JPH04120049A - Urea derivative, composition containing urea derivative and functional thin film - Google Patents

Abstract

NEW MATERIAL:An urea derivative obtained by substituting at least one aryl group of an N,N'-diarylurea with a 10-22C long-chain alkyl group, long-chain fluoroalkyl group or their derivative. EXAMPLE:The compound expressed by formula. USE:A sensor having high substrate selectivity, a carrier used in the transportation and extraction of substrate, a sustained release agent, a reaction agent, etc. A functional thin film. It is an interesting compound to give a film containing hydrophilic urea groups having controlled direction. PREPARATION:Various functional groups other than aryl group are introduced into the aryl group of an arylamine and further 10-22C long-chain alkyl groups are introduced by amidation, imidation, esterification, etherification, etc., to obtain a long-chain arylamine. The objective diarylurea derivative is obtained by reacting the long-chain arylamine with an isocyanate produced by converting a similarly synthesized arylamine derivative with phosgene, etc.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention has promising applications as a sensor with high substrate selectivity, a carrier used for transportation and extraction of substrates, a sustained release agent 1 reaction field, etc. The present invention relates to a urea derivative and a functional thin film formed from the urea derivative.

[Prior Art] Sensors that respond to chemical substances are called chemical sensors, and include (1) ion sensors such as pH sensors, (2) gas sensors, and (3) biosensors. An ion sensor detects the concentration of a chemical substance contained in a liquid to be measured as a change in membrane potential of an ion-sensitive membrane. There are a wide variety of gas sensors.For example, semiconductor gas sensors measure changes in electrical resistance when gas molecules are adsorbed, and potentiostatic and galvanic cell-type gas sensors utilize electrochemical redox. It is something to do. In these ion sensors and gas sensors, the physical properties of the sensitive part change depending on the object to be detected, and the amount of change is extracted as a detection signal. In addition, many of the objects to be measured are inorganic molecules.

On the other hand, the detection of organic molecules can be carried out in medical testing 1 fermentation 9 food industry,
It is needed in many fields such as bioengineering. As this detection means, a biosensor such as an enzyme sensor is used. This biosensor uses a biological material that can selectively recognize a specific substance, and extracts changes in the substance involved in a chemical reaction with the substance to be measured as a detection signal.

In other words, conventional biosensors select biological substances that have a specific reaction with the target substance, and detect oxygen using ion sensors, gas sensors, etc.

It provides products such as hydrogen peroxide. By combining it with an ion sensor or a gas sensor, it becomes possible to detect many types of organic molecules, and also to measure trace amounts.

[Problem to be solved by the invention] However, conventionally used biosensors have a complex structure because the sensing part and the signal generating part are configured separately due to their function. . Moreover, sensors that use immobilized enzymes have the disadvantage that the activity of the enzyme changes over time and that the operating temperature is limited to around the physiological temperature determined by the type of enzyme.

In this regard, there is a need to develop organic sensors that have a sensing and response mechanism similar to ion sensors and gas sensors that target inorganic compounds, and some experimental research is being conducted. For example, Okahata et al.
eprints, Japan Vol, 37. No
, 10p3309-3311 (1988), using a quartz crystal oscillator coated with a bilayer membrane and a porous polymer membrane,
They discovered that the weight, membrane potential, membrane resistance, etc. change when various types of aqueous alcohols are adsorbed onto the bilayer membrane, and report that it can be used as a sensor. Molecular discrimination here is performed by partitioning hydrophobic molecules into the hydrophobic layer of the membrane.

In addition, Odashima et al. reported a catechol-sensitive sensor using a liquid film containing a fat-soluble macrocyclic polyamine as a molecular recognition element [3rd Biofunction-Related Chemistry Symposium Preliminary Lectures, p. 165-167 (19881). Reports have found that catechols, which are neutral molecules, exhibit potential responsiveness, and the mechanism of potential responsiveness is suggested to be proton dilation due to host-guest hydrogen bond interaction. .

However, the sensor reported by Okahata et al. has the drawback that the target compounds are limited to fat-soluble compounds. On the other hand, the cause of the response of Odashima et al.'s sensor is not clear, and since it is a liquid film type sensor, the amount of physical property that can be measured is limited to potential changes. Also, the host you are using
Since the guest interaction is in solution, it is necessary to synthesize molecules that bind the analyte in solution.

Therefore, it has the disadvantage of low selectivity, sensitivity, and operability.

Therefore, an object of the present invention is to provide a substance useful as a novel organic sensor corresponding to the types of ion sensors, gas sensors, etc. described above. In addition to sensors, we also offer new urea derivatives that are used as carriers used for substrate transport and extraction, reaction sites that provide sustained release agent 2-reaction catalysts, and functions produced using films using these derivatives. The purpose is to provide thin films.

[Means for Solving the Problem] In order to achieve the object, the urea derivative of the present invention has N
, at least one of the aryl groups of N'-diarylurea
One of them is substituted with a long-chain alkyl group having 10 to 22 carbon atoms, a long-chain fluoroalkyl group, or a derivative thereof. At this time, the aryl group can be further substituted with a functional group other than those mentioned above.

