WO2006062110A1 - Piperazine derivative - Google Patents

Abstract

A compound represented by the formula (I): [wherein R1 represents C3-9 branched alkyl; R2 represents, e.g., linear or branched, C2-9 alkyl optionally substituted by halogen, etc.; and X represents oxygen, etc.] (provided that the following cases are excluded: the case where R1 is tert-butyl, R2 is 2-methylpropyl, phenyl, tert-butyl, benzyl, or cyclohexyl, and X is oxygen and the case where R1 is tert-butyl, R2 is adamantly, neopentyl, or cyclohexylethenyl, and R3 is a single bond); or a pharmaceutically acceptable salt of the compound. The compound and salt have inhibitory activity against metabotropic glutamate receptor 1. They are hence useful for the treatment of diseases such as convulsion, acute pain, inflammatory pain, chronic pain, psychofunctional disorders including schizophrenia, and anxiety.

Description

 Piperazine derivatives Technical field

 The present invention relates to a piperazine derivative useful in the field of medicine. This compound acts as an inhibitor of metapotropic glutamate receptor 1 and is used for cerebral disorders such as convulsions, acute pain, inflammatory pain, chronic pain, cerebral infarction or transient ischemic attack, schizophrenia, etc. It is useful as a therapeutic and / or prophylactic agent for diseases such as mental dysfunction, anxiety and drug dependence.

 Light

 Background art

 Glutamate is a transductor that mediates excitatory transmission in the central nervous system. Glutamate is responsible for many important brain functions such as neuronal survival and death, differentiation and proliferation, neuronal and glial development, and plastic changes in neurotransmission efficiency in the mature or developing brain, in addition to various neurotransmitter effects. (E.g., Annuanore Review OB Biophysics and Biomolecular Str. (See 1994).

 Based on pharmacological and molecular biological studies, mammalian central nervous system glutamate receptors are classified into two types: ion channel glutamate receptors and metabotropic glutamate receptors (hereinafter referred to as “mG l uR”). Has been. The ion channel type glutamate receptor is a complex of different subunit proteins, and is an ion channel that is opened and closed by the binding of a ligand. On the other hand, mG 1 uR is conjugated to GTP binding protein and acts by regulating intracellular second messenger production or ion channel activity via GTP binding protein (for example, Brain Research Reviews (B rain Research Re vi ews), 26, 230 (1998)).

Previous studies have reported that mG 1 uR exists as eight different subtypes of mG 1 uR 1-8. These are divided into three subgroups according to amino acid sequence homology, signal transduction, and pharmacological properties. Group I (mG l uRl and 5) activates phospholipase C for intracellular signaling, and Group II (mG 1 uR2 and 3) and Group III (mG 1 uR4, 6, 7, and 8) adenylate. By regulating cyclase activity, it suppresses forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP). Group II is also selectively activated by LY354740 as described in, for example, Journal of Medical Chemistry, 42 卷, page 1027 (1999). 4 activates selectively. Furthermore, various receptors are expressed in a wide range of brain and nervous systems, except for mG 1 uR6, which exists specifically in the retina, and each of them has a characteristic brain distribution, and each receptor has a different physiological are thought to play a role (for example, neuro-chemistry one International (N eurochemistry I nternationa 1), 24 Certificates, 439 (1994)及Pi ® bite Lesbian journal O blanking off Ryoichi Mako ports for ¹ to (Eu ropean J ournalof Ph a rma cology, ύ / 5 卷, page 277 (1999)).

 There have been various reports on the role of mG 1 uR in the nervous system. In the following (1) to (7), a part of the relationship between mG 1 uR 1 and various diseases is specifically shown.

 (1) 3, 5-Dihydroxyphe ny glycine (hereinafter referred to as DHPG), an agonist selective to Group I, has been reported to cause convulsions when administered intraventricularly (for example, (See Journal of Neuroscience Research, Vol. 51, p. 339 (1998)).

On the other hand, in tests using mG 1 uR 1 selective antagonists, pentyienetetrazole, which has been widely used for evaluating the effects of anticonvulsants, has been treated with RS— 1— am inoindan— 1, 5-dicarboxylic acid (hereinafter referred to as “anti-convulsants”). AI DA) has a dose-dependent anticonvulsant effect (see, for example, Neuro ph armaco 1 ogy), 37 卷, 1465 (1998)) Exhibits inhibitory effects on sound-induced convulsions in sexually active mice and rats (for example, Eu ropean Journal of Pharmacology, Volume 368, 17 (1999)) See). In addition, LY456236, another selective antagonist, has been reported to reduce convulsions duration and extent in kindled rat amygdala known as a model of human convulsions (eg, neuropharmacology (Ne uropha rma cology), 43, 308 (2002)). The above suggests the anticonvulsant action of mG 1 uR 1 antagonists.

 (2) It has been reported that allergic pain and hypersensitivity to mechanical stimulation or hypersensitivity to thermal stimulation occur in rats when DHPG is administered intrathecally (eg, Neuroreport, 9 卷, (See page 1169 (1998)).

 -On the other hand, in the study using antagonists, when AI DA is administered into the brain, the threshold of pain perception increases (for example, the Journal of Pharmacologic and Experimental Therapeutics (TL hejournaloi Ph a rma colo gy & Ex peri me nta 1 Therapeutics), 281 卷, 721 (1997)), and spinal cord injury hyperalgesia model (eg, Journal of Neurotrauma (J ourna 1 of Neurotrauma), Vol. 19, p. 23 (2002)) and arthritis models (eg, The Journal of Pharmacology and Experimental Therapeutic Ikes (I hej ou rnalo I Pharmorology) Exp er ime nta 1 Therapeutics), 300 卷, p. 149 (2002)), etc. It has been tell. These findings suggest the possibility of having an analgesic effect on not only acute pain but also inflammatory pain and chronic pain.

(3) The following reports suggest the protective action against cerebral disorders such as cerebral infarction or transient ischemic attack. Inhibitory effect of AI DA on hippocampal delayed neuronal death observed in transient global cerebral ischemia-reperfusion model (eg, Neurophar ma co 1 ogy, 3 8 卷, 1607 Page (1999) and Neuroscience Letters, 293 卷, page 1 (2000)), mG 1 u R 1 selective antagonist (3 a S, 6 a S) — 6 a— naphta 1 en— 2— y 1 methy 1 1 5— me t hy 1 iaen— hexa hy dro— eye 1 openta [c] furan— 1— one (hereinafter “BAY36— 7620”) reduces the volume of cerebral cortical infarction in a rat subdural hemorrhage model. (See Eu ropean Journal IP harmacology), 428 卷, 203 (2001)) Chopi and other selective antagonists R 12849 4 reduced total infarct volume in rat middle cerebral artery ligation model ( For example, see Neuropharmacology-(Neuropharmacology), 43, 295 (2002)).

(4) Increased locomotor activity was observed when DHPG was administered into the nucleus accumbens, and the effect was similar to the response when dopamine receptor stimulants were administered (for example, the BIO Journal) (See hu ropean Journal of Neuroscience, Vol. 13, p. 2157 (2001)).

For example, P sychopha rma co 1 ogy, 141 卷, page 45 (1999), when DHPG was administered into the nucleus accumbens, experimental animal models and integration It is described that prepulse inhibition disorder observed in patients with ataxia occurred. These reactions caused by DHPG are similar to those observed with dopamine receptor stimulants such as apomorphine or dopamine-releasing drugs such as amphetamine and methamphetamine. On the other hand, existing antipsychotic drugs are thought to exert their effects by suppressing excessively excited dopamine nerves. Therefore, DH PG showed a reaction similar to dopamine stimulation, suggesting that mG 1 u R 1 and mG 1 uR 5 are involved in mental dysfunction in the nucleus accumbens. This suggests the possibility of improving the symptoms.

 (5) There is a report that the selective antagonist R128494 increased drinking water with punishment in the Voge 1 type conflict test using rats, which is widely used as an evaluation system capable of detecting the anxiolytic effects of drugs. (See, for example, Nu uropha rma co 1 ogy, 43, 295 (2002)). This result suggests that the mG 1 uR 1 antagonist may have an anxiolytic effect.

 (6) In Non-Patent Document 16 described above, it is said that BAY 36-7620, which is a mG luR1 selective antagonist, suppresses brain self-stimulation promoted by MK-801, an NMDA receptor antagonist. There is a description. Since many of the NMDA receptor antagonists are clinically clear to cause dependence, this test system is considered to be a model that reflects part of the dependence due to MK-801. . Therefore, the above-described paper suggests that selective antagonists of the mG 1 u R 1 receptor may be drug-dependent therapeutic agents.

 (7) In a study in which extracellular potentials were recorded using brain slices containing rat hypothalamic nuclei, an increase in the frequency of action potentials was observed by local application of DHPG (eg, plain research (B rain Re search), 766 卷, 162 (1997)

This suggests that mG l uRl or mG l u R 5 activates the hypothalamic nucleus. It is well known that the excitation of the subthalamic nucleus is characteristic of Parkinson's disease. Therefore, a mG 1 u R 1 selective antagonist may be useful as a therapeutic agent for Parkinson's disease.

Also, the following formula (A)

(For example, refer to WO 2003/007954).

Compound (A) is a synthetic intermediate of a compound that inhibits NMP (Matrix Metaroprotease) activity, and there is no description that suggests that the compound exhibits mG 1 uR 1 inhibitory activity. There is no description to do. Disclosure of the invention

 An object of the present invention is to provide a novel piperazine derivative having mG l uRl inhibitory action. The present inventors have intensively studied to develop a compound having an mG 1 uR 1 inhibitory action, and found that the compound according to the present invention is effective as a compound having an mG 1 uR 1 inhibitory action. Based on V, the present invention has been completed.

 That is, the present invention

(1) Formula (I)

[Where

R ¹ represents a branched alkyl group having 3 to 9 carbon atoms,

R ² is

 (a) a linear or branched alkyl group having 2 to 9 carbon atoms which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group (in the case of a branched alkyl group) The branched alkyl groups may be bonded to each other to form a cycloalkyl group, and the carbon atom constituting the cycloalkyl group is substituted with 1 or 2 oxygen atoms. Ok)

 (b) an alkenyl group,

 (c) an aralkyl group or an aryl group which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, or

 (d) represents a bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms,

X represents an oxygen atom, CH ₂ or a single bond. Wherein R ¹ is a tert-butyl group, R ² is a 2-methylpropyl group, a phenyl group, a tert-butyl group, a benzyl group or a cyclohexyl group, and X is When it is an oxygen atom, except that R ¹ is a tert-butyl group, R ² is an adamantyl group, neopentyl group or cyclohexyl ether group, and R ³ is a single bond) Acceptable salt,

(2) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a tert-butyl group, a 2,2-dimethylpropyl group, an isopropyl group or a 3,3-dimethylbutyl group. (3) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group,

 (4) The compound according to (2) or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom,

 (5) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein X is a single bond,

(6) The compound according to (2) or a pharmaceutically acceptable salt thereof, wherein R ² is a linear or branched alkyl group having 2 to 9 carbon atoms,

(7) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein R ² is an alkenyl group,

(8) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein R ² is an aralkyl group,

(9) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein R ² is an aryl group.

