JP2002105085A - New imidazothiazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new imidazothiazole derivative and a medicine having metabotropic glutamate receptor (hereinafter referred to mGluR) actions and more particularly specifically acting on the mGluR1 and useful as a prophylactic and therapeutic agent for cerebral infarction. SOLUTION: This imidazothiazole derivative is represented by the following general formula (1) (wherein, R1 and R2 are each the same or different and H, a lower alkyl or a cycloalkyl; R3 is H or a lower alkyl; R4 and R5 are each the same or different and H, a halogen, nitro, a substitutable lower alkyl, a substitutable aryl, a substitutable heteroaryl, C(=O)-R9, an NH-C(=O)-O-lower alkyl or the like; and X is oxygen or H). The medicine comprises the imidazothiazole derivative as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel imidazothiazole derivative or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Glutamate acts as a neurotransmitter in the central nervous system of mammals (Mayer ML ann).
d Westbrook GL, Prog. Neurobiol., 28 (1987) 197-2
76). Recent studies have revealed the importance of glutamate in higher cranial nerve function. Glutamate is released from nerve terminals and regulates neuronal cell activity or neurotransmitter release via glutamate receptors located in the postsynaptic membrane or nerve terminals. Glutamate receptors are currently classified into two broad categories from various pharmacological and physiological studies. One is a built-in ion channel and the other is a metabotropic receptor (Hollmann M. and Heinemann
S., Annu. Rev. Neurosci., 17 (1994) 31-108). According to molecular biology studies, metabotropic glutamate receptors (hereinafter referred to as mGluR) have mGluR1 to mGluR1
It has been reported that there are eight different subtypes of GluR8. mGluR is mediated by phospholipase, inositol triphosphate (IP3),
Calcium and receptor signaling (mGluR1 and mGluR1
GluR5) and a receptor (mGluR2, mGluR3, mGluR2) that couples to Gi protein and suppresses cAMP production.
luR4, mGluR6, mGluR7 and mGluR
8). These receptors show different distributions in the brain. For example, mGluR6 does not exist in the brain but only on the retina, and it is presumed that each receptor plays a different physiological role ( Nakanishi
S., Neuron 13 (1995) 1031-1037).

[0003] So far, a compound selective for mGluR has been reported as compared with a glutamate receptor having a built-in ion channel (Hayashi Y. et al., Br. J. Pharmacol. 1
07 (1992) 539-543; Hayashi Y. et al., J. Neurosci. 1
4 (1995) 3370-3377), studies using these compounds have reported the association between mGluR and various disease states below. mGluR agonist (1S, 3R) -1-aminocyclopentane-1,3-dicarboxylic acid (hereinafter (1S,
3R) -ACPD) induces epilepsy (Tizzano JP et al., Neurosci. Lett., 1
62 (1993) 12-16; McDonald JW et al., J. Neurosc.
i., 13 (1993) 4445-4455). Furthermore, (S) -4-mGluR1 antagonists and mGluR2 agonists
The effectiveness of carboxy-3-hydroxyphenylglycine (hereinafter referred to as (S) -CHPG) in various epilepsy models has been reported (Dalby, NO & Thomsen, C. et al.
J. Pharmacol. Exp. Ther., 276 (1996) 516-522). Electrophysiological experiments have demonstrated that mGluR is involved in transmitting painful stimuli to spinal dorsal horn neurons (Young, MR et al., Neuropharmacology, 33 (1994)).
141-144; ibid, 34 (1995) 1033-1041). Furthermore, in rats, it has been reported that (S) -CHPG has an effect of delaying the avoidance response to thermal and mechanical pain stimuli (Young, MR et al., Br. J. Pharmacol., 114 (199).
5) 316P). (1S, 3R) -ACPD and (RS) 3,5-dihydroxyphenylglycine (hereinafter, referred to as 3,5-DHPG) are administered in minute amounts to the brain parenchyma of a mouse or rat, or when administered systemically, cause neuronal death with convulsions. Cause (Li
partit, M. et al., Life Sci., 52 (1993) PL85-90; McDo
nald, JW et al., J. Neurosci., 13 (1993) 4445-445
5; Tizzano, JP, et al., Neuropharmacology, 34 (1
995) 1063-3067). This is because mGluR1 and mGluR1
It is believed that this is due to the activation of R5. It is well known that chronic administration of benzodiazepines results in dependence. On days 2 and 3 after continuous administration of benzodiazepine for 7 days, (1S, 3R) -A
It has been reported that CPD mGluR-mediated turnover of inositol phospholipids is increased, suggesting that mGluR is involved in the development of benzodiazepine withdrawal syndrome (Mortensen, M. et al., J. Pharmaco
l. Exp. Ther., 274 (1995) 155-163).

That is, the above reports show that compounds acting on mGluR1 show epilepsy, pain, neurodegenerative diseases (cerebral insufficiency after heart bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord injury, head injury, Alzheimer's disease) , Huntington's chorea, amyotrophic lateral sclerosis, AIDS-induced dementia,
For perinatal hypoxia, cardiac arrest, hypoglycemic neuron damage, visual impairment and retinopathy, idiopathic and drug-induced Parkinson's disease), anxiety, stress disorders (benzodiazepine withdrawal syndrome, irritable bowel syndrome) Indicates that it is useful.
In addition, compounds that act on mGluR1 may cause seizures, migraine, urinary incontinence, mental illness, opiate tolerance and withdrawal symptoms, cocaine withdrawal symptoms, anxiety, vomiting, cerebral edema, chronic pain, and late onset due to impaired neurotransmission by glutamate. It is also considered useful for sexual dyskinesis. In addition, WO
In 99/44639, since the efficacy of an mGluR1 antagonist in a rat cerebral infarction model was confirmed, it is considered to be useful as a prophylactic / therapeutic agent for cerebral infarction. Examples of the imidazothiazole derivative include JP-A-2-178289.
And JP-A-2-306917 describe imidazo [2,1
-B] It has been shown that a compound having an acetyl group or an ethoxycarbonyl group at the 2-position of thiazole has an anti-ulcer effect and a brain function improving effect.
An imidazothiazole derivative having an azetidine carbonyl substituted at the 2-position is shown as a synthetic intermediate.
On the other hand, dihydroimidazo [2,1-b] thiazole derivatives are disclosed in US Pat.
No. 4985, EP200134 shows that a dihydroimidazothiazole derivative substituted at the 2-position with phenylalkylaminocarbonyl has an immunopotentiating effect,
J. Med. Chem., (1981), 24 (5), 604-609 states that an alkyl group, ethoxycarbonyl group,
A dihydroimidazothiazole derivative having a methylsulfonyl group or the like at the 3-position having an alkyl group or a phenyl group or a hexahydrothiazolobenzimidazole derivative having a methyl group at the 3-position is disclosed. However, neither of these documents discloses or suggests that the imidazothiazole derivative has a metabotropic glutamate receptor action. Conventionally, as a compound having a metabotropic glutamate receptor agonist, a compound having an amino acid or peptide structure (JP-A-7-267908)
), A compound having a thieno [2,3-b] indole structure (see WO95 / 25110), a cyclopropachromenecarboxylic acid derivative (see JP-A-8-169888), and a 3-vinylindole derivative (WO97 / 051).
09), pyridino [2,3-b] indole derivatives (see WO 97/05137), 2-amino-2-
Cyclobutylpropionic acid derivative (JP-A-10-120)
635), imidazobenzothiazole derivatives (WO98
No./06724), thiazolobenzimidazole derivatives (see WO 99/44639) and 1,2-oxazine derivatives (WO 00/26198).

[0005]

The above compounds and the like are known as drugs acting on metabotropic glutamate receptors, but compounds having more excellent metabotropic glutamate receptor action are desired. An object of the present invention is to provide an imidazothiazole derivative and a salt thereof, which have an excellent metabotropic glutamate receptor action and are a new basic skeleton, and further provide a drug containing these.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and have found that imidazothiazole derivatives have a strong activity on metabotropic glutamate receptors, thereby completing the present invention. Reached. That is, the present invention relates to a medicament containing a thiazolobenzimidal derivative represented by the following general formula (I) or a salt thereof as an active ingredient, and an agent acting on a metabotropic glutamate receptor.

