JPH06271566A - Imidazole-based compound - Google Patents

Abstract

PURPOSE:To obtain a new compound useful for treating Alzheimer's disease, etc., as energitizer, sleep modifier, brain metabolism activator, anticonvulsant, etc. CONSTITUTION:A compound of formula I (m is 4-6; A is S or O; R1 is H, lower alkyl or aralkyl; R2 and R3 are H or lower alkyl; R4 is H, alkyl, cycloalkyl, etc.; R5 is lower alkyl, lower alkenyl, etc.) such as N-cyclohexyl-N',N '-[1,5-[3-(4(5)-1H-imidazolyl)pentanediyl]]-S-methylisothiourea. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III {in the formula II and the formula III [X is halogen or p- toluenesulfonyloxy group; R5-X is (R5)2SO4 or (R5)3O<+>BF4]}. In the case where X is halogen or p-toluenesulfonyloxy group, the reaction is carried out in a methanol solution, etc., under cooling with ice for 1-10 hours.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an imidazole compound useful as a histamine H ₃ receptor antagonist.

[0002]

BACKGROUND OF THE INVENTION Histamine, an endogenous compound which is physiologically active in mammals, exerts its action by interacting with certain sites called receptors.
One type of receptor is known as the histamine H ₁ receptor (Ash and Schild, Brit J Pharmaco Chemocera (Ash and Schill).
d, Brit. J. Pharmac. Chemothe
r. ), 27 427 (1966)), the action of histamine mediated by these receptors was reported to be mepyramine (mepyamine).
It is blocked by H ₁ antagonists such as
The second type of receptor is known as the histamine H ₂ receptor (Black et al., Black (Black).
et al. , Nature), 1972 236 , 3
85), it is not blocked by mepyramine, but it is blocked by H ₂ antagonists such as burimamide or cimetidine.

In recent years, research on the central histamine neuron system has progressed, and it has become clear that the histamine neuron system exerts an influence over a wide range of the central nervous system. According to previous studies, histamine in the central region has brain functions, especially hypothalamic functions (sleep / wake rhythm,
It is also known to control endocrine, feeding / watering behavior, sexual behavior, etc.). In addition, the presence of histamine H ₃ receptor, which is an autoreceptor, has been proved in the presynaptic membrane of this neuron.

This third type of histamine H ₃ receptor has been identified (eg, Arrang et al.
t al. ), Nature 1987, 327 , 117
And Van der Werff et al.
erf et al. ), Trends Pharma Pharmacological Sciences (Trends Pharma)
col. Sci. ) 10,159 (1989)), it will be stimulated by H ₃ agonists such as (R)-.alpha.-methylhistamine, thioperamide (Thioperamid
Blocked by H ₃ antagonists such as e).

The histamine H ₃ receptor regulates the histamine level in the brain, and it is known that the histamine H ₃ receptor antagonist can raise the histamine level in the brain. Furthermore, it has been reported that histamine regulates the release of acetylcholine, noradrenaline, serotonin, etc. from nerve endings via the histamine H ₃ receptor.

The compounds having a histamine H ₃ receptor antagonistic action are described in, for example, JP-A-61-267574 and EP-A-494010 in addition to the above-mentioned thioperamide.

[0007]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention As a result of further research in consideration of the above circumstances, the present inventors have found that histamine H
We have succeeded in synthesizing a novel compound having ₃ receptor antagonism and completed the present invention.

[0008]

The present invention provides a compound represented by the following general formula (I):

[0009]

[Chemical 2]

[In the formula, m represents an integer of 4 to 6. A
Represents S or O, R ₁ represents hydrogen, a lower alkyl group or an aralkyl group, R ₂ and R ₃ represent hydrogen or a lower alkyl group, which may be the same or different, and R ₄ is , Hydrogen, a linear or branched alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, and R ₅ is a lower alkyl group,
It represents a lower alkenyl group, a lower alkynyl group or an optionally substituted aralkyl group. ] Or a pharmaceutically acceptable salt thereof.

When tautomerism occurs in the general formula (I), tautomers are also included. Further, in the general formula (I), when an optically active substance is present, the optically active substance is also included. The terms used in the substituents R _{1 to} R ₅ described in the general formula (I) of the present invention (including those common to R _{1 to} R ₅ ) will be further described.