 (10) The compound represented by the formula (I) is

 1,4-dione neopentinorexoxy carboninole piperazine,

 1 1 t e r t—Butoxycarboru 4— (2, 2, 2-trichloroethoxycarbonyl) 1 piperazine,

 1 t er t-Butoxycarbolulu 4-pentyloxycarbolupiperazine,

1- tert-butoxycarbonyl 4-l-pentylmethyloxycarbonyl 2-piperazine, 1 tert-butoxycarbonyl _ 4--hexylmethyloxycarbonyl 1-piperazine, 1 tert-butoxycarbonyl— 4 — (1-Methylcyclopropylmethyloxycarbonyl) monopiperazine,

 1-t e r t-butoxycarbonyl 4 1 neopentyloxycarbonylbiperazine,

1- (ethoxycarbonyl) 1-4- (neopentinoreoxycarbonyl) piperazine,

 1-tert-butoxycarbonyl-4- (1-methylcyclohexylmethyloxycarbonyl) 1 piperazine,

 1—ter t-butoxycarbonyl 4— (1, 2, 2-trimethylpropyloxycarbonyl) monopiperazine,

1 neopentyloxycarbonyl— 4— (1, 2, 2-trimethylpropyloxycarbonyl) 1 piperazine,

 1-tert-butoxycarbonyl-4- (4-methyl-tetrahydropyran-4-ylmethyloxycarbonyl) piperazine,

 1-Neopentyloxycarbonyl— 4— (2,2,2-trifluoro-1,1-dimethylethynoxycarbonyl) -piperazine,

 1-ter teptoxycarbonyl— 4— (1-methylcyclopentylmethyloxycarbonyl) -piperazine,

 1 tert-butoxycarbonyl-4- (5-methyl_ [1,3] dioxane-5-ylmethyloxycarbonyl) 1piperazine,

1-Isopropyloxycarbolulu 4 Neopentyloxycarbolupiperazine,

 1 1 (2-hydroxymethyl 1 2 -propoxycarbonyl) 1 4 -neopentyloxycarbonyl 1 piperazine,

 1 (m-phenylbenzoyl) 1 4-ter t-ptoxycarbonyl 1 piperazine,

1-Silic Mouth Pentyleyl Carbonyl 4-lu-tert-butoxycarbolulupiperazine, 1 Noradamantyl carbolulu 4-tert-butoxycarbolupiperazine,

1 (2, 2, 3, 3-tetramethyl-cyclopropylcarbonyl) 1 4-tert-butoxycarbonyl-piperazine,

 1-succinoxyhexyl carbonyl carbonyl 4-tert-butoxycarboluropiperazine, 1- (2,2-dimethylpropyl) carbonyl-4-1 (2,2-dimethylpropyl) oxycarbolulupiperazine,

 1- (4,4-Dimethyl-2-pentenoyl) — 4— tert-Butoxycarbolurpiperazine, 1— (3,3-Dimethylptyl) carborulu 4— tert-Butoxycarbolupiperazine, 1-( 3,3-dimethylbutyl) carbonyl-4-isopropyloxycarbonyl-piperazine, 1- (3,3-dimethylbutyl) carbonyl _4 (2-fluoro-1,1-dimethylethyl) oxycarbopiperazine, or

 1- (2-Fluoro-1,1,1-dimethylethylcarbonyl) -4one neopentylcarbonyl loopiperazine or the pharmaceutically acceptable salt thereof,

[式中、 (11) Formula (I)

[Where

R ¹ represents a branched alkyl group having 3 to 9 carbon atoms,

R ² is

 (a) may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group! /, a linear or branched alkyl group having 2 to 9 carbon atoms (branched alkyl group) In the case of a group, branched alkyl groups may be bonded to each other to form a cycloalkyl group, and the carbon atoms constituting the cycloalkyl group are 1 or 2 oxygen atoms. May be replaced),

 (b) an alkenyl group,

 (c) an aralkyl group or an aryl group which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, or

 (d) represents a bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms,

X represents an oxygen atom, CH ₂ or a single bond. An mG 1 uR 1 antagonist comprising as an active ingredient a compound represented by the formula:

(12) The compound or pharmaceutically acceptable salt thereof according to (11) above, wherein R ¹ is tert-butyl group, 2,2-dimethylpropyl group, isopropyl group or 3,3-dimethylmethyl group M

G 1 uR 1 antagonist,

(13) an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group,

(14) mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom, (15) an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein X is a single bond,

(16) an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ² is a linear or branched alkyl group having 2 to 9 carbon atoms;

(17) an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ² is an alkenyl group,

(18) An mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ² is an aralkyl group,

(19) An mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ² is an aryl group;

 (20) Formula (I) Force '

1, 4-Geo Neopentino Lexican Lebonino Lepi Piperazine,

 1-t e r t-butoxycarbonyl mono 4— (2, 2, 2-trichloro ethoxycarbonyl) monopiperazine,

1-tert-butoxycarbono-nor 4- (2-methylpropyloxycarbonyl) -piperazine, 1-tert-butoxycarboninole 4-phenoxycarboninolepiperazine,

1—t e r t—butoxycarbolulu 4-pentyloxycarbolupiperazine,

1 1 tert-Butoxycarbonyl 4-lupiperazine, 1-tert-Butoxycarbonyl piperazine 4-Hexylmethyloxycarbonyl piperazine, 1- tert-Butoxycarboninole 4 — (1-Methinoresic propylmethyloxycarbonyl)-piperazine,

 1-tert-butoxycarbonyl mono 4-neopentoxycarbonylbiperazine,

1-(ethoxycarbonyl) -4--(neopentyloxycarbonyl) piperazine,

1—ter t-ptoxycarbonyl mono 4 -— (1-methylcyclohexylmethyloxycarbonyl) monopiperazine,

 1—ter t-butoxycarbonyl 1- (1, 2, 2-trimethylpropyloxycarbonyl) 1 piperazine,

 1-neopentyloxycarbonyl 1-41 (1, 2, 2-trimethylpropyloxycarbonyl) 1 piperazine,

1-t er t 1-butoxycarbonyl 4 _ (4-methyl-tetrahydropyran—4-ylmethyloxycarbonyl) 1 piperazine,

 1-neopentyloxycarbonyl _ 4 1 (2,2,2-trifluoro-1,1-dimethylethyloxycarbonyl) 1piperazine,

 1—t er t-butoxycarbonyl 4-— (1-methyl pentylmethyloxycarbonyl) -piperazine,

 1 1 t e r t-Butoxycarbonyl 4 1 (5-Methyl- [1,3] dioxane-5-ylmethyloxycarbonyl) —piperazine,

 1-isopropyloxycarbonyl 1-neopentyloxycarbolupiperazine,

1 (2-hydroxymethyl-2-propoxycarbonyl) 1-neopentyloxycarbonyl 1 Piperazine,

 1-adamantane carbonyl 4-t e r t 1 butoxyca boninole 1 piperazine,

 1-1 (m-Ferpenzoinole) 1 4 1 t e r t-Butoxycarbolupiperazine,

 1-sic pentylylcarbonyl 4-rut-butoxycarbonyl-loopiperazine, 1-nordamantylcarbonyl-1-41 tert-butoxycarbonyl-piperazine,

 1— (2,2,3,3,3-Tetramethylmonocyclopropylcarbonyl) — 4—ter t-butoxyboni ^ / lepiperazine,

 1-hexoxylcarbonyl carbonyl 4-ter t-butoxycarbolupiperazine,

1— (2,2-dimethylpropyl) carbonyl mono 4 -— (2,2-dimethylpropyl) oxycarboluluperazine,

 1-Cyclohexenoleacryloinole _ 4—t e r t—toxicanololepirpyrazine,

 1 1 (4,4-Dimethyl 1 2 -Pentenoyl) 1 4 tert-Butoxycarboninole piperazine, 1 1 (3,3 1 dimethylbutinole) Carbonyl 4-tert-Butoxycarbo-Lupiperazine, 1 1- (3,3-Dimethylbutinole) carbonyl 1-Isopropyloxycarbonyl loopiperazine, 1- (3,3-Dimethylbutyl) carbonyl 1- (2-Funoleo _ 1,1-dimethylethyl) Kishikanoleboninole piperazine, or

 (1) (2-Fluoro-1,1,1-dimethylethylcarbonyl) (1) 4-neopentylcarbonyl (1) piperazine compound described in (1 1) above or a pharmaceutically acceptable salt thereof, mG 1 u R l antagonist,

 (2 1) Convulsions, acute pain, inflammatory pain or chronic pain, brain containing the compound according to any one of (1 1) to (2 0) or a pharmaceutically acceptable salt thereof as an active ingredient Infarction or epilepsy relates to therapeutic and / or preventive agents for brain disorders such as transient cerebral ischemic attacks, mental dysfunctions such as schizophrenia, anxiety, drug dependence and / or Parkinson's disease. BEST MODE FOR CARRYING OUT THE INVENTION

 The meanings of terms used in the present specification will be described below, and the compounds according to the present invention will be described in more detail.

 Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term “Γ lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a ptyl group, an isobutyl group, and a sec_ptyl group. Tert-butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl Xyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1 ', 3-dimethylbutyl group Group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1-eth -2-methylpropyl group and the Ru mentioned.

The “lower alkoxy group” means a group in which a hydrogen atom of a hydroxy group is substituted with the lower alkyl group. For example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butyl group. Toxyl group, tert-butoxy group, pentyloxy group, isopentyloxy group.

And an isohexoxy group.

Formula (I) according to the present invention

[In the formula, each symbol is the same as above] In order to more specifically disclose the compound represented by formula (I), various symbols used in formula (I) will be described with specific examples.

Examples of the branched alkyl group having 3 to 9 carbon atoms represented by R ¹ include isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group. 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group Group, 1, 2, 2-trimethylpropyl group, 1-ethyl-2-methylpropyl group, etc., among which tert-butyl group, 2,2-dimethylpropyl group, isopropyl The group is preferably a 3,3-dimethylpropyl group, more preferably a tert-butyl group or a 2,2-dimethylpropyl group.

The linear or branched alkyl group having 2 to 9 carbon atoms represented by R ² includes a cycloalkyl group having 3 to 9 carbon atoms or a cycloalkylalkyl group formed by bonding branched lower alkyl groups to each other. It is. The carbon atoms constituting the cycloalkynole group having 3 to 9 carbon atoms or the cycloalkylalkyl group in the cycloalkylalkyl group may be substituted with 1 or 2 oxygen atoms.

Specific examples of the linear or branched alkyl group having 2 to 9 carbon atoms represented by R ² include, for example, an ethyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isoamyl group, and a neopentyl group. Tyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group Group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-Ethylptyl group, 2-Ethylbutyl group, 1,2,2_trimethylpropyl group, 1-Ethyl-2-methylpropyl group, Cyclopropyl group, Cyclobutyl group, Cyclopentyl group , Cyclohexyl group, 2, 2, 3, 3-tetramethyl monocyclopropyl group, cyclopentylethyl group, cyclohexylethyl group, 2 monoisopropyl 1-methyl-cyclohexyl group, 1-methyl monocyclopentylmethyl group 1-methylcyclopropylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclopentylethyl group, cyclohexylethyl group, tetrahydropyran-2-ylmethyl group, tetrahydropyran-1- Examples include a methyl group, a tetrahydropyran-4-ylmethyl group, a 4-methyltetrahydropyran-4-ylmethyl group, a 5-methyl_ [1,3] dioxane-5_ylmethyl group, and the like.

The linear or branched alkyl group having 3 to 9 carbon atoms may be substituted 1 to 3 with a group selected from the group consisting of a halogen atom, a lower alkoxy group and an alkoxycarbonyl group. Group 2 Or if they have 3, they may be the same or different.

 Examples of the halogen atom of the substituent include the same groups as the halogen atom defined above. Examples of the lower alkoxy group for the substituent include the same groups as the lower alkoxy group defined above.

 The alkoxycarbonyl group of the substituent means a group in which an alkoxy group as defined above and a force group are bonded. For example, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a propoxy group. Examples thereof include a carbonyl group and a tert-butoxycarbonyl group.

The alkenyl group represented by R ² means a linear or branched alkenyl group having 2 to 9 carbon atoms. In addition, the branched alkenyl group includes a case where branched alkyl groups on the alkenyl group are bonded to each other to form an alkyl group.

