HK1075037B

HK1075037B - Unsaturated 1-amino-alkylcyclohexane nmda, 5ht3 and neuronal nicotinic receptor antagonists

Info

Publication number: HK1075037B
Application number: HK05107277.4A
Authority: HK
Inventors: C‧G‧R‧帕森斯; M‧亨里希; W‧丹尼兹; I‧卡尔温什; V‧考斯; A‧伊金森斯; M‧戈尔德
Original assignee: 莫茨药物股份两合公司
Priority date: 2001-11-07
Filing date: 2002-11-07
Publication date: 2009-06-19

Description

Unsaturated 1-amino-alkylcyclohexane NMDA, 5HT3 and neuronal nicotinic receptor antagonists

Background

1. Field of the invention

The present invention relates to the use of the compounds as NMDA, 5HT₃And nicotinic receptor antagonists, pharmaceutical compositions containing the same, methods of making the same, and methods of using the same for treating CNS disorders involving glutamatergic, 5-hydroxytryptamine-ergenic, and nicotinic transmission disorders, for treating immunomodulatory disorders, and for treating infectious diseases.

2. Description of the Prior Art

NMDA antagonists

Antagonism of N-methyl-D-aspartate (NMDA) type glutamate receptors has potentially broad therapeutic applications [19]. Functional inhibition of NMDA receptors can be achieved by binding at different recognition sites, e.g., major transmitter site, strychnine-insensitive glycine site (glycine)_B) Polyamine sites and within cation channelsBy the action of the phencyclidine site. NMDA receptor channel blockers act in a non-competitive "use-dependent" manner, indicating that they typically block only open channels. It is believed by many that this use dependence means that a stronger activation of the receptor will result in a greater degree of antagonism. This mode of action is also understood to mean that such antagonists may be particularly effective when over-activation of the NMDA receptor is anticipated, for example in epilepsy, ischemia and trauma. However, initial clinical trials with the selective, high affinity, strongly use-dependent uncompetitive NMDA receptor antagonist (+) -5-methyl-10, 11-dihydro-5H-dibenzocycloheptene-5, 10-imine maleate ((+) -MK-801) have been disappointing. That is, the therapeutic effect on epilepsy is poor, with some significant psychoactive side effects at therapeutic doses. These observations, together with the fact that phencyclidine abusers exhibit similar psychiatric symptoms, lead one to conclude that uncompetitive antagonism of the NMDA receptor may not be a promising therapeutic approach.

However, the use of more elaborate electrophysiological methods suggests that different non-competitive antagonists do not differ, since factors such as the rate of receptor blockade (switching kinetics) and the voltage dependence of this effect may also determine their pharmacodynamic profile in vivo, i.e., therapeutic safety. Paradoxically, agents with low to moderate, rather than high, affinity may be desirable. These findings have led to a renewed consideration of the concept of uncompetitive antagonism of NMDA receptors in drug development [19, 22 ]. Uncompetitive NMDA receptor antagonists meeting the above criteria, such as amantadine and memantine, have been used clinically for several years in the treatment of parkinson's disease and dementia, respectively, and have produced few side effects at therapeutic doses used to treat the respective indications.

In view of the above evidence, we have developed a series of novel uncompetitive NMDA receptor antagonists based on unsaturated 1-aminoalkylcyclohexane structures. The present study focused on comparing NMDA receptor antagonistic properties of these unsaturated 1-aminoalkylcyclohexane derivatives in a receptor binding assay, electrophysiological studies, a convulsive model, and two motor impairment models. The substitution of these unsaturated 1-aminoalkylcyclohexanes is described in detail in Table 1.

5-HT₃Receptor antagonists

5-HT₃The receptor is a cation permeable ligand-gated ionizing receptor. 5-HT in the human body₃Receptors appear most densely on enterochromaffin cells within the gastrointestinal mucosa, which are innervated by vagal afferent nerves and the rearmost region of the brain stem, which forms the trigger zone for chemical receptors.

Due to 5-HT₃Receptors have high density not only in the posterior region but also in the hippocampal and amygdala regions of the limbic system, and thus 5-HT has been implicated₃Selective antagonists may have psychotropic effects (Greenshaw)& Silverstone，1997)。

Indeed, early animal studies suggested that 5-HT₃Receptor antagonists, in addition to their well-understood anti-emetic use, may be very useful clinically in many areas. They include anxiety disorders, schizophrenia, drug and alcohol abuse disorders, depressive disorders, cognitive disorders, Alzheimer's disease, cerebellar tremor, Parkinson's disease treatment-related psychosis, pain (migraine and irritable bowel syndrome), and appetite disorders.

Neuronal nicotinic receptor antagonists

Currently, 10 alpha subunits (alpha 1-10) and 4 beta (beta 1-4) subunits of nicotinic receptors are known. The α 4 β 2 receptor is probably most prevalent within the CNS, particularly in the hippocampus and striatum. They form non-selective cation channels with slow and incomplete desensitization currents (type II). Homomeric α 7 receptors are both presynaptic and postsynaptic and are found in the hippocampus, motor cortex and limbic system, and peripheral autonomic nervous system. These receptors are characterized by their high Ca²⁺Permeability and rapid and strong desensitization (form 1A). Alterations in nicotinic receptors have been implicated in a number of diseases. They include Alzheimer's disease,Parkinson's disease, Tourette's syndrome, schizophrenia, drug abuse, nicotine abuse and pain.

Based on the observation that nicotinic agonists nicotine itself appears to have a beneficial effect, the development of drugs to date has been aimed at finding selective nicotinic agonists.

On the other hand, it is not clear whether the efficacy of nicotinic agonists in, for example, tourette's syndrome and schizophrenia is due to activation or inactivation/desensitization of neuronal nicotinic receptors.

The effect of an agonist on a neuronal nicotinic receptor strongly depends on its contact time. Rapid reversible desensitization occurs in milliseconds, decline stops in seconds (rundown), irreversible inactivation of α 4 β 2 and α 7-containing receptors occurs in hours, and their upregulation occurs in days.

In other words: the effect of nicotinic "agonists" may in fact be due to partial agonism, inactivation and/or desensitization of neuronal nicotinic receptors. In turn, appropriate concentrations of neuronal nicotinic receptor channel blockers may produce the same effects as reported for nicotinic agonists in the above indications.

The invention

It has now been found that a series of unsaturated 1-aminoalkylcyclohexanes have significant and unexpected NMDA, 5HT₃And nicotinic receptor antagonistic activity. By virtue of the above characteristics, these substances are suitable for the treatment of a variety of CNS disorders involving glutamatergic, 5-hydroxytryptamine-ergic and nicotinic transmission disorders, with immunomodulatory potency and anti-infectious disease properties. These compounds are preferably combined with one or more pharmaceutically acceptable diluents, carriers, or excipients to form pharmaceutical compositions thereof.

Objects of the invention

It is an object of the present invention to provide novel pharmaceutical compounds-unsaturated 1-aminoalkylcyclohexane NMDA, 5HT₃And nicotinic receptor antagonists and pharmaceutical compositions thereof. It is another object of the present invention to provide a novel method for treating, eliminating, alleviating, or ameliorating adverse CNS disorders related to glutamatergic, 5-hydroxytryptamine-ergic, nicotinic transmission disorders, for treating immunomodulatory disorders and for treating infectious diseases, by using a compound of the present invention or a pharmaceutical composition containing a compound of the present invention. It is another object of the present invention to provide a process for preparing the unsaturated 1-aminoalkylcyclohexane active ingredient. Other objects of the present invention will become apparent hereinafter and will be apparent to those skilled in the art.

Summary of The Invention

The contents considered to be included in the scope of the present inventionEspeciallySummarized in the following text:

a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof

Wherein:

-R^＊is- - - (A)_n--(CR¹R²)_m--NR³R⁴，

-n + m is 0, 1 or 2,

-A is selected from linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆)，

-R¹And R²Independently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight or branched chainLower alkynyl (C)₂-C₆)，

-R³And R⁴Independently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆) Or together form an alkylene radical (C)₂-C₁₀) Or alkenylene (C)₂-C₁₀) Or together with N to form optionally substituted C_1-6Alkyl and/or C_2-6An alkenyl-substituted 3-7 membered azacycloalkane or azacycloalkene,

-R⁵independently selected from linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆) Or R is⁵Combines with the carbon to which it is attached and an adjacent carbon to form a double bond,

R_p、R_q、R_rand R_sIndependently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆) Or R is_p、R_q、R_rAnd R_sIndependently may combine with the carbon to which it is attached and an adjacent carbon to form a double bond, or R_p、R_q、R_rAnd R_sIndependently may form a double bond with the U or Y to which it is attached,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that R_pAnd R_qAt least one of which is not hydrogen and R_rAnd R_sAt least one of which is not hydrogen,

and with the proviso that when U-Z is equal to cyclohexane then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAnd R_sAt least one of which is a straight-chain or branched lower-bond alkenyl group (C)₂-C₆) Or straight-chain or branched lower alkynyl (C)₂-C₆)；

A method of treating a living animal to alleviate a condition treatable by an NMDA antagonist, comprising the step of administering to said living animal an amount of a compound selected from the group consisting of compounds of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

-R¹And R²Independently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆)，

-R⁵、R_p、R_q、R_rand R_sIndependently selected from hydrogen, linear or branched lower alkyl (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆) Or R is⁵、R_p、R_q、R_rAnd R_sIndependently may combine with the carbon to which it is attached and an adjacent carbon to form a double bond, or R_p、R_q、R_rAnd R_sIndependently may form a double bond with the U or Y to which it is attached,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that when U-Z is equal to cyclohexane then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAt least one of which is a straight or branched lower alkenyl group (C)₂-C₆) Or straight-chain or branched lower alkynyl (C)₂-C₆)；

A method of treating a living animal to alleviate a condition wherein a compound is selected for its immunomodulatory, antimalarial, anti-borna virus, or anti-hepatitis c, anti-trypanosomiasis, and anti-HSV capabilities, comprising the step of administering to said living animal an amount of a compound selected from the group consisting of a compound of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

A method of treating a living animal to alleviate a condition treatable by an NMDA antagonist, said condition selected from the group consisting of: excitotoxicity selected from the group consisting of ischemia during stroke, trauma, hypoxia, hypoglycemia, glaucoma and hepatic encephalopathy,

a chronic neurodegenerative disease selected from the group consisting of Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron disease, mitochondrial dysfunction, Korsakoff's syndrome, and Creutzfeldt-Jakob disease,

other disorders involving long-term plastic changes in the central nervous system selected from chronic pain, drug tolerance, dependence and addiction (e.g., opioids, cocaine, benzodiazepines)Nicotinoids, nicotine, and alcohol), and

epilepsy, tardive dyskinesia, L-DOPA-induced dyskinesia, schizophrenia, anxiety, depression, acute pain, spasticity and tinnitus,

comprising the step of administering to said living animal an amount of a compound selected from the group consisting of compounds of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

A method for treating a living animal to relieve the symptoms of a human suffering from 5HT₃A method of treating a condition with a receptor antagonist, comprising the step of administering to said living animal an amount of a compound selected from the group consisting of compounds of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

-R¹And R²Independently selected from hydrogen, linear or branched lowerAlkyl radical (C)₁-C₆) Straight-chain or branched lower alkenyl (C)₂-C₆) And straight-chain or branched lower alkynyl (C)₂-C₆)，

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

A method of treating a living animal to alleviate a condition treatable by a neuronal nicotinic receptor antagonist comprising the step of administering to said living animal an amount of a compound selected from the group consisting of compounds of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that when U-Z is equal to cyclohexane then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAt least one of which is a straight or branched lower alkenyl group (C)₂-C₆) Or straight or branchedLower alkynyl (C)₂-C₆)；

A method for treating a living animal to relieve the symptoms of a human suffering from 5HT₃A method of treatment of a condition with a receptor antagonist, said condition selected from the group consisting of anxiety disorders, depressive disorders, schizophrenia and treatment-related psychoses, drug and alcohol abuse disorders, cognitive disorders, alzheimer's disease, parkinson's disease, cerebellar tremor, migraine, appetite disorders, Inflammatory Bowel Syndrome (IBS), and emesis, comprising the step of administering to said living animal an amount of a compound selected from the group consisting of a compound of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

A method of treating a living animal to alleviate a condition treatable by a neuronal nicotinic receptor antagonist, said condition selected from the group consisting of tourette's syndrome, anxiety disorders, schizophrenia, drug abuse, nicotine abuse, cocaine abuse, dyskinesia (huntington's disease, L-DOPA-induced), Attention Deficit Hyperactivity Disorder (ADHD), alzheimer's disease, parkinson's disease and pain, comprising the step of administering to said living animal an amount of a compound selected from the group consisting of a compound of formula I:

wherein:

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

The use of a compound of formula I as defined in combination with the above methods and optical isomers thereof and pharmaceutically acceptable acid or base addition salts thereof, in the manufacture of a medicament for use in any such method; and

a pharmaceutical composition comprising a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, in combination with one or more pharmaceutically acceptable diluents, excipients and/or carriers:

wherein:

-R^＊is- - - (A)_n--(CR¹R²)_m--NR³R⁴，

-n + m is 0, 1 or 2,

provided that U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that R_pAnd R_qAt least one of which is not hydrogen and R_rAnd R_sAt least one of which is not hydrogen

And with the proviso that when U-Z is equal to cyclohexane then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAnd R_sAt least one of which is a straight or branched lower alkenyl group (C)₂-C₆) Or straight-chain or branched lower alkynyl (C)₂-C₆)。

Detailed Description

The following detailed description and detailed examples are illustrative only and should not be taken as limiting.