[0007]

Embedded image (The symbols in the formula have the following meanings: R ¹ , R ² : the same or different, hydrogen, lower alkyl, or cycloalkyl R ³ : H, or lower alkyl R ⁴ , R ⁵ : the same or different , H, halogen, nitro,
Optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, -C (= O)
—R ⁹ , —NH—C (＝ O) —O-lower alkyl,

Embedded image Ring A: The ring may have one or two double bonds in the ring, a ring atom may be a carbon atom, or 1-3 carbon atoms may be a heteroatom, and a substituent may be present on the ring. Optionally substituted carbocycle or optionally substituted aromatic heterocycle R ⁶ , R ⁷ : same or different, H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted Good heteroaryl, -C (= O) -O-lower alkyl,
—C (＝ O) —R ⁹ , or may form an optionally substituted cycloalkyl or saturated heterocycle. R
^6a : ＮN (R ¹⁰ ) R ¹¹ R ⁸ : H or lower alkyl R ⁹ : H, OH, or saturated heterocycle R ¹⁰ , R ¹¹ : same or different H, lower alkyl which may be substituted or Together they may have other heteroatoms as ring atoms and may form an optionally substituted heteroaryl or saturated heterocycle. X: oxygen atom or H

Embedded image Here, the agonist or ligand is an antagonist (anta
gonist) and / or agonist.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by formula (I) will be further described as follows. In the definition of the general formula in this specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. "Lower alkyl" is C1-6 alkyl, preferably C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, t-butyl, and more preferably C1-3 alkyl. Preferred substituents of "optionally substituted lower alkyl" include aryl, saturated heterocycle, heteroaryl, halo, OH, -O-cycloalkyl, carboxyl, -C (= O) -O-NH2,- C
(= O) -O-lower alkyl or lower alkyl-O-
And amino which may be mono- or di-substituted with lower alkyl which may be substituted with. The "lower alkylene" is C1-6 alkylene, preferably C1-4 alkylene such as methylene, ethylene, propylene, isopropylene and t-butylene, more preferably C1-3 alkylene. “Aryl” is a 6 to 14 membered aromatic hydrocarbon ring group as a whole, including biphenyl. Preferably, they are phenyl, naphthyl, biphenyl and the like, which may have one or more substituents. “Cycloalkyl” means a 3- to 8-membered cycloalkyl, preferably cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which may have one or more substituents.

"Heteroaryl" is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom, or a 2-membered heteroaryl fused to a benzene ring or another heterocycle. A ring system heteroaryl, which includes pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, thiophene, thiopyran, furan, pyran, dioxolan, thiazole, isothiazole, thiadiazole, thiazine, oxazole , Isoxazole, oxadiazole, furazane, dioxazole, oxazine, oxadiazine, dioxazine, triazine, tetrazole and the like. Examples of the condensed heteroaryl include indole, isoindole, indazole, quinoline, quinazoline, quinoxaline, isoquinoline, benzimidazole, benzothiophene, benzothiazole, benzofuran, benzofurazan, imidazopyridine, imidazopyrazine, pyridopyridine, phthalazine, naphthyridine, indolizine, and purine. Quinolinidine, cinnoline, isocoumarin, chroman and the like. These may have one or more substituents.
"Saturated heterocycle" means a 3- to 8-membered saturated heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom, and includes pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine. , Oxirane, oxetane, tetrahydrofuran, tetrahydropyran,
[1,4] dioxane, tetrahydrothiophene,
[1,4] dithiane, hexahydroazepine and the like. "Halo" means a halogen atom, for example,
It means fluorine, chlorine, bromine and iodine atoms. In the ring A, "the ring may have one or two double bonds, any one to four carbon atoms in the ring may be substituted with another hetero atom, and a substituent on the ring "A 3- to 8-membered carbocycle which may have a ring" means, when the bond between the atom shared by the ring A and the imidazothiazole ring is a single bond, the ring shown in the above definition of cycloalkyl, and 3 When the bond between the shared atoms is a double bond, a 5- to 8-membered cycloalkene, which may have one double bond; Means an unsaturated heterocycle. 3-8
As the member-saturated heterocycle, the rings shown in the definition of the above-mentioned saturated heterocycle are meant. The cycloalkene means a ring having one or two double bonds at any position of the ring shown in the definition of cycloalkyl, and is preferably cycloheptene or cyclohexene. The 5-8 membered unsaturated hetero ring having one or two double bonds means a ring having one or two double bonds at any position of the ring shown in the definition of the saturated hetero ring. Pyridine, tetrahydroazepine and the like are preferred. "Aromatic heterocyclic ring which may be substituted" of ring A
Represents a ring shown in the definition of heteroaryl above.

The optionally substituted aryl, heteroaryl, saturated heterocycle, cycloalkyl or A ring may have 1 to 3 substituents on the ring. The substituent means a normal substituent commonly used in the art for the group to be substituted, but may be a lower alkyl optionally substituted with OH, OH, lower alkyl-O-CO-, lower alkyl-O-. , Lower alkyl-O-lower alkyl-, lower alkyl-O-lower alkyl-O-, lower alkyl-S
-, Lower alkyl-S (= O)-, lower alkyl-S
(O) _2- , lower alkyl-C (= O)-, lower alkyl-C (= O) -O-, lower alkyl-CO-NH-,
Halogeno lower alkyl, halogeno lower alkyl-O-,
Halogeno lower alkyl-O-lower alkyl-, substitutable cycloalkyl, substitutable cycloalkyl-lower alkyl-, halogen atom, cyano, NO2 _, NH2 _, oxo, carboxyl, lower alkyl may be substituted. Carbamoyl, a substituted mono- or di-lower alkyl-amino,
Lower alkyl-O-, one or two lower alkyl or lower alkyl-C (= O)-or lower alkyl-OC substituted with mono- or di-lower alkyl-amino;
Amino, amino-O optionally substituted with (= O)-
-, A sulfamoyl optionally substituted with one or two lower alkyls, a substituted aryl, a substituted aryl-lower alkyl, a substituted aryl-lower alkyl-O
-, Substitutable aryl-O-, substitutable aryl-S
-, Substituted aryl-CO-, substituted aryl-S
O-, optionally substituted aryl -SO ₂ -, optionally substituted, aryl -CO-NH-, optionally substituted, aryl -SO ₂ -NH-,
Substitutable heterocycle, substitutable heterocycle —O—, substitutable heterocycle —S—, substitutable heterocycle —CO—, substitutable heterocycle —SO—, substitutable heterocycle —SO ₂ —, Substitutable heterocycle—lower alkyl—, substitutable heterocycle—C
O-NH-, heterocyclic -SO ₂ -NH- substitutable, optionally substituted heterocyclic - lower alkyl -O-, optionally substituted heterocyclic - lower alkyl -CO-, an optionally substituted heterocyclic - lower alkyl - O-lower alkyl- and the like. Preferably, a halogen atom, lower alkyl, lower alkyl-O
-, Lower alkyl-C (= O)-, lower alkyl-O-
C (= O)-, lower alkyl-S-, lower alkyl-S
(= O)-, lower alkyl-S (O) _2- , lower alkyl-O-lower alkyl-O-, cyano, nitro, oxo (= O), substitutable mono- or di-lower alkyl-amino,
Lower alkyl-O-, one or two lower alkyl or lower alkyl-C (= O)-or lower alkyl-OC substituted with mono- or di-lower alkyl-amino;
Amino, amino-O optionally substituted with (= O)-
-, Carbamoyl optionally substituted by lower alkyl, sulfamoyl optionally substituted by one or two lower alkyls, carboxyl, halogeno lower alkyl, halogeno lower alkyl-O-, halogeno lower alkyl-O-lower alkyl —, Substitutable aryl-O—, substitutable aryl-C (＝ O) —, optionally substituted heterocycle, substitutable heterocycle—lower alkyl—, substitutable heterocycle— O-, a substitutable heterocycle-CO-, a substitutable heterocycle-lower alkyl-O-, a substitutable heterocycle-lower alkyl-CO-, a substitutable heterocycle-lower alkyl-O-lower alkyl- Or an OH group. In addition,
The above “substitutable” means that it may have a substituent. Examples of these substituents are lower alkyl,
Halogen, cyano, lower alkyl-O-, aryl lower alkyl are preferred. Preferred substituents of "optionally substituted aryl", "optionally substituted saturated heterocycle" or "optionally substituted heteroaryl" include lower alkyl, OH, -O-lower alkyl, -C
(= O) -lower alkyl, -lower alkylene-aryl, heteroaryl, -lower alkylene-heteroaryl, -lower alkylene-C (= O) -O-lower alkyl, -CHO, halo, lower alkyl, mono or di Examples include amino, carboxyl, and the like, which may be substituted.

The compounds of the present invention have optical isomers (optically active substances, diastereomers, etc.) depending on the kind of the group. In addition, some of the compounds of the present invention have an amide bond or a double bond, and tautomers or geometric isomers based on the amide bond also exist. The present invention includes a separated form or a mixture of these isomers. The compounds of the present invention form salts with acids or bases. Salts with acids include inorganic acids such as mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid,
Acid addition salts with organic acids such as lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned. Salts with bases include sodium, potassium, magnesium,
Examples thereof include salts with inorganic bases such as calcium and aluminum, organic bases such as methylamine, ethylamine, meglumine, and ethanolamine, and salts and ammonium salts with basic amino acids such as lysine, arginine, and ornithine. Further, the compound of the present invention can form hydrates, solvates with ethanol and the like, and polymorphs.

