TW200407120A - Unsaturated 1-amino-alkylcyclohexane NMDA, 5HT3, and neuronal nicotinic receptor antagonists - Google Patents

Abstract

Unsaturated 1-Amino-alkylcyclohexane compounds which are systemic-ally-active as NMDA, 5HT3, and nicotinic receptor antagonists, pharmaceutical compositions comprising the same, method of preparation thereof, and method of treating CNS disorders which involve disturbances of glutamatergic, serotoninergic, and nicotinic transmission, treating immunomodulatory disorders, and antimalaria, antitrypanosomal, anti-Borna virus, anti-HSV and anti-Hepatitis C virus activity.

Description

200407120 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs .. ^ tW! A7 _____B7_ V. Description of the Invention (1) Background of the Invention I. Field of Invention The systemic activity of NMDA, 5HT3 and nicotinic receptor antagonists is unsaturated 1- Amino-alkylcyclohexane compounds, pharmaceutical compositions containing them, preparation methods thereof, and methods for treating CNS disorders involving glutamate-induced conduction, heparin-induced transmission, and nicotine conduction disorders, And use it to treat immune disorders and treat infectious diseases. 2. Conventional technology The antagonism of glutamate receptors of the NMDA antagonist N-methyl-D-aspartate (NMD A) type may be used in many treatments [19]. Acts on different recognition sites, such as the initial transporter site located in the cation channel, the lignan-insensitive glycine site (glycine b), the polyamine site, and phencyclidine Site, can achieve functional inhibition of NMDA receptors. NMDA receptor tract blockers act in a non-competitive "use-dependent" manner, meaning that they generally block only the ion channels in the open state. "Use-dependence" has been interpreted many times to mean that stronger receptor activation should cause a greater degree of antagonism. This mode of action has been further used to suggest that such antagonists may be particularly useful in situations where predictable overactivation of the NMDA receptors, such as in epilepsy, ischemia and trauma. However, it is selective, high-affinity, and highly use-dependent (please read the notes on the back before filling out this page). Competitive NMDA receptor antagonist (. +) — 5 —methyl-1 〇, 11 —5H-dibenzocycloheptene hydrogen 1 〇-imine cis-monobutyrate ((This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 200407120 A7 _B7 __ V. Description of the invention (2) (Please read the notes on the back before filling this page) +) — MK-80 1) The initial clinical experience is disappointing. In other words, the effect is not good in patients with epilepsy, but there are obviously some mental side effects at the therapeutic dose used. These observations, coupled with phencyclidine abusers experiencing similar psychotic symptoms, led us to the conclusion that the antagonism of non-competitive NMDA receptors may not be a viable treatment. However, when using more elaborate current physiology methods, the results indicate that: factors such as the rate of receptor block (on-off kinetics) and the voltage-dependence of this effect can determine The pharmacokinetic properties, that is, the safety of treatment, are therefore not equal between different non-competitive NMDA antagonists. Paradoxically, reagents with low to moderate affinity, rather than high affinity, may be more satisfactory. Such findings have led us to rethink the concept of resistance to non-competitive NMDA receptors when drugs are issued [19, 22]. Non-competitive NMDA receptor antagonists, such as amantadine and memantine (which can meet the above criteria) have been used in the clinical treatment of Parkinson's disease and dementia for many years, and in their individual instructions The side effects do rarely occur at the therapeutic dose. In the light of the above evidence, we have issued a series of novel non-competitive NMDA receptor antagonists based on the unsaturated 1-amino-alkylcyclohexane structure. This study sought to compare the NMDA receptor antagonistic properties of these unsaturated 1-amino-alkylcyclohexane derivatives in receptor-connection analysis, galvanophysiological experiments, a twitch model, and two sports injury models. The substitution of these unsaturated 1-amino-alkylcyclohexanes is detailed in Table 6. This paper size applies Chinese National Standard (CNS) A4 specification (2I0X297 mm) -6-200407120 A7 ______B7 V. Description of the invention (3) 5 — HT3 receptor antagonist 5 — HT3 receptor is' allowing cations to penetrate The complex guards its gate to the ionotropic receptor. In humans, the density of 5-HT3 receptors is highest in intestinal chromaffin cells in the gastrointestinal mucosa (which is covered with vagal afferent nerves) and in the gill cleft caudal region of the brainstem (which triggers the formation of chemical receptors). Because 5-HT3 receptors have high densities not only in the caudal region of the gill cleft, but also in the hippocampal and almond regions of the peripheral system, it has been suggested that 5-HT3 selective antagonists may have a mental effect (Ge Linxiao and Shiwei Shidong, 1977) Indeed, early animal studies have suggested that 5-HT3 receptor antagonists can be used in many clinical fields in addition to their well-known anti-vomiting uses. . These include: anxiety, schizophrenia, drug and alcohol abuse, depression 'cognitive disorders, Alzheimer's disease, cerebellar tremor, psychosis associated with the treatment of Parkinson's disease, pain (migraine and irritability) Bowel syndrome) and appetite disorders. Neuron nicotinic receptor antagonists Currently, ten alpha subunits (αΐ-10) and four yS subunits (ySl-4) of nicotine receptors are known. Α4 / 32 receptors may be CNS, especially The most common receptor in the hippocampus and striatum. They form non-selective cation channels with slow, incomplete desensitization of ion current (type Π). The same X-spectrum α 7 receptors are present both pre- and post-synapticly, and can be found in the hippocampus, motor cortex and peripheral systems, and the peripheral autonomic nervous system. These receptors are characterized by their high Ca 2+ permeability and fast and powerful I --------- (Please read the precautions on the back before filling out this page) Ordering Intellectual Property of the Ministry of Economy ¾ Employee Consumer Cooperatives印 tr) ί-Η This paper size is applicable to China National Standard (CNS) Α4 specification (210 × 297 mm) -7-200407120 A7 B7___ V. Description of the invention (4) (Please read the precautions on the back and fill in this page first ) Desensitization reaction (type 1 A). Many diseases involve changes in nicotinic receptors. These diseases include: Alzheimer's disease, Parkinson's disease, Torred's syndrome, schizophrenia, substance abuse, nicotine abuse, and pain. According to observations, the nicotine of the nicotine agonist itself seems to have benefits, and to date, selective nicotine agonists have been found to help develop drugs. On the other hand, the role of nicotinic agonists in, for example, Torred's syndrome and schizophrenia is due to activation or deactivation / desensitization of neuron nicotinic receptors. The effect of agonists on neuronal nicotinic receptors depends mainly on the period of exposure. The desensitization that can be reversed quickly occurs in milliseconds, and the relaxation occurs in seconds. The irreversible deactivation of the receptor containing α4 / 32 and α7 occurs in hours, and Its positive regulation occurs within a few days. In other words, the effect of the nicotine π agonist " may actually be due to the partial synergy, deactivation and / or desensitization of the neuron nicotinic receptor. That is, a moderate concentration of a neuronal nicotinic receptor channel blocker can produce the same effect as that produced by a nicotine agonist in the above indications. According to the present invention, the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has found that a range of unsaturated 1-aminoalkylcyclohexanes has excellent and unexpected NMD A, 5T3 and neuronic nicotinic receptor antagonistic activity. Due to the above properties, these substances are suitable for the treatment of a wide range of CNS disorders involving glutamate-induced conduction, heparin-induced transmission, and nicotine conduction disorders for immunomodulation and anti-infectious diseases. These compounds are preferably in the form of their pharmaceutical composition (where they are compatible with one or more pharmacologically acceptable ^ Paper size applies Chinese National Standard (CNS) A4 specification (210'〆297 mm) 7〇Z " 200407120 Ministry of Economic Affairs Printed by the Intellectual Property Bureau's Consumer Cooperative if A7 B7 V. Description of the Invention (5) The diluent, carrier or excipient exists together). OBJECTS OF THE INVENTION One of the objects of the present invention is to provide novel pharmaceutical compounds and pharmaceutical compositions thereof. Such pharmaceutical compounds are unsaturated amine alkyl cyclohexanone compounds used as NMDA, 5T3, and receptor antagonists. Another object of the present invention is to provide treatment, elimination, alleviation, alleviation or improvement of glutamate-induced conduction, heparin-induced transmission and shielding by using the pharmaceutical compound of the present invention and the pharmaceutical composition containing the same. Examine the CNS disorders of conduction disorders to treat immunoregulatory disorders and treat infectious diseases. Another object of the present invention is to provide a method for producing an active ingredient of unsaturated 1-aminoalkylcyclohexane. Other purposes will become clearer in the following, and other purposes will be clear to those skilled in the art. Description of the Invention Therefore, I believe that what is contained in the present invention can be described, in particular, in the following text: A compound selected from the group of compounds of formula I:

Rq Rr Among them: (Read the notes on the back before filling in this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -9- 200407120 A7 B7 V. Description of the invention (6 R * is-(A) n- (CR'R2) m-NR3R4, n + m = 0, 1, or 2, A is selected from the following groups: straight-chain or branched lower alkyl and. (Please read the notes on the back before filling this page) (Ci-C6), straight-chain Type or branched lower alkenyl (C2-C6) linear or branched lower alkynyl (C2-C6),-R1 and R2 are independently selected from the following groups: hydrogen, linear Or lower branched lower alkyl (Q-C6), straight or branched lower alkenyl (c2-c6), and straight chain or lower branched lower alkynyl (c2-c6 ) One R3 and R4 are independently selected from the group consisting of: hydrogen, straight chain or branched lower alkyl ((^-(: 6), straight chain or branched lower alkenyl (C2 —C6), and lower or straight-chain or branched lower alkynyl (C2-C6), or together form an alkylene (C2-C1G) or alkenyl (C2-C1 ()) or start with N Forms a 3-7-membered azacycloalkane or azacycloalkene, including substituted (sinyl (Cl-C6), Alkenyl (C2-C6)) 3-7-members of nitrogen heterocyclic ring or nitrogen heterocyclic ring storage, Intellectual Property Office of the Ministry of Economic Affairs 8 X Consumer Cooperative Seal — R5 is independently selected from the following groups: linear Or lower branched alkyl (C!-C6), straight or branched lower alkenyl (c2-c6), straight or branched lower alkynyl (c2-C6) ), Or R5 and its attached carbon and an adjacent carbon are combined to form a double bond, —RP, Rq, &, and RS are independently selected from the following groups: hydrogen, linear or branched comparison Low alkyl (C! ~ C6), straight or branched lower alkenyl (C2-C6), and straight or branched lower alkynyl (C2-C6), or Rp, Rq, Rr, and Rs can be independently connected to the carbon-10- This paper size applies to the Chinese National Standard (CNS) A4 specification (2〗 0 X 297 mm) 200407120 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and the Industrial Cooperative Cooperative A7 B7 V. Description of the invention (7) and the next adjacent carbon are combined to form a double bond, or RP, Rq, Rr, and Rs can independently form a double bond with the U to which they are connected, or with the Y to which they are connected Its prerequisites U—V-W-X— Υ-Z is selected from: cyclohexane, cyclohex-2-ene, cyclohex-2-ene, cyclohex-1,4-diene, cyclohex-1,5— Diene, cyclohexa-2,4-diene, and cyclohexa-2,5-diene, and the prerequisites are that at least one of RP and Rq is not hydrogen, and at least one of R, and Rs is not hydrogen, and The prerequisite is that when u-z is equal to the ring house, then-(a) _ (CW) m-, R3, R4, R5, Rp, Rq, Rr, and Rs are at least _ linear or branched Lower alkenyl (C2-C6) or linear or branched lower alkynyl (C2-C6), and its optical isomers and pharmaceutically acceptable acid or base addition salts thereof; A method of treating a living animal 'to alleviate a condition treatable by an NMD A antagonist, comprising the step of administering to the living animal a quantity of a compound effective to alleviate the condition, the compound being selected from the group of compounds of formula T

This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 〇χ 297mm) -11-— Clothing: IT (Please read the precautions on the back before filling this page) 200407120 A7 B7 V. Description of the invention (8 ) Where: ~ R * is-(A) n-(CRiR2) m- NR3R4, ~ n + m = 〇, 1 or 2, and A is selected from the following groups: linear or branched lower alkanes (Cl ~ c6), linear or branched lower alkenyl (c2-c6), and linear or branched lower alkynyl (C2-c6), ~ R1 and R2 are independent The ground is selected from the group consisting of: hydrogen, straight or branched lower alkyl (Ci-Cs), straight or branched lower alkenyl (C2-C6), and straight or branched Lower branched alkynyl (C2—C6) (Please read the notes on the back before filling out this page) Member of the Intellectual Property Bureau of the Ministry of Economic Affairs X Consumer Cooperatives ip R3 and R4 are independently selected from the following groups: hydrogen, linear Type or branched lower alkyl (Mo-(: 6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl ( C2-C6), or together Forms an alkylene (c2-C1Q) or alkenyl (c2-c1 ()) or forms a 3-7-membered azacycloalkane or azacycloalkene with N, including substituted (alkyl (G — C6), substituted alkenyl (C2 — C6)) 3- 7-membered azacycloalkane or azacycloalkene, R5, RP, Rq, Rr, and Rs are independently selected from the following groups : Hydrogen, straight or branched lower alkyl (C!-C6), straight or branched lower alkenyl (C2-C6), and straight or branched lower alkyl Lower alkynyl (C2-C6), or R5, Rp, Rq, Rr, and Rs can independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, or Rp, Rq, Rr, the paper The Zhang scale is applicable to the Chinese National Standard (CNS) A4 specification (2) 0X297 mm. -12- 200407120 A7 B7 V. Description of the invention (9) and Rs can be independently formed with the U 'connected to them or with the connected ones. Double bond, and its prerequisite is u—V—W—X—Y—z is selected from the group consisting of: cyclohexane, cyclohexyl, cyclohexyl, 2-ene, cyclohexyl, 3-oxo, cyclohexyl, 1, 3 —Dienecyclohexa-1,4 —dienecyclohexa-1,5 — one storage Huanjiyi 2, 4 — Yicanhuanji 2 '5 — Yican (Please read the notes on the back before filling out this page) Member of the Intellectual Property Bureau of the Ministry of Economic Affairs X 印 Printed by the cooperative and its prerequisite is U- When Z is equal to cyclohexane, then-(a) n- (CR'R2) m-, R3, R4, R5, Rp, Rq, Rr has at least one lower alkenyl group which is linear or branched (C2 -c6) or linear or branched lower fast group (C2-c6) 'its optical isomers and its pharmaceutically acceptable acid or base addition salts; a treatment of living animals, to ease the condition A method of selecting a compound having the following efficacy: immunomodulatory, anti-malarial, anti-Bonavirus, or anti-hepatitis C, anti-trypanosomal, and anti-HSV, the method comprising administering to the living animal a The number of steps that can effectively alleviate the condition, and the compound is selected from the group of compounds of formula I: This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -13-200407120 A7 B7 V. Invention Explanation (1〇)

(Please read the notes on the back before filling this page) Where:-R * is-(A) „-(CRiR2) m-NR3R4, — n + m = 0, 1, or 2, A is selected from the following groups : Linear or branched lower alkyl (Ci-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-c6), one R1 and R2 are independently selected from the group: hydrogen 'straight chain or branched lower alkyl (Ci-C6), straight chain or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6), member of the Intellectual Property Bureau of the Ministry of Economic Affairs, X Consumer Cooperative Seal. 潆 — R3 and R4 are independently selected from the following groups: hydrogen, Straight or branched lower alkyl (0-0: 6), straight or branched lower alkenyl (c2-c6), and straight or branched lower alkyne (C2 — c6), or together form C2—Cio or alkenyl (C2—Cio) or form a 3-7-membered azacycloalkane or azacycloalkene with N, Including Substituted (Institute (Cl-C6) 'Substituted Commission (C2-C6)) The 3-7-membered azacycloalkane or azacycloalkene 'R5, Rp, Rq, Rr, and Rs are independently selected from the following groups: hydrogen, linear or branched lower courtyard (Ci -C6), straight or branched lower alkenyl (C2-C6), and straight · chain or branched lower alkynyl (c2-c6), or R5, Rp, Rq, Rr , And Rs can be independently connected to the size of the paper to which it is connected. The Chinese National Standard (CNS) A4 specification (210x297 mm) -14-200407120 Five A7, Invention Note (11) and the next adjacent carbon are combined to form A double bond, or Rp, Rq, Rr, and

Rs can independently form a double bond with the U to which it is connected, or with γ to which it is connected, and ~ its prerequisite is υ—V-w—x—Υ— Z is selected from: cyclohexane, cyclohex-1 Monoene, cyclohexyl 2-ene, cyclohexyl 3-ene, cyclohexyl-1,3-dienecyclohex-1,4, dienecyclohex-1,5-dienecyclohex-2,4 —Diene, and cyclohex-2,5 —diene and its prerequisite is that when U-Z is equal to cyclohexane, then one (A) η _ (Please read the precautions on the back before filling this page) ( CRi2)

R

At least one of IT R5, Rp, Rq, and Rr is a consumer-cooperative printed age-J. Type or lower alkenyl (c2-c6) or linear or branched Lower alkynyl (C2-C6), its optical isomers and its pharmaceutically acceptable acid or addition salt; a method for treating surviving animals to alleviate conditions that can be treated with NMDA antagonists, wherein the Conditions treated by NMDA antagonists are selected from the group consisting of excitotoxicity selected from the group consisting of ischemia during stroke, trauma, hypoarterial hypoxemia, hypoglycemia, glaucoma, and hepatic encephalopathy. Chronic neurodegenerative diseases from the following groups: Alzheimer's disease, Chinese paper standards apply to Chinese National Standard (CNS) A4 specifications (210X 297 mm) —15 · 200407120 A7 __ B7 V. Description of the invention (12) Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic collateral sclerosis, AID S-neurodegeneration, pontine cerebellar atrophy, Torred disease, motor neuron disease, Glandular dysfunction, Korsak syndrome Group 'and Creutzfeldt-Jakob disease, and other disorders related to long-term shaping changes in the central nervous system selected from the group: chronic pain, drug tolerance, drug dependence, and Addictions (eg, opioids, coca tests, benzodiazepines, su, and alcohol), and epilepsy, tardive dyskinesia, dyskinesia caused by L-DOPA, schizophrenia, Anxiety, depression, acute pain, cramps, and tinnitus 5 This treatment includes the step of administering to the surviving animal an amount of a compound effective to alleviate the condition, the compound being selected from the group of compounds of formula I R5 R *

V • Rs ----------- (Please read the notes on the back before filling out this page) Ministry of Economic Affairs, Intellectual Property Bureau, Consumer Corporation, ::: Read Among them:

Rq Rr R * is-(A) n— (cWR2) m— NR3R 'n + m = 0, 1, or 2, A is selected from the following groups: linear or branched lower alkyl, linear Type or branched lower alkenyl (C2-C6), and linear or branched lower alkyne c6) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) · 16 200407120 A7 _____B7 V. Description of the invention (13)-R1 and R2 are independently selected from the following groups: hydrogen, straight chain or lower branched chain (Cl-c6), straight chain or branched chain Lower alkynyl (C2-C6), and linear or branched lower alkynyl (c2-c6)-r3 and R4 are independently selected from the group consisting of hydrogen, linear or branched Lower alkyl (G-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (c2-c6), or together Alkenyl (c2—c1 ()) or alkenyl (c2—C1Q) or together with N to form a 3- 7-membered nitrogen heterocyclic ring or nitrogen heterocyclic ring, including substituted (alkyl ( q — C6), substituted alkenyl (C2 — C6)) 3-7-membered azacycloalkane or Azacyclene,