The scheme is as follows: examples 1 and 2

Example 1.

3, 3, 5, 5-tetramethyl-1-vinylcyclohexylamine hydrochloride (5).

a) Ethyl 2- (3, 3, 5, 5-tetramethylcyclohexylidene) acetate (2).

To a stirred solution of triethyl phosphonate acetate (49.32g, 222mmol) in anhydrous THF (180ml) under argon was added NaH (8.8g, 222mmol, 60% suspension in mineral oil) in small portions while cooling with ice water. Stirring was continued for 1 hour at room temperature, then a solution of 3, 3, 5, 5-tetramethylcyclohexanone (30.85g, 200mmol) was added over 10 minutes and the resulting mixture was refluxed for 22 hours. The mixture was then poured onto ice (400g), the product extracted with diethyl ether (4X 150ml) and MgSO₄The extract is dried. After evaporation of the solvent in vacuo, the oily residue was distilled at 145 deg.C (11mm Hg) to give 36.8g (86%) of 2 as an oil.¹HNMR(CDCl₃TMS): 0.96 and 0.98 (12H in total, s, 3, 5-CH)₃)；1.27(3H，t，CH₃-ethyl); 1.33(2H, m, 4-CH)₂) (ii) a 1.95 and 2.65 (4H in total, s, 2, 6-CH)₂)；4.14(2H，q，CH₂-ethyl) and 5.69ppm (1H, s, ═ C-H).

b)2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethanol (3).

To LiAlH₄(1.7g, 45mmol) in 60ml of anhydrous Ether A stirred solution of acetate 2(3.2g, 15mmol) in Ether (20ml) was added dropwise) The solution was cooled with ice water. Stirring was continued for 1 hour and the remaining LiAlH was destroyed with water₄. The aqueous layer was separated and extracted twice with ether (30 ml). The combined extracts were washed with brine (50ml) and MgSO₄And (5) drying. After concentration in vacuo, the oily residue was purified by Kugelrohr short path distillation (150 ℃ C., 170 ℃ C., 11mm Hg) to give 3(2.3g, 89%) as an oil.¹H NMR(CDCl₃，TMS)：0.92(6H，s，3，5-CH₃)；1.10(1H，br s，OH)；1.28(2H，s，4-CH₂) (ii) a 1.87 and 1.94 (4H, s, 2, 6-CH in total)₂)；4.16(2H，d，7Hz，CH₂O) and 5.50ppm (1H, t, 7Hz, ═ C-H).

c)2, 2, 2-trichloro-N- (3, 3, 5, 5-tetramethyl-1-vinylcyclohexyl) acetamide (4).

To a solution of alcohol 3(0.8g, 4.7mmol) in diethyl ether (5ml) was added NaH (0.22g of 55% dispersion in mineral oil (0.22 mmol)). The reaction mixture was cooled to-10 ℃ and a solution of trichloroacetonitrile (0.68g, 4.7mmol) in diethyl ether (3ml) was added dropwise. The solution was allowed to warm to room temperature and the solvent was evaporated. And pentane (8ml) containing methanol (0.018ml) was added to the residue. The resulting mixture was filtered through a pad of celite and evaporated. The remaining oil was dissolved in xylene (10ml) and refluxed for 10 hours. A large amount of xylene was distilled off under reduced pressure (11mm Hg) and the residue was purified by flash chromatography on silica gel (hexane, hexane-ethyl acetate, 10: 1) to give 4(0.98g, 66%) as an oil.¹H NMR(CDCl₃，TMS)：0.95(6H，s，3，5-CH₃)；1.18(6H，s，3，5-CH₃)；1.1-1.5(2H，m，4-CH₂)；1.32(2H，d，15Hz，2，6-CH₂)；2.15(2H，d，15Hz，2，6-CH₂)；5.08(1H，d，11Hz，＝CH₂)；5.13(1H，d，18Hz，＝CH₂) (ii) a 5.85(1H, dd, 18 and 11Hz ═ HC) and 6.7ppm (1H, br s, NH).

d)3, 3, 5, 5-tetramethyl-1-vinylcyclohexylamine hydrochloride (5).

Amide 4(0.32g, 1mmol) and powdered NaOH (0.4g, 10mmol) in DMSO (3ml) at room temperature) The mixture was stirred for 7 days. The reaction mixture is washed with H₂O (20ml) was diluted and stirred at room temperature overnight. The product was extracted with hexane (3X 10 ml). The combined extracts were washed with brine (20ml), dried over NaOH and filtered through a pad of celite. To the resulting solution was added a 4M HCl in dry ether (0.5ml) and the solvent was evaporated. The residue was treated with acetonitrile (10ml) and the precipitate was collected on a filter and treated with P under vacuum₂O₅Drying afforded 5(0.12g, 53%) as a colorless solid.¹H NMR(CDCl₃TMS): 0.98 and 1.01 (12H in total, s, 3, 5-CH)₃) (ii) a 1.19 and 1.29 (total 2H, average d, 14Hz, 4-CH)₂)；1.62(2H，d，13.5Hz，2，6-CH₂)；1.72(2H，br s，H₂O)；2.16(2H，d，13.5Hz，2，6-CH₂) (ii) a 5.46 and 5.73(2H, all d, 18 and 11Hz, ═ CH₂) (ii) a 6.16(1H, dd, 18 and 11Hz, ═ CH) and 8.24ppm (3H, br s, NH)₃ ⁺)。

Example 2.

N, 3, 3, 5, 5-pentamethyl-1-vinylcyclohexylamine hydrochloride (7).

a) Methyl 3, 3, 5, 5-tetramethyl-1-vinylcyclohexylcarbamate (6).

Amine hydrochloride 5(0.25g, 1.2mmol) and Na were added at room temperature₂CO₃A mixture of (0.73g, 6.9mmol) and THF (6ml) was stirred for 1 hour. Methyl chloroformate (0.27ml, 3.45mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with diethyl ether (20ml), filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10: 1) to give 6(0.24g, 87%) as a colorless solid with a melting point of 61-63 ℃.¹H-NMR(CDCl₃TMS): 0.92 and 1.15 (12H in total, s, 3, 5-CH)₃)；1.00-1.40(4H，m，4-CH₂And 2, 6-CH); 2.00(2H, d, 14Hz, 2, 6-CH); 3.62(3H, s, CH)₃N); 4.72(1H, br s, NH); 5.00 and 5.06 (total of 2H, average d, 10.5 and 17Hz, ═ CH₂) And 5.83ppm (1H, dd, 10.5 and 17Hz, ═ CH).

b) N, 3, 3, 5, 5-pentamethyl-1-vinylcyclohexylamine hydrochloride (7).

Mixing LiAlH₄A mixture of (0.28g, 7.4mmol) and carbamate 6(0.22g, 0.92mmol) in THF (22ml) was refluxed for 12 hours. It was then cooled in an ice bath and water (20ml) was added dropwise. The resulting suspension was extracted with hexane (3X 20ml) and the combined extracts were washed with brine (20 ml). The extract was dried over NaOH, filtered and treated with a 2.4M solution of HCl in ether (1 ml). The resulting suspension was evaporated to dryness. The residue was treated with diethyl ether (10ml) and acetonitrile (1 ml). The precipitate was collected on a filter and treated with P under vacuum₂O₅Drying afforded 7(0.11g, 52%) as a colorless solid.¹H-NMR(CDCl₃TMS): 1.00 and 1.02 (12H in total, s, 3, 5-CH)₃) (ii) a 1.23 and 1.32 (total 2H, average d, 15Hz, 4-CH)₂)；1.72(2H，d，13Hz，2，6-CH)；2.15(2H，d，13Hz，2，6-CH)；2.45(3H，t，5Hz，CH₃N); 5.64 and 5.69 (total of 2H, all d, 11 and 17Hz, ═ CH₂) (ii) a 5.98(1H, dd, 11 and 17Hz, ═ CH) and 9.30ppm (2H, br s, NH)₃ ⁺)。

The scheme is as follows: examples 3 and 4

Example 3.

1-allyl-3, 3, 5, 5-tetramethylcyclohexylamine hydrochloride (11).

a) 1-allyl-3, 3, 5, 5-tetramethylcyclohexanol (8).

To a 1M stirred ether solution of allyl magnesium bromide (60ml, 60mmol) was added dropwise a solution of 3, 3, 5, 5-tetramethylcyclohexanone (3.86g, 25mmol) in dry diethyl ether (20 ml). The mixture was stirred at room temperature for 1 hour and boiled under reflux for 10 minutes. Then it is cooled with ice water and treated with NH₄A saturated aqueous solution of Cl (40ml) was carefully handled. The organic layer was separated and washed with water and brine. With anhydrous MgSO₄After drying, the solution was concentrated under vacuum. The residue is fractionated under reduced pressure to give 3.5g (72%) of 8 having a boiling point of 98-100 ℃ C/12 mmHg.¹H NMR(CDCl₃，TMS)：0.88(6H，s，3，5-CH_3eq)；1.20(6H，s，3，5-CH_3ax)；0.95-1.60(6H，m，2，4，6-CH₂)；2.15(2H，d，7.5Hz，CH₂C＝)；4.95-5.30(2H，m，＝CH₂) And 5.65-6.20ppm (1H, m, ═ CH).

b) 1-allyl-1-azido-3, 3, 5, 5-tetramethylcyclohexane (9) and 1-methyl-2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethyl azide (10).

To a solution of cyclohexanol 8(1.96g, 10mmol) in dry benzene (20ml) was added azidotrimethylsilane (12mmol) under argon. To this cooled (5 ℃ C.) solution was slowly added BF by syringe over 20 minutes₃＊OEt₂(12 mmol). The mixture was stirred for 6 hours, then water was slowly added. The organic layer was separated and washed with NaHCO₃Washed with saturated aqueous solution and brine, over MgSO₄And (5) drying. Filtration and evaporation of the solvent while maintaining the temperature below 25 ℃ gave an oil which was isolated by silica gel column chromatography (ligroin). The fraction with an Rf of 0.85 (hexane) was collected. The solvent was evaporated to give 9 as a colorless oil (0.26g, 11.7%).¹H NMR(CDCl₃，TMS)：0.89(6H，s，3，5-CH_3eq)；0.90(1H，d，14Hz，4-CH_ax)；1.05(2H，d，14Hz，2，6-CH_ax)；1.18(6H，s，3，5-CH_3ax)；1.37(1H，d，14Hz，4-CH_eq)；1.60(2H，d，14Hz，2，6-CH_eq)，2.29(2H，d，7Hz，CH₂C＝)；4.95-5.25(2H，m，＝CH₂) And 5.65-6.15ppm (1H, m, ═ CH).

The additional fraction (Rf 0.65 (hexane)) was evaporated to give 0.425g (20.3%) of azide 10 as a colorless oil.¹H NMR(CDCl₃TMS): 0.91(6H, s), 0.94(3H, s) and 0.96(3H, s, 3 ', 5' -CH)₃)；1.23(3H，d，6.5Hz，1-CH₃)；1.26(2H，s，4`-CH₂) (ii) a 1.89(2H, s) and 1.96(2H, s, 2 ', 6' -CH)₂) (ii) a 4.31(1H, dq, 6.5 and 9.5Hz, 1-CH) and 5.21ppm (1H, dm, 9.5Hz, ═ CH).

c) 1-allyl-3, 3, 5, 5-tetramethylcyclohexylamine hydrochloride (11).

A solution of azide 9(0.221g, 1.0mmol) in dry ether (4ml) was added dropwise over 10 minutes to a stirred suspension of lithium aluminium hydride (0.152g, 4mmol) in ether (10 ml). The mixture was stirred for 4 hours and then treated with 20% aqueous NaOH (8 ml). The aqueous layer was separated and extracted with diethyl ether (2X 15 ml). The combined organic extracts were washed with brine and dried with NaOH. The filtrate was treated with anhydrous HCl in ether and evaporated. To the solid residue was added anhydrous ether and it was collected on a filter, washed with anhydrous ether to give 11(0.105g, 47%) as a colorless solid.¹H NMR(CDCl₃，TMS)：1.03(6H，s，3，5-CH_3eq)；1.06(6H，s，3，5-CH_3ax)；1.29(2H，s，4-CH₂)；1.63(2H，d，13Hz，2，6-CH_ax)；1.80(2H，d，13Hz，2，6-CH_eq)、2.71(2H，d，7Hz，CH₂C＝)；5.10-5.40(2H，m，＝CH₂) (ii) a 5.75-6.25(1H, m, ═ CH) and 8.25ppm (3H, br s, NH₃ ⁺)。

Example 4.

1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine hydrochloride (24).

