation.
The organic phase was separated, dried with Na2SO4 and the drying agent filtered.
The organic phase was distilled at normal pressure.
The boiling point is 150-162 °C.
The yield is 10.4 g (17%)
The mean value of the 1H-NMR (DMSO-d6) is 1.93 (2 H, m); 3.23 (3 H; s); 3.44 (2 H, t); 3.66 (2 H, t).
Magnesium (1.62 g, 66.8 mmol) and I2 in abs diethylether (25 ml) were added to abs ether (12 ml) under argon atmosphere and temporary heating with a solution of 1-Chlor-4-methoxy-butan (8.19 g, 66.8 mmol) and stirred for 1 h under reflux until the magnesium was largely dissolved.
The solution was then frozen for 24 hours at room temperature, then put under ice with NH4Cl solution (20% solution, 80 ml) and water (100 ml), the organic phase was separated and the aqueous phase was extracted with ether (3 x 100 ml).
The combined organic phases were washed with saturated NaCl solution (80 ml) and water (80 ml), dried with Na2SO4 and compressed i.v.
The raw product was purified by flash chromatography with chloroform/methanol (50:1 ⇒ 20:1 ⇒ 9:1).
Production: 6.44 g (59%) of yellow oil
The following information is provided in the summary of the information provided by the Authority and the Authority.
The [8- ((4-Methoxy-butyl) - 1,4-dioxa-spiro[4.5]dec-8-yl]-dimethyl amine (C-3) (6.44 g, 23.7 mmol) was dissolved in water (9.3 ml), mixed with HCl (14.6 ml) and stirred at room temperature 4 d.
The reaction mixture was washed with ether (2 x 50 ml), the solution was then alkalinized with 5N NaOH and extracted with dichloromethane (3 x 50 ml), the combined organic phases were washed with water (50 ml), dried with Na2SO4, filtered and the solvent i.V. removed.
Production: 4.91 g (91%) of yellow oil
The following information is provided in the summary of the product characteristics and the manufacturer's specifications:
3-Methoxypropan-1-ol (47.1 g, 50 ml, 0.523 mol) was dissolved in pyridine (41.3 g, 42.6 ml, 0.523 mol), cooled to 10 °C and dripped with thionyl chloride (93.3 g, 56.9 ml, 0.784 mol) at 10-30 °C under vigorous stirring, with a steady precipitation and stirring for 3 hours at 65 °C.
The solution was poured on a mixture of ice (130 g) and concentrated HCl (26 ml). The aqueous solution was extracted with ether (2 x 20 ml) and the combined organic phases were washed with K2CO3 solution.
The desiccant was filtered and the organic phase was washed with K2CO3 solution until the alkaline reaction, the organic phase was separated, washed with water and dried over K2CO3, filtered and distilled at normal pressure.
The boiling point is 113 °C.
The yield is 41.2 g (72%) of colourless liquid
The mean value of the 1H-NMR (DMSO-d6) is 1.93 (2 H, m); 3.23 (3 H; s); 3.44 (2 H, t); 3.66 (2 H, t).
Magnesium (10.0 g, 92 mmol) and I2 in abs diethyl ether (30 ml) were transferred to abs ether (15 ml) by drip treatment of 1-Chlor-3-methoxypropane (10.0 g, 92 mmol) in an argon atmosphere and temporary heating, and the solution was stirred for 60 min under reflux, after which the magnesium was not completely dissolved.
A solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decan-8-carbonitrile B-1 (9.68 g, 46 mmol) was dripped into 30 ml of THF by freezing. A heavy precipitation was produced and 100 ml of THF was allowed to pass through to improve mixing. The mixture was stirred at room temperature for 24 h. The solution was put under freezing with a 20% NH4Cl solution (100 ml) and water (120 ml),the organic phase was separated and the aqueous phase was extracted with ether (3 x 120 ml).
The combined organic phases were washed with saturated NaCl solution (120 ml) and water (120 ml), dried with Na2SO4 and pressed in 1 ml.
9.8 g of raw product were purified by flash chromatography with CHCl3/MeOH (50:1 ⇒ 20:1 ⇒ 9:1).
Production: 8.11 g (75%) of yellow oil
The mean value of the 1H-NMR (DMSO-d6) is 1.44 (8 H, m); 1.62 (4 H, m); 2.25 (6 H, s); 3.21 (3 H, s); 3.31 (2 H, m); 3.82 (4 H, s).
The following information is provided in the summary of the product characteristics and the manufacturer's specifications:
The amine C-4 (8.11 g, 31.5 mmol) was dissolved in water (12 ml), put under ice cooling with concentrated HCl (19.5 ml) and stirred for 3 days at room temperature. The reaction mixture was washed with ether (2 x 75 ml). The solution was then alkaline with 5N NaOH and extracted with dichloromethane (3 x 75 ml). The combined organic phases were washed with water (75 ml), dried with Na2SO4, filtered and the solvent was removed in the vacuum.
Production: 6.03 g (90%) of yellow oil
The mean value of the dose of the active substance is 1.44 (4 h, m); 1.68 (2 h, m); 1.88 (2 h, m); 2.00 (1 h, m); 2.05 (1 h, m); 2.20 (6 h, s); 2.41 (2 h, m); 3.22 (3 h, s); 3.28 (2 h, m).
The following information is provided in the summary of the product characteristics and the data to be collected:
For a solution of aminonitryl B-1 (10.5 g, 50 mmol) in abst. THF (150 ml), 2M cyclohexyl magnesium chloride solution in ether (62.5 ml, 125 mmol) was dripped at 5-10 °C for 15 min under argon and ice cooling and then stirred at room temperature overnight. To prepare the reaction mixture, 20 per cent ammonium chloride solution (50 ml) and water (50 ml) were added under ice cooling and extracted with ether (3 x 100 ml). The organic phase was washed with sodium chloride solution saturated with water, dried with sodium sulphate and i.e. vacuum cleaned. The residual bleach was then reduced by flash chromatography (20/OHCl) with CHCl.
Production: 1.18 g (9%) of colourless oil
The mean value of the dose of the active substance is calculated as follows:
After completion of hydrolysis, the reaction mixture was extracted with ether (2 x 10 ml), the aqueous solution was alkalized by 5N sodium chloride ice cooling, the reaction mixture was extracted with dichloromethane (3 x 20 ml), the organic phase was dried with sodium sulphate and i.i. vacuum condensed. The raw material (637 mg) was purified by flash product chromatography with CHCl3/OH (9:1) Me.
Production: 366 mg (37%) of colourless oil
The mean value of the dose of the active substance is 1.08 (5 H, m); 1.68 (8 H, m); 1.99 (4 H, m); 2.29 (2 H, s), 2.41 (6 H, s).
A solution of aminonitryl B-1 (10.5 g, 50 mmol) in abst. THF (150 ml) was dripped into ether (62.5 ml, 125 mmol) for 15 min under argon and ice, 2M cyclopentylmagnesium bromide solution in ether (62.5 ml, 125 mmol) at 5-10 °C and then stirred at room temperature for 72 h. To prepare the reaction mixture, 20% ammonium chloride solution (50 ml) and water (50 ml) were added under ice and extracted with ether (3 x 100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried with sodium sulphate and i. e. e. e. e. The remaining vacuum was narrowed by flash chromatography with CHOHCl3/Me (40:1): CHOHCl3/Me (20:1) separated by a separate chromatograph with a further product, which was not yet obtained.
Production: 692 mg (5%) of colourless oil
The mean value of the dose of the active substance is 1.23 (2 H, m); 1.46 (9 H, m); 1.69 (4 H, m); 2.04 (1 H, m); 2.23 (6 H. s); 3.86 (4 H, s).
The C-6 (0.68 g, 2.68 mmol) ketal was diluted with 6 N hydrochloric acid (5 ml) and stirred overnight at room temperature. After completion of hydrolysis, the reaction mixture was extracted with ether (2 x 20 ml), the aqueous solution was made alkaline by 5 N sodium salts, extracted with dichloromethane (3 x 10 ml), the organic phase was dried with sodium sulphate and compressed i.v.
Production: 424 mg (76%) of colourless oil
The mean value of the dose of the active substance is 1.28 (2 H, m); 1.54 (8 H, m); 1.99 (4 H, m); 2.14 (1 H, m); 2.29 (6 H, s).
The following information is provided in the Annex to Regulation (EC) No 1831/2003:
A solution of B-2 (3.50 g, 15.6 mmol) in tetrahydrofuran (50 ml) was dripped at 0 °C under argon to a 2 M solution of butylmagnesium chloride in tetrahydrofuran (20 ml, 40 mmol) and stirred overnight at room temperature. The reaction mixture was then gently mixed with saturated ammonium chloride (60 ml) under ice-cooling, the pH corrected to 10 with baking soda and extracted with diethyl ether (3 × 50 ml). The combined organic phases were dried with sodium sulphate and vacuum-sealed.
The raw product was re-sold without refining.
A solution of C-7 (4.43 g, 17.3 mmol) in acetone (15 ml) was first diluted with water (2.5 ml) and then with concentrated hydrochloric acid (2.5 ml) and stirred over the weekend at room temperature.
Production: 2.08 g (57%) of yellow oil
The mean value of the dose for each dose is calculated by dividing the dose by the mean value of the dose for each dose.
A solution of 1,4-dioxaspiro[4,5]decan-8-on (3.9 g, 25 mmol), N-benzylmethylamine (3.32 g, 3.54 ml, 27.5 mmol) and 1,2,3 triazole (2.07 g, 30 mmol) in toluene (40 ml) was heated for 8 h at the Dean-Stark backflow separator and, after cooling to room temperature, the reaction solution was injected directly into the mixture.
The reaction solution of benzylmethyl[8-(4H-[1,2,3]triazine-1-yl)-1,4-dioxaspiro[4.5]dec-8-yl]amine (20 ml, approximately 25 mmol) was dripped at 0 °C under an argon stream into a 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (50 ml, 100 mmol). The mixture was heated to room temperature and stirred for 2 h and then poured into saturated ammonium chloride solution (60 ml). The phases were separated, the aqueous was extracted with diethyl ether (3 30 ml), the combined organic phases with sodium sulphate and i.e. vacuum. The raw product was pressed into dichloromethane, the insoluble parts were pressed into a cylinder (46 × 7 cm) and then cleaned with the ethanol filter (e.g. 7 × 20 cm) and the rest of the vacuum filter (e.g. 7.6 × 7.6 cm) and vacuum cleaned with the ethanol filter (e.g.
Production: 3.4 g (43% over two stages), colourless oil
The mean value of the measurements performed was 1.75 to 1.75 Hz (dMSO-d6): 0.90 (t, 3H, J = 6.8 Hz); 1.18 to 1.33 (m, 4H); 1.36 to 1.47 (m, 4H); 1.51-1.59 (m, 2H); 1.70 to 1.93 (m, 4H); 2.03 (3 H, s); 3.57 (s, 2H); 3.85 (s, 4H); 7.15 to 7.25 (m, 1 H); 7.27 to 7.36 (m, 4 H).
A solution of D-8 (3.40 g, 10.7 mmol) in acetone (70 ml) was mixed with water (10 ml) and 37% hydrochloric acid (14.1 ml) and stirred at room temperature for 5.5 h. Then a slowly saturated potassium carbonate solution was dripped onto the mixture until pH 10 was reached. The mixture was extracted with diethyl ether (4 × 40 ml), the combined organic phases were dried with sodium sulphate and vacuum-pressed.
yield: 2.3 g (74%) yellowish oil
The mean value of the measurements of the 1H-NMR (DMSO-d6) is 0.91 (t, 3H, J = 6.74 Hz); 1.20-1.37 (m, 5H); 1.48-1.59 (m, 2H); 1.78 (dt, 2H, J = 13.7 and 5.5 Hz); 2.00-2.17 (m, 4H); 2.09 (s, 3H); 2.50-2.60 (m, 1H); 3.66 (s, 2H); 7.12-7.26 (m, 1H); 7.26-7.38 (m, 4H).
To make a solution of 1,4-Dioxaspiro[4.5]decan-8-on (10.0 g, 64 mmol) in dichloromethane (100 ml), molysib 4 Å (20 g) and 4-methoxybenzylamine (11.8 g, 83 mmol) were added.
The mean value of the measurements performed was 1.81 (t, J = 6.3 Hz, 2H); 1.89 (t, J = 6.3 Hz, 2H); 2.50 (t, J = 6.3 Hz, 4H); 3.74 (s, 3H); 3.95 (s, 4H); 4.45 (s, 2H); 6.83 (d, J = 8.6 Hz, 2H); 7.18 (d, J = 8.6 Hz, 2H).
The maximum residue levels for the active substance in the feed additive and the active substance in the feed additive and the active substance in the feed additive shall be established on the basis of the following formula:
For the solution of 1,4-Dioxaspiro[4.5]dec-8-ylide) -(4-methoxybenzyl) amine (17.6 g, 64 mmol) in dichloromethane (120 ml), a 1 M solution of allylmagnesium bromide (100 ml, 100 mmol) was dripped in diethyl ether and the reaction mixture stirred at room temperature for 4 h. The mixture was then poured on a saturated ammonium chloride solution (100 ml) under ice cooling and extracted with dichloromethane (3 × 40 ml). The combined organic phases were compacted with sodium sulphate and i.i. vacuum-treated. The residue was cleaned by flash chromatography (400 g, 20 × 7.6 cm) with methanol chloride (100.1).
Production: 10.8 g (53%) of brown oil
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Concentrated hydrochloric acid (0.5 ml) was added to a solution of (8-Allyl-1,4-Dioxaspiro[4.5]dec-8-yl) -(4-Methoxybenzyl) amine (C-9) (1.0 g, 3.15 mmol) in acetone (10 ml) and water (0.5 L) and the mixture was stirred at room temperature for 16 h. The solution was then mixed with saturated sodium hydrocarbonate (40 ml) and extracted with dichloromethane (3 × 40 ml). The combined organic phases were dried with sodium sulphate and vacuum-sealed.
The yield is 864 mg (100%) of brown oil.
The NH signal could not be identified, but the detection of the signal was not possible due to the presence of a small number of other substances, including the presence of a small number of particles in the sample.
The following are the active substances which may be used in the active substance:
In analogy with the synthesis of benzyl- ((1,4-dioxaspiro[4.5]dec-8-ylide) amine (see building block E-13), 1,4-dioxaspiro[4.5]decan-8-on was quantitatively converted to iminin-phenyl ((1,4-dioxaspiro[4.5]dec-8-ylide) amine by water cleavage with aniline.
The subsequent reaction of phenyl ((1,4-dioxaspiro[4.5]dec-8-yliden) amine with allylmagnesium bromide (by analogy with C-13) produced the desired (8-Allyl-1,4-dioxaspiro[4.5]dec-8-yl) penyl amine (C-10) with good yield.
Concentrated hydrochloric acid (0.5 ml) was added to a solution of C-10 (333 mg, 1.22 mmol) in acetone (10 ml) and water (0.5 ml) and the mixture was stirred for 2 days at room temperature. The reaction mixture was then mixed with saturated sodium hydrocarbonate solution (40 ml) and extracted with dichloromethane (3 × 40 ml). The combined organic phases were dried with sodium sulphate and vacuum-pressed.
The following table shows the results of the analysis:
The melting point is 76-78 °C.
The mean of the measurements performed was approximately 0.01% for the 1H-NMR (400 MHz, d6-DMSO): 1.78 (dt, J = 13.0, 4.6 Hz, 2H); 2.06-2.29 (m, 4H); 2.49 (m, 4H); 5.00 (dd, J = 10.1, 1.9 Hz, 2H); 5.30 (s, 1H); 5.65-5.87 (m, 1H); 6.58 (t, J = 7.2 Hz, 1H); 6.82 (dd, J = 8.5 Hz, 2H); 7.07 (m, 2H).