Production method In the present specification, the symbols in the general production method, reference, examples and tables have the following meanings. Me: methyl Et: ethyl Pro: n-propyl i-Pro: iso-propyl Bu: n-butyl t-Bu: tert-butyl c-Pr: cyclopropyl c-Hex: cyclohexyl c-Hept: cycloheptyl Pen: pentyl Py: pyridyl Ph: phenyl Bn: benzyl Ac: acetyl Boc: t-butoxycarbonyl

(First production method: production of imidazo [2,1-b] thiazole and dihydroimidazo [2,1-b] thiazole rings)

Embedded image (Wherein, R ^{1 to} R ⁵ are as described above, R ^a and R ^b are lower alkyl groups, R ^c is hydrogen or COOR ^b , (CO) N
The (R ¹⁾ R ^2, the R ⁵ in R ^d is CH ₂ R ^d, and X ¹ represents a halogeno group, X ² is a halogeno group or ^{O (CO) R 3a,,} R
^3a represents a lower alkyl group. ) Imidazo [2,1 which is the basic skeleton of compound (I) of the present invention
-B] thiazoles (6), (11) and (17) are of the formula 1,
It can be manufactured by the methods shown in 2, 3, and 4. That is, as shown in the formula 1, 2-mercaptoimidazole (1) and haloketone (2) are mixed with an alcohol solvent such as EtOH or MeOH, or tetrahydrofuran (hereinafter THF), dimethylformamide (hereinafter DMF), acetone, 2-butanone ( MEK),
By reacting in an inert solvent such as MeCN in the presence of a base such as NaOH, KOH, NaH, K ₂ CO _{3, and} under neutral conditions from room temperature to heating conditions, (3) is obtained, which is converted to an acid halide Or acid anhydride (4) and pyridine (Py),
After N-acylation in the presence of a base such as NaOAc to give (5), this is further heated in the presence of the same base to give (6). As shown in Formula 2, diamine (7) is converted to carbon disulfide or 1,1′-thiocarbonyldiimidazole and an inert solvent such as THF or DMF or MeOH.
(8) by reacting in a solvent such as the above or a mixed solvent thereof with water from room temperature under heating to obtain (8). Then, (8) and haloketone (9) are converted from (1) to (3) By reacting under the same conditions as in the above), dihydroimidazothiazole (10) can be obtained. Further, (10) is reacted with an oxidizing agent such as MnO _{2 in} a solvent such as DMF under heating or heated with a Pd-carbon catalyst or the like in a solvent such as ethylene glycol and the like to obtain (11). Is obtained. Further, as shown in Formulas 3 and 4, 2-aminothiazole (12) is reacted with haloketone (13) or haloacetylene (15) under the same conditions as Formulas (1) to (3). (14) or (16), and (14) is H ₂ SO ₄ , HC
l, by reacting in the presence of an acid such as HBr, AcOH or trifluoroacetic acid (TFA) in a solvent such as EtOH or THF, or by using the acid itself as a solvent at room temperature to under heating; ) Can be converted to (11) and (17) by reacting in a solvent such as EtOH, MeOH, or THF in the presence of a base such as NaOEt from room temperature to heating.

(Second Production Method: Production of Alcohol Body)

Embedded image(Where R^eIs R^Four, R^FiveAny of R^fIs hydrogen, lower
An alkyl group represented by R^gRepresents a lower alkyl group, A¹Is a substituent
Optionally a lower alkylene or -A¹-CH _Two-OH
As

Embedded image R ^{1 to} R ⁸ and R ^6a are as described above. Formulas 5 to 7 are processes for producing the compound of the present invention (I) wherein R ⁴ or R ⁵ has an alcohol. That is, Equation 5
Reacts a compound (18) in which at least one of R ⁴ and R ⁵ is hydrogen with paraformaldehyde or an aqueous formaldehyde solution under heating in the presence of an acid such as sulfuric acid or formic acid. When both R ⁴ and R ⁵ are hydrogen,
In the reaction, the 5-position of the imidazo [2,1-b] thiazole ring is prioritized. Formula 6 shows that the compound (20) in which either R ⁴ or R ⁵ is a ketone or an aldehyde is THF, Et ₂ O
The reaction is carried out with an organic metal reagent such as alkyllithium, alkylmagnesium halide or the like in an inert solvent under cooling, preferably at -78 ° C. Further, Formula 7 shows that a compound (22) in which either R ⁴ or R ⁵ has a carboxyl group is reacted with a metal hydride such as BH ₃ or LiAlH ₄ in an inert solvent such as THF under heating from room temperature. Alternatively, (22) is converted into an acid chloride, an active ester, and an acid anhydride by a conventional method, and then reacted with a metal hydride such as NaBH ₄ under cooling to room temperature. After converting the carboxylic acid into an ester, Et
It can also be produced by reduction with LiBH ₄ , LiAlH ₄ or the like in a solvent such as OH or THF under cooling to room temperature and, if necessary, under heating.

(Third production method: production of aldehyde and ketone bodies)

Embedded image (In the formula, R ^{1 to} R ³ , R ^{e, f} and A ¹ are as described above.) Formulas 8 to 10 represent R ⁴ or R ⁵ in the compound (I) of the present invention.
Is a method for producing a compound having a ketone or aldehyde group. That is, Formula 8 is a general formylation reaction of an aromatic ring, and a compound (18) in which at least one of R ⁴ and R ⁵ is hydrogen is reacted with an inert solvent such as CHCl _{3 in the} presence of POCl ₃ and DMF. Alternatively, the reaction is carried out while heating using DMF itself as a solvent. The reaction can also be carried out in a TFA solvent under heating in the presence of hexamethylenetetramine. When both R ⁴ and R ⁵ are hydrogen, the reaction takes precedence at the 5-position of the imidazo [2,1-b] thiazole ring.
Formulas 9 and 10 are oxidations of alcohols, and compounds (25) or (2) in which either R ⁴ or R ⁵ has an alcohol.
3) is reacted in the presence of SO ₃ .Py in a DMSO solvent at room temperature, or in an inert solvent such as CH ₂ Cl ₂ , DMSO, (COC
l) React with ₂ and Et ₃ N from -78 ° C to room temperature. Further, (25) or (23) is reacted with a Dess-Martin reagent in a halogen-based solvent such as 1,2-dichloroethane (hereinafter, DCE) under cooling to room temperature. Further, in addition to the above-mentioned oxidation reaction, it can be produced by a usual oxidation reaction, specifically, oxidation with chromate, potassium permanganate or the like.

(Fourth Production Method: Production of Carboxylic Acid)

Embedded image (Wherein, R ⁱ represents a lower alkyl group, and R ^1-5 , R ^{b, e} ,
A ¹ is as described above. Formulas 11, 12, and 30 are processes for producing compound (I) of the present invention or a compound in which R ⁴ or R ⁵ in the synthetic intermediate thereof has a carboxyl group. Formulas 11 and 12 show the hydrolysis of an ester. Compounds (27) or (28) having an ester group in either R ⁴ or R ⁵ can be converted to a base such as NaOH or KOH or a compound such as H ₂ SO ₄ or HCl. MeOH, Et in the presence of acid and water
The reaction is carried out in a solvent such as OH, THF, 1,4-dioxane, water or the like or a mixed solvent thereof from room temperature to heating. Equation 30 is the oxidation of the aldehyde, KMnO ₄ , Ag ₂ O, MnO ₂ or N
This is performed using an oxidizing agent such as aClO ₂ .

(Fifth Production Method: Production of Amide Compound)

Embedded image (In the formula, R ^{k, m} together form a saturated heterocyclic ring,
R ^{1 to} R ⁵ , R ^e and A ¹ are as described above. Formulas 13 to 15 are processes for producing a compound having an amide bond in the compound (I) of the present invention. That is, Formulas 13 and 14 represent compounds (28 ′) or (2) having a carboxyl group.
After 2) is reacted with a halogenating agent such as SOCl ₂ or (COCl) ₂ to form an acid chloride, the corresponding primary or secondary amine (29) or (31) is reacted with Et ₃ N, Py or the like. In the presence of an organic base or an inorganic base such as NaHCO ₃ , K ₂ CO ₃ , 1,2-dichloroethane (hereinafter DCE), CH ₂ Cl ₂ , CHC
inert solvent l ₃ etc., or a two-layer system solvent thereof with water, or at room temperature from ice-cooling to base its Py such as solvent and reacted under warming if necessary. Also,
In addition, a method of reacting a carboxylic acid with an amine through a mixed acid anhydride, a method of using POCl ₃ as a condensing agent in a Py solvent, a method of using diphenylphosphoryl azide (DPPA),
A conventional method such as a method of directly performing amidation in the presence of a suitable condensing agent such as 1,1′-carbonyldiimidazole (hereinafter, CDI) can be used. It is also possible by a method such as heating the ester corresponding to the carboxylic acid (28 ′) with the amine. Formula 15 is an amidation of an aromatic ring, and the compound (33) is lithiated with a base such as n-BuLi or LiN (i-Pr) ₂ in an inert solvent such as THF under cooling, preferably at −78 ° C. And reacted with the isocyanate (34) at the same temperature to room temperature.

(Sixth production method: production of carbamic acid ester)

Embedded image (Wherein R ⁿ represents a lower alkyl group, and R ^1-5 , R ^e , A ¹
Is as described above. Formula 16 is a method for producing the compound of the present invention (I) wherein R ⁴ or R ⁵ has a carbamic acid ester. That is, the compound (22), which is a Curtius rearrangement of a carboxyl group and has a carboxyl group at either of R ⁴ and R ⁵ , is subjected to ordinary azidation conditions, specifically, in an inert solvent such as DMF under ice cooling. From a method of reacting with an azidating agent such as DPPA at room temperature, or after passing through an acid chloride or acid anhydride,
An acid azide is prepared by reacting with an azidating agent such as NaN _{3 and the} like. Heat as solvent.