Specific examples of the alkenyl group represented by R ² include, for example, a butyl group, a allyl group, a 1-butenyl group, a 2-butenyl group, a 1-pentul group, a 3,3-dimethyl-1-butyr group, and a 2-cyclo group. And hexylvinyl group.

Examples of the aralkyl group represented by R ² include a phenylmethyl group and a phenylethyl group.

Examples of the aryl group represented by R ² include a phenyl group and a naphthyl group.

When R ² is an aralkyl group or an aryl group, a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group is substituted with 1 to 3 in the aralkyl group or aryl group. 3 may be present, and when it has 2 or 3 substituents, these may be the same or different. Examples of the halogen atom of the substituent include the same groups as the halogen atom defined above.

 Examples of the lower alkyl tomb of the substituent include the same groups as the lower alkyl group defined above.

 Examples of the lower alkoxy group of the substituent include the same groups as the lower alkoxy group defined above.

Examples of the bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms represented by R ² include an adamantyl group, a noradamantyl group, and a norbornyl group.

Preferable embodiments of the compound (I) according to the present invention include, for example, the case where R ¹ is a tert-butyl group or a 2,2-dimethylpropinole group and X is an oxygen atom.

In addition, a preferred embodiment of the compound (I) according to the present invention includes, for example, a case where R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group, and X is CH ₂ .

In addition, as a preferred embodiment of the compound (I) according to the present invention, for example, R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group, and R ² is a straight chain or branched carbon number 2 Or an alkyl group of 9 to 9.

In addition, preferred embodiments of the compound (I) according to the present invention include, for example, the case where R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group, and R ² is an aralkyl group. .

In addition, a preferred embodiment of the compound (I) according to the present invention includes a case where R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group, and R ² is an aryl group.

 From the above, specific examples of the compound (I) related to this effort include

1, 4—Gineopentyloxycarbonyl piperazine,

 1-ter t-butoxycanolbonyl-41 (2, 2, 2-trichloroethoxycarbonyl) -piperazine,

1 1 tert-butoxycarbonyl-4 1 (2-methylpropyloxycarbonyl) 1 piperazine, 1 1 tert-butoxycarbonyl 4 4-phenoxycarbonyl piperazine, 1-tert-butoxycarbolulu 4-1-pentyloxycarboninolepiperazine, 1-tert-butoxycarbonylolevonir 4-cyclopentylmethinoreoxycanolepipiperazine, 1- tert-butoxycarbolulu 4-sic Oral hexylmethinoreoxycanolebonyl-piperazine, 1-tert-butoxycarbonyl 4-pi (1-methylcyclopropylmethyloxycarbonyl) -piperazine,

 1-t er t-butoxycarbonyl 4-ru-neopentyloxycarbonylpiperazine,

 1— (ethoxycarbonyl) 1 4— (neopentyloxycarbonyl) piperazine,

 1-ter t-butoxycarbonyl 4 _ (1-methylcyclohexylmethyloxycarbonyl) 1 piperazine,

 1-ter t-butoxycarbonyl 4 (1: 2, 2-trimethylpropyloxycarbonyl) -piperazine,

 1-neopenti / reoxycarbonyl 4 (1; 2,2-trimethylpropyloxycarbonyl) 1 piperazine,

 1—t e r t—Butoxycarbonyl 4 (4-'Metinole tetrahydrodropiran 4-ylmethinoleoxycarbonyl) -piperazine,

 1-neopentinoreoxycanololebonyl-4 (2: 2, 2,2-trifluoro-1,1-dimethyl monoethyloxycarbonyl) monopiperazine,

 1—t er t-butoxycanol bornyl 4 (1--methyl pentylmethyloxycarbonyl) 1 piperazine,

 1-tert-butoxycarbonyl 4- (5-methyl- [1,3] dioxane-5-ylmethyloxycarbonyl) -piperazine,

 1 isopropyloxycarbonyl 4 1 neopentyloxydipiperazine,

 1- (2-hydroxymethyl-1-2-propoxycarbonyl) -4 neopentyloxycarbonyl-piperazine,

1-adamantane force luponyl 4-t er t-butoxycarbonyl loopiperazine,

 1— (m-phenylbenzoyl)-4-t e r t-butoxycarbopirpiperazine,

 1-cyclopentylethylcarbonyl 1-tert-butoxycarbolurpiperazine,

1-noradamantyl carbonyl 4-ter t-ptoxycarbolulupiperazine,

 2,2,3,3-tetramethyl monocyclopropyl carboluene 41 tert-butoxycarbolulu piperazine,

 1-succinoxyhexylcarbonyl 1--tert-butoxycarbonylpiperazine, 1- (2,2-dimethylpropyl) carbonyl 4_ (2,2-dimethylpropyl) oxycarbo ^ /-piperazine,

 1-cyclohexinoleacryloyl 4-tetra-butoxycarbolupiperazine,

1— (4,4-Dimethyl-1-2-pentenol) 1 4-tert-Butoxycarbonyl-piperazine, 1 1 (3,3-Dimethylbutyl) Carbonyl 4-4-tert-Ptoxycarbolurpipeperazine, 1 1 (3 , 3 -dimethylptyl) carbolulu 4-isopropyloxycarbolupiperazine, 1-1 (3, 3 -dimethylbutyl) carbonyl 1-4 (2-fluoro- 1, 1-1 dimethylethinole) oxycarbolupiperazine, Or 1- (2-Fluoro-1,1-dimethylethylcarbonyl) 1-4-neopentylcarbonyl loopiperazine and the like can be mentioned.

 Next, the manufacturing method of the compound based on this invention is demonstrated.

Compound according to the present invention (I-1)

 (1-1)

 [Wherein each symbol is the same as described above] can be produced, for example, by the following method.

 [Where each symbol is the same as above]

 (Process 1)

 This step is a method for producing the compound (I 1 1) according to the present invention by reacting 1-Boc-piperazine (1) with the compound (2).

 This reaction is described in literature (for example, peptide synthesis basics and experiments, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6, Pe rg amon Press, 1991, etc.), a method according to it, or a combination thereof with a conventional method may be used to carry out a normal amide formation reaction, that is, using a condensing agent well known to those skilled in the art. It can be carried out by an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, etc. available to those skilled in the art. Examples of such amide-forming reagents include thionyl chloride, chlorohydryl, N, N-dicyclohexylenocarposimide, 1_methyl-2-promopyridinium iodide, N, N, -carbonyldiimidazole. , Diphenylphosphoryl chloride, diphenylphosphoryl azide, N, N ′ —disuccinimidyl carbonate, N, N ′ —disuccinimidyloxalate, 1_ethyl 1- (3-dimethylaminopropyl ) Carbodiimide hydrochloride, ethyl chloroformate, isobutyl chloroformate, or benzotriazo-1-yl succiris (dimethylamino) phosphonium hexafluorophosphate, among which, for example, thionyl chloride, 1 1- (3-Dimethylaminopropyl) carbodiimide hydrochloride, N, N-disic To carboxymethyl </ Rekarubojiimido hexa fluoro phosphate, etc., or base Nzotoriazo one 1- pray one Okishi to single tris (dimethylcarbamoyl Ruamino) Fosufoniumu are preferred. In the amide formation reaction, a base and a condensation aid may be used together with the amide forming reagent.

Examples of the base used include trimethylamine, triethylamine, N, N-diisopropinoleethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylmethylaniline, 1,8-diazabicyclo [5 4.0 0] tertiary aliphatic amines such as Wundeker 7-Yen (DBU), 1, 5—azabicyclo [4. 3. 0] Nona 5-Yen (DBN); Examples thereof include aromatic amines such as 4-dimethylaminopyridine, picoline, noretidine, quinoline, and isoquinoline. Among them, tertiary aliphatic amines are preferable, and particularly, for example, triethylamine, N, N-diisopropylethylamine. Min or pyridine is preferred.

 Examples of the condensation aid used include N-hydroxybenzotriazol hydrate, N-hydroxysuccinimide, N-hydroxy_5-norbornene-2,3-dicarboxyimide, or 3-hydroxysilane. , 4-dihydro-1,4-oxo-1,2,3-benzotriazole and the like, and for example, N-hydroxybenzotriazole and the like are preferable.

 The amount of compound (2) or its reactive derivative used varies depending on the type of compound and solvent used and other reaction conditions, but usually 1 to 50 equivalents, preferably 1 equivalent to 1 equivalent of compound (1) 2 to 10 equivalents.

 Examples of the compound (2) used include 3-cyclohexylpropionic acid, 3-cyclopentenorepropionic acid, 3-noradamantanecarboxylic acid, 2,2,3,3-tetramethylcyclopropanecarboxylic acid, Examples include 4-methylpentanoic acid, cinnamic acid, cyclohexylcarboxylic acid, 3,3-dimethylbutyric acid, 4,4-dimethylpentanoic acid, and the like.

 Compound (2) can also be produced by a force using a commercially available product, or a method well known to those skilled in the art using a commercially available product as a raw material, or a method analogous thereto.

 The amount of the amide-forming reagent used varies depending on the type of compound and solvent used and other reaction conditions. Usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of normal compound (1) It is. The amount of the condensation aid used varies depending on the compound used, the type of solvent and other reaction conditions, but is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (1). is there.

The amount of base used varies depending on the type of compound and solvent used and other reaction conditions. Normal compound (1) 1 to 50 equivalents, preferably 2 to 5 equivalents per 1 equivalent .

 The reaction solvent used in this step is not particularly limited. Specifically, for example, black mouth form, chlorohymethylene, pyridine, THF, jetyl ether, DMF, NMP, dioxane, toluene, benzene or Xylene and the like can be mentioned, and among these, pyridine, black mouth form, and THF are preferred.

 The reaction temperature in this step is usually from 1 78 ° C to 1550 ° C, preferably from 0 ° C to 50 ° C. The reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 12 hours. The base, amide formation reagent, and condensation aid used in this step can be used alone or in combination.

 The compound (1-1) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

In addition, the compound according to the present invention (1-2)

 (1-2)

[In the formula, each symbol is the same as described above] includes, for example, that it can be produced by the following method. [Where each symbol is the same as above]

 (Process 2)

 This step is a method for producing the compound (1-2) according to the present invention by reacting the compound (1) with the compound (3).

 Examples of the compound (3) used in this process include 2,2-dimethylpropyl chloroformate, 2,2,2-trichloroethyl chloroformate, pentyl chloroformate, and 2-methinoreprovir. Examples include chloroformate, 2-ethylhexylchloroformate, and butylchloroformate.

 Compound (3) can be produced by using a commercially available product or by a method well known to those skilled in the art using a commercially available product as a raw material.

 The amount of compound (3) used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (1).

 The reaction in this step may be performed in the presence of a base.

 Examples of bases that can be used include trimethylenoamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylenorealin, 1,8-diazabixic mouth [5. 4. 0] Wundeker 7-Yen (DBU), 1, 5 — Azabicyclo [4. 3. 0] Tertiary aliphatic amines such as Nona 5-Yen (DBN); for example, pyridine, 4 -Aromatic amines such as dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc., among which pyridine or triethylamine are preferred. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, black mouth form, methylene chloride, pyridine, acetonitrile, THF, jetyl ether, DMF, NMP, dioxane, toluene, benzene or Xylene and the like. Among these, black mouth form is preferable.

 The reaction temperature is usually -78 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

 The reaction time is usually 30 minutes to 48 hours, preferably 6 hours to 24 hours.

 The compound (1-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

 Compound (1-2) can also be produced, for example, by the following method.