The following are the active substances which may be used in the active substance:
A solution of 1,4-Dioxaspiro[4.5]deca-8-on (5.46 g, 35 mmol) and aniline (3.35 g, 3.28 ml, 36 mmol) in toluene (100 ml) was heated for 15 h at the water separator, supplemented with anhydrous sodium sulphate (2 g).
After complete reconstitution, the reaction solution was reduced to i. v. and the residue was dissolved in anhydrous tetrahydrofuran.
The mean value of the measurements performed was 1.70 (t, 2H, J = 6.7 Hz); 1.86 to 1.94 (m, 2H); 2.21 (t, 2H, J = 6.8 Hz); 2.35 (t, 2H, J = 7.0 Hz); 3.91 to 3.94 (m, 4H); 6.67 to 6.71 (m, 2H); 6.96 to 7.04 (m, 1H); 7.24 to 7.31 (m, 2H).
A solution of 1,4-Dioxaspiro[4.5]decan-8-on (6.20 g, 39.6 mmol) in dichloromethane (65 ml) was mixed with molesieb 4 Å (12.5 g) and aniline (3.80 g, 3.73 ml, 40.8 mmol) and stirred at room temperature over the weekend.
The mean value of the test chemical is calculated as the following:
A solution of (1,4-Dioxaspiro[4.5]dec-8-ylide) phenylamine (17 mmol) was dripped at 0 °C under argon to a 1.6 M solution of n-butyllithium in n-hexane (27 ml, 42 mmol), then the reaction mixture was slowly heated to room temperature and stirred overnight. The reaction mixture was then put under ice cooling with water (40 ml) and extracted with diethyl ether (3 × 50 ml). The combined organic solvents were flash-eaten and the residue was purified by vacuum chromatography (100 g, 20 × 4.0 cm) with cyclohexane/ethylacetate (9:1) and 1% triethylamine.
C-11:
Production: 645 mg (13%) of brown oil
The mean value of the dose of the active substance is calculated by dividing the dose by the mean value of the dose of the active substance.
Production: 1.01 g (24%) of brown oil
The mean value of the 1H-NMR (DMSO-d6) is 0.78 (t, 3H, J = 7.0 Hz); 1.12 to 1.30 (m, 4H); 1.57 to 1.87 (m, 4H); 2.0 to 2.14 to 2.15 (m, 2H); 2.19 to 2.31 (m, 2H); 2.40 to 2.60 (m, 2H, superimposed on the DMSO signal); 5.25 (s, 1H); 6.55 (t, 1H, J = 7.2 Hz); 6.77 (d, 2H, J = 8.6 Hz); 7.00 to 7.09 (m, 2H).
In addition, a mixture of C-11 and E-11 (816 mg, approximately 20%) was obtained.
A solution of (1,4-Dioxaspiro[4.5]dec-8-ylide) phenylamine (39.6 mmol) was dripped at 0 °C under argon to a 1.6 M solution of n-butyllithium in n-hexane (63 ml, 98 mmol). The reaction mixture was then slowly heated to room temperature and stirred overnight. The reaction mixture was then refrigerated with water (40 ml) and extracted with diethyl ether (3 × 50 ml). The combined organic phases were dried with sodium sulphate, i.e. vacuumed and the residue was cleaned by flash-squeezing (100 cm, 20 g × 4.0 g) with cyclohexane/ethylacetate (9:1) and 1 % triethylamine.
Production: 2.83 g (25%) of brown oil
A solution of C-11 (645 mg, 2.23 mmol) in acetone (15 ml) was mixed with water (2.5 ml) and concentrated hydrochloric acid (2.5 ml) and stirred over the weekend at room temperature, then the reaction mixture was alkaline (pH 10) with potassium carbonate solution, extracted with diethyl ether (3 × 30 ml), the combined organic phases were dried with sodium sulphate and compressed i.v.
The following are the main characteristics of the product:
The mean value of the 1H-NMR (DMSO-d6) is 0.78 (t, 3H, J = 7.0 Hz); 1.16-1.26 (m, 4H); 1.65-1.78 (m, 4H); 2.04-2.13 (m, 2H); 2.21-2.29 (m, 2H); 2.42-2.58 (2H, overlapped by the DMSO signal); 5.25 (s, 1H); 6.55 (t, 1H, J = 7.2 Hz); 6.77 (d, 2H, J = 7.7 Hz); 7.03 (d, 2H, J = 7.3 Hz); 7.07 (d, 2H, J = 7.3 Hz).
A solution of morpholine (4.79 g, 4.8 ml, 55 mmol), 1,4-dioxaspiro[4.5]dec-8-on (7.8 g, 50 mmol) and 1,2,3-triazole (4.14 g, 60 mmol) was heated in toluene (50 ml) in a preheated flask for 7 h under return flow at the water separator, then a 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (100 ml, 200 mmol) was dripped to 0 °C with argon to make the solution, so that the internal temperature remained below 30 °C. The reaction mixture was stirred for 2 h at room temperature and then cooled in ice-water to produce 20 per cent ammonium chloride (120 ml) solution. The organic phase was separated by a cyclohexane (120 g × 100 cm) (1700 ml) and mixed with ethanol and ethanol (167 ml) and extracted with ethanol (120 g/ ml) and ethanol (267 ml) The organic phase was separated by a cyclohexane (120 g/ ml) (120 g/ ml) and mixed with ethanol (167 ml) and ethanol (167 ml) and e.
Production: 3.86 g (27%) of colourless oil
The mean value of the test chemical is calculated as the following:
After 24 h, the reaction solution was mixed with another 6 M of hydrochloric acid (2.5 ml), stirred at room temperature for another 20 h, then alkaline (pH∼10) with 25% potassium carbonate solution and extracted with diethyl ether (3 × 25 ml). The combined organic phases were dried with sodium sulphate and i.
Production: 2.18 g (76%) of colourless oil
The mean value of the 1H-NMR (CDCl3) is 0.90 (t, 3 H, J = 7.0 Hz); 1.09 to 2.23 (m, 12 H); 2.55 (dd, 2 H, J = 14.3, 5.8 Hz); 2.59-2.65 (m, 4 H); 3.67 to 3.73 (m, 4 H).
To make a solution of 1,4-Dioxaspiro[4.5]decan-8-on (10.0 g, 64 mmol) in dichloromethane (100 ml), 4 Å (20 g) molesieb and benzylamine (8.90 g, 83 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The suspension was then filtered and the filtrate was pressed into a vacuum.
Production: 15.6 g (99%) of yellowish oil
The mean value of the test chemical is calculated as the mean value of the test chemical in the range from 0 to 100 mg/kg for the test chemical.
The maximum residue levels for the active substance in the feed additive and the active substance in the feed additive and the active substance in the feed additive shall be established on the basis of the following formula:
A solution of benzyl- ((1,4-dioxaspiro[4.5]dec-8-yliden) amine (15.6 g, 63.7 mmol) in dichloromethane (120 ml) was dripped with 1 M solution of allylmagnesium bromide (127 ml, 127 mmol) and stirred at room temperature for 72 h. The mixture was then carefully poured on a saturated ammonium chloride solution (100 ml) under ice-cooling and extracted with dichloromethane (3 × 40 ml). The combined organic phases were dried with sodium phosphate, i.e. vacuum-sealed and the residue was cleaned by flash chromatography (400 g, 20 × 7.6 cm) with chlorine / methanol (10 × 0.2).
Production: 5.92 g (32%) of brown oil
The mean of the measurements performed was approximately 0.01% for the 1H-NMR (300 MHz, d6-DMSO): 1.25-1.52 (m, 4H); 1.53-1.66 (m, 2H); 1.74-1.87 (m, 2H); 2.20 (d, J = 7.4 Hz, 2H); 3.59 (s, 2H); 3.83 (s, 4H); 4.89-5.19 (m, 2H); 5.86 (tdd, J = 14.9, 10.4, 7.3 Hz, 1H); 7.20 (t, J = 7.0 Hz, 1H); 7.20-7.35 (m, 4H).
The following are the active substances which may be used in the active substance:
Concentrated hydrochloric acid (2 ml) was added to a solution of C-13 (500 mg, 1.74 mmol) in acetone (20 ml) and water (2 ml) and the mixture was stirred at room temperature for 16 h. The reaction mixture was then mixed with sodium hydrocarbonate solution (40 ml) and extracted with ethyl acetate (3 × 40 ml).
The following table shows the percentage of the total production of the product concerned in the Union:
The NH signal could not be identified, but the detection of the NH signal was not possible, and the detection of the NH signal was not possible.
The maximum residue levels for the active substance shall be as follows:
To a solution of 1.4 dioxaspiro[4.5]decan-8 on (3.9 g, 25 mmol) in toluene (40 ml), pyrrolidine (1.95 g, 2.29 ml, 27.5 mmol), 1,2,3-triazole (2.07 g, 30 mmol) and molysib 4 Å (7.14 g) were added, stirred at 90 °C for 7 h, then decanted and immediately recycled.
The reaction mixture was stirred overnight at room temperature and then poured into saturated ammonium chloride solution (60 ml). The phases were separated and the aqueous phases were extracted with diethyl ether (3 × 70 ml). The combined organic phases were purified with sodium sulphate, i.e. vacuum, and the residue (12 g) by flash chromatography (400 g, 7.6 x 20 cm) with ethyl acetate methanol (9:1)
yield: 2.70 g (40% over two stages), brown oil (C-14)
The mean value of the dose for each dose is calculated by dividing the dose by the mean value of the dose for each dose.
A solution of C-14 (2.70 g, 10.1 mmol) in acetone (100 ml) was added to water (10.0 ml) and 37% hydrochloric acid (14.0 ml) and stirred overnight at room temperature. The mixture was then slowly dripped with 4 M sodium salts until pH 10 was reached. The mixture was extracted with diethyl ether (4 × 40 ml), the combined organic phases were dried with sodium sulphate and compressed into i. cru. The vacuum product (2.6 g) was cleaned by flash chromatography (260 g, 30 × 5.6 cm) with ethyl acetate / methanol (9:1)
The following are the results of the analysis of the results of the analysis of the test method:
In a heated flask, a solution of piperidine (1.87 g, 2.17 ml, 22 mmol), 1,4-dioxaspiro[4.5]dec-8-on (3.12 g, 20 mmol) and 1,2,3-triazole (1.66 g, 24 mmol) was added to toluene (20 ml) with molybdenum 4 Å and stirred for 7 h at 104 °C. This solution was then decanted from the molybdenum.
In a heated flask, a 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (22 ml, 44 mmol) was dripped at 0 °C with 0.6 M solution of the newly prepared triazole derivative in toluene (18 ml, 11 mmol) in a heated flask, for 1 h. The mixture was stirred at room temperature for 2 h and then dripped to 20 % ammonium chloride solution (24 ml) under ice-water cooling. The organic phase was separated and the aqueous phase extracted with diethyl (4 × 20 ml). The combined organic phases were washed with 2 N natron (30 ml) and water (20 ml) and vacuumed with sodium sulphate and i.i. The product was vacuumed (1.9 × 22 cm) by flashcylograph (100 × 22 cm) and cleaned with ethanol (1 × 22 cm).
The following are the results of the analysis of the results of the analysis of the test method:
6 M saline acid (5 ml) was added to a solution of C-15 (1.0 g, 3.6 mmol) in acetone (15 ml) The reaction solution was stirred at room temperature for 6 days, then alkaline (pH~9) with 25% potassium carbonate solution and extracted with diethyl ether (3 × 20 ml) The combined organic phases were dried with sodium sulphate and compressed i.v.
The test chemical is used to determine the concentration of the test chemical in the test medium.
In a heated flask, a solution of N-methylpiperazine (2.60 g, 2.88 ml, 26 mmol), 1,4-Dioxaspiro[4.5]decan-8-on (3.90 g, 25 mmol) and 1,2,3-Triazole (1.87 g, 27 mmol) was heated in toluene (25 ml) for 6 h at the water separator under reflux.
The reaction solution was then transferred to a sealed measuring cylinder and the raw product was reused.
To make a solution of the newly prepared triazole derivative (12.5 mmol) in toluene (12 ml), a 2 M n-butylmagnesium chloride solution in tetrahydrofuran (15 ml, 30 mmol) was dripped under argon to keep the internal temperature below 24 °C. After completion of the addition, the reaction mixture was stirred at room temperature for 2 h and then cooled to 0 °C and dripped to a 20 % ammonium chloride solution (50 ml), the aqueous phase was extracted with diethyl ether (3 × 40 ml), the combined organic phases were washed with 2 N natronla (70 ml) and water (70 ml), dried with sodium sulphate and vacuum i.e. tightly closed.
The raw product C-16 (3.57 g) was further processed.
A solution of C-16 (3.57 g, 12.0 mmol) in acetone (15 ml) was first diluted with water (2.5 ml) and then with concentrated hydrochloric acid (2.5 ml) and stirred over the weekend at room temperature.
The following is the list of the main components of the test chemical:
The maximum residue levels for the active substance shall be as follows:
A solution of lodmethylcyclopentan (31.5 g, 150 mmol) was dripped into the ether (30 ml) in the ether (30 ml) with argon to make the ether (150 ml) slightly settle, then boiled for 30 min in the backflow, cooled to RT and dripped with a solution of 8-dimethylamino-1,4-dioxospiro[4.5]decan-8-carbonitrile B-1 (10.5 g, 50 mmol) in the ether (30 ml). The solution started to boil and a white solid fell out. It was dripped and then stirred overnight for 6 h. The reaction mixture was boiled in the ether (20 mL) with a 20% E-L-OH (200 mL) solution.
The following information is provided for the purpose of the calculation of the yield:
The mean value of the dose of the active substance is calculated as follows:
(8-Cyclopentylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl) -dimethylamine (13.4 g, 50 mmol) was transferred to 5% sulphuric acid (600 mL) at room temperature and stirred 3 days at RT. The reaction solution was extracted with ether (2 x 50 mL). The aqueous phase was then cooled in an ice bath with 5N NaOH and extracted with dichloromethane (3 x 50 mL). The organic phase was dried using Na2SO4 and vacuum-pressed to dry.
The yield is 8.46 g (76%), colourless crystals.
The mean value of the dose of the active substance is calculated as follows:
The maximum residue levels for the active substance are:
Other, not containing added sugar or other sweetening matter
5-fluorisinate (10 mmol) was dissolved in a mixture of ethanol/pyridine/acetic acid (50 ml, 15: 5: 2) and heated for 14 h in a return flow with ethyl potassium malonate (1.87 g, 11 mmol) to control the reaction by DC (eluent: ethylacetate/hexane 1:1). The solvent mixture was distilled in a vacuum for processing. The residue was absorbed into ethylacetate (50 ml) and dispersed with (50 ml). After phasic separation, the second phase was extracted twice with ethylacetate (30 ml each). The combined organic phases were dried with 2 N HCl (50 ml), washed over NaSO4 and pressed to 20 ml. To achieve a vacuum solution of 89% solution, the solvent was washed in a vacuum solution of 12 ml and dried at a temperature of 10 °C. The solution was washed in a vacuum solution of 10 ml.
The following table shows the results of the analysis of the data collected by the Member States in the context of the monitoring of the application of the principles of sound financial management and the application of the principles of sound financial management:
The resulting aldol product (10 mmol) was dissolved in absolute THF (20 ml) under atmosphere of air. The solution was then placed in a water bath cooled with BH3×THF (40 ml, 1 M solution, 40 mmol) and stirred at room temperature for 14 h. The reaction was monitored by DC. After the reaction was completed, the reaction solution was given to a mixture of ethyl acetate (50 ml) and H2O (50 ml). After phase separation, the aqueous phase was extracted twice with ethyl acetate (30 ml each). The combined organic phases were dried over Na2SO4 and pressed in a vacuum. The residue was filtered over silica with ethyl acetylated.