The lower alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-
Butyl group, tert-butyl group, n-pentyl group, n-
A hexyl group etc. are illustrated. The linear or branched alkyl group is preferably one having 1 to 8 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, an iso- group.
Propyl group, n-butyl group, iso-butyl group, sec
-Butyl group, tert-butyl group, n-pentyl group, n
-Hexyl group, 1,1-dimethylpropyl group, 1,2-
Examples thereof include dimethylpropyl group and 1,2,2-trimethylpropyl group.

The cycloalkyl group has 3 to 1 carbon atoms.
A cycloalkyl group of 0 is preferred. The cycloalkyl group includes a monocycloalkyl group exemplified by a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like, as well as a polycycloalkyl group such as a bicycloalkyl group and a tricycloalkyl group. Examples of the group include a norbornyl group, for example, an exo-2-norbornyl group, an endo-2-norbornyl group, a 3-pinanyl group, a bicyclo [2.2.2] oct-2-yl group, and a tricycloalkyl group. , Adamantyl group,
Examples include 1-adamantyl group and 2-adamantyl group. The cycloalkyl group may be substituted with an alkyl group or the like.

The cycloalkylalkyl group is preferably a cycloalkyl group having 3 to 10 carbon atoms and a linear or branched alkyl group having 1 to 3 carbon atoms, specifically, a 1-cyclohexylethyl group. , 1-cyclopropylethyl group and the like. As the lower alkenyl group, a linear or branched alkenyl group having 3 to 6 carbon atoms is preferable. Specifically, an allyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, cis-
2-butenyl group, trans-2-butenyl group, 3-methyl-2-butenyl group and the like are exemplified.

The lower alkynyl group has 3 to 6 carbon atoms.
The alkynyl group of is preferable, and specific examples thereof include a 2-propynyl group and the like. The aryl group which may be substituted is preferably a halogen, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a cyano group, a phenyl group which may be substituted with a nitro group or a naphthyl group.

Specifically, phenyl group, 1-naphthyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4
Examples include -chlorophenyl group, 4-trifluoromethylphenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 2-tolyl group and 3-tolyl group. . The aralkyl group is preferably a benzyl group or a trityl group.

The aralkyl group which may be substituted includes halogen, trifluoromethyl group, lower alkyl group, lower alkoxy group, lower alkylthio group, cyano group and phenyl group which may be substituted with nitro group or naphthyl group. And an arylalkyl group consisting of a linear or branched alkyl group having 1 to 4 carbon atoms is preferable. In particular,
Benzyl group, α-methylbenzyl group, phenethyl group, 3
-Phenylpropyl group, 4-phenylbutyl group, 4-chlorobenzyl group, 4-fluorobenzyl group, 4-methoxybenzyl group, 4-chloro-α-methylbenzyl group, 4
-Fluoro-α-methylbenzyl group, 4-methoxy-α
-Methylbenzyl group and the like are exemplified.

These compounds are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, lactic acid, ascorbic acid, fumaric acid, oxalic acid, methanesulfonic acid and ethanesulfone. It is possible to form pharmaceutically acceptable acid addition salts with acids, p-toluenesulfonic acid and the like. The compound of the present invention is synthesized by the following formula.

[0019]

[Chemical 3]

(X represents halogen or a paratoluenesulfonyloxy group, or R ₅ —X represents (R ₅ ) ₂ SO ₄ or (R ₅ ) ₃ O ⁺ BF ₄ ^— . Other substituents are the same as those described above. Synonyms) The compound (II) is a compound known from JP-A-61-267574, EP publication 494010 and the like.

The compound (I) of the present invention can be obtained by reacting the compound (II) with the compound (III). In the reaction formula, when X represents halogen, it is preferably iodine. The reaction is such that when X is a halogen or a paratoluenesulfonyloxy group,
For example, it is performed in a methanol solution or a 10% hydrochloric acid-methanol solution. When R ₅ —X is (R ₅ ) ₂ SO ₄ , it is performed without solvent or in benzene, for example.

When R ₅ —X is (R ₅ ) ₃ O ⁺ BF ₄ ^— , it is carried out, for example, in a dichloromethane solution. As the reaction conditions, when X is a halogen or a paratoluenesulfonyloxy group, the reaction is performed under ice cooling for about 1 to 10 hours. R ₅
When -X is (R ₅ ) ₂ SO ₄ , it is 2 at 70 to 120 ° C.
Heating for about 6 hours is exemplified.

When R ₅ -X is (R ₅ ) ₃ O ⁺ BF ₄ ⁻ , it is exemplified at 0 ° C. to room temperature for about 12 to 24 hours. After the reaction, the obtained compound is a known method, for example, recrystallization,
It is isolated and purified in the form of acid addition salt or free base by TLC, adsorption chromatography and the like. Further, in the case of purifying in the form of an acid addition salt, a method of once forming a picrate and then converting it into a desired acid addition salt is useful.