A solution of 1-methyl-2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethyl azide (10) (0.33g, 1.5mmol) in dry diethyl ether (4ml) was added dropwise over 10 minutes to a stirred suspension of lithium aluminum hydride (0.152g, 4mmol) in diethyl ether (15 ml). The mixture was stirred for 4 hours and then treated with 20% aqueous NaOH (8 ml). The aqueous layer was extracted with diethyl ether (15ml 2X). The organic extracts were combined, washed with brine and dried with NaOH. The filtrate was treated with anhydrous HCl in ether and evaporated under vacuum. To the solid residueAnhydrous diethyl ether was added thereto, and it was collected on a filter and washed with anhydrous diethyl ether to give 24(0.18g, 54%) as a colorless solid.¹H NMR(CDCl₃TMS): 0.89(6H, s), 0.92(3H, s) and 0.98(3H, s, 3 ', 5' -CH)₃)；1.27(2H，s，4`-CH₂)；1.47(3H，d，6.5Hz，3-CH₃)；1.84(1H，d，13.5Hz，2`-CH)；1.87(2H，s，6`-CH₂) 2.06(1H, d, 13.5Hz, 2' -CH); 4.17(1H, dq, 6.5 and 9.5Hz, 2-CH); 5.35(1H, d, 9.5Hz, ═ CH) and 8.25ppm (3H, br s, NH₃ ⁺)。

The scheme is as follows: examples 5, 6 and 7

Example 5.

1- (1-allyl-3, 3, 5, 5-tetramethylcyclohexyl) piperidine hydrochloride (13).

a)1- (3, 3, 5, 5-tetramethyl-1-cyclohexenyl-1) piperidine (12).

Piperidine (1.2 equiv.) and 3, 3, 5, 5-tetramethylcyclohexanone were condensed by heating in benzene while azeotropically removing water. The starting material was removed under vacuum distillation conditions (100 ℃ C./10 mm Hg) to obtain a crude product. As an amber oil.¹H NMR(CDCl₃TMS): 0.94(6H, s) and 0.97(6H, s, 3 ', 5' -CH)₃)；1.25(2H，s，4`-CH₂) (ii) a 1.40-1.70(6H, m, piperidine 3, 4, 5-CH)₂)；1.76(2H，s，6`-CH₂) (ii) a 2.60-2.85(4H, m, piperidine 2, 6-CH)₂) And 4.40ppm (1H, s, ═ CH).

b)1- (1-allyl-3, 3, 5, 5-tetramethylcyclohexyl) piperidine hydrochloride (13).

To a solution of enamine 12(2.1g, 9mmol) in THF (20ml) was added acetic acid (0.675g, 11.25 mmol). The mixture was stirred for 5 minutes and addedZinc powder (0.74g, 11.25mgA) was charged. A solution of allyl bromide (1.63g, 13.5mmol) in THF (5ml) was then added dropwise and the mixture was stirred at room temperature for 6 hours. Adding Na₂CO₃The aqueous solution and the resulting mixture were extracted with diethyl ether. The extract was washed with brine, and anhydrous MgSO₄Dried and concentrated under vacuum. The residue was separated by silica gel column chromatography (hexane, 5% EtOAc in hexane). The fraction with Rf 0.85 (hexane-EtOAc, 13: 2) was collected, evaporated and treated with anhydrous HCl in ether. The precipitate was filtered and washed with hexane-EtOAc mixture to give 13(0.79g, 29%) as a colorless solid.¹H NMR(CDCl₃，TMS)：1.07(6H，s，3`，5`-CH_3eq)，1.10(6H，s，3`，5`-CH_3ax) (ii) a 1.34(1H, d, 12.2Hz) and 1.45(1H, d, 12.2Hz, 4' -CH)₂)；1.70-1.95(6H，m，2`，6`-CH_axAnd piperidine 3, 5-CH, 4-CH₂，)；2.37(2H，d，13.4Hz，2`，6`-CH_eq) (ii) a 2.40-2.70(2H, m, piperidine 3, 5-CH); 2.76(2H, d, 7.2Hz, CH)₂C ═ C); 2.75-3.00(2H, m, piperidine 2, 6-CH); 3.64(2H, d, 11.6Hz, piperidine 2, 6-CH); 5.13(1H, d, 9.6Hz) and 5.24(1H, d, 17.8Hz, ═ CH₂) (ii) a 5.85-6.15(1H, m, ═ CH) and 10.72ppm (1H, br s, NH).

Example 6.

1- [3, 3, 5, 5-tetramethyl-1- (3-methyl-2-butenyl) cyclohexyl ] piperidine hydrochloride (14).

Prepared from piperidine 12 following the procedure for compound 13 (example 5, b) using 4-bromo-2-methyl-2-butene instead of allyl bromide. Yield: 20 percent.¹H NMR(CDCl₃TMS): 1.07 and 1.08 (12H in total, s, 3 ', 5' -CH)₃) 1.32 and 1.44(2H, average d, 14.2Hz, 4-CH)₂) (ii) a 1.69 and 1.76(6H, s, ═ C (CH)₃)₂) (ii) a 1.68-1.96(4H, m, 3, 5-CH and 4' -CH)₂，)；1.84(2H，d，13.4Hz，，2`，6`-CH_ax)；2.31(2H，d，13.4Hz，，2`，6`-CH_eq)；2.40-2.80(4H，m，N(CH)₂，3，5-CH)；2.60(2H，d，7.2Hz，CH₂C＝)；3.63(2H，d，10.4Hz，N(CH)₂) (ii) a 5.31(1H, t, 6.8Hz, ═ CH) and 10.55ppm (1H, br s, NH).

Example 7.

1- [3, 3, 5, 5-tetramethyl-1- (2-propynyl) cyclohexyl ] piperidine hydrochloride (15).

Prepared from piperidine 12 following the procedure for compound 13 (example 5, b) using 3-bromopropyne instead of allyl bromide. Yield: 6 percent.¹H NMR(CDCl₃，TMS)：1.07(6H，s，3`，5`-CH_3eq)，1.11(6H，s，3`，5`-CH_3ax) (ii) a 1.23 and 1.44 (total 2H, average d, 14.3Hz, 4' -CH)₂) (ii) a 1.75-2.00(4H, m, piperidine 3, 5-CH, 4-CH)₂，)；1.91(2H，d，13.2Hz，2`，6`-CH_ax)；2.28(1H，s，HCC)；2.34(2H，d，13.2Hz，2`，6`-CH_eq) (ii) a 2.40-2.70(2H, m, piperidine 3, 5-CH); 2.81(2H, s, CH)₂CC); 2.85-3.10(2H, m, piperidine 2, 6-CH); 3.69(2H, d, 10.2Hz, piperidine 2, 6-CH) and 11.12ppm (1H, brs, NH).

The scheme is as follows: examples 8 and 9

Example 8.

2- (3, 3, 5, 5-tetramethyl-1-vinylcyclohexyl) ethylamine hydrochloride (19).

a) Ethyl 2- (3, 3, 5, 5-tetramethyl-1-vinylcyclohexyl) acetate (16).

A mixture of triethyl orthoacetate (18.6ml, 102mmol), 2- (3, 3, 5, 5-tetramethyl-cyclohexylidene) ethanol (3) (4.63g, 25.4mmol) and propionic acid (0.19ml, 2.5mmol) was heated at 145 ℃ for 10 h. Ethanol was distilled off from the mixture during the reaction. The reaction mixture was cooled and poured into water (100 ml). Extraction with hexane (2X 50ml)Taking aqueous phase and mixing the combined organic phase with 5% KHSO₄Aqueous solution (50ml) and brine (50 ml). The extract is extracted with MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel (ligroin and ligroin-ethyl acetate, 100: 2) to give 16(4.64g, 73%) as an oil.¹H-NMR(CDCl₃，TMS)：0.91(6H，s，3，5-CH₃)；1.01(6H，s，3，5-CH₃) (ii) a 1.23(3H, t, 7Hz, ethyl CH)₃)1.00-1.30(4H，m，4-CH₂And 2, 6-CH); 1.86(2H, d, 13Hz, 2, 6-CH); 2.22(2H, s, CH)₂C ═ O); 4.08(2H, q, 7Hz, ethyl CH₂) (ii) a 5.06 and 5.07 (total of 2H, average d, 11 and 17.5Hz, ═ CH₂) And 5.95ppm (1H, dd, 11 and 17.5Hz, -CH ═ CH).

b)2- (3, 3, 5, 5-tetramethyl-1-vinylcyclohexyl) acetic acid (17).

A solution of NaOH (1.03g, 25.8mmol) and acetate 16(1.3g, 5.15mmol) in methanol (26ml) was refluxed for 3 hours. The mixture was cooled to room temperature and poured into water (100 ml). The aqueous phase was acidified with concentrated aqueous HCl and extracted with hexane (3X 30 ml). The combined organic phases were washed with brine and CaCl₂Dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10: 1) to give 17(0.7g, 71%) as a colorless solid with a melting point of 92-94 ℃.¹H-NMR(CDCl₃，TMS)：0.92(6H，s，3，5-CH₃)；1.02(6H，s，3，5-CH₃)；1.00-1.30(4H，m，4-CH₂And 2, 6-CH); 1.90(2H, d, 14Hz, 2, 6-CH); 2.27(2H, s, CH)₂C ═ O); 5.11 and 5.13 (total 2H, average d, 11 and 18Hz, ═ CH₂) (ii) a 5.99(1H, dd, 18 and 11Hz, ═ CH) and 10.80ppm (1H, br s, COOH).

c)2- (3, 3, 5, 5-tetramethyl-1-vinylcyclohexyl) acetamide (18).

N-hydroxysuccinimide (0.25g, 2.2mmol) and N, N' -dicyclohexylcarbodiimide (0.45, 2.2mmol) were added to a solution of cyclohexylacetic acid 17(0.45g, 2mmol) in THF (5 ml). At room temperature willThe mixture was stirred for 18 hours and cooled in an ice bath. Adding 25% NH at one time₄Aqueous OH (2ml) and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered off and washed with diethyl ether (30 ml). The organic phase of the filtrate was separated and washed with 5% KHSO₄Aqueous solution (10ml) and brine. The extract is extracted with MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel (ligroin-ethyl acetate, 4: 1 to 1: 1) to give 18(0.34g, 76%) as a colourless solid with a melting point of 44-46 ℃.¹H-NMR(CDCl₃，TMS)：0.91(6H，s，3，5-CH₃)；1.02(6H，s，3，5-CH₃)；1.00-1.30(4H，m，4-CH₂And 2, 6-CH); 1.85(2H, d, 14Hz, 2, 6-CH); 2.13(2H, s, CH)₂C ═ O); 5.18 and 5.19 (total of 2H, average d, 18 and 11Hz, ═ CH₂) (ii) a 5.40 and 5.60 (total 2H, s, NH)₂) And 6.03ppm (1H, dd, 18 and 11Hz, ═ CH).

d)2- (3, 3, 5, 5-tetramethyl-1-vinylcyclohexyl) ethylamine hydrochloride (19).

A mixture of LiAlH4(0.41g, 11mmol) and amide 18(0.30g, 1.4mmol) in THF (18ml) was refluxed for 17 hours. It was then cooled in an ice bath and water (30ml) was added dropwise. The resulting suspension was extracted with hexane (3X 30ml) and the combined organic phases were washed with brine. The extract was dried with NaOH, filtered and concentrated to a volume of-10 ml. A solution of 4.8M HCl in ether (1ml) was added and the resulting suspension was evaporated to dryness. The residue was treated with acetonitrile (5ml) and the precipitate was collected on a filter and dried with NaOH in vacuo to give 19(0.16g, 50%) as a colourless solid.¹H-NMR(CDCl₃，TMS)：0.89(6H，s，3，5-CH₃)；1.02(6H，s，3，5-CH₃) (ii) a 0.90-1.80(8H, m, ring proton and ethylamine-2-CH)₂)；2.92(2H，br s，CH₂N); 5.05 and 5.15(2H, all d, 18 and 11Hz, ═ CH₂) (ii) a 5.77(1H, dd, 18 and 11Hz, ═ CH) and 8.10ppm (3H, br s, NH)₃ ⁺)。

Example 9.

3- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine hydrochloride (32).

Triethylamine (0.25ml, 1.76mmol) and diphenylphosphoryl azide (0.38ml, 1.76mmol) were added to a solution of acid 17(0.36g, 1.6mmol) in benzene (6 ml). The mixture was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. To the residue was added cold (about 5 ℃ C.) concentrated aqueous HCl (3 ml). The resulting mixture was stirred at room temperature for 18 hours and made strongly basic by the addition of 10% aqueous NaOH. Hexane (20ml) was added to the mixture and the two phases were filtered. The precipitate was washed with hexane (2X 5ml) and water (2X 5 ml). The organic phase of the filtrate was separated. The aqueous phase was washed with hexane (2X 10 ml). The combined organic phases were washed with brine (10ml), dried over NaOH and filtered. A solution of 4.8M HCl in ether (1ml) was added and the resulting suspension was evaporated. The residue was recrystallized from acetonitrile and from P under vacuum₂O₅Drying afforded 32(0.1g, 43%) as a colorless solid.¹H-NMR：(CDCl₃TMS): 0.90 and 0.92 (total 12H, s, c-Hex-3, 5-CH)₃)；1.23(2H，s，c-Hex-4-CH₂) (ii) a 1.86 and 1.92 (4H in total, s, c-Hex-2, 6-CH)₂) (ii) a 2.49(2H, q, 7Hz, propylamine-2-CH₂) (ii) a 2.98(2H, t, 7Hz, propylamine-1-CH₂) (ii) a 5.15(1H, t, 7Hz, ═ CH-) and 8.30ppm (3H, br s, NH)₃ ⁺)。

The scheme is as follows: examples 10 and 11

Example 10.