This urea derivative can be formed into a film by LB method, cast method 1 dispersion method, etc., and can also be immobilized on a solid surface by physical adsorption or chemical adsorption using a silane coupling agent or the like.

In addition, the functional thin film of the present invention is formed by the urea derivative LB method, casting method, or dispersion method, and by organizing the molecules,
It has urea groups oriented on the surface. Furthermore, this functional thin film can be fixed to a solid surface by physical or chemical adsorption.

[Function] The urea derivative used in the present invention has the following structure, and has aryl groups introduced at the N- and N'- positions of the urea group, and at least one of the aryl groups has a carbon number of 10 to 10. It has a structure in which 22 alkyls, fluoroalkyls, or derivatives thereof are substituted. By forming a film from this compound, an interesting compound in which the direction of the urea group, which is the parent wood group, is controlled can be obtained.

Etter et al., J, A+ser, Chew, S
oc, Vol, 110p, 5896-5897
(1988) synthesized 3-bis(m-dinitrophenyl)urea and crystallized it from a proton acceptor solution such as acetone, THE, or DMSO, which formed a specific structure with the proton acceptor. It has been reported that inclusion crystals with urea are formed. At this time, by introducing an electron-withdrawing group such as a nitro group to the m-position of the phenyl group, the In these systems, it is possible to form inclusion crystals with the substrate.
Inclusion crystals are formed in organic solvents.

On the other hand, in the present invention, a thin film is formed by introducing an alkyl group into an aryl urea group, the orientation of the urea group is controlled, and a specific substrate is bound using the site. These derivatives are manufactured using the LB method.

Forming a film by a casting method or a dispersion method provides a functional thin film that can be used in various solvents including water and has high density, high sensitivity, and selectivity.

Various other functional groups are introduced into the aryl group of the arylamine, and a long-chain alkyl having 10 to 22 carbon atoms is further introduced by amidation, imidization, esterification, etherification, etc. to synthesize a long-chain arylamine. - The diarylurea derivative of the present invention can be obtained by reacting a similarly synthesized arylamine derivative with isocyanate made using phosgene or the like. The following equation shows an example of the synthesis process.

(The following is the margin of this page) The synthesized urea derivative has self-assembly properties. For example, when deploying this urea derivative on an aqueous liquid surface,
The hydrophilic group -NH-C〇-NH- is directed toward the interface, and the hydrophobic group R
takes the form of an array in which the rays are oriented in opposite directions. Furthermore, when the thin film developed at the interface is accumulated on the substrate, LBI[li that maintains this orientation can be obtained. At this time, even when mixed with other film-forming compounds such as lecithin and long-chain dialkyl ammonium salts, LB maintains the properties of urea derivatives.
Obtaining pus.

In addition, when forming a film by a casting method in which a urea derivative dissolved in an organic solvent such as acetone or chloroform is cast onto a substrate such as a glass plate and air-dried, an appropriate method may be used, regardless of the development method. A similar self-assembly of molecules occurs when dispersed in water to form liposomes.

When the obtained thin film is fixed to a solid surface by physical or chemical adsorption, it is stabilized.

Oriented urea groups selectively bind substrates through hydrogen bond formation. For example, when a monomolecular film is formed using an aqueous liquid containing various nucleosides, water-soluble peptides, and water-soluble polymers, the film formation behavior exhibits different substrate selectivity depending on the substrate.

The urea group has two (NH) groups with hydrogen bonding properties, and can have many combinations of hydrogen bonds with these >NH groups and multiple functional groups of the nucleoside. This combination changes the strength of the interaction that occurs between the two compounds, and the behavior during film formation changes depending on the strength and the molecular size of the substrate compound.

Utilizing this property, the functional thin film of the present invention can be used as a sensor in a wide range of fields.

Furthermore, when the urea derivative of the present invention is crystallized from a suitable solvent containing a substrate, it selectively forms inclusion crystals with the substrate.

Substrates incorporated into urea derivatives are extracted with hot medium.

It can be dissociated and taken out from the thin film or inclusion crystal by pH adjustment, heat treatment, etc. Therefore, carriers used for transporting and extracting substrates, sustained release agents for drugs, etc. in the pharmaceutical field, and carriers that gradually release substrates 1
It can also be used as a reaction site to provide a reaction catalyst. For example, the release rate between nucleosides can be controlled because the bond strength between various nucleosides varies.

1 Nidiaryl-4 Monostearylamine (I) 20.0g was added to ethanol 3
00mJ2, suspended 30.0g of anhydrous potassium carbonate, and dissolved 20°Og of alkyl bromide in EtOH10.
The solution stirred at 0 mJ2 was gradually added dropwise at room temperature, and the mixture was heated to reflux overnight. This allows distearylamine (II
) was obtained.

Next, 5.0 g of distearylamine (II) was added to anhydrous T
After dissolving in 150 mj2 of HF and adding 1.52 g of triethylamine thereto, a solution of 2.64 g of 4-nitrobenzenecarboxylic acid chloride dissolved in 30+nj2 of THF was gradually added dropwise at room temperature, and the mixture was stirred for 3 hours. Thereby, 5.57 g of 4-nitrobenzenedialkylamide (I[I) was obtained according to the reaction of the following formula.

