JP3176137B2 - Biuret derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

In Alzheimer's senile dementia, which has been increasing in recent years, degeneration and loss of acetylcholinergic nerves, which are basal ganglia neurons, are deeply related to memory impairment, decreased intellectual activity, and the like. J. Whitehouse
Et al., Science, Vol. 215, No. 1
237 (1982)｝ As a result, it is said that as a result, abnormalities occur in the synthesis of neurotransmitters that function to transmit information in the brain, and dementia symptoms progress. From these points, cholinesterase inhibition, activation of acetylcholine nerve activity, muscarinic acetylcholine receptor (M ₁ )
Research on drugs targeting acetylcholine, such as agonists, is in progress.

[0003] On the other hand, research on trophic factors FGF, EGF, NGF and the like related to the maintenance of nerve cells is also in progress. These act basically on specific cells and are thought to play an important role in the differentiation of undifferentiated neurons, the survival of mature and mature neurons, and the maintenance of function. Among them, NGF
(Nerve growth factor) is thought to extend the process of cells and exert some action during the period from the generation of nerve cells to death, and their potential as Alzheimer's disease drugs is also being studied. However, the compounds of the present invention have not been reported for the above-mentioned neurotrophic factor activity.

[0004]

An object of the present invention is to provide a novel compound having a neurotrophic factor activity involved in maintenance of nerve cells.

[0005]

Means for Solving the Problems As a result of intensive studies on compounds having a biuret structure, the present inventors have found a novel biuret derivative having a neurotrophic factor activity and completed the present invention.

Hereinafter, the present invention will be described. The present invention provides a compound of the formula [1]

Embedded image (Wherein R ¹ and R ² are an alkyl group having 1 to 5 carbon atoms or a benzyl group) and salts thereof. In the present invention, the alkyl group is a linear or branched one, for example, a methyl group, an ethyl group,
Propyl, isopropyl, butyl, pentyl and the like.

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

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

Embedded image

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

In obtaining the compound of the formula [4], 80
It is preferred to heat at ℃. 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 addition of the alkoxide to the 2-position, and a mercaptide of the formula [3] having high nucleophilicity is generated. This is 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 a sulfur atom. Such a rearrangement reaction is not known for N-cyanoiminothiazolidine.

[0011]

Industrial Applicability According to the present invention, there is provided a compound exhibiting a neurotrophic factor activity involved in maintenance of nerve cells.

[0012]

Next, the present invention will be described in more detail with reference to examples and test examples. Example 60% sodium hydride (0.21 g) was suspended in DMF (5 ml) under a nitrogen stream, and benzyl alcohol (0.55 ml) was removed over time with ice cooling to obtain an alkoxide. To this was added 3-benzyl-2- (N-cyanoimino) thiazolidine (1.09 g), and the mixture was stirred at 80 ° C for 4 hours. After the reaction, 0.5 ml of water was added and 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 eluted with a fraction eluted with chloroform-methanol. 1.) 1.26 g of urea sodium salt were 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, chloroform extraction was performed. After the solvent was distilled off, 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

[0016] 1- (2-benzyl-thio-ethyl) -1-methyl-biuret (Compound _{E) MS m / z 267 (} C 12 H 2 0N 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 rat cerebral cortex were placed in a polyethyleneimine-coated 24-multiwell plate at 1.6.
1 × 10 ⁶ cells were seeded, and a serum-free medium DF (a mixture of Dulbecco's minimum essential medium and Ham F-12 medium in an equal amount) was added thereto, and the mixture was incubated at 37 ° C. in a 5% carbon dioxide gas culture tank for 24 hours.
And cultured. Thereafter, the test compound was replaced with a DF medium adjusted to a predetermined concentration, and the culture was continued under the same conditions for 72 hours. After completion of the culture, the culture solution was removed, and an MTT {3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide} solution adjusted to a predetermined concentration was added. After culturing for 4 hours, the supernatant was removed, and the cultured neurons 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 taken as 100, and the activity was regarded as neurotrophic factor activity. Table 1 shows the results obtained using the above method.

[0018]

[Table 1]

────────────────────────────────────────────────── ─── Continuation of front page (56) Reference US Pat. No. 3,671,501 (US, A) Bull. Soc. Chim. Fr. (1974), 7-8, Pt. 2,1497-1505 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 323/00 A61K 31/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] [Claim 1] (In the formula 1, R ¹ and R ² are an alkyl group having 1 to 5 carbon atoms or a benzyl group.) And a salt thereof.