The following are the main components of the test method:
LiAlH4 (1.99 g, 52.3 mmol) was introduced into a 60 ml flask of THF with argon and (5-hydroxy-1H-indol-3-yl) acetic acid (5.00 g, 26.2 mmol) was added to a 100 ml flask of THF for 30 min. The solution was boiled for 3 h under reflux. The solution was added to the solution under ice cooling with THF (10 mL) and H2O (4 mL) and stirred for 30 min. The solution was filtered over cellite, rinsed with dichloromethane (150 mL) and the filtrate was closed in i.v.
Production: 2.17 g (47%)
The mean value of the 1H-NMR (DMSO-d6) is 2.74 (2 H, m); 3.60 (3 H, m); 6.58 (1 H, m); 6.78 (1 H, s); 6.99 (1 H, s); 7.08 (1 H, d); 10.5 (1 H, bs).
Example AA-1:
Tryptopholic F-1 (484 mg, 3.00 mmol) and ketone E-1 (507 mg, 3.00 mmol) were dissolved in dichloromethane (25 ml) and replaced with methanosulfonic acid (316 mg, 3.30 mmol). The reaction solution was stirred overnight at room temperature. Methansulfonic acid (316 mg, 3.30 mmol) was added again and another 3 were stirred. The reaction solution was alkaline with 1 N NaOH, the org phase was separated and the water phase was extracted with dichloromethane (15 ml). The combined phases were organically dried over Na2SO4, filtered and the solvent was cleaned under reduced pressure. The raw product was sequenced with CHOH (103/Cl) etromegaly.
yield: 672 mg (72%); white solid
The mean value of the 1H-NMR (DMSO-d6) is 0.85 (3 H, t); 1.23 to 1.75 (8 H, br. m); 2.14 (2 H, br. m); 2.28 (6 H, br. s); 2.01 (6 H, s); 2.66 (2 H, t); 3.89 (2 H, t); 6.93 (1 H, t); 7.01 (1 H, t); 7.29 to 7.37 (2 H, 2 d); 10.80 (1 H).
The citrate was obtained by dissolving the newly produced spiroether (0.66 g, 2.11 mmol) in hot EtOH (10 ml) and citric acid (405 mg, 2.11 mmol) in hot EtOH (2 ml).
The following is the list of active substances in the feed additive:
The mean value of the dose of the active substance is calculated as the following: 1H-NMR (DMSO-d6): 0.89 (3 H, t); 1.53 (2 H, m); 1.62 (4 H, br. t); 1.67 (2 H, br. t); 2.12 (2 H, br. t); 2.55 (6 H, s); 2.57-2.70 (4 H, m); 3.90 (2 H, t); 6.97 (1 H, t); 7.05 (1 H, t); 7.35-7.39 (2 H, 2 d); 10.73 (1 H, br).
The following are the active substances which may be used in the active substance:
4-dimethylamino-4-ethyl cyclohexanone E-1 (600 mg, 3.55 mmol) and 5-fluoro-tryptopholic F-2 (852 mg, 3.55 mmol) were presented under argon in CH2Cl2 (15 ml) and then mixed with methanesulfonic acid (250 μl, 3.89 mmol). The solution was stirred at room temperature for 72 h, mixed with 1 N NaOH until the alkaline reaction and extracted with CH2Cl2 (3 x 20 ml). The org. phase was dried over NaSO2SO4 and vacuumed. The residue was purified by flask H chromatography with CHCl3/OH (20:1, 4:1, 1:1+1% TEAMe).
The resulting nonpolar cyclization product (164 mg, 0.496 mmol) was dissolved in hot ethanol (5 ml) and the citric acid dissolved in hot ethanol (90 mg, 0.496 mmol) was added.
The following is the list of active substances and mixtures:
The mean value of the 1H-NMR (DMSO-d6) is 0.88 (3 H, t); 1.47 (2 H, m); 1.53-1.87 (8 H, m); 2.05 (2 H, t); 2.48 (6 H, m); 2.60 (4 H, m); 3.91 ((2 H, t); 6.83 (1 H, m); 7.12 (1 H, m); 7.35 (1 H, m); 10.74 (1 H, s).
Tryptamine H-1 (528 mg, 3.30 mmol) and ketone E-1 (507 mg, 3.30 mmol) were dissolved in methanol (15 ml) and stirred overnight. The methanol was removed at reduced pressure, the residue was absorbed in dichlorethane (15 ml) and replaced with trifluoroacetic acid (494 mg, 3.30 mmol). The reaction solution was stirred at room temperature for 72 h, alkalinized with 1 N NaOH, the org phase was separated and the aqueous phase was extracted with dichloromethane (15 ml). The three combined org phases were dried over NaSO4, filtered and the solvent removed at reduced pressure. The raw product was chromatographically purified with CHCl (13/OHMeCl:4) in columns.
The yield is 265 mg (26%) white solid
The mean value of the 1H-NMR (DMSO-d6) is 0.85 (3 H, t); 1.32-1.48 (6 H, br. m); 1.82 (2 H, br. t); 2.11 (2 H, br. t); 2.25 (6 H, s); 2.53 (2 H, t); 2.96 (2 H, t); 6.78 (2 H, dt); 6.95 (1 H, dt); 7.29 (2 H, d); 10.49 (br, 1 H, t).
The following information is provided in the summary of the presentation:
The citrate was obtained by mixing the newly produced spiroamine (0.25 g, 0.80 mmol) in hot EtOH (10 ml) and citric acid (0.15 g, 0.80 mmol) dissolved in hot EtOH (1 ml).
The yield is 347 mg (86%) white solid
The melting point is 228 to 230 °C.
The following are the most commonly reported effects of the drug on the brain:
Cyclohexanone E-2 (394 mg, 2 mmol) and tryptopholic F-1 (322 mg, 2 mmol) were presented in CH2Cl2 (15 ml) with argon, followed by methanesulfonic acid (142 μl, 2.2 mmol) and stirred at room temperature for 24 h.
The solution was treated with 1 N NaOH and extracted with CH2Cl2 (3 x 15 ml). The org phase was dried with Na2SO4 and compressed in vacuum. The residue was purified with CHCl3/MeOH (9:1) by flask chromatography and then decrystallized from ethanol.
The yield is 330 mg (49%)
The free base NMR spectra were evaluated because the citrate spectra were poorly resolved.
The mean value of the 1H-NMR (DMSO-d6) is 0.91 (3 H, t); 1.25 (6 H, m); 1.55 (4 H, m); 1.73 (2 H, m); 2.11 (2 H, m); 2.26 (6 H, s); 2.66 (2 H, t); 3.91 (2 H, t); 6.98 (2 H, m); 7.32 (2 H, m); 10.72 (1 H, s).
The following are the most commonly used medicines:
The citrate was obtained by dissolving the newly produced spiroether (150 mg, 0.44 mmol) in hot ethanol (5 ml) and adding the citric acid (84 mg, 0.44 mmol) dissolved in hot ethanol (1 ml), then cooling the solution to room temperature and stirring for 2 h. The white precipitate AA-4 was vacuumed and vacuum dried.
The following information shall be provided for the purpose of the analysis:
4-Butyl-4-dimethylaminocyclohexanone E-2 (394 mg, 2 mmol) and 5-fluoro-tryptopholic F-2 (482 mg, 2 mmol) were presented in CH2Cl2 (15 ml) with argon and then added to trifluoromethanesulfonic acid (194 μl, 2.2 mmol).
The solution was mixed with 1 N NaOH and extracted with CH2Cl2 (3 x 15 ml). The org phase was dried over Na2SO4 and vacuumed. The residue was cleaned by FlasH chromatography with CHCl3/MeOH (9:1 to 1:1).
The yield is 119 mg (16%)
The free base NMR spectra were evaluated because the citrate spectra were poorly resolved.
The mean value of the 1H-NMR (DMSO-d6) is 0.90 (3 H, t); 1.19 (6 H, m); 1.54 (4 H, m); 1.67 (2 H, m); 2.12 (2 H, m); 2.24 (6 H, s); 2.59 (2 H, t); 3.88 (2 H, t); 6.83 (1 H, m); 7.12 (1 H, m); 7.28 (1 H, m); 10.85 (1 H, s).
The maximum residue levels for the active substance in the feed additive and in feed flavouring premixtures shall be as follows:
The corresponding citrate was formed by the spiroether which had just been produced, this spiro compound (119 mg, 0.33 mmol) was dissolved in hot ethanol (5 ml) and the citric acid (63 mg, 0.33 mmol) dissolved in hot ethanol was added.
The following information shall be provided in the form of a summary of the results of the analysis:
The melting point is 217 to 220 °C.
Example AA-6 was produced in the same way as AA-5, but the citrate was isolated instead of the hemicitrate.
E-2 (4.0 g/ 20.3 mmol) and fluorotriptopholic F-2 (4.89 g/ 20.3 mmol) were presented under argon in CH2Cl2 (50 ml) and then methane sulphonic acid (1.44 ml/22.33 mmol) was added and stirred at room temperature for 48 h. For processing, the approach was shifted to 1 N NaOH and stirred vigorously for 10 min. The phases were separated, the aqueous phase was extracted with CH2Cl2 (1 x 30 ml), a solid was removed, which was sucked out and decrystallized from ethanol. The organic phase was dried over Na2SO4 and vacuumed. The residue was also decrystallized from ethanol.
Production: 1.9 g (26%)
The resulting cycling product (1.0 g, 2.77 mmol) was dissolved in hot ethanol (5 ml). Citric acid (0.528 g, 2.77 mmol) dissolved in hot ethanol was added. The solution was cooled to room temperature, leaving a white precipitate. The precipitate (AA-6) was sucked and vacuum dried.
The following shall be added to the list of products:
3- ((2-hydroxyethyl) -H-indol F-3 (620 mg, 3.49 mmol) and ketone E-2 (680 mg, 3.49 mmol) were presented in abs.CH2Cl2 (100 ml) under argon, put under ice-cooling with TMS triflate (686 μl, 3.55 mmol) in CH2Cl2 (2 ml) and stirred at room temperature for 30 min. The solution was stirred at room temperature for another 16 h. H2O (22 ml) and K2CO3 (490 mg, 3.55 mmol) were added for processing and stirred at room temperature for 20 min. The phases were separated. The aqueous phase was extra-dried with dichloromethane (2 x 20 ml). The organic phase was vacuumed over Na2SO4 and i.e. vacuum-sealed.
The resulting cycling product (100 mg, 0.273 mmol) was dissolved in hot ethanol (5 ml), citric acid (52 mg, 0.273 mmol) was added, the solution was cooled to room temperature and a white precipitate was produced, and precipitate AA-7 was vacuum dried.
Efficacy: 48 mg (31%), according to NMR there are no citrate signals
Note: It is likely that trifluoroacetic acid was accidentally introduced, resulting in a trifluoroacetic acid salt instead of the citrate desired.
The following information shall be provided in the form of a summary of the results of the analysis:
The melting point is 265-269 °C
The mean value of the dose of the active substance is calculated by dividing the dose by the mean value of the dose of the active substance.
The following is a list of the active substances that may be used in the active substance:
3- ((2-hydroxy-ethyl) -H-indol F-3 (2.68 g, 15.09 mmol) and ketone E-2 (2.94 g, 15.09 mmol) were presented in abs.CH2Cl2 (100 ml) under argon and put in CH2Cl2 (5 ml) under ice cooling with the triflate (2.96 ml, 15.34 mmol) and stirred at room temperature for 30 min. The solution was stirred for another 16 h at room temperature. H2O (110 ml) and K2CO3 (2.45 g) were added for processing and stirred at room temperature for 20 min. The phases were separated. The aqueous phase was extracted with dichloromethane (2 x 20 ml). The organic phase was dried over Na2SO4 and i.e. vacuum. The back was vacuum-sealed and purified by Fomat-H-chromatography (93/OH-Cl) and crystallised in a crystallised state.
The yield is 476 mg (9%)
The newly obtained spiroether (471 mg, 1.32 mmol) was dissolved in hot ethanol (5 ml). The citric acid (245 mg, 1.32 mmol) dissolved in hot ethanol was added. The solution was cooled to room temperature, with no white precipitation. The solution was vacuumed to dry.
The following information is provided for the purpose of the calculation of the yield:
The solution was reconstituted by refrigeration with 1 N of sodium methanol (130 ml) and stirred for 20 min at room temperature. The phases of the solution were separated cold. The brown crystalline phase was extracted with 1,2-dichlorethane (270 ml). The organic particles were extracted by concentrating the hydrogen (50 ml) with the liquid solids. The liquid was washed with 60 ml of methanol (60 ml) and dissolved in a water-filled filter. The liquid was then removed and the liquid was dissolved in a water-filled filter (60 ml) and the remaining 67 ml of the methanol (60 ml) were removed.
The filtrate was compressed and the residue (2.4 g) chromatographically separated [silica gel 60 (130 g); methanol (500 ml), methanol/triethylamine (100: 1.1,5 l) ]. The nonpolar spiroamine was obtained along with impurities (1.02 g). This fraction was dissolved and extracted with cold methanol (10 ml). The resulting solid (332 mg) was a pure nonpolar product. The nonpolar spiroamine was obtained at a total yield of 44 % (2.28 g) with a melting point of 180-182 °C. The polar spiroamine was obtained in a further fraction at a yield of 12 % (622 mg) with a melting point of 93-96 °C.
The newly produced nonpolar spiroamine (92 mg, 0.27 mmol) was dissolved in hot ethanol (5 ml). The citric acid (51 mg, 0.27 mmol) dissolved in hot ethanol was added. The solution was cooled to room temperature, resulting in a white precipitate. The precipitate AA-9 was filtered and vacuum dried.
The following information shall be provided in the form of a summary of the results of the analysis:
Acetyl chloride (0.126 ml, 139 mg, 1.77 mmol) was dissolved in argon in abs. dichloromethane (5 ml) and transferred to room temperature with the free base of the more unpolar spiroamine AA-9 (200 mg, 0.59 mmol), dissolved in dichloromethane (15 ml), within 30 min. After 15 min, a precipitate was visible, which had dissolved again at the end of the addition. After a reaction time of 30 min, a precipitate was formed again. Another 21 h was stirred at room temperature. For processing, the colourless solution was transferred to water (10 ml) and 1N natron solution (5 ml) and stirred for 1 h. The phases were separated. The wet phase was extracted with dichloromethane (20 ml). The organic phase was mixed with 60 ml (20 ml) of water, which was obtained by mixing ethyl methanol (20 mg/ml) and ethyl chloride (20 mg/ml) into a dry powder.
The following information is provided for the purpose of the calculation:
The melting point is between 163 °C and 166 °C.
The newly produced nonpolar amide (125 mg, 0.327 mmol) was dissolved in ethanol (5 ml) at 50 °C and replaced with an ethanol solution (3 ml) of citric acid (70 mg, 0.36 mmol). After a reaction time of 3 h at room temperature, the colourless citrate AA-10 was separated by filtration and washed with ethanol (2 × 3 ml). The nonpolar amide was obtained as citrate at a yield of 63% (118 mg) and a melting point of 220-222 °C.
Cyclopentan carbonate chloride (0.215 ml, 234 mg, 1.77 mmol) was dissolved in argon in a mixture of dichloromethane (5 ml) and transferred to the nonpolar spiramine (nonpolar free base of AA-9, 200 mg, 0.59 mmol) dissolved in dichloromethane (15 ml) at room temperature for 45 min. It was stirred for another 1.5 h at room temperature. The colourless solution was mixed with water (10 ml) and 1 N of baking soda (5 ml) and stirred for 1 h. The phases were separated. The colourless phase was extracted with dichloromethane (20 ml). The combined organic phases were washed with water (20 ml), dried and pressed. An oil-coated oil (325 mg) was obtained, which was chromatographed on 87 mg (40 mg) of amylaceous oil, in a 60 mg (222 ml) hydride (hydrogel) of amylase (which was obtained by pressing 40 mg (350 ml) of amylase in a 60 mg (222 mg) hydrogel.