R

Rp, Rq, Rr, and Rs are independently selected from the group consisting of hydrogen, straight chain or branched lower alkyl (Q-C6), straight chain or branched lower alkenyl (C2 -C6), and linear or branched lower alkynyl (C2-C6), or R5, RP, Rq, Rr, and Rs can be independently combined with the carbon to which it is attached and the next adjacent carbon to A double bond is formed, or Rp, Rq, Rr, and Rs can independently form a double bond with the u to which they are connected, or a double bond with the Y to which they are connected. The prerequisite is υ— V—W—X—Υ—Z is selected from: cyclohexane, cyclohex-1-ene, cyclohex-2—ene ', cyclohex-3—ene, ene (please read the Please fill in this page again for the matters needing attention) Huanji—1,3— This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297mm) -17-200407120 A7 B7 V. Description of the invention (14) Huanji-1, 4-diene, cyclohex-1,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene, and the prerequisites are when U-Z is equal to cyclohexane ,then (A) ^-(CE ^ R2) m-, R3, R4, R5, Rp, Rq, at least one of the lower alkenyl (C2-C6) linear or branched or linear or branched Lower chain alkynyl (C2-C6) 'its optical isomers and its pharmaceutically acceptable acid or base addition salts; a method of treating surviving animals to alleviate conditions treatable by 5HT3 receptor antagonists , Which includes the step of administering to the living animal an amount of a compound that can effectively alleviate the condition ', and the compound is selected from the compounds of formula 1 (please read the precautions on the back before filling this page)

Rq Rr Consumption Cooperative of Intellectual Property of Employees of Intellectual Property Bureau, Ministry of Economic Affairs Among them: — R * is-(A) n- (CWR2) m- NR3R4, — n + m = 〇, 1 or 2 '— A is selected from the following groups: Linear or branched lower alkyl (Ci-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl ( C 2 — C6) '-R1 and R2 are independently selected from the following groups: hydrogen, linear or this paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) _ 18-200407120 A7 B7 V. Description of the invention (15 Branched lower alkyl (Q-C6), linear or branched lower storage group (C2-C6), and linear or branched lower alkynyl ( c2-c6) —r3 and R4 are independently selected from the group consisting of hydrogen, straight chain or branched lower alkyl (mounta-(: 6), straight chain or branched lower alkenyl (C2-c6), and linear or branched lower alkynyl (c2-c6) 'or together form an alkylene (c2-c1G) or an alkenyl (c2-c1 ()) or with N — Forming a 3-7-membered azacycloalkane or azacycloalkene, Including substituted (alkyl (Ci-C6), substituted alkenyl (c2-c6)) 3- 7-membered azacyclic ring or azacycloolefin, R5, Rp, Rq, Rr, and Rs Is independently selected from the group consisting of: hydrogen, a lower chain alkyl group or a branched lower alkyl group ((^-(: 6), a lower chain alkyl group (C2-C6), or a branched chain, and Linear or branched lower alkynyl (C2-C6), or R5'RP'Rq, Rr, and Rs can independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, Or Rp, Rq ,, and Rs can form a double bond with u connected to them or γ connected with them independently, and (please read the precautions on the back before filling this page) T i fee of the Intellectual Property Bureau of the Ministry of Economic Affairs社 社 印 -.V.ffcjJ-Kv Ά'4 The prerequisite is U—V—W—X—γ—ζ is selected from cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclo Hexan-3ene, cyclohexyl-1,3-dienecyclohexyl-1,4-diene The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -19-200407120 A7 B7 V. Invention Description (16 1,5-diene, cyclohexa-2,4-diene, and cyclohexa-2,5-diene, and the prerequisite is that when U-Z is equal to cyclohexane, then (A) n- (CR'R2)

R (Please read the notes on the back before filling this page)

At least one of Rp, Rq, and Rr is a linear or branched lower alkenyl group (C2-C6) or a linear or branched lower alkynyl group (C2-C6). Its optical isomers and A pharmaceutically acceptable acid or base addition salt thereof; a method for treating a surviving animal to alleviate a condition treatable by a neuronal nicotinic receptor antagonist, comprising administering to the surviving animal an amount effective to alleviate the condition A step of a compound selected from the group of compounds of formula I:

X

I

Rr where-R * is-(A)--(CRT) m- NR3R4, — n + m = 0, 1, or 2, intellectual property of the Ministry of Economic Affairs ^ 7 Employee Consumer Cooperative Cooperative Seal TM '々 A series is selected from the following groups : Linear or branched lower alkyl (Ci-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6) '-R1 and R2 are independently selected from the following groups: hydrogen, linear or branched lower courtyard (Ci-C6), linear or branched lower;; : Hickey (C2-C6), and linear or branched lower alkynyl (C2-C6), (CNS) (21〇X 297 ^ t)-20-200407120 A7 ________B7 __ 5. Description of the invention (17) (Please read the notes on the back before filling this page) ~ R3 and R4 are independently selected from the following groups: hydrogen, linear or branched lower alkyl (Ci-Cd, linear) Lower branched alkenyl (C2-C6), and lower chain straight-chain or branched alkynyl (C2-C6) 'or together form an alkylene (C2-C1G) or alkylene ( C2-C1G) or together with N to form a 3-7-membered azacycloalkane or azacycloalkene Including substituted (alkyl (Ci-C6), substituted alkenyl (C2-C6)) 3-7-membered azacycloalkene or azacycloalkene, R5, RP, Rq, Rr, and Rs Are independently selected from the group consisting of hydrogen, lower alkyl (chain-C6), straight or branched, lower alkenyl (C2-C6), or straight chain Or a branched lower alkynyl (C2-C6), or R5, RP, Rq, Rr, and Rs can independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, or Rp, Rq, Rr, and Rs can independently form a double bond with the u to which they are connected, or with the Y to which they are connected, and one of the prerequisites is υ— V— w_X-Υ—Z is selected from the group consisting of: Hexadecene-1, cyclohexan-2-ene, Intellectual Property Bureau of the Ministry of Economic Affairs, a X consumer it, cyclohexan-3ene, cyclohexan-1,3-dioxane, cyclohexan-1,4-diene , Cyclohexyl-1,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene, and the prerequisite is that when U-Z is equal to Xiangjiyuan 'then one ( A) n-Chinese paper standard (CNS) ) A4 specification (2 丨 0X 297 mm) -21 200407120 A7 B7 V. Description of the invention (18) (Please read the notes on the back before filling this page) (CRiR2) m—, R3, R4, R5, Rp, Rq, Rr have at least—lower alkenyl (C2-C6) linear or branched or lower alkynyl (C2-C6) linear or branched, their optical isomers and their A pharmaceutically acceptable acid or base addition salt; a method of treating surviving animals to alleviate conditions treatable by a 5HT3 receptor antagonist, wherein the condition treatable by a 5 HT3 antagonist is selected from the group consisting of: anxiety Disorders, depression, schizophrenia and treatment-related psychosis, drug and alcohol abuse disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease, cerebellar tremor, migraine, anorexia, inflammatory bowel syndrome IBS), and vomiting, the method comprises the step of administering to the surviving animal an amount of a compound effective to alleviate the condition, and the compound is selected from the group of compounds of formula I:

Rq Rr Where: The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the number of stamps. R * is-(A) n- (CRl2) m- NR3R4, — n + m = 0, 1, or 2, — A is selected from the following groups : Linear or branched lower alkyl (Ci-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-c6),-R1 and R2 are independently selected from the group consisting of hydrogen, straight chain or branched lower alkyl (ci-c6), straight chain or branched lower olefin- 22- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 200407120 A7 B7 V. Description of the invention (19) group (C2-C6), and straight chain or branched lower alkynyl group (C2-c6), (Please read the notes on the back before filling out this purchase)-R3 and R4 are independently selected from the following groups: hydrogen, linear or branched lower alkyl (G-C6) , Linear or branched lower alkenyl (C2-c6), and linear or branched lower alkynyl (c2-c6), or together form an alkylene (c2-c1C)) Or alkenyl (c2-c1 ()) or together with N to form a 3-7-member Azetane or azacycloalkene, including substituted (alkyl (Q-C6), substituted alkenyl (C2-C6)) 3-7 members, azacycloalkane or azacycloalkene, R5 R, Rp, Rq, Rr, and Rs are independently selected from the group consisting of: hydrogen, straight chain or branched lower alkyl ((^-(: 6), straight chain or branched lower Alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6), or R5, RP, Rq, Rr, and Rs can be independently attached to the carbon and next ^ Adjacent carbons are combined to form a double bond 'or Rp' Rq 'Rr' and Rs can independently form a double bond with the U to which they are connected, or with the Y to which they are connected, and-its prerequisite is U-V — W—X-Υ-ζ is selected from · Cyclone Institute, Intellectual Property Bureau of the Ministry of Economic Affairs, i X Consumer Co., Ltd., Cyclohexanone-1, Diene, Cyclohexan-2-ene, Cyclohexan-3-ene, Cyclohexane Hexa-1,3 — a kind of 'cyclohex-1,4-diene, cyclohex-1,5-diene, and cyclohex-2,4-diene This paper is applicable to Chinese National Standards (CNS) Α4 Specifications (210X297 mm) · 23-200407120 Seal of Intellectual Property Cooperative Cooperative of the Ministry of Economic Affairs of the Ministry of Industry rt A7 B7 V. Description of Invention (20) Cyclohexan-2,5-diene, and its prerequisite is that when U-Z is equal to cyclohexane, then one (a ) n- (CRi2) m—, R3, R4, Rp, Rq, Rr At least one of which is linear or branched lower alkenyl (C2-C6) or linear or branched lower Block (C 2-c 6), its optical isomers and its pharmaceutically acceptable acid or base addition salts; a treatment of surviving animals to alleviate conditions that can be treated with neuronal nicotinic receptor antagonists Method, wherein the condition treatable by a neuron nicotinic receptor antagonist is selected from the group consisting of Torred's disease, anxiety, schizophrenia, substance abuse, nicotine abuse, cocaine abuse, exercise Difficulty (Huntington's disease, caused by L-DOPA), Attention Deficit Hyperactivity Disorder (ADHD), Alzheimer's disease, Parkinson's disease, and pain, this method includes administering a quantity to the surviving animal A step effective in alleviating the condition of the compound selected from the group of compounds of formula I:

— N + m = 〇, 1 or 2 '-A is selected from the group consisting of a linear or branched lower alkenyl group (Cl-C6), a linear or branched lower alkenyl group ( C2-C6), and linear or branched lower alkynyl (C2_C6), this paper size is applicable to f surface household fresh (CNS) grid (21GX297 public attack) -24 --- ^^ clothing;-order ------ ~ (Please read the notes on the back before filling this page) 200407120 A7 ____B7 V. Description of the invention (21)-R1 and r2 are independently selected from the following groups: hydrogen, linear or branched Lower alkyl (q-c6), lower alkenyl (c2-c6), straight or branched, and lower alkynyl (C2-C6)-R3, straight or branched And R4 are independently selected from the group consisting of hydrogen, straight chain or branched lower alkyl ((^-(: 6), straight chain or branched lower alkenyl (c2-c6) , And linear or branched lower alkynyl (c2-c6), or together form an alkylene (c2-c1 ()) or an alkenyl (C2-C1G) or form a 3 with N -7-membered azacycloalkane or azacycloalkene, including substituted (Ci-C6) ' Substituted strips (C2-C6)) 3-7-membered azacycloalkanes or azacycloalkenes, R5, RP, Rq'Rr, and Rs are independently selected from the following groups: hydrogen, linear or Lower alkyl (B-C6) with branched chain, lower alkenyl (C2-C6) with straight or branched chain, and lower alkynyl (C2-C6) with straight or branched chain , Or R5 'RP, Rq, Rr, and Rs may independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, or RP, Rq, Rr, and Rs may independently with the U to which they are attached , Or it forms a double bond with the Y to which it is connected, and-its prerequisite is U-VW-X-Υ-Z is selected from the group consisting of: cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclo Hex-3-ene, cyclohexyl-1,3-diene, I ---------- (Please read the notes on the back before filling this page)

, 1T Consumers' Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs, India: -'J. This paper size is applicable to China National Standard (CNS) A4 specification (21〇 × 297mm) -25-200407120 (CRi2) m—, R:

R A7 B7 V. Description of the invention (22) Cyclohexan 1,4-diene, cyclohexan 1,5-diene, cyclohexan 2,4-diene, and cyclohexan 2,5-diene And its prerequisite is that when UZ is equal to cyclohexane, then at least one of (A) η RP, Rq, Rr is linear or branched lower alkenyl (C2-C6) or linear or Branched lower alkynyl (C2-C6), its optical isomers and its pharmaceutically acceptable acid or base addition salts; and a pharmaceutical composition having a compound selected from the group of compounds of formula I Compound: (Please read the notes on the back before filling in this page)

Rs Industrial and Consumer Cooperatives of the Ministry of Economic Affairs and Smart Finance Bureau and where R * is-(A) n- (CR'R2) m- NR3R4 n + m = 0, 1, or 2, A is selected from the following groups: linear or Lower branched lower alkyl (Ci-C6), straight or branched lower alkenyl (C2-C6) Lower chain or lower branched alkynyl (C2-C6), — R1 And R2 are independently selected from the group consisting of: hydrogen, straight or branched lower alkyl (C i-C6) _, straight or branched lower alkenyl (c2-c6), And straight-chain or branched lower alkynyl (c2 — c6) This paper size applies to Chinese National Standard (CNS) A4 specifications (2) OX 297 mm) -26-200407120 A7 _B7 V. Description of the invention (23 ) (Please read the notes on the back before filling out this page)-R3 and R4 are independently selected from the following groups: hydrogen, linear or branched lower alkyl (Ci-Ce), linear or Lower alkenyl (C2-C6) with branched chain, and lower alkynyl (C2-C6) with straight or branched chain, or together form C2-CiQ or C2 — Cl.) Or together with N to form a 3- 7-member Azacyclic ring or azacyclo ring, including substituted (alkyl (C!-C6), substituted alkenyl (C2-C6)) 3-7-membered azacycloalkane or azacycloalkene , R5, Rp, Rq, Rr, and Rs are independently selected from the group consisting of: hydrogen, linear or branched lower alkyl (Ci-Cd, linear or branched lower alkenyl) (C2-C6), and linear or branched lower alkynyl (C2-C6), or R5, RP, Rq, Rr, and Rs can independently combine with the carbon to which it is attached and the next adjacent carbon倂 to form a double bond 'or Rp, Rq, Rr, and Rs can independently form a double bond with the U to which they are connected, or a double bond with the Y to which they are connected, and one of the prerequisites is U—V—W—X— Υ—Z is selected from the group consisting of: cyclohexane, cyclohexene 2-ene, the consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs: ¾. Cyclohex-3-ene, cyclohex-1, 4-diene, cyclohexyl 1,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene, and the prerequisite is that at least one of RP and Rq is not hydrogen, and this paper standard applies to China Standard (CNS) A4 specification (210X 297 (27) 200407120 A7 B7 V. Description of the Invention At least one of (24) and Rs is not hydrogen, and its prerequisite is that when U-Z is equal to cyclohexane, then (A) n-(CRiR2) m— , R3, R4, R5, Rp, Rq, Rr, and Rs have at least one of straight or branched lower alkenyl (C2-C6) or straight or branched lower fast (C2 -C6) ^ and one or more pharmaceutically acceptable diluents, excipients or carriers. Detailed description of the invention The following details and detailed examples are only used to illustrate the invention. Table: Examples 1 and 2 instead of limitation (please read the precautions on the back before filling this page) Ministry of Economic Affairs and Intellectual Property Bureau S X Consumer Corporation

