JPH06271567A - 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; R1 is H, lower alkyl or aralkyl; R2 and R3 are H or lower alkyl; R4 is H, alkyl, cycloalkyl, (substituted) aryl, etc.; R5 is H, lower alkyl, (substituted) aralkyl, etc.] such as N-cyclohexyl- N',N'-[1,5-[3-(4(5)-1H-imidazolyl)pentanediyl]]formamidine. The compound of formula I is obtained by reducing a compound of formula III by using a catalyst such as Raney nickel. The reaction is carried out in ethanol under cooling with water for 10 minutes to about 5 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 THE INVENTION As a result of further studies in consideration of the above circumstances, the present inventors succeeded in synthesizing a novel compound having a histamine H ₃ receptor antagonistic action, and the present invention Was completed.

[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. 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 group, a cycloalkyl group, a cycloalkylalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group,
R ₅ represents hydrogen, a lower alkyl group, an optionally substituted aryl 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.

The aryl group which may be substituted includes halogen, trifluoromethyl group, lower alkyl group, lower alkoxy group, lower alkylthio group, cyano group, phenyl group which may be substituted with nitro group or naphthyl group. preferable. 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, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a cyano group and a phenyl group which may be substituted with a nitro group or a naphthyl group and the number of carbon atoms. An arylalkyl group consisting of 1 to 4 linear or branched alkyl groups is preferable.

Specifically, benzyl group, α-methylbenzyl group, phenethyl group, 3-phenylpropyl group, 4-
Phenylbutyl group, 4-chlorobenzyl group, 4-fluorobenzyl group, 4-methoxybenzyl group, 4-chloro-
Examples of the α-methylbenzyl group, 4-fluoro-α-methylbenzyl group, 4-methoxy-α-methylbenzyl group and the like.

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. Hereinafter, a specific method for synthesizing the compound of the present invention will be described. (1)

[0019]

[Chemical 3]

(Substituents are defined the same as above) Compound (II) is a compound known from JP-A-61-267574, EP Publication 494010 and the like. Compound (I
The compound (I-1) of the present invention can be obtained by subjecting I) to a reduction treatment using a catalyst such as Raney Ni. The reaction is performed in ethanol, for example. The reaction conditions are, for example, about 10 minutes to 5 hours under ice cooling. (2)

[0021]

[Chemical 4]

The first step is preferably carried out in an organic solvent such as dichloromethane. The reaction conditions are, for example, at room temperature for about 1 to 30 hours. The second step is preferably performed in a solvent such as absolute ethanol. The reaction conditions are, for example, room temperature for about 1 to 5 days. (3)

[0023]

[Chemical 5]

The first step is preferably carried out in an organic solvent such as benzene or xylene. The reaction conditions are, for example, 40 to 60 ° C. and 10 minutes to 3 hours. The second step is also preferably performed in an organic solvent such as benzene or xylene. The reaction conditions are, for example, 80 to 100 ° C. and about 1 to 10 hours. (4)

[0025]

[Chemical 6]

The first step is preferably carried out in a solvent such as ethanol. The reaction conditions are, for example, room temperature for about 6 to 24 hours. The second step is preferably performed in a polar solvent such as water, methanol or ethanol. The reaction conditions are, for example, about 1 minute to 24 hours at room temperature. (5)

[0027]

[Chemical 7]

The first step is preferably carried out under the same conditions as in the first step (4). The second step is also preferably performed under the same conditions as in the second step (4). (6)

[0029]

[Chemical 8]

(X represents halogen or OCOEt.) The first step is a usual amidation reaction. The second step is preferably performed in an organic solvent such as benzene. The reaction conditions are, for example, at room temperature for about 1 to 30 hours. The third step is also preferably performed in an organic solvent such as benzene. The reaction conditions are, for example, 65 to 70 ° C. and about 1 to 15 hours.

After the reaction, the obtained compound is isolated and purified in the form of an acid addition salt or a free base by a known method such as recrystallization, 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, histamine H ₃
It exhibits favorable antagonistic properties towards the receptor and the ability to increase the release of cerebral histamine exhibited by the derivatives according to the invention, these properties making these compounds the first compounds of this kind to be useful in human and veterinary medicine. It is what 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.

