JPH08301825A - 3'-substituted-(2-carboxycyclopropyl)glycine - Google Patents

Abstract

PURPOSE: To obtain a 3'-substituted-(2-carboxycyclopropyl)glycine which is an antagonist for kainic acid type L-glutamic acid receptors to be a clue to the development of a glutamic acid receptor blocker. CONSTITUTION: This compound of the formula (R is a lower alkenyl or a lower alkyl), e.g. (2S,1'R,2'S,3'R)-2-(2-carboxy-3-ethylenecyclopropyl)glycine. The exemplified compound is obtained by deprotecting (1R,7S,8R,9R)-3-aza-9-t- butyldimethylsilyloxymethyl-4,4-dimethyl-5-oxatricyclo [6.1.0.0<3.7> ] nonan-2-one, oxidizing the resultant compound, introducing an olefin thereinto with a Tebbe reagent, opening the ring, passing the obtained compound through protection of OH and NH2 , affording a pyrrolidone derivative, carrying out the methanolysis, providing a dimethyl ester derivative by Jones oxidation of the deprotected OH group and esterification, further saponifying the resultant ester derivative with an alkali and then deprotecting the saponification product with an acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cyclopropylglycine derivative that plays an important role in the study of L-glutamic acid receptors, and more specifically, kainic acid type L-
3'-Substitution-, which is a glutamate receptor agonist
It relates to (2-carboxycyclopropyl) glycine.

This compound provides a clue to the development of L-glutamic acid receptor blockers through the study of kainic acid type L-glutamic acid receptor agonists.
It can be expected to be applied to the treatment of neurological disorders such as epilepsy, Huntingson's disease, Parkinson's disease, and neuromutation. Furthermore, the present compound is expected to give important findings for elucidating the L-glutamic acid accepting mechanism from the correlation between the conformation and activity of L-glutamic acid and its related compounds.

[0003]

2. Description of the Related Art L-Glutamic acid is used as a transmitter of excitatory nerve stimulation in the central nervous system of mammals, and as a neuroexcitotoxin that destroys nerve cells and causes various brain and nerve diseases. It is attracting attention as a substance that is important in the formation of

The L-glutamic acid receptor is linked to such various physiological functions, and by the introduction of an exogenous agonist group, the following three subtypes, that is, (a). NMDA (N-methyl-D-aspartic acid)
Type (b). KA (kainic acid) type (c). AMPA (α-amino-3-hydroxy-5-
It is classified into three subtypes of (methyl-4-isoxazolpropionic acid) type. Also, KA
The (kainic acid) type and the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid) type may be collectively referred to as a non-NMDA type.

Conventionally, NMDA type receptors are considered to be the center of neuroexcitotoxins, and it is presumed that nerve cells are destroyed by excessive activation of the receptors, which in turn trigger various neurological diseases. ing.

Regarding the NMDA type receptor, the present inventors have established (2S, 1'R, 2'S) -2- (2-
It is disclosed that carboxycyclopropyl) glycine is a potent NMDA type agonist that surpasses NMDA, and that the folded conformation of glutamic acid activates the NMDA receptor (JP-A-1-09356).
3).

Among the non-NMDA type receptors, K
The A-type receptor has been found to cause epileptiform lesions in rats by kainic acid itself, and to exhibit neuronal cell somatic depletion, and this KA-type receptor is associated with neuronal cell death. It is thought that
Furthermore, in recent years, it has been found from molecular biological studies that types 5 to 7 (iGluR5 to 7) of ion channel type L-glutamic acid receptors (hereinafter abbreviated as iGluR) correspond to KA type receptors. There is.

[0008]

However, as the KA type agonist, only kainoids (general term for compounds having a kainic acid skeleton in the molecule) such as domoic acid and acromainic acid derived from natural products are known. Therefore, development of selective agonists / antagonists in studying the function of the receptor is desired.

[0009]

The present inventors have previously synthesized (2S, 1'R, 2'R, 3'R) -2- (2-carboxy-3-methoxymethylcyclopropyl) glycine. (T
-MCG-IV, the compound described in Example 8 of JP-A-3-261748) and (2S, 1'R, 2'S) -2-
Since (2-carboxy-4-methylidenecyclopentyl) glycine (CPG-IV, the compound described in Example 3 of JP-A-5-125025) is a KA-type agonist, this KA-type configuration The locus request was presumed to be the folded type of glutamic acid. Furthermore, by superimposing them with kainic acid, it was found that the substituents on the ring occupy almost the same space as the isopropenyl group of kainic acid, which plays an important role in the activity expression.