 (1)

 (1-2)

Process 5 [Where each symbol is the same as above]

 (Step 3) This step is a method for producing compound (5) by reacting compound (4) with carbonyldiimidazole (hereinafter abbreviated as “CD I”).

 The amount of CD I used is usually 1 to 2 equivalents, preferably 1.1 to 1.3 equivalents, relative to 1 equivalent of compound (4).

 Examples of the compound (4) to be used include (1-methylcyclopentyl) methanol, cyclopentenolemethanol, (1-methinorecyclohexenole) methanol, cyclohexenolemethanol, 3,3-dimethylbutane-2-ol. , (1-methylcyclopropyl) methanol, cyclopropylmethanol, (4-methyl-tetrahydropyran-4-yl) methanol, (tetrahydropyran-4-yl) methanol, (tetrahydropyran-1-3-inole) Examples include methanol, (tetrahydropyran-2-ylole) methanol, (5-methyl-1- [1,3] dioxane-5-yl) methanol, and [1,3] dioxane-1-ylmethanol.

 The reaction in this step may be performed in the presence of a base.

 Examples of the base to be used include trimethylamine, triethylamine, N, N-diisopropylenoethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8-diazabicycle mouth [ 5. 4. 0] Wundeker 7-Yen (DBU), 1,5-azabicyclo [4. 3. 0] Nona 5-Yen (DBN) and other tertiary aliphatic amines; for example, pyridine, 4-dimethyl Examples thereof include aromatic amines such as aminopyridine, picoline, lutidine, quinoline and isoquinoline, and among these, pyridine and triethylamine are preferable.

 The amount of the base to be used is generally 0.1 to 10 equivalents, preferably 0.1 to 2 equivalents, relative to 1 equivalent of compound (4).

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, chlorophonolem, methyl chloride, pyridine, acetonitrile, THF, jeti ac-ter, DMF, NMP, dioxane, toluene, benzene, xylene, etc. Of these, black mouth form or acetonitrile is preferred.

 The reaction temperature is usually _78 ° C to 150 ° (: preferably 0 ° C to 50 ° C).

 The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 6 hours.

 The compound (5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc., or without isolation. It can be attached to the process.

 (Step 4) This step is a method for producing compound (6) by reacting compound (5) obtained in step 3 with methyl iodide.

 The amount of methyl iodide used in this step is usually 1 equivalent to 1 equivalent to 1 equivalent of compound (5).

5 equivalents, preferably 1 to 2 equivalents. '

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include black mouth form, salt methylene chloride, acetonitrile, THF, DMF, NMP, dioxane, etc. Among these, acetonitrile Is preferred.

 The reaction temperature is usually 0 ° C to 50 ° C, preferably 0 ° C to 30 ° C.

The reaction time is usually 1 to 12 hours, preferably 3 to 6 hours. The compound (6) thus obtained can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography or the like without isolation. It can be attached to the process.

 (Step 5) This step is performed according to the present invention by reacting the compound (6) obtained in the above step (4) with 1-Boc-piperazine (1) in the presence of a base. This is a method for producing a compound (1-2). The amount of compound (6) used is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (1).

 The amount of the base used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1).

 Specific examples of the base to be used include triethylamine, pyridine, 4-dimethylaminoviridine and the like.

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include black mouth form, methylene chloride, acetonitrinol, THF, DMF, NMP, dioxane, and the like. Mouth form is preferred.

 The reaction temperature is usually 0 ° C to 50 ° C, preferably 10 ° C to 30 ° C.

 The reaction time is usually 1 hour to 24 hours, preferably 5 hours to 10 hours.

 The compound (1-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.

In addition, the compound (1-3) according to the present invention can be produced, for example, by the following method.

(7-2)

 (1-3)

[Wherein X ₂ represents an oxygen atom or CH 2, and R ² is the same as defined above]

 (Step 6) This step is a method for producing the compound (7-2) by removing the Boc group of the compound (7) using TFA (trifluoroacetic acid).

 Compound (7) can be produced by the same method as in step 1 or 2, a method analogous thereto, or a combination of these with a conventional method.

The reaction in this step is carried out according to a method described in the literature (for example, Protecti V e Gr ou psin Organic Synthesis, TW G reen, 2nd edition, John Wile y & S ons, 1991, etc.), a method according to this method, or a combination of these and conventional methods. The compound (7-2) thus obtained can be obtained by known separation and purification means such as concentration, concentration under reduced pressure, It can be isolated and purified by solvent extraction, solvent extraction, reprecipitation, chromatography, etc., or can be subjected to the next step without isolation and purification.

 (Step 7) This step is a method for producing the compound (1-3) according to the present invention by reacting the compound (7-2) obtained in the step 6 with the compound (3). .

 Specific examples of the compound (3) to be used and the amount of the compound (3) to be used are the same as in Step 2 above. The reaction in this step may be performed in the presence of a base.

 Examples of the base to be used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylenoreaniline, 1,8-diazabixic mouth [ 5. 4. 0] Wunde force 1—7-Yen (DBU), 1, 5-azabicyclo [4. 3. 0] Nona _5—Yen (DBN) and other tertiary aliphatic amines; for example, pyridine, 4— Examples thereof include aromatic amines such as dimethylolaminopyridine, picoline, lutidine, quinoline and isoquinoline, and among these, pyridine and triethylamine are preferable.

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include chloroform, chlorohimethylene, pyridine, acetonitrile, THF, jetyl ether, DMF, NMP, dioxane, toluene, benzene, and xylene. Of these, black mouth form is preferred.

 The reaction temperature is usually from 78 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

 The reaction time is usually 30 minutes to 48 hours, preferably 6 hours to 24 hours.

 The compound (1-3) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

 The compound (1-4) according to the present invention can be produced, for example, by the following method.

 (1-4)

[Wherein R ³ represents a linear or branched alkyl group having 1 to 7 carbon atoms. ]

 (Step 8) This step is a method for producing a compound (8-2) by reacting the compound (8) with triphenylphosphine in the presence of a base and then treating with a base.

 The amount of triphenylphosphine used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (8).

The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, black mouth form, salty methylene, acetonitrile, and ethanol 4 ^, THF, DMF, NMP, dioxane, tonoleene, Examples thereof include benzene and xylene, and among these, toluene is preferable.

 The reaction temperature is usually 50 ° C to 150 ° C, preferably 80 ° C to 120 ° C.

The reaction time is usually 1 hour to 24 hours, preferably 2 hours to 4 hours. The compound thus obtained is isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or treated with a base without isolation and purification. To do. Examples of the base used in this step include aqueous solutions of sodium hydroxide, hydroxide power, hydrogen carbonate power, sodium carbonate, and the like.

 The amount of the base used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (8).

The compound (8-2) thus obtained can be isolated or purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.

 (Step 9) This step is a method for producing the compound (1-4) according to the present invention by reacting the compound (8-2) obtained in the step 8 with the compound (9). .

 The amount of the compound (9) used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (8-2).

 Examples of the compound (9) to be used include pivalaldehyde, cyclohexanecarbaldehyde, cyclopentanecarbaldehyde, 1-methylcyclohexanecarbaldehyde, 1-methinocyclic mouth pentanecarbaldehyde and the like. Of these, pivalaldehyde, 1-methylcyclohexane aldehyde, 1-methylcyclopentanecarbaldehyde, etc. are preferred.

 The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include chlorohonolem, salt methylene, pyridine, acetonitrile, THF, methanolol, ethanol, DMF, toluene, benzene, and xylene. Of these, THF is preferred.

 The reaction temperature is generally 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

 The reaction time is usually 1 hour to 48 hours, preferably 5 hours to 20 hours.

The compound (26) thus obtained can be isolated or purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. it can. The piperazine compound according to the present invention can exist as a pharmaceutically acceptable salt, and the salt includes the above (1), (1-1), (1-2), (I_3) Or it can manufacture in accordance with a conventional method using the compound represented by (I-4).

 Examples of the acid addition salt include hydrohalides such as hydrochloride, hydrofluoride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate, Inorganic acid salts such as carbonates; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; aryl sulfonic acids such as benzene sulfonate and p-toluene sulfonate Salts: Organic acid salts such as fumarate, succinate, tamate, tartrate, oxalate and maleate; and acid addition salts which are organic acids such as amino acids such as glutamate and aspartate Can be mentioned.

 In addition, when the compound of the present invention has an acidic group in the group, for example, when it has a carboxyl group or the like, the corresponding pharmaceutical agent can also be obtained by treating the compound with a base. Can be converted to an acceptable salt. Examples of the base addition salt include, for example, alkaline metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, ammonium salts, guanidine, triethylamine, and dioxy hexylamine. Salt.

Furthermore, the compounds of the present invention may exist as any hydrate or solvate of the free ichthy compound or its salt. Les

 Conversely, conversion from a salt or ester to a free compound can also be performed according to a conventional method.

 In addition, the compound according to the present invention may have a stereoisomer or a tautomer such as an optical isomer, a diastereoisomer, a multiple isomer, or the like depending on the mode of the substituent. Needless to say, all of these isomers are included in the compounds of the present invention. Furthermore, it goes without saying that any mixture of these isomers is also included in the compounds according to the present invention.

The compound according to the present invention, the aromatic hydrogen in the compound tritium, a methyl group in _{^{3 H 3 C, 1 4 CH}} 3, 1 1 CH 3, fluorine in ^{1 8} F, carbo - Le group It can also be used as a radiolabel by converting the carbon of isotopes such as ¹¹ C.

 The usefulness of the compound represented by the formula (1), (I-1), (I_2), (I-3) or (1-4) as a pharmaceutical is proved in the following test examples, for example. .

 mG 1 uR 1 inhibitory action

 Using the compounds described in Example 4, Example 18, Example 20 and Example 27 according to the present invention, mG 1 u R 1 inhibitory action was measured.

 Using LI POFECTAM I NE (manufactured by GibeBRL), cDNA of human metabotropic glutamate receptor 1 a (mG 1 uR 1 a) was transfected into CHO cells, and mG 1 uR 1 a A stable expression strain was obtained. CHO cells expressing mG 1 uRla are 10% dialyzed fetal bovine serum, 1% proline, 100 un its / ml penicil 1 in ^ 0. lmg / ml strept omy cinsulfate, 2 mM glutamine in DMEM medium In culture.

 (Measurement of intracellular calcium concentration)

 On the day before the measurement, 96 μl Black Plate (Packard, V i ewP late) mG 1 uR 1 a-expressing CHO cells plated at 50 000 cells per well, 4 μΜ Fluo-3 in the CO 2 incubator Incubated for 1 hour. Next, the cells were washed 4 times with HB SS solution containing 2 OmM HEPES and 2.5 mM Probenecid, and then the intracellular calcium was measured using Flourescence Imaging Rapid Reader (FLIPR, Molecular Devices). Concentration was measured. The test compound and glutamic acid were prepared using an HBSS solution containing 20 mM HEPES and 2.5 mM Probenecide. The test compound was added 5 minutes before the agonist stimulation, and 10 / M glutamic acid was used as the agonist.

 As a result of the above test, the compounds described in Example 4, Example 18, Example 20 and Example 27 with respect to mG 1 uR 1 were not observed to have agonist properties up to 10 / zM. In addition, the calcium increase that was increased by 10 / xM glutamic acid was suppressed in a dose-dependent manner, and its I C 50 value is shown in Table 1 below.

