JPH0616621A - Biuret derivative - Google Patents

Abstract

PURPOSE:To provide a new biuret derivative having a neurotrophic factor activity relating to the maintenance of neurocytes. CONSTITUTION:The biuret derivative of formula I (R<1>, R<2> are 1-5C alkyl, benzyl), e.g. 1-benzyl-1-(2-benzyl thioethyl)biuret derivative. For example, 1- benzyl-1-(2-benzylthioethyl)biuret. The biuret derivative of formula I is obtained e.g. by reacting a 2-cyanoiminothiazolidine of formula 2 with an alkoxide of formula: R<2>OW (M is alkali metal), heating the produced compound of formula 3, dissolving the produced cyanourea derivative alkali metal salt of formula 4 in water, adding an acid to the solution, and subsequently thermally refluxing the solution.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a biuret derivative having a neurotrophic factor activity involved in the maintenance of nerve cells.

[0002]

2. Description of the Related Art In Alzheimer-type senile dementia, which has been increasing in number in recent years, degeneration and loss of acetylcholinergic nerves, which are basal ganglia neurons, are deeply involved in memory disorders, intellectual activity decline, etc. {R. J. Whitehouse
Et al., Science, Volume 215, Volume 1.
237 (1982)}, and as a result, it is said that dementia symptoms progress due to abnormalities in the synthesis of neurotransmitters that function to transmit information in the brain. From these points, cholinesterase inhibition, acetylcholine nerve activation, muscarinic acetylcholine receptor (M ₁ )
Research on drugs targeting acetylcholine, such as agonists, is underway.

On the other hand, research on trophic factors FGF, EGF, NGF and the like related to the maintenance of nerve cells is also underway. It is considered that they basically act on specific cells and play an important role in differentiation of undifferentiated nerve cells, survival of mature or mature nerve cells, and maintenance of function. Above all, NGF
(Nerve growth factor) is thought to extend cell projections and exert some action during the course of nerve cell development to death, and its potential as an Alzheimer's drug is also being investigated. However, the above-mentioned neurotrophic factor activity has not been reported for the compound of the present invention.

[0004]

DISCLOSURE OF THE INVENTION The present invention is to provide a novel compound having a neurotrophic factor activity involved in the maintenance of nerve cells.

[0005]

Means for Solving the Problems The inventors of the present invention conducted extensive studies on compounds having a biuret structure, and as a result, found a novel biuret derivative having neurotrophic factor activity and completed the present invention.

The present invention will be described below. The present invention provides the formula [1]

[Chemical 2] (In Chemical Formula 2, R ¹ and R ² are an alkyl group having 1 to 5 carbon atoms or a benzyl group.) A biuret derivative and a salt thereof. In the present invention, the alkyl group is a straight chain or branched chain group, for example, a methyl group, an ethyl group,
Examples include a propyl group, an isopropyl group, a butyl group, and a pentyl group.

The salt of the compound represented by the formula [1] of the present invention means a pharmacologically acceptable salt, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, acetic acid, lactic acid or tartaric acid. , Fumaric acid, maleic acid, trifluoroacetic acid, methanesulfonic acid, and other salts with organic acids.

The compound of the formula [1] can be obtained, for example, by the following method.

[Chemical 3]

Alcohols (eg C ₁ -C ₅ lower alcohols or benzyl alcohol) and alkali metals (N
a, K, etc.) or alkali metal hydride (NaH, Li
H, KH and the like) and an alkoxide (R ² OM, in which R ² has the same meaning as above and M is an alkali metal) and ² of the formula [2] in which the 3-position is substituted with R ² . -Cyanoiminothiazolidine (which can be synthesized according to the method described in JP-A-48-91064) is heated with a solvent (for example, benzene, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof). Thereby, an alkali metal salt of the cyanourea derivative of the formula [4] is obtained. After dissolving this thing in water,
The biuret derivative of the formula [1] is obtained by adding an acid (for example, hydrochloric acid, sulfuric acid, acetic acid, etc.) and heating under reflux.

To obtain the compound of formula [4], 80 in DMF
It is preferable to heat at 0 ° C. Furthermore, it was newly found that the alkyl group of the alkoxide used in this reaction was rearranged to a sulfur atom. In this reaction, it is considered that the C (2) -S bond is selectively cleaved after the alkoxide is added to the 2-position, and a mercaptide of the formula [3] having high nucleophilicity is generated. This compound is O because of the electron-withdrawing property of the cyanoimino group.
It is considered that the —R ² bond is easily cleaved and the alkyl group R ² of the alkoxyl group is rearranged to the sulfur atom. In N-cyanoiminothiazolidine, such rearrangement reaction is not known.

[0011]

INDUSTRIAL APPLICABILITY According to the present invention, a compound having a neurotrophic factor activity involved in the maintenance of nerve cells is provided.