The resulting amide (186 mg, 0.427 mmol) was dissolved in ethanol (8 ml) at 60 °C and replaced with an ethanol solution (3 ml) of citric acid (90 mg, 0.47 mmol). A precipitation immediately began. After a reaction time of 2 h at room temperature, the colourless citrate AA-11 was separated by filtration and washed with ethanol (2 × 3 ml). The more unpolar amide was obtained as a citrate at a yield of 69% (183 mg) with a melting point of 228-230 °C.
3,3-dimethylbutyric acid chloride (0.246 ml, 238 mg, 1.77 mmol) was dissolved in argon in abs. dichloromethane (5 ml) and mixed at room temperature with the free base of the more unpolar spiroamine AA-9 (200 mg, 0.59 mmol), dissolved in dichloromethane (15 ml), for 30 min. After a reaction time of 24 h, the yellow solution was mixed with water (10 ml) and 1 N sodium hyaluronic acid (5 ml) and stirred for 1 h. The phases were separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic phases were washed with water (20 ml), dried and pressed. This produced a colourless oil (322 mg) which was chromatographed on a 40 mg (40 mg), 400 mg (400 mg) ethanol (400 mg) of methanol (400 mg), and only 60 mg (400 mg) ethyl methacrylate (400 mg) was obtained as a colourless oil.
The acylation was repeated as described above, the reaction solution remained colourless, but the reaction was stopped after 1.5 h. After chromatographic separation of the reaction mixture [silica gel 60 (40 g; ethyl acetate (250 ml) ], the amide was obtained at a yield of 78% (200 mg) as a colourless solid with a melting point of 220-222 °C.
The resulting nonpolar amide (230 mg, 0,525 mmol) was dissolved in ethanol (8 ml) at 50 °C and mixed with an ethanol solution (4 ml) of citric acid (111 mg, 0,578 mmol).
The more unpolar spiroamine AA-12 was obtained as citrate at a yield of 66% (219 mg) at a melting point of 216 to 218 °C.
3,4-dimethoxyphenylacetyl chloride (380 mg, 1.77 mmol) was dissolved in argon in abs. dichloromethane (5 ml) and transferred to room temperature with the free base of the nonpolar spiroamine AA-9 (200 mg, 0.59 mmol), dissolved in dichloromethane (15 ml), within 50 min. A precipitation immediately occurred. It was stirred for another 1.5 h at room temperature. The approach was stirred with water (10 ml) and 1 N of baking soda (5 ml) and 1 h for processing. The phases were separated. The aqueous phase was extracted with dichloromethane (20 ml). The combined organic polymers were dried with water (20 ml), magnetically and oily. This resulted in a pressed oil (357 mg) which was chromatographed on a 60 mg (40 mg, 130 ml) of ethyl methacrylate (2,5-150 ml) in a 75 °C solution of ethyl ethanol (2,5-130 mg/ml); the oil was dissolved in a 75 mg (1,5-150 ml) of amylacyl ethanol (2,5-150 mg/ml) as a colourless solid.
The newly obtained unpolar amide (216 mg, 0.417 mmol) was dissolved at 60 °C in ethanol (11 ml) and replaced with an ethanol solution (3 ml) of citric acid (89 mg, 0.46 mmol). After a reaction time of 5 h at room temperature, the colourless citrate was separated by filtration and washed with ethanol (2 × 3 ml). The unpolar amide was obtained as citrate AA-13 at a yield of 92 % (270 mg) and a melting point of 188-190 °C.
The free base of the nonpolar spiroamine AA-9 (204 mg, 0.6 mmol) was suspended in acetonitrile (30 ml) and mixed with ethyl isocyanate (0.052 ml, 47 mg, 0.66 mmol). The reaction mixture was heated for 6 h to return to flow. The clear solution was compressed. The oily residue was absorbed in diethyl ether (20 ml) and washed with water (5 ml). After drying and compressing, the nonpolar urea was obtained as a colourless solid at a yield of 57% (139 mg) with a melting point of 154-158°C.
The newly obtained nonpolar urea (139 mg, 0.4 mmol) was dissolved in ethanol (10 ml) and replaced with an ethanol solution (5 ml) of citric acid (85 mg, 0.44 mmol). After a reaction time of 20 h at room temperature, the colourless citrate was separated by filtration. Since the product had a greasy consistency, it was washed with diethyl ether (2 × 3 ml).
4-Methoxybenzylisocyanate (0.75 mmol) was dissolved in acetonitrile (30 ml) with triethylamine (0.07 ml, 511 mg, 5 mmol) and the free base of the nonpolar spiroamine AA-9 (170 mg, 0.5 mmol) dissolved. The reaction mixture was heated for 6 h to boil, making the reaction solution clear. Since no transposition was detectable in the DC, further 7 h was reheated under recoil. The approach was injected. The solid colourless residue was dissolved with diethyl ether, the suspension was stirred for 15 min and then sucked. The nonpolar urea AA-15 was obtained at a yield of 92 (200 mg).
The free base of the nonpolar spiroamine AA-9 (200 mg, 0.59 mmol) was diluted with water (0.04 ml) and dissolved at 0°C in 95 per cent formic acid (0.6 ml, 732 mg, 15.9 mmol). At this temperature, 37 per cent aqueous formaldehyde (0.46 ml, 178 mg, 5.9 mmol) was added, stirred in an ice bath for 10 min and the solution was heated for 1 h at 100 °C. Under ice cooling, the beige solution was stirred with water (5 ml) and 1 N Natron (15 ml). The cloudy mixture was stirred at room temperature for 30 min, stirred with dichloromethane (20 mg) and stirred for another 30 min. The phases were separated. The phases were obtained by mixing the phases with hydrochloromethane (15 mg) and hydrochloromethane (15 mg) in a 60 mg (250 mg) liquid solution of ethylene glycol (225 mg) and a 60 mg (250 mg) extract of ethylene glycol (225 mg) in a water-based solution.
The newly obtained nonpolar spiroamine (51 mg, 0.144 mmol) was dissolved in ethanol (2 ml) at 60 °C and mixed with an ethanol solution (2 ml) of citric acid (64 mg, 0.316 mmol). After a reaction time of 6 h, the citrate 5/6 was extracted as a colourless solid, washed with ethanol (2 × 2 ml) and diethyl ether (2 × 5 ml). The nonpolar spiroamine was obtained as hygroscopic citrate AA-16 at a yield of 47% (37 mg).
A solution of E-7 (500 mg, 2 mmol) and 5-fluorotriptophol F-2 (430 mg, 2.4 mmol) in anhydrous dichloromethane (25 ml) was refrigerated with trifluoromethane sulphonic acid (450 mg, 265 μl, 3 mmol) and stirred overnight at room temperature. The reaction mixture was then stirred with 0.5 N of baking soda (10 ml), stirred for 2 h at room temperature, the organic phase was separated and the aqueous phase was extracted with dichloromethane (2 × 20 ml). The combined organic phases were dried with sodium sulphate and vacuumed. The product was cleaned by flash chromatography (100 g, 20 cm × 4.0 cm) with cyclohexalatin triethylamine (9:1) and 1 % ethyl ether.Other
yield: 469 mg (53%), white solid
The melting point is between 112 and 121 °C.
The mean value of the measurements performed was 1.65-1.73 (m, 2H); 2.02 to 1.3 (m, 2H); 2.22 to 2.48 (m, 2H); 2.62 (t, 2H, J = 5.3 Hz); 3.88 (t, 2H, J = 5.3 Hz); 6.80 to 6.88 (m, 1 H); 7.11 (dd, 1H, J = 9.8, 2.3 Hz); 7.31 (dd, 1H, J = 8.8, 4.6 Hz); 10.67 (s, 1H).
The value of all the materials of Chapter 9 used does not exceed 20% of the ex-works price of the productThe following are the frequencies: 4 (d, J = 4 Hz); 108.2 (d, J = 26 Hz); 111.9 (d, J = 10 Hz); 126.1 (d, J = 10 Hz); 132.4; 141.9; 156.7 (d, J = 231).
The resulting spiroether (366 mg, 0.98 mmol) was mixed in hot isopropanol (60 ml) with citric acid (232 mg, 1.21 mmol) in isopropanol (5 ml).
The following table shows the results of the analysis:
The following shall be added to the list of active substances:
The mean value of the dose for each dose is calculated by dividing the dose by the mean value of the dose for each dose.
A solution of E-8 (500 mg, 1.73 mmol) and 2- ((5-fluor-1H-indol-3-yl) ethanol F-2 (311 mg, 1.73 mmol) in anhydrous dichloromethane (30 ml) was refrigerated with trifluoromethane sulphonic acid (346 mg, 204 μL, 2.30 mmol) and stirred at room temperature overnight. The reaction mixture was then stirred with 0.5 m of baking soda (17 ml) and stirred for 1 h at room temperature. The phases were separated, the aqueous phase was extracted with dichloromethane (3 20 ml), the combined organic phases were dehydrated with sodium sulphate and i.e. vacuum dried. The raw product (954 mg) was purified by flash heating, 20 g (100 cm × 3.6 g) × cyclohexane (9:1) / cyclohexane.
The yield is 424 mg (56%).amorphous white solid AA-18
The melting point is 58-62 °C.
The mean value of the measurements performed was 1.87 to 1.87 Hz (t, 2H, J = 6.79 Hz); 1.88 to 1.87 Hz (t, 4H); 1.8 to 1.8 to 1.96 Hz (m, 4H); 2.10 to 2.3 Hz; 2.63 to 5.2 Hz (t, 2H, J = 5.2 Hz); 3.62 to 3.2 Hz; 3.89 to 5.2 Hz (t, 2H, J = 5.2 Hz); 6.87 to 7.13 Hz (dt, 1H, J = 9.1 and 2.5); 7.24 to 7.35 Hz (t, 2H, J = 9.8 and 2.4 Hz); 11.03 to 11.03 Hz (m, 5H).
The mean value of the measurements performed in the controlled dose range was approximately 13C-NMR (DMSO-d6): 14.3; 22.1; 23.1; 25.1; 25.4; 26.4; 30.3; 31.5; 34.1; 53.4; 56.5; 58.8; 71.7; 102.4 (d, J = 23 Hz); 105.6 (d, J = 5 Hz); 108.3 (d, J = 26 Hz); 111.The following are the main components of the test method:
A solution of E-11 (368 mg, 1.5 mmol) and 2- ((5-fluor-1H-indol-3-yl) ethanol F-2 (269 mg, 1.5 mmol) in anhydrous dichloromethane was mixed with trifluoromethane sulphonic acid (300 mg, 177 μl, 2.0 mmol) at 10 °C as quickly as possible and stirred overnight at room temperature. For turnover control, a sample (0.5 ml) was taken, washed with 0.5 N sodium nitrate and the organic phase was dried with sodium sulphate. Following completion, the reaction mixture was mixed with 0.5 N nitrate (10 ml), stirred for 2 h at room temperature, the organic phase was separated, the aqueous phase was extracted with sodium nitrate (2 × 20 ml), the organic phase was combined with extracted sodium nitrate and iodide.The raw product was then purified by flash chromatography (18 g, 20 × 2.0 cm) with cyclohexane/ethylacetate (9:1) and 1% triethylamine.
The yield is 327 mg (54%), white solid AA-19
The melting point is 150-162 °C
The mean value of the dose for each dose group is given in the table below: 1H-NMR (DMSO-d6): 0.87 (t, 3H, J = 6.9 Hz); 1.25-1.35 (m, 4H); 1.77-1.97 (m, 10H); 2.64 (t, 2H, J = 5.2 Hz); 3.90 (t, 2H, J = 5.3 Hz); 4.92 (s, 1H): 6.50 (t, 1H, J = 7.1 Hz); 6.75 (d, 2H, J = 7.9 Hz); 6.83-6.90 (m, 1H); 7.02 (t, 2H, J = 7.8 Hz); 7.14 (dd, 1H, J = 9.8, 2.5 Hz); 7.30 (dd, 1H, J = 7.9 Hz).The time taken for the measurement of the sound pressure is given by the following equation:
The following are the most common types of radiation emitted by the electromagnetic field:
The reaction mixture was stirred at room temperature for 20 h, then mixed with 0.5 M sodium permanganate (20 ml) and stirred at room temperature for 3 h. The organic phase was separated, the aqueous phase was extracted with dichloromethane (3 20 ml), the combined organic phases were washed with sodium chloride solution (50 × 20 ml), the dry phase was washed with vacuum sulphate and iodine. The isomer was separated by a flash (115 × 14 cm) with cyclohexane (1 × 22 ml).Other
Fraction 1: Unpolar diastereoisomer, AA-20A yield: 259 mg (32%) white solid
The following shall be added to the list of active substances:
The mean value of the measurements of the test chemical is given by the following formulae:
The total number of doses administered to the population was approximately 13 C-NMR (CDCl3):14.1; 22.5; 23.8; 26.7 (2 C); 26.9; 30.3 (2 C); 33.4; 45.1 (C); 56.1; 59.6; 68.5 (2 C); 72.3; 103.3 (d, J = 23 Hz); 107.5 (d, J = 4 Hz); 109.The fraction of the polar diastereoisomer is the fraction of the polar diastereoisomer in the ratio of 7 (d, J = 26 Hz); 111.3 (d, J = 10 Hz); 127.6 (d, J = 10 Hz); 132.1; 141.2; 157.9 (d, J = 235 Hz).
The yield is 335 mg (42%), white solid
The melting point is 238 to 241 °C.
The mean value of the measurements of the 1H-NMR (CDCl3) was 0.98 (t, 3H, J = 6.4 Hz); 1.30-2.05 (m, 14H); 2.63-2.68 (m, 4H); 2.75 (t, 2H, J = 5.3 Hz); 3.68-3.72 (m, 4H); 3.99 (t, 2H, J = 5.4 Hz); 6.90 (dt, 1H, J = 9.3, 2.4 Hz); 7.12 (dd, 1H, J = 9.4, 2.0 Hz); 7.24 (dd, 1H, J = 8.8, 4.3 Hz); 7.63 (s, 1 H).
The total number of samples of the active substance is estimated at approximately 10 mg/kg.The following are the main types of the test:
The polar diastereomer added in example AA-20 is continued as example AA-21.
AA-21 (polar diastereoisomer) is a chemical compound with a molecular weight of less than 0,01 g/cm3
The yield is 335 mg (42%), white solid
The melting point is 238 to 241 °C.
The mean value of the measurements of the 1H-NMR (CDCl3) was 0.98 (t, 3H, J = 6.4 Hz); 1.30-2.05 (m, 14H); 2.63-2.68 (m, 4H); 2.75 (t, 2H, J = 5.3 Hz); 3.68-3.72 (m, 4H); 3.99 (t, 2H, J = 5.4 Hz); 6.90 (dt, 1H, J = 9.3, 2.4 Hz); 7.12 (dd, 1H, J = 9.4, 2.0 Hz); 7.24 (dd, 1H, J = 8.8, 4.3 Hz); 7.63 (s, 1 H).
The active substance is a mixture of the following compounds:
Example AA-22:
The ketone E-4 (275 mg, 1.26 mmol) and tryptopholic F-1 (206 mg, 1.26 mmol) were dissolved in 10 ml of dichloromethane, mixed with argon and methanosulfonic acid (0.13 ml, 2.05 mmol) and stirred at room temperature for 20 h.