 (table 1)

 Pharmacological test example

Inhibitory effects of compounds on behavioral activity in mice increased by methamphetamine Using a male ICR (CD-I) mouse (20—40 g), the amount of activity was measured using a behavior amount measuring apparatus (manufactured by Neuroscience) that senses animal movement with an infrared sensor. A compound or an appropriate solvent was administered to mice, and the amount of behavior was measured for 60 minutes immediately after administration of physiological saline or methamphetamine 30 minutes later. During the measurement period, the difference between the behavior amount of the methamphetamine administration group and the behavior amount of the solvent administration group was defined as 100%, and the evaluation was expressed by% inhibition of the behavior amount of the test compound group. The amount of behavior during 60 minutes after administration was significantly increased by subcutaneous administration of methamphetamine (2 mg / kg). The increase in the amount of behavior due to methamphetamine was clearly suppressed by the intraperitoneal administration of the compound (3 O mg / kg) having a harmful effect of m G 1 u R 1 PI according to the present invention 30 minutes before methamphetamine administration. . The results are shown in Table 2.

 From the above results, it was found that the present compound shows a strong antagonistic action against methamphetamine. The compound according to the present invention has an mG 1 u R 1 inhibitory action. Here, the “mG lu R l inhibitory action” may be any substance that inhibits the function of m G 1 u R 1, for example, MG 1 u R 1 antagonistic activity and non-antagonistic mG 1 u R 1 receptor antagonistic activity.

 The compound represented by the general formula (I) can be administered orally or parenterally, and by formulating it into a form suitable for such administration, convulsions, acute pain, inflammation using the same Sexual pain, chronic pain, cerebral infarction or transient cerebral ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence, treatment and Z or preventive for Parkinson's disease.

 When the compound of the present invention is used clinically, it can be administered after various preparations by adding pharmaceutically acceptable additives according to the administration form. Various additives that are usually used in the pharmaceutical field can be used as additives in such cases. For example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch , Microcrystalline wax, white petrolatum, magnesium anolemate metasilicate, anhydrous calcium phosphate, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hard Castor oil, Polybulol pyrrolidone, Magnesium stearate, Light anhydrous key acid, Talc, Vegetable oil, Benzylanolate Λ ^, Gum arabic, Propylene glycol Lumpur, poly Anore sharp ring Ricoh Honoré, consequent b dextrin or hydroxycarboxylic cyclodextrin and the like.

 Examples of dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field. Liquid preparations may be dissolved or suspended in water or other suitable medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or puddle sugar solution as necessary, and buffering agents and preservatives may be added.

 These preparations can contain the compound of the present invention in an amount of 1.0 to 100% by weight, preferably 1.0 to 60% by weight. These preparations may also contain other therapeutically effective compounds.

The compounds of the present invention can be used in combination with other agents useful for the treatment of metabolic disorders and eating disorders. The individual components of such a combination are divided at different times or simultaneously during the treatment period. Or can be administered in a single formulation. Thus, the present invention should be construed to include all simultaneous or different time administrations, and administration in the present invention should be construed as such.

 The compounds of the present invention can be used for convulsions, acute pain, inflammatory pain, chronic pain, cerebral infarction or transient ischemic attack, psychiatric disorders such as schizophrenia, anxiety, drug dependence, Parkinson's disease It can be used in combination with drugs that are effective for such purposes (hereinafter referred to as “combined drugs”). Such drugs can be administered simultaneously, separately or sequentially in the prevention or treatment of the disease. When the compound of the present invention is used simultaneously with one or more concomitant drugs, it can be a pharmaceutical composition in a single dosage form. However, in combination therapy, the composition containing the compound of the present invention and the concomitant drug may be administered to the administration subject in different packages, simultaneously, separately or sequentially. They may be administered at different times.

 The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. The administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such dosage forms include 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate preparation of the compound of the present invention and the concomitant drug. 3) Simultaneous administration of the two preparations obtained through the same route of administration, 3) The time difference of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug in the same administration route 4) Simultaneous administration of two kinds of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, 5) Separately administering the compound of the present invention and the concomitant drug Administration of two types of preparations obtained by formulation in different routes of administration (for example, the compound of the present invention; administration in the order of concomitant drugs, or administration in the reverse order) It is done. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, disease and the like.

 When the compound of the present invention is used, for example, in a clinical setting, the dose and frequency of administration vary depending on the sex, age, body weight, symptom of the patient, and the type and range of the intended treatment effect, but generally administered orally. In the case of adult, per day, 0.01 ~: L 0 O mg Z kg, preferably 0.03 ~: 1 mg Z kg can be divided into 1 ~ several times, or in the case of parenteral administration 0.001 to 1 O mg / kg, preferably 0.0 1 to 0.1 mg / kg is preferably administered in 1 to several divided doses.

 (Example)

The ability to explain the present invention more specifically with reference to the following formulation examples, examples and reference examples The present invention is not limited by these.

Formulation Example 1

The compound of Example 1 (10 parts), heavy magnesium oxide (15 parts) and lactose (75 parts) are uniformly mixed to obtain a powdery or finely divided powder of 3500 μm or less. This powder is put into a capsule container to make a force push agent. Formulation Example 2

After uniformly mixing 5 parts of the compound of Example 1, 5 parts of starch, 6 parts of lactose, 1 part of crystalline cellulose, 1 part of crystalline cellulose, 3 parts of polybutyl alcohol and 30 parts of distilled water, the mixture was crushed and granulated. Then dry! Sieve with /, to obtain granules with a diameter of 1 4 10 0 to 1 7 7 μπι.

Formulation Example 3

A granule is prepared in the same manner as in Formulation Example 2, and then 3 parts of calcium stearate is added to 96 parts of this granule, followed by compression molding to produce a tablet having a diameter of 1 O mm. Formulation Example 4

To 90 parts of the granules obtained by the method of Formulation Example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate are added and compression-molded to form tablets with a diameter of 8 mm. A sugar-coated tablet is prepared by adding a mixed suspension of basic carbonated lucium.

For the silica gel column chromatography of the examples, Wako Pure Chemical Industries, Ltd. Wakoge 1 (registered trademark) C-300 or Biotage KP-Si 1 (registered trademark) S i 1 ica prepacked column was used. For the preparative thin-layer chromatography, Kieselgel ^™ 60F _{25 4 J} Art. 57 44 manufactured by Merck & Co. was used. Basic silica gel column chromatography is manufactured by Fuji Silicon Chemical Co., Ltd.

0 rex (registered trademark) NH (100-250me sh or 200-35 Ome sh) was used. ¹ H—NMR is from V arian G emini (20 OMH z, 30 OMH ζ) _Λ Mercury (4

00 MHz), In ova (40 OMH z), and tetramethylsilane as a standard substance. Mass spectra were measured by electrospray ionization (ES I) or atmospheric pressure chemical ionization (APC I) using micromass ZQ manufactured by Watters.

 The meanings of the abbreviations in the following examples are shown below.

 i—B u: isoptyl group

n-Bu: n-Putinole group

t -B u: t e r t—Putinole group

 B o c: t e r t-ptoxycanoleponinole group

 M e: methyl group

E t: Ethyl group

 P h: Phenyl group

 1 Pr: Isopropyl group

n-P r: n-propyl group

CDC 13: Heavy black mouth Holm

CD ₃ OD: Heavy methanol

DMSO-d ₆ : Heavy dimethyl sulfoxide

The meanings of the abbreviations in the nuclear magnetic resonance spectrum are shown below.

 S: Singlet

d: Doublet

d d: Dub Nore doublet

d t: Double triplet

d d d: Dub Nore Dub Nore Doublet

 S e p t: Septet

t: Triplet

m: Manolet plate

b r: Broad

b rs: Broadsync 'let

q: Quartet

J: Coupling constant H z: Hertz

Example 1

4-di-Neopentyloxycarbonyl piperazine

185 mg of anhydrous piperazine was dissolved in 3 ml of pyridine, and 0.60 ml of neopentyl black formate was prepared and stirred at room temperature for 2 hours. The reaction mixture was diluted with jetyl ether, washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 60 mg of the title compound as a colorless solid.

¹ HNMR (300 MHz, CDC 1 ₃ ) δ: 0.95 (18 H, s), 3. 49 (8H, s), 3. 81 (4H, s)

Example 2

 1—t e r t—Butoxycarbolulu 4 1 (2, 2, 2—Trichloroethoxycarbonyl) 1 Piperazine

 1 1 Boc-piperazine 4 Omg was dissolved in 1 ml of pyridine, and 0.02 ml of 2,2,2-trichloroethyl chloroformate was added and stirred at room temperature for 3 hours. The reaction mixture was diluted with Jetylether, washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 62 mg of the title compound as a colorless solid.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 1. 47 (9 Η, s), 3. 40—3.60 (8H, m). 4.76 (2H,. S)

Example 3

1—t e r t—Ptoxycarbonyl 4 1— (2 1 methylpropyloxycarbonyl) _-piperazine

The title compound was obtained as a colorless solid in the same manner as in Example 2, except that 2,2,2,2-trichlorodiethyl chloroformate was replaced with isoptyl chloroformate.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 0.93 (6 H, d, J = 6.4 Hz), 1. 46 (9 H, s), 1. 90- 1.98 (1 H, m) , 3. 30— 3. 50 (8H, m), 3. 87 (2H, d, J = 6.8H z) Example 4

 t e r t-Butoxycarboninole 1-Phenoxycarbonyl loopiperazine

The title compound was obtained as a colorless solid in the same manner as in Example 2 except that phenyl chloroformate was used in place of 2,2,2-trichlorodiethyl chloroformate.

¹ HNMR (40 OMH z, CDC 1 ₃ ) δ: 1. 48 (9 Η, s), 3. 40- 3. 70 (8H, m), 7. 05-7. 38 (5 H, m)

Example 5

 1 1 t e r t 1 Butoxycarbonyl 1 4-pentyloxycarbonyl-piperazine

The title compound was obtained as a colorless solid in the same manner as in Example 2 except that n-pentyl chloroformate was used in place of 2,2,2-trichlorodiethyl chloroformate.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 0.91 (3Η, t, J = 6.4 Hz), 1. 46 (9 H, d, J = 0.8 Hz), 1. 25— 1. 75 ( 6 H, m), 3.40 (4H, brs), 3.42

(4H, b r s), 4.08 (2H, t, J = 6.4H z)

Example 6

1-t er t 1-Butoxycarbonyl 1 4-Cicylpentylmethyloxycarbolupiperazine

シクロペンタンメタノール 20 Omgをクロ口ホルム 2m 1に溶解し、 CD I 33 Omgを加え、室 温にて 6時間攪拌した。反応液をクロ口ホルムで希釈し、飽和食塩水で洗浄後、無水硫酸マグネシゥ ムで乾燥した。 溶媒を減圧留去し、残渣をァセトニトリル 4m 1で溶解し、 ョウイ匕メチル 500 1 を加え、 室温にて 3時間攪拌した。 反応液の溶媒を減圧留去した後、残渣をクロ口ホルム 4mlで溶 解し、 1 _B o c—ピぺラジン 19 Omg、 トリェチルァミン 420 /ι 1を加え、室温にて 2時間攪 拌した。 反応液をクロ口ホルムで希釈し、 飽和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥した。 溶媒を減圧留去後、 残渣をシリ力ゲルク口マトグラフィー （クロ口ホルム/メタノ一ル= 10/1) で精製し、 表題化合物 95 m gを無色固体として得た。

Cyclopentanemethanol 20 Omg was dissolved in black mouth form 2 ml, CD I 33 Omg was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in acetonitrile 4 ml 1, added with methyl methyl 500 1 and stirred at room temperature for 3 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was dissolved in 4 ml of black form, 1_Boc-piperazine 19 Omg and triethylamine 420 / ι 1 were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (black mouth / methanol = 10/1) to obtain 95 mg of the title compound as a colorless solid.

¹ HNMR (40 OMHz, CDC 1 ₃ ) 6: 1.20—1.80 (8 H, m), 1.46 (9H, s), 2. 16— 1. 24 (1 H, m), 3. 34 (4H, brs), 3. 42 (4H, brs), 3. 97 (2H, d, J = 6.8 H z )

Example 7

 1-tert tertoxycarbonyl — 4-cyclohexylmethyloxycarbonyl piperazine

The title compound was obtained as a colorless solid by the same method as in Example 6 using hexane hexanemethanol instead of cycline pentanemethanol.