OH

Example The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) · 28-200407120 A7 ___B7_ V. Description of the invention (25) 3,3,5,5-tetramethyl-1-vinyl ring Hexylamine hydrochloride (5) ° (Please read the notes on the back before filling this page) a) 2— (3,3,5,5-tetramethylcyclohexylene) ethyl acetate (2) ° Under argon, add small portions of NaH (8.8 g, 222 mmol, 60% suspension in mineral oil) to the stirred phosphonic acid in dry THF (180 ml). Triethyl acetate (49.32 g, 222 mmol) and cooled with ice water. Stirring was continued at room temperature for 1 hour, and then a solution of 3,3,5,5-tetramethylcyclohexanone (30.85 g, 200 mmol) was added thereto over a period of 10 minutes, and the resulting mixture was Reflux for 22 hours. Then, it was poured onto ice (400 g), and the product was extracted with diethyl ether (4 x 150 ml), and the extract was dried over MgS04. After the solvent was evaporated in a vacuum, the oily residue was distilled (11 mm Hg) at 145 ° C to produce 36.8 g (86%) 2 of this oil. Ji-Wu NMRCCDCh, TMS) 5: 0.96 and 0.98 (all 12H, two s, 3, 5-CH3); 1.27 (3H, t, CH3-ethyl); 1.33 (2H, m, 4-CH2); 1.95 and 2.65 (all 4H, two s, 2,6-CH2); 4.14 (2H, q, CH2-ethyl) and 5.69ppm (1H, s, = C -Η). b) 2- (3,3,5,5-tetramethylcyclohexylene) ethanol (3); acetate 2 (3.2 g, 15 mmol) in diethyl ether (20 ml) The solution was added drop by drop to a stirred Li A1H4 solution (1.7 g, 45 mmol) in dry ether (60 ml), and cooled with ice water while the paper was scaled to Chinese National Standard (CNS) A4 Specifications (210X297 mm) _ 29-200407120 A7 _ B7___ V. Description of the invention (26) (Please read the precautions on the back before filling this page). After stirring continuously for 1 hour, the remaining Li A1H4 was destroyed with water. The aqueous layer was separated and extracted twice with diethyl ether (30 ml). The combined extract was washed with brine (50 ml) and dried over MgS04. After concentration in a vacuum, the oily residue was purified by Kugelrohi * short-path distillation (150-170 ° C, 11 mm Hg) to produce 3 (2.3 g, 89%). For an oil. iH-NMRCCDCh, TMS) 5: 0.92 (6H, s, 3, 5-CH3); 1.10 (1H, br s, OH); 1.28 (2h, S, 4-CH2); 1.87 and 1.94 (all 4H, two Species s, 2, 6-CH2); 4.16 (2H, d, 7Hz, CH20) and 5.50ppm (1H, t, 7Hz, = C-H) ° c) 2 '2,2-dichloro- (3, 3,5,5-tetramethyl-1-vinylcyclohexyl) acetamide (4). Add NaH (0.22 g, 55% dispersion in mineral oil (0.22 mmol)) to alcohol 3 (0.8 g, 4.7 in diethyl ether (5 ml)), printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Millimoles) in solution. The reaction mixture was cooled to -10 ° C, and a trichloroacetonitrile solution (0.68 g, 4.7 mmol) in diethyl ether (3 ml) was added dropwise thereto. The solution was allowed to warm to room temperature and the solvent was evaporated. To the residue was added pentane (8 ml) containing methanol (0.018 ml). The resulting mixture was filtered through a pad of salt and evaporated. The residual oil was dissolved in xylene (10 ml) and refluxed for 10 hours. Most of the xylene was distilled off under reduced pressure (1 mm Hg), and the residue was then placed on a silica gel by flash chromatography (hexane, hexane-ethyl acetate, 10: 1) Purification was performed to yield 4 (0.98 g, 66%) as an oil. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -30-200407120 A7 ------ B7_ V. Description of the invention (27) 1H ^ NMR (CDC13 j TMS) 5: 0.95 (6H, s, 3, 5. CH3); 118 (6H, s, 3, 5-CH3); 1.1- 1.5 (2H, m, 4_ CH2);! 32 (2H, d, i5HZ, 2, 6-CH2); 2.15 (2H, d, 15Hz, 2, 6-CH2); 5.08 (1H, d, 11Hz, = CH2); 5.03 (1H, d, 18Hz, = CH2); 5.85 (1H, dd, 18, and 11Hz) ,-HC =) and 6.7pm (1H 'br s, NH). d) 3,3,5,5-tetramethyl-i-ethylenecyclohexylamine hydrochloride (5). Amidine 4 (0.32 g, 1 mmol) in DMSO (3 ml) and A mixture of powdered NaOH (0.4 g, 10 mmol) was stirred at room temperature for seven days. The reaction mixture was diluted with 0 (20 ml) and stirred overnight at room temperature. The product was extracted with hexane (3 × 10 ml). The combined extract was washed with brine (20 ml), dried over NaOH, and filtered through a pad of salt. 4M HC1 in dry ether (0.5 ml) was added to the resulting solution, and the solvent was evaporated. The residue was treated with acetonitrile (10 ml), and the precipitate was collected on a filter, and dried in a vacuum over P205 to give 5, which was a colorless solid (0.12 g '5 3 ° / 〇). ^ -NMRCCDCh J TMS) 5: 0.98 fD 1.01 (all 12H, two s, 3, 5-CH3); 1.19 and 1.29 (all 2H, two d, 14Hz, 4-CH2); 1.62 ( 2H, d, 13.5Hz, 2, 6-CH2); 1.72 (2H, br s, H2O); 2.16 (2H, d, 13.5Hz, 2, 6-CH2); 5.46 and 5.73 (2H, two kinds of d, 1 8 and 1 1 Hz, = CH2); 6. 16 (1H, dd, 1 8 and 11 Hz, = CH) and 8.24 ppm (3H, br s' NH3 +) 0 This paper standard applies Chinese National Standard (CNS) Α4 Specifications (210x297 mm) -31 · (Please read the notes on the back before filling out this page)-Order the staff consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Yin Le 200407120 A7 B7 V. Invention Description (28) Example 2 (Please Please read the notes on the back before filling in this page) N, 3,3,5 '5 -pentamethyl-1 -ethanylcyclohexylamine hydrochloride (7) 〇a) 3,3,5,5 —Tetramethyl-1,1-vinylcyclohexylaminocarbamate (6). Amine hydrochloride 5 (0.25 g, 1.2 mmol) and Na2C03 (0.73 g, 6.9 mmol) in THF (6 ml) were stirred at room temperature for 1 hour. Methyl chloroformate (0.27 ml, 3.45 mmol) was added, and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with diethyl ether (20 ml), filtered and evaporated to dryness. The crude product was purified on silica gel by flash chromatography (light petroleum ether-ethyl acetate, 10: 1) to give a colorless solid 6 (0.24 g, 87%) with a melting point of 61-63 ° C. Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, iH-NMRCCDCh, TMS) 5: 0.92 and 1.15 (all 12H, two s, 3, 5- CH3); 1.00- 1.40 (4H, m, 4- CH2 and 2 , 6-CH); 2.00 (2H, d, 14Hz, 2, 6-CH); 3.62 (3H, s, CH3N); 4.72 (111, 1 ^ 5, 1 ^ 11); 5.00 and 5.06 (all 211, Two (1,10.5 and 17z, = CKh) and 5,83ppm (1H, dd, 10.5 and 17Hz, = CH). B) N, 3,3,5,5-Pentamethyl-1-Ethyl Cyclohexylamine hydrochloride (7). A mixture of LiAlH4 (0.28 g, 7.4 mmol) and urethane 6 (0.22 g, 0.92 mmol) in THF (22 ml). The paper size applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) · 32-200407120 Α7 ____ Β7 V. Description of the invention (29) Floating liquid, and washing the combined extract with brine (20 ml). The extract was dried over NaOH, filtered and treated with 2.4M HC1 in diethyl ether (} ml). The resulting suspension was evaporated to dryness. The residue was treated with diethyl ether (10 ml) and acetonitrile (1 ml). The precipitate was collected on a filter and dried in a vacuum over P205 to obtain 7 (0.11 g, 52%) as a colorless solid. iH-NMR ^ CDCh, TMS) 5: 1.00 and 1.02 (all 12H, two s, 3, 5-CH3); 1.23 and 1.32 (all 2H, two d, 15Hz, 4-CH2); 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 (all 2H, two (1, 11 And 171 ^, = (: 112); 5.98 (111, dd, 1 1 two 17Hz, = CH) and 9.30ppm (2H, br s, NH3 +). Chart: Examples 3 and 4, OH * surface-based magnesium Bromine, Ming "TMSN„ BF, OEt2 (Please read the notes on the back before filling this page)

1 .LiAIH4, Et20 2.HCI, Et20 10

NH * HCI

1. LiAIH4, Et20 2. HCI, Et20 I Me 35

NH * HCI MERZ33 / dln Use Chinese National Standard (CNS) A4 specification (210X297 mm) 200407120 A7 B7

Guang: · * Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China I. 5. Description of the Invention (30 Example 3. 1-allyl-3,3,5,5-tetramethylcyclohexylamine hydrochloride (11) 0a) 1-allyl-3,3,5,5-tetramethylcyclohexanol (8). A solution of 3,3,5,5-tetramethylcyclohexanone (3.86 g, 25 mmol) in dry ether (20 ml) was added dropwise to the stirred 1M ether of propylmagnesium bromide The solution (60 ml, 60 mmol). The mixture was stirred at ambient temperature for 1 hour and boiled under reflux for 10 minutes. Then, it was cooled with ice water and carefully treated with a saturated aqueous NH4C1 solution (40 ml). The organic layer was separated and rinsed with water and brine. After drying over anhydrous MgS04, the solution was concentrated in a vacuum. The residue was fractionated under reduced pressure to yield 3.5 g (72%) 8 with a boiling point of 98-100 ° C / 12 mmHg. 'H-NMRCCDCh, TMS) 5: 0.88 (6H, s, 3, 5 · CH3eq); 1.20 (6H, s, 3, 5-CH3ax); 0.95- 1.60 (6H, m, 2, 4, 6-CH2 ); 2.1 5 (2H, d, 7.5Hz, CH2C =); 4.95- 5.3 0 (2H, m, = CH2) and 5.65- 6.20ppm (] H, m, = CH). I Book: Order Aw (please read the notes on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -34-200407120 A7 B7 V. Description of Invention (31) (Please Read the precautions on the back before filling out this page) b) 1-Chloropropyl-1—Heptyl—3 '3' 5,5-Tetramethylcyclohexane (9) and 1-methyl-2— (3 , 3,5,5-tetramethylcyclohexylene) ethyl azide (10). Under argon, azidotrimethanol (12 mmol) was added to a solution of cyclohexanol 8 (1.96 g, 10 mmol) in dry benzene (20 mL). Via syringe, B F 3 * Ο E12 (12 mmol) was slowly added to this cooled (5 ° C) solution in 20 minutes. The mixture was stirred for 6 hours and then water was added slowly. The organic layer was separated, washed with saturated aqueous NaHC03 solution and brine, and dried over MgS04. After filtration, the solvent was evaporated, and the temperature was maintained below 25 ° C to produce an oil. This oil was separated on a silica gel (light petroleum ether) by column chromatography to collect Rf0, 8 5 (Hexane). Evaporation of the solvent gave 9 (0.26 g, 11.7%) as a colorless oil. W-NMR ^ CDCh, TMS) 5: 0.89 (6H, s, 3, 5-CH3eq); 0.90 (lH, d, 14Hz, 4-CHax); 1.05 (2H, d, 14Hz, 2, 6 -CHax); 1.18 (6H, s, 3, 5-CH3ax); 1.37 (lH, d'14Z, 4-CHeq); 1.60 (2H, d, 14Hz, 2, 6-CHeq), 2.29 (2H, d , 7Hz, CH2C =); 4.95- 5.25 (2H, m, = CH2) and 5.65-Printed by S Industrial Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economy if 6 · 1 5 ppm (1 H, m '= CH) 0 Evaporation (Rf 0.65 (hexane)) of a liquid separation yielded 0.425 g (20.3%) of azide 10 '. This was a colorless oil. ] H-NMR (CDC13, TMS) 5: 0.91 (6H, S) '0.94 (3H's), & 0.96 (3H, s, 3, 5, 5, -CH3); 1.23 (3H, d, 0.5Hz ,: l-CH3); 1.26 (2H, s, 4,-CH2); 1.89 (2H, s) and 196 (2H, this paper size applies the Chinese National Standard (CNS) A4 specification (210x 297 mm) -35-200407120 A7 _ B7 V. Description of the invention (32) s, 2, 6, 6'-CH2); 4.31 (1H, dq, 6.5 and 9.5Hz, 1-CH) and 5.2 1 ppm (1 Η, dm, 9.5Hz, = CH). c) 1-allyl-3,3,5,5-tetramethylcyclohexylamine hydrochloride (11). Azide 9 (0.221 g, 1.0 mmol) in dry ether (4 ml) was added dropwise over 10 minutes to stirred lithium aluminum hydride (10 ml) in ether (10 ml). 0.12 g, 4 mmol) in suspension. 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 (2 X 15 ml). The combined organic extracts were washed with brine and dried over NaOH. The filtered solution was treated with a dry HC1 solution in diethyl ether and evaporated. Dry diethyl ether was added to the solid residue and collected on a filter, and washed with dry diethyl ether to give 11 (0.105 g, 47%) as a colorless solid. 1H-NMR (CDC13 J TMS) 5: 1.03 (6H, s, 3, 5-CH3 e (1); 1.06 (6H, s, 3, 5-CH3ax); 1.29 (2H, s, 4- CH2); 1.63 (Please read the notes on the back before filling this page) (2H, d, 13Hz, 2, 6-CHax); 1.80 (2H, 1 d, 1 3 Hz j 2, 6-CHeq), 2.71 ( 2H, d, 7Hz, CH2C =); 5.10- 5.40 (2H, m Employee Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy, Graphic Arts iJ., = CH 2); 5 · 7 5-6.2 5 (1 H, m, = CH) and 8 2 5 ppm (3 H, brs, NH3 +) o Example 4 1 — (3,3,5,5 —tetramethylcyclohexylene) — 2 —propylamine hydrochloride (24). This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) _ 36-200407120 A7 B7 V. Description of the invention (33) 1-methyl-1 2- (3) in dry diethyl ether (4 ml) , 3,5,5-tetramethylcyclohexylene) ethyl azide ΐ0 (0.33 g, 1.5 mmol) solution was added dropwise to ether (15 ml) over 10 minutes In a stirred suspension of lithium aluminum hydride (0.152 g, 4 mmol). The mixture was stirred for 4 hours, and then ° / 〇 NaOH aqueous solution (8 ml). It was extracted with diethyl ether (2 X 15 ml). The organic extracts were combined, washed with brine, and dried over NaOH. Treat the filtered solution with dry HC1 solution and evaporate it in a vacuum. Add dry ether to the solid residue, collect it on the filter, and rinse with dry ether to produce 24 (0.18 g, 54 %). IH-NMR ^ CDCh, TMS) 0 · 89 (6H, s), 0.92 (3Η, s) and 0.98 (3Η, s, 3,, 5'-CH3); 1.27 (2Η, s, 4'-CH2); 1.47 (3H, d, 6.5Hz, 3-CH3); 1.84 (lH, d, 13.5z, 2, -CH); 1.87 (2H, s, 6,-CH2) , 2.06 (lH, 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 +). Charts: Examples 5, 6 and 7 (Please read the notes on the back before filling out this page) Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperative ^ Bad

This paper size applies to Chinese National Standard (CNS) A4 specifications (2) 0X 297 mm -37-200407120 A7 _____B7_ V. Description of the invention (34) Example 5. (Please read the precautions on the back before filling this page ) 1- (1-allyl-3,3,5,5-tetramethylcyclohexyl) hexahydropyridine hydrochloride (1 3). a) 1- (3,3,5,5-tetramethyl- 1-cyclohexyl-1) hexahydrogen than D (12). Prepared by heating in benzene, condensing hexahydropyridine (1.2 equivalents) with 3,3,5,5-tetramethylcyclohexanone, and removing water by azeotropic distillation. The crude product was obtained by removing the starting material under vacuum distillation (100 ° C / 10 mm Hg). Amber oil. iH-NME ^ CDCh, TMS) 5: 0.94 (6H, s) and 0.97 (6H, s, 3, 5, 5, CH3); 1.25 (2H, s, 4,-CH2); 1.40- 1.70 (6H, m, hexahydropyridine 3, 4, 5-CH2); 1.76 (2H, s, 6'-CH2); 2.60- 2.85 (4H, m, hexahydropyridine 2, 6-CH2) and 4.40ppm (1H, s = CH) ob) 1— (1-allyl-3,3,5,5-tetramethylcyclohexyl) Printed by the Intellectual Property of the Ministry of Economic Affairs and Industrial Cooperative Cooperatives Hydrochloride (1 3) Acetic acid (0.675 g, 11.25 mmol) was added to a solution of enaminel 2 (2.1 g, 9 mmol) in THF (20 ml). The mixture was stirred for 5 minutes, and zinc powder (0.74 g, 11.25 mmol) was added. Then, a solution of allyl bromide (ι.63 g, 13.5 mmol) in THF (5 ml) was added dropwise thereto, and the mixture was stirred at ambient temperature for 6 hours. Adding Na2C03 aqueous solution and extracting it with ether _ _-This paper size applies Chinese National Standard (CNS) A4 specification (2) 0X 297 mm -38- 200407120 A7 _B7 _V. Description of the invention (35) . The extract was rinsed with brine, dried over anhydrous MgS04, and concentrated in a vacuum. The residue was separated by silica gel column chromatography (hexane, 5% EtOAc in hexanes). Rf 0.85 was collected (hexane-EtOAc, 13: 2). After evaporation, it was treated with a dry HC1 solution in ether. The precipitate was filtered off and washed with a hexane-EtO Ac mixture to obtain a colorless solid 13 (0.79 g, 29%). 1H-NMR (CDC13 j TMS) 5: 1.07 (6H ^ s ^ 35? 55-CH3eq), 1.10 (6H, s, 3 ', 5'-CH3ax); 1.34 (1H, d, 12.2Hz) and 1.45 ( 1H, d, 12.2Hz, 4, -CH2); 1.70-1.95 (6H, m, 2 ', 6, -CHax and hexahydropyridine 3,5-CH, 4-CH2); 2.37 (2H, d , 13.4Hz, 2,6, CHeq); 2.40- 2.70 (2H, hexahydropyridine 2,6-CH); 3.6 4 (2H, d, 11.6Hz, hexahydropyridine 2,6-CH); 5.13 ( 1H, d, 9.6Ηζ) and 5.24 (111, (1, 17.81 ^, = (: 112); 5.85-6.15 (1H, m, = CH) and 10.72ppm (1H, br s, NH). (Please read the notes on the back before filling out this page) Member of the Ministry of Economic Affairs, Intellectual Property Bureau, X Consumer Co., Ltd .: || £; Example 6 1— [3,3,5,5 —Tetramethyl-1— 3-methyl-2-butenyl) cyclohexyl] hexahydropyridine hydrochloride (14). Starting from hexahydropyridine 12, it was prepared according to the procedure for preparing compound 13 (Example 5, b). , But substituted allyl bromide with 4-bromo-2-methyl-2-butene. Yield: 20%. H-NMRCCDCh, TMS) 5: 1.07 and 1.0 8 (all 12H, two s, 3 ,, 5,-CH3), 1 · 32 and 1.44 (2H, two kinds of d, 14.2Hz, 4,-CH2); 1.69 and 1.76 (6H 'two kinds of s, = C (CH3) 2); 1.68- This paper size applies to Chinese national standards (CNS) A4 specification (210X297 mm) -39-200407120 A7 B7 V. Description of invention (36) (Please read the precautions on the back before filling this page) 1.96 (4H, m, 3, 5-CH and 4- CH2); 1.84 (2H, d, 13.4Ηζ, 2 ', 6,-CHax); 2.31 (2Η, d, 13.4Hz, 2', 6,-CHeq); 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); 5.31 (1H, t, 6.8HZ , = CH) and 10.55 ppm (1H, br s, NH). Example 7 1- [3,3,5,5-tetramethyl-1- (2-propynyl) cyclohexyl] hexahydropyridine hydrochloride (14). Starting from hexahydropyridine 12, it was prepared according to the procedure for preparing compound 13 (Example 5, b), but allyl bromide was replaced with 3-bromopropyne. Yield: 6% 1H-NMR (CDC13 5 TMS) 5: 1.07 (6H, s, 3 ,, 5 '-CH3 eq), 1.11 (6H, s, 3', 5,-CH3ax); 1.23 and 1.4 4 ( All 2H, two kinds of d, 14.3Hz, 4'-CH2); 1.75- 2.00 (4H, m, hexahydrocyclodine 3, 5-CH, 4-CH2); 1.91 (2H, d, 13.2Hz, 2 ', 6,-CHax); 2.28 (1H, s, HCC); 2.34 (2H, d, 13.2Hz, 2', 6,-CHe (i) Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperative, India; 2.40- 2.70 (2H, m, hexahydropyridine 3, 5- CH); 2.81 (2H, s, CH2CC); 2.85- 3.10 (2H, m, hexahydropyridine 2, 6-CH); 3.69 (2H, d, 1 0.2 Hz, hexahydropyridine 2, 6-CH) and 1 1. 12 ppm (1H, br s, NH). Chart: Examples 8 and 9 This paper size applies Chinese National Standard (CNS) A4 specification (21 OX 297 mm) -4〇- 200407120 V. Description of the invention (37) A7 B7