After addition of 1 N NaOH (10 ml) and CH2Cl2 (20 ml), stir for 10 min, separate the phases, extract the aqueous phase twice with CH2Cl2, wash the combined organic phases with water, dry over Na2SO4 and compress the solution i.e. the remaining residue was purified by flask H chromatography with CHCl3/MeOH (20:1).
The yield is 327 mg (73%)
When converted with a molar amount of citric acid into ethanol, citrate AA-22 was omitted as solid.
The following is the list of active substances and mixtures:
The mean value of the 1H-NMR (DMSO-d6) is 1.35-1.56 (8 H, m); 1.71 (2 H, m); 2.14 (2 H, t); 2.26 (6 H, s); 2.64 (2 H, t); 3.25 (3 H, s); 3.36 (2 H, t); 3.89 (2 H, t); 6.95 (2 H, m); 7.32 (2 H, m); 10.72 (1 H, bs), free base.
The active substance is a mixture of the following compounds:
The ketone E-4 (426 mg, 2 mmol) and 5-fluoro-tryptopholic F-2 (362 mg, 2 mmol) were dissolved in dichloromethane (10 ml), placed under argon with methanesulfonic acid (0.14 ml, 2.2 mmol) and stirred at room temperature for 24 h. After addition of 1 N NaOH (10 ml), the phases were separated, the aqueous phase was extracted with CH2Cl2 (((3 x 10 ml), the combined organic phases were washed with water (10 ml), dried with Na2SO4 and the solution was compressed i. i. The remaining residue was separated by flask chromatography with CH:13/OH (20 meCl) methanol.
Other
| Ausbeute: | 408 mg (54 %) unpolarere Verbindung |
| 218 mg (29 %) polarere Verbindung |
When the nonpolar compound was converted into ethanol with a molar amount of citric acid, the citrate was found to be a colourless solid.
The following is the list of active substances and mixtures:
The mean value of the dose of the active substance is calculated as the following:
The ketone E-4 (426 mg, 2 mmol) and tryptamine H-1 (320 mg, 2 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 20 h. The solvent was then removed in the vacuum, the residue was dissolved in DCE (20 ml), added with trifluoroacetic acid (2 ml) and stirred at room temperature for 5 h. After adding 1N NaOH (10 ml) and CH2Cl2 (10 ml), stirring continued for 20 min, separating the phases, extracting the aqueous phase with CH2Cl2 (2 x 10 ml), washing the combined organic phases with water (10), drying with Na2SO4 and narrowing the solution in the vacuum. The residue was cleaned by triiodothymethylamine chromatography (9:13/OH) with a pH of 4:1 (1 ml).
Other
| Ausbeute: | 350 mg (49 %) unpolarere Verbindung, verunreinigt mit Ausgangsketon |
| 321 mg (45 %) polarere Verbindung, verunreinigt |
The conversion of the nonpolar compound with a molar amount of citric acid into ethanol produced a colourless solid called citrate AA-24.
The test chemical is used to determine the concentration of the active substance in the test chemical.
The melting point is 247 to 248 °C.
The mean value of the dose of the active substance is 1.44-1.55 (4 H, m); 1.79 (6 H, m); 2.33-2.63 (12 H, m); 2.86 (2 H, m); 3.25 (3 H, s); 3.38 (4 H m); 7.00 (1 H, m); 7.07 (1 H, m); 7.39 (2 H, m); 11.04 (1 H, bs).
The ketone E-3 (455 mg, 2 mmol) and tryptopholic F-1 (326 mg, 2 mmol) were dissolved in dichloromethane (10 ml) in abs, mixed with argon and methanesulfonic acid (0.14 ml, 2.2 mmol) and stirred at room temperature for 24 h. After adding 1 N NaOH (15 ml) and CH2Cl2 ml, stirred for 10 min (25 min), separated the phases, ex-tracted the aqueous phase twice with CH2Cl2 (10 ml), washed the combined organic phases with water (10 ml), dried Na2SO4 and cleaned the solution in a vacuum. The remaining residue was purified by bottle chromatography with CHCl3/HCl3/MeOH (20:1)
The yield is 687 mg (93%).
When converted with a molar amount of citric acid into ethanol, citrate AA-25 was found to be a colourless solid.
The following table shows the results of the analysis:
The melting point is 214-215 °C
The mean value of the 1H-NMR (DMSO-d6) is 1.33 (2 H, m); 1.51 (4 H, m); 1.75 (4 H, m) 1.95 (2 H, t); 2.14 (2 H, t); 2.66 (10 H, m); 3.31 (3 H, s); 3.36 (2 H), 3.90 (2 H, s); 6.98 (2 H, m); 7.38 (2 H, m); 10.88 (1 H, bs), citrate.
The following is a list of the active substances that may be used in the active substance:
The ketone E-3 (426 mg, 2 mmol) and 5-fluoro-tryptopholic F-2 (362 mg, 2 mmol) were dissolved in dichloromethane (10 ml), placed under argon with methanesulfonic acid (0.14 ml, 2.2 mmol) and stirred at room temperature for 24 h. After addition of 1N NaOH (10 ml) reaction of the solution, the phases were separated, the aqueous phase was extracted with CH2Cl2 (3 x 10 ml), the combined organic phases were washed with water (10 ml), dried with Na2SO4 and the solution was vacuumed. The resulting residue was separated by HF flask chromatography with CHCl3/OHMe (20:1).
The yield is 613 mg (79%)
When converted with a molar amount of citric acid into ethanol, citrate AA-26 was found to be a colourless solid.
The melting point is 216-218 °C.
The mean value of the 1H-NMR (DMSO-d6) is 1.12 (2 H, m); 1.50 (4 H, m); 1.68 (4 H, m) 1.86 (2 H, t); 2.06 (2 H, t); 2.56 (10 H, m); 3.22 (3 H, s); 3.34 (5 H m); 3.87 (2 H, s); 4.34 (1 H, bs); 6.81 (1 H, t); 7.11 (1 H, m); 7.34 (1 H, m); 10.81 (1 H, bs), citrate.
The following is a list of the active substances that may be used in the active substance:
The ketone E-3 (455 mg, 2 mmol) and tryptamine H-1 (320 mg, 2 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 20 h. The solvent was then removed in the vacuum, the residue was dissolved in DCE (20 ml), added with trifluoroacetic acid (2 ml) and stirred at room temperature for 5 h. After adding 1 N NaOH (10 ml) and CH2Cl2 (10 ml), stirring continued for 30 min, separating the phases, extracting the aqueous phase with CH2Cl2 (2 x 10 ml), washing the combined organic phases with water (10 ml), drying over Na2SO4 and narrowing the solution in a vacuum. The resulting solution was cleaned by triiodothymethylamine chromatography without CH13:113:1 (9 ml) with a pH of 1 ± 1%.
The yield is 273 mg (37%), the compound is more nonpolar
335 mg (48%) more polar compound, not contaminated
The conversion of the unpolar diastereomer with a molar amount of citric acid into ethanol produced citrate AA-27 as a colourless solid.
The following is the list of active substances and mixtures:
The mean of the measurements of the dose of the active substance is as follows:
The ketone E-6 (235 mg, 1.1 mmol) and tryptopholic acid F-1 (180 mg, 1.12 mmol) were dissolved in dichloromethane (5 ml) and mixed with methanesulfonic acid (0.1 ml, 1.5 mmol) in argon and stirred at room temperature for 20 h. After adding 1N NaOH (5 ml) and CH2Cl2 (10 ml), stirring continued for 10 min, separating the phases, extracting the aqueous phase twice with CH2Cl2, washing the combined organic phases with water, drying (Na2SO4) and compressing the solution i.e. vacuum. The remaining residue was cleaned by flask chromatography with CHCl3/OHMe (20:1).
yield: 361 mg, obtained by mixing the substance, the citrate AA-28 was obtained as a colourless solid when converted with a molar amount of citric acid into ethanol.
The following is the list of active substances and their metabolites:
The dose of the active substance is based on the following criteria: - the dose of the active substance is equal to or greater than the maximum dose of the active substance, and - the dose of the active substance is equal to or greater than the maximum dose of the active substance.
The ketone E-6 (209 mg, 1.0 mmol) and tryptamine H-1 (160 mg, 1.0 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 20 h. The solvent was then removed in the vacuum, the residue dissolved in dichlorethane (10 ml), added with trifluoroacetic acid (1.0 ml) and stirred for 5 d at room temperature. After adding 1 N NaOH (10 ml) and CH2Cl2 (10 ml), stirring continued for 20 min, separating the phases, extracting the aqueous phase twice with CH2Cl2, washing the combined organic phases with water, drying (NaSO24) and narrowing the solution in the vacuum. The residue was cleaned by CHH3/OH chromatography (20:1).When converted with a molar amount of citric acid into ethanol, citrate AA-29 was found to be a colourless solid.
The following is the list of active substances and their metabolites:
Since the NMR spectra of citrate were poorly resolved, the NMR spectra of free bases were given.
The following data are available for the control group: - 1H-NMR (DMSO-d6): 1.43 (12 H, m); 1.80 (2 H, t); 2.07 (3 H, m); 2.35 (6 H, s); 2.55 (2 H, m); 2.00 (2 H, t); 3.00 (2 H, t); 3.37 (1 H, bs); 6.96 (2 H, m); 7.30 (2 H, m); 10.55 (1 H, s).The following table shows the information required for the calculation of the average annual turnover of the company:
The ketone E-5 (175 mg, 0.78 mmol) and tryptopholic F-1 (126 mg, 0.78 mmol) were dissolved in dichloromethane (5 ml) and mixed with methanesulfonic acid (0.07 ml, 1.1 mmol) in argon and stirred at room temperature for 72 h. After adding 1N NaOH (5 ml) and CH2Cl2 (10 ml), stirring continued for 10 min, separating the phases, extracting the aqueous phase twice with CH2Cl2, combining the organic phases with washed, dried (Na2SO4) and vacuum-sealed solution. The resulting residue was purified by flask H-chromography with CHCl3/OHMe (20:1) mo.
The following is the list of active substances and their metabolites:
The mean value of the dose of the active substance is calculated as the following:
The following are the active substances which may be used in the active substance:
The ketone E-5 (137 mg, 0.61 mmol) and 5-fluoro-tryptopholic F-2 (109 mg, 0.61 mmol) were dissolved in a mixture of dichloromethane (4 ml), placed under argon with methanesulfonic acid (0.065 ml, 1.0 mmol) and stirred at room temperature for 48 h. After adding 1 N NaOH (5 ml) and CH2Cl2 (10 ml), stirred for another 20 min, separated the phases, extracted the aqueous phase twice with CH2Cl2, washed the combined organic phases with water, dried (Na2SO4) and the solution i.e. vacuum. The remaining residue was narrowed by bottle chromatography with CHCl3/H20/MeOH. The molar amount was converted to citric acid in a solid of AA-31 pure as ethanol.
The following is the list of active substances and their metabolites:
The mean value of the dose of the active substance is calculated as the following:
The maximum residue levels for the active substance in the feed additive and the maximum residue levels for the active substance in the feed additive and the active substance in feed additive shall be as follows:
The ketone E-5 (175 mg, 0.78 mmol) and tryptamine H-1 (125 mg, 0.78 mmol) were dissolved in methanol (8 ml) and stirred at room temperature for 20 h. The solvent was then removed in the vacuum, the residue was dissolved in dichlorethane (10 ml), added with trifluoroacetic acid (0.8 ml) and stirred at room temperature for 4 h. After adding 1 N NaOH (5 ml) and CH2Cl2 (10 ml), stirring continued for 20 min, separating the phases, extracting the aqueous phase twice with CH2Cl2, washing the combined organic phases with water, bleaching them, drying them (Na2SO4) and narrowing the solution in the vacuum. The residue was cleaned by CHF-OH-H3/Cl1 crystallography (9:1).
The following table shows the results of the analysis:
Citrate: melting point between 228 and 299 °C
Free base NMR spectra:
The mean value of the dose of the active substance is 1.13 (6 H, m); 1.72 (10 H, m); 1.97 (2 H, m); 2.59 (10 H, m); 3.88 (2 H, m); 6.86 (1 H, t); 7.14 (1 H, m); 7.32 (1 H, m); 10.74 (1 H, s).
The following information is provided in the summary of the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary of product characteristics and the information provided in the summary:
The resulting spiroether (140 mg, 0.38 mmol) was dissolved in hot ethanol (4 ml) and added to ethanol (2 ml) with a solution of citric acid (73 mg, 0.38 mmol).
The following information shall be provided in the form of a summary of the results of the analysis:
The melting point is 228 to 299 °C.
The polar spiroether (90 mg, 0.26 mmol) produced by example AA-9 was dissolved in hot ethanol (5 ml). The citric acid dissolved in hot ethanol (48 mg, 0.26 mmol) was added. The solution was cooled to room temperature, leaving a white precipitate. The precipitate was filtered and vacuum dried.
The following information shall be provided in the form of a summary of the results of the analysis:
The free base of the polar spiroether from example AA-2 (142 mg, 0.429 mmol) was dissolved in hot ethanol (5 ml) and the citric acid (78 mg, 0.429 mmol) dissolved in hot ethanol was added.
The following is the list of active substances and mixtures:
The mean value of the dose of the active substance is 1.05 (3 H, t); 1.64 (2 H, m); 1.94 (6 H, m); 2.48 (2 H, m); 2.55 (6 H, s); 3.89 (2 H, t); 6.87 (1 H, m); 7.14 (1 H, m); 7.29 (1 H, m); 11.04 (1 H, s).
The ketone E-4 (426 mg, 2 mmol) and tryptamine H-1 (320 mg, 2 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 20 h. The solvent was then removed in the vacuum, the residue was dissolved in DCE (20 ml), added with trifluoroacetic acid (2 ml) and stirred at room temperature for 5 h. After adding 1 N NaOH (10 ml) and CH2Cl2 (10 ml), stirring continued for 20 min, separating the phases, extracting the aqueous phase with CH2Cl2 (2 x 10 ml), washing the combined organic phases with water (10), drying with Na2SO4 and narrowing the solution in the vacuum. The residue was cleaned by triiodothymethylamine chromatography (9:13/OH) with a pH of 4:1 (1 ml).
yield: 350 mg (49%) nonpolar compound, contaminated with parent ketone 321 mg (45%) polar compound, contaminated
When the polar compound was converted into ethanol with a molar amount of citric acid, citrate AA-35 was found to be a colourless solid.
The following is the list of active substances:
The melting point is 228 to 299 °C.
The mean value of the 1H-NMR (DMSO-d6) is 1.65 (4 H, m); 1.88 (4 H, m); 2.05 (4 H, m); 2.47-2.59 (10 H, m); 2.69 (2 H, t); 3.18 (2 H, t); 3.30 (3 Hs); 3.43 (2 H, m); 6.97 (1 H, m); 7.07 (1 H, m); 7.33 (2 H, m); 10.95 (1 H, bs).
The ketone E-4 (426 mg, 2 mmol) and 5-fluoro-tryptopholic F-2 (362 mg, 2 mmol) were dissolved in dichloromethane (10 ml), placed under argon with methanesulfonic acid (0.14 ml, 2.2 mmol) and stirred at room temperature for 24 h. After addition of 1 N NaOH (10 ml), the phases were separated, the aqueous phase was extracted with CH2Cl2 (3 x 10 ml), the combined organic phases were washed with water (10 ml), dried with Na2SO4 and the solution was compressed i. i. The remaining residue was separated by flask chromatography with CHCl:13/OH (20 ⇒ reMeMe) methanol.
Other
| Ausbeute: | 408 mg (54 %) unpolarere Verbindung |
| 218 mg (29 %) polare Verbindung |
The polarisation of ethanol with a molar amount of citric acid did not result in precipitation, so the solution was narrowed to give a white, amorphous solid AA-36.