¹ HNMR (400MHz, CDC 1 ₃ ) δ: 0.85— 1. 05 (2Η, m), 1. 05— 1. 3 5 (4H, m), 1. 46 (9 H, s), 1. 50— 1. 80 (5H, m), 3. 41 (4H, brs), 3. 42 (4H, brs), 3. 89 (2H, d, J = 6.4H z)

Example 8

 1—t e r t—Ptoxycarbonyl 4-ru (1-methylcycloxypropylmethyloxycarbonyl) -piperazine

The title compound was obtained as a colorless solid in the same manner as in Example 6 except that 1-methylcyclopropanemethanol was used instead of the cyclopentanemethanol.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 0.33— 0.38 (2H, m), 0.45— 0.5 0 (2H, m), 1. 1 2 (3H, s), 1. 46 (9 H, s), 3. 35-3. 50 (8H, m), 3. 88 (2H, s)

Example 9

 1-ter t-toxycarbonyl-4-neopentyloxycarbonylbiperazine

The title compound was obtained as a colorless solid in the same manner as in Example 2, except that neopentyl chloroformate was used instead of 2,2,2-trichlorodiethyl chloroformate.

¹ HNMR (200 MHz, CDC 1 ₃ ) δ: 0.95 (9Η, s), 1.47 (9H, s), 3.39 -3.50 (8H, m), 3.80 (2H, s) Example 10

 1-(Ethoxycarboninole) 1 4- (Neopentyloxycarbonyl) Piperazine

 1) 1-(Neopentyloxycarbonyl) piperazine trifluoroacetate production

1- (tert-top, toxicanoreponinole) -4--(neopentyloxycarbonyl) piperazine obtained in Example 9 was added to 5 .42 g of trifluoroacetic acid 10 ml, and then at room temperature for 30 minutes. Stir. Excess trifluoroacetic acid was distilled off under reduced pressure to obtain 4.48 g of the title compound as a colorless solid.

 2) 1-(Ethoxycarbonyl) 1 4 1 (Neopentyloxycarbonyl) Piperazine

 To 167 mg of 1- (neopentyloxycarbonyl) piperazine trifluoroacetate was added 2 ml of pyridine and 50 μ1 of ketyl formate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with Jettier®, washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 88 mg of the title compound as a colorless solid.

¹ HNMR (300 MHz, CDC 1 ₃ ) δ: 0.95 (9 h, s), 1. 27 (3 h, t, j = 7.1 hz), 3. 48 (4 h, s), 3. 80 (2 h, s), 4. 16 (2 h, q, J = 7.1 hz) ESI—MS Found: m / z 273.2 [M + H] +

Example 11

 1-t er t 1-butoxycarbonyl 1- (1-methyl hexylmethyloxycarbonyl) 1

The title compound was obtained as a colorless solid in the same manner as in Example 6 except that 1-methylcyclohexane hexane methanol (Tetra rhedron Lett rs, 2000, 41, 2945) was used in place of the cyclopentane methanol.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 0.94 (3Η, s), 1. 13— 1. 70 (10 H, m), 1. 46 (9H, s), 3. 35-3. 55 (8 H, m), 3. 85 (2H, s)

Example 12

1— tert-butoxycarbolulu 4— (1, 2, 2-trimethylpropyloxycarbonyl) 1 piperazine

The title compound was obtained as a colorless solid in the same manner as in Example 6 except that 33-dimethyl-1,2-ptanol was used instead of cyclopentanemethanol.

¹ HNMR (40 OMHz CDC 1 ₃ ) δ 0.91 (9Η, d, J = 1.2 Hz 1.16 (3 H, dd, J = 0.8, 6. 4 Hz), 1.46 (9H, d , J = 1. 8 H z), 3. 41 (4H, brs), 3. 43 (4H, brs 4. 54-4. 63 (1H, m)

Example 13

 One neopentyloxycarbonyl 4- (1._ 2.one 2-trimethylpropyloxycarbonyl) -piperazine

 1-B 0 c-piperazine 1 1 (neopentyloxycarbonyl) piperazine trifluoroacetate obtained in Example 10 was used, and the title compound was obtained as a colorless solid in the same manner as in Example 12. Got as.

¹ HNMR (400MHz CDC 1 ₃ ) δ 0.91 (9 Η, s), 0.95 (9H, s), 1.16 (3 H, d, J = 6. OH z), 3.47 (8H , s), 3. 79 (2H, s), 4. 55-4. 62 (1 H, m)

Example 14

 1 1 t e r t-Ptoxycarbonyl 1 4— (4-Methyl-tetrahydropyran 1 4-ylmethyloxycarbonyl) -piperazine

The title compound was obtained as a colorless solid in the same manner as in Example 6 except that (4-methyltetrahydropyran-1-yl) methanol (W 02003022801) was used instead of cyclopentanemethanol. ¹ HNMR (400MHz CDC 1 ₃ ) δ 1. 06 (3Η, s), 1. 28— 1. 36 (2H, m), 1. 47 (9H, s), 1. 45- 1. 66 (2H, m), 3.42 (4H, brs), 3.44 (4H brs), 3.58-3.76 (4H, m), 3.90 (2H, s) Example 1 5

 1-Neopentyloxycarbonyl 4 2-Trifunoleolone 1,1-Dimethylethyloxycarboxyl) —Piperazine

 The title compound was obtained as a colorless solid in the same manner as in Example 13, except that 2-trifluoromethyl-1,2-propanol was used instead of 3,3-1dimethyl-1,2-butanol.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 0.95 (9 Η, s), 1. 6 9 (6 H, s), 3. 44 (4H, brs), 3. 47 (4H, brs) , 3. 79 (2H, s)

 E S I -MS Fo und: m / z 355.2 [M + H] +

Example 1 6

 1-t er t-toxycarbonyl 4-ru (1 methinoresic pentylmethyloxycarbonyl)-

シクロペンタンメタノールの代わりに文献記載の方法 （ジャーナル ォブ アメリカン ケミカル ソサイエティー （ J. A. C. S.)、 2002年、 第 1 24巻、 1 2106頁） に準じて製造した 1 —メチルシクロペンタンメタノールを用い、実施例 6と同様の方法により表題化合物を無色固体とし て得た。

Example 6 using 1-methylcyclopentanemethanol prepared according to the method described in the literature instead of cyclopentanemethanol (Journal of American Chemical Society (JACS), 2002, Vol. 1, 24, 1 2106) The title compound was obtained as a colorless solid by the same method as described above.

¹ HNMR (40 OMH z, CDC 1 ₃ ) δ: 1. 02 (3 Η, s), 1. 30— 1. 75 (8 H, m), 1. 46 (9H, s), 3. 41 ( 4H, brs), 3.43 (4H, brs), 3.87 (2H, s)

 E S I MS F o und: m / z 271.3 [M—t B u + H] +, 22 7. 3 [M—B o c + H] +

Example 1 7

1-tert-Putoxycarbonyl-4- (5-methyl-1- [1,3] dioxane-5-ylmethyloxycarbonyl) —piperazine '

The title compound was obtained as a colorless solid in the same manner as in Example 6 except that 5-hydroxymethyl-5-methyl-1,3-dioxane was used in place of the cyclopentanemethanol.

¹ HNMR (400 MHz, CDC 1 ₃ ) δ: 0.87 (3 Η, s), 1. 47 (9H, s), 3. 35-3.50 (1 OH, m), 3. 8 1 ( 2H, d, J = 1 1.2H z), 4.22 (2H, s), 4.68 (1 H, d, J = 5. 6 H z), 4.93 (1H, d, J = 6.OH z)

Example 1 8

 1-sopropyloxycarbonyl—4 neopentyloxycarbonyl loopiperazine

The title compound was obtained as a colorless solid by the same method as in Example 10 using isopropyl ethyl formate instead of ethyl ethyl formate.

1 HNMR (300 MHz, CDC 1 ₃ ) δ: 0.95 (9 Η, s), 1.25 (6H, d, J = 6.0 Hz), 3. 47 (8 H, s), 3.80 ( 2H, s), 4.94 (1H, hep, J = 6.0 Hz) ESI MS Found: m / z 287.2 [M + H] +

Example 1 9 ^:

 -(2-Hydroxymethyl-2-propoxycarbonyl) 1-Neopentyloxycarbonyl piperazine

 1) 1-(2-Benzyloxymethyl-1,2-propoxycarbonyl) —4, (tert-butoxycarbonyl) Piperazine

Methods described in the literature instead of sucrose pentane methanol (for example, journals

Op American Chemicanor Society (J.A.C.S.), 1992, 1 1 4th, 177

The title compound was obtained as a colorless solid in the same manner as in Example 6 using 2-benzyloxymethyl 1-2_propanol produced according to

2) 1 1 (2-Benzyloxymethyl-2-propoxycarbonyl) —4— (Neopentyloxycarbonyl) _Preparation of piperazine 1 1 (2-Benzyloxymethyl-2-propoxycarbonyl) 1 1 1 (tert-butoxycarbonyl) Piperazine (439 mg) was added with 1 Oml of formic acid and stirred at room temperature for 5 hours. Excess formic acid was distilled off under reduced pressure, ethyl acetate was added to the residue, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in 1 ml of pyridine, neopentyl chloroformate 180 M 1 was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by thin layer gel chromatography (hexane Z ethyl acetate = 7/3) to obtain 148 mg of the title compound as a colorless solid.

 3) 1-(2-Hydroxymethyl-2-propoxycarbonyl) —4— (Neopentyloxycarbonyl) Piperazine

 1— (2-Benzyloxymethyl— 2-propoxycarbonyl) —4— (Neopentyloxycarbonyl) Piperazine 148 mg was dissolved in a mixture of methanol 5 m 1 and ethyl acetate 5 m 1 to prepare a catalyst. An amount of palladium hydroxide-carbon was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The reaction solution was filtered and the solvent was distilled off under reduced pressure. The residue was purified by thin layer silica gel chromatography (hexane / ethyl acetate = 1/1) to obtain 52 mg of the title compound as a colorless solid.

¹ HNMR (300MHz, CDC ") δ: 0.95 (9Η, s), 1.41 (6H, s), 3.47 (8H, brs), 3.67 (2H, s), 3.81 (2H, s)

E S I MS F o un d: m / z 339.2 [M + H] +

Example 20

1—Adamantane Renolulu 4 1 t e r t—Butoxycarbolupiperazine

1-Boc-piperazine (1.20 g) was dissolved in pyridine (10 ml), 1-adamantanecarbonyl chloride (1.53 g) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with jetyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 4/1) to obtain 1.58 g of the title compound as a colorless solid. ¹ HNMR (30 OMH z, CDC 1 ₃ ) δ: 1. 47 (9 Η, s), 1. 73 (6 H, brs), 1. 99 (6H, brs), 2. 05 (3H, brs) , 3. 39- 3. 43 (4H, m), 3. 64-3. 67 (4H, m)

 AP c I Foun d: m / z 349. 3 [M + H] +

Example 21

1- (m-phenylbenzoyl) -4- tert-butoxycarboninolepiperazine

 1) 1 1 (m-Promobenzoyl) 1 4 1 (t e r t-Ptoxycarb) Manufacture of piperazine

1 Dissolve 982 mg of Boc-piperazine in 5 ml of pyridine, add 1.13 g of m-bromobenzoic acid and 1.18 g of 1-ethyl-3_ (3-dimethylaminopropyl) carbodiimide hydrochloride The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with jetyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl acetate = 4/1) to obtain 1.4 mg of the title compound as a colorless solid.