The results of these studies show low toxicity, advantageous antagonistic properties towards the histamine H ₃ receptor and the ability to increase the release of cerebral histamine exhibited by the derivatives of the present invention, which properties are associated with them. It is the first compound of this type to be useful in human and veterinary medicine. Application of their therapeutic is especially those whose function is related to the central nervous system and peripheral organs, which is controlled by the histamine H ₃ receptor.

The drug of the present invention can be administered to humans orally, intravenously, lingually, nasally, rectally and parenterally, and the active ingredient is used as a therapeutically suitable excipient or diluent. Can be combined with liquid. Each unit dose is 0.5-100m
It is advantageous to include g of active ingredient and the daily dose can vary from 0.5 to 200 mg of active ingredient.

[0026]

INDUSTRIAL APPLICABILITY The imidazole compound of the present invention is a cerebral metabolism stimulant, an anticonvulsant, an analgesic, a food intake regulator, a body temperature regulator for the treatment of psychostimulants, sleep regulators, Alzheimer's disease and the like. It can be used as an endocrine regulator.
Furthermore, PET (Positron Emission To
It can also be used as a labeling compound for the imaging of histamine H ₃ receptors with the use of a mography.

[0027]

EXAMPLES In order to describe the present invention in more detail, examples will be described, but the present invention is not limited thereto. Example 1

[0028]

[Chemical 4]

N-cyclohexyl-N ', N'-[1,
Synthesis of 5- [3- (4 (5) -1H-imidazolyl) pentanediyl]]-S-methylisothiourea dihydrochloride N-cyclohexyl-N ′, N ′-[1,5- [3-
(4 (5) -1H-imidazolyl) pentanediyl]]
10% hydrochloric acid-methanol solution (20 ml) of thiourea (thioperamide) (500 mg) was added to iodomethane (4.
85 g) was added, and the mixture was stirred under ice cooling for 5 hours. The reaction solvent was evaporated under reduced pressure, the residue was dissolved in ethanol and treated with activated carbon. Further, recrystallization from ethanol-ether was performed to obtain the above compound (339 mg) as a yellow powder.

Mp. 145 ° C. (decomposition) IR (KBr) 3400, 2900, 1590, 1450, 1400 ¹ H-NMR (MeOH-d ₄ ) 8.85 (s, 1H) 7.43 (s, 1H) 4.25 (d, J = 13.7 Hz, 2H) 3.98 (tt, J = 11, 4.0 Hz, 1H) 3.57 (td, J = 13.4, 2.5 Hz, 2H) 3.25 (tt, J = 11,4 Hz, 1H) 2.65 (s, 3H) 2.32-2.10 (m, 2H) 2.05-1.10 (m, 12H) Example 2 N-cyclohexyl-N ', N' -[1,5- [3-
(4 (5) -1H-imidazolyl) pentanediyl]]
Synthesis of -S-methylisothiourea dimaleate The above compound was synthesized according to Example 1.