[0033]

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.

[0034]

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

[0035]

[Chemical 9]

N-cyclohexyl-N ', N'-[1,
Synthesis of 5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] formamidine dihydrochloride N-cyclohexyl-N ′, N ′-[1,5- [3-
(4 (5) -1H-imidazolyl) pentanediyl]]
Raney Ni (about 1 g) was added to a solution of thiourea (thioperamide) (200 mg) in ethanol (5 ml), and the mixture was stirred under ice cooling for 1 hour. The supernatant was removed by decantation, and the solvent was evaporated under reduced pressure to give a white powder. This powder was dissolved in ethanol (5 ml), a hydrochloric acid ethanol solution (5.6N 0.25 ml) was added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The solvent was distilled off under reduced pressure to give the above compound (175 m
g) was obtained. Blue powder.

The reaction formula is shown below.

[0038]

[Chemical 10]

The analytical data of the obtained title compound are shown below. ^{IR (KBr) 3400,2920,1690,1620,1450 1 H-} NMR (MeOH-d 4) δ: 8.89 (s, 1
H), 8.09 (brs, 1H), 7.43 (s, 1
H), 4.20 (brd, J = 13.5 Hz, 1H),
3.95 (brd, J = 12.9 Hz, 1H), 3.6
1 (td, J = 12.6, 2.7 Hz, 1H), 3.5
0-3.30 (m, 2H), 3.22 (tt, J = 1
1.8, 3.7 Hz, 1H), 2.40-2.10
(M, 2H), 2.10-1.60 (m, 7H), 1.
60-1.10 (m, 5H) Example 2 N- (1-adamantyl) -N ', N'-[1,5-
Synthesis of [3- (4 (5) -1H-imidazolyl) pentanediyl]] formamidine dihydrochloride N- (1-adamantyl) -N ′, N ′-[1,5-
[3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea (13.2 g) in ethanol (200
ml) solution, Raney Ni (200 g) was added under ice cooling,
Stir for 1.5 hours. After the reaction was completed, the supernatant was decanted, and the residual Raney Ni was washed with ethanol. The supernatant and the washing solution were combined and filtered, and then 10% hydrochloric acid methanol solution (300 ml) was added to the filtrate under ice cooling, and
Stir for 0 minutes. The solvent was distilled off to obtain 10.5 g of a crude product of the above compound.

A crude product of the above compound (10.5) was added to a solution of picric acid (20.0 g) in methanol (350 ml).
A solution of g) in methanol (140 ml) was added, followed by water (700 ml). The precipitated yellow powder is collected by filtration,
By recrystallizing from methanol-acetone-ether as a yellow powder, the picrate of the above compound (8.7) was obtained.
2 g) was obtained.