The inventors of the present invention have shown that the compound having the activating factor of these substituents is 3'- represented by the formula (1).
Substituted-2- (2-carboxycyclopropyl) glycine:

[0011]

Embedded image (In the formula, R is a lower alkenyl group or a lower alkyl group)

## STR1 ## This compound is glutamic acid KA
The present invention was completed by discovering that it is an agonist of a type receptor. That is, according to the present invention, 3'-substitution-
(2-carboxycyclopropyl) glycine (1),
It can be provided as an agonist of glutamate KA type receptor. 2- which is one of the compounds of the present invention
The (2-carboxy-3-ethylenecyclopropyl) glycine (1a) (that is, the compound of the formula (1) in which R is a vinyl group) is, for example, a known compound (1R, 7S, 8
R, 9R)-3-aza -9-t-butyldimethylsilyloxy-4,4-dimethyl-5-oxatricyclo [6.1.0.0 ^3.7] nonan-2-one (2) (JP Described as compound 4 in Kaihei 3-261748)
Starting from, the scheme shown below:

[0013]

Embedded image

(In the scheme, Me represents a methyl group, and T
BS represents t-butyldimethylsilyl group, and Boc represents t
Represents a butoxycarbonyl group. ). That is, t-butyldimethylsilyl compound (2)
Is deprotected to give a hydroxymethyl form, which is oxidized to the aldehyde form (3). This is reacted with Tebbe's reagent to convert the terminal aldehyde into an olefin to give an olefin body (4). Next, after opening the oxazolane ring portion, the hydroxyl group and the amino group are protected to obtain a pyrrolidone body (5). This is subjected to methanolysis to obtain a methyl ester body (6). The alcohol body obtained by deprotecting the t-butyldimethylsilyl group of this compound is Jones-oxidized to a carboxylic acid body and then esterified to obtain a dimethyl ester body (7). By subjecting this to alkali saponification and deprotection with acid, the desired 2- (2-carboxy-3-ethylenecyclopropyl) glycine (1a) can be obtained. Furthermore, 2- (2-carboxy-3-, which is one of the present invention,
Ethylcyclopropyl) glycine (1b) (ie,
In order to obtain a compound of formula (1) in which R is an ethyl group, according to the above scheme, the ethylene group of compound (6), which is the above intermediate, is reduced to an ethyl group, and then t
The hydroxyl body obtained by deprotecting the -butyldimethylsilyl group is Jones-oxidized and then esterified to obtain a dimethyl ester body (8). This is deprotected with alkali saponification and acid to give the desired 2- (2-carboxy-3-
Ethylcyclopropyl) glycine (1b) can be obtained. Further, if an alkenyl group is introduced into the aldehyde (3) with a Wittig reagent or a Honer-Emmons reagent according to the method shown here, R is a propenyl group, a butenyl group, an isobutenyl group,
A compound such as a carboxyethylene group can be synthesized. Further, by reducing these intermediates, a compound of formula (1) in which R is a propyl group, a butyl group, an isobutyl group, a carboxyethyl group or the like can be synthesized.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention, 2- (2-carboxy-3-
Ethylenecyclopropyl) glycine (1a) and 2- (2
-Carboxy-3-ethylcyclopropyl) glycine (1
b) is an electrophysiology method using rat spinal motor nerves (Ots
uka & Konishi, Nature, 252, 733-734, 1974). The strength of the ethylene form (1a) was almost the same as that of kainic acid and NMDA, and that of the ethyl form (1b) was about 1/4. As a result of using an antagonist, it was found that both compounds activate both NMDA type receptors and non-NMDA type receptors. Rat C-fibe is also highly sensitive to KA type receptors
Electrophysiology test using r (Evans et. al., Br. J. Pha
rmacol., 91, 531-537, 1987) shows that the ethyl form (1
b) showed almost the same strong activity as kainic acid, and the ethylene form (1a) was about 1/3 of that. Therefore, it was confirmed that the compound of the present invention is an agonist of KA type receptor. These will lead to research on glutamate receptors, including elucidation of the activation mechanism of receptors, and will provide a clue to the development of glutamate blockers.

[0017]

EXAMPLES Next, the synthesis of the compounds of the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited to these.