White powder (mp. 138-141 ° C.) IR (KBr) 1580, 1490, 1390, 1370, 1200,
^{1080,990,865 1 H-NMR (MeOH-} d 4) 8.64 (s, 1H) 7.31 (s, 1H) 6.26 (s, 4H) 4.24 (d, J = 13.8Hz , 2H) 4.05-3.90 (m, 1H) 3.53 (td, J = 11.3, 2.0 Hz, 2H) 3.19 (tt, J = 11.7, 3.95 Hz, 1H) ) 2.64 (s, 3H) 2.25-2.15 (m, 2H) 2.08-1.65 (m, 7H) 1.65-1.10 (m, 5H) Example 3 N- (Exo-2-norbornyl) -N ', N'-
Synthesis of [1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]]-S-methylisothiourea dihydrochloride N- (exo-2-norbornyl) -N ', N'-
[1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea (11.6 g) and 10%
To a solution consisting of hydrochloric acid-methanol solution (580 ml),
Iodomethane (41 ml) was added under ice cooling. After stirring under ice cooling for 5 hours, the mixture was stirred at room temperature for 2 hours. The reaction solvent was evaporated under reduced pressure, and the residue was dissolved in MeOH (150 ml). Picric acid (28.8 g) was added to MeOH (400 ml).
Was added to the solution dissolved in, followed by water (1200 ml). The precipitated yellow powder was collected by filtration and recrystallized from acetone-ether to obtain 21.9 g of the picrate of the above compound as a yellow powder. Add this to 3N HCl (650
ml) and free picric acid was removed and washed with nitromethane. The aqueous layer was evaporated under reduced pressure, and the residue was ethanol-
By recrystallizing from ether, 8.77 g of the above compound was obtained as white crystals. mp. 170.5 to 171.5 ° C IR (KBr) 3650-3225, 3225-2660, 1595,
1448, 1387, 1360, 1255, 1093
824 ¹ H-NMR (D ₂ O) δ: 8.66 (d, J = 1.3 Hz, 1 H) 7.33 (s, 1 H) 4.24 (d, J = 13.6 Hz, 2 H) 3. 98-3.88 (m, 1H) 3.63-3.48 (m, 2H) 3.27 (dddd, J = 3.7, 3.7, 11.7,
11.7 Hz, 1H) 2.62 (s, 3H) 2.42-2.33 (m, 2H) 2.32-2.22 (m, 2H) 1.97-1.80 (m, 3H) 1.66-1.46 (m, 4H) 1.35-1.24 (m, 2H) 1.23-1.14 (m, 1H) Example 4 N- (1-adamantyl) -N ', N '-[1,5-
Synthesis of [3- (4 (5) -1H-imidazolyl) pentanediyl]]-S-methylisothiourea dihydrochloride According to Example 3, N- (1-adamantyl) -N ′,
The above compound was synthesized from N '-[1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea. ¹ H-NMR (DMSO-d ₆ ) δ: 15.16-15.01 (brs, 1H) 14.55-14.33 (brs, 1H) 9.09 (s, 1H) 8.98 (s, 1H) 7.49 (s, 1H) 4.09 (d, J = 14.2 Hz, 2H) 3.62-3.35 (m, 2H) 3.27-3.07 (m, 1H) 2. 64 (s, 3H) 2.28-2.00 (m, 1H) 2.00-1.74 (m, 2H) 1.74-1.60 (m, 6H) Example 5 N- (2, 2-dimethyl-1-methylpropyl)-
Synthesis of N ', N'-[1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]]-S-methylisothiourea dihydrochloride According to Example 3, N- (2 2-Dimethyl-1-methylpropyl) -N ', N'-[1,5- [3- (4
The above compound was synthesized from (5) -1H-imidazolyl) pentanediyl]] thiourea. ¹ H-NMR (D ₂ O) δ: 8.65 (d, J = 1.4 Hz, 1H) 7.30 (s, 1H) 4.46-4.13 (m, 3H) 3.68-3 .46 (m, 2H) 3.38-3.19 (m, 1H) 2.60 (s, 3H) 2.27 (d, J = 13.0Hz, 2H) 1.98-1.71 (m , 2H) 1.30 (d, J = 6.9 Hz, 3H) 0.97 (s, 9H) Example 6 N- (4-chlorobenzyl) -N ′, N ′-[1,5-
Synthesis of [3- (4 (5) -1H-imidazolyl) pentanediyl]]-S-methylisothiourea dihydrochloride According to Example 3, N- (4-chlorobenzyl)-
The above compound was synthesized from N ', N'-[1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea. ¹ H-NMR (D ₂ O) δ: 8.65 (d, J = 1.3 Hz, 1 H) 7.48 (d, J = 8.5 Hz, 2 H) 7.36 (d, J = 8.5 Hz) , 2H) 7.31 (s, 1H) 4.86 (s, 2H) 4.30 (d, J = 14.0Hz, 2H) 3.73-3.49 (m, 2H) 3.41-3 .18 (m, 1H) 2.55 (s, 3H) 2.37-2.19 (m, 2H) 2.00-1.72 (m, 2H) Example 7 N-phenethyl-N ', N ′-[1,5- [3- (4
(5) -1H-Imidazolyl) pentanediyl]]-S
Synthesis of -Methylisothiourea dihydrochloride According to Example 3, N-phenethyl-N ', N'-