1.DPPA, Et3N, benzene, reflux 2. aq. HCI 3. MeCN, reflux

NH2 * HCI 1. LiAIH4, THF 2. HCI, Et20

ΝΗοΉ0Ι (Please read the precautions on the back before filling this page) Example 8 2— (3,3,5,5-tetramethyl-1-vinylcyclohexyl) ethylamine hydrochloride (19). a) 2- (3-Ethyl acetate (1 6) 3,5,5-tetramethyl-1-vinyl.cyclohexyl) o-triethyl acetate (I8.6 ml, 102 mmol), 2_ (3,3,5,5-tetramethylmonocyclohexylene) ethanol (3) (4.63 g., Printed by the Intellectual Property Office Staff Fee Cooperative of the Ministry of Economy 25.4 mmol) and propionic acid (0.19 ml, 2.5 mmol) ) The mixture was heated at 145 ° C for 10 hours. During the reaction, ethanol was distilled off from the mixture. The reaction mixture was cooled and poured into water (100 ml). The aqueous phase was extracted with hexane (2x50 ml), and the combined organic phase was washed with 5% KHS04 aqueous solution (50 ml) and brine (50 ml). The extract was dried over Mg S 04, filtered, and evaporated. The residue was purified on silica gel by flash chromatography (light petroleum ether and light petroleum ether-ethyl acetate, 100: 2) to give 16 (4.64 g, 73%) as an oil. This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -41-200407120 Employee Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs 卬 f ^-• 1 A7 B7 V. Description of Invention (38) 'H-NMRCCDCla ^ TMS) 5: 0.91 (6H, s, 3, 5- CH3); 1.01 (6H's '3' 5- CH3); 1.23 (3H, t, 7Hz ethyl CH3) 1.00- 1.30 (4H 'm' 4 -CH2 and 2 '6- ch); 1.86 (2H, d, 13Hz, 2, 6-CH); 2.22 (2H, s, CH2C = 〇); 4.〇8 (2H, q, 7Hz, ethyl CH2 ); 5.06 and 5.07 (all 2H, two d, 11 and 17.5Hz, = CH2) and 5.95ppm (1H, dd, 1 1 and 17.5Hz, _ CH =) 〇b) 2 one (3, 3 '5 , 5-tetramethyl, 1-vinylcyclohexyl) acetic acid (1 7) NaOH (1.03 g, 25.8 mmol) in methanol (26 ml) and acetate 16 (1.3 g, 5 · 15 millimolar) solution 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 HC1 aqueous solution and extracted with hexane (3 x 30 ml). The combined organic phase was washed with brine, dried over CaCl2, filtered and evaporated. The residue was purified on silica gel by flash chromatography (light petroleum ether-ethyl acetate, 10: 1) to yield 17 (0.7 g, 71%), which is a colorless solid with a melting point of 92 — 94 ° C. 1H-NMR (CDC13 ^ TMS) (5: 0.92 (6H, s, 3, 5-CH3); 1.02 (6H, s, 3, 5-CH3); 1.00- 1.30 (4H, m, 4- CH2 And 2, 6-CH); 1.90 (2H, d, 14Hz, 2,6-CH); 2.27 (2H, s, CH2C = 0); 5.11 and 5.13 (all 2H, two d, 11 and 18Hz, = CH2); 5.99 (1H, dd, 1 8 and 1 1Hz, = CH) and 10.80ppm (1H, br s, COOH). (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese national standards (CNS) A4 specifications (210X297 mm) _ 42-200407120 Consumption cooperation stamp of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs: f: A7 _B7_ V. Description of the invention (39) c) 2— (3, 3, 5, 5 — Tetrafluorenyl-1 monovinylcyclohexyl) Acetylamine (18). Add N-hydroxysuccinimide (0.25 g, 2.2 mmol) and N, N'-dicyclohexylcarbodiimide (0.45 g, 2.2 mmol) to the ring in THF (5 ml) Hexylacetic acid 17 (0.45 g, 2 mmol). The mixture was stirred at room temperature for 18 hours and cooled in an ice bath. An aliquot of a 25% aqueous solution of NΗ40Η (2 ml) was added thereto, 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% KHS04 (10 ml) and brine. The extract was dried over MgS04, passed through an oven and evaporated. The residue was purified on silica gel by flash chromatography (light petroleum ether-ethyl acetate, 4: 1 to 1: 1) to yield 18 (0.34 g, 7 6%) as a Colorless solid with a melting point of 44-46 ° C. iH-NMRCCDCh, TMS) 5: 0.91 (6H, s, 3, 5- CH3); 1.02 (6H, s, 3, 5- CH3); 1.00- 1.30 (4H, m, 4- CH2 and 2, 6- CH); 1.85 (2H, d, 14z, 2, 6-CH); 2.13 (2H, s, CH2C = O); 5.18 and 5.19 (all 2H, two d, 18 and 11Hz, = CH2); 5.40 and 5.60 (all 2H, two br s, NH2) and 6.03ppm (1H, dd, 1 8 and 11 Hz, = CH). d) 2— (3,3,5,5-tetramethyl-1-ethylenecyclohexyl) ethylamine hydrochloride (〖9). LiAlH4 (0.41 g, n millimoles) in THF (18 ml) This paper is sized for China National Standard (CNS) A4 (2! OX297 ^^. 43 ·-(Please read the precautions on the back before (Fill this page) 200407120 A7 ____B7 V. Description of the invention (40) (Please read the precautions on the back before filling this page)) and the mixture of ammonium 1 8 (0.3 0 g, 1.4 mmol) is refluxed for 17 hours Then, the mixture was cooled in an ice bath, and water (30 ml) was added dropwise thereto. The resulting suspension was extracted with hexane (3 x 30 ml) and washed with brine. Organic phase. The extract was dried over NaOH, filtered and concentrated to a volume of about 10 ml. 4.8 M HC1 in diethyl ether (1 ml) was added thereto, and the resulting suspension was evaporated to dryness. Acetonitrile (5 Ml) and the residue was collected on a filter and the precipitate was collected in a vacuum and dried over NaOH to give 19 (0.16 g, 50%) as a colorless solid. W-NMR ^ CDCh, TMS) ά: 0.89 (6H, s, 3, 5- CH3); 1.02 (6H, s, 3, 5- CH3); 0 · 90- 1.80 (8 H, m, ring proton and ethylamine-2-CH2); 2.92 (2H, br s, CH2N); 5 · 0 5 and 5 · 15 (2H, two kinds of d, 18 and 11 Hz, = CH2); 5.77 (1H, dd, 18 and 11 Hz, = CH) and 8 · 1 Oppm (3H, br s, NH3 +). Example 9 3- (3,3,5,5-tetramethylcyclohexylene) propylamine hydrochloride (32). The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the Consumer Cooperative Co., Ltd. incorporated triethylamine (0.25 ml, 1.76 mmol) and diphenylphosphonium azide (0.38 ml '1.76 hamol) into benzene ( 6 ml) of a solution of acid 17 (0.36 g, 1.6 mmol). The mixture was refluxed for 2 hours, cooled to room temperature, and evaporated to dryness. Add a cold (~ 5 ° C) concentrated HC1 water solution (3 ml) to the residue. The resulting mixture was stirred at room temperature for 18 hours and made strong base by adding a 10% aqueous NaOH solution. This paper size applies to Chinese National Standard (CNS) A4 size (210x 297 mm) _ 44-200407120 A7 ___B7 _ V. Description of the invention (41) (Please read the precautions on the back before filling this page) Hexane ( 20 ml) was added to the mixture, and both phases were filtered. Rinse the precipitate with hexane (2 X 5 mL) and water (2 X 5 mL). The organic phase of the filtrate was separated. Rinse the aqueous phase with hexane (2 X 10 ml). The combined organic phases were washed with brine (10 ml), dried over NaOH and filtered. A 4.8 M HC1 solution in diethyl ether (1 ml) was added thereto, and the resulting suspension was evaporated. The residue was recrystallized from acetonitrile and dried in a vacuum over P205 to give 32 (0.1 g, 43%) as a colorless solid. W-NMi ^ CDCh, TMS) d: 0.90 and 0.92 (all 12H, two s, c- Hex- 3, 5- CH3); 1.23 (2H, s, c- Hex- 4 · CH2); 1.86 And 1.92 (all 4H, two s, c- Hex- 2,6- CH2); 2.49 (2H, q, 7Hz, propylamine-2-CH2); 2.9 8 (2H, t, 7Hz, propylamine-1-CH2 ); 5.15 (1H, t, 7Hz, = CH-) and 8.3 Op pm (3 H, br s, NH3 +). Table: Example 10 and printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Example 10,

2.HCI, Et20

NH * HCI

I.LiAIH., ZnCL This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) -45-200407120 Printed by the Consumer Cooperatives of the 4th Bureau of Smart Finance of the Ministry of Economic Affairs-* A7 B7 42) 2 mono (3,3,5,5-tetramethylcyclohexylene) ethylamine hydrochloride (22). a) 3,3,5,5-Tetramethylcyclohexyleneacetonitrile (20). The dispersion in mineral oil (0.96 g, 24 mmol) was added to a solution of diethyl cyanomethylphosphonate (4.25 g, 24 mmol) in THF (30 ml), and ice Cool it with water. The mixture was stirred for 30 minutes, and a solution of 3,3,5,5-tetramethylcyclohexanone (3.08 g, 20 mmol) in THF (10 ml) was added dropwise thereto. The cooling bath was removed and the mixture was stirred at room temperature for 72 hours. It was poured into ice-water (100 ml) and extracted with diethyl ether (3 > < 50 ml). The combined organic phases were washed with brine, dried over Mg S04, filtered and evaporated. The crude product was purified on silica gel by flash chromatography (light petroleum ether-ethyl acetate, 10 ·· 1) to yield 20 (2.38 g, 71%) as a colorless oil. W-NMRCCDCh, TMS) 5: 0.97 and 1.01 (all 12H, two s, 3 ', 5'-CH3); 1.36 (2H, s, 4,-CH2); 2.01 (2H, s' 2, -CH2); 2.26 (2Η's' 6,-CH2) and 5.14ppm (1Η, s, = CH) 〇b) 2- (3,3,5,5-tetramethylcyclohexylene) ethylamine hydrogen Chlorate (22). A suspension of LiA1H4 (0 68 g, 8 mmol) in diethyl ether (30 mL) was cooled in an ice bath, and a 1 M Z n C12 solution (9 mL, 9 mmol) in diethyl ether was cooled. ) Join it. Stir the resulting mixture ^ paper size and use "Chinese National Standard (CN: S) A4 size (210X 297 mm) (Please read the precautions on the back before filling this page) 200407120 A7 B7 V. Description of the invention (43 ) Stir for 15 minutes, and dropwise add a solution of nitrile 20 (1 g, 6 mmol) in diethyl ether (30 ml) while maintaining the temperature at 0-5 C. Remove the ice bath ' The mixture was stirred at room temperature for 24 hours. Water (30 ml) and 20% aqueous NaOH solution (20 ml) were added thereto, and simultaneously cooled in an ice bath. Extracted with diethyl ether (4 x 50 ml) Aqueous phase. The combined organic phase was washed with brine (50 ml), dried over Na0H, filtered and evaporated. The residue was subjected to cogillot short-range steaming at 160 ° C / 20 mm Hg Purify under the column. Dilute the distillate with diethyl ether and add 4.SM HC1 solution in diethyl ether (3 ml). Collect the resulting precipitate on the filter and wash with diethyl ether (3 x 5 ml) And dried in a vacuum over NaOH to produce 22, which is a colorless solid. 1 H-NMR (CDC13 j TMS) 5: 0.91 and 0.92 (all 12H, two s, 3, 5, CH3); 1.2 8 (2H, s, 4'- CH2); 1.89 and 1.93 (all 4H, two Species s, 2 ', 6'- CH2); 3.62 (2H, d, 7Hz, CH21S [); 5.41 (1Η, t, 7Hz,-C = CH) and 8 · 3 ppm (3 H, br s, NH3 + ). (Please read the notes on the back before filling out this page) Example of the Intellectual Property Office of the Ministry of Economic Affairs 1 1 2-(3, (23). A) 2-5 Tetramethylammonium hexyl) propylamine gas chloride Acid salt 5-tetramethylcyclohexylene) propionitrile (21) Consumer Press uses diethyl (1-cyanoethyl) phosphonate according to the method used to prepare compound 20 (Example 10, a) The process can be prepared. The result can be obtained as nitrile 21. This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) -47-200407120 A7 B7 V. Description of the invention (44) is a colorless oil with a yield of 4 1%. (Please read the notes on the back before filling this page) 1H-NMR (CDC13, TMS) 5: 0.96 and 1.00 (all 12H, two s, c- Hex- 3, 5- CH3); 1.34 ( 2H, s, c- Hex- 4- CH2); 1.9 1 (3H, s, c Nitrile-3-CH3); 2.04 and 2.2 8ppm (all 4H, two s, c-Hex-2,6-CH2). b) 2- (3,3,5,5-tetramethylcyclohexylene) propylamine hydrochloride (23) starting from Cyanide 21 and following the steps used to prepare compound 22 (Example 10, b) preparation. As a result, amine hydrochloride 23 was obtained as a colorless solid. iH-NME ^ CDCh, TMS) ά: 0.92 and 0.93 (all 12H, two s, c- Hex- 3, 5- CH3); 1.27 (2H, s, c- Hex- 4- CH2); 1.89 (3H , S, propylamine-3-CH3); 1.99 and 2.01 (all 4H, two s, c- Hex- 2,6-CH2); 3.64 (2H, br s, propylamine-1-CH2) and 8.40ppm (3 H, br s, NH3 +) o Graph: Example 1 2 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ¾

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -48- 200407120 A7 B7 V. Description of invention (45

Example 1 2. (E, Z 3 —diethyl-5,5-dimethylcyclohexylene, Ministry of Economic Affairs, Intellectual Property Bureau, GX Consumer Co., Ltd., India-based) — 2 —propylamine hydrochloride (28). 〇 1 -Allyl-3,3-diethyl-5.5-dimethylcyclohexanol (26) 〇 3,3-diethyl-5,5 -di in dry ether (5 ml) A solution of methylcyclohexanone (25) (1.47 g, 8.06 mmol) was added dropwise to a 1M ether solution of stilbene propyl epidermis (20 ml, 20 hamol). The mixture was stirred at ambient temperature for 1 hour and boiled under reflux for 10 minutes. Then, it was cooled with ice water and treated with a saturated aqueous NH4C1 solution (40 ml). The organic layer was separated and rinsed with water and brine. After drying over anhydrous MgS04, the solution was concentrated in a vacuum. The residue was purified on silica gel by column chromatography (light petroleum ether). Rf 0.7 was collected (hexane: EtOAc, 13: 2). Evaporation of the solvent yielded 26 (1.35 g, 74%) as a colorless oil. ! H-NMR (CDCl3 J TMS) δ: 0.74 (6Η't, 7Hz 'ethyl 2CH3); 0,88 (3Η, s, 5-CH3eq); 1.19 (3Η, s, 5-CH3ax) ; 0.80- 2.05 (10H, m '2' 4 '6- CH2 and ethyl 2CH2); 2.14 (2H, d, 7Hz, CH2C =); 4.95- 5 · 30 (2H, m, = CH2) and 5.65 -6.20ppm (1H, m, = CH) 0 b) (£, 2) — 1-methyl-1 2- (3, 3-diethyl — 5.5 — (Please read the precautions on the back before filling this page ) This paper size applies Chinese National Standard (CNS) A4 specification (2i0x 297 mm) -49-200407120 A7 ___B7_ V. Description of the invention (46) Dimethylcyclohexylene) ethyl azide (27). (Please read the notes on the back before filling this page.) Starting from cyclohexanol 26, it was prepared according to the steps used to prepare compounds 9 and 10 (Example 3, b). As a result, azide 27 was obtained, which was a colorless oil with a yield of 15%. iH-NMRCCDCh, TMS) 5: 0.73 and 0.74 (all 6H, two t, 7Hz, 2CH3 ethyl); 0.91, 0.94, and 0.97 (all 6H, all s, 5 ', 5, CH3); 1.10- 1.45 (4Η, m, 2CH2 ethyl); 1.22 (3Η, d, 6.5Hz, 1.CH3); 1.26 (2Η, s, 4, -CH2); 1.89 (2Η, s), and 1.97 ( 2Η, m, 2, 6'-CH2); 4.08- 4.48 (1Η, m, 1-CH) & 5.18ppm (lH, dm, 9.5Hz, = CH). c) (E, Z) — 1- (3,3-diethyl-5.5-dimethylcyclohexylene)-2-propylamine hydrochloride (28). Starting from azide 27, it was prepared according to the procedure used to prepare compound 24 (Example 4). As a result, amine hydrochloride 28 was obtained as a colorless solid with a yield of 16%. 1H-NMR (CDC13 j TMS) 5: 0.72 (6H ^ br t »7Hz» 2CH3, ethyl), 0.90, 0.92, and 0.98 (all 6H, all 8, 5, and 6) 5, -CH3); 1.25 (6H, m, 4'-CH2 and 2CH2 ethyl); 1.47 (3H, d, 6.5Hz, 2-CH3); 1.70-2.25 (2H, brAB q, 13Hz, 2, CH2); 1.87 (2H, s, 6'-CH2), 4.18 (1H, m, 2-CH); 5.34 (1H, brd, 9.5Hz, = CH) and 8.38ppm (3H, br s, NH3 +) 〇 This paper size applies the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) _ 50 _ 200407120 A7 ______B7 V. Description of the invention (47) Chart: Example 1 3

(Please read the precautions on the back before filling this page) Example 13 2 —Methyl-1— (3,3,5,5—Tetramethylcyclohexylene) —2—Propanylamine Hydrochloride (3 1 ). a) 2-Methyl-1- (3,3,5,5-tetramethylcyclohexylene) -2-propanol (29). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ¾ Add a solution of acetate 2 (2.14 g, 10 mmol) in diethyl ether (20 ml) to a 1.6 M MeLi solution (26 ml, 40 mmol) in diethyl ether Ear), and chill it with an ice bath. The reaction mixture was stirred at room temperature for 1 hour. Then, it was cooled in an ice bath, and a drop of saturated NHUC1 aqueous solution (20 ml) was dropped into it. The aqueous phase was extracted with diethyl ether (2 × 30 ml). The combined organic phases were washed with brine (30 ml), dried over MgS04, filtered and evaporated. The residue was purified by cogillo short-range distillation (100 ° C / 4 mmHg) to give 29 (1.86 g, 86%) as a colorless oil. ^ -NMRCCDCh J TMS) 5: 0.91 and 0.9 6 (all 12H, two kinds of s, c-Hex · 3,5-CH3); 1.25 (2H, s, c- Hex- 4 · CH2); 1.3 8 (6H , S,-C (CH3) 20); 1.79 and 2.23 (two kinds of 2H, two kinds of s This paper size applies to China National Standard (CNS) A4 specifications (2) OX 297 mm) -51-Intellectual Property Bureau, Ministry of Economic Affairs g (Industrial and Consumer Cooperative Cooperative Seal) 200407120 A7 ____ B7_ V. Description of the Invention (48), c- Hex- 2,6- CH2) and 5.39ppm (lH, s = CH_). b) 2 —Azido- 2— Methyl 1- (3,3,5,5-tetramethylcyclohexylene) propane (30). BF3Et20 (0.3 ml, 2.4 mmol) was added to a solution of alcohol 29 (0.42 g, 2 mmol) in benzene (4.5 ml) and TMSN3 (0.31 ml, 2.4 mmol) over a 3 minute period. And cooled with an ice bath on one side. The reaction mixture was stirred at 5-10 ° C for 1 hour and filtered through a short silica gel column. The solution was evaporated and the residue was purified on silica gel (light petroleum ether) by flash chromatography analysis to give 30 (0.30 g, 64%) as a colorless oil. , TMS) 5: 0.92 and 0.98 (all 12H, two s, c-Hex- 3, 5- CH3); 1.27 (2H, s, c- Hex- 4- CH2); 1.40 (6H, s, -C (CH3) 2N3); 1.85 and 2.23 (two 2H, two s, c- Hex- 2,6- CH2) and 5.27ppm (1H, s = CH-). c) 2-methyl-l- (3,3,5,5-tetramethylcyclohexylene) -2-propanamine hydrochloride (31). Starting from the azide (30), it was prepared by the same procedure used to prepare the amine 24 (Example 4). As a result, amine hydrochloride 31 was obtained as a colorless solid with a yield of 69%. ^ -NMRiCDCls 5 TMS) δ: 0.91 and 0.9 8 (all l 2Η, two kinds of s, c- Hex- 3, 5- CH3); 1.26 (2Η 's' c · Hex- 4- CH〗) ; 1.6 8 (6H, s,-C (CH3) 2N); 1.84 and 2.10 (two 2H, two s clothing ^ IT f, please read the precautions on the back before filling this page) This paper size applies to Chinese national standards (CNS) A4 specifications (2) 0X 297 mm -52-200407120 A7 B7 V. Description of the invention (49) 'Hex- 2,6- CH2); 5.15 (1H, s, = CH-) and 8.5ppm ( 3H, br s, NH3 +). Chart · Examples 1 4 and 1 5