 2) 1 1 (m-phenylbenzoyl) 1 4 — (tert-butoxycarbonyl) 1 Piperazine production 1 1 (m-bromobenzoyl) 1 4 — (tert-butoxycarbonyl) piperazine 408 mg di-dioxane 1 Om To this, 293 mg of phenylpolonic acid, tetrakis (triphenylphosphine) paradium (0) 32 Omg and 912 mg of potassium carbonate were added and heated to reflux for 1 hour. The reaction mixture was diluted with Jetylether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane Z ethyl acetate = 7/3) to obtain 25 mg of the title compound as a colorless solid.

¹ HNMR (30 OMHz, CDC 1 ₃ ) δ: 1. 47 (9Η, s), 3. 39— 3. 82 (8H, m), 7. 35— 7.68 (9 H, m)

 E S I—MS Foundation: m / z 367. 3 [M + H] +

Example 22

 1—Successed Pentylecetyl Force Rubonir 4—ter t-Butoxycarbonyl Monopiperazine

1-Boc-piperazine (265mg) is dissolved in 2m1 of pyridine, 0.26-ml of 3-cyclopentylpropionic acid and 462mg of 1-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride are added, Stir at room temperature for 2 hours. The reaction mixture was diluted with jetyl ether, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane acetate = 7/3) to obtain 175 mg of the title compound as a colorless solid.

1 HNMR (300 MHz, CDC 1 ₃ ) δ: 1. 07— 1. 14 (2Η, m), 1. 47 (9H, s), 1. 50— 1. 81 (9 H, m), 2. 32 — 2. 37 (2H, m), 3. 38— 3. 44 (6 Η, · m), 3. 57-3. 61 (2H, m)

E SI I MS Found: m / z 31 1.4 [M + H] +

Example 23 1-nordamantyl carbolulu 4-tert-butoxycarboninolebiperazine

 The title compound was obtained as a colorless solid in the same manner as in Example 22 except that 3-noradamantancanolevonic acid was used in place of 3-sucral pentylbropionic acid.

¹ HNMR (300 MHz, CDC 1 ₃ ) δ: 1. 47 (9H, s), 1. 60—1.71 (4H, m), 1. 85-1.90 (4H, m), 2. 05- 2. 09 (2H, m), 2. 32 (2H, brs), 2. 74-2. 79 (1H, m), 3. 40—3.44 (4H, m), 3.56— 3. 60 (4H, m) ESI -MS Found: m / z 335.2 [M + H] +

Example 24

 1- (2, 2, 3, 3-Tetramethyl monocyclopropylcarbonyl) — 4— t er t-Butoxyboninolepiperazine

The title compound was obtained as a colorless solid in the same manner as in Example 22 except that tetramethylcyclopropanecarboxylic acid was used in place of 3-cyclopentylbropionic acid.

¹ HNMR (300 MHz, CDC 1 ₃ ) δ: 1.03 (1H, s), 1.16 (6 H, s), 1.18 (6 H, s), 1.47 (9H, s), 3 39— 3. 56 (8H, m)

E S I -MS Found: m / z 31 1.2 [M + H] +

Example 25

 1-hexoxylcarbonyl carbonyl 4-tert-butoxycarbolupiperazine

 The title compound was obtained as a colorless solid in the same manner as in Example 22 except that 3-cyclohexylbropionic acid was used instead of 3-cyclopentylbropionic acid.

¹ HNMR (300 MHz, CDC 1 ₃ ) δ: 0.89—0.97 (2Η, m), 1.16—1.29 (4H, m), 1.47 (9H, s), 1.51— 1. 73 (7H, m), 2. 31— 2. 36 (2 H, m), 3. 38- 3. 44 (6H, m), 3. 57-3. 60 (2H, m)

ES I -MS Fo und: m / z 325.2 [M + H] + Example 26

 1 (2, 2-Dimethylpropyl) Carbonyl 4 1 (2, 2-Dimethylpropyl) Oxycarboline Piperazine

1 (Neopentyloxycarbonyl) piperazine trifluoroacetate 19 6 mg obtained in Example 10 was dissolved in pyridine 2m 1, and 3, 3-dimethylbutyric acid 80 μ 1 and 1-ethyl 1 3- (3-Dimethylaminopropyl) Carbodiimide hydrochloride (143 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with jetyl ether, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by thin layer silica gel chromatography (hexane Z ethyl acetate = 7/3) to obtain 28 mg of the title compound as a colorless solid.

1 HNMR (300 MHz, CDC 1 ₃ ) 5: 0. 95 (9 H, s), 1. 06 (9H, s), 2. 28 (2 H, s), 3. 46-3. 51 (6 H , m), 3.62-3.66 (2H, m), 3.81 (2 H, s)

 E S I -MS Fo und: m / z 299. 2 [M + H] +

Example 27

1-Cyclohexylacryloylene 4-one tert-butoxycarbonyl loopiperazine

 1) 1 _Triphenylphosphoranilidenecarbonyl 4-ter butyl

Manufacture of cicarboni loopiperazine

The method described in the literature (Tetrahedrone (T e t a h e d r o n), 1998,

No. 54, page 3999) 1- (Promoacetyl) 1- (Tert-butoxycarbonyl) Piperazine 5.3 g of toluene in 4 Om 1? Then, 5.46 g of triphenylphosphine was added and heated under reflux for 2 hours. After cooling, the precipitate was collected by filtration and dried, and then 10 ml of THF and 3 Oml of 1N aqueous solution of sodium hydroxide and sodium hydroxide were added and stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.30 g of the title compound as a colorless solid.

2) 1-Hexylacryloyl 4-methyl ester-production of ptoxycarbolulupiperazine

1-triphenylphosphranylidenecarbonyl 4-l-tert-butoxycarbonyl loopiperazine 62 lmg was dissolved in THF 3 ml, cyclohexanecarbaldehyde was 265 mg, and the mixture was stirred at room temperature for 15 hours. After distilling off the reaction solution under reduced pressure, the residue was subjected to silica gel chromatography (hexane / ethyl acetate).

 33

1 The title compound 1 37 mg was obtained as a colorless solid.

¹ HNMR (30 OMH z CDC 1 ₃ ) δ 1. 1 1— 1. 79 (10, m), 1. 47 (9H, s), 2. 10-2. 19 (1 H, m), 3. 40- 3.65 (8H, m), 6.16 (1 H, d J = 15.2Hz), 6.86 (1 H, dd, J = 6. 8 and 15.2Hz)

E S I -MS Foun d m / z 323.2 [M + H] +

Example 28

 1 —— (4.— 4—Dimethyl-1-pentenoyl) 4-—t e r t—Butoxycarbonyl-piperazine

The title compound was obtained as a colorless solid in the same manner as in Example 27 except that pivalaldehyde was used in place of hexane carbaldehyde.

1 HNMR (200MHz CDC 1 ₃ ) δ 1.09 (9 Η, s), 1.48 (9H, s), 3.42-3.66 (8H, m), 6.10 (1H d, J = 1 5. 4H z), 6. 92 (1H d, J 1 5. 4H z)

 E S I -MS Foun d m / z 297. 4 [M + H] +

Example 29

 1- (3,3-Dimethylbutyl) carbonyl 1_t e r t-Butoxycarbolupiperazine

 3 4 4-Dimethylvaleric acid prepared according to the method described in the literature (for example, Tetrahedron, 1999, 55th page, 815 pages, etc.) instead of monocyclic pentylbropionic acid In the same manner as in Example 22, the title compound was obtained as a colorless solid.

¹ HNMR (300MHz CDC 1 ₃ ) δ 0.92 (9Η, s), 1. 47 (9H, s), 1. 51-1. 56 (2H, m), 2. 27-2. 33 (2H m ), 3. 40-3. 61 (8H, m) ESI -MS Foun dm / z 299.2 [M + H] +

Example 30

 1 (3 3-dimethylptyl) carbolulu 4 1 isopropyloxycarbolupiperazine

(3,, -3-Dimethylbutyl) Carbonyl monopiperazine Trifluoroacetate 1- (3,3-Dimethylbutyl) carbonoluene 41 obtained in Example 29 tert-Butoxycanolenyl pipiperazine 3. 1 ml of trifluoroacetic acid was added to 6.7 g and 1 g at room temperature. Stir for hours. Excess trifluoroacetic acid was distilled off under reduced pressure to obtain 5.71 g of the title compound as a colorless solid.

2) Manufacture of 1- (3,3-dimethylbutyl) carboru 4 monoisopropyloxy carbolupiperazine

 106 mg of 1- (3,3-dimethylptyl) carbonyl piperazine trifluoroacetate was dissolved in 2 ml of pyridine, and 42 μ1 of isopropyl acetate was added, followed by stirring at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by thin layer silica gel chromatography (hexane へ ethyl acetate = 2/1) to obtain 66 mg of the title compound as a colorless solid.

¹ HNMR (300 MHz, CDC 1 ₃ ) δ: 0.92 (9Η, s), 1. 26 (6H, d, J = 6.3 H z), 1. 5 1-1. 56 (2H, m) , 2. 27-2. 33 (2 H, m), 3. 41— 3. 6 0 (8 H, m), 4. 64 (1H, sept, J = 6.3 Hz)

E S I -MS F o n d: ./ z 28 5. 1 [M + H] +

Example 3 1

 1-(3, 3——Dimethylptyl) carboruyl 41 (2-Fluoroyl 1._ 1-dimethylethyl) oxycarbonyl-piperazine

 1) 1 1 (t e r t 1 Butoxycarbonyl) 4— (1 1 Fluoro 2-Methyl 1-propoxy power Luponyl) Preparation of piperazine

1 Monofluoro-2-methyl-2-propanol prepared by the method described in the literature (Journalo fMe dicina 1 Chemistry, 199 1, pp. 34, 29) was added to cyclopentanemethanol. Instead, the title compound was obtained as a colorless solid in the same manner as in Example 6.

 2) Preparation of 1- (3,3-dimethylbutyl) carbonyl-1- (2-fluoro-1,1-dimethylethyl) oxycarbonyl-piperazine

1- (tert-Butoxycarbonyl) 1-4- (1-Fluoro-2-methyl-2-propoxycarbonyl) piperazine 328 mg was added with 5 ml of formic acid and stirred at room temperature for 3 hours. Excess formic acid was distilled off under reduced pressure, ethyl acetate was added to the residue, washed with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in 2 ml of pyridine, and 146 mg of 4,4-dimethylvaleric acid and 22 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added at room temperature. For 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by thin layer silica gel chromatography (black mouth / methanol = 19/1) to obtain 20 mg of the title compound as a colorless solid. ¹ HNMR (300 MHz, CDC) δ: 0.92 (9 H, s), 1. 49 (6H, d, J = 1. 8 Hz), 1. 51-1. 57 (2H, m) '2. 27 -2. 32 (2H, m), 3. 40— 3. 60 (8H, m), 1 4. 48 (2H, d, J = 47.4 Hz)

 E S I One MS F o und: m / z 31 7. 1 [M + H] +

Example 32

 1-1 (2-Fluoro 1, 1-Dimethylethylcarbonyl) 1 4 1 Neopentylcarbolupipera

1- (tert-butoxycarbonyl) —4— (1-1fluoro-2-methyl-2-propoxycarbonyl) piperazine obtained in Example 31 was added to 286 mg of trifluoroacetic acid, and stirred at room temperature for 15 minutes. did. Excess trifluoroacetic acid was distilled off under reduced pressure, the residue was dissolved in pyridine 2m1, neopentyl chloroformate 1401 was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 1% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by thin layer silica gel chromatography (hexane へ ethyl acetate = 7/3) to obtain the title compound (64 mg) as a colorless solid.