Example 1. (2S, 1'R, 2'S, 3'R)-
2- (2-carboxy-3-ethylenecyclopropyl)
Synthesis of glycine (1a): Step 1. (1R, 7S, 8R, 9R) -3-Aza-
4,4-dimethyl-9-formyl-5-oxatricyclo [6.1.0.0 ^3.7] Synthesis nonane-2-one (3): (1R, 7S , 8R, 9R) -3- aza - 9-t-
Butyldimethylsilyloxymethyl-4,4-dimethyl-5-oxatricyclo [6.1.0.0 ^3.7 ] nonan-2-one (2) (described as compound 4 in JP-A-3-261748) (220mg, 0.70mmo
Tetranormal-butylammonium fluoride (1M / THF solution, 1.05 ml) was added to a tetrahydrofuran (hereinafter abbreviated as THF) solution (10 ml) of 1) under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ether / methanol = 9/1) to give a hydroxymethyl derivative (109 m
g, 99%) was obtained.

Hydroxymethyl derivative (120 mg, 0.6
Pyridinium dichromate (PDC) (456 mg, 1.21 m) in a methylene chloride solution (2 ml) of 0 mmol).
(mol) was added and stirred for 18 hours. After diluting with ether, magnesium sulfate was added and filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ether) to obtain the title compound (3). (Yield 85
mg, 72% yield).

Properties: colorless oily substance ¹ H-NMR (400 MHz, CDCl ₃ , δpp
m): 1.44 (s, 3H), 1.55 (s, 3H), 2.16 (ddd, 1H, J
= 2.5, 3.5, 3.5 Hz), 2.35 (ddd, 1H, J = 3.5, 5.0,
6.0Hz), 2.68 (dd, 1H, J = 2.5, 6.0 Hz), 3.48 (dd,
1H, J = 8.5, 8.5 Hz), 4.01 (dd, 1H, J = 6.0, 8.5
Hz), 4.61 (ddd, 1H J = 5.0, 6.0, 8.5 Hz), 9.48 (d,
1H, J = 3.5 Hz).

Step 2. (1R, 7S, 8R, 9R)
Synthesis of 3--3-aza-4,4-dimethyl-9-ethylene-5-oxatricyclo [6.1.0.0 ^3.7 ] nonan-2-one (4): Compound (3) (130 mg, 0. 66
mmol) in a THF solution (20 ml) under cooling at −78 ° C. with Tebbe reagent (μ-chloro-μ-methylene- [bis (cyclopentadiene) titanium] dimethylaluminum) (0.5 M toluene solution, 1.32 ml). After the addition, the mixture was stirred at -20 ° C for 20 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ether) to give the title compound (4).
(Yield 82 mg, Yield 64%)

Properties: colorless oily substance ¹ H-NMR (400 MHz, CDCl ₃ , δpp
m): 1.45 (s, 3 H), 1.55 (s, 3 H), 1.73 (ddd, 1
H, J = 3.0, 3.5, 9.0 Hz), 1.76 (ddd, 1 H, J = 3.5,
5.5, 5.5 Hz), 2.12 (dd, 1 H, J = 3.0, 5.5 Hz), 3.
50 (dd, 1 H, J = 8.5, 9.0 Hz), 3.99 (dd, 1 H, J =
6.0, 8.5 Hz), 4.53 (ddd, 1 H, J = 5.5, 6.0, 9.0 H
z), 5.03 (dd, 1 H, J = 1.0, 10.5 Hz), 5.16 (dd, 1
H, J = 1.0, 17.0 Hz), 5.35 (ddd, 1 H, J = 9.0, 10.
5, 17.0 Hz).

Step 3. (1R, 4S, 5R, 6R)
-3-aza-3-Nt-butoxycarbonyl-4-t
Synthesis of -butyldimethylsilyloxymethyl-6-ethylenebicyclo [3.1] hexan-2-one (5): Compound (4) (82 mg, 0.42 mmol) in methanol (3 ml) was added camphorsulfonic acid (CSA). )
(10 mg) was added, and the mixture was stirred at room temperature for 20 hours. 2,6-lutidine (20 μl) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The operation of dissolving the residue in benzene and distilling off the solvent under reduced pressure was repeated 3 times to completely remove methanol. The residue was dissolved in methylene chloride (3 ml), t-butyldimethylsilyl trifluoromethanesulfonate (146 μl, 0.63 mmol) and 2,6-lutidine (147 μl, 1.26 mmol) were added under ice cooling, and the mixture was stirred for 20 minutes. . A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. 5% organic layer
After washing with an aqueous citric acid solution and water, drying over magnesium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (ether) to obtain a lactam body.