2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethylamine hydrochloride (22).

a)3, 3, 5, 5-tetramethylcyclohexyleneacetonitrile (20).

60% NaH mineral oil dispersion (0.96g, 24mmol) was added to diethyl cyanomethylphosphonate (4.25g, 24mmol) in THF (3)0ml) was added to the solution while cooling with ice water. The mixture was stirred for 30 minutes and a solution of 3, 3, 5, 5-tetramethylcyclohexanone (3.08g, 20mmol) in THF (10ml) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 72 hours. It was poured into ice water (100ml) and extracted with diethyl ether (3X 50 ml). The combined organic phases were washed with brine, over MgSO₄Dried, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (ligroin-ethyl acetate, 10: 1) to give 20(2.38g, 71%) as a colorless oil.¹H-NMR(CDCl₃TMS), δ: 0.97 and 1.01 (12H in total, s, 3 ', 5' -CH)₃)；1.36(2H，s，4`-CH₂)；2.01(2H，s，2`-CH₂)；2.26(2H，s，6`-CH₂) And 5.14ppm (1H, s, ═ CH).

b)2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethylamine hydrochloride (22).

Mixing LiAlH₄A suspension of (0.68g, 18mmol) in diethyl ether (30ml) was cooled in an ice bath and 1M ZnCl was added₂In diethyl ether (9ml, 9 mmol). The resulting mixture was stirred for 15 minutes and a solution of nitrile 20(1g, 6mmol) in diethyl ether (30ml) was added dropwise while maintaining the temperature at 0-5 ℃. The ice bath was then removed and the mixture was stirred at room temperature for 24 hours. Water (30ml) and 20% aqueous NaOH (20ml) were added while cooling with an ice bath. The aqueous phase was extracted with diethyl ether (4X 50 ml). The combined organic phases were washed with brine (50ml) and dried with NaOH, filtered and evaporated. The residue was purified by Kugelrohr short path distillation at 160 ℃/20mm Hg. The distillate was diluted with ether and 4.8M HCl in ether (3ml) was added. The resulting precipitate was collected on the filter, washed with diethyl ether (3 × 5ml) and dried under vacuum with NaOH to give 22 as a colorless solid.¹H-NMR(CDCl₃TMS): 0.91 and 0.92 (12H in total, s, 3 ', 5' -CH)₃)；1.28(2H，s，4`-CH₂) (ii) a 1.89 and 1.93 (4H, s, 2 ', 6' -CH, total)₂)；3.62(2H，d，7Hz，CH₂N); 5.41(1H, t, 7Hz, -C ═ CH) and 8.3ppm (3H, br s, NH)₃ ⁺)。

Example 11.

2- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine hydrochloride (23).

a)2- (3, 3, 5, 5-tetramethylcyclohexylidene) propionitrile (21).

Prepared according to the procedure for compound 20 (example 10, a) using diethyl (1-cyanoethyl) phosphonate. Nitrile 21 was obtained as a colorless oil in 41% yield.¹H-NMR：(CDCl₃TMS): 0.96 and 1.00 (total of 12H, s, c-Hex-3, 5-CH)₃)；1.34(2H，s，c-Hex-4-CH₂) (ii) a 1.91(3H, s, propionitrile-3-CH)₃) (ii) a 2.04 and 2.28ppm (total 4H, s, c-Hex-2, 6-CH)₂)。

b)2- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine hydrochloride (23).

Prepared from nitrile 21 following the procedure for compound 22 (example 10, b). Amine hydrochloride 23 was obtained as a colorless solid.¹H-NMR：(CDCl₃TMS), δ: 0.92 and 0.93 (12H total, s, c-Hex-3, 5-CH)₃)；1.27(2H，s，c-Hex-4-CH₂) (ii) a 1.89(3H, s, propylamine-3-CH)₃) (ii) a 1.99 and 2.01 (4H in total, s, c-Hex-2, 6-CH)₂) (ii) a 3.64(2H, br s, propylamine-1-CH)₂) And 8.40ppm (3H, br s, NH)₃ ⁺)。

The scheme is as follows: example 12

Example 12.

(E, Z) -1- (3, 3-diethyl-5, 5-dimethylcyclohexylidene) -2-propylamine hydrochloride (28).

a) 1-allyl-3, 3-diethyl-5, 5-dimethylcyclohexanol (26).

To a stirred solution of allylmagnesium bromide (20ml, 20mmol) in 1M ether was added dropwise 3,3-diethyl-5, 5-dimethylcyclohexanone (25) (1.47g, 8.06mmol) in dry diethyl ether (5 ml). The mixture was stirred at room temperature for 1 hour and boiled under reflux for 10 minutes. Then it is cooled with ice water and treated with NH₄Work-up with a saturated aqueous solution of Cl (40 ml). The organic phase was separated and washed with water and brine. With anhydrous MgSO₄After drying, the solution was concentrated under vacuum. The residue was purified by silica gel column chromatography (light petroleum ether). The fraction with an Rf of 0.7 (hexane: EtOAc, 13: 2) was collected. The solvent was evaporated to give 26(1.35g, 74%) as a colorless oil.¹H NMR(CDCl₃TMS): 0.74(6H, t, 7Hz, ethyl 2CH₃)；0.88(3H，s，5-CH_3eq)；1.19(3H，s，5-CH_3ax)；0.80-2.05(10H，m，2，4，6-CH₂And 2CH of ethyl₂)；2.14(2H，d，7Hz，CH₂C＝)；4.95-5.30(2H，m，＝CH₂) And 5.65-6.20ppm (1H, m, ═ CH).

b) (E, Z) -1-methyl-2- (3, 3-diethyl-5, 5-dimethylcyclohexylidene) ethyl azide (27).

Prepared from cyclohexanol 26 following the procedure for compounds 9 and 10 (example 3, b). Azide 27 was obtained as a colorless oil in 15% yield.¹H NMR(CDCl₃TMS): 0.73 and 0.74 (total 6H, average t, 7Hz, 2 CH)₃Ethyl); 0.91, 0.94 and 0.97 (total of 6H, all s, 5' -CH)₃)；1.10-1.45(4H，m，2CH₂Ethyl); 1.22(3H, d, 6.5Hz, 1-CH)₃)；1.26(2H，s，4`-CH₂) (ii) a 1.89(2H, s) and 1.97(2H, m, 2 ', 6' -CH)₂) (ii) a 4.08-4.48(1H, m, 1-CH) and 5.18ppm (1H, dm, 9.5Hz, ═ CH).

c) (E, Z) -1- (3, 3-diethyl-5, 5-dimethylcyclohexylidene) -2-propylamine hydrochloride (28).

Prepared from azide 27 following the procedure for compound 24 (example 4). Amine hydrochloride 28 was obtained as a colorless solid in 16% yield.¹H NMR(CDCl₃，TMS)：0.72(6H，br t，7Hz，2CH₃Ethyl), 0.90, 0.92 and 0.98 (total 6H,all of s, 5' -CH₃)；1.25(6H，m，4`-CH₂And 2CH₂Ethyl); 1.47(3H, d, 6.5Hz, 2-CH)₃)；1.70-2.25(2H，br AB q，13Hz，2`-CH₂)；1.87(2H，s，6`-CH₂) 4.18(1H, m, 2-CH); 5.34(1H, br d, 9.5Hz, ═ CH) and 8.38ppm (3H, br s, NH₃ ⁺)。

The scheme is as follows: example 13

Example 13.

2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine hydrochloride (31).

a) 2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propanol (29).

A solution of acetate 2(2.14g, 10mmol) in diethyl ether (20ml) was added to a solution of 1.6MMeLi in diethyl ether (26ml, 40mmol) while cooling in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. It was then cooled in an ice bath and saturated NH was added dropwise₄Aqueous Cl solution (20 ml). The aqueous phase was extracted with diethyl ether (2X 30 ml). The combined organic phases were washed with brine (30ml) and MgSO₄Dried, filtered and evaporated. The residue was purified by Kugelrohr short path distillation (100 ℃/4mm Hg) to give 29(1.86g, 86%) as a colorless oil.¹H-NMR：(CDCl₃TMS): 0.91 and 0.96 (12H total, s, c-Hex-3, 5-CH)₃)；1.25(2H，s，c-Hex-4-CH₂)；1.38(6H，s，-C(CH₃)₂O); 1.79 and 2.23 (s 2H, s-Hex-2, 6-CH)₂) And 5.39ppm (1H, s, ═ CH-).

b) 2-azido-2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexylidene) propane (30).

BF is added within 3 minutes₃Et₂O (0.3ml, 2.4mmol) is addedAdd alcohol 29(0.42g, 2mmol) and TMSN₃(0.31ml, 2.4mmol) in benzene (4.5ml) while cooling with an ice bath. The reaction mixture was stirred at 5-10 ℃ for 1 hour and filtered through a short silica gel column. The solution was evaporated and the residue was purified by flash chromatography on silica gel (ligroin) to give 30(0.30g, 64%) as a colorless oil.¹H-NMR(CDCl₃TMS): 0.92 and 0.98 (total of 12H, s, c-Hex-3, 5-CH)₃)；1.27(2H，s，c-Hex-4-CH₂)；1.40(6H，s，-C(CH₃)₂N₃) (ii) a 1.85 and 2.23 (s, c-Hex-2, 6-CH, 2H, 6H, 2H₂) And 5.27ppm (1H, s, ═ CH-).

c) 2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine hydrochloride (31).

Prepared from azide 30 by the same procedure as for amine 24 (example 4). Amine hydrochloride 31 was obtained as a colorless solid in 69% yield.¹H-NMR(CDCl₃TMS): 0.91 and 0.98 (12H total, s, c-Hex-3, 5-CH)₃)；1.26(2H，s，c-Hex-4-CH₂)；1.68(6H，s，-C(CH₃)₂N); 1.84 and 2.10 (s, c-Hex-2, 6-CH, 2H, S, H₂) (ii) a 5.15(1H, s, ═ CH-) and 8.5ppm (3H, br s, NH)₃ ⁺)。

The scheme is as follows: examples 14 and 15

Example 14.

3, 5, 5-trimethyl-2-cyclohexen-1-amine hydrochloride (35).

a) 3-azido-1, 5, 5-trimethyl-1-cyclohexene (34).

To a cooled (0 ℃ C.) solution of sodium azide (0.81g, 12.5mmol) in CH₂Cl₂(5ml) suspension was added 53% H dropwise₂SO₄Aqueous solution (8 ml). The mixture was stirred for 10 min, then 3, 5, 5-trimethyl-2-cyclohexanol (33) (0.70g, 5mmol) in CH was added₂Cl₂(8ml) solution. The mixture was stirred for 20 hours, poured into ice water and washed with NH₄OH aqueous solution neutralization and use of CH₂Cl₂And (4) extracting. The extract was washed with brine and MgSO₄And (5) drying. Filtration and evaporation of the solvent while maintaining the temperature below 25 ℃ gave an oil which was isolated by silica gel column chromatography (light petroleum ether). The fraction with an Rf of 0.8 (hexane) was collected. The solvent was evaporated to give 34 as a colorless oil (0.365g, 44%).¹H NMR(CDCl₃TMS): 0.89 and 1.01 (total 6H, s, 5, 5-CH)₃)；1.34(1H，m，c-4-CH)；1.55-1.95(3H，m，4-CH，6-CH₂)；1.71(3H，s，1-CH₃) (ii) a 3.90(1H, m, 3-CH) and 5.39ppm (1H, s, C ═ CH).

b)3, 5, 5-trimethyl-2-cyclohexen-1-amine hydrochloride (35).

Prepared from azide 34 following the procedure for the preparation of compound 11 (example 3, c). Amine hydrochloride 35 was obtained as a colorless solid in 57% yield.¹H NMR(CDCl₃TMS): 0.89 and 1.03 (total 6H, s, 5, 5-CH)₃)；1.25-2.15(4H，m，4，6-CH₂)；1.72(3H，s，3-CH₃) (ii) a 3.88(1H, m, 1-CH); 5.41(1H, s, C ═ CH) and 8.40ppm (3H, br s, NH)₃ ⁺)。

Example 15.

1, 3, 5, 5-tetramethyl-2-cyclohexen-1-amine hydrochloride (40).

a)1, 3, 5, 5-tetramethyl-1, 3-cyclohexadiene (37) and 1, 5, 5-trimethyl-3-methylene-1-cyclohexene (38).