1 HNMR (300 MHz, CDC 1 ₃ ) δ: 0.95 (9Η, s), 1. 49 (6H, d, J = 1. 7 Hz), 3. 42—3.47 (8H, m), 3. 80 (2H, s), 4. 48 (2H, d, J = 47.4 Hz)

 ES I— MS Foun d: m / z 319: '1 [M + H] + industrial applicability

 The compound according to the present invention or a pharmaceutically acceptable salt thereof has a potent mG 1 uR 1 inhibitory action, and not only convulsions and acute pain but also inflammatory pain, chronic pain, cerebral infarction or transient It is useful for the treatment and / or prevention of brain disorders such as cerebral ischemic attacks, mental dysfunction such as schizophrenia, anxiety, drug dependence, and diseases such as Z or Parkinson's disease.

Claims

1. Formula (I)

 (I) Or a pharmaceutically acceptable salt thereof, In the above formula, R ¹ represents a branched alkyl group having 3 to 9 carbon atoms, R ² represents the following (a :), (b), (c) or (d)  (a) a linear or branched alkyl group having 2 to 9 carbon atoms which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group, and a branched alkyl group In the case of a group, branched alkyl groups may be bonded to each other to form a cycloalkyl group, and the carbon atom constituting the cycloalkyl group is substituted with 1 or 2 oxygen atoms. May be)  (b) Alkenyl group,  (c) an aralkyl group or an aryl group which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, or  (d) a bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms; X represents an oxygen atom, CH ₂ or a single bond; However, an R ¹ force St _e rt - butyl group, R ² is 2 _ methylpropyl group, phenyl group, tert- butyl group, a benzyl group or a cyclohexyl group, and, when X is an oxygen atom R ¹ is a tert-butyl group, R ² is an adamantyl group, neopentyl group or cyclohexyl ethenyl group, and R ³ is a single bond) or a pharmaceutically acceptable product thereof salt. 2. R ¹ is a tert-butyl group, 2, 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a 2-dimethylpropyl group, an isopropyl group or a 3,3-dimethylbutyl group. 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group.  4. The compound according to claim 2, wherein X is an oxygen atom, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 2, wherein X is a single bond, or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R ² is a linear or branched alkyl group having 2 to 9 carbon atoms. 7. The compound or pharmaceutically acceptable salt thereof according to claim ² , wherein R ² is an alkenyl group. 8. The compound according to claim ² , wherein R ² is an aralkyl group, or a pharmaceutically acceptable salt thereof. 9. The compound or pharmaceutically acceptable salt thereof according to claim ² , wherein R ² is an aryl group.  10. The compound represented by formula (I) is  1,4—Gineopentyloxycarbonyl monopiperazine, 1 1 tert-Butoxycarbolulu 4— (2, 2, 2—Trichlorodiethoxycarbonyl) -piperazine, 1 1 tert-butoxycarbonyl 1 4 1 pentyloxycarbonyl 1-tert-butoxycarbonyl 1-tert-butoxycarbonyl 1-cyclohexylmethyloxycarbo 2-Lupiperazine-1 1 tert-Butoxycarbolulu 4— (1-Methylcycloxypropylmethyloxycarbonyl) 1-ter t-butoxycarbonyl_4-neopentyloxycarbonylbiperazine,  1 (Ethoxycarbonyl) 1 4- (Neopentyloxycarbonyl) Piperazine,  1-tert-butoxycarbonyl 4-ru (1-methylcyclohexenoremethyloxycarbonyl) 1- tert-butoxycarbolulu 4 (1, 2, 2-trimethylpropyloxycarbonyl) monopiperazine,  1 Neopentinoreoxy power Noreboninole 1 (1, 2, 2—Limethylpropyloxycarbonyl) 1 1—t e r t—butoxycanoleponinole 4 (4-methyl-tetrahydropyran-4-ylmethyloxycarbonyl) -piperazine,  1-Neopentyloxycarbonyl 4 (2,2,2-trifluoro-1,1-dimethyl-ethinoreoxycarbonyl) -piperazine,  1 1 t e r t-Butoxycarboninole 1 (1-methylcyclopentylmethyloxycarbonyl)- 1—ter t-butoxycarbonyl 4-ru (5-methyl-1- [1,3] dioxane-5-ylmethyloxycarbonyl) piperazine,  1-Isopropyloxycarbonyl 1-Neopentyloxycarbolupiperazine,  1 (2-Hydroxymethyl-2-propoxycarbonyl) 1 4 1 Neopentyloxycarbonyl 1 1 (m-Phenolevenzoinole) 1 4— tert-Butoxycanoleboninolebiperazine,  —Silph Mouth Pentyleyl Carbonyl Luo 41-terti-Butoxy Carbonyl Lupiperazine, Mono-Noradamantyl Carbonyl 4-N-r tert-Butoxy Carbonyl Lupiperazine,  1 (2, 2, 3, 3—tetramethyl-cyclopropylcarbonyl) 1 4 1 tert-butoxycarbonyl: Renault piperazine,  4-cyclohexylethylcarbonyl 1-tert-butoxycarbonylpiperazine,  (2, 2-dimethylpropyl) carbolulu 4 (2,2-dimethylpropyl) oxycarbolululuperazine,  1 1 (4,4-Dimethyl 1 2 -Pentenoyl) 1 4 1 tert _Butoxycarbolupiperazine, 1 1 (3,3-Dimethylptyl) Carbonyl 1 4-tert-Butoxycarbonyl 1 Piperazine, 1 1 (3, 3 —Dimethylbutyl) carbolulu 4-isopropyloxycarbolurpiperazine, 1- (3,3-dimethylbutyl) carbonyl 4- (2-funoleo 1,1-dimethylethyl) oxycarbonyl monopiperazine, or 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 1 (2-funoleo 1, 1, 1-dimethylethylcarbonyl) 1 4-neopentylcarbonyl piperazine. 1 1. Formula (I) R ² -X ヽ ~~ IO— R ¹  (I)  [Where R ¹ represents a branched alkyl group having 3 to 9 carbon atoms, R ² is  (a) a linear or branched alkyl group having 2 to 9 carbon atoms which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group (in the case of a branched alkyl group) The branched alkyl groups may be bonded to each other to form a cycloalkyl group, and the carbon atom constituting the cycloalkyl group is substituted with 1 or 2 oxygen atoms. Good),  (b) an alkenyl group,  (c) an aralkyl group or an aryl group which may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a hydroxy group, or  (d) a bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms, X represents an oxygen atom, CH ₂ or a single bond. ] MG 1 uR 1 antagost, which comprises a compound represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. 1 2. R ¹ is a tert-butyl group, a 2,2-dimethylpropyl group, an isopropyl group or a 3,3-dimethylbutyl group, wherein the compound or pharmaceutically acceptable salt thereof is an active ingredient And m G 1 uR 1 antagonist. ' 1 3. An mG 1 uR l antagonist comprising the compound according to claim 11 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ¹ is a tert-butyl group or a 2,2-dimethylpropyl group.  14. An mG 1 uRl antagonist comprising as an active ingredient the compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom.  1 5. An m G 1 uR 1 antagonist comprising, as an active ingredient, the compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein X is a single bond. 16. The mG 1 uR l antagonist comprising as an active ingredient the compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ² is a linear or branched alkyl group having 2 to 9 carbon atoms. 1 7. An mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ² is an alkenyl group. 18. An mG 1 uR 1 antagonist comprising the compound according to claim 11 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ² is an aralkyl group. 1 9. An mG 1 uR 1 antagonist comprising as an active ingredient the compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ² is an aryl group.  20. Formula (I) 1)  1,4-di-neopentyloxycarbolupiperazine, 1-tert-Butoxycanenolevonyl 4- (1-, 2-, 2-trichloroethoxycarbonyl) -pi Perazine,  1—ter t-butoxycarbonyl 4-(2-methylpropyloxycarbonyl) piperazine,  1-tert-butoxycarbonyl mono 4-phenoxycarbolupiperazine,  1-tert-butoxycarbonyl mono 4-pentyloxycarbolupiperazine,  1-tert-butoxycarbonyl mono 4-cyclopentylmethyloxycarbonylpiperazine, 1- tert-butoxycanolepononolei 4-cyclohexenoremethyloxycanonoleboninolebiperazi ert-butoxycarbonyl mono 4 _ (1-methylcyclopropylmethyloxycarbonyl

Piperazine,  1—t e r t—butoxycanole le boninore 4 1 neopenti / reoxycarbonino lepiperazine,  1— (Ethoxycarbonyl) 14-1 (Neopentyloxycarbonyl) Piperazine,  1-t er t-butoxycarbonyl 4-one (1-methylcyclohexylmethyloxyl) monopiperazine,,  1 _ t er t-Butoxycarbonyl 4- (1-, 2-, 2-trimethylpropyloxycarbonyl) -piperazine,  1-Neopentyloxycarbonyl 4- (1-, 2-, 2-trimethylpropyloxylphenyl) -piperazine,  i—te 1-t-butoxycarbonyl mono 4 -— (4-methyl monotetrahydropyran mono 4-ylmethyl oxylphenyl) -piperazine,  1-neopentyloxy force / reponyl 4- (2,2,2,2_trifluoro-1,1-dimethyl-ethyloxycarbonyl) monopiperazine,  1-tert-butoxycarbonyl mono 4 _ (1-methylcyclopentylmethyloxycarbonyl) monopiperazine,  1-tert-butoxycarbonyl 4- (5-methyl-1- [1,3] dioxane-1-5-methylmethoxycarbonyl) -piperazine,  1-sopropyloxycarbonyl _ 4 neopentyloxycarbonyl piperazine, 1— (2-hydroxymethyl-2-propoxycarbonyl) 1 4 _neopentyloxycarboxyl norepiperazine,  1—adamantane carbolulu 4-t e rt tbutoxy carbolupiperazine, 1— (m-phenylbenzi / le) 1 4 1 t e r t—butoxycarbolupiperazine, 1-succinyl pentylethyl carbonyl 4-41 t er t-butoxycarbonyl 1-piperazine, 1-noradamantyl carbonyl 1- 4-t er t tert-butoxycarbonyl 2-piperazine, 1 (2, 2, 3, 3 -tetramethyl monocyclopropylcarbonyl) — 4 1 t er t-butoxyboni ^ /-piperazine,  1-cyclohexylhexinorecanolbonyl 4-1 t e r t-butoxycarbonino lepiperazine, 1 (2, 2-dimethylpropyl) carbonyl 4-(2, 2-dimethylpropyl) oxyboninolebiperazine, 1-Hexinolecryloinole 1-tert-Butoxycarbolupiperazine,  1 1 (4, 4 1 dimethyl 2-pentenoyl) 1 4 1 t e t t 1 Butoxycarpino looppiperazine,  1- (3,3-dimethylbutyl) carbolulu 4-tert-butoxycarboluropiperazine, 1- (3,3-dimethylbutyl) carbonyl mono4-monoisopropyloxy lupo-lupiperazine, 1 _ (3 , 3-Dimethylbutyl) Carbolu 41 (2-Fluoro-1,1-dimethylethyl) oxycanoponi-piperazine, or  1- (2-Fonoleolo 1,1-dimethylethylcarbonyl) 14-neopentylcarbonyldipiperazine, m G 1 comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient u R 1 Antagost.  21. Convulsions, acute pain, inflammatory pain or chronic pain, cerebral infarction or transient, comprising as an active ingredient the compound according to any one of claims 11 to 20 or a pharmaceutically acceptable salt thereof A therapeutic and / or prophylactic agent for brain disorders such as spontaneous cerebral ischemic attacks, mental dysfunction such as schizophrenia, anxiety, drug dependence, and diseases such as Z or Parkinson's disease.