The lactam body thus obtained was dissolved in THF (5 ml), and di-t-butyl dicarbonate (145 μl,
0.64 mmol), triethylamine (133 μl,
0.96 mmol), 4-dimethylaminopyridine (2
0 mg, 0.16 mmol) was added and stirred for 40 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of citric acid and water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ether / hexane = 1/1) to give the title compound (5 Was obtained (amount 137 mg, yield 89%).

Properties: colorless oily substance ¹ H-NMR (400 MHz, CDCl ₃ , δpp
m): 0.06 (s, 3 H), 0.07 (s, 3 H), 0.89 (s, 9 H),
1.50 (s, 9 H), 2.03 (m, 1 H), 2.10 (m, 2 H), 3.64
(dd, 1 H, J = 8.0, 9.0 Hz), 4.10 (dd, 1 H, J = 3.
5, 9.0 Hz), 4.21 (ddd, 1 H, J = 3.5, 5.0, 8.0 Hz),
5.02 (dd, 1 H, J = 1.0, 10.0 Hz), 5.14 (dd, 1 H,
J = 1.0, 16.5 Hz), 5.35 (ddd, 1 H, J = 7.5, 10.0,
16.5 Hz).

Step 4. (2S, 1'R, 2'S, 3'R)
Synthesis of -Nt-butoxycarbonyl-2- (2-carboxy-3-ethylenecyclopropyl) glycine dimethyl ester (7): Lithium hydroxide (10 mg) was added to a methanol solution (2 ml) of compound (5) at room temperature. It was stirred for 2 hours. The reaction solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give methyl ester (6). This is methanol (2m
It was dissolved in l), CSA (10 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give an alcohol compound.

The obtained alcohol compound was converted into acetone (3 m
It was dissolved in 1), the Jones reagent was added under ice cooling, and the mixture was stirred for 2 hours. 2-Propanol was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue obtained was added with an ether solution of diazomethane to form a methyl ester. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ether / hexane = 1/1) to obtain the title compound (7) (yield 67 mg, yield 63%).

Properties: colorless oily substance ¹ H-NMR (400 MHz, CDCl ₃ , δpp
m): 1.46 (s, 9 H), 1.51 (ddd, 1 H, J = 6.0, 9.0,
10.0 Hz), 1.90 (dd, 1 H, J = 5.5, 9.0 Hz), 2.43 (m,
1 H), 3.71 (s, 3 H), 3.72 (s, 3 H), 4.51 (m, 1 H),
5.01 (d, 1 H, J = 10.0 Hz), 5.17 (dd, 1 H, J = 1.0,
17.0 Hz), 5.41 (ddd, 1 H, J = 7.5, 10.0, 17.0 H
z).

Step 5. (2S, 1'R, 2'S, 3'R)
Synthesis of 2- (2-carboxy-3-ethylenecyclopropyl) glycine (1a): Compound (7) (67m
g, 0.21 mmol) in methanol solution (1 ml) was added with 1M aqueous sodium hydroxide solution (0.8 ml) under ice cooling, and the mixture was stirred for 3 hours. Methanol was distilled off under reduced pressure, the pH was adjusted to 2 with 1M hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. The residue obtained by concentration under reduced pressure was cooled with ice and methylene chloride-trifluoroacetic acid (1: 1,
1 ml) and stirred for 15 minutes. The residue obtained by concentration under reduced pressure is subjected to ion exchange resin column chromatography Dowe.
It was applied to x-50X4 (100-200 mesh), washed with water, and then eluted with 1M aqueous ammonia. The operation of dissolving the obtained ammonium salt in a small amount of water and distilling off the solvent under reduced pressure was repeated until the pH of the solution became 3, and the precipitated crystals of the title compound were collected by filtration (yield 37 mg, yield 92).
%).