(Seventh Production Method: Production of Amino Form)

Embedded image (Wherein R ^{o, p} are the same or different and are hydrogen, a lower alkyl group which may have a substituent, or a heteroaryl or a saturated hetero group which may have another hetero atom as a ring atom together. In the ring, R ^{x and y} are the same or different and each represents a hydrogen or a lower alkyl group, X ² represents a halogeno group or a sulfonyloxy group, and R ^1-5 , ^Re and A ¹ are as described above. 17 to 19 and 31 to 33 are compounds of the present invention (I) wherein R ⁴ or R ⁵ has an amino group, or 2
This is a method for producing a compound in which the position substituent is an aminomethyl group. That is, Formula 17 is an alkylation reaction of an amine with an alkyl halide or a sulfonic acid alkyl ester, wherein an alcohol (23) and a halogenating agent such as SOCl ₂ , POCl ₃ , hydrochloric acid, and the like are mixed in an inert solvent such as DCE. Alternatively, the reaction is carried out under cooling to room temperature using the halogenating agent itself as a solvent, and if necessary, under heating, or
N _3, the presence of a base Py like, in an inert solvent or Py of DCE such at room temperature from under ice-cooling, methanesulfonyl chloride, p
-By reacting with toluenesulfonyl chloride or the like to give (37), which is converted to the corresponding amine (38) with DMF, C
H ₃ CN, acetone, inert solvent such as _{CH 2 Cl 2, K 2 CO} 3, NaH
The reaction is carried out in the presence of an inorganic base such as CO ₃ or an organic base such as Et ₃ N or an excess amount of (38) itself as a base at room temperature to under heating. Formulas 18 and 33 are reductive amination reactions in which a formyl compound or ketone compound (26) or (63) is converted to an amine (38) or (57) by DCE, C
In an inert solvent such as HCl ₃ , or in acetic acid or MeOH, acetic acid, an acid such as Ti (Oi-Pr) ₄ , NaB (OAc) ₃ H in the presence of a Lewis acid,
Reaction with reducing agents such as NaBH ₃ CN, NaBH ₄
l, In a solvent such as MeOH, a catalyst is heated under dehydration conditions as needed in the absence of a catalyst or in the presence of an acid catalyst such as p-toluenesulfonic acid to form an imine, which is then reacted with the above reducing agent. Formula 31 is a Mannich reaction in which the compound (18) is heated in a solvent such as MeOH in the presence of an acid such as acetic acid in the presence of an acid such as acetic acid. Equation 19 is the reduction of the azide, DMF Compound (37) with an azide agent of NaN _3, etc., THF, in an inert solvent such as DCE, K ₂ optionally C
The azide form (40) is obtained by reacting from room temperature to heating in the presence of a base such as O ₃ , which is further reacted with a metal catalyst such as a Pd-carbon catalyst or PtO in a solvent such as EtOH under a hydrogen atmosphere. The reaction is carried out at room temperature. LiAlH ₄ or Ph as a reducing agent
_The usual method using 3P can also be used. Formula 32 is a reduction of an amide, and the amide (30) is converted to THF, E
Reaction with a metal hydride such as LiAlH ₄ or BH ₃ in an inert solvent such as t ₂ O is performed at room temperature to under heating.

(Eighth Production Method: Production of Ether Form)

Embedded image (Wherein R ^q is an optionally substituted lower alkyl group, a cycloalkyl ^{group, R 1~5, R e, X} 2, A 1 is as defined above.) Equation 20 is the invention This is a method for producing a compound in which R ⁴ or R ⁵ in compound (I) has an ether group. That is, the compound (37) having a leaving group at R ⁴ or R ⁵ and the corresponding alcohol (42) are reacted with an alcohol (42) in an inert solvent such as THF or DMF, or using the alcohol to be reacted as a solvent.
The reaction is carried out from room temperature to heating in the presence of a base such as H. (Ninth production method: synthesis of alkyl-substituted product)

Embedded image (Wherein, R ^r and R ^s represent R ⁶ and R ⁷ , respectively.
R ^1-3 , R ^6,7,8 and R ^{e, f, g} are as described above. Formulas 21 and 22 are compounds (45) and (46) of the present compound (I) wherein R ⁴ or R ⁵ is a lower alkyl group.
It is a manufacturing method of. That is, the compound (65) or (21) in which either R ⁴ or R ⁵ is an alkenyl group or a 1-hydroxyalkyl group is placed in a solvent such as EtOH or AcOH under a hydrogen atmosphere and optionally under pressure. , Pd-C, PtO and the like in the presence of a metal catalyst from room temperature to heating. The compound (21) can also be produced by reduction with Et ₃ SiH or the like in an inert solvent such as CH ₂ Cl ₂ or CH ₃ CN or in TFA at room temperature.

(Tenth Production Method; Production of Alkenyl Form)

Embedded image (In the formula, X ³ represents PO (OEt) ₃ or P ⁺ (Ph) ₃ , and R ^1-3 , R ⁸ , ^{Re, r , s,} are as described above.) Formulas 23 to 25, Formula 34 is a compound of the present invention (I)
^A compound (44) wherein ⁴ or R ⁵ is a lower alkenyl group,
This is the production method of (52). That is, Formula 23 is a compound (1
8) is reacted with the corresponding aldehyde (47) in a solvent such as acetic acid, propionic acid or butyric acid under heating, or in an inert solvent such as Tol using concentrated sulfuric acid as a catalyst and heating. To react. When both R ⁴ and R ⁵ are hydrogen, the reaction takes precedence at the 5-position of the imidazo [2,1-b] thiazole ring. Equations 24 and 25 are Horner-Emons or Wi
It is a tting reaction. Formula 24 shows that a formyl compound (24) and a phosphate ester (48) can be converted to T
The reaction is carried out in an inert solvent such as HF under cooling or, if necessary, under heating. Equation 25 shows that halide (49) and P
Phosphate or phosphonium salt (50) and ketone (5) produced from (OEt) ₃ or Ph ₃ P by a conventional method.
1) is reacted with a solvent such as THF or DMSO in the presence of a base such as NaH, t-BuOK or NaOEt. Formula 34 is a dehydration reaction of the alcohol compound (64), which is heated in a solvent such as Tol or dioxane in the presence of an acid catalyst such as p-toluenesulfonic acid.

(Eleventh Production Method: Production of Bromo Form)

Embedded image (Wherein, R ¹ ~R ^3, R ^e are as defined above.) Equation 26 is the method for producing compound (53) R ⁴ or R ⁵ is bromo group in the present compound (I). That is, the compound (18) is reacted with bromine in a solvent such as acetic acid or carbon tetrachloride, if necessary, by adding concentrated hydrochloric acid under ice-cooling to heating. When both R ⁴ and R ⁵ are hydrogen, the reaction takes precedence at the 5-position of the imidazo [2,1-b] thiazole ring. (Twelfth manufacturing method: production of aryl bodies)

Embedded image(Where R^tIs an aryl group which may have a substituent,
Represents a aryl group; ¹~ R^Three, R^eIs as described above.
You. Formula 27 is a compound represented by the formula (I)^Four, R^FiveAny of
This is a method for producing a compound (55) in which is an aryl group.
That is, the bromo compound (53) and the boronic acid (54) were converted to Pd (PPh
_Three)_FourPd catalyst such as, and Na_TwoCO_ThreeIn the presence of bases such as DME
The reaction is carried out in a solvent under heating.

(Thirteenth production method: production of nitro compound)

Embedded image (Wherein, R ¹ ~R ^3, R ^e are as defined above.) Equation 28 is the method for producing compound (28) R ⁴ or R ⁵ is a nitro group in the present compound (I). That is, compound (18) is converted to nitric acid-sulfuric acid, nitric acid-acetic acid, nitric acid-
The reaction is carried out with acetic anhydride at room temperature under ice-cooling and, if necessary, under heating. It can also be produced by a method using a nitrating agent such as nitronium tetrafluoroborate in an inert solvent such as Tol, CH ₃ CN, THF, sulfolane or the like from a low temperature to a heating temperature. When both R ⁴ and R ⁵ are hydrogen, the reaction takes precedence at the 5-position of the imidazo [2,1-b] thiazole ring. (14th production method: production of N-aryl compound)

Embedded image (The R ^u heteroaryl group wherein, X ⁴ is a halogen radical, R ^{1 to 3} are as defined above.) Formula 29 compounds with which the invention compound (I) has an arylamino group (58) It is a manufacturing method of. That is, the amino form (5
7) The halogenated aryl (59) is heated in an inert solvent such as DMF, or in the absence of a solvent, in the presence or absence of a base such as K ₂ CO ₃ , or Pd, Cu or the like. In the same manner in the presence of a catalyst.

The above-mentioned production method is not limited to the substituents in the formula, but is widely applied when the compound of the present invention has the same substituent. The compound of the present invention thus produced can be isolated as a free form or as a salt thereof.
Purified. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be separated by selecting an appropriate starting compound or by utilizing a difference in physical properties between the isomers. For example, optical isomers can be obtained by selecting appropriate raw materials.
Alternatively, it can be converted to a stereochemically pure isomer by a racemic resolution method of a racemic compound (for example, a method of conducting a diastereomeric salt with a general optically active base and performing an optical resolution).

[0025]

The compound of the present invention is a compound having a strong action on metabotropic glutamate receptor. Therefore, the compound of the present invention is useful as an agent for preventing or treating a disease in which mGluR1 is considered to be involved, preferably cerebral infarction.

A preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients and other additives usually used in the preparation of preparations. Pharmaceutical carriers and excipients may be solid or liquid, such as lactose, magnesium stearate,
Examples include starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. The drug may be administered orally in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral infusions such as intravenous and intramuscular injections, suppositories, and transdermals. Good. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration subject.
1 to 1,000 mg, preferably 50 to 20 per day
It is orally administered once to several times a day in the range of 0 mg, or is administered intravenously once to several times a day in the range of 1 to 500 mg per adult per day, or Intravenous administration for 1 hour to 24 hours per day. Of course, as mentioned above, the dosage varies under various conditions, so that an amount smaller than the above dosage range may be sufficient. As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium aluminate.
The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or with a film of a gastric or enteric substance. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Containing ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by producing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

[0028]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. The method for producing the starting compounds used in the examples will be described as reference examples. (The abbreviations used below are the same as in the production method.) NMR: Nuclear magnetic resonance spectrum (measured by TMS internal standard ( expressed in ppm)) Reference Example 1 2-chloro-N-cyclohexyl-N-methylacetoa
Under ice cooling CHCl ₃ (100 ml) solution of Setamido diketene (15 g), slowly N- methylcyclohexylamine (15 g) was added, followed by stirring for 3 hours at room temperature. Then, the reaction solution was cooled with ice, and SO ₂ C
l ₂ (15 ml) was slowly added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (hereinafter, column chromatography) (eluent; n-hexane (hereinafter, Hex): EtOAc = 10: 1 to 4: 1) to give the title compound (22.9 g). Obtained as an oil. MS (FAB): 232 (M + 1) Reference Example 2 2-amino-N-cyclohexyl-N, 4-dimethylthio
Azole-5-carboxamide A solution of the compound of Reference Example 1 (69 g) in EtOH (300 ml) was added to thiourea (2
3 g) was added and the mixture was heated under reflux for 4 hours. The reaction solution was water (800 ml)
And adjusted to pH 10 by adding 28% aqueous NH ₃ under ice-cooling. The precipitate was collected by filtration and washed with water to give the title compound (74 g) as pale-brown crystals. MS (FAB): 254 (M + 1)

Reference Example 3 Ethyl imidazo [2,1-b] thiazole-2-cal
To a solution of boxylate KOH (3.3 g) in EtOH (80 ml) was added 2-mercaptoimidazole (5.0 g), and the mixture was heated under reflux for 30 minutes. After cooling the reaction solution on ice, ethyl 2-chloroacetoacetate (6.9 ml)
Was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with CHCl ₃ , dried over anhydrous Na ₂ SO ₄ , and then the solvent was distilled off under reduced pressure to obtain crude crystals of ethyl 2- (2-imidazolylthio) acetoacetate (11 g). . This was further dissolved in DMF (30 ml), Py (7.4 ml), formic acetic anhydride
(8.1 ml) was added and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, extracted with CHCl ₃ , dried over anhydrous Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (eluent: Hex: Et
OAC = 2: 1), and the obtained crystals were washed with diisopropyl ether to give the title compound (2.6 g) as pale-yellow crystals. MS (FAB): 197 (M + 1) Reference Example 4 2-amino-3- (2-oxopropyl) -4-methyl
Imidazo [2,1-b] thiazole. Bromate 2-amino-4-methylthiazole (102 g) in acetone (1
L) The solution was added with bromoacetone (149 g), and the mixture was stirred at room temperature for 15 hours. The precipitate was collected by filtration and washed with acetone to give the title compound (202 g). Reference Example 5 3,6-Dimethylimidazo [2,1-b] thiazole A suspension of the compound of Reference Example 4 (202 g) in EtOH (1 L) was refluxed for 5 hours. After cooling the reaction solution, it was concentrated under reduced pressure, and water (500 m
l) and partitioned with EtOAc (500 ml). The aqueous layer was neutralized with NaOH (33 g), brine was added until saturation, and the mixture was extracted with EtOAc. The organic layer was washed with saturated saline, dried over anhydrous MgSO ₄ , and the solvent was distilled off under reduced pressure to obtain the title compound (120 g) as crystals. MS (FAB): 153 (M + 1)

Reference Example 6 Methyl (2-aminothiazol-5-yl) carboxy
Shireto added EtOH thiourea (45g) (200ml) was added methyl 2-chloro-3-oxopropionate (40 g) was heated to reflux for 4 hours. The reaction solution was cooled on ice, diluted with water (300 ml), and then diluted with 28%
An aqueous NH ₃ solution (10 ml) was added and stirred. The precipitate is collected by filtration,
After washing with water, the title compound (26.4 g) was obtained as yellow crystals. MS (FAB): 159 and (M + 1) Reference Example 7 (2-aminothiazol-yl) carboxylic acid of the compound of Reference Example 6 MeOH in (10 g) (200 ml) 1M-NaOH aqueous solution (116 ml) was added After stirring at 50 ° C. for 2 hours, the mixture was further stirred at room temperature for 6 hours. 1M-HCl aqueous solution was added to the reaction solution, and the precipitate was collected by filtration and washed with water to give the title compound.
(6.16 g) was obtained as yellow crystals. MS (EI): 144 (M +) Reference Example 8 2-amino-N-cyclohexyl-N-methylthiazolate
L -5-Carboxamide A solution of the compound of Reference Example 7 (6.16 g) in DMF (200 ml) was added with 1,3-
Dicyclohexylcarbodiimide (10.6 g), 1-hydroxybenzotriazole (6.97 g), and N-methylcyclohexylamine (16.7 ml) were added, and the mixture was stirred at 60 ° C for 7 hours. The reaction solution was concentrated under reduced pressure, and 1M-HCl aqueous solution (250 ml)
Was added and stirred. Insoluble matter was removed by filtration, and 1M-NaOH
After adding an aqueous solution (280 ml) and neutralizing, the precipitate was collected by filtration, and water and E
The title compound (6.82 g) was obtained as pale brown crystals by washing with tOAc. MS (FAB): 340 (M + 1)

Reference Example 9 Methyl trans-4a, 5,6,7,8,8a-hex
Sahydrothiazolo [3,2-a] benzimidazole-
2-carboxylate. Hydrochloride trans-octahydro-2H-benzimidazole-
To a solution of 2-thione (3.12 g) in EtOH (20 ml) -THF (10 ml) was added methyl 2-chloro-3-oxopropionate (2.73 g), and the mixture was heated under reflux for 6 hours. The reaction solution was partitioned between a saturated aqueous solution of NaHCO ₃ and EtOAc, and the organic layer was extracted with a 1M aqueous solution of HCl. The extracted aqueous layer was neutralized with NaHCO ₃ , extracted with CHCl ₃ , dried over anhydrous Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. After dissolving the residue in acetone, a 4M-HCl.EtOAc solution was added and the mixture was stirred, and the precipitate was collected by filtration and washed with acetone to give the title compound (1.78 g) as colorless crystals. MS (FAB): 239 (M + 1) Reference Example 10 methyl 5,6,7,8-tetrahydrothiazolo [3
2-a] Benzimidazole-2-carboxylate It was produced in the same manner as in Example 2 from the compound of Reference Example 9. MS (FAB): 237 (M + 1)

Reference Example 11 5,6,7,8-tetrahydrothiazolo [3,2-a]
The compound was prepared in the same manner as in Reference Example 7 from the compound of Reference Example 10 of benzimidazole-2-carboxylic acid . MS (FAB): 223 (M + 1) Reference Example 12 ethyl 2-[(1H-imidazo [4,5-c] pyridi
2--2- yl) thio] acetoacetate 2-mercapto-1H-imidazo [4,5-c] pyridine (1.06 g) in EtOH (50 ml) was added with KOH (0.51 g) and stirred at room temperature for 30 minutes. Stirred. Then, ethyl 2-chloroacetoacetate (1.17 ml) was added thereto, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was diluted with acetone, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent; EtOAc) to give the title compound (1.01 g). MS (FAB): 280 (M + 1) Reference Example 13 ethyl 3-methylthiazolo [3 ', 2': 1,2] imi
Dazo [5,4-c] pyridine-2-carboxylate The compound of Reference Example 12 (0.91 g) was dissolved in concentrated sulfuric acid (5 ml).
Stirred at C for 2 hours. Pour the reaction mixture into ice water and add 28% N
And neutralized with H ₃ aq. The precipitate was collected by filtration and washed with water to give the title compound (0.14 g). MS (FAB): 262 (M + 1)