The picrate was mixed with 3N hydrochloric acid, and the released picric acid was removed with nitromethane and washed. The aqueous layer was evaporated under reduced pressure, and the residue was recrystallized from ethanol-ether to give 3.51 g of the above compound as a white powder.
Obtained. mp. 240 ° C. (decomposition) IR (KBr) 2800, 1682, 1602, 1460, 1348,
1065,950,795,600 ¹ H-NMR (D ₂ O) δ: 8.62 (s, 1H),
7.80 (s, 1H), 7.29 (s, 1H), 4.0
7 (d, J = 13.9 Hz, 1H), 3.91 (d, J
= 13.8 Hz, 1H), 3.58 (td, J = 13.
3,2.9 Hz, 1 H), 3.28 (td, J = 13.
3,2.9 Hz, 1H), 3.21 (tt, J = 11.1.
5,3.6Hz, 1H), 2.31-2.05 (m, 5
H), 1.55 (m, 14H) Example 3 N-cyclohexyl-N ', N'-[1,5- [3-
(4 (5) -1H-imidazolyl) pentanediyl]]
Synthesis of formamidine dihydrochloride According to Example 2, N-cyclohexyl-N ', N'-
The above compound was synthesized from [1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea (thioperamide). ¹ H-NMR (MeOH-d ₄ ) δ: 8.89 (s, 1
H), 8.09 (brs, 1H), 7.43 (s, 1
H), 4.20 (brd, 13.5 Hz, 1H), 3.
95 (brd, J = 12.9 Hz, 1H), 3.61
(Td, J = 12.6, 2.7 Hz, 1H), 3.50
-3.30 (m, 2H), 3.22 (tt, J = 11.
8, 3.7 Hz, 1H), 2.40-2.10 (m, 2
H), 2.10-1.60 (m, 7H), 1.60-
1.10 (m, 5H) Example 4 N- (exo-2-norbornyl) -N ', N'-
Synthesis of [1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] formamidine dihydrochloride According to Example 2, N- (exo-2-norbornyl)
The above compound was synthesized from -N ', N'-[1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] thiourea. ¹ H-NMR (D ₂ O) δ: 8.63 (d, J = 1.0)
Hz, 1H), 7.88 (s, 1H), 7.30 (s,
1H), 4.05 (d, J = 14.2Hz, 1H),
3.86 (d, J = 13.6 Hz, 1H), 3.75-
3.47 (m, 2H), 3.40-3.12 (m, 2
H), 2.42-2.28 (m, 2H), 2.21.
(D, J = 11.7 Hz, 2H), 1.93-1.71
(M, 3H), 1.64-1.38 (m, 4H), 1.
37-1.03 (m, 3H) Example 5 N- (2,2-dimethyl-1-methylpropyl)-
Synthesis of N ', N'-[1,5- [3- (4 (5) -1H-imidazolyl) pentanediyl]] formamidine dihydrochloride According to Example 2, 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: 8.64 (d, J = 1.4)
Hz, 1H), 7.90 (d, J = 2.6Hz, 1
H), 7.30 (d, J = 1.0 Hz, 1H), 4.0
8 (d, J = 13.5 Hz, 1H), 3.89 (d, J
= 13.3 Hz, 1H), 3.71-3.52 (m, 1
H), 3.47-3.16 (m, 3H), 2.24.
(D, J = 12.1 Hz, 2H), 1.96-1.67
(M, 2H), 1.28 (d, J = 6.9Hz, 3
H), 0.94 (s, 9H) Example 6 N- (4-chlorobenzyl) -N ', N'-[1,5-
Synthesis of [3- (4 (5) -1H-imidazolyl) pentanediyl]] formamidine dihydrochloride According to Example 2, 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, 1H), 8.05 (s, 1H), 7.55-7.
44 (m, 2H), 7.36 (d, J = 8.5Hz, 2
H), 7.31 (s, 1H), 4.63 (s, 2H),
4.12-3.84 (m, 2H), 3.77-3.57
(M, 1H), 3.38 (ddd, J = 12.8, 1
2.8, 2.9Hz, 1H), 3.26 (dddd, J
= 11.6, 11.6, 3.5, 3.5Hz, 1H),
2.25 (d, J = 12.9 Hz, 2H), 1.99-
1.68 (m, 2H) Example 7 N-phenethyl-N ', N'-[1,5- [3- (4
(5) -1H-Imidazolyl) pentanediyl]] formamidine dihydrochloride Synthesis According to Example 2, 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: 8.65 (d, J = 1.4)
Hz, 1H), 7.55-7.22 (m, 7H), 3.
98-3.82 (m, 1H), 3.82-3.54.
(M, 3H), 3.54-3.36 (m, 1H), 3.
36-3.04 (m, 2H), 3.04-2.80
(M, 2H), 2.32-2.04 (m, 2H), 1.
77-1.40 (m, 2H) Example 8 N- (3-fluorophenyl) -N ', N'-[1,5
Synthesis of 2- [3- (4 (5) -1H-imidazolyl) pentanediyl]] formamidine dimaleate N- (3-fluorophenyl) -N ′, N ′-[1,5
-[3- (4 (5) -1H-Imidazolyl) pentanediyl]] thiourea (10.1 g) in ethanol (40
Raney Ni (150 g) was added to the solution (0 ml) under ice cooling, and the mixture was stirred for 4 hours. After the reaction was completed, the supernatant was decanted, the residual Raney Ni was washed with ethanol, and the supernatant and the washing solution were combined and filtered. The solvent of the filtrate was distilled off to obtain 4.93 g of the free base of the above compound as a pale yellow powder.