Properties: colorless crystals Melting point: 163.5-165.0 ° C. [α] _D : -38.7 ° (c = 0.51, H ₂ O) IR (film, cm ^-1 ): 3011, 2876 , 2357, 2334, 1637,
^{1568, 1452, 1402. 1 H-} NMR (400MHz, D 2 O, δppm): 1.6
9 (ddd, 1 H, J = 6.0,9.0, 9.0 Hz), 1.94 (dd, 1 H,
J = 5.0, 9.0 Hz), 2.13 (ddd, 1 H, J = 5.0,6.0, 8.5
Hz), 4.05 (d, 1 H, J = 9.0 Hz), 5.06 (dd, 1 H, J
= 1.0, 10.5 Hz), 5.24 (dd, 1 H, J = 1.0, 17.0 Hz),
5.57 (ddd, 1 H, J = 8.5, 10.5, 17.0Hz).

Embodiment 2 FIG. (2S, 1'R, 2'S, 3 '
R) -2- (2-carboxy-3-ethylcyclopropyl
Le) Glycine (1b) synthesis step 1. (2S, 1'R, 2'S, 3'R) -N-
Synthesis of tert-butoxycarbonyl-2- (2-carboxy-3-ethylcyclopropyl) glycine dimethyl ester (8) Intermediate (6) (39 mg, 0.098 mm) in the synthesis of ethylene body (1a)
was dissolved in ethyl acetate, 10% palladium-carbon catalyst (5 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hour.
The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was dissolved in methanol (2 ml) and the ion exchange resin Amberlyst (1
0 mg) was added and the mixture was stirred at room temperature for 3 hours. The resin-free filtrate was concentrated under reduced pressure, the residue was dissolved in acetone (3 ml), the Jones reagent was added under ice-free conditions, and the mixture was stirred for 2 hours. 2 in the reaction solution
-Propanol was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue obtained was added with an ether solution of diazomethane to form a methyl ester. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ether / hexane = 1/1) to obtain the title compound (8). (Yield 18 mg, Yield
(58%)

Properties Colorless oily substance: ¹ H-NMR (400 MHz, CDCl ₃ , δppm): 0.95 (t, 3 H,
J = 7.5 Hz), 1.16 (m, 1 H), 1.23 (ddd, 2 H, 7.5,
7.5, 10.0 Hz), 1.46 (s, 9 H), 1.60 (m, 1 H), 1.77
(m, 1 H), 3.70 (s, 6 H), 4.43 (m, 1 H), 5.20 (m, 1
H)

Step 2. (2S, 1'R, 2'S,
Synthesis of 3′R) -2- (2-carboxy-3-ethylcyclopropyl) glycine (1b) Compound (8) (18 mg, 0.057 mmol) in methanol
(1 ml) under ice-cold 1M aqueous sodium hydroxide solution (0.8
(ml) was added and stirred for 3 hours. Methanol was distilled off under reduced pressure, pH was adjusted to 1 with 1 M hydrochloric acid, and the mixture was stirred for 18 hours. The residue obtained by concentration under reduced pressure was dissolved in TFA-water and subjected to ion exchange resin column chromatography Dowex-50x4 (100-200 mesh),
After washing with water, it was eluted with 1 M aqueous ammonia. The operation of dissolving the obtained ammonium salt in a small amount of water and distilling off the solvent under reduced pressure was repeated until the aqueous solution reached pH 3 to obtain the title compound 1b. (Yield 8.6 mg, Yield 75%)

[Α] _D + 14.0 ° (c 0.86, H ₂ O) ¹ H-NMR (400 MHz, D ₂ O, δppm): 0.97 (t, 3 H, J
= 7.0 Hz), 1.38 (m, 1H), 1.43 (m, 1 H), 1.48 (m, 2
H), 1.74 (dd, 1 H, J = 6.0, 8.0 Hz), 3.94 (d, 1 H,
J = 8.0 Hz).

[0035]

INDUSTRIAL APPLICABILITY According to the present invention, 3'-substituted- (2-carboxycyclopropyl) glycine (1) can be provided as an agonist of glutamic acid KA type receptors. This compound will lead to the study of glutamate receptors, including the elucidation of the mechanism of KA type receptors, and will provide a clue to the development of glutamate receptor blockers.

Claims (5)

[Claims] 1. The following formula (1): 3'-substituted- (2-carboxycyclopropyl) glycine represented by the formula (wherein R is a lower alkenyl group or a lower alkyl group). 2. The compound according to claim 1, wherein R is a lower alkenyl group. 3. The compound according to claim 1, wherein R is a lower alkyl group. 4. The compound according to claim 2, wherein R is a vinyl group. 5. The compound according to claim 3, wherein R is an ethyl group.