To a stirred solution of methyl magnesium iodide (15ml, 30mmol) in 2M ether was added dropwise a solution of 3, 5, 5-trimethyl-2-cyclohexen-1-one (36) (1.38g, 10mmol) in dry ether (15 ml). The mixture was stirred for 1 hour, cooled with ice water and carefully treated with 15% CH₃Aqueous COOH (15ml) was treated. The mixture was stirred for an additional hour. The organic layer was separated and washed with water and saturated NaHCO₃And (4) washing with an aqueous solution. With MgSO₄After drying, the solution was concentrated under vacuum. The residue was purified by flash chromatography (ligroin, Rf 0.95 (hexane)) to give a mixture of 37 and 38 (0.955g, 70%) (7: 10 based on GC) as an oil.¹H NMR(CDCl₃TMS): 0.89, 0.98 and 1.03 (total 10.2H, all s, 5, 5-CH)₃) (ii) a 1.55-2.20 (total of 12.6H, m, CH)₂C ═ and CH₃C＝)；4.69(2H，dm，4Hz，＝CH₂) (ii) a 5.06(0.7H, m, ═ CH); 5.50(0.7H, sept, 1.5Hz, ═ CH) and 5.92ppm (1H, m, ═ CH).

b) 3-azido-1, 5, 5, 5-tetramethyl-1-cyclohexene (39).

Prepared from a mixture of 37 and 38 following the procedure for preparation of compound 34 (example 14, a). Azide 39 was obtained as a colorless oil in 43% yield.¹H NMR(CDCl₃TMS): 0.93 and 0.99 (total 6H, s, 5, 5-CH)₃)；1.31(3H，s，1-CH₃) (ii) a 1.36 and 1.62 (total 2H, average d, 13Hz, 4-CH)₂)；1.72(5H，s，1-CH₃，6-CH₂)；5.32(1H，s，C＝CH)。

c)1, 3, 5, 5-tetramethyl-2-cyclohexen-1-amine hydrochloride (40).

Prepared from azide 39 following the procedure for preparation of compound 11 (example 3, c). Amine hydrochloride 40 was obtained as a colorless solid in 60% yield.¹H NMR(CDCl₃TMS): 0.96 and 1.07 (total 6H, s, 5, 5-CH)₃)；1.56(3H，s，1-CH₃)；1.73(3H，s，3-CH₃)；1.60-2.05(4H，m，4，6-CH₂) (ii) a 5.49(1H, s, C ═ CH) and 8.27ppm (3H, br s, NH)₃ ⁺)。

The scheme is as follows: example 16

Example 16.

1, 3, trans-5-trimethyl-cis-3-vinylcyclohexylamine hydrochloride (45).

a)3, 5-dimethyl-3-vinylcyclohexanone (42).

A1M solution of vinylmagnesium bromide in THF (90ml, 90mmol) was cooled to-20 deg.C in a dry ice-acetone bath under inert atmosphere and CuCl (4.45g, 45mmol) was added in one portion. The mixture was stirred for 30 minutes and a solution of 3, 5-dimethyl-2-cyclohexen-1-one (41) (3.73g, 30mmol) in THF (40ml) was added dropwise while maintaining the reaction temperature at-20 ℃. The cooling bath was taken away and the reaction mixture was allowed to reach room temperature for 2 hours. Saturated NH was added thoroughly while cooling with an ice bath₄Aqueous Cl solution (50 ml). Hexane (150ml) was then added and the aqueous layer was separated and extracted with hexane (2X 100 ml). The combined organic extracts were extracted with 20% aqueous acetic acid (100ml) and saturated NaHCO₃Aqueous (3X 200ml) washes. The extract is extracted with MgSO₄Dried, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (ligroin-ethyl acetate, 20: 1) to give 42(2.4g, 52%) as a colorless oil.¹H-NMR(CDCl₃，TMS)：0.99(3H，d，6Hz，5-CH₃)；1.11(3H，s，3-CH₃) (ii) a 1.2-2.6(7H, m, ring proton); 4.94 and 5.01 (total 2H, average d, 17 and 10.5Hz, CH₂And 5.64ppm (1H, dd, 17 and 11Hz, ═ CH).

b)1, 3, trans-5-trimethyl-cis-3-vinylcyclohexanol (43).

A solution of ketone 42(1g, 6.6mmol) in diethyl ether (10ml) was added to a solution of 1.6M methyllithium in diethyl ether (12ml, 19.6mmol) while cooling in an ice bath. The resulting mixture was stirred at 0-5 ℃ for 1 hour and saturated NH was added well₄Aqueous Cl solution (10 ml). The aqueous layer was separated and extracted with diethyl ether (2X 15 ml). The combined organic phases were washed with brine (20ml) and MgSO₄And (5) drying. The extract was filtered and evaporated. The crude product was passed through a flash silica gelPurification by chromatography (3% ethyl acetate in light petroleum ether). Cyclohexanol 43(0.82g, 74%) was obtained as a colorless oil and used in the next step without characterization.

c) 1-azido-1, 3, trans-5-trimethyl-cis-3-vinylcyclohexane (44).

Prepared from cyclohexanol 43 following the procedure for preparation of compound 9 (example 3, b). Azide 44 was obtained as a colorless oil in 17% yield.¹HNMR(CDCl₃，TMS)：0.94(3H，d，6.5Hz，5-CH₃)；0.97(3H，s，3-CH₃)；1.27(3H，s，1-CH₃) (ii) a 0.7-2.0(7H, m, ring proton); 4.95 and 4.97 (total of 2H, average d, 18 and 11Hz, ═ CH₂) And 5.77ppm (1H, dd, 18 and 11Hz, ═ CH).

d)1, 3, trans-5-trimethyl-cis-3-vinylcyclohexylamine hydrochloride (45).

Prepared from azide 44 following the procedure for preparation of compound 11 (example 3, c). Amine hydrochloride 45 was obtained as a colorless solid in 32% yield.¹H-NMR(CDCl₃，TMS)：0.92(3H，d，6.5Hz，5-CH₃)；0.96(3H，s，3-CH₃)；1.45(3H，s，1-CH₃)；0.8-2.1(9H，m，2，4，6-CH₂5-CH and H₂O); 4.94 and 4.97(2H, all d, 18 and 11Hz, ═ CH₂) (ii) a 5.76(1H, dd, 18 and 11Hz, ═ CH) and 8.26ppm (3H, br s, NH)₃ ⁺)。

The scheme is as follows: example 17

Example 17.

2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -4-pentenyl amine hydrochloride (49).

a) Ethyl 2-cyano-2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) acetate (47).

Copper (I) chloride (0.05g, 0.5mmol) was added to a solution of 1M methylmagnesium iodide in diethyl ether (15ml, 15mmol) cooled under argon (-10 ℃ C.) and stirred for 5 min. A solution of acetate 46(2.5g, 10mmol) in THF (25ml) was then added dropwise over 20 minutes, keeping the temperature below 0 ℃. The mixture was stirred for 1 hour with saturated NH₄Aqueous Cl was quenched and extracted with ether. The extract was washed with brine, and anhydrous MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel (ligroin-ethyl acetate, 20: 1) to give 47(1.5g, 56.5%) as a colorless oil.¹H NMR(CDCl₃TMS): 1.01, 1.07 and 1.09 (12H, s, 3 ', 5' -CH altogether)₃) (ii) a 1.00-1.85(6H, m, ring CH); 1.30(3H, s, 1' -CH)₃)；1.33(3H，t，7Hz，CH₃-ethyl); 3.44(1H, s, 2-CH) and 4.27ppm (2H, q, 7Hz, OCH)₂)。

b) 2-cyano-2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -4-pentenoic acid ethyl ester (48)

To a solution of cyanoacetate 47(1.25g, 4.71mmol) in anhydrous DMSO (10ml) was added sodium hydride (0.284g, 7.09 mmol; 60% dispersion in mineral oil). The mixture was stirred at 50 ℃ for 30 minutes and cooled to 20 ℃. Allyl bromide (0.86g, 7.1mmol) was added thereto and the mixture was stirred at room temperature for 3 hours and then at 50 ℃ for 30 minutes. The mixture was cooled, treated with water and extracted with diethyl ether. The extract was washed with water and brine, and anhydrous MgSO₄Dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel (ligroin-ethyl acetate, 20: 1) to give 48(0.92g, 63.7%) as a colorless oil.¹H NMR(CDCl₃，TMS)：0.98(6H，s，3`，5`-CH_3eq)；1.11(6H，s，3`，5`-CH_3ax) (ii) a 1.00-1.85(6H, m, ring CH); 1.31(3H, t, 7Hz, CH)₃-ethyl); 1.33(3H, s, 1' -CH)₃) (ii) a 2.42 and 2.86 (total of 2H, ddd, 13 and 7Hz, 3-CH)₂)；4.02(2H，q，7Hz，OCH₂)；5.05-5.37(2H，m，＝CH₂) And 5.55-6.05ppm (1H, m, ═ CH).

c)2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -4-pentenyl amine hydrochloride (49)

To a solution of ester 48(0.9g, 2.95mmol) in DMSO (10ml) was added water (0.53ml, 2.95mmol) and lithium chloride (0.25g, 5.9 mmol). The mixture was stirred at 175 ℃ and 180 ℃ for 3 hours, then cooled and water (30ml) was added. The mixture was extracted with diethyl ether. The extract was washed with water and brine, and anhydrous MgSO₄Dried, filtered and concentrated to a volume of 10 ml. The resulting solution was added dropwise to a suspension of lithium aluminum hydride (0.25g, 6.6mmol) in diethyl ether (15ml) and stirred at reflux for 3 hours. The mixture was cooled and treated with 20% aqueous NaOH and extracted with ether. The extract was washed with brine, dried with NaOH, filtered and treated with anhydrous HCl in ether. After evaporation of the solvent, the residue was purified by silica gel chromatography (chloroform-methanol, 20: 1) to give 49(0.245g, 31%) as a colorless solid.¹H NMR(DMSO-D₆TMS): 0.92, 0, 96 and 1.04 (15H, all, 3 ', 5' -CH, total)₃And 1' -CH₃) 1.00-1.65 (total 6H, m, ring-CH)₂)；1.85-2.40(3H，m，3-CH₂，4-CH)；2.60-3.10(2H，m，CH₂N)；4.90-5.25(2H，m，＝CH₂) (ii) a 5.62-6.10(1H, m, ═ CH) and 7.92ppm (3H, br s, NH₃ ⁺)。

Pharmaceutical composition

The active ingredients of the present invention may be formulated together with one or more conventional adjuvants, carriers, or diluents, in the form of pharmaceutical compositions and unit dosages thereof, and in such form may be used as: solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the above liquids, are all used orally; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. The pharmaceutical compositions and unit dosage forms thereof may contain conventional or new ingredients in conventional or specific proportions, with or without other active compounds or ingredients, and the unit dosage form may contain any suitable effective amount of the active ingredient commensurate with the daily dosage range to be employed. Tablets containing 20 to 100mg of active ingredient per tablet, or more broadly, 10 to 250 mg of active ingredient, are suitable representative unit dosage forms.

Method of treatment

Because of their high activity and their low toxicity, which together present a highly advantageous therapeutic index, an effective amount of an active ingredient of the invention, preferably accompanied, concurrent or together with one or more pharmaceutically acceptable excipients, carriers, or diluents, particularly and preferably in the form of a pharmaceutical composition thereof, can be administered to a subject in need thereof, such as a living animal (including a human) by oral, rectal, or parenteral (including intravenous and subcutaneous) or, in some cases, even topical routes of administration, to treat, alleviate, or ameliorate, alleviate, or eliminate an indication or condition responsive to an active ingredient of the invention, or an indication or condition representatively listed herein. Suitable dosage ranges are generally from 1 to 1000 mg per day, preferably from 10 to 500 mg per day, in particular from 50 to 500 mg per day, depending on the precise mode of administration, form of administration, the indication to be treated, the individual to be treated and the body weight of the individual to be treated, and the preference and experience of the attending or veterinary physician.

Examples of representative pharmaceutical compositions

The reaction product can be processed into tablets, coated tablets, capsules, drops, suppositories, injections, infusions and the like with the aid of common solvents, excipients and carriers, and can be used therapeutically by oral, rectal, parenteral and other routes of administration. Representative pharmaceutical compositions are as follows.

(a) Tablets containing the active ingredients of the invention, suitable for oral administration, may be prepared by conventional tableting techniques.

(b) For suppositories, any conventional suppository base may be incorporated into the active ingredients of the invention by conventional means, for example polyethylene glycol which is solid at normal room temperature but melts at or near body temperature.

(c) For sterile solutions for parenteral administration (including intravenous and subcutaneous administration), ampoules or IV-drip bottles may be aseptically filled and autoclaved according to conventional techniques, e.g. filtration, of the active ingredient of the invention with customary amounts of conventional ingredients, e.g. sodium chloride, and appropriate amounts of double distilled water.

Other suitable pharmaceutical compositions will be apparent to those skilled in the art.

The following examples are also illustrative only and should not be construed as limiting the invention.

Example 18

Tablet formulation

A suitable formulation for a tablet containing 10 mg of active ingredient is as follows:

example 19

Tablet formulation

Another suitable formulation for a tablet containing 100mg of active ingredient is as follows:

example 20

Capsule preparation

A suitable formulation for a capsule containing 50 mg of active ingredient is as follows:

the above components are filled into gelatin capsules.