Example 1 N-cyclohexyl-N-methylimidazo [2,1-
b] Thiazole-2-carboxamide. To a solution of the hydrochloride salt of Reference Example 3 (2.5 g) in MeOH (100 ml) was added a 1M-NaOH aqueous solution (30 ml), the mixture was stirred at room temperature for 2 hours, and further heated under reflux for 15 minutes. After cooling the reaction solution to room temperature, a 1M-HCl aqueous solution (100 ml) was added, and the solvent was distilled off under reduced pressure. MeOH residue
And the undesired substances were removed by filtration, and the solvent was again distilled off under reduced pressure to give imidazo [2,1-b] thiazole-2-carboxylic acid. Crude crystals of the hydrochloride were obtained. This crude crystal
(1.7 g) was dissolved in DMF (30 ml), N-methylmorpholine (3.3 ml) and ethyl chloroformate (1.43 ml) were added at −20 ° C., and the mixture was stirred at the same temperature for 30 minutes, and further N-methylmorpholine was added. Methylcyclohexylamine (2.61 ml) was added, and the mixture was stirred at room temperature for 3 hours.
Water was added to the reaction solution, extracted with EtOAc, 1M-NaOH aqueous solution,
The extract was washed with water and saturated saline, and dried over anhydrous Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (eluent: Hex: Et
After purification by OAc = 1: 1), the title compound (300 mg) was obtained as pale brown crystals by converting into a hydrochloride in a conventional manner. _{NMR (DMSO-d 6);} δ8.68 (br, 1H), 8.03 (s, 1H), 7.72 (s, 1H),
3.80-4.30 (br, 1H), 2.70-3.20 (br, 3H), 1.45-1.85 (m, 7H),
1.25-1.45 (m, 2H), 1.00-1.25 (m, 1H). Example 2 N-cyclohexyl-N, 3-dimethylimidazo [2,
1-b] thiazole-2-carboxamide. Hydrochloride A solution of the compound of Example 96 (5.1 g) in DMF (90 ml) was heated with stirring at 140 ° C., and MnO ₂ (7.0 g) was slowly added thereto, followed by stirring at the same temperature for 7 hours. After further adding MnO ₂ (7.0 g) and stirring for 1 hour, the reaction solution was cooled to room temperature, and insolubles were removed by filtration. The filtrate was separated with an aqueous solution of EtOAc-1M-NaOH, and the organic layer was washed with saturated saline. After evaporating the solvent under reduced pressure, the residue was evaporated.
The layers were separated with an aqueous solution of CHCl ₃ -1M-HCl, and the aqueous layer was washed with CHCl ₃ . The water in the aqueous layer was distilled off under reduced pressure, and the residue was recrystallized from EtOH / Et ₂ O to give the title compound (3.9 g) as colorless crystals. _{NMR (DMSO-d 6);} δ8.17 (d, 1H), 7.77 (d, 1H), 2.90 (s, 3H),
2.45 (s, 3H), 1.46-1.84 (m, 7H), 1.00-1.38 (m, 3H).

Embodiment 3N-cyclohexyl-N, 3,6-trimethylimidazo
[2,1-b] thiazole-2-carboxamide MethA: 2 in a suspension of the compound of Reference Example 2 (74 g) in DMF (700 ml).
-Chloroacetone (58 ml) was added, and the mixture was heated under reflux for 18 hours.
The reaction solution was concentrated under reduced pressure, and the residue was treated with EtOAc-1M NaOH aqueous solution.
For liquid separation. The aqueous layer was further extracted with EtOAc, and the organic layers were combined.
And washed with water. Anhydrous Na_TwoSO_FourAfter drying with
Distill off and purify the residue by column chromatography (eluent: EtOAc)
To give the title compound (27 g) as pale brown crystals.
Was. MethB: 60% NaH (0.53 g) in DMF (15 ml) under ice-cooling,
A solution of the compound of Example 95 (3.65 g) in DMF (30 ml) was added to
Stirred at room temperature for 1 hour. Then add MeI (1.23m, l) to this.
Then, the mixture was stirred at room temperature for 1 hour. Pour the reaction solution into ice water,
Extracted with EtOAc and washed with water and brine. Anhydrous MgSO_Four
After drying in vacuo, the solvent is evaporated under reduced pressure to give the title compound.
(3.66 g) was obtained. NMR (DMSO-d₆); δ7.95 (d, 1H), 3.60-4.25 (br, 1H), 2.90 (s,
3H), 2.42 (s, 3H), 2.40 (d, 3H), 1.45-1.90 (m, 7H), 1.20-1.4
5 (m, 2H), 0.95-1.20 (m, 1H).N-cyclohexyl-5-formyl-N, 3,6-tri
Methylimidazo [2,1-b] thiazole-2-carbo
Oxamide DMF (205 g), CHCl_Three(400 ml) under ice-cooling in a mixed solution of POCl_Three(Four
29g) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 30 minutes.
Was. This was followed by the addition of the compound of Example 3 (117 g) in CHCl _Three(400m
l) The solution was added dropwise over 30 minutes, and the mixture was refluxed for 15 hours. Anti
After cooling the reaction solution, pour it into ice water and add CHCl_ThreeExtract with 10% que
Acid solution, saturated NaHCO_ThreeAqueous solution, water, saturated saline solution
Washed. Anhydrous Na_TwoSO_FourAnd evaporate the solvent under reduced pressure.
And gave the title compound (92 g). NMR (DMSO-d₆); δ9.87 (s, 1H), 2.89 (s, 3H), 2.62 (s, 3H), 2.
56 (s, 3H), 1.47-1.82 (m, 7H), 1.18-1.40 (m, 2H), 1.05-1.17
(m, 1H).

Example 29 Ethyl {2-[(cyclohexyl) (methyl) carba
Moyl] imidazo [2,1-b] thiazole-6-i
To a mixed solution of the compound of Reference Example 8 (3.65 g) in EtOH (90 ml) and THF (90 ml) was added ethyl 4-chloroacetoacetate (2.48 ml).
Was added and sealed at 140 ° C. for 6 hours. The solvent was distilled off under reduced pressure, and the residue was suspended in a 1M aqueous solution of NaOH and EtOAc. Insoluble matters were removed by filtration, followed by separation. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: CHCl ₃ : EtOAc = 2: 1) to give the title compound. (2.31 g) was obtained. _{NMR (CDCl 3); δ7.70 (} s, 1H), 7.45 (s, 1H), 4.21 (q, 2H), 3.75
(s, 2H), 3.03 (brs, 3H), 1.29 (t, 3H), 1.00-1.95 (m, 10H). Example 48 N-Cyclohexyl-N, 3,6-trimethyl-5-
(2-Methyl-1-propen-1-yl) imidazo
[2,1-b] thiazole-2-carboxamide. hydrochloric acid
Salt The compound of Example 3 (500 mg), isobutyraldehyde (1.38
n-butyric acid (5 ml) was added to the mixture, and the mixture was heated and stirred at 180 ° C. for 13 hours. Then, isobutyraldehyde (1.38 ml) was added and the mixture was further stirred at the same temperature for 3 hours. After cooling the reaction solution, EtOAc, 2
Separate with an aqueous solution of M-NaOH, wash the organic layer with water, dry anhydrous MgSO ₄
And dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent; Hex: EtOAc = 2: 1 to 1: 1), and then recrystallized from EtOH / Et ₂ O as a hydrochloride by a conventional method. The title compound (436 mg) was obtained as colorless crystals. _{NMR (DMSO-d 6);} δ6.24 (s, 1H), 2.89 (s, 3H), 2.42 (s, 3H), 2.
19 (s, 3H), 1.95 (s, 3H), 1.68 (s, 3H), 1.45-1.90 (m, 7H), 1.0
0-1.45 (m, 3H).

Example 53 Ethyl (E) -3- {2-[(cyclohexyl) (meth
Tyl) carbamoyl] -3,6-dimethylimidazo
[2,1-b] thiazol-5-yl} -2-methyla
Crylate. Triethyl 2-phosphonopropionate (73.4 g) was added to a suspension of the hydrochloride 60% NaH (12.3 g) in THF (310 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled again, and
A solution of the compound (89.4 g) in THF (270 ml) was added dropwise over 1 hour, stirred at the same temperature for 2 hours, and further stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, extracted with EtOAc, and washed with a saturated aqueous solution of NH ₄ Cl and brine. The organic layer was extracted with a 1M-HCl aqueous solution, the aqueous layer was neutralized with a 28% aqueous NH ₃ solution, and then extracted again with EtOAc.
Extracted. The organic layer was washed with water and saturated saline, and then dried over anhydrous Mg.
It was dried over SO ₄ and the solvent was distilled off under reduced pressure. The residue was treated with EtOH (280 m
l), 4M-HCl.EtOAc solution (78 ml), EtOAc (1500 ml)
Was added and stirred under ice cooling. The precipitate was collected by filtration to give the title compound (88 g) as colorless crystals. _{NMR (DMSO-d 6);} δ7.69 (s, 1H), 4.22 (q, 2H), 3.40-4.50 (b
r), 2.89 (s, 3H), 2.42 (s, 3H), 2.19 (s, 3H), 1.89 (d, 3H), 1.4
5-1.80 (m, 7H), 1.29 (t, 3H), 1.00-1.40 (m, 3H). Example 56 (E) -3- ｛2-[(cyclohexyl) (methyl) ca
Rubamoyl] -3,6-dimethylimidazo [2,1-
b] Thiazol-5-yl} -2-methylacrylic acid To a solution of the compound of Example 53 (87.6 g) in EtOH (200 ml) at room temperature was added a 1M aqueous solution of NaOH (500 ml), and the mixture was stirred at the same temperature for 3 hours. did. This was neutralized with a 1M-HCl aqueous solution (300 ml), and the precipitate was collected by filtration and washed with water to give the title compound (70 g) as colorless crystals. _{NMR (DMSO-d 6);} δ12.62 (s, 1H), 7.73 (s, 1H), 3.80-4.20 (b
r, 1H), 2.89 (s, 3H), 2.40 (s, 3H), 2.11 (s, 3H), 1.83 (d, 3H),
1.50-1.80 (m, 7H), 1.20-1.45 (m, 2H), 1.00-1.20 (m, 1H).