[0012]

EXAMPLES Next, the present invention will be described in more detail with reference to examples and test examples. Example Under a nitrogen stream, 60% sodium hydride (0.21 g) was suspended in DMF (5 ml), and benzyl alcohol (0.55 ml) was removed with cooling under ice over time to obtain an alkoxide. 3-Benzyl-2- (N-cyanoimino) thiazolidine (1.09 g) was added thereto, and the mixture was stirred at 80 ° C. for 4 hours. After the reaction, 0.5 ml of water was added, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and N-cyano-N'-benzyl-N '-(2-benzylthioethyl was obtained by elution with chloroform-methanol. ) 1.26 g of urea sodium salt was obtained. This was dissolved in water (5 ml), hydrochloric acid (5 ml) was added, and the mixture was heated at 100 ° C. for 7 minutes.
After the reaction, it was extracted with chloroform. After distilling off the solvent, the residue was recrystallized from ethanol to obtain 0.67 g of 1-benzyl-1- (2-benzylthioethyl) biuret (Compound C). _{MS m / z 343 (C 18} H 21 N 3 O 2 S) m. p. 107.5-108.0 ° C ¹ H-NMR (CDCl ₃ ) δ; 2.59 (2H,
t, J = 7.2), 3.39 (2H, t, J = 7.
2), 3.72 (2H, s), 4.44 (2H, s),
^{_{7.14-7.36 (10H, m) IR (}} CHCl 3) cm -1; 3550,3350,1
715, 1680

In the same manner as above, the following compounds were obtained from the corresponding starting materials. 1-Benzyl-1- (2-methylthioethyl) biuret (Compound A) MS m / z 267 (C ₁₂ H ₁₇ N ₃ O ₂ S) m. p. 92.0-93. g ° C. (recrystallized from ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ; 2.12 (3H,
s), 2.53 (2H, t, J = 7.2), 3.54
(2H, t, J = 7.2), 4.57 (2H, s),
^{_{7.2-7.4 (5H, m) IR (}} CHCl 3) cm -1; 3500,3300,1
710, 1680

1-benzyl-1- (2-ethylthioethyl) biuret (Compound B) MS m / z 281 (C ₁₃ H ₁₉ N ₃ O ₂ S) m. p. 90.0-92.0 ° C (recrystallized from ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H,
t, J = 7), 2.55 (2H, q, J = 7), 2.6
8 (2H, t, J = 7), 3.53 (2H, t, J =
7), 4.57 (2H, s), 7.20-7.37 (5
^{_{H, m) IR (CHCl 3}} ) cm -1; 3500,3330,1
715, 1680

1- (2-Ethylthioethyl) -1-methylbiuret (Compound D) MS m / z 205 (C ₇ H ₁₅ N ₃ O ₂ S) m. p. 92.0-93.0 ° C (recrystallized from ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t,
J = 7), 2.59 (2H, q, J = 7), 2.71
(2H, t, J = 7), 3.01 (3H, s), 3.5
3 (2H, t, J = 7) IR (CHCl ₃ ) cm ⁻¹ ; 3500, 3320, ¹
710,1670

1- (2-benzylthioethyl) -1-methylbiuret (Compound E) MS m / z 267 (C ₁₂ H _{2 0} N ₃ O ₂ S) m. p. 133.0-133.5 ° C (recrystallized from ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ; 2.58 (2H, t,
J = 7), 2.90 (3H, s), 3.41 (2H,
t, J = 7), 3.75 (2H, s), 7.26-7.
^{_{34 (5H, brs) IR (}} CHCl 3) cm -1; 3500,3300,1
710,1670

Test Example Measurement of neurotrophic factor activity Cells prepared from the cerebral cortex of a rat fetus were placed in a polyethyleneimine-coated 24-multiwell plate for 1.6.
1 × 10 ⁶ cells were seeded, serum-free medium DF (a mixture of Dulbecco's minimum essential medium and Ham's F-12 medium in equal amounts) was added, and 37 ° C. in a 5% carbon dioxide culture tank for 24 hours.
It was cultured in. Then, the test compound was replaced with a DF medium prepared to a predetermined concentration, and the culture was continued for 72 hours under the same conditions. After completion of the culture, the culture solution was removed, and an MTT {3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide} solution prepared to have a predetermined concentration was added. After culturing for 4 hours, the supernatant was removed and the cultured nerve cells were extracted with DMSO and the absorbance was measured. On the other hand, the absorbance at the time of culturing without adding the test compound was set to 100, which was defined as the neurotrophic factor activity. The results obtained using the above method are shown in Table 1.

[0018]

[Table 1]

Claims (1)

[Claims] Claims: (In Chemical formula 1, R ¹ and R ² are an alkyl group having 1 to 5 carbon atoms or a benzyl group.) A biuret derivative and a salt thereof.