Example 21

Injection solution

A suitable formulation for an injection containing 1% active ingredient is as follows:

example 22

Liquid oral preparation

A suitable formulation for a 1 litre liquid mixture containing 2mg of active ingredient per ml of mixture is as follows:

example 23

Liquid oral preparation

Another suitable formulation for a 1 litre liquid mixture containing 20 mg of active ingredient per ml of mixture is as follows:

example 24

Liquid oral preparation

Another suitable formulation for a 1 litre liquid mixture containing 2mg of active ingredient per ml of mixture is as follows:

example 25

Aerosol formulation

180g of aerosol solution contained:

15ml of this solution are placed in an aluminium aerosol can, which is closed with a metered dose valve and is pressurized at 3.0 bar.

Example 26

TDS formulations

100 grams of solution contained:

1.8ml of this solution was placed on a fleece covered with an adhesive backing. The system is closed by a protective liner that is removed prior to use.

Example 27

Nanoparticle (nanoparticle) formulations

10g of polybutylcyanoacrylate nanoparticles contain:

the polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1N HCl/ethanol mixture as polymerization medium. Finally the nanoparticles in the suspension were freeze-dried in vacuo.

Pharmacological-overview

The active ingredients of the present invention, as well as their pharmaceutical compositions and methods of treatment, are characterized by unique advantageous and unpredictable properties, making the subject matter claimed herein as a whole non-obvious. The compounds of the present invention and their pharmaceutical compositions have shown the following valuable properties and characteristics in standard accepted reliability tests:

they are systemically active, uncompetitive NMDA receptor antagonists, have rapid blocking/deblocking (unblocking) kinetics, and are highly voltage dependent, and are therefore useful in the treatment, elimination, alleviation, mitigation, and amelioration of conditions responsive thereto, and in the treatment of various CNS disorders involving deregulation of glutamatergic transmission, by application or administration to a living animal host.

These compounds are also systemically active, non-competitive 5HT₃And neuronal nicotinic receptor antagonists and thus can be used to treat, eliminate, alleviate, and ameliorate conditions responsive thereto, and to treat various CNS disorders involving 5-hydroxytryptamine or nicotinic transmission disorders by application or administration to a living animal host.

Method

Receptor binding studies

Male Sprague-Dawley rats (200- & 250g) were decapitated and their brains were removed rapidly. The skin layer was dissected and homogenized in 20 volumes of ice-cold 0.32M sucrose solution with a glass-polytetrafluoroethylene homogenizer. The resulting tissue homogenate was centrifuged at 1000Xg for 10 minutes. The precipitate was discarded and the supernatant was centrifuged at 20,000Xg for 20 minutes. The resulting pellet was then resuspended in 20 volumes of distilled water and centrifuged at 8000Xg for 20 minutes. The supernatant and buffy coat were then centrifuged at 48,000Xg for 20 minutes in the presence of 50mM Tris-HCl, pH 8.0. The pellet was then resuspended and recentrifuged 2-3 times (48,000Xg, 20 min) in the presence of 50mM Tris-HCl, pH 8.0. All centrifugation steps were performed at 4 ℃. After resuspension in 5 volumes of 50mM Tris-HCl pH 8.0, the membrane suspension was rapidly frozen at-80 ℃.

On the day of analysis, the membranes were thawed, washed 4 times by resuspension in 50mM Tris-HCl pH 8.0 and centrifugation at 48,000Xg for 20 minutes, and finally resuspended in 50mM Tris-HCl pH 7.4. The amount of protein in the final membrane preparation was determined (250-500. mu.g/ml) according to the method of Lowry et al (1951). Will 2³H]- (+) -MK-801(23.9Ci/mmol, 5nM, Dupont NEN) was incubated with glycine (10. mu.M), glutamic acid (10. mu.M), and 125-250. mu.g protein (total volume 0.5ml) and different concentrations of the active agent tested (10 concentrations in duplicate) in vials. The incubation was continued at room temperature for 120 minutes (equilibrium was reached under the conditions used). Unlabeled (+) -MK-801 (10. mu.M) was added to define non-specific binding. The incubation was stopped with a millipore filter system. 4ml of ice-cold assay buffer were applied to a glass fiber filter (Schleicher)&Schuell) onThe samples were rinsed 2 times under constant vacuum. After separation and washing, the filters were placed in scintillation fluid (5 ml; Ultima Gold) and the radioactivity retained on the filters was determined using a conventional Liquid scintillation counter (Hewlett Packard, Liquid scientific analyser). 4.6nM of³H]The Kd of- (+) -MK-801 was determined by Scatchard analysis and used to calculate the affinity of the displacer as Kd value according to the Cheng Prussoff relationship. Most antagonists were tested in 3-7 separate experiments.

NMDA and neuronal nicotinic receptor subtype expression in Xenopus oocytes

Adult female Xenopus laevis (Xenopus laevis) was anesthetized in 0.2% tricaine on ice for 15 minutes prior to surgery. Oocytes were removed and incubated in 2mg/ml collagenase (type II) in the absence of Ca²⁺Oocyte ringer's solution (82.5mM NaCl, 2mM KCl, 2mM MgCl)₂5mM HEPES, pH 7.5) at room temperature for 30 minutes, and incubated with OR-2(100mM NaCl, 2mM KCl, 1mM MgCl)₂，2mM CaCl₂5mM HEPES, pH 7.5). The remaining follicular cell layer was removed manually with small forceps and the oocytes were kept in OR-2. The RNA was dissolved in DEPC-treated sterile distilled water. NMDA NR1a subunit RNA was mixed 1: 1 with NR2A subunit RNA. Similarly, neuronal nicotinic α 4RNA was mixed 1: 1 with β 2 subunit RNA. 50-100 nanoliters of each RNA mixture were injected into the cytoplasm of the oocyte using a Nanoliterijector (world Precision instruments). These oocytes were cultured in OR-2 at 19 ℃ for the next 3-6 days.

Electrophysiological responses were obtained 2-6 days after injection using a standard two-electrode voltage clamp method (GeneClamp 500 amplifier). These electrodes have a resistance of 0.2-0.4M Ω and are filled with 3 MKCl. Recordings were made in the custom room with 2-3 second exchange times. Preparation of Ca-free²⁺Bath liquid of (1) to avoid Ca²⁺Induced Cl-current (100mM NaCl, 2mM KCl, 5mM HEPES, 2mM BaCl)₂pH 7.35). 1mM trough for 30-40 seconds was manually co-applied every 2-3 minutes to oocytes clamped at-70 mVAnd amino acid and 10. mu.M glycine to activate NMDA receptor. Neuronal nicotinic receptors were activated by applying 100. mu.M acetylcholine every 2-3 minutes for 20-30 seconds to oocytes clamped at-70 mV. After obtaining a stable control response, a complete concentration-response curve of the antagonist was obtained by pre-incubation at 6-7 different concentrations at log 3 intervals.

Results from stable cells were only accepted for inclusion in the final assay, i.e., showed at least 50% recovery of response to NMDA after removal of the assayed antagonist. Despite this, recovery from the effects of drugs is not always 100%, due to a minor decrease (rundown) or increase (runup) in some cells. When present, this was always compensated by basing the% antagonism at each concentration on both control and recovery and assuming that the decrease was a linear time course. All antagonists were evaluated at 6-7 concentrations for at least 4 cells at steady state block. Equilibrium blockade is achieved within 1-3 agonist applications, depending on antagonist concentration.

Kinetic experiments were performed in Xenopus oocytes expressing the NR1a/2A receptor by applying different concentrations of unsaturated amino-alkyl-cyclohexane (normally 5, in a log 3 dosing regimen) for 10-20 seconds in the continuous presence of glutamic acid (100. mu.M and glycine 10. mu.M) for 90-180 seconds. The perfusion system used for these experiments is an improved oocyte delivery system that enables rapid wash-in and wash-out of agonists and antagonists with a variation time of less than 1 second. The windows program TIDA was used for exponential fitting and most reactions fit well through a single exponent. The same system was used to obtain the voltage dependence of the block, but the bath contained flufenamic acid (100 μ M) to block endogenous voltage activation and Ca²⁺Activated Cl^-The current is applied. And, Ba²⁺(2mM) reduced concentration of Ca²⁺(0.2mM) replacement. By higher concentrations of antagonist (typically about 10 times the IC)₅₀) After equilibration block, 5 ramps (ramp) were generated from-70 mV to +30mV in 20 seconds. Similar skewing occurred in the baths and on glutamic acid without antagonist, before antagonist application and after recovery responseAnd (6) sloping. The leakage without glutamate was subtracted from the glutamate and glutamate + antagonist curves. The voltage-dependence was then determined by comparing the glutamate and glutamate + antagonist curves.

NMDA and nicotine patch clamp

Hippocampus was harvested from rat embryos (E20-E21) and transferred to calcium and magnesium free Hank's buffered saline (Gibco) on ice. After 8 min pre-incubation with 0.66% trypsin/0.1% DNase (Sigma), cells were mechanically dissociated in 0.05% DNase/0.3% ovomucoid (Sigma). The dissociated cells were then centrifuged at 18 Xg for 10 minutes and resuspended in minimal essential medium (Gibco) at 150,000 cells/cm²Was plated on plastic petri dishes (Falcon) pre-coated with poly-L-lysine (Sigma). With NaHCO₃HEPES buffered minimal essential Medium feeder cells supplemented with 5% fetal bovine serum and 5% horse serum (Gibco) at 37 deg.C with 5% CO₂And incubation at 95% humidity. After approximately 7 days of in vitro culture, further glial mitosis was inhibited with cytosine- β -D-arabinofuranoside (20M Sigma), and the medium was then replaced completely. Thereafter, the medium fraction was replaced twice a week.

Patch-clamp recordings were made from these neurons in whole cell mode with polished glass electrodes (4-6m) at room temperature (20-22 ℃) with the aid of EPC-7 amplifiers (List). The test substance is applied by switching channels of a custom made rapid superfusion system with a common outflow (10-20ms exchange time). The contents of the intracellular solution were as follows (mM): CsCl (120), TEACl (20), EGTA (10), MgCl₂(1)、CaCl₂(0.2), glucose (10), ATP (2), cAMP (0.25); the pH was adjusted to 7.3 with CsOH or HCl. The extracellular solution had the following basic composition (mM): NaCl (140), KCl (3), CaCl₂(0.2), glucose (10), HEPES (10), sucrose (4.5), tetrodotoxin (TTX 3 ANG 10)^-4). Glycine (1M) was present in all solutions: at a concentration sufficient to activate about 80-85% of the glycine B receptors. For final results analysis, only stable cells produced resultsAre included, i.e., their response to NMDA is at least 75% restored after suppression by the tested antagonist.

5-HT ₃ Patch clamp

N1E-115 cells were purchased from the European Collection of cell cultures (ECACC, Salisbury, UK) and stored at-80 ℃ until further use. These cells were cultured at 100,000 cells/cm²Was plated on plastic petri dishes (Falcon) and treated with NaHCO₃PerHEPES buffered Minimal Essential Medium (MEM) supplemented with 15% fetal bovine serum (Gibco) and 5% CO at 37 deg.C₂And incubation at 95% humidity. The medium was completely replaced every day. Once every three days, cells were treated with trypsin-EDTA (1% in PBS), resuspended in MEM and, after centrifugation at 1000rpm for 4 minutes, reseeded on new petri dishes.

Patch-clamp recordings were made at-70 mV from lifted (lifted) cells at room temperature (20-22 ℃) with a polished glass electrode (2-6 M.OMEGA.) in whole cell mode with the aid of EPC-7 amplifiers (List) 2-3 days after seeding. The contents of the intracellular solution were as follows (mM): CsCl (130), HEPES (10), EGTA (10), MgCl₂(2)、CaCl₂(2) K-ATP (2), Tris-GTP (0.2), D-glucose (10); the pH was adjusted to 7.3 with CsOH or HCl. The extracellular solution had the following basic composition (mM): NaCl (124), KCl (2.8), HEPES (10), pH adjusted to 7.3 with NaOH or HCl.

After the entire cell configuration was established, the cells were lifted from the glass matrix and 5-hydroxytryptamine (10 μ M), memantine, and unsaturated amino-alkyl-cyclohexane derivatives were applied at different concentrations using a rapid superfusion apparatus. These elevated cells were contacted with 5-hydroxytryptamine free or 5-hydroxytryptamine containing solutions using a piezo transducer driven dual barrel applicator pipette. A 2 second pulse of 5-hydroxytryptamine was delivered every 60 seconds. The putative antagonist was dissolved in aqua-bidest and diluted to the desired concentration with a bath solution. For final outcome analysis, only the results produced by stable cells were accepted for inclusion, i.e., their response to 5-hydroxytryptamine was at least 50% recovered after compound removal. Nevertheless, the recovery from the action of the drug is not always 100% due to the decrease in some cells (10% < ═ 10% in 10 minutes). When present, this was always compensated by basing the% antagonism at each concentration on both control and recovery and assuming that the decrease was a linear time course. All antagonists were evaluated at 3-6 concentrations for at least 5 cells at steady state block. Equilibrium blockade is achieved within 2-5 agonist applications, depending on antagonist concentration.