Example 58 N-Cyclohexyl-5-[(E) -3-oxo-2-
Methyl-1-propen-1-yl] -N, 3,6-tri
Methylimidazo [2,1-b] thiazole-2-carbo
Compounds of Kisamido Example 60 (56.3g), Et ₃ N in (65.1ml) DMSO (312m
l) SO ₃ .Py (74.5 g) was added to the solution under water cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with EtOAc, washed with a 5% aqueous citric acid solution, water and saturated saline, dried over anhydrous MgSO ₄ and the solvent was distilled off under reduced pressure to give the title compound (48
g) was obtained. _{NMR (CDCl 3); δ9.65 (} s, 1H), 7.43 (s, 1H), 3.90-4.30 (br),
2.96 (s, 3H), 2.52 (s, 3H), 2.25 (s, 3H), 1.89 (d, 3H), 1.00-
2.00 (m, 10H). Example 60 N-cyclohexyl-5-[(E) -3-hydroxy-
2-methyl-1-propen-1-yl] -N, 3,6-
Trimethylimidazo [2,1-b] thiazole-2-ca
Compounds of Rubokisamido Example 56 (52.6 g) in THF (150 ml) was added 1,1 '
-Add carbonyldiimidazole (50 g) and add 50
Stirred for minutes. The reaction solution was treated with NaBH ₄ (23.8 g) in water (75 m
l) The solution was added dropwise over 35 minutes under ice-cooling and stirred at the same temperature for 30 minutes. The reaction solution was poured into ice water, extracted with EtOAc,
Washed with water and saturated saline. The organic layer was extracted with a 1M-HCl aqueous solution, neutralized with a 28% NH ₃ aqueous solution, and then extracted again with EtOAc.
After washing with water and saturated saline, drying over anhydrous MgSO ₄ and distilling off the solvent under reduced pressure gave the title compound (48.9 g). _{NMR (CDCl 3); δ6.50 (} s, 1H), 4.26 (s, 2H), 3.90-4.20 (br),
2.94 (s, 3H), 2.45 (s, 3H), 2.18 (s, 3H), 1.71 (s, 3H), 1.00-
1.90 (m, 10H).

Example 61 5-[(E) -3-chloro-2-methyl-1-propene
-1-yl] -N-cyclohexyl-N, 3,6-tri
Methylimidazo [2,1-b] thiazole-2-carbo
Oxamide. The compound of Example 60 (1.5 g) was added to the hydrochloride SOCl ₂ (3 ml), and the mixture was stirred at room temperature for 1 hour. Toluene (80 ml) was added to the reaction solution, and the mixture was stirred. The precipitate was collected by filtration, and washed with toluene to give the title compound (1.54 g) as colorless crystals. NMR (DMSO-d ₆ ); δ 6.73-6.80 (br, 1H), 4.42 (s, 2H), 2.89 (s,
3H), 2.41 (s, 3H), 2.20 (s, 3H), 1.48-2.00 (m, 10H), 1.20-1.
48 (m, 2H), 1.00-1.20 (m, 1H). Example 69 N-cyclohexyl-5-{(E) -3-[(2-meth
Xylethyl) amino] -2-methyl-1-propene-1
-Yl} -N, 3,6-trimethylimidazo [2,1-
b] Thiazole-2-carboxamide. Fumarate.
0.5 Compound hydrates Example 58 at room temperature in DCE (450 ml) solution of (48 g), A
cOH (0.65 ml) and 2-methoxyethylamine (17.6 ml) were added, and the mixture was stirred at the same temperature for 30 minutes. Then add NaB (OAc) ₃ H
(86.5 g) and the mixture was further stirred for 1 hour. The reaction solution neutralized with NaHCO ₃ was poured into ice water and extracted with CHCl _3. 10% organic layer
Extracted with aqueous citric acid solution, washed the aqueous layer with CHCl ₃ ,
and extracted with CHCl ₃ and neutralized with NaOH. The organic layer was washed with water and saturated saline, dried over anhydrous MgSO ₄ and the solvent was distilled off under reduced pressure.
The residue was dissolved in EtOH, fumaric acid (9.34 g) was added, and the mixture was stirred. After evaporating the solvent under reduced pressure, the residue was recrystallized from a mixed solvent of EtOH and EtOAc to obtain the title compound (31.9 g) as colorless crystals. _{NMR (DMSO-d 6);} δ6.58 (s, 1H), 6.54 (S, 2H), 3.80-4.10 (br,
1H), 3.51 (t, 2H), 3.46 (brs, 2H), 3.28 (s, 3H), 2.87 (s, 3H),
2.79 (t, 2H), 2.38 (s, 3H), 2.07 (s, 3H), 1.67 (d, 3H), 1.45-
1.85 (m, 7H), 1.18-1.35 (m, 2H), 1.04-1.17 (m, 1H).

Example 73 N-Cyclohexyl-5-[(E) -2-methyl-3-
Morpholino-1-propen-1-yl] -N, 3,6-
Trimethylimidazo [2,1-b] thiazole-2-ca
Luboxamide. Compound of dihydrochloride Example 61 at room temperature in DMF (10 ml) solution of (200 mg),
Add morpholine (0.42 ml) and K ₂ CO ₃ (995 mg) and add 3 at the same temperature.
Stirred for hours. Water was added to the reaction solution and extracted with EtOAc,
After washing with water and a saturated saline solution, it was dried over anhydrous MgSO ₄ and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (eluent; CHC
The product was purified by l ₃ : MeOH = 100: 1) and converted into a hydrochloride by a conventional method to obtain the compound of Example 72 (180 mg) and the compound of Example 40 as a by-product. _{NMR (DMSO-d 6);} δ11.30-11.60 (br, 1H), 6.87-6.95 (br, 1
H), 3.88-4.04 (m, 8H), 3.30-3.43 (m, 1H), 2.95-3.25 (m, 2
H), 2.89 (s, 3H), 2.44 (s, 3H), 2.20 (s, 3H), 1.89-1.95 (br, 3
H), 1.45-1.85 (m, 7H), 1.00-1.45 (m, 3H). Example 84 N-cyclohexyl-N-methyl-5,6,7,8-te
Trahydrothiazolo [3 ', 2': 1,2] imidazo
[5,4-c] pyridine-2-carboxamide. 2 hydrochloric acid
A 37% aqueous formaldehyde solution (0.64 ml) was added to a solution of the compound of Example 30 (300 mg) in MeOH (10 ml), and the mixture was heated with stirring at 80 ° C. for 40 minutes. After cooling the reaction solution, the solvent was distilled off under reduced pressure and Et.
Liquid separation was performed with OAc and a 1M-NaOH aqueous solution. After washing the organic layer with water,
Extracted with 1M-HCl aqueous solution and washed with EtOAc. Water was distilled off under reduced pressure, and the residue was recrystallized from MeOH / EtOAc to give the title compound (120 mg) as colorless crystals. _{NMR (DMSO-d 6);} δ10.06 (brs, 2H), 8.57 (br, 1H), 5.85 (br),
4.43 (brs, 2H), 4.18 (br, 1H), 3.42 (brs, 2H), 3.09 (brs, 3
H), 2.98 (brs, 2H), 1.00-1.85 (m, 10H).

Example 95 N-cyclohexyl-3,6-dimethylimidazo [2,
1-b] Thiazole-2-carboxamide To a solution of the compound of Reference Example 5 (2.34 g) in THF (30 ml) was added a 1.54 M-BuLi Hex solution (10 ml) at -50 ° C under an argon atmosphere, and the mixture was heated to the same temperature. And stirred for 30 minutes. After the reaction solution was further cooled to -60 ° C, cyclohexyl isocyanate (2 ml) was added, and the mixture was stirred for 30 minutes while heating to -30 ° C. Ice water was added to the reaction solution, extracted with EtOAc, washed with water and brine, and dried over anhydrous MgSO ₄ . The solvent was distilled off under reduced pressure, and the residue was recrystallized from Hex / EtOAc (1/1) to give the title compound.
(3.68 g) was obtained. _{NMR (CDCl 3); δ7.13 (} s, 1H), 5.53 (brd, 1H), 3.82-3.99 (m, 1
H), 2.69 (s, 3H), 2.36 (s, 3H), 1.12-2.08 (m, 10H). Example 96 N-cyclohexyl-5,6-dihydro-N, 3-dimethyl
Thilimidazo [2,1-b] thiazole-2-carboxy
Samide. To a solution of the compound of Reference Example 1 (2.3 g) in 2-butanone (50 ml) was added ethylenethiourea (1 g), and the mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and washed with 2-butanone to give the title compound (2.9 g) as colorless crystals. _{NMR (DMSO-d 6);} δ10.24 (s, 1H), 4.20-4.45 (m, 4H), 3.80-4.
00 (m, 1H), 2.87 (s, 3H), 2.19 (s, 1H), 1.40-1.85 (m, 7H), 1.0
0-1.40 (m, 3H).

The structures and physical properties of the compounds of the Examples are shown in Tables 1 to 6.
Shown in The symbols in the table are as follows. Ex: Example number Ref: Reference example number neo-Pen: neopentyl i-Bu: isobutyl Data in brackets [] indicates a reference production method. Meth: General production method number sp: By-product (Other abbreviations used are the same as those in the production method.) Examples of the table are described in [] in the table.
It synthesize | combined from suitable raw material compound similarly to the Example and the manufacturing method. In the column chromatography, silica gel was used as a filler.