The mean of the measurements was approximately 0.01% for the two samples, and the mean of the measurements was approximately 0.01% for the two samples.
The polar spiroamine (free base of AA-9, 133 mg, 0.39 mmol) was suspended in acetonitrile (30 ml) and replaced with ethyl isocyanate (0.034 ml, 31 mg, 0.43 mmol). The reaction mixture was heated for 1.5 h to return to flow. After cooling to room temperature, a colourless solid crystallized. After extraction, the polar urea AA-37 was obtained at a yield of 46% (74 mg) with a melting point of 182-184 °C.
The solution was stirred at room temperature for 24 h. The solution was stirred with 1 N NaOH and extracted with dichloromethane (3 x 15 ml). The organic phase was dried over Na2SO4 and compressed in the vacuum. The residue was cleaned by flash chromatography with CH3/ClOH (9:1:1:1:1).
Other
| Ausbeute: | |
Fraction 2 (862 mg, 2.52 mmol) was dissolved in hot ethanol (5 ml). Citric acid (480 mg, 2.52 mmol) dissolved in hot ethanol was added. The solution was cooled to room temperature, leaving a white precipitate. The precipitate AA-38 was filtered and vacuum dried.
The following table shows the results of the analysis:
The ketone E-3 (455 mg, 2 mmol) and tryptamine H-1 (320 mg, 2 mmol) were dissolved in methanol (10 ml) and stirred at room temperature for 20 h. The solvent was then removed in the vacuum, the residue was dissolved in DCE (20 ml), added with trifluoroacetic acid (2 ml) and stirred at room temperature for 5 h. After adding 1N NaOH (10 ml) and CH2Cl2 (10 ml), stirring continued for 30 min, separating the phases, extracting the aqueous phase with CH2Cl2 (2 x 10 ml), washing the combined organic phases with water (10 ml), drying over Na2SO4 and narrowing the solution in a vacuum. The resulting solution was cleaned by triiodothyronine chromatography with CH13:13/OH without triiodothyronine (9 ml) with a pH of 4:1.
Other
| Ausbeute: | 273 mg (37 %), unpolarere Verbindung |
| 335 mg (48 %), polare Verbindung, verunreinigt |
The polar diastereomer was converted into ethanol with a molar amount of citric acid and the citrate AA-39 was found to be a colourless solid.
The following is the list of active substances and mixtures:
The mean value of the dose of the active substance is calculated as the following:
A solution of E-13 (398 mg, 1.64 mmol) and 2- (((5-fluor-1H-indol-3-yl) ethanol F-2 (293 mg, 1.64 mmol) in absolute dichloromethane (20 ml) was mixed with trifluoromethane sulphonic acid (328 mg, 556 μl, 2.18 mmol) at room temperature and stirred for 16 h at room temperature. The reaction solution was then mixed with 0.5 M sodium leach (10 ml) and stirred 2 h at room temperature. The phases were separated and the aqueous phase was extracted with dichloromethane (3 × 30 ml). The combined organic phases were densified with sodium sulphate and i.e. vacuumed.
The yield is 649 mg (98%) of slightly yellowish solid
The melting point is 45-48 °C.
The mean value of the measurement of the test chemical is calculated as the mean value of the measurement of the test chemical.The following are the most common types of radiation exposure: • radiation exposure (see Figure 1); • radiation exposure (see Figure 2); • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 3). • radiation exposure (see Figure 4.
The following are the active substances which may be used in the active substance:The number of the test is determined by the following equation:
One of the resulting spiroether (300 mg, 0.74 mmol) in isopropanol was added to a solution of citric acid (142 mg, 0.74 mmol) in isopropanol (1.2 ml) at 70 °C. The product was reconstituted as hemicitrate AA-40 when cooled.
The following table shows the results of the analysis:
The melting point is 133 °C.
The mean of the measurements performed was 1.75 to 1.80 (m, 6H); 1.9 to 2.18 (m, 2H); 2.32 (d, J = 7.2 Hz, 2H); 2.57 (d, J = 15.2 Hz, 1H); 2.65 (dd, J = 12.8, 9.5 Hz, 3H); 3.84 (s, 2H); 3.88 (t, J = 5.2 Hz, 2H); 4.34 (s, 1H); 5.09 to 5.21 (m, 2H); 5.95 (tdd, J = 17.3, 10.0, 7.2 Hz, 1H); 6.80 to 6.92 (m, 1H); 7.14 (dd, J = 9.9, 2.5 Hz, 1H); 7.24 to 7.45 (m, 4H); 7.49 to 7.57 (m, 2H); 10.72 (s, 1H).
The maximum residue levels for the active substance in the feed additive shall be as follows:
A solution of E-10 (277 mg, 1.14 mmol) and 2- ((5-fluor-1H-indol-3-yl) ethanol F-2 (170 mg, 1.14 mmol) in absolute dichloromethane (20 ml) was mixed with trifluoromethane sulphonic acid (342 mg, 580 μl, 2.28 mmol) at room temperature and stirred at room temperature for 16 h. The reaction solution was then mixed with 0.5 M sodium permanganate (10 ml) and stirred at room temperature for 2 h. The phases were separated and the aqueous phase was extracted with dichloromethane (3 × 30 ml). The combined organic phases were densified with sodium sulphate, i.e. e. dry and the residue was cleaned by flash photography (2006 × 5.6 cm): cyclohexane (5→ 1 / 3) with ethanol.Other
AA-41:
The following table shows the results of the analysis:
The melting point is 52-54°C.
The mean value of the measurements performed was 1.60-2.14 (m, 8H); 2.64 (t, J = 5.1 Hz, 2H); 2.77 (d, J = 6.8 Hz, 2H); 3.90 (t, J = 5.1 Hz, 2H); 4.98 (s, 1H); 5.11 (dd, J = 13.7, 2.6 Hz, 2H); 5.73-5.91 (m, 1H); 6.53 (t, J = 7.2 Hz, 1H); 6.80 (d, J = 7.7 Hz, 2H); 6.87 (dd, J = 9.6, 2.6 Hz, 1H); 7.04 (t, J = 7.9 Hz, 2H); 7.15 (dd, J = 9.9, 2.6 Hz, 1H); 7.30 (dd, J = 8.7 Hz, 1H); 11.06 (s, 1H).
The following shall be used for the calculation of the maximum sound level:The following is a list of the most commonly used synonyms for the word "DMSO": 22.0; 30.4; 30.9; 35.4; 54.0; 58.9; 71.4; 102.5 (d, J = 23 Hz); 105.6; 108.3 (d, J = 26 Hz); 111.6; 115.5; 115.9; 117.1; 126.6; 128.5; 132.1; 135.1; 141.5; 147.1; 155.7 (d, J = 230 Hz).
A solution of E-9 (843 mg, 3.08 mmol) and 2- ((5-fluor-1H-indol-3-yl) ethanol F-2 (552 mg, 3.08 mmol) in absolute dichloromethane (30 ml) was mixed with trifluoromethane sulphonic acid (600 mg, 4.0 mmol) at room temperature and stirred for 72 h at room temperature. Then further trifluoromethane sulphonic acid (300 mg, 2.0 mmol) was added and stirred again for 16 h. The reaction solution was then mixed with 0.5 ml of sodium hypochlorite (10 ml) and stirred for 2 h at room temperature. The phases were separated and the remaining phase was extracted with dichloromethane × 30 ml. The phases were compressed with organic tri sulphate and vacuum i.e.
The yield is 1.32 g (99%) of yellow solid AA-42
The melting point is 54-56 °C.
The maximum value of the measurement shall be calculated as follows:The following are the most commonly used doses of DMSO: 1.50 (d, J = 11.9 Hz, 2H); 1.72 (m, 4H); 1.91 (d, J = 14.4 Hz, 2H); 2.55 (d, J = 5.0 Hz, 2H); 2.64 (t, J = 5.0 Hz, 2H); 3.63 (d, J = 2.9 Hz, 2H); 3.72 (s, 3H); 3.88 (dd, J = 5.2, 4.8 Hz, 2H); 5.18 (m, 3H); 5.88-6.04 (m, 1H); 6.80-6.93 (m, 4H); 7.08-7.17 (m, 1H); 7.27 (m, 2H); 11.01 (s, 1H).
The maximum residue levels for the active substance shall be as follows:The number of the test chemical is determined by the following equation:
A solution of E-14 (1.06 g, 4.7 mmol) and 2- ((5-fluor-1H-3-yl) ethanol F-2 (854 mg, 4.7 mmol) in anhydrous dichloromethane (60 ml) was refrigerated and mixed with argon and trifluoromethane sulphonic acid (949 mg, 552 μL, 6.3 mmol) and stirred for 1 day at room temperature. Further trifluoromethane sulphonic acid (300 mg, 174 μL, 2 mmol) was added and stirred again for 1 day at room temperature. The reaction mixture was then stirred with 0.5 m sodium chloride (48 ml) and stirred for 20 minutes. The phases were separated, the phase was mixed with water chloride (2 × 20 ml) and the organic phase was combined with a flash of extracted sodium sulphate (180 ml) by extracting the organic product.20 × 5.6 cm) cleaned with chloroform / methanol (95:5).
The yield is 370 mg (19%) of yellow solid (fraction 1)
The product was present as a hydrochloride, the hydrochlorocarbon probably derived from the chloroform used for chromatography.
The mean value of the measurements of the test chemical is calculated as follows:The time of the test is the time between the start of the test and the end of the test.
The mean value of the sampling intervals for the samples of the active substance is calculated from the sampling intervals for the samples of the active substance.
In addition, contaminated product (fraction 2.322 mg, 17%) and unrecycled ketone (fraction 3.227 mg, 23%) were obtained.
The 1H-NMR spectrum of the raw product mixture showed that only one diastereoisomer and the alkene had been formed, but the latter was not isolated.
A solution of fraction 1 (350 mg, 0.83 mmol) in chloroform (20 ml) was washed with sodium hydrogen carbonate solution, the organic phase was dried with sodium sulphate and the solution was compressed into an i.v.
The following is the list of active substances in the feed additive:
The melting point is 70 °C.
The mean value of the measurements of the two groups of samples was calculated using the following formulae: 1.38-1.42 (m, 2H); 1.48 (d, 2H, J = 12.8 Hz); 1.74 (d, 2H, J = 12.8 Hz); 1.74-1.84 (m, 4H); 1.88 (dt, 2H, J = 13.5, 2.9 Hz); 2.04 (dt, 2H, J = 13.2, 3.2 Hz); 2.69 (t, 4H, J = 5.8 Hz); 2.74 (t, 2H, J = 5.4 Hz); 3.99 (t, 2H, J = 5.4 Hz); 6.87 (dt, 1H, J = 9.1, 2.5 Hz); 7.11 (dd, 1H, J = 9.5, 2.4 Hz); 7.23 (dt, 1H, J = 8.7, 4.3 Hz); 7.90 (dd, 1 Hz).
The mean value of the measurements performed was calculated using the following formulae:
A solution of the newly obtained yellow solid (free base of fraction 1) (180 mg, 0.46 mmol) in hot ethanol (15 ml) was added to a hot solution of citric acid (90 mg, 0.46 mmol) in ethanol (1.2 ml), resulting in a white precipitate which was filtered after cooling.
The following table shows the results of the analysis:
The melting point is 198-199 °C
The mean value of the measurements performed was 1.44 to 1.64 (m, 4H); 1.71 (br d, 2H, J = 12.7 Hz); 1.90 (br s, 6H); 2.12 (br t, 2H, J = 12.7 Hz); 2.57 (d, 2H, J = 15.0 Hz); 2.63 (t, 2H, J = 4 Hz); 2.66 (d, 2H, J = 15.0 Hz); 3.07 (br s, 4H); 3.89 (t, 2H, J = 5.1 Hz); 6.87 (dt, 1H, J = 9.1, 2.4 Hz); 7.15 (dd, 1H, J = 9.9, 2.3 Hz); 7.37 (dd, 1H, J = 4.45, 8.4 Hz); 10.64 (s), 1H, J = 11.0 Hz; and approximately 2-3 hours (from 2 to 3 hours).
The reaction mixture was stirred at room temperature for 20 h, then mixed with 0.5 M sodium salts (36 ml) and stirred at room temperature for 2.5 h. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3 × 20 ml). The combined organic phases were then separated by sodium dichloromethane solution (40 ml) washed with tricarboxylic acid. The isomer was then separated by a vacuum tube (1 × 3 × 3 cm) and a flash (1 × 3 × 3 cm) with ethylacetyl ethylacetate (1 × 3 × 3 cm) and 23 ml of ethylacetate.Other
The following is added to the list of active substances:
The following table shows the results of the analysis:
The melting point is between 126 and 130 °C.
The mean value of the measurements of the test chemical is given by the following formulae:
The total number of samples of the active substance shall be calculated by dividing the total number of samples of the active substance by the total number of samples of the active substance.The following is a list of the components of the equation:
The following are the main characteristics of the product:
The mean value of the measurements of the 1H-NMR (CDCl3) was 0.97 (t, 3H, J = 6.4 Hz); 1.29-1.80 (m, 18H); 2.63-2.68 (m, 4H); 1.99 (t, 2H, J = 11.2 Hz); 2.54-2.63 (m, 4H); 2.74 (t, 2H, J = 5.4 Hz); 3.99 (t, 2H, J = 5.4 Hz); 6.89 (dt, 1H, J = 9.0, 2.4 Hz); 7.12 (dd, 1H, J = 9.4, 2.2 Hz); 7.21-7.25 (m, 1 H); 7.63 (s, 1 H).
A 0.5 M solution of citric acid in 2-propanol (1.38 ml, 0.69 mmol) was added to a hot solution of the polar diastereomer (fraction 2.20 mg, 0.55 mmol) in 2-propanol (25 ml), prepared in the example AA-44.
The following table shows the results of the analysis:
The melting point is 236-238 °C.
The mean value of the measurements performed was calculated as follows: 1.18 (t, 2H, J = 6.9 Hz); 1.21 to 2.06; 2.56 (d, 2H, J = 15.1 Hz); 2.47 (d, 2H, J = 15.1 Hz); 2.65 (t, 2H, J = 5.1 Hz); 2.90 (br s, 4H); 3.90 (t, 2H, J = 5.1 Hz, 2H); 6.89 (ddd, 1H, J = 9.6, 8.9, 2.6 Hz); 7.16 (dd, 1H, J = 9.9, 2.5 Hz); 7.29 to 7.35 (m, 1 H); 11.03 (s, 1 H).
A solution of E-16 (631 mg, 2.5 mmol) and 5-fluorotriptophol F-2 (449 mg, 2.5 mmol) in anhydrous dichloromethane (25 ml) was refrigerated with trifluoromethane sulphonic acid (900 mg, 530 μl, 6 mmol) and stirred at room temperature over the weekend. For the control of turnover, a sample (0.5 ml) was taken, washed with 0.5 N of baking soda and the organic phase was dried with sodium sulphate. After complete implementation, the reaction mixture was stirred with 0.5 N of baking soda (10 ml), stirred for 2 h at room temperature, the aqueous phase was combined with extra 2 × 20 ml of dichloromethane (2 × 20 ml) which were dried with organic phosphates. The product was vacuum-dried and ejected using a vacuum tube.20 × 5,7 cm) cleaned with methanol.
The first group:
The yield is 144 mg (14.0%) of white solids.
The melting point is 74-81 °C
The mean value of the measurements performed was 1.68 (t, 2H, J = 12.2 Hz); 2.04 (t, 2H, J = 13.0 Hz); 2.23 (s, 3H); 2.42 to 2.48 (m, 4H); 2.52-2.57 (m, 3H); 2.62 (t, 2H, J = 5.4 Hz); 3.88 (t, 2H, J = 5.4 Hz); 6.86 (dt, 1H, J = 9.3, 2.6 Hz); 7.12 (dd, 1H, J = 9.9, 2.5 Hz); 7.37 (dd, 1H, J = 8.7, 4.6 Hz); 10.57 (s, 1 Hz).