In vivo

Anticonvulsant activity

5 NMR female mice (18-28g) were housed per cage for Maximal Electric Shock (MES) and motor injury testing. All mice were given ad libitum access to water and food during a 12 hour light-dark cycle (lights on 6 in the morning) and at controlled temperature (20. + -. 0.5 ℃). All tests were performed between 10 a.m. and 5 a.m. If not specifically indicated, the test active agents were administered by intraperitoneal injection 30 minutes prior to induction of convulsions (see below). All compounds were dissolved in 0.9% physiological saline.

The MES test is performed together with a muscle relaxant action (traction reflex) test and a movement coordination (rotation lever) test. For the traction reflex test, the mouse forepaws were placed on a horizontal bar and were required to place all 4 paws on the wire within 10 seconds. To test for movement disorders (motor coordination), mice were placed on an accelerated rotating bar and asked to remain on the bar for 1 minute. Only mice that failed to meet the criteria in all three replicates of each test were considered to exhibit muscle relaxation or movement disorders, respectively. After these tests were performed, MES (100Hz, 0.5 second shock duration, 50mA shock intensity, 0.9ms pulse duration, Ugo Basile) was performed by corneal electrodes. The presence of tonic convulsions was scored (tonic extension of the hind paw, minimum angle to body is 90). The aim is to quantify the dose responseThe Litchfield Wilcoxon test yields an ED of all the parameters noted (anticonvulsant activity and motor side effects)₅₀. ED of side effects (dyskinesia or muscle relaxation)₅₀Divided by ED which antagonizes electroconvulsive convulsions₅₀As Therapeutic Index (TI).

Statistical analysis

IC was calculated in patch clamp and binding studies using Grafit computer program (Erithocus Software, England) according to four parameter logistic equation₅₀. Ki values for the binding assays were then determined according to the method of Cheng and Prusoff. Binding values are given as mean ± SEM of 3-5 tests (performed in duplicate each time).

In each in vivo test, 4-7 doses of antagonist (5-8 animals per dose) were tested to enable the calculation of the graded ED according to the probability analysis (Litchfield and Wilcoxon)₅₀And correcting for 0% -100% effects. ED (electronic device)₅₀Given as 95% confidence limits (Cl). Pearson product moment correlation assay (Sigma Stat, Jandel Scientific) was used to compare in vitro potency and in vivo anticonvulsant activity.

Results

MRZ number

The chemical name is represented using the MRZ number. These MRZ numbers and the chemical names represented by them are shown in "MRZ LIST".

MRZ LIST

MRZ	Chemical name
MRZ	Chemical name	2/657	1-amino-2, 4, 4, 6, 6-pentamethyl-cyclohex-2-ene hydrochloride
2/749	1- (1-aminoethyl) -3, 3, 5, 5-tetramethylcyclohexene	2/657
2/749	1- (1-aminoethyl) -3, 3, 5, 5-tetramethylcyclohexene	2/759	1-vinyl-3, 3, 5, 5-tetramethylcyclohexylamine
2/1005	1-amino-3, 3, 5, 5-tetramethyl-1-cyclohexene	2/759	1-vinyl-3, 3, 5, 5-tetramethylcyclohexylamine
2/1005	1-amino-3, 3, 5, 5-tetramethyl-1-cyclohexene	2/1021	2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethylamine
2/1023	1-amino-3, 3, 5-trimethyl-2-cyclohexene	2/1021	2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethylamine
2/1023	1-amino-3, 3, 5-trimethyl-2-cyclohexene	2002	1, 3, 5, 5-tetramethyl-2-cyclohexen-1-amine

2005	1-allyl-3, 3, 5, 5-tetramethylcyclohexylamine
2005	1-allyl-3, 3, 5, 5-tetramethylcyclohexylamine	2006	1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine
2008	1- (3, 3-diethyl-5, 5-dimethylcyclohexylidene) -2-propylamine	2006	1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine
2008		2009	Cis-3-vinyl-1, 3, trans-5-trimethylcyclohexylamine
2010	2-methyl-1- (3, 3, 5, 5-tetramethyl-1-cyclohexen-1-yl) -2-propylamine	2009	Cis-3-vinyl-1, 3, trans-5-trimethylcyclohexylamine
2010		2013	1- (1-allyl-3, 3, 5, 5-tetramethylcyclohexyl) piperidine
2014	2- (1-vinyl-3, 3, 5, 5-tetramethylcyclohexyl-1) ethylamine	2013	1- (1-allyl-3, 3, 5, 5-tetramethylcyclohexyl) piperidine
2014	2- (1-vinyl-3, 3, 5, 5-tetramethylcyclohexyl-1) ethylamine	2015	1- [3, 3, 5, 5-tetramethyl-1- (3-methyl-2-butenyl) cyclohexyl]Piperidine derivatives
2016	1- [3, 3, 5, 5-tetramethyl-1- (2-propynyl) cyclohexyl]Piperidine derivatives	2015
2016		2017	2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -4-pentenylamine
2018	3-(3，3，5，5-tetramethylcyclohexylidene) propylamine	2017	2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -4-pentenylamine
2018	3-(3，3，5，5-tetramethylcyclohexylidene) propylamine	2019	2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine
2020	2- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine	2019
2020	2- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine	2021	N-methyl-1-vinyl-3, 3, 5, 5-tetramethylcyclohexylamine
2026	N-allyl-1, 3, 3, 5, 5-pentamethylcyclohexylamine	2021	N-methyl-1-vinyl-3, 3, 5, 5-tetramethylcyclohexylamine

Binding MK-80

All the compounds are substituted by³H]- (+) -MK-801 with Ki values of 1-83. mu.M (see Table 1).

TABLE 1

MRZ	Group (g)roup)	[H]MK-801Ki	SEM	n	NMDA IC(μM)	SEM	N
MRZ	Group (g)roup)	[H]MK-801Ki	SEM	n	NMDA IC(μM)	SEM	N	2/657	Ethylene ring (ethylene ring)	13.43	1.15	3
2/749	Ethylene ring	10.76	1.49	3				2/657	Ethylene ring (ethylene ring)	13.43	1.15	3
2/749	Ethylene ring	10.76	1.49	3				759	Ethylene	1.18	0.20	6	3.28	0.60	6

	(ethylene)
	(ethylene)							2/1005	Ethylene ring	13.63	1.43	4
2/1021	Ethylene	2.15	0.32	6	0.33	0.05	6	2/1005	Ethylene ring	13.63	1.43	4
2/1021	Ethylene	2.15	0.32	6	0.33	0.05	6	1023	Ethylene ring	49.60	8.09	6
2000	Neramexane sulfate	1.68	0.00	3				1023	Ethylene ring	49.60	8.09	6
2000	Neramexane sulfate	1.68	0.00	3				2002	Ethylene ring	5.70	0.48	3
2005	Ethylene	9.35	0.12	3	12.60	5.68	6	2002	Ethylene ring	5.70	0.48	3
2005	Ethylene	9.35	0.12	3	12.60	5.68	6	2006	Ethylene	10.06	0.40	3
2008	Ethylene	8.07	0.57	3	2.74	0.22	6	2006	Ethylene	10.06	0.40	3
2008	Ethylene	8.07	0.57	3	2.74	0.22	6	2009	Ethylene	22.32	0.88	3	58.17	8.87	6
2013	Ethylene	49.21	11.73	3				2009	Ethylene	22.32	0.88	3	58.17	8.87	6
2013	Ethylene	49.21	11.73	3				2014	Ethylene	3.12	0.67	3	0.10	0.01	6
2015	Ethylene	83.04	30.98	3				2014	Ethylene	3.12	0.67	3	0.10	0.01	6
2015	Ethylene	83.04	30.98	3				2016	Ethylene	42.22	13.60	3	71.17	14.66	6
2017	Ethylene	6.79	0.51	3	1.19	0.16	6	2016	Ethylene	42.22	13.60	3	71.17	14.66	6
2017	Ethylene	6.79	0.51	3	1.19	0.16	6	2018	Ethylene	20.18	2.80	3	37.06	13.37	6
2019	Ethylene	73.06	8.67	3				2018	Ethylene	20.18	2.80	3	37.06	13.37	6
2019	Ethylene	73.06	8.67	3				2020	Ethylene	7.45	0.69	3
2021	Ethylene	6.54	0.72	3	12.73	0.50	6	2020	Ethylene	7.45	0.69	3
2021	Ethylene	6.54	0.72	3	12.73	0.50	6	2010	Ethylene ring	44.88	13.91	3
2026	Ethylene				29.56	1.64	6	2010	Ethylene ring	44.88	13.91	3

Results for representative compounds are reported in figure 1.

NMDA receptor subtype expression in Xenopus oocytes

Blockade of NMDA receptors by MRZ 2/759 was determined at-70 mV for 100 seconds in xenopus oocytes expressing NR1a/2A receptors by applying different concentrations (0.1-100 μ M, in log 3 dosing regimen) for 10 seconds in the continuous presence of glutamate (100 μ M) and glycine (10 μ M) (fig. 2, left). The efficacy (IC) of MRZ 2/759 was determined by plotting the percent block versus antagonist concentration and then fitting the curve to a logarithmic equation (FIG. 2, right panel)₅₀＝1.99μM，Hill 0.75)。

Patch clamp

The steady-state inward current response of freshly dissociated hippocampal neurons to NMDA (200M at-70 mV versus 1M glycine) was antagonized by MRZ 2/759. The peak and steady state currents are affected to a similar extent, making their effect unlikely in glycine_BThe site is mediated. The apparent use-and voltage-dependence of their blocking effects strongly confirms the noncompetitiveness of this antagonism. See fig. 3.

Anticonvulsant activity

The results of MES and muscle relaxant action are shown in table 2.

TABLE 2

MRZ	MESED50	MFSCL	Muscle relaxation ED50	Muscle relaxation CI	Movement disorder ED50	Movement disorder CI	TI muscle relaxation	TI movement disorders
MRZ	MESED50	MFSCL	Muscle relaxation ED50	Muscle relaxation CI	Movement disorder ED50	Movement disorder CI	TI muscle relaxation	TI movement disorders	2/657	＞30		＞30		＞30
2/749	26.58	20.7-34.1	38.64	28.6-52.1	37.14	30.0-46.0	1.5	1.4	2/657	＞30		＞30		＞30
2/749	26.58	20.7-34.1	38.64	28.6-52.1	37.14	30.0-46.0	1.5	1.4	2/759	14.84	9.6-23.1	12.76	10.3-15.9	15.00	11.4-19.8	0.9	1.0
2/1005	20.48	9.6-43.9	35.66	26.1-48.7	26.83	16.1-44.8	1.7	1.3	2/759	14.84	9.6-23.1	12.76	10.3-15.9	15.00	11.4-19.8	0.9	1.0
2/1005	20.48	9.6-43.9	35.66	26.1-48.7	26.83	16.1-44.8	1.7	1.3	2/1021	29.46	17.8-48.9	16.50	10.9-25.0	23.09	15.2-35.0	0.6	0.8
2/1023	＞50		＞50		＞50				2/1021	29.46	17.8-48.9	16.50	10.9-25.0	23.09	15.2-35.0	0.6	0.8
2/1023	＞50		＞50		＞50				2002	26.14	21.0-32.5	33.96	27.1-42.6	52.98	27.8-100.8	1.3	2.0
2005	37.34	33.9-41.1	39.75	32.6-48.4	49.34	37.2-65.5	1.1	1.3	2002	26.14	21.0-32.5	33.96	27.1-42.6	52.98	27.8-100.8	1.3	2.0
2005	37.34	33.9-41.1	39.75	32.6-48.4	49.34	37.2-65.5	1.1	1.3	2006	57.02	31.4-103.4	44.62	39.4-50.5	40.88	31.4-58.9	0.8	0.7
2008									2006	57.02	31.4-103.4	44.62	39.4-50.5	40.88	31.4-58.9	0.8	0.7
2008									2009	＞50		＞50		＞50
2010	＞50		＞50		＞50				2009	＞50		＞50		＞50

2013	＞50		＞50		＞50
2013	＞50		＞50		＞50				2014	47.82	21.5-106.5	13.95	6.3-31.1	25.83	18.3-36.4	0.3	0.5
2015	＞50		＞50		＞50				2014	47.82	21.5-106.5	13.95	6.3-31.1	25.83	18.3-36.4	0.3	0.5
2015	＞50		＞50		＞50				2016	＞50		＞50		＞50
2017	36.88	29.1-46.7	35.63	30.0-42.3	33.72	25.0-45.4	1.0	0.9	2016	＞50		＞50		＞50
2017	36.88	29.1-46.7	35.63	30.0-42.3	33.72	25.0-45.4	1.0	0.9	2018	78.54	35.0-176.3	29.43	23.4-37.0	26.70	19.2-37.0	0.4	0.3
2019	＞50		＞50		＞50				2018	78.54	35.0-176.3	29.43	23.4-37.0	26.70	19.2-37.0	0.4	0.3
2019	＞50		＞50		＞50				2020	26.06	20.4-33.3	34.46	29.1-40.8	27.57	18.7-40.7	1.3	1.1
2021	13.58	21.5-20.7	21.42	18.0-25.4	24.68	20.1-30.2	1.6	1.8	2020	26.06	20.4-33.3	34.46	29.1-40.8	27.57	18.7-40.7	1.3	1.1
2021	13.58	21.5-20.7	21.42	18.0-25.4	24.68	20.1-30.2	1.6	1.8	2023	＞30		＞30		＞30
2026	25.38	21.1-30.5	26.67	23.2-30.7	37.64	21.8-65.1	1.1	1.5	2023	＞30		＞30		＞30

＊＊＊＊＊

From the foregoing, it will be clear that the present invention provides new, valuable and unexpected uses and applications of the compounds of the invention (which include the active substances of the invention), as well as new pharmaceutical compositions, methods of preparation and methods of treatment using the same, all having the features and advantages more particularly enumerated above.