The above compound was synthesized from [1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea. ¹ H-NMR (D ₂ O) δ: 8.64 (d, J = 1.3 Hz, 1H) 7.51-7.24 (m, 6H) 4.18-3.96 (m, 4H) 3 .42 (t, J = 12.3 Hz, 2H) 3.30-3.10 (m, 1H) 3.01 (t, J = 6.5 Hz, 2H) 2.31 (s, 3H) 2.27 -2.11 (s, 2H) 1.85-1.54 (m, 2H) Example 8 N- (3-fluorophenyl) -N ', N'-[1,5
Synthesis of-[3- (4 (5) -1H-imidazolyl) pentanediyl]]-S-methylisothiourea N- (3-fluorophenyl) -N ', N'-[1,5
-[3- (4 (5) -1H-Imidazolyl) pentanediyl]] thiourea (456 mg) and a solution of 10% hydrochloric acid-methanol solution (20 ml) was added with iodomethane (1.0 ml) under ice cooling, followed by ice cooling. Stir under 5 hours. The reaction solvent was distilled off under reduced pressure, and the obtained residue was added to MeOH.
It was dissolved in (150 ml), saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography (chloroform / methanol = 20/1 → 10 /
1), and 381 mg of the above compound as a resinous substance
Obtained. IR (KBr) 3060, 2920, 2830, 1563, 1182
^{1116,1093,772,748,692 1 H-NMR (DMSO-} d 6) δ: 11.93 (brs, 0.4H) 11.80 (brs, 0.6H) 7.53 (s, 1H) 7 .24 (dd, J = 8.2 Hz, 15.2 Hz, 1
H) 6.85 (brs, 1H) 6.73 (dt, J = 2.0 Hz, 8.3 Hz, 1H) 6.66-6.49 (m, 2H) 3.04 (t, J = 11. 5Hz, 2H) 2.11 (s, 3H) 1.95 (d, J = 10.8Hz, 2H) 1.58 (q, J = 11.7Hz, 2H) Example 9 N-phenyl-N ', N '-[1,5- [3- (4
(5) -1H-Imidazolyl) pentanediyl]]-S
Synthesis of -Methylisothiourea dihydrochloride According to Example 8, N-phenyl-N ', N'-[1,
The above compound was synthesized from 5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea. ¹ H-NMR (DMSO-d ₆ ) δ: 12.24-11.43 (brs, 1H) 7.52 (s, 1H) 7.22 (t, J = 7.7Hz, 2H) 6.93 ( t, J = 7.3 Hz, 1H) 6.77 (s, 1H) 6.76 (d, J = 7.3 Hz, 2H) 4.15 (d, J = 13.0 Hz, 2H) 3.00 ( t, J = 12.0 Hz, 2H) 2.88-2.66 (m, 1H) 2.09 (s, 3H) 1.96 (d, J = 12.6 Hz, 2H) 1.58 (dq, J = 3.2Hz, 12.3Hz, 2
H) Experimental Example Arrang et al. (Nature 327 , 117-12)
3 (1987)), the affinity of the present compound of the example for the histamine H ₃ receptor was examined in a binding experiment using rat cerebral cortex membrane and [ ³ H] (R) -α-methylhistamine. did. The Ki value of this compound for histamine H ₃ receptor (dissociation constant for histamine H ₃ receptor) was 40 to 700 nM. Also, histamine H
_1- receptor-induced histamine-induced guinea pig isolated ileal contractile action (Ash et al., Br. J. Pharmac. Che
mother. 27 427-439 <1966>) and histamine-inducing guinea pig isolated right atrial positive chronotropic effect via histamine H ₂ receptor (Black et al., Na.
Almost no effect was observed on true 236, 385-390 <1972>) even when the compound was applied at 1 mM. This indicates the high selectivity of this compound for the histamine H ₃ receptor.

Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location C07D 403/04 209 7602-4C 223 7602-4C (72) Inventor Hiroshi Sakashita 2-25 Otani, Otani, Hirakata, Osaka No. 1 Incorporated Midori Cross Central Research Institute (72) Inventor Kazuki Murakami Invited 2-25-1 Otani, Hirakata City, Osaka Prefecture Incorporated Midori Cross Central Research Institute (72) Masanori Sugiura Invited by Hirakata City, Osaka Prefecture 2-25-1 Otani Midori Cross Central Research Institute Co., Ltd.

Claims (1)

[Claims] 1. A compound represented by the following general formula (I): [In formula, m represents the integer of 4-6. A is S or O
R ₁ represents hydrogen, a lower alkyl group, or an aralkyl group, R ₂ and R ₃ represent hydrogen or a lower alkyl group, which may be the same or different from each other, and R ₄ is
Hydrogen, a linear or branched alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R ₅ is a lower alkyl group, a lower alkyl group An alkenyl group,
It represents a lower alkynyl group or an optionally substituted aralkyl group. Or a pharmaceutically acceptable salt thereof.