In addition, two blended fraction 2 & 3 fractions (652 and 213 mg, 84%) were obtained as yellow oil containing the spiro ether and a by-product in a ratio of approximately 9:1.
A solution of fractions 2 & 3 (796 mg, 1.93 mmol) in boiling ethanol (15 ml) was mixed with a solution of citric acid (928 mg, 4.8 mmol) in hot ethanol (8 ml).
The following table shows the results of the analysis:
The melting point is 213-220 °C
The mean value of the 1H-NMR (DMSO-d6) is 0.90 (t, 3H, J = 6.9 Hz); 1.15 to 1.37 (m, 7H); 1.51-1.63 (m, 4H); 1.71 (t, 2H, J = 12.8 Hz); 1.99 (t, 2H, J = 13.0 Hz); 2.46 to 2.80 (m, 16H, overlapped by the DMSO signal); 3.12 (br s, 4H); 3.89 (t, 2H, J = 5.4 Hz); 6.89 (dt, 1H, J = 9.4, 2.6 Hz); 7.15 (dd, 1H, J = 9.8, 2.4 Hz); 7.35 (dd, 1H, J = 8.7, 4.5 Hz); 10.49 (s, 1 Hz).
The total number of doses administered to each patient was calculated by dividing the total dose by the total dose of the drug administered to each patient.
The example AA-47 is the citrate of the nonpolar diastereomer (fraction 1) obtained from example AA-38.
Indol F-3 (2.17 g, 12.2 mmol) and ketone E-2 (2.37 g, 12.2 mmol) were presented in a 100 ml flask of dichloromethane under argon, were refrigerated with TMS triflate (2.37 ml, 14.4 mmol) in dichloromethane (5 ml) and stirred for 30 min at RT. The solution was stirred for another 16 h at RT. For processing H2O (85 ml) and K2CO3 (1.90 g) were added and stirred for 20 min at RT. The phases were separated. The aqueous phase was extracted with dichloromethane (2 x 40 ml). The organic phase was dried over Na2SO4 and vacuumed. The residue was cleaned by flash chromatography with CHCl (91/OH3/OH 1:1, MeCl).
Other
| Ausbeute: | unpolares Diastereomer 1.12 g (26 %) |
| polares Diastereomer 0.911 g (21 %) |
The resulting nonpolar diastereomer (991 mg, 2.78 mmol) was dissolved in hot ethanol and added to ethanol (5 ml) with citric acid (529 mg, 2.78 mmol).
The yield is 567 mg (38%)
The melting point is 240-241 °C
The mean value of the dose of the active substance is calculated as the following: 1H-NMR (DMSO-d6): 0.92 (3 H, t); 1.29 (4 H, m); 1.46 (2 H, m); 1.75 (4 H, t); 1.85 (2 H, t); 2.10 (2 H, m); 2.54-2.69 (10 H, m); 3.87 (2 H; t); 6.54 (1 H, d); 6.68 (1 H, s); 7.16 (1 H, d); 8.51 (1 H, s; OH); 10.53 (1 H, s).
The total number of patients with a history of renal failure was estimated at approximately 58,500.
The polar diastereomer (900 mg, 2.52 mmol) obtained in example AA-48 was dissolved (poorly soluble) in hot ethanol/dioxane (5 ml, 30 ml) and then citric acid (480 mg, 2.52 mmol) was dissolved and added to hot ethanol (5 ml).
The yield is 874 mg (63%)
The melting point is 160-170 °C
The mean value of the 1H-NMR (DMSO-d6) is 0.97 (3 H, t); 1.43 (4 H, m); 1.65 (2 H, m); 1.92 (9 H, m); 2.51-2.67 (10 H, m); 3.88 (2 H; t); 6.58 (1 H, d); 6.70 (1 H, s); 7.12 (1 H, d); 8.56 (1 H, s, OH); 10.63 (1 H, s).
The total number of patients with a history of renal failure was estimated at approximately 58,528 in the United States.
The ketone E-17 (223 mg, 1.0 mmol) and 5-fluoro-tryptopholic acid (179 mg, 1.0 mmol) were dissolved in dichloromethane (10 ml), mixed with methanosulfonic acid (0.1 ml, 1.5 mmol) under argon and stirred at RT 3 d. After adding 1 N NaOH (10 ml) and CH2Cl2 (20 ml), stirring for 10 min, separating the phases, extracting the aqueous phase twice with CH2Cl2, combining the organic phases with washed, dried (Na2SO4) and i.i. Vacuum. The remaining residue was separated by flash chromatography with CH3/OH (20:1) Vacuum was isolated at 388 mg. It was isolated when it was dissolved in solid hydrogen, e.g. CH2Cl2, NMCl2, i.i.Cl2 and NaCl4 via a solution of NaCl2 and NaCl4 in water.
yield: 310 mg (81%), only 1 diastereomer was formed
The following is a list of the active substances that are considered to be toxic if they are administered to the human body:
The amine (310 mg, 0.81 mmol) was dissolved in hot ethanol (10 ml) and mixed with a solution of citric acid (155 mg, 0.81 mmol) in hot ethanol (5 ml).
The yield was 316 mg (81%), which was hemicitrate.
The melting point is 222-223 °C
The mean value of the active substance is 1.11 (2 H, m); 1.48-1.98 (15 H, m); 2.15 (2 H, m); 2.58 (6 H, s); 2.65 (11 H, m); 3.89 (2 H, m); 6.83 (1 H, m); 7.15 (1 H, m); 7.37 (1 H, m); 10. (1 H, bs); 11.01 (1 H, s), the hemicitrate.
The maximum residue levels for the active substance are the following:
Cinnamic acid chloride (441 mg, 2.65 mmol) was dissolved in abs tetrahydrofuran (30 ml) under argon and transferred to abs tetrahydrofuran (15 ml) at room temperature with the free base, the nonpolar spiroamine (300 mg, 0.88 mmol) produced by example AA-9, dissolved in abs tetrahydrofuran (15 ml), within 20 min. This produced a strong precipitation. After a reaction time of 1.5 h, the reaction mixture was diluted with water (10 ml), dissolved with 1 Nron saline (10 ml) under ice cooling and then stirred for 2 h. Tetrahydrofuran was removed from the vacuum. A solid was removed by filtration and washed with water (3 10 ml) separated. The raw product was chromatographed (408 mg) on 60 [500 ml] of ethyl nitrate;The more unpolar amide was obtained as a colourless solid at a yield of 76 % (314 mg).
The resulting nonpolar amide (296 mg, 0.63 mmol) was suspended at 80 °C in ethanol (14 ml) and mixed with an ethanol solution (3 ml) of citric acid (133 mg, 0.69 mmol). A solid was released from the clear solution when cooled to room temperature. It was stirred at room temperature for 16 h. The mixture was stored at 5 °C for 2 h. The colourless solid was separated by filtration and washed with diethyl ether (3 × 3 ml).
The more unpolar citrate AA-51 was obtained at a yield of 85% (302 mg) as a hemicitrate with a melting point of 154-157 °C.Other
The total number of samples of the active substance is estimated at approximately 10 mg/ kg.
Cinnamic acid chloride (C, 441 mg, 2.65 mmol) was dissolved in abs tetrahydrofuran (30 ml) under argon and transferred to room temperature with the free base, the polar spiroamine (300 mg, 0.88 mmol, dissolved in abs tetrahydrofuran (15 ml) produced by example AA-9, within 20 min. This resulted in a slight precipitation. After a reaction time of 1.5 h, the reaction mixture was diluted with water (10 ml), dissolved with 1 N of sodium sulphate (10 ml) under ice cooling and stirred for 1 h. Tetrahydrofuran was removed in a vacuum. This resulted in a solid which was separated by filtration and washed with water (384 mg, 0.88 mmol, dissolved in abs tetrahydrofuran (15 ml). This was obtained by using a chromatograph (50 mg) on a 60 × 43 × 50 mmol (methyl ethanol) powder. The solid was dissolved in a coloured powder (177 mg/mL) of amylase (43%).
The concentration of the active substance in the active substance is calculated as follows:
The resulting polar amide (157 mg, 0.334 mmol) was dissolved in ethanol (5 ml) and mixed with an ethanol solution (2 ml) of citric acid (72 mg, 0.37 mmol). It was stirred at room temperature for 16 h without precipitation being observed. The mixture was compressed, absorbed in ethanol (2 ml) and slowly mixed with diethyl ether (30 ml). After 1.5 h a colourless solid was separated by filtration and washed with diethyl ether (3 × 3 ml). The polar citrate AA-52 was obtained at a yield of 73% (161 mg).
For the determination of the solubility of the compounds, a series of tests was used by dilution of a 20 mg/ ml solution in DMSO with an aqueous buffer solution. During the passage of medicinal products through the digestive tract, the medicinal products are exposed to different pH values. In the stomach, pH values of 1-3 are expected, and following the gastric passage in the intestine, pH values of 6-8 are expected. Since solubility can be pH dependent, aqueous buffers were used at different pH values (pH 1.100 mM HCl; pH 2.10 mM HCl; pH 4.50 mM citric acid titrated with 1 NOH; pH 6.50 mM sodium citrate, titrated with 1 NCl; pH 7.50 mM Tris; pH 8.H.Tris) at the pH temperature of the final solution.
Since DMSO promotes the formation of metastable supersaturated aqueous solutions at increasing concentrations, the stock solutions were diluted 1:100 in aqueous buffer. The solutions were shaken in closed vessels for at least 15 hours. 10 μl of DMSO stock solution was diluted in 990 μl of aqueous buffer and placed in suitable vessels (e.g. Eppendorf vessels) so that the concentration was constant at 1 % v/v. Finally, the solutions were decentrifuged and samples of the residual were transferred to two sample vessels which clearly de-acetonized 50% of the aceton equivalent in 0,1 NCl.
The calibration solutions were obtained by dilution of the DMSO stock solutions in methanol (1:100). From these dilutions further dilutions were produced in methanol (1:100, 1:200, 1:400 and 1:800). Samples were analysed by RP-HPLC with UV detection. Linear calibration equations were derived by regression analysis, generally with correlation coefficients above 0.95. The experimentally determined calibration solutions were used to determine the concentrations of the compounds in the buffer solutions. The experiment described allowed maximum concentrations of 200 μg/ml of the substance in buffer to be determined. Higher solubilities could not be quantified.
The correlation between solubility and variation of R3 was shown by the following compounds.
R1 = R2 = CH3; R5 = R6, R7 = R9, R10 = H, R8 = F, X = O
Other
| AA-8 | 200 µg/ml bei pH 1-9 | |
| AA-23 | Ca 180 µg/ml bei pH 1-7 | |
| AA-5 | 2,9 µg/ml (pH 1); 17,7 µg/ml (pH 2); 5,9 µg/ml (pH 4); 8,7 µg/ml (pH 6); 3,3 µg/ml (pH 7); 0,2 µg/ml (pH 8) | |
| AA-2 | Ca 30 µg/ml bei pH 1-7 | |
| AA-22 | 197,6 µg/ml (pH 1); 154,2 µg/ml (pH 2); 154,0 µg/ml (pH 4); 176,7 µg/ml (pH 6); 153,5 µg/ml (pH 7); 46,4 µg/ml (pH 8); 2,1 µg/ml (pH 9) | |
| V-1 | 1,9 µg/ml (pH 2); 0,4 µg/ml (pH 6); 0,8 µg/ml (pH 7), 0,9 µg/ml (pH 8); 0,04 µg/ml (pH 9) | |
| V-2 | > 5 µg/ml | |
| V-3 | 2,7 µg/ml (pH 1), 2,8 µg/ml (pH 2); 1,7 µg/ml (pH 4), 1,5 µg/ml (pH 6), 0,4 µg/ml (pH 7); 0,4 µg/ml (pH 8); 0,4 µg/ml (pH 9) | |
| V-4 | 1,9 µg/ml (pH 1); 6,4 µg/ml (pH 4); 3,8 µg/ml (pH 6); 1,7 µg/ml (pH 7); 5,1 µg/ml (pH 8); 0,5 µg/ml (pH 9) | |
| V-5 | 1,9 µg/ml (pH 1); 3,1 µg/ml (pH 4); 3.2 µg/ml (pH 7); 2,0 µg/ml (pH 8); 0,6 µg/ml (pH 9) |
The compounds of the invention have an exceptionally high affinity for the ORL1 or μ-opioid receptor, which is on the same order of magnitude as the two comparator compounds, but have a higher solubility.
A small pH dependence of solubility was observed between pH 1 and pH 8. Below pH 8 the solubility of the compounds decreases.
The cyclohexane derivatives of generic formula I were tested in a receptor binding assay with 3H-nociceptin/orphanine FQ on membranes of recombinant CHO-ORL1 cells, using the test system presented by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824), where the 3H-nociceptin/orphanine FQ concentration was 0.5 nM. The binding acid was obtained with 20 μg of membrane protein per 200 μl of ED in 50 mM of heps, pH 7.4, 10 mM MgCl2 and 1 mMTA. The binding to the ORL1 receptor was determined by 1 mg of WPA-S Sham Sham-Pharmacin (Pharmacin Kiiburg, once known as S S S S Sham-Pharmacin), measured as a percentage of the free-floating antifungal acid in the inhibition table at room temperature (c = 1 μM) and inhibition at c = 1 μM.
The receptor affinity for the human μ-opioid receptor was determined in a homogeneous microtiter plate approach by dilution series of the substituted spirocyclic cyclohexane derivative to be tested 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 nmol/l of the radioactive ligand [3H] naloxone (NET719, NENEN, Zaventem, Belgium) and 1 mg WPA-SPA (WPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPA-SPAThe percentage of displacement of the radioactive ligand from its binding to the human μ-opioid receptor was determined at a concentration of the test substance of 1 μmol/l and reported as the percentage inhibition (% inhibition) of the specific binding. The percentages were calculated from the displacement by varying concentrations of the compound at different concentrations to a general inhibition of the radioactive ligand at a concentration of 50 per cent of the IC 0650 inhibiting the inhibition of the radioactive ligand.The conversion using the Cheng-Prusoff relation yielded Ki values for the test substances.
The mice were individually placed in a test cage and the tail base exposed to the focused heat beam of an electric lamp (tail-flick type 50/08/1.bc, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from the lighting of the lamp to the sudden flickering of the tail (pain latency) in untreated mice was 3 to 5 seconds. Before the solutions containing the compound of the invention or the respective comparison solutions were applied, the mice were pre-tested twice within five minutes and the mean of these measurements was calculated as the mean of the previous test.
The solutions of the compound of the invention of the general formula I and the comparator solutions were then administered intravenously. Pain measurements were carried out 10, 20, 40 and 60 minutes after each intravenous application. The analgesic effect was determined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula:
The time T0 is the latency time before application, the time T1 is the latency time after application of the combination of active substances and the time T2 is the maximum exposure time (12 seconds).
In two cases, the test was performed in the rat in an analogue manner.