Me · Me Λ 36

(Please read the precautions on the back before filling this page) Example 14 '5 -Trimethyl-1 -cyclohexene-1 -amine hydrochloride (35) a) 3 -Azido-1 Trimethyl Base 1 Cyclohexene (34) Employee Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 卬 still add 53% H2S04 aqueous solution (8 ml) dropwise in cooled (0 ml) sodium azide in CH2C12 (5 ml) (0.8 gram, 2.5 millimoles) suspension. The mixture was stirred for 10 minutes, and then a solution of 3,5,5-trimethyl-2-cyclohexanol (33) (0.70 g, 5 mmol) in CH2C12 (8 ml) was added. The mixture was stirred for 20 hours, poured into ice water, neutralized with an aqueous solution of NH 4 0 H, and extracted with CH 2 Ch. The size of this paper is based on the standard of Chinese papers (CNS) A4 (210X 297 mm) -53-200407120 A7 B7 5. The description of the invention (50) (Please read the precautions on the back before filling this page) Wash extraction And dried over MgS04. After filtration, the solvent was evaporated and the temperature was maintained below 25 ° C to produce an oil. This oil was separated on silica gel by column chromatography (light petroleum ether). Rf 0.8 fractions were collected (hexane). Evaporation of the solvent yielded 34 (0.3 65 g, 44%) as a colorless oil. iH-NMR ^ CDCh, TMS) 5: 0 · 89 and 1.0 1 (all 6Η, two kinds of s, 5,5-CH3); 1.34 (1Η, m, c- 4-CH); 1.5 5-1.9 5 ( 3Η, m, 4- CH, 6-CH2); 1 · 7 1 (3 H, s, 1 · CH3); 3.90 (1H, m, 3- CH) and 5.39ppm (1H, s, C = CH ). b) 3,5,5-trimethyl-2-cyclohexene-1-amine hydrochloride (35). Starting from azide 34, according to the method used to prepare compound 1 1 (Example 3, c ). As a result, amine hydrochloride 35 was obtained as a colorless solid with a yield of 57%. (Stamped and stamped by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs) i5. IH-NMRCCDCh, TMS) 5: 0 · 89 and 1.03 (all 6H, two types of s, 5, 5-CH3); 1.25 · 2.15 (4Η, m, 4 , 6-CH2); 1.72 (3Η, s, 3-CH3); 3.88 (lH, m, 1-CH); 5.41 (lH, s, C = CH) and 8.40ppm (3H, br s , NH3 +). Example 1 5 1,3,5,5-tetramethyl-2-cyclohexene-1 monoamine hydrochloride (40) 〇a) 1,3,5,5-tetramethyl-1,3 —Cyclohexanone; (: Greek (37) and this paper size are applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) -54-200407120 A7 B7 V. Description of the invention (51 1, 5, 5 — Three top A mixture of 3,3-methyl-1, cyclohexene (3 8) · 3,3,5-trimethyl-1,2-cyclohexene-1, one ketone (3 6) (1.3 g, 10 mmol) was added dropwise to a stirred 2 M ether solution of methyl iodide (15 ml, 30 mmol). The mixture was stirred for 1 hour with ice It was cooled with water and carefully treated with 15% CH3COOH aqueous solution (15 ml). The mixture was stirred for another hour. The organic layer was separated and washed with water and saturated NaHC03 aqueous solution. After drying over MgS04, the solution Concentrated in a vacuum. The residue was purified by flash chromatography (light petroleum ether, RfO. 95 (hexane)) to give a mixture of 37 and 38 (0.95 5 g, 70%) (7: 10 According to GC) This is an oil. ^ -NMRCCDCb J TMS) δ: 0.89, 0.98 and 1.03 (all 10.2Η, all s, 5, 5-CH3); 1.55- 2.20 (all 12.6Η, m , CH2C = and CH3C =); 4.69 (2H, dm, 4Hz, = CH2); 5.06 (0.7H, m, = CH); 5.50 (0.7H, sep, 1.5Hz, = CH) and 5.92ppm (1 H, m, = CH) 0 (Please read the precautions on the back before filling out this page) Industrial and Consumer Affairs Bureau, Intellectual Property Bureau, Ministry of Economic Affairs, Printed by the Society b) 3 —Azide based—1,5,5 '5—Tetramethyl The radical 1-cyclohexene (39) ° was prepared according to the procedure for preparing compound 34 (Example 14, a) starting from a mixture of 37 and 38. As a result, azide 9 was obtained, which is a colorless oil with a yield of 43%. iH-NMRCCDCh, TMS) 〇: 0.93 and 0.99 (full 咅 β 6H, two kinds of s, 5, 5-CH3); 1.3] (3 Η, s, bu CH3); 1.36 and 1.6 2 (all paper sizes are applicable to China National Standard (CNS) A4 specification (210 乂 29 * 7mm) -55-s, 1- CH3, 6 200407120 A7 B7 V. Description of the invention (52)

2H, two kinds of d, 13Hz, 4-CH2); 1.72 (5H CH2); 5.32 (1H, s, C = CH). c) 1,3,5,5-5-tetramethyl-2-cyclohexene-1-amine hydrochloride (40). Starting from azide 39, it was prepared according to the procedure used to prepare compound 1 1 (Example 3, c). As a result, amine hydrochloride 40 was obtained as a colorless solid with a yield of 60%. iH-NMRCCDCh, TMS) 6: 0.96 and 1.07 (all 6H, two s, 5, 5-CH3); 1_56 (3H, s, 1-CH3); 1.73 (3H, s, 3- CH3); 1.60- 2 · 05 (4H, m, 4, 6-CH2); 5.49 (1H, s, C = CH) and 8.27ppm (3H, br s, NH3 +) o Graph: Example 16 (Please read the note on the back first Please fill in this page again for details) Member of the Ministry of Economic Affairs' Property Bureau £ Consumption Cooperative Association m 〇

Me BF3 * 〇B2 1.LiAIH4-Me 2.HCI OH TMSN,

Me

Me 44

-56- This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) 200407120 A7 _____B7_ V. Description of Invention (53) Example 16 (Please read the precautions on the back before filling this page) 1, 3 , Trans-5-trimethyl-cis-3-vinylcyclohexylamine hydrochloride (4 5). a) 3,5-Difluorenyl-3-vinylcyclohexanone (42) A 1M solution of vinylmagnesium bromide in THF (90 ml, 90 mmol) in an inert atmosphere on dry ice -Cool to -20 ° C in an acetone bath and add CuCl2 (4.45 g, 45 hamol) in one portion. The mixture was stirred for 30 minutes, and 3,5-dimethyl-2-cyclohexene-1-one (41) (3.73 g, 30 mmol) was consumed by employees of the Intellectual Property Office of the Ministry of Economic Affairs in THF (40 ml). Cooperative seal— ^ ear) solution was added dropwise while maintaining the reaction temperature at -20 ° C. The cooling bath was removed and the reaction mixture was allowed to reach room temperature for 2 hours. Add saturated aqueous NH4C1 solution (50 ml) and cool in an ice bath. Then, hexane (150 ml) was added, the aqueous layer was separated, and it was extracted with hexane (2 x 100 ml). The combined organic extract was washed with a 20% aqueous acetic acid solution (100 mL) and a saturated NaHC03 aqueous solution (3 x 200 mL). The extract was dried over MgS04, filtered and evaporated. The crude product was purified on silica gel by flash chromatography (light petroleum ether-ethyl acetate, 20: 1) to produce 42 (2.4 g, 52%) as a colorless oil. iH-NMR ^ CDCh, TMS) 5: 0.99 (3H, d, 6HZ, 5-CH3); 1.11 (3H, s, 3-CH3); 1.2- 2.6 (7H, m, ring proton); 4.94 and 5.01 ( All 2H, two d, 17 and 1.05 Hz, CH2 =) and 5.64 ppm (1H, dd, 17 and 11 Hz, = CH). This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -57-200407120 A7 B7 V. Description of the invention (54) b) 1, 3, trans-5-trimethyl-cis-3 —Vinylcyclohexanol (43 ml. A solution of ketone 42 (1 g, 6.6 mmol) in diethyl ether (10 ml) was added to a 1.6 M solution of methyl lithium in diethyl ether (12 ml, 1 9 · 6 mmol) and cooling in an ice bath. Stir the resulting mixture at 0-5 ° C for 1 hour, then add all saturated NH4C1 aqueous solution (10 ml). Separate the aqueous layer and separate Extract with ether (2 x 15 ml). Wash the combined organic phase with brine (20 ml) and dry it over MgS04. The extract is filtered and evaporated. The crude product is 'silicon' on silica gel. Purified by layer analysis (3% ethyl acetate in light petroleum ether). As a result, cyclohexanol 4 3 (0.8 2 g, 74%) can be produced. This is a colorless oil, which can be used without identification In the next step, c) 1-azido-1,3, trans-1, 5-trisyl, cis-3, vinyl ring Alkyl (44). Starting from cyclohexanol 43, it was prepared according to the procedure used to prepare compound 9 (Example 3'b). As a result, azide 44 was obtained as a colorless oil with a yield of 17%. i-NMR ^ CDCU, TMS) 5: 0.94 (3H, d, 6.5 Hz, 5-CH3); 0.97 (3H, s, 3-CH3); 1.27 (3H, s, 1-CH3); 〇 .7-2.0 (7 H, m, ring protons); 4.95 and 4.97 (all 2H, two d, 18, and 11Hz, = CH2) and 5.77ppm (1H, dd, 18, and 11Hz, = CH) Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 58-(Please read the notes on the back before filling this page)

, 1T Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 卬 #; .r.: .-. 200407120 A7 _B7_ _ V. Description of the invention (55) d) 1, 3, trans-5-dimethyl-cis-1 3 -Ethylcyclohexylamine hydrochloride (4 5). Starting from azide 44, it was prepared according to the procedure used to prepare compound 1 1 (Example 3, c). As a result, amine hydrochloride 45 was obtained, which was a colorless solid with a yield of 32%. iH-NMR ^ CDCh, TMS) j: 0.92 (3H, d, 6.5 Hz, 5-CH3); 0.96 (3H, s, 3-CH3); 1.45 (3H, s, 1-CH3); 0.8-2.1 (9H , 2,4,6-CH2,5-CH and H20); 4.94 and 4.97 (2H, two kinds of d, 18 and 11Hz, = CH2); 5.76 (1H, dd, 18 and 11Hz, = CH) and 8.26 ppm (3H, br s, NH3 +). Table: Example 17 (Please read the precautions on the back before filling this page)

MeMgl Μθ Me iMe Iθ CN Ally

47 COOEt

NaH, DMSO

CuCI cat. Me Me Example 17. 2 — (1, Hydrochloride (49) a) 2 —Ethyl cyanoacetate (47) CN _ 1.DMSO Je f / —nh2 * hci s_ ^ LiCI, H20 COOEt 2. LiAIH4 MeX 3. HCI 49 3,5,5-pentamethylcyclohexyl) 4 4-pentenylamine 2— (1,3,3,5,5—pentamethylcyclohexyl) Intellectual property of the Ministry of Economic Affairs The paper size of the printed copy of the Bureau ’s Consumer Cooperatives applies the Chinese National Standard (CNS) A4 specification (2! 0X 297 mm) -59-200407120 A7 _B7_ V. Description of the invention (56) Copper chloride (I) (0.05 grams, 0.5 millimolar) add chilled in argon (a 10 ° C) in diethyl ether

1M (15 ml, 15 mmol), and the mixture was stirred for 5 minutes. A solution of acetate 46 (2.5 g, 10 mmol) in THF (25 ml) was added dropwise over 20 minutes while maintaining the temperature below 0 ° C. The mixture was stirred for 1 hour and quenched with saturated aqueous NH4C1. Then, it was extracted with diethyl ether. The extract was rinsed with brine, dried over anhydrous Mg S04, rinsed and evaporated. The residue was purified on a silica gel by flash chromatography (light petroleum ether-ethyl acetate, 20: 1), and the result was 47 (1.5 g, 56.5%), which was a colorless oil. iH-NMRCCDCU, TMS) 5: 1.01, 1.07, and 1.09 (all 咅 12H, s, 3, 5, 5, CH3); 1.00- 1.85 (6H, m, ring CH); 1.30 (3H, s, l '-CH3); 1.33 (3H, t, 7Hz, CH3-ethyl); 3.44 (1H, s, 2.CH) and 4.27ppm (2H, q, 7Hz, OCH2). 3,3,5,5-Pentamethylcyclohexyl) b) 2 —Cyano—2 — 4 Ethylpentenoate (48) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the note on the back first) Please fill in this page again) Add sodium hydride (0.2 84 g, 7.09 mmol; 60% mineral oil dispersion) cyanoacetate 47 (1.25 g '4.7 1 mmol) in anhydrous DMSO (10 ml) ) Solution. The mixture was stirred at 50 ° C for 30 minutes' and cooled to ~ 2CTC. Allyl bromide (0.66 g, 7.1 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours, and then stirred at 50 ° C for 30 minutes. The mixture was cooled, treated with water and extracted with diethyl ether. Rinse the extract with water and saturated saline, and apply the extract to the Chinese paper standard (CNS) A4 (210X297 mm) -60-200407120 A7 _____B7__ at the scale of this paper without paper size. 5. Description of the invention (57) (Please read the back first (Notes to fill in this page again) Dried on water MgS04, filtered and evaporated. The residue was purified on silica gel by flash chromatography (light petroleum ether-ethyl acetate, 20: 1) to produce 48 (0.92 g, 63.7%), which is a colorless oil. iH-NMRCCDCU, TMS) 6: 0.98 (6H, s, 3, 5,-CH3 eq); 1.11 (6H, s, 3 ', 5,-CH3ax); 1.00- 1.85 (6H, m, ring CH); 1.3 1 (3H, t, 7 Hz, CH3-ethyl); 1.3 3 (3 H, s, 1,-CH3); 2.42 and 2.86 (all 2H, two dd, 13 and 7Hz , 3-CH2); 4.02 (2H, q, 7Hz, 〇CH2); 5.05-5.3 7 (2H, m, = CH2) and 5.55-6.05ppm (1H, m, = CH) 〇c) 2-(1 , 3,3,5,5-pentamethylcyclohexyl) -4-pentenamine hydrochloride (49). Water (0.53 ml, 2.95 mmol) and lithium chloride (0.25 g, 5.9 mmol) were added to the ester 48 (0.9 g) in DM SO (10 ml)

Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs consumed a solution of the cooperative (India H ′ 2.95 mmol). Stir the mixture at 175-180 ° C for 3 hours, then cool it, and add water (30 ml). Take the mixture with a diethyl ether rod. The extract was washed with water and saturated brine, and the extract was dried over anhydrous MgS04, filtered, and concentrated to a volume of 0 ml. The resulting solution was added dropwise to a suspension of lithium aluminum hydride (0.25 g, 6.6 mmol) in diethyl ether (15 ml). The mixture was cooled, treated with a 20% aqueous NaOH solution, and extracted with diethyl ether. After rinsing with brine, the extract was dried over NaOH, filtered and treated with an anhydrous hydrogen chloride solution in diethyl ether. After the solvent was evaporated, the residue was purified on silica gel by 'color-layer analysis' (chloroform-methanol, 20: 1) to produce 49 (-61-this paper size applies Chinese National Standard (CNS) A4 specifications ( 210X 297 mm) 200407120 A7 B7 V. Description of the invention (58) 0.245 g, 31%) This is a colorless solid. (Please read the precautions on the back before filling this page) iH-NMI ^ DMSO- D6, TMS) 6: 0.92, 0.96 and 1.04 (all 15H, all s, 3, 5'- CH3 and 1, CH3), 1. 〇〇1.6 5 (all 6H, m, ring-CH2); 1.85- 2.40 (3H, m, 3-CH〗, 4- CH) 2.60- 3.10 (2H, m, CH2N); 4.90-5 · 25 (2H, m, = CH2); 5.62_ 6.10 (1H, m, = CH) and 7.92ppm (3H, br s, NH3 +) o Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs of Pharmaceutical Composition The active ingredients, plus one or more traditional adjuvants, carriers or diluents, can be used to make pharmaceutical composition types and unit dosages, and this type can be used in the following types: solid type, such as: coated or uncoated Coated tablets, or filled capsules, or liquids, such as: solutions, suspensions, emulsions, elixirs' or capsules with the same substance, all of which are for oral use; suppositories or capsules for rectal administration , Or a sterile injection solution (including intravascular or subcutaneous) for parenteral administration. Such pharmaceutical compositions and their unit dosage forms may contain traditional or new ingredients' in traditional or special proportions, with or without additional active compounds or ingredients, and such unit dosage forms may contain any An effective amount of a suitable active ingredient in a daily dosage range. Therefore, lozenges containing 20 to 100 mg, or more broadly, 10 to 250 mg of active ingredient per lozenge are suitable representative unit dosage forms. Treatment method This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -62- 200407120 A7 B7 V. Description of the invention (59) (Please read the precautions on the back before filling this page) Due to the activity of the present invention The elements are highly active and low toxic, and exhibit the most favorable therapeutic index. Therefore, they can be administered to individuals who need them, such as: living animals (including humans), to treat, alleviate, or improve, reduce, Or exclude indications or conditions that are sensitive to this element, or the representative indications or conditions listed elsewhere in this application, it is more appropriate to combine its effective amount with one or more pharmaceutically acceptable endowments Combinations of tablets, carriers, or diluents are administered simultaneously or together, especially in the form of pharmaceutical compositions. The route of administration can be oral, rectal or parenteral (including intravascular and subcutaneous). Or, in some cases, it can even be administered locally. As a rule, the appropriate dosage range is 1 to 1000 mg per day, preferably 10 to 500 mg per day, especially 50 to 5000 mg per day. The best way is: exactly how and how Type administration, the indications for which the administration is directed, the individuals involved and the weight of the individuals involved, and the preferences and experience of the clinician or visiting vet. Example of a representative pharmaceutical composition: Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 1 :::! The reaction product can be made into tablets, coated tablets, capsules, drips by using common solvents, adjuvants and carriers. , Suppositories, injections and injectable preparations, etc., and can be administered therapeutically by oral, rectal, parenteral and other routes. Representative pharmaceutical compositions are as follows: (a) Lozenges containing active ingredients suitable for oral administration can be prepared by conventional tableting techniques. (b) In terms of suppositories, any general suppository base can be used (such as polyethylene glycol which is solid at normal room temperature but will melt at or about body temperature) This paper applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) -63-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs --- 200407120 A7 __B7 V. Description of the Invention (60)), which is incorporated into the active ingredients by the usual steps. (c) In the case of sterile solutions for parenteral (including intravascular and subcutaneous) routes, active ingredients are added with conventional ingredients such as sodium chloride and double distilled water. According to traditional procedures, such as: Filter, aseptically pour into an injection bottle or IV drop bottle and autoclave. Other suitable pharmaceutical compositions will be immediately apparent to those skilled in the art. The following examples are only used to illustrate and not limit the present invention. Example 1 Formulation of lozenges Suitable formulations for preparing lozenges containing 10 mg of active ingredient are as follows: ._ ^ _ mg of active ingredient 10 lactose 63 microcrystalline cellulose 21 talc 4 magnesium stearate 1 gelatinous two Silicon oxide 1 Example 2 Lozenge formula Another suitable formula for preparing lozenges containing 1000 mg of active ingredient is as follows: This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) _ 64- I ----------- Ί--IT ------ (Please read the notes on the back before filling out this page) 200407120 A7 B7 V. Description of the invention (61) mg active ingredient 100 potato Starch 20 Polyvinylpyrrolidone coated film and pigmented film The coating material consists of: 10 lactose 100 microcrystalline cellulose 80 gel 10 polyvinylpyrrolidone, crosslinked 10 talc 10 magnesium stearate 2 Colloidal silica 2 Pigment 5 (Please read the precautions on the back before filling in this page)

Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, India. Example 3 Capsule formula A suitable formula for preparing a capsule containing 50 mg of active ingredient is as follows: This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) -65 -200407120

7 B V. Description of the invention (62) mg active ingredient 50 corn starch 20 divalent calcium phosphate 50 talc 2 colloidal silica 2 scooped into a capsule 0 Example 4 A solution for injection is used to prepare a solution containing 1 The suitable formula of the solution for injection of% active ingredient is as follows: mg of active ingredient 12 mg of sodium chloride 8 made of sterile water 1 ml (please read the precautions on the back before filling this page) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperative seal: 1 Example 5 Preparation of liquid oral formula A suitable formula of 1 liter of liquid mixture containing 2 mg of active ingredient in 1 ml of the mixture is as follows: This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -66- 200407120 A7 B7 V. Description of the invention (63) grams of the Ministry of Economy, Intellectual Wealth and Finance, 4th Bureau, Consumer Consumption Co., Ltd. Yin Weng-. The active ingredient sucrose, glucose, sorbitol, orange flavor, sunset yellow, adding pure water to make the total volume 1 〇mL 2 250 300 150 10 Example 6 Liquid oral formulation Another preparation containing 1 liter of the liquid mixture in a mixture The formula is as follows: 2 mg of active ingredient 1 g of active ingredient 20.00 tragacanth gum 7.00 glycerin 50.00 sucrose 400.00 methyl para-hydroxyperbenzoate 0.50 propyl para-hydroxyperbenzoate 0.05 black vinegar 1 flavor soluble red Add pure water to make the total volume 1000 milliliter 0.02 (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 specification (2) 0X 297 mm) -67 -200407120 A7 _____B7 V. Description of the Invention (64) (Please read the notes on the back before filling out this page) Example 7 Liquid oral formula Another preparation of 1 liter of liquid mixture containing 2 mg of active ingredient in 1 ml of mixture Suitable formulations are as follows: Active ingredient 2 Sucrose 400 Bitter orange peel flavor 20 Sweet orange peel flavor 15 Add pure water to make a total volume of 10,000 ml Example 8 Spray formulation 180 grams of spray solution contains • g ___ active ingredient 10 oil Acid 5 Ethanol 8 1 Pure water 9 Tetrafluoroethane 75 Employee Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China-· .. 15 ml of solution was poured into aluminum In a spray can, the pressure was capped by a dosing valve '3 · 0 bar and discharged. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -68-200407120 A7 B7 V. Description of the invention (65 Example 9 TDS formula 100 grams solution contains grams of active ingredient ethanol polyethylene glycol dimethylene Maple hydroxyethyl cellulose pure water 10.0 57.5 7.5 5.0 0.4 19.6 (Please read the precautions on the back before filling this page) Place 1.8 ml of the solution on a fiber web covered with an adhesive support foil. This system is made of A protective liner that can be removed before use. Sealed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Example 10 Extremely fine particle formulation. 10 grams of polybutylcyanoacrylate. Extremely fine particles contain: grams of active ingredient 1 8 8 polyhydroxyalkylene. Butyl cyanoacrylate mannitol sodium chloride. 75 0.05 1.00 0.01 0.10 This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) -69-200407120 A7 B7 V. Description of the invention (66 (Please read first Note on the back, please fill out this page again) Polybutyranoacrylate ultrafine particles are prepared by emulsion polymerization in a water / 0.1 N HC1 / ethanol mixture as a polymerization medium. The ultrafine particles in suspension are finally lyophilized under vacuum. Pharmacology-describes the active elements of the present invention, their pharmaceutical compositions and the treatment methods performed by them are characterized by their unique advantages and Unexpected properties make the "overall subject matter" of the scope of the patent as applied herein not obvious. The compound and its pharmaceutical composition have shown the following valuable properties and characteristics in an accepted standard and reliable test procedure ... It is an active, non-competitive NMDA receptor antagonist with fast blocking / deblocking kinetics and strong voltage dependence. Therefore, it can be used by or administered to surviving animal hosts. To treat, eliminate, alleviate, alleviate and improve the response to treat various CNS disorders involving glutamate-induced disturbances of transmission. Employees of the Intellectual Property Office of the Ministry of Economic Affairs and Consumer Affairs Co., Ltd. These compounds are also active, non Competitive 5HT3 and neuron nicotinic receptor antagonists, therefore, can be used for treatment and elimination by administering or administering to living animal hosts Reducing, alleviating and improving the response status to treat various CNS disorders involving heparin or nicotine conduction disorders. Receptor connection. This paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -7. 200407120 A7 B7 V. Description of the Invention (67) (Please read the notes on the back before filling this page) Male Sprague-Dawley rats are decapitated and quickly removed from their brains. The cortical area was dissected and homogenized in a 20-fold volume of ice-cold 0.3 2M sucrose using a glass-iron homogenizer. The homogenate was centrifuged at 1000xg for 10 minutes. The small nine was discarded, and the supernatant was centrifuged at 20,000 Oxg for 20 minutes. The resulting small nine was resuspended in 20 times the volume of distilled water and centrifuged at 8000 xg for 20 minutes. Then, the supernatant and the yellow layer of the blood clot were centrifuged in the presence of 50 mM Tris-HC1, pH 8.0 at 48,000 xg for 20 minutes. Then, Xiaojiu was resuspended and centrifuged in the presence of 50 mM Tris-HC1, pH 8.0 at 48,000 xg for 20 minutes. All centrifugation steps were performed at 4 □. After resuspension in 5-fold volume of 50 mM Tris-HC1, pH 8.0, the membrane suspension was quickly frozen at -80 ° C. On the day of analysis, the membrane was thawed and resuspended four times by resuspending it in 5 OmM Tris-HC1, pH 8.0, centrifugation at 48,000 xg for 20 minutes, and finally resuspending it in 50 mM Tris- HC1, pH 7.4 Wisdom Assets of the Ministry of Economic Affairs of the PRC-Pui Gong 1 works as a printing house. The amount of protein (25-500 micrograms / ml) in the final membrane product was determined according to the method of Raleigh, et al. (1951). Combine [3H]-(K) -MK-80 1 (23.9 Curie / millimol, 5nM, Dupont NEN) with glycine (10 μM), glutamate (1 0 // Μ ) And 1 2 5-250 micrograms of protein (total volume 0.5 ml) and different concentrations of test reagents (10 concentrations' duplicate) were added to the vial to start the incubation. Continue incubation at room temperature for 120 minutes (equilibrium under the conditions used). Non-specific connections are defined by adding the unlabeled (+)-ΜΚ — 801 (10 μM). A Millipor filter system was used to terminate the incubation. Applicable Chinese National Standard (CNS) A4 specification (210X 297 mm) at this paper size -71-200407120 A7 _B7 _ V. Description of invention (68) (Please read the precautions on the back before filling this page) Continue vacuuming In the case of washing, the sample was washed twice on a glass fiber filter with 4 ml of ice-cold analysis buffer (Schleicher & Schuell). After separation and washing, the filter was placed in a scintillation liquid (5 ml; Ultima Gold) and the radioactivity retained on the filter was measured using a conventional liquid scintillation counter (HP, liquid scintillation analyzer). Scatcher analysis was used to determine the Kd of 4.6nM 〔3H〕 — (+) —MK— 801, and it was used to calculate the affinity of the surrogate according to the relationship of Cheng & Prusoff, as Kd 値. Most antagonists were tested in 3 to 7 separate experiments.

Employees of the 4th Bureau of the Ministry of Economic Affairs and the Intellectual Property Co., Ltd.—Industrial Cooperatives—Industry " V. Performance of NMDA and neuron nicotinic receptor subtypes in toad oocytes before surgery. In Tricaine, anesthetize on ice for 15 minutes. Remove the oocytes and place them at room temperature in a concentration of 2 mg / ml in Ca2 + -free oocytes Ringer's solution (82.5 mM NaCl, 2 mM KC1, 2 mM MgCl2, 5 mM HEPES, pH 7. 5) Incubate for 30 minutes in collagenase (type Π), and rinse thoroughly with OR-2 (100 mM NaCl, 2 mM KC1, 1 mM MgCl2, 2 mM CaCl2, 5 mM HEPES, pH 7.5). The remaining follicular cell layer was removed by hand with fine forceps and the oocytes were stored in OR-2. Dissolve RNA in DEPC-treated sterile distilled water, and mix NMDA NRla subunit RNA with NR2A subunit RNA in a 1: 1 ratio. Similarly, the neuron nicotine a4 RNA and β2 subunit RNA were mixed 1: 1. Using 50 to 100 nanoliters of each RNA mixture using a nanoliter syringe (the world's precise paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -72-200407120 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs: Cheng: A7 _ _B7_ V. Description of the Invention (69) Apparatus) is injected into the cytoplasm of oocytes. The next 3 to 6 days, the oocytes were incubated in OR-2 at 19 ° C. Two to six days after injection, a standard two-pole voltage-clamp method (gene clamp 500 amplifier) was used to obtain an electrophysiological response. The resistance of the electrode is between 0.2 and 0.4MΩ, and it is filled with 3M KC1. Records are made in a custom box and exchange time is 2-3 seconds. A Ca2 + -free electrolyte was prepared to avoid the Cl_ flux induced by Ca2 + (100 mM NaCl, 2 mM KCM, 5 mM HEPES, 2 mM B aCl2, pH 7.35). Every 2 to 3 minutes, ImM glutamate and 10 μM glycine are co-administered to oocytes sandwiched at 70 mV for 30 to 40 seconds by manual operation to activate the NMDA receptor. Neuronal nicotinic receptors are activated by applying 100 μM acetylcholine to oocytes sandwiched at -70 mV every 2 to 3 minutes for 20 to 30 seconds. After a stable control response is obtained, 6-7 different concentrations can be pre-incubated at a concentration interval of index 3 to obtain the full concentration-response curve for the antagonist. Only results from stable cells were accepted in the final analysis, i.e. after removal of the test antagonist, it was shown that at least 50% of the response to NMDA was restored. Regardless of this, there is a slight rundown or runup in some cells, so it is not always possible to recover from the drug action to 100%. When this condition exists, it can always be compensated by the% antagonistic starting point for each concentration established on the control and recovery curve, assuming a linear time course of this relaxation. All antagonists were evaluated in stable blocking at 6-7 concentrations in at least 4 cells. Depending on the concentration of the antagonist, equilibrium blocking can be achieved after 1-3 agonist doses. (Please read the precautions on the back before filling this page) This paper size applies to Chinese National Standards (CNS) A4 specifications (210X 297 mm) -73-200407120 A7 B7 V. Description of the invention (70) (Please read the back Note: Please fill in this page again.) The kinetic experiment was performed by the following method: In the case of glutamate (100 μM) and glycine (10 μM) for 90-180 seconds, the concentration of Saturated amine-alkylcyclohexanes are applied (usually at a concentration of 5 in a one-to-three administration method) to the toad oocytes exhibiting NRla / 2A receptors for 10-20 seconds. The perfusion system used in these experiments is a modified oocyte carousel system that allows agonists and antagonists to be quickly washed in and washed out in less than one second of replacement time. Using the TID A program used by Windows to make the index fit, most of the responses can be well-fitted by a single index. The same system was used to assess the voltage-dependency of the blocking effect, but the electrolyte contained flufenamic acid (ΙΟΟμΜ) to block the endogenous voltage—Member of Intellectual Property of the Ministry of Living Economy, X Consumer Cooperative, India And Ca2 + -activated C1-flow. Also, Ba2 + (2mM) was replaced with a low concentration of Ca2 + (0.2mM). After achieving a balanced block with a higher concentration of antagonist (usually about 10 times the IC5Q), 5 ramps are emitted in a 2-second period from -70 Mv to + 30 mV. With regard to electrolytes and glutamates without antagonists, similar slopes occurred before the antagonist was applied and after the reaction was restored. The flow that exuded in the absence of glutamate was subtracted from the curve of glutamate and glutamate plus antagonist. The voltage-dependence can then be determined by comparing the curves of glutamate and glutamate plus antagonist. NMDA and nicotine patch clamps take hippocampal regions from rat embryos (E2 0 to E2 1) and transfer them to Hanks buffered saline solution (Gil -74-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) 200407120 A7 B7 V. Description of Invention (71) (Please read the precautions on the back before filling this page) Gibco) in. The cells were mechanically separated in 0.05% DNAase / 0.3% ovomucoid (Sigma). The isolated cells were then centrifuged at 18xg for 10 minutes, resuspended in the minimum required medium (Gibco), and plated at a density of 150,000 cells / cm2 on pre-coated poly-L-lysine Acid (Sigma) on a plastic petri dish (Falcon). NaHC03 / HEPES buffered minimum necessary medium supplemented with 5% fetal bovine blood pupa and 5% horse blood pupa (Djibouco) to supply cells with nutrients and incubated at 37 ° C with 5% C02, humidity For 95% of the environment. After approximately 7 days in a glass tube, further glial fission was inhibited with cytosine-Η-D-arabinose furanoside (20 μM sigma), and then the medium was completely replaced. After that, the media is partially replaced twice a week. The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs attacked ...-- In the whole-cell mode, at room temperature (20-22 ° C), the EPC-7 amplifier (Lister) was used to grind Light glass electrodes (4-6mΩ) were made from these neurons to make patch clamp records. The test substance was applied by swapping the channels of a custom-made rapid superfusion system with a common outflow (10-20 milliseconds exchange time). The contents of the intracellular solution are as follows (mM): CsCl (120), TEAC1 (20), EGTA (10), MgCl2 (1), CaCl2 (0.2), glucose (10), ATP (2), cAMP ( 0.25); adjust pH to 7.3 with CsOH or HC1. The extracellular solution has the following basic components (mM): NaCl (140), KC1 (3), CaCl2 (0.2), glucose (10), HEPES (10) 'sucrose (4.5), tetrodotoxin_ (ΤΤΧ3 # 1 (Τ 4). Glycine (1 μM) is present in all solutions at a concentration sufficient to activate about 80-8 5% glycine beta receptor. This paper standard applies Chinese National Standard (CNS) Α4 Specifications (210X 297mm) -75-200407120 A7 ____ B7 V. Description of the invention (72) (Please read the notes on the back before filling out this page) Only the results from stable cells are accepted in the final analysis, that is, removed After the suppression caused by the tested antagonist, the response to NMDA returned at least 75%. 〇5—HT3's benzazepin was purchased from European Cell Collection (ECACC, Salisbury, UK). N1E — 115 Cells were stored at 80 ° C until further use. Cells were seeded at a density of 100,000 cells / cm² in plastic Petri dishes pre-coated with poly-L-lysine (Sigma) ( Falcon) with NaHC03 / HEPES buffer supplemented with 15% fetal bovine blood 淸Low essential medium (MEM) supplies the cells with nutrients and incubates them at 37 ° C with 5%. 02 and 95% humidity. The medium is completely changed once a day. Once every three days, trypsin is first used. Treat the cells with EDTA (in 1% PBS), resuspend the cells in MEM, and centrifuge the cells at 1000 rpm for 4 minutes. Then re-seek the cells in fresh plastic culture dishes.

Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, I. In the whole-cell mode, at room temperature (20-22 ° C), using the EPC-7 amplifier (Liszt (List)) to grind 2 to 3 days after inoculation. Light glass electrode (2-6M Ω), at -70mV, make patch clamp records from the floating cells. The contents of the intracellular solution are as follows (mM): CsCl (130), HEPES (10), EGTA (10), MgCl2 (2), CaCl2 (2), K — ATP (2), Tris-GTP (0 2), D-glucose (10); adjust pH to 7.3 with CsOH or HC1. Extracellular solution has the following basic components (mM) ·· NaCl (124), KC1 (2.8), this paper size applies to Chinese National Standard (CNS) A4 specification (21 OX 297 mm) -76: 200407120 A7 _____ B7 _ V. Description of the invention (73) HEPES (10), adjust pH to 7.3 with NaOH or HC1. (Please read the precautions on the back before filling this page) After establishing the whole-cell configuration, let the cells float from the glass matrix, and use a rapid superfusion device to transfer different concentrations of heparin (10 μM), beauty Mantine and unsaturated amine-alkylcyclohexane derivatives are applied to the cells. The floating cells were exposed to a heparin-free or heparin-containing solution using a double-tube-shaped dropper pipette driven by a piezoelectric transducer. Twenty-one second heparin pulses are delivered every 60 seconds. The putative antagonist was dissolved in secondary water and diluted to the desired concentration with electrolytic solution. In the final analysis, only results from stable cells were accepted ', that is, those that showed a response to at least 50% after removing the compound. Regardless of this, it is not always possible to recover to 100% from the action of the drug due to the fatigue in some cells (< = 10% during a period of 10 minutes). When this condition exists, it can always be compensated by the% antagonistic starting point for each concentration established on the control and recovery curves, assuming a linear time course of this relaxation. All antagonists were evaluated in at least 5 cells with stable blocking at 3-6 concentrations. Depending on the concentration of the antagonist, the balance can be reached after the agonist is administered 2 to 5 times. The staff of the Intellectual Property Bureau of the Ministry of Economic Affairs and the Co-operative Society of the Ministry of Economic Affairs can prevent the convulsive activity. Mice (1 s to 28 grams) were tested by Maximum Electroshock Method (MES) and Poor Behavior. All rats were maintained under a 12-hour light-dark cycle (illuminated at 6 a.m.) and a controlled temperature (20 ± 0.5 ° C), and were provided with water and food (optional). All experiments -77- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21〇 < 297 mm) 200407120 A7 B7 V. The invention description (M) is performed between 10 a.m. and 5 a.m. If not otherwise specified, the test agent is injected into the mouse via i.p. 30 minutes after inducing convulsions (see below). All compounds were dissolved in 0.9% physiological saline. (Please read the precautions on the back before filling out this page.) Keys for Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Perform the MES test together with tests on muscle relaxation (traction reflex) and motion coordination function (rotary lever). For the traction reflex test, the mice were placed with their forelimbs on a horizontal bar and asked to place all four limbs on the cable within 10 seconds. To test for poor coordination (motor coordination), the mice were placed on an accelerating rotating rod and asked to remain on the rod for 1 minute. Only those mice that failed to meet the criteria in each of the three replicates were identified as muscle relaxants or poor coordination, respectively. After these tests, MES (100 Hz, 0.5 second shock period, 50 mA shock intensity, 0.9 ms pulse period, Ugo Basile) was then performed through the corneal electrode. Record the points for the presence of rigid twitches (the rigid extension of the hind limbs and the angle of the body must be at least 90 degrees). The purpose was to use the Litchfield Wilcoxon test to obtain ED50s for all scoring variables (anticonvulsant activity and motor side effects) to quantify the dose response. The therapeutic index (TI) is ED5G with the side effect (poor coordination or muscle relaxation) of ED50 which is the antagonistic effect of electroconvulsions. Statistical analysis Using the Grafit computer program (Arisak Software, UK), the IC50S in the patch clamp and connection analysis was calculated according to a four-variable logic formula. Then, based on Qian & Prusov, the Ki 连接 of connection analysis is decided. The connection angle shown is the average of 3 to 5 measurements (each repeated twice). The paper size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -78-200407120 ΑΊ ------ -B7 V. Description of the invention (75) SEM 〇 In each in vivo test, each of 4 to 7 antagonist doses (5-8 animals per dose) was tested to analyze according to the probability (Li Chefeide & Wickerson) g ten grades ED5GS, the correction effect is 0% to 100%. ed5gS is expressed as the 95% confidence limit (ci). Pearson product differential correlation analysis (sigma Stat ’Jandale Technology) was used to compare the potency in vivo and the anticonvulsant activity in vivo. Result MRZ number Use the MRZ number to represent the chemical name. The MRZ number and its individual chemical name are shown in the MMRZ form (please read the precautions on the back before filling out this page) Employees ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs φ-f This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X 297 mm) -79-200407120 A7 __B7 V. Description of the invention (76) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs T: MRZ form MRZ Chemical name 2/657 1-Amine-2,4,4 , 6,6-pentamethyl-cyclohex-2-ene hydrochloride 2/749 1- (1-aminoethyl) -3,3,5,5-tetramethylcyclohex-1 · ene 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-tetramethylcyclohexylene) ethylamine 2/1023 1 · amino_3,3,5 · trimethyl-2-cyclohexene 2002 1,3,5,5 -Tetramethyl-2-cyclohexene-1-amine 2005 1-allyl-3,3,5,5-tetramethylcyclohexylamine 2006 1- (3,3,5,5-tetramethyl Cyclohexylene) -2-propylamine 2008 1- (3,3-diethyl-5,5-dimethylcyclohexylene) -2-propylamine 2009 cis-ethenyl-1,3, trans-5- Trimethylcyclohexylamine 2010 2-methyl-l- (3,3,5,5-tetramethyl-bucyclohexen-1-yl) -2-propylamine 2013 Bu (1-allyl_3,3,5,5-tetramethylcyclohexyl) hexahydropyridine 20 14 2- (1-vinyl-3,3,5,5-tetramethylcyclohexyl- 1) Ethylamine 2015 1- [3,3,5,5-tetramethyl-1- (3-methyl-2-butenyl) cyclohexyl] hexahydrobidine 2016 1- [3,3, 5,5-tetramethyl-1- (2-propynyl) cyclohexyl] hexahydropyridine 2017 2- (1,3,3,5,5 · pentamethylcyclohexyl) -4-pentenamine 2018 3- (3,3,5,5-tetramethylcyclohexylene) propylamine 2019 2-methyl-l- (3,3,5,5-tetramethylcyclohexylene) -2-propylamine 2020 2- (3,3,5,5-tetramethylcyclohexylene) propylamine 202 1 N-methyl-1-vinyl-3,3,5,5-tetramethylcyclohexylamine 2026 N-allyl- 1,3,3,5,5-Pentamethylcyclohexylamine paper size is applicable to China National Standard (CNS) A4 (210X297 mm) _ 80-(Please read the precautions on the back before filling this page) 200407120 A7 B7 V. Description of the invention (77) All compounds connected to MK-80 are substituted for [3H] -KM with Ki 値 between 1 and 83 μM. See the table (please read the precautions on the back before filling this page)