Free base (4.73 g) of ethanol (2
Maleic acid (4.17 g) in ethanol (2 ml)
(0 ml) solution was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Ether (50 ml) was added, and the precipitated white powder was collected by filtration to obtain 7.54 g of the above compound as a white powder. mp. 148-150 ° C IR (KBr) 3400, 2950, 2800, 1690, 1570,
1470, 1360, 1190, 985 ¹ H-NMR (D ₂ O) δ: 8.60 (d, J = 1.3
Hz, 1H), 8.40 (s, 1H), 7.50-7.
35 (m, 1H), 7.14-6.98 (m, 3H),
6.22 (s, 4H), 4.26 (brd, J = 14.
0Hz, 1H), 4.05 (brd, J = 13.6H
z, 1H), 3.74 (ddd, J = 12.9, 12.
9, 2.8 Hz, 1 H), 3.48 (ddd, J = 1)
2.9, 12.9, 2.4 Hz, 1H), 3.25 (t
t, J = 11.6, 3.6 Hz, 1H), 2.27 (b
rd, J = 12.7 Hz, 2H), 1.94 (ddd,
J = 12.3, 8.3, 4.2 Hz, 1H), 1.81
(Ddd, J = 12.5, 8.5, 4.2 Hz, 1
H), Example 9 N-phenyl-N ', N'-[1,5- [3- (4
(5) -1H-Imidazolyl) pentanediyl]] formamidine Synthesis N-phenyl-N ′, N ′-[1,5- [3- (4
(5) -1H-Imidazolyl) pentanediyl]] Thiourea (572 mg) in ethanol (25 ml) was added Raney Ni (about 4 g) under ice cooling, and the mixture was stirred for 2.5 hours. After the reaction was completed, the supernatant was removed by decantation, and the residual Raney Ni was washed with ethanol. The supernatant and the washing solution were combined and filtered, and then the solvent was distilled off. The obtained crude product of the above compound was subjected to silica gel column chromatography (chloroform / methanol = 10/1 →
(5/1 → 3/1) to obtain 211 mg of the above compound as a foamy substance. IR (KBr) 3620-2380, 1616, 1582, 760, 6
^{95 1 H-NMR (DMSO-} d 6) δ: 12.96-1
0.67 (brs, 1H), 7.73 (s, 1H),
7.52 (s, 1H), 7.20 (t, J = 7.8H
z, 2H), 6.98-6.86 (m, 3H), 6.7.
8 (s, 1H), 4.67-4.03 (m, 1H),
4.03-3.62 (m, 1H), 3.62-2.87
(M, 2H), 2.87-2.66 (m, 1H), 2.
04-1.83 (m, 1H), 1.50 (dddd, J
= 12.2, 12.2, 12.2, 4.1 Hz, 2H) Experimental Example In a binding experiment using rat cerebral cortex membrane and [ ³ H] (R) -α-methylhistamine, the histamine H ₃ receptor was detected. The affinity of the present compound of the example was examined. The Ki value of this compound for the histamine H ₃ receptor (dissociation constant for the histamine H ₃ receptor) was 5 to 200 nM. Further, histamine-induced ileal contraction of guinea pigs mediated by histamine H ₁ receptor (Ash et al., Br. J. Pha).
rmac. Chemother. 27 427-439
<1966>) and histamine-inducing guinea pig isolated right atrial positive chronotropic effect via histamine H ₂ receptor (B
rack et al., Nature 236, 385-390.
The effect on <1972>) was hardly observed 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 code Internal reference number FI Technical display location C07D 403/04 209 7602-4C 223 7602-4C (72) Inventor Masanori Sugiura Invited Otani, Hirakata, Osaka 2-25-1 Midori Cross Central Research Institute Co., Ltd. (72) Inventor Tsuyoshi Fukaya 2-25-1 Otani Otani, Hirakata City, Osaka Prefecture 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. R ₁ represents hydrogen, a lower alkyl group, or an aralkyl group, and R ₂ and R
₃ represents 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 or an optionally substituted aryl. Represents a group or an optionally substituted aralkyl group, and R ₅ represents hydrogen, a lower alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group. Or a pharmaceutically acceptable salt thereof.