The high activity of the active agents and compositions thereof of the present invention as demonstrated by the provided test results indicates their utility based on their valuable activity in humans as well as lower animals. However, clinical evaluation in humans has not yet been completed. It should be clearly understood that the sale and marketing of any compounds and compositions for human use falling within the scope of the present invention must be pre-approved by a governmental agency, such as the U.S. federal food and drug administration, responsible for and authorizing passage of such decisions.

Summary of the invention

The unsaturated 1-amino-alkylcyclohexanes of the present invention are a novel class of systemically active, uncompetitive NMDA receptor antagonists with fast block/unblock kinetics and strong voltage dependence. Due to their modest potency and associated rapid kinetics, they are useful in the treatment of a variety of CNS disorders involving deregulated glutamatergic transmission.

The compounds of the invention are therefore found to be useful in the treatment of the following disorders in the living animal body, especially in humans. 1. Excitotoxicity, such as ischemia during stroke, trauma, hypoxia, hypoglycemia, glaucoma and hepatic encephalopathy. 2. Chronic neurodegenerative diseases, such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron diseases, mitochondrial dysfunction, Korsakoff syndrome, Creutzfeldt-Jakob disease. 3. Other disorders associated with chronic degeneration of the central nervous system selected from chronic pain, drug tolerance, dependence and addiction (e.g. opioids, cocaine, benzodiazepines)Steroids, nicotine, and ethanol). 4. Epilepsy, tardive dyskinesia, schizophrenia, anxiety, depressive disorders, acute pain, spasticity, and tinnitus.

Furthermore, the compounds of the present invention were also found to be neuronal nicotinic receptors and 5HT₃A receptor antagonist. The compounds of the invention thus find utility in the treatment of disorders in the living animal body, particularly humans, in nicotinic and 5HT₃For symptomatic and neuroprotective purposes in receptor-mediated indications (e.g. emesis, nicotine abuse, schizophrenia, cerebellar tremor, IBS, migraine, depressive disorders, cognitive disorders, psychosis associated with parkinson's disease treatment, and appetite disorders).

Furthermore, as indicated, the compounds of the present invention are also effective in indications unrelated to the above mechanisms of action, exhibiting immunomodulatory activity, antimalarial and antitrypanosoma efficacy, anti-bonna virus, anti-HSV and anti-hepatitis c virus activity, due at least in part to their amine substituents.

Methods of treatment of the living animal body with the compounds of the present invention for inhibiting the progression or ameliorating selected disorders herein, as previously described, are carried out by any of the normally accepted pharmaceutical routes, using selected dosages effective to ameliorate the particular disorder desired.

Use of a compound of the invention for the preparation of a medicament for treating a living animal to inhibit the progression or alleviate a selected disease or condition, particularly for treating a living animal with an NMDA receptor antagonist, a neuronal nicotinic receptor antagonist, 5HT₃The use of antagonists, or of compounds having immunomodulatory activity, antimalarial and antitrypanosomal potency, anti-borna disease virus and anti-HSV and anti-hepatitis c virus activity, for the treatment of sensitive diseases or conditions, is carried out in a conventional manner and comprises the steps of: mixing an effective amount of a compound of the invention with a pharmaceutically acceptable diluent, excipient, or carrier, and methods of treatment, pharmaceutical compositions, and use of a compound of the invention in the manufacture of a medicament.

Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically acceptable excipient, diluent or carrier include tablets, capsules, injections, liquid oral preparations, aerosols, TDS preparations and nanoparticle preparations, whereby the medicament is prepared for oral, injectable or dermal use in accordance with the foregoing.

＊＊＊＊＊

It is to be understood that this invention is not limited to the specific details of operation, or to particular compositions, methods, operations, or embodiments shown and described, as obvious modifications and equivalents will be apparent to those skilled in the art, and that this invention is therefore intended to be limited only by the full scope of what is legally required to be accorded to the following claims.

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Claims

1. A compound selected from formula I, optical isomers thereof and pharmaceutically acceptable acid or base addition salts thereof

Wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is- - - (A)_n--(CR¹R²)_m--NR³R⁴，

-n + m is 0, 1 or 2,

a is selected from linear or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆An alkynyl group,

-R¹and R²Independently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆An alkynyl group,

-R³and R⁴Independently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or together form C₂-C₁₀Alkylene or C₂-C₁₀Alkenylene or together with N optionally substituted by C_1-6Alkyl and/or C_2-6An alkenyl-substituted 3-7 membered azacycloalkane or azacycloalkene,

-R⁵independently selected from linear or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or R⁵Combines with the carbon to which it is attached and an adjacent carbon to form a double bond,

R_p、R_q、R_rand R_sIndependently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or R_p、R_q、R_rAnd R_sIndependently may combine with the carbon to which it is attached and an adjacent carbon to form a double bond, or R_p、R_q、R_rAnd R_sIndependently may form a double bond with the U or Y to which it is attached,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that when the ring represented by U-V-W-X-Y-Z is cyclohexane, then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAnd R_sAt least one of them being a straight or branched chain C₂-C₆Alkenyl or straight-chain or branched C₂-C₆Alkynyl.

2. The compound of claim 1, selected from the group consisting of:

1-vinyl-3, 3, 5, 5-tetramethylcyclohexylamine;

2- (3, 3, 5, 5-tetramethylcyclohexylidene) ethylamine;

1-amino-3, 3, 5-trimethyl-2-cyclohexene;

1, 3, 5, 5-tetramethyl-2-cyclohexen-1-amine;

1-allyl-3, 3, 5, 5-tetramethylcyclohexylamine;

1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine;

1- (3, 3-diethyl-5, 5-dimethylcyclohexylidene) -2-propylamine;

cis-3-vinyl-1, 3, trans-5-trimethylcyclohexylamine;

2-methyl-1- (3, 3, 5, 5-tetramethyl-1-cyclohexen-1-yl) -2-propylamine;

1- (1-allyl-3, 3, 5, 5-tetramethylcyclohexyl) piperidine;

2- (1-vinyl-3, 3, 5, 5-tetramethylcyclohexyl-1) ethylamine;

1- [3, 3, 5, 5-tetramethyl-1- (3-methyl-2-butenyl) cyclohexyl ] piperidine;

1- [3, 3, 5, 5-tetramethyl-1- (2-propynyl) cyclohexyl ] piperidine;

2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -4-pentenylamine;

3- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine;

2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexylidene) -2-propylamine;

2- (3, 3, 5, 5-tetramethylcyclohexylidene) propylamine;

n-methyl-1-vinyl-3, 3, 5, 5-tetramethylcyclohexylamine;

n-allyl-1, 3, 3, 5, 5-pentamethylcyclohexylamine;

and optical isomers and pharmaceutically acceptable acid or base addition salts thereof.

3. A pharmaceutical composition for treating a condition requiring NMDA, 5-HT₃Or a neuronal nicotinic receptor antagonist or for the alleviation of a condition treatable by a compound selected for its immunomodulatory, antimalarial, anti-bonavirus, anti-hepatitis c, anti-trypanosoma and/or anti-HSV potency, said composition comprising a compound as claimed in claim 1 or claim 2, in combination with one or more pharmaceutically acceptable diluents, excipients and/or carriers.

4. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the manufacture of a medicament for treating a living animal to alleviate a condition treatable by an NMDA antagonist:

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

a is selected from linear or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight-chain or branchedChain C₂-C₆An alkynyl group,

-R⁵、R_p、R_q、R_rand R_sIndependently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or R⁵、R_p、R_q、R_rAnd R_sIndependently may combine with the carbon to which it is attached and an adjacent carbon to form a double bond, or R_p、R_q、R_rAnd R_sIndependently may form a double bond with the U or Y to which it is attached,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that when the ring represented by U-V-W-X-Y-Z is cyclohexane, then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAt least one of them being a straight or branched chain C₂-C₆Alkenyl or straight-chain or branched C₂-C₆Alkynyl.

5. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the manufacture of a medicament for treating a living animal to alleviate a condition, wherein the medicament has immunomodulatory, antimalarial, anti-borna disease virus, or anti-hepatitis c, anti-trypanosome, and anti-HSV efficacy:

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

6. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the manufacture of a medicament for treating a living animal to alleviate a condition treatable by an NMDA antagonist, said condition selected from the group consisting of: excitotoxicity selected from ischemia during stroke, trauma, hypoxia, hypoglycemia, glaucoma and hepatic encephalopathy,

chronic neurodegenerative diseases selected from the group consisting of Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-neurodegeneration, olivopontocerebellar atrophy, Tourette's syndrome, motor neuron diseases, mitochondrial dysfunction, Korsakoff's syndrome and Creutzfeldt-Jakob disease,

other disorders involving prolonged plastic changes in the central nervous system selected from chronic pain, drug tolerance, dependence and addiction, and

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

-R⁵、R_p、R_q、R_rand R_sIndependently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight chainOr branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or R⁵、R_p、R_q、R_rAnd R_sIndependently may combine with the carbon to which it is attached and an adjacent carbon to form a double bond, or R_p、R_q、R_rAnd R_sIndependently may form a double bond with the U or Y to which it is attached,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

7. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the preparation of a medicament for treating a living animal to alleviate conditions susceptible to 5HT₃Use of a medicament for the treatment of a condition treated with a receptor antagonist:

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

8. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the manufacture of a medicament for treating a living animal to alleviate a condition treatable by a neuronal nicotinic receptor antagonist:

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

-R³and R⁴Independently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or together form C₂-C₁₀Alkylene or C₂-C₁₀Alkenylene or together with N optionally substituted by C_1-6Alkyl and/or C_2-6Alkenyl-substituted 3-7 membered azacycloalkanesOr an azacyclo-olefin, or a pharmaceutically acceptable salt thereof,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

9. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the preparation of a medicament for treating a living animal to alleviate conditions susceptible to 5HT₃Use of a medicament for the treatment of a condition selected from anxiety disorders, depressive disorders, schizophrenia and treatment-related psychoses, drug and alcohol abuse disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease, cerebellar tremor, migraine, appetite disorders, inflammatory bowel syndrome and emesis,

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

-R⁵、R_p、R_q、R_rand R_sIndependently selected from hydrogen, straight or branched C₁-C₆Alkyl, straight or branched C₂-C₆Alkenyl and straight or branched C₂-C₆Alkynyl, or R⁵、R_p、R_q、R_rAnd R_sIndependently may combine with the carbon to which it is attached and an adjacent carbon to form a double bond, or R_p、 R_q、R_rAnd R_sIndependently may form a double bond with the U or Y to which it is attached,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

10. Use of a compound selected from the group consisting of compounds of formula I, optical isomers thereof, and pharmaceutically acceptable acid or base addition salts thereof, for the manufacture of a medicament for treating a living animal to alleviate a condition treatable by a neuronal nicotinic receptor antagonist selected from the group consisting of tourette's syndrome, anxiety disorders, schizophrenia, drug abuse, nicotine abuse, cocaine abuse, movement disorders, attention deficit hyperactivity disorder, alzheimer's disease, parkinson's disease, and pain,

wherein:

-U, V, W, X, Y and Z represent a carbon atom,

-R^＊is (A)_n-(CR¹R²)_m-NR³R⁴，

-n + m is 0, 1 or 2,

provided that the ring represented by U-V-W-X-Y-Z is selected from:

cyclohexane,

Cyclohex-1-ene,

Cyclohex-2-enes, a pharmaceutically acceptable salt thereof,

Cyclohex-3-enes, a pharmaceutically acceptable salt thereof,

Cyclohexa-1, 3-diene,

Cyclohexa-1, 4-diene,

Cyclohexa-1, 5-diene,

Cyclohexa-2, 4-diene and

a mixture of a cyclohexa-2, 5-diene,

and with the proviso that when the ring represented by U-V-W-X-Y-Z is cyclohexane, then- (A)_n-(CR¹R²)_m-、R³、R⁴、R⁵、R_p、R_q、R_rAt least one of which is straightChain or branch C₂-C₆Alkenyl or straight-chain or branched C₂-C₆Alkynyl.

11. The use of claim 6, wherein the addiction is to opioids, cocaine, benzodiazepinesAddiction to steroids, nicotine, alcohol.

12. Use according to claim 10, wherein the dyskinesia is dyskinesia in huntington's disease and L-DOPA-induced dyskinesia.