、 1T Seal of Consumer Cooperative of Employees of Intellectual Property Bureau of the Ministry of Economic Affairs -81-This paper size is applicable to Chinese National Standard (CNS) A4 Specification (210X297 mm) 200407120 Employee Consumption Cooperative of Employees of Intellectual Property Bureau of Ministry of Economic Affairs of India 5. Description of Invention (' ) ^ MRZ group [3H] MK-801Ki SEM η NMDA ICso (mM) SEM N 2/657 Ethyl ring 13.43 1.15 3 2/749 Ethyl ring 10.76 1.49 3 2/759 Ethyl 1.18 0.20 6 3.28 0.60 6 2/1005 Ethyl ring 13.63 1.43 4 2/1021 Ethyl ring 2.15 0.32 6 0.33 0.05 6 1023 Ethyl ring 49.60 8.09 6 2000 Neramexane sulphate 1.68 0.00 3 2002 Ethyl ring 5.70 0.48 3 2005 Ethyl 9.35 0.12 3 12.60 5.68 6 2006 Ethyl 10.06 0.40 3 2008 Ethyl 8.07 0.57 3 2.74 0.22 6 2009 Ethyl 22.32 0.88 3 58.17 8.87 6 2013 Ethyl 49.21 11.73 3 2014 Ethyl Base 3.12 0.67 3 0.10 0.01 6 2015 Ethyl 83.04 30.98 3 2016 Ethyl 42.22 13.60 3 71.17 14.66 6 2017 Ethyl 6.79 0.51 3 1.19 0.16 6 2018 Ethyl 20.18 2.80 3 37.06 13.37 6 2019 Ethyl 73.06 8.67 3 2020 Ethyl 7.45 0.69 3 2021 Ethyl 6.54 0.72 3 12.73 0.50 6 2010 Ethyl 44.88 13.91 3 2026 Ethyl 29.56 1.64 6 (Please read the precautions on the back before filling this page ) This paper scale applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) -82- 200407120 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (79) The results of the representative compounds are recorded in Figure 1 in. The expression of NMDA receptor subtypes in toad oocytes MRZ 2/759 blocks the NMDA receptor via -70mV, glutamate (100 # Μ) and glycine (10 / / M) For 100 seconds, MRZ 2/759 at different concentrations (from 0.1 to 100 μM in a pair of 3 doses) was applied to the toad oocytes exhibiting the NRla / 2A receptor The cells were measured for 10 seconds (Figure 2, left). The efficacy of MRZ 2/7 5 9 (I <: 5 () = 1.99 μM, slope 0.75) was obtained by plotting the percentage of block against the antagonist concentration, and then fitting the curve according to a logical formula (Figure 2, right). Patch clamp MRZ 2/759 antagonizes the steady inflow response of freshly isolated hippocampal neurons to NMDA (20 0 // M plus glycine 1 // M, at -70mV). Spikes and constant flow are affected to a similar degree, so their effect does not appear to be mediated at the glycine b position. Its well-understood use of blocking reactions—and its voltage-dependence—are a strong support for the non-competitive nature of this antagonism. See Figure 3. The results of in vivo anti-convulsant activity MES and muscle relaxation are presented in Table 2. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -83 (Please read the precautions on the back before filling this page) 200407120 Printed by the Intellectual Property Bureau Employee Consumer Cooperatives of the Ministry of Economic Affairs • -Γ- A7 B7 V. Description of the invention (80) Table 2 MRZ MES ED50 MES CL Muscle relaxation ED50 Muscle relaxation Cl Ataxia ED50 Ataxia Cl Ti Myorelaxation Ή Ataxia 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 2/1021 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 U 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 2009 > 50 > 50 > 50 2010 > 50 > 50 > 50 2013 > 50 > 50 > 50 2014 47.82 21.5 -46.7 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 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 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 (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) -84-200407120 A7 _ B7 _ V. Description of the invention (81) (Please read the notes on the back before filling this page) In short, it can be seen from the foregoing that the present invention provides The novel, valuable and unexpected applications and uses of the compounds of the present invention and their novel pharmaceutical compositions as active ingredients of the invention, as well as methods for preparing them, as well as treatment methods therefrom, all of which have the foregoing Features and advantages enumerated. From the tests described, it is confirmed that the high activity of the active agent of the present invention and its composition is a functional expression of its valuable activity in humans and lower animals. However, clinical evaluations in humans have not been completed. I understand clearly: The distribution and sale of any compound or composition used in the human body within the scope of the present invention must of course first be obtained and appointed by a government agency responsible for refereeing such issues, such as the US Federal Food and Drugs Guanli Bureau's Approval Conclusions The Consumer Cooperative Seal of the Intellectual Property Bureau of the Ministry of Economic Affairs «: This unsaturated 1-amino-academic cyclohexanone class represents a novel class of systemically active, non-competitive NMDA receptor antagonists. Fast blocking / deblocking kinetics and strong voltage-dependence. From the viewpoint of its modest potency and related rapid kinetics, it is effective in treating a variety of CNS diseases involving glutamate-induced conduction disturbances. Therefore, these compounds are useful for treating the following disorders in living animals, especially humans. 1. Excitotoxicity, such as ischemia in stroke, trauma, hypoxemia, hypoglycemia, glaucoma, and hepatic encephalopathy. 2. Chronic neurodegenerative diseases, such as: Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, muscular dystrophy -85- This paper standard applies to Chinese national standards (CNS) A4 specification (210X297 mm) 200407120 A7 ________B7 I. Description of the invention (θ ^ ~ ^ (Please read the notes on the back before filling out this page) Collateral sclerosis, aids-neurodegeneration, aponectomyocerebellar atrophy , Torred's disease, motor neuron disease, mitochondrial dysfunction, Korsak syndrome, and Klezfeld-Jekkober's disease. 3. Others are selected from the following disorders and central nervous system Disorders related to long-term shape changes: chronic pain, drug tolerance, dependence, and addiction (eg, opiates, cocaine, benzodiazepines, nicotine, and alcohol). 4. Epilepsy , Tardive dyskinesia, schizophrenia, anxiety, depression, acute pain, cramps, and tinnitus. Furthermore, these compounds have been found to be neuronal serotonin receptors and 5ht3 receptor antagonists. Therefore, the compounds of the present invention can be used for Healing moving objects 'Especially disorders in humans, including symptoms mediated by nicotine and 5 HT3 receptors (eg, vomiting, nicotine abuse, schizophrenia, cerebellar tremor, IB s, migraine, depression, cognitive disorders, and Barkin Treatment of psychiatric disorders and appetite disorders) for the purpose of symptom protection and neuroprotection. In addition, as already explained, the compounds of the present invention are at least partly attributed to their amine substituents. Indications irrelevant to the mechanism of action can also be effective and show immunomodulatory activity, anti-malarial and anti-trypanosomal activity, anti-Boona virus, anti-HSV, and anti-hepatitis C virus activity. ≫-· Intellectual Property Bureau, Ministry of Economic Affairs Employees' Co-operation Co-Operator's praise; The treatment of living objects with the compounds of the present invention to inhibit the aggravation of or alleviate the disease selected therein can be performed by any of the usual acceptable pharmaceutical routes, as previously described It is carried out at a dose which can effectively reduce the specific disease to be alleviated. The method for manufacturing a pharmaceutical product using the compound of the present invention is a usual method including the following steps OK ... Mix an effective amount of the compound of the present invention with a pharmaceutically acceptable diluent, excipient, or carrier. These medicines can be used on this paper to apply the Chinese National Standard (CNS) A4 specification (210X297 mm)- 86-200407120 A7 B7 V. Description of the Invention (83) (Please read the notes on the back before filling out this page) to treat living animals in order to inhibit the selected disease or condition (especially those for NMDA receptor antagonists, Neuronal nicotinic receptor antagonists, 5ΗΤ3 receptor antagonists are sensitive to treatment, or are shown to exhibit immunomodulatory activity, antimalarial and antitrypanic efficacy, anti-Bona virus, anti-HSV and anti-hepatitis C Diseases or conditions that are sensitive to the treatment of virally active compounds) continue to worsen or alleviate the disease or condition, as well as methods of treatment, pharmaceutical compositions, and the use of compounds of the invention to make pharmaceuticals. Representative pharmaceutical compositions prepared by mixing the active ingredients with suitable pharmaceutically acceptable excipients, diluents, or carriers, including: lozenges, capsules, injection solutions' liquid oral formulations, spray formulations, TDS formulations , And extremely fine particle formulations, whereby it can also be used for the manufacture of oral, injectable or dermal drugs according to the foregoing. It should be understood that the present invention is not limited to the exact operating details shown or described, or the exact composition, method, steps or examples, as obvious improvements and equivalents should be clear to those skilled in the art. Therefore, the present invention contains all the contents which can be legally based on the scope of the patent application attached hereto. . Imprint of Employee Cooperatives in the Intellectual Property Bureau of the Ministry of Economic Affairs; References 1. RL Frank, HK Hall (195 0) American Chemical Society Journal 72: 1645-1648. 2. GA Hiegel, P. Burk. (1 973) Organic Chemistry Journal 3 8: 3637-3639. This paper size is applicable to Chinese National Standard (CNS) A4 (2 丨 0297mm)-37 · 200407120 A7 B7 V. Description of Invention (84) 3. NF Firrell, PW Hickmott. ( 1 970) Chemical Society Periodicals [j C: 7 16- 719. (Please read the notes on the back before filling this page) 4. GH Posner, LL Frye. (1 984) 1 sr. J. Chem. 24: 88-92. 5. GL Lemiere, TA van Osselaer, FC Anderweireldt. (1 978) Bull. Soc. Chim. Beig. 87: 77 1-782. 6. HO House? JM Wilkins. (1 976) Journal of Organic Chemistry 4 1: (25) 403 1-4033. 7. AR Greenaway, WB Whalle. (1 9 7 6) J. Chem. Soc. PT 1: 1 3 8 5- 1 3 89. 8. S. Matsuzawa, Y. Horiguchi, E. Nakamura, I. Kuwajima. (1 9 8 9) Tetrahedron 4 5: (2) 3 4 9-3 62. 9. HO House, WF Fischer. (1 968) Journal of Organic Chemistry 3 3 : (3) 949- 956. 10. Chiurdoglu, G.? Maquestiau 5 A. (1 954) Bull. Soc. Chim. Belg. 63: 3 57- 3 78. Employee Consumer Cooperative Cooperatives' Seal of the Monetary and Financial Bureau of the Ministry of Economic Affairs) 11. Zaidlewicz5M., Uzarewicz A., Zacharewicz, W. (1 964) Roczniki Chem. 38: 5 9 1-5 9 7. 12. Crossley, AW, Gilling, C. (1910) Journal of the Chemical Society 2 218. 13. Z aid 1 ewicz, M. , Uz ar e wi cz, A. (19 71) Roczniki

Chem. 45: 1 1 87- 1 1 94. 14. Lutz3E.T., Van der Maas? JH (1981) Spectrochim. This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -88- 200407120 A7 _B7 V. Description of the invention (85)

Acta, A. 3 8 A: 283. (Please read the notes on the back before filling this page) 15. Lutz, ET, van der Maas, JH (19 8 1) Spectrochim. Acta, A.37A: 1 29- 1 34. 16. Ramalingamk., Balasubramanian, M., Baliah, V. (1971) Indian Chemical Journal 1 0: 3 66- 3 69. 17. Hamlin, KE5 Freifelder, M (1 95 3) American Chemical Society Periodic Stem u 75: 369- 3 73. 18. Hassner, A., Fibinger, R., Andisik, D. (1984) Organic Chemistry Period Dry [J 49: 4237-4244. 19. W. Danysz, CG Parsons, I. Bresink, G. Quack (1 995) Drug News Outlook 8: 26 1-277. 20. JD Leander, RRLawson, PL, Ornstein, D. M. Zimmerman (1 988) Brain Research 448: 1 1 5- 120. 21. CG Parsons, G. Quack, I. Bresink, L. Baran, E. Przegalinski, W. Kostowski, P. Krzascik, S. Hartmann, W. Danysz (1 995). Neuropharmacology 3 4: 1 23. 9 72) • Neurobiology 2: 97- 1 05. 24 · Dichter, M. (1 987) Brain study 149 ·· 279. This paper size is applicable to China National Standard (CNS) A4 (210X297 mm).

Claims (1)