Other
| Beispiel | Struktur ohne Salz Salzform s. Beispielbeschreibung | Diastereomer | Tail-flick Maus i. v. % Hemmung [10 µg/kg) | ||
| AA-1 | Eines von 2 möglichen Diastereomeren | 0.0031 | 0.0005 | 90% (100 µg/kg) | |
| GRTE6490 | |||||
| AA-2 | GRTE6559 | Unpolareres Diastereomer | 0.0120 | 0.0003 | n. d. |
| AA-3 | Eines von 2 möglichen Diastereomeren | 0.0012 | 0.0003 | n. d. | |
| GRTE6562 | |||||
| AA-4 | GRTE6282 | Eines von 2 möglichen Diastereomeren | 0.0002 | 0.0005 | 75% |
| AA-5 | GRTE6283 | Eines von 2 möglichen Diastereomeren | 0.0016 | 0.0009 | 60% |
| AA-6 | GRTE6859 | ||||
| Eines von 2 möglichen Diastereomeren | 0.0009 | 0.0007 | |||
| AA-7 | GRTE7131 | ||||
| Eines von 2 möglichen Diastereomeren | 0.0025 | 0.0002 | n. d. | ||
| AA-8 | GRTE7235 | ||||
| Eines von 2 möglichen Diastereomeren | 0.2600 | 0.0250 | |||
| AA-9 | GRTE6359 | ||||
| Unpolareres Diastereomer | 0.0001 | 0.0003 | n. d. | ||
| AA-10 | GRTE6762 | ||||
| Unpolareres Diastereomer | 0.0002 | 0.0003 | 75% | ||
| AA-11 | GRTE6874 | Unpolareres Diastereomer | 0.0006 | 0.0012 | n. d. |
| AA-12 | GRTE6785 | Unpolareres Diastereomer | 0.0015 | 0.0009 | n. d. |
| AA-13 | GRTE6853 | Unpolareres Diastereomer | 0.0006 | 0.0006 | n. d. |
| AA-14 | GRTE6675 | Unpolareres Diastereomer | 0.0002 | 0.0003 | n. d. |
| AA-15 | GRTE6783 | polareres Diastereomer | 0.0002 | 0.0004 | n. d. |
| AA-16 | GRTE6786 | Unpolareres Diastereomer | 0.0002 | 0.0004 | n. d. |
| AA-17 | GRTE7243 | 0.0066 | 0.0018 | n. d. | |
| Eines von 2 möglichen Diastereomeren | |||||
| AA-18 | GRTE7175 | - | 0.3733 | n. d. | |
| AA-19 | GRTE7055 | Eines von 2 möglichen Diastereomeren | - | 1.9400 | n. d. |
| AA-20 | GRTE7123 | Unpolareres Diastereomer | - | 36% | n. d. |
| AA-21 | GRTE7172 | 36% | n. d. | ||
| AA-22 | GRTE6697 | Eines von 2 möglichen Diastereomeren | 0.0006 | 0.0002 | n. d. |
| AA-23 | GRTE6701 | Unpolareres Diastereomer | 0.0050 | 0.0003 | 100% (46,4 µg/kg) |
| AA-24 | GRTE6699 | Unpolareres Diastereomer | 0.0003 | 0.0003 | n. d. |
| AA-25 | GRTE6790 | Eines von 2 möglichen Diastereomeren | 0.0032 | 0.0002 | n. d. |
| AA-26 | GRTE6793 | polareres Diastereomer | 0.0243 | 0.0004 | n. d. |
| AA-27 | GRTE6791 | Unpolareres Diastereomer | 0.0014 | 0.0004 | n. d. |
| AA-28 | GRTE6343 | Eines von 2 möglichen Diastereomeren | 0.0001 | 0.0006 | 90% |
| AA-29 | GRTE6564 | Eines von 2 möglichen Diastereomeren | 0.0001 | 0.0002 | n. d. |
| AA-30 | GRTE6362 | Eines von 2 möglichen Diastereomeren | 0.0004 | 0.0007 | n. d. |
| AA-31 | GRTE6421 | Eines von 2 möglichen Diastereomeren | 0.0012 | 0.0015 | n. d. |
| AA-32 | GRTE6363 | Eines von 2 möglichen Diastereomeren | 0.0001 | 0.0002 | n. d. |
| AA-33 | GRTE6360 | Polareres Diastereomer | 0.2500 | 0.3400 | n. d. |
| AA-34 | GRTE6558 | Polareres Diastereomer | 1.0767 | n. d. | |
| AA-35 | GRTE6698 | polareres Diastereomer | 26% | n. d. | |
| AA-36 | GRTE6700 | polareres Diastereomer | 1.7500 | 0.0633 | n. d. |
| AA-37 | GRTE6759 | polareres Diastereomer | 0.2750 | n. d. | |
| AA-38 | GRTE6799 | polareres Diastereomer | 1.2600 | 0.3650 | n. d. |
| AA-39 | GRTE6792 | polareres Diastereomer | 3.7900 | 1.0433 | n. d. |
| AA-40 | GRTE7053 | Eines von 2 möglichen Diastereomeren | 0.3167 | n. d. | |
| AA-41 | GRTE7176 | 3.8033 | n. d. | ||
| AA-42 | GRTE6283 | Eines von 2 möglichen Diastereomeren | 53% | n. d. | |
| AA-43 | GRTE7236 | Eines von 2 möglichen Diastereomeren | 47% | 94% | n. d. |
| AA-44 | GRTE7337 | Unpolareres Diastereomer | 42% | n. d. | |
| AA-45 | GRTE7338 | Polareres Diastereomer | 44% | n. d. | |
| AA-46 | GRTE7342 | Eines von 2 möglichen Diastereomeren | 34% | n. d. | |
| AA-47 | Unpolareres Diastereomer | 0.0003 | 0.0006 | n. d. | |
| AA-48 | Unpolareres Diastereomer | 98% | 0.0005 | n. d. | |
| AA-49 | Polareres Diastereomer | 27% | 1.3 | n. d. | |
| AA-50 | Eines von 2 möglichen Diastereomeren | 0.0052 | 0.0027 | n. d. | |
| AA-51 | Unpolareres Diastereomer | 0.0043 | 0.0030 | n. d. | |
| AA-52 | Polareres Diastereomer | 0.6600 | 0.1200 | n. d. |
38 g of one of the spirocyclic cyclohexane derivatives of the invention, here example 3, is dissolved in 1 l of water for injection at room temperature and then adjusted to isotonic conditions by addition of anhydrous glucose for injection.
Claims (14)
- Spirocyclic cyclohexane derivatives of the general formula I whereinR1 and R2 independently of one another represent H; C1-5-alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or poly-substituted or unsubstituted; C3-8-cycloalkyl, in each case saturated or unsaturated, mono- or poly-substituted or unsubstituted; aryl, unsubstituted or mono- or poly-substituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, in each case mono- or poly-substituted or unsubstituted;or the radicals R1 and R2 together represent CH2CH2OCH2CH2, CH2CH2NR11CH2CH2 or (CH2)3-6,wherein R11 denotes H; C1-5-alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or poly-substituted or unsubstituted; C3-8-cycloalkyl, in each case saturated or unsaturated, mono- or poly-substituted or unsubstituted; aryl or heteroaryl, in each case mono- or poly-substituted or unsubstituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, in each case mono- or poly-substituted or unsubstituted;R3 represents C1-8-alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or poly-substituted or unsubstituted;R5 represents =O; H; C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; COOR13, CONR13, OR13; C3-8-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted or mono- or poly-substituted;R6 represents H; F, Cl, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13, NR14R15; C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-8-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted or mono- or poly-substituted;or R5 and R6 together denote (CH2)n where n = 2, 3, 4, 5 or 6, wherein individual hydrogen atoms can also be replaced by F, Cl, Br, I, NO2, CF3, OR13, CN or C1-5-alkyl;R7, R8, R9 and R10 independently of one another represent H, F, Cl, Br, I, NO2, CF3, OR13, SR13, SO2R13, NHC(=O)NR14R15, SO2NR14R15, SO2OR13, CN, COOR13, NR14R15; C1-5-alkyl, C3-8-cycloalkyl, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted or mono- or poly-substituted;wherein R13 denotes H; C1-5-alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; C3-8-cycloalkyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted or mono- or poly-substituted;R14 and R15 independently of one another denote H; C1-5-alkyl, in each case saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted; or C3-8-cycloalkyl, in each case saturated or unsaturated, unsubstituted or mono- or poly-substituted; aryl or heteroaryl, unsubstituted or mono- or poly-substituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, unsubstituted or mono- or poly-substituted;or R14 and R15 together form CH2CH2OCH2CH2, CH2CH2NR16CH2CH2 or (CH2)3-6,wherein R16 denotes H; C1-5-alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or mono- or poly-substituted;X represents O, S, SO, SO2 or NR17;R17 represents H; C1-5-alkyl, saturated or unsaturated, branched or unbranched; COR12 or SO2R12,wherein R12 denotes H; C1-5-alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or poly-substituted or unsubstituted; C3-8-cycloalkyl, in each case saturated or unsaturated, mono- or poly-substituted or unsubstituted; aryl or heteroaryl, in each case mono- or poly-substituted or unsubstituted; or C1-3-alkyl-bonded aryl, C3-8-cycloalkyl or heteroaryl, in each case mono- or poly-substituted or unsubstituted; OR13; NR14R15;wherein "alkyl substituted" or "cycloalkyl substituted" denotes alkyl or cycloalkyl substituted by F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2 and"aryl substituted" or "heteroaryl substituted" denotes aryl or heteroaryl substituted by F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2,in the form of the racemate; of the enantiomers, diastereoisomers, mixtures of the enantiomers or diastereoisomers or of an individual enantiomer or diastereoisomer; of the bases and/or salts of physiologically acceptable acids or cations,with the exception of the compound2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine.
- Spirocyclic cyclohexane derivatives according to claim 1, wherein R1 and R2 independently of one another represent H, C1-5-alkyl, branched or unbranched, saturated or unsaturated, unsubstituted or mono- or poly-substituted, or phenyl or benzyl, unsubstituted or mono- or poly-substituted, or together represent a ring and denote (CH2)3-6.
- Spirocyclic cyclohexane derivatives according to claim 1, wherein R3 represents ethyl, n-propyl, 2-propyl, allyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl, in each case unsubstituted or mono- or poly-substituted by OH, OCH3 or OC2H5.
- Spirocyclic cyclohexane derivatives according to claim 1, wherein the radical R5 represents H, CH3, COOH, COOCH3, CH2Ophenyl, wherein the phenyl radical can be substituted by F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2, or CH2OH.
- Spirocyclic cyclohexane derivatives according to claim 1, wherein R6 can denote H; methyl, ethyl, CF3, benzyl or phenyl, wherein the benzyl or phenyl radical can be substituted by F, Cl, Br, I, CN, CH3, C2H5, NH2, NO2, SH, CF3, OH, OCH3, OC2H5 or N(CH3)2.
- Spirocyclic cyclohexane derivatives according to claim 1, wherein R7, R8, R9 and R10 independently of one another denote H; C1-5-alkyl, branched or unbranched, unsubstituted or mono- or poly-substituted; F, Cl, Br, I, CF3, OH, OCH3, NH2, COOH, COOCH3, NHCH3, thienyl, pyrimidinyl, pyridyl, N(CH3)2 or NO2.
- Spirocyclic cyclohexane derivatives according to any one of claims 1 to 6, wherein X represents O.
- Spirocyclic cyclohexane derivatives according to any one of claims 1 to 6, wherein X represents NR17.
- Spirocyclic cyclohexane derivatives according to claim 1 from the group:4',9'-dihydro-N, N-dimethyl-4-ethyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-ethyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-ethyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-hydroxy-4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2,2,2-trifluoroacetate6'-hydroxy-4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-methylcarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-cyclopentylcarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-(2,2)-dimethylpropanecarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-(3,4-dimethoxybenzylcarbonyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-ethylaminocarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-4-methoxybenzylaminocarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine2',3',4',9'-tetrahydro-N, N-d imethyl-4-butyl-2'-methyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N-ethyl-N-methyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N-benzyl-N-methyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine6'-fluoro-4',9'-dihydro-N-phenyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine4-butyl-6'-fluoro-4-(N-morpholino)-1',3',4',9'-tetrahydrospiro[cyclohexane-1,1'-pyrano[3,4-b]indole]4-butyl-6'-fluoro-4-(N-morpholino)-1',3',4',9'-tetrahydrospiro[cyclohexane-1,1'-pyrano[3,4-b]indole]4',9'-dihydro-N,N-dimethyl-4-methoxypropyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-d ihyd ro-N, N-d imethyl-4-methoxypropyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-(3-methoxypropyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate4',9'-dihydro-N,N-dimethyl-4-(4-methoxybutyl)-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-(4-methoxybutyl)-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-(4-methoxybutyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-ethyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-(3-methoxypropyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-methoxypropyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-ethylaminocarbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-(4-methoxybutyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N-benzyl-4-allyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-fluoro-4',9'-dihydro-N-phenyl-4-allyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine6'-fluoro-4',9'-dihydro-N-(4-methoxybenzyl)-4-allyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amineN-{6'-fluoro-4',9'-dihydro-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-yl}-pyrrolidine, 2-hydroxy-1,2,3-propanetricarboxylateN-{6'-fluoro-4',9'-dihydro-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-yl}-piperidineN-{6'-fluoro-4',9'-dihydro-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-yl}-piperidine, 2-hydroxy-1,2,3-propanetricarboxylateN-{6'-fluoro-4',9'-dihydro-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-yl}-n-methylpiperazine, 2-hydroxy-1,2,3-propanetricarboxylate4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate6'-hydroxy-4',9'-dihydro-N,N-dimethyl-4-butyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate2',3',4',9'-tetrahydro-N,N-dimethyl-4-butyl-2'-(2-phenylethenecarbonyl)-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indol]-4-amine, 2-hydroxy-1,2,3-propanetricarboxylate,optionally also in the form of a mixture.
- Process for the preparation of spirocyclic cyclohexane derivatives according to any one of claims 1 to 9, characterised in that a starting material of the general formula E is reacted, with the addition of acid or trimethylsilyl esters thereof, for example trifluoromethanesulfonic acid trimethylsilyl ester, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, methanesulfonic acid or trifluoroacetic acid, in a suitable solvent, for example dichloroethane, dichloromethane, chloroform, acetonitrile, diethyl ether or nitromethane, with a starting material of the general formula F or H, wherein the radicals R1 to R3 and R5 to R10 have the meanings given in claim 1.
- Process for the preparation of spirocyclic cyclohexane derivatives according to claim 1 in which X denotes NR17 and R17 denotes COR12 or SO2R12, characterised in that a spirocyclic cyclohexane derivative in which X denotes NH is reacted, with the addition of base, for example triethylamine, with an anhydride or an acid chloride, preferably with microwave radiation.
- Process for the preparation of spirocyclic cyclohexane derivatives according to claim 1 in which X denotes SO or SO2, characterised in that a spirocyclic cyclohexane derivative in which X denotes S is oxidised with the aid of an oxidising agent, for example H2O2.
- Medicament comprising at least one spirocyclic cyclohexane derivative according to any one of claims 1 to 9 and optionally comprising suitable additives and/or auxiliary substances and/or optionally further active ingredients.
- A spirocyclic cyclohexane derivative according to any one of claims 1 to 9 for use for the treatment of pain, especially acute, neuropathic or chronic pain, anxiety, stress and stress-associated syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicament abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, impaired hearing, deficient intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive or anaesthetic or for co-administration in the case of treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for modulation of motor activity, for modulation of neurotransmitter secretion and treatment of neurodegenerative diseases associated therewith, for the treatment of withdrawal symptoms and/or for reducing the addictive potential of opioids.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102007009235A DE102007009235A1 (en) | 2007-02-22 | 2007-02-22 | Spirocyclic cyclohexane derivatives |
| DE102007009235.2 | 2007-02-22 | ||
| PCT/EP2008/001270 WO2008101659A1 (en) | 2007-02-22 | 2008-02-19 | Spirocyclic cyclohexane derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1136828A1 HK1136828A1 (en) | 2010-07-09 |
| HK1136828B true HK1136828B (en) | 2013-11-22 |
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