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

[0045]

[Table 4]

[0046]

[Table 5]

[0047]

[Table 6]

Production Example N-cyclohexyl-6-glycylamino-N-methyl
Thiazolo [3,2-a] benzimidazole-2-cal
Boxamide dihydrochloride 1) N-cyclohexyl-N-methylthiazolo [3,
2-a] benzimidazole-2-carboxamide Refer to ethyl thiazolo [3,2-a] benzimidazole-2-carboxylate which can be produced in the same manner as in Reference Example 3 from 2-mercaptobenzimidazole and ethyl 2-chloroacetoacetate. By following the same procedure as in Example 7, thiazolo [3,2-a] benzimidazole-2-
A carboxylic acid was obtained. This was further added to SOCl _{2 in the} presence of a DMF catalyst.
To give thiazolo [3,2-a] benzimidazole-2-carboxylic acid chloride, which was further reacted with an excess amount of N-methylcyclohexylamine in DCE to give the title compound. 2) 6-Amino-N-cyclohexyl-N-methylthiazolo [3,2-a] benzimidazole-2-carboxamide 1) The compound obtained in 1) was prepared under the usual nitration conditions, that is, concentrated sulfuric acid.
N-cyclohexyl-N-methyl-6-nitrothiazolo [3,2-a] benzimidazole-2-carboxamide was obtained by nitrating with fuming nitric acid, which was further subjected to the usual nitro group reduction conditions, that is, THF and MeOH. The title compound was obtained by reduction with Na ₂ S ₂ O ₄ in a mixed solvent. 3) A solution of the compound (0.33 g) obtained in 2) and N- (t-butoxycarbonyl) glycine (0.53 g) in DMF (15 ml) was cooled under ice-cooling.
HCl (0.58 g) was added and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water, the precipitate was collected by filtration, washed with water, and dried under reduced pressure. The obtained crystals were dissolved in a mixed solvent of MeOH / EtOAc, and a 4M.HCl.EtOAc solution was added thereto, followed by further stirring. The precipitate was collected by filtration, washed with EtOAc, and recrystallized from a mixed solvent of MeOH / EtOAc to give the title compound (180 mg). NMR (DMSO-d ₆ ): δ 11.29 (s, 1H), 9.20 (brs, 1H), 8.70
(s, 1H), 8.43 (br), 7.85 (br), 7.77 (d, 1H), 7.57 (d,
1H), 4.23 (br, 1H), 3.88 (brd, 2H), 3.18 (brs, 3H),
1.00-1.85 (m, 10H).

(Test Method) The effect of the compound of the present invention on mGluR1 was confirmed by the following test method. mGluR
MGl as a method for confirming the effect of a compound acting on
Although an evaluation system using uR1-expressing cells is known, the evaluation system is complicated because of the use of cells and the like.
The action of the compound of the present invention has a selective and strong action on mGluR1 (6-amino-N-cyclohexyl-N, 3-dimethylthiazolo [3,2-a] benzimidazole-2-carboxamide) (WO99 / 44639) was confirmed by a binding experiment using a tritium label. The above compound was synthesized from a phosphatidylinositol (PI) hydrolysis system using mGluR1α-expressing cells (Nature 38).
3, 89-92, 1996) for the reaction of glutamic acid.
_It has a high inhibitory activity of ₅₀ = 24 nM. ([ ³ H]-(6-amino-N-cyclohexyl-N, 3-
Dimethylthiazolo [3,2-a] benzimidazole-
Production method of 2-carboxamide) The synthesis of the tritium label used in the binding experiment was performed using 3-methylthiazolo [3,2-
a] 6-amino-N-cyclohexyl-3-methylthiazolo [3,2-a] benzimidazole-2-carboxamide synthesized from benzimidazole-2-carboxylic acid and cyclohexylamine according to Production Example 1 described in WO99 / 44639. It was prepared by selective N-methylation of amides with NaH, [ ³ H] -methyl iodide (CT ³ I) in DMF. Specific activity: 83 Ci / mmol (Amersham)

(Preparation of Rat Cerebellar P2 Membrane Fraction) Rat (Wi
star, male, 9-12 weeks of age), and the cerebellum was removed. The weight was measured and homogenized with 7-10 volumes of a 0.32 M sucrose solution. After centrifugation at 900 xg for 15 minutes, the supernatant was stored in another container (in ice). The sediment was homogenized again with the same amount of 0.32 M sucrose solution as in the first time, and centrifuged at 900 xg for 15 minutes. Combine the supernatant obtained at this time with the supernatant obtained earlier.
Centrifugation was performed at 15,000 xg for 20 minutes. Settle 5 mM Tris-HC
l, homogenized at pH 7.4 and centrifuged at 15,000 xg for 15 minutes. This operation was repeated once. 50 m sinking
Homogenize with M Tris-HCl, pH 7.4, 15 at 15,000xg
Centrifugation was performed for minutes. Settle an appropriate amount of 50 mM Tris-HCl, pH
Homogenized at 7.4, aliquoted and stored at -80 ° C.

(Binding Experiment) The binding experiment was performed by modifying the method of Thomsen et al. 50 mM Tr as assay buffer
is-HCl, 2.5 mM CaCl ₂ , pH 7.4 was used. [ ³ H]-(6-
Amino-N-cyclohexyl-N, 3-dimethylthiazolo [3,2-a] benzimidazole-2-carboxamide) (specific activity; 83 Ci / mmol; Amersham), test compound and about 0.1 mg of rat cerebellar P2 membrane The fraction was suspended in a test tube or a 96-well microplate so as to have a total volume of 200 μL, and incubated at room temperature (about 25 ° C.) for 45 minutes. End of incubation is Whatman GF / Bfi
This was performed by a filtration method using lter. The radioactivity was measured with a liquid scintillation counter. K _D in saturation experiments
The value was 47 nM and Bmax was 3.9 pmol / mg protein. About 20 nM [ ³ H] -6-amino-N-cyclohexyl-N, 3-dimethylthiazolo [3,2-a] benzimidazole-2-carboxamide was used in the competition experiment, and the specific binding was the total binding amount. Among them, 10 μM N-cyclohexyl-6-glycylamino-N-methylthiazolo [3,2-a] benzimidazole-2-carboxamide (Production example IC ₅₀ = 20 nM,
(a PI hydrolysis system using mGluR1α-expressing cells). The test compounds were evaluated by determining the binding inhibition rate on specific binding. BIO- for protein quantification
RAD DC protein assay (BIO-RAD) was used. Bovine serum albumin was used as a standard substance. References: Thomsen-C; Mulvihill-ER; Haldeman-B; Pic
kering-DS; Hampson-DR; Suzdak-PD, A pharmacologica
l characterization of the mGluR1 alpha subtype of
themetabotropic glutamate receptor expressed in a
cloned baby hamster kidney cell line., Brain-Res.
1993 Aug 13; 619 (1-2): 22-8 The above test confirmed that the compound of the present invention is a compound that specifically binds to mGluR1.

[0052]

According to the present invention, a novel imidazothiazole derivative which specifically acts on mGluR1 is provided.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Masaji Okada 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited (72) Inventor Atsushi Ohara 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Company Limited (72) Inventor Kenji Negoro 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Eisuke Nozawa 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture, Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Takashi Ukubo Ibaraki 21 Miyukigaoka, Tsukuba, Japan Pref. (72) Shuichi Sakamoto Inventor 21 Miyukigaoka, Tsukuba, Ibaraki Pref. F-term (reference) UU01 4C086 AA01 AA02 AA03 CB27 MA01 MA04 NA14 ZA02 ZA05 ZA06 ZA08 ZA12 ZA15 ZA16 ZA18 ZA29 ZA71 ZC39 ZC41

Claims (2)

[Claims] An imidazothiazole derivative represented by the following general formula (I) or a salt thereof. Embedded image (The symbols in the formula have the following meanings: R ¹ , R ² : the same or different, hydrogen, lower alkyl, or cycloalkyl R ³ : H, or lower alkyl R ⁴ , R ⁵ : the same or different , H, halogen, nitro,
Optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, -C (= O)
—R ⁹ , —NH—C (＝ O) —O-lower alkyl, Ring A: The ring may have one or two double bonds in the ring, a ring atom may be a carbon atom, or 1-3 carbon atoms may be a heteroatom, and a substituent may be present on the ring. Optionally substituted carbocycle or optionally substituted aromatic heterocycle R ⁶ , R ⁷ : same or different, H, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted Good heteroaryl, -C (= O) -O-lower alkyl,
—C (＝ O) —R ⁹ , or may form an optionally substituted cycloalkyl or saturated heterocycle. R
^6a : ＮN (R ¹⁰ ) R ¹¹ R ⁸ : H or lower alkyl R ⁹ : H, OH, or saturated heterocycle R ¹⁰ , R ¹¹ : same or different H, lower alkyl which may be substituted or Together they may have other heteroatoms as ring atoms and may form an optionally substituted heteroaryl or saturated heterocycle. X: oxygen atom or H 2. A medicament comprising the imidazothiazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.