200407120 A8 B8 C8 D8 Patent application scope 1 compound selected from the formula R5 R * VX Rp / Ah, Rs Rq Rr where: R * is one (A) n— (CRi2) m- NR3R4, n + m = 0, 1, or 2, A is selected from the following groups: linear or branched Lower alkyl (please read the precautions on the back before filling this page) and member X of the Intellectual Property Bureau of the Ministry of Economic Affairs (C!-C6), linear or branched lower alkenyl (c2 — C6) linear or branched lower alkynyl (C2-C6),-R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched lower alkyl (Ci- c6), linear or branched lower alkenyl (c2-c6), and linear or branched lower alkynyl (c2-c6)-R3 and R4 are independently selected from the following Group: Hydrogen, lower alkyl with straight chain or branched chain (G-Cd, lower alkenyl with linear or branched chain (C2-C6), and lower lower with linear or branched chain Alkynyl (C2-C6), or together form an alkylene (C2-C1Q) or alkenyl (C2-C1 ()) or form a 3-7-membered azacycloalkane or aza with N Cycloolefins, including substituted (alkyl (G — C6), substituted The alkenyl group (C2 — C6)) 3 — 7-membered azacycloalkane or azacycloalkene '-R5 is independently selected from the following groups: · Straight-chain or branched than the paper size applicable to China National Standard (CNS) A4 specification (210X297 mm) 90- 200407120 A8 B8 C8 D8 VI. Patent application scope 2 Low alkyl (Ci — c6), linear or branched lower alkenyl (c2 — c6 ), Linear or branched lower alkynyl (C2-C6), or .R5 and its attached carbon and an adjacent carbon to form a double bond,-Rp, Rq, Rr, and Rs system Independently selected from the group consisting of hydrogen, lower alkyl (G-C6), straight or branched, lower alkenyl (c2-C6), or straight or branched Lower branched lower alkynyl (C2-C6), or Rp, Rq, Rr, and Rs can independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, or Rp, Rq, Rr And Rs can independently form a double bond with the U to which they are connected, or with the Y to which they are connected. The prerequisite is that U-V-W-X-Υ -Z is selected from: cyclohexane, cyclohex-2 —Ene, cyclohex-3—ene, Cyclohexyl-1,4-diene, cyclohexyl-1,5-diene, cyclohexyl-2,4-diene, and cyclohex-2,5-diene, and the prerequisites are at least Rp and Rq One is not hydrogen, and at least one of Rr, and Rs is not hydrogen, and its prerequisite is that when U-Z is equal to cyclohexane 'then-(A) n-(CRlR2) m-, R3, R4, R5, Rp At least one of Rq, Rq, Rr and Rs is a linear or branched lower alkenyl (C2-C6) or a linear or branched lower alkynyl (C 2-C 6) 'and Optical isomers and their pharmaceutically acceptable acid or base addition salts. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -91-" ---------- -(Please read the notes on the back before filling out this page),? T Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs:!: R 200407120 A8 B8 C8 D8 Patent Application Scope 3 2 Pharmaceutical composition for a condition treated by an NMD A antagonist, comprising an effective amount of a compound selected from the group of compounds of formula I: R5 R * Rs K Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs where:-R * is-(A) n- (CR'R2) m- NR3R4 ^-n + m = 0, 1, or 2, A is selected from the following Groups: linear or branched lower alkyl (Cl-c6), linear or branched lower alkenyl (C2-c6), and linear or branched lower alkyne (C2-c6), one of R1 and R2 is independently selected from the group consisting of: hydrogen, linear or branched lower alkyl (Ci-Cd, linear or branched lower storage group) (C2-C6), and straight or branched lower alkynyl (C2-C6), R3 and R4 are independently selected from the following groups: hydrogen, straight or branched lower alkyl (G-C6), linear or branched lower alkenyl (C2 -C6), and linear or branched lower alkynyl (C2-C6), which form the extension base (C2 — CiQ) or alkenyl (C2 — ClQ) or together with] ^ to form a 3-7-membered azacycloalkane or azacycloalkene, including substituted (alkyl (C! — C6), Substituted alkenyl (C2 — C6)) 3-7 — Gong (Please read the notes on the back before filling Page) 1 ^^., 1T This paper size is applicable to Chinese National Standard (CNS) A4 specification (21 0 × 297 mm) -92- 200407120 A8 B8 C8 D8 Six, azacycloalkane or azacycloolefin applied for patent scope 4 , R5, RP, Rq, Rr, and Rs are independently selected from the group consisting of: hydrogen, linear or branched lower alkyl (Ci-Cd, linear or branched lower alkenyl) (C2-C6), and linear or branched lower alkynyl (C2-C6), or R5, RP, Rq, Rr, and Rs can independently combine with the carbon to which it is attached and the next adjacent carbon倂 to form a double bond, or Rp, Rq, Rr, and Rs may independently form a double bond with the U to which they are connected, or with the Y to which they are connected, the prerequisite is U-ν-W-X-Υ -Z is selected from the group consisting of: cyclohexane, cyclohexyl 1-storage, cyclohexyl 2-synthesis, cyclohexyl 3-ene, cyclohexyl-1, 3-dihexylcyclohexyl-1, 4-dioxane, Cyclohexyl-1,5-diene, cyclohex-2,4-diene, and cyclohexyl-2,5-di ·, and its prerequisite is that when U-Z is equal to cyclohexane, then one (person ） „一 (CRiR2) m —, R3 At least one of R4, R5, Rp, Rq, Rr is a linear or branched lower alkenyl group (C2-C6) or a linear or branched lower alkynyl group (C 2-C 6), Its optical isomers and their pharmaceutically acceptable acid or base addition salts, plus one or more pharmaceutically acceptable diluents, excipients or carriers. ---------- 0 I, (Please read the notes on the back before filling out this page} Order the printed paper size of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs to apply the Chinese National Standard (CNS) A4 specification (210X297 Mm) -93-200407120 A8 B8 C8 D8 VI. Application for patent scope 5 3.-A pharmaceutical composition for alleviating the disease, which can be treated by the selected compound with the following efficacy: immunomodulatory, anti-malaria , Anti-Bonas virus, or anti-hepatitis C, anti-trypanosomes, and anti-HSV, the pharmaceutical composition comprises an effective amount of a compound selected from the group of compounds of formula I: R5 R * Rq Rr where:-R * is one (A) n- (CWR2) m — NR3R4,-n + m = 0, 1, or 2,-A is selected from the following groups: linear or branched lower Alkyl (Ci-C6), linear or branched lower alkenyl (C2-C6), and · linear or branched lower alkynyl (c2-c6),-R1. And R2 is independently selected from the group consisting of hydrogen, lower alkyl (chain-branched) with straight or branched chain, lower alkenyl (C2-C6) with straight or branched chain, and straight chain Or branched lower alkynyl (C2-C6) 5 R3 and R4 are independently selected from the group consisting of hydrogen, straight-chain or branched lower alkyl (Ci-C6), straight-chain Or branched lower alkenyl (c2-C6), and linear or branched lower alkynyl (C2-C6), or together form an alkylene (C2-C1Q) or alkylene ( C2— C1C)) or together with N to form a 3-7 -membered azacycloalkane or azacycloalkene, including the substituted paper " _ 94-one '-(Please read the back Please fill in this page for matters needing attention) Order printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs? 200407120 A8 B8 C8 D8 patent application scope 6 (alkyl (Ci-C6), substituted alkenyl (c2-c6)) 3-7-membered azacycloalkane or azacycloalkene, (Please read the back first Please note this page to fill in this page) R5 'RP, Rq, Rr, and Rs are independently selected from the following groups: hydrogen, linear or branched lower alkyl (Ci-Cd, linear or Branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6), or R5, Rp, Rq, Rr, and Rs can be independently connected to the The carbon and the next adjacent carbon are condensed to form a double bond, or RP, Rq, Rr, and Rs can independently form a double bond with the U to which they are connected, or with the γ to which they are connected, and-its prerequisite is u —V—w-Χ—Υ- ζ is selected from the group consisting of: cyclohexane, cyclohexyl 1-ene, cyclohex-2 — susceptible 'cyclohexan — 3 — storage, cyclohexan — 1, 3 — suspicion, ring Hex-1,4-diene, cyclohex-1,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, First The condition is that when U-Z is equal to cyclohexane, then one (eight) 11 — (CWR2) m —, R3, R4, R5 'Rp, Rq, Rr at least one is linear or branched lower Alkenyl (C 2-C 6) or linear or branched lower fast group (C 2-C 6), its optical isomers and their pharmaceutically acceptable acid or base addition salts, 95 -This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 200407120 A8 B8 C8 ____ D8 6. The scope of patent application 7 plus one or more pharmaceutically acceptable diluents, excipients or carriers. 4 A pharmaceutical composition for alleviating conditions selected from the following groups that can be treated by NMDA antagonists: Excitatory toxicity selected from the group: · Stroke, trauma, hypoarterial hypoxia, hypoglycemia, glaucoma, and liver The ischemia during the cerebral encephalopathy is selected from the group of chronic neurodegenerative diseases: Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, multiple sclerosis, muscular atrophic collaterals Sclerosis, AIDS-neurodegeneration, oligopontine cerebellar atrophy, Reed's disease, motor neuron disease, mitochondrial dysfunction, Korsak syndrome, and Klezfeld-Jekkober's disease, others selected from the following groups are associated with long-term changes in the central nervous system Disorders: chronic pain, drug tolerance, dependence and addiction (eg opiates, cocaine, benzodiazepines, nicotine, and alcohol), and epilepsy, delayed exercise Difficulty, dyskinesias caused by L-DOPA, schizophrenia, anxiety, depression, acute pain, cramps, and tinnitus. This pharmaceutical composition comprises an effective amount of a compound selected from the group of compounds of formula I: Rq Rr This paper size is applicable to China National Standard (CNS) A4 (210X297mm) "96- ---------- 0 -I (Please read the precautions on the back before filling this page), π f Employees' Cooperative Cooperative Association of the Intellectual Property Bureau of the Ministry of Economic Affairs #, ¾ 200407120 A8 B8 C8 D8 k, patent application scope 8 where: —R * is-(A) n- (CRl2) NR3R4, — n + m = 0, 1 or 2. One A is selected from the following groups: linear or branched lower alkyl (Ci-C6), linear or branched lower storage group (C2-C6), and linear Or branched lower alkynyl (C2-C6) '-R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched lower alkyl (Ci-Cd, linear or Lower alkenyl (C2-C6) with branched chain and lower alkynyl (C2-C6) with straight or branched chain ------------ (Please read the back Please fill in this page again.) Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R3 and R4 are independently selected from the following groups: hydrogen, linear or branched lower alkyl (q-C6), linear Lower branched alkenes (C2—C6), and straight or branched lower alkynyl (C2-C6), or together form C2—Cio or C2—Cio or N— · To form a 3-7-membered azacycloalkane or azacycloalkene, including substituted (alkyl (Ci-C6), substituted alkenyl (c2-C6)) 3-7-membered nitrogen Heterocycloalkanes or azetines, R Rp, Rq, Rr, and Rs are independently selected from the group consisting of hydrogen, straight-chain or branched lower alkyl (Ci-Cs), straight-chain or Lower alkenyl (C 2-C6) branched, and lower alkynyl (C2-C6) straight or branched, or R5, Rp 'Rq, Rr, and Rs can be independently The connected carbon and the next adjacent carbon are combined to form a double bond, or Rp, Rq, Rr, and Rs may independently form a double bond with the U to which they are connected, or with the γ to which they are attached, and -97- 本Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 200407120 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 ::::: A8 B8 C8 D8 VI. Application for patent scope 9-its prerequisite is u-V — W-X— Y—Z Selected from: Cyclohexanone, Cyclohexanone-1, Cyclohexanone 2-ene, Cyclohexan-3-ene, Cyclohexan-1,3-diene, Cyclohexan-1,4-diene, Cyclohexane -1,5-diene, cyclohex-2,4-diene, and cyclohex-2,5-diene, and the prerequisite is that when U-Z is equal to cyclohexane, then (a) n — (CRiR2) m—, R3, R4, R5, Rp, Rq, Rr At least one of the lower cannyl (^ 2-C6) which is linear or branched or linear or branched lower Alkynyl (C 2-C 6), its optical isomers and their pharmaceutically acceptable acid or base addition salts, plus one or more pharmaceutically acceptable diluents, excipients or carriers. 5. —A pharmaceutical composition for alleviating conditions treatable by a 5HT3 receptor antagonist, which contains an effective amount of a compound selected from the group of compounds of the formula I: (Please read the precautions on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) -98-200407120 A8 B8 C8 D8 VI. Application for patent scope 10 Of which: — R * is-(A) n- (CR'R2) m -NR3R4, — n + m = 0, 1, or 2, — A is selected from the following groups: · Linear or branched lower alkyl (Ci-C6), linear or branched Lower alkenyl (C2-C6), and straight-chain or branched lower alkynyl (C2-C6) '-R1 and R2 are independently selected from the group consisting of hydrogen, straight-chain or branched Lower alkyl (Ci-Cd, linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6) R3 and R4 are independent The ground is selected from the group consisting of hydrogen, lower alkyl (Ci-Cs), straight or branched, lower alkenyl (C2 to C6), or straight or branched Lower branched alkynyl (C2 — C6), or together form C2 — CiQ or C2 — CiQ or form a 3- 7-membered nitrogen heterocyclic ring with N — · Alkanes or azacycloolefins, including substituted (alkyl (D-C6), substituted Alkenyl (C2 — C6)) 3-7-membered azacyclic ring or azacycloolefin, R5, Rp, Rq, Rr, and Rs are independently selected from the following groups: hydrogen, linear or branched Lower alkyl (Ci-Cs), lower alkenyl (C2-C6), straight or branched, and lower alkynyl (C2-C6), straight or branched, or R5 'RP' Rq 'Rr, and Rs may independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, or RP, Rq, Rr, and Rs may independently with the U to which they are attached, or It forms a double bond with the Y connected to it, and this G-scale scale is suitable for financial and financial county (CNS) 8 4 test (210X297 public director) Q9-· " (Please read the precautions on the back before filling this page) Order f Employees 'Cooperative Cooperative Printing Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ::::: 200407120 Employees' Cooperative Cooperative Cooperative Printings of the Intellectual Property Bureau of the Ministry of Economic Affairs .. :::! v—w— X—Υ—Z is selected from the group consisting of cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3-ene, cyclohex-1,3-diene, ring One, one, four, two , Cyclohexyl 1,5-two storage, cyclohexyl 1, 2, 4 and 2 and cyclohexyl 1, 2,5-diene, and the prerequisite is that when U-Z is equal to the cyclohexyl courtyard 'then one ( A) η-(CRlR2) m —, R3, R4, R5, Rp, Rq, Rr At least one of them is a linear or branched lower flammable group (C2-C6) or a linear or branched Lower alkynyl (C 2-C 6), its optical isomers and their pharmaceutically acceptable acid or base addition salts, plus one or more pharmaceutically acceptable diluents, excipients or carriers . 6. A pharmaceutical composition for alleviating a condition that can be treated with a neuron receptor antagonist, which comprises an effective amount of a compound selected from the group of compounds of formula 1: (Please read the precautions on the back before (Fill in this page) This paper size applies to China National Standard (CNS) A4 (210X 297 mm) -iOO-200407120 Α8 Β8 C8 D8 Intellectual Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives, India and the United States, the scope of patent application 12 of which:- One (A) (CR'R2) m— NR3R4, — n + m = 0, 1 or 2, — A is selected from the group consisting of a lower alkyl group (Ci-C6), straight or branched, Linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6),-R1 and R2 are independently selected from the group consisting of: hydrogen , Linear or branched lower alkyl (G-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6) R3 and R4 are independently selected from the group consisting of hydrogen, a lower alkyl group with a straight or branched chain (Yang-C6), and a lower alkenyl group with a straight or branched chain (C2 —C6), and linear or branched lower alkynyl (c2 — C6), or together form a C2-CiQ or C2-ClQ or with N —. A 3-7-membered azacycloalkane or azacycloalkene, including Substituted (alkyl (Ci-C6), substituted alkenyl (c2-C6)) 3-7-membered azacyclic ring or azacyclic ring, R5, Rp, Rq, Rr 'and Rs are Independently selected from the group consisting of hydrogen, lower alkyl with straight or branched chain (Shan-06), lower alkyl with straight or branched chain (C2-C6), and straight or Lower branched lower alkynyl (c2-C6) 'or R5' Rp, Rq, Rr, and Rs can independently combine with the carbon to which they are attached and the next adjacent carbon to form a double bond, or Rp, Rq , Rf, and Rs can independently form a double bond with the U to which they are connected, or with the γ to which they are connected, and ------------ (Please read the precautions on the back before filling this page ), ^ Τ f This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -101 200407120 A8 B8 C8 D8 Application scope of patent 13 The prerequisite is U-V-W-X-Y-Z system selection From: Cyclohexane, cyclohexyl-1, cyclohexyl-1, cyclohexyl-1, cyclohexyl-1, cyclohexyl-1, cyclohexyl-1, cyclohexyl-2 3, diene-4, dican 5 — Two; ϋ 4-diene and (please read the back first (CW) Member of the Intellectual Property Bureau of the Ministry of Economic Affairs X Consumer Cooperative fv Λ-cyclohex-2,5-diene and its prerequisite is that when U-Z is equal to cyclohexane, then one (A ) η-, R3, R4, R5, Rp, and Rr have at least one of straight or branched lower alkenyl (c2-C6) or straight or branched lower alkynyl (C 2 -C 6), its optical isomers and their pharmaceutically acceptable acid or base addition salts, plus one or more pharmaceutically acceptable diluents, excipients or carriers. 7. A pharmaceutical composition for alleviating a condition treatable by a 5HT3 receptor antagonist, the condition being selected from the group consisting of anxiety, depression, schizophrenia and treatment-related psychosis, drug and alcohol abuse disorders, cognitive disorders Alzheimer's disease, Parkinson's disease, cerebellar tremor, migraine, anorexia, inflammatory bowel syndrome (IBS) and vomiting. This pharmaceutical composition comprises an effective amount of a compound selected from the group of compounds of formula I: This paper size applies to China National Standard (CNS) A4 (210X297 mm) -102-200407120 A8 B8 C8 D8 Patent Application Scope 14 (Please read the notes on the back before filling this page) where: R * is-(A) n- (cVR2) m- NR3R4, — n + m = 0, 1, or 2, A is selected from the following groups : Linear or branched lower alkyl (Ci-C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6), one of R1 and R2 is independently selected from the group consisting of hydrogen, straight chain or branched lower alkyl (Q-C6), straight chain or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6) 5 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs: One R3 and R4 are independently selected from the following groups: hydrogen, Straight or branched lower alkyl (Mo-C6), straight or branched lower alkenyl (C2-C6), and straight or branched lower alkynyl ( C2 — C6), or together form Shen Yuanji (C2 — Cl.) Or Shen Keji (C2 — Cl.) Or with N — k to form a 3-7-membered azacyclic courtyard or azacycloolefin , Including substituted (alkyl (G-C6), substituted alkenyl (C2-C6)) 3- 7-membered azacycloalkanes or azacycloalkenes, R5, Rp, Rq, Rr, and Rs are independently selected from the group consisting of: hydrogen, straight-chain or branched lower alkyl (Ci-C6 ), Straight-chain or paper-bound paper scales are applicable to the Chinese National Standard (匚 奶) six 4 specifications (210 fathers, 297 public directors): 103- " printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 200407120 A8 B8 C8 __ D8 points Lower patented alkenyl group (C2-c6) with 15 chains, and linear or branched lower alkynyl group (c2-C6), or R5, Rp, Rq, Rr, and Rs can be independently Combine with the carbon to which it is attached and the next adjacent carbon to form a double bond, or RP, Rq, Rr, and Rs may independently form a double bond with the U to which they are attached, or with the Y to which they are attached, and- The prerequisite is that U—V—W—X—Υ—Z is selected from: cyclohexane, cyclohex-1-ene, cyclohex-2-ene, cyclohex-3—ene, cyclohex-1, 3— Diene cyclohexa-1,4-dienecyclohexa-1,5-dienecyclohexa-2,4-diene, and cyclohexa-2,5-diene and the prerequisites are when U-Z In cyclohexane, at least one of (A) η — (CRXR2) m-, R3, R4, R5, Rp, Rq, Rr is a linear or branched lower alkenyl group (C2-C6) Or linear or branched lower alkynyl (C2-C6), its optical isomers and their pharmaceutically acceptable acid or base addition salts, plus one or more pharmaceutically acceptable dilutions Agent, excipient or carrier. 8. A pharmaceutical composition for alleviating a condition treatable by a neuronal nicotinic receptor antagonist, the condition being selected from the group consisting of Torred's disease, anxiety, schizophrenia, drug abuse, nicotine abuse, paleotherapy Abusine, difficulty in exercise (Hangzhou paper size applies Chinese National Standard (CMS) A4 specification (210 X 297 mm) -104 orders * (Please read the precautions on the back before filling this page) 200407120 A8 B8 C8 D8 々 16 、 Application scope of patent 16 Tinton's disease caused by L-DOPA), Attention Deficit Hyperactivity Disorder (ADHD), Alzheimer's Disease, Parkinson's Disease and Pain. This pharmaceutical composition contains an effective amount of Compounds selected from the group of compounds of formula I: Where: — R * is — (A) (CVR2) m- NR3R4, — n + m = 0, 1, or 2, — A is selected from the group consisting of a linear or branched lower alkyl group (Ci — C6), linear or branched lower alkenyl (C2-C6), and linear or branched lower alkynyl (C2-C6), — R1 and R2 are independently selected from The following groups: hydrogen, linear or branched lower alkyl (〇 ^ -〇: 6), linear or branched lower alkenyl (c2-C6), and linear or branched Lower branched lower alkynyl (C2-c6) R3 and R4 are independently selected from the following groups: hydrogen, straight-chain or branched lower alkyl (, Ci-C6), straight-chain or Branched lower alkenyl (C2-Ce), and linear or branched lower alkynyl (c2-c6), or together form an alkylene (C2-C1Q) or alkylene (c2- C1 ()) or together with N to form a 3-7-membered azacycloalkane or azacycloalkene, including substituted (alkyl (C!-C6), substituted alkenyl (c2-c6 )) 3 — 7 ~ Member, .. Zhang scales are applicable to Chinese national standard (milk milk) 8 4 specifications (210 father 297 mm) -105- ------------ (Please read the precautions on the back before filling out this page), 1T Printed by the Consumers ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200407120 Employees’ Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (Print:%) * A8 B8 C8 D8 VI. Application for patent range 17, azacycloalkane or azacycloalkene 'R5, Rp, Rq, Rr, and Rs are independently selected from the following groups: hydrogen, linear Lower or lower branched alkyl (Cl — C6), lower or lower branched alkenyl (c2-C6), and lower or lower branched alkynyl (C2-C6) ), Or R5, Rp, Rq, Rr, and Rs may independently combine with the carbon to which they are connected and the next adjacent carbon to form a double bond 'or Rp, and Rs may independently connect with u, or Forms a double bond with γ to which it is connected, and-its prerequisite is U-V-W-X-Υ-ζ is selected from the group consisting of cyclohexane, cyclohexyl 1-ene, cyclohexyl 2 -ene, cyclohexyl Hexa-3ene, cyclohex-1,3-diene, cyclohex-1,4-diene, cyclohex-1,5-diene, cyclohex-2,4-diene, and cyclohex-1 2,5 — Ercan, and its prerequisites When U-Zn is equal to cyclohexane, 'then one person is a man') ^ (CR! R2) m-, R3, R4, r5, Rp, Rq, Rr At least one of the lower alkenyl group is linear or branched (C2-C6) or linear or branched lower block (C2-C6) 'its optical isomers and their pharmaceutically acceptable acid or base addition salts' plus one or more pharmaceuticals Acceptable diluents, excipients or carriers. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) _ 106 = · (Please read the precautions on the back before filling this page), 1T Ρ.