Obtained 4-nitrobenzenedialkylamide (rn)
After dissolving 5.75 g in 300 mff of THF and suspending 1.75 g of 5% palladium carbon, H2 was bubbled through. As shown in the following reaction formula, the nitro group is reduced and the 4-amine benzene alkylamide (rV) is converted to 3.4
I got 6g.

This 4-aminobenzene alkylamide (rv) 1.0
64 g was dissolved in 30 mff of benzene, and a solution of 284 mg of 4-nitrobenzene isocyanate dissolved in 5 mI2 of benzene was gradually added at room temperature and stirred overnight to obtain 628 mg of the target compound (V). The yield at this time was 47.0%.

Compound (V) has a melting point of 68.9 to 69.3°C, and as a result of elemental analysis, C: 4.67%, H: 10.58%, N:
:6.94%. This analysis value is the calculated value C near 4.41%, )l: 10.37% obtained from the chemical formula.
,Nia, were substantially in agreement with 18%. Moreover, the IR value of compound (V) is 1694 cm-' (νc=o)
, 1601.1567 cm-' (δNH), 1628c
m-' (tertiary amide).

In addition, 0.80 g of 4-aminobenzene alkylsulfonamide (VT) obtained in the same manner was dissolved in 30 mj2 of benzene, and 5 m of a benzene solution containing 0.06 g of triphosgene was added.
Gradually add ε and stir at 90°C overnight to obtain the target compound (■
) was obtained. The yield of compound (■) at this time was 67.3%.

(Vl) (■) The obtained compound (■) has a melting point of 55.8 to 56.4°C
As a result of elemental analysis, Cnia: 3.40%, H: 1
It was 1.45%, N: 4.0596. This analysis value is the calculated value obtained from the chemical formula, that is, C near 3.64
%, H: 11.45%.

N: 4.11%, which was substantially the same. Moreover, the IR value of compound (■) is 1711 cm-' (vC=01.
1593.1548 cm-(δNH), 11450 m interest (νSo,).

Example 2 5 mg of diaryl urea derivative (v) produced in a blinded laboratory was dissolved in 10 mJ2 of chloroform or benzene.
A monomolecular film was created by developing at 0 μC and compressing at a speed of 0.2 mm/sec.

In addition, the surface pressure during compression was kept at a constant value of 20 mN/m, and the substrate was moved up and down at a constant speed of 20 mm/min, so that the monomolecular film formed on the water surface was accumulated on the substrate and LB
II [was obtained.

Note that various materials such as glass, quartz, polymer film, graphite, and silver were used as the substrate.

The obtained LB film had a Z-shaped structure as a result of the cumulative behavior.

Similarly, with the diarylurea derivative (■) synthesized in Example 1, it was possible to form a monomolecular film and an LB film.

3: LB pus mold manufacturing device as a sensor If the aqueous phase contains a substance that serves as a substrate for the monolayer constituent molecules, when producing a monolayer as in Example 2, the surface pressure and molecules By monitoring the occupied area, the effect of the substrate on the monolayer can be investigated.

For example, diaryl urea derivative (V) was developed on the surface of various nucleoside aqueous solutions (0,0037M) at 20°C to prepare a monomolecular film at a compression rate of 0.2 mm/sec, and the surface pressure and occupied area curves were obtained. It was measured. The measurement results are shown in FIG. 1 as a surface pressure-molecular occupied area curve when adenosine and thymidine were used as substrates.

The surface pressure for a given occupied area varies depending on the type of nucleoside. The type of nucleoside contained in the aqueous solution can be identified by measuring the surface pressure at that time under conditions where an appropriate occupied area is set. Furthermore, if the type of nucleoside contained in the aqueous solution is known, the concentration of the nucleoside aqueous solution can be determined based on the measured surface pressure.

It is presumed that these substrate specificities are derived from the ease of hydrogen bond interaction between the substrate and the urea derivative.

4:! The interaction between the substrate and the urea derivative can also be investigated from the IR spectrum of crystals prepared in a homogeneous organic solvent system.

The substrate and the urea derivative (V) synthesized in Example 1 are 1=1
Table 1 shows the IR spectrum absorption changes of the crystals obtained from the EtOH solution adjusted to the ratio.

(Hereafter, the margins of this page) Table 1 = IR spectrum absorption change (νC=O] The obtained IR spectrum is C of urea unit =O absorption is 1694 cm 1 to 1720 It had shifted to around cm-'.

This is thought to be caused by hydrogen bonding between the urea derivative and the substrate. Furthermore, the amount of shift and intensity differed depending on the type of substrate.

From this, it is inferred that the urea derivative of the present invention forms clathrate crystals with respect to nucleosides, sugars, water-soluble polymers, and the like.

5: A solution of 5 mg of the urea derivative (V) obtained in Example 1 in chloroform or benzene 10 mε was heated at 20°C.
The plate was developed on an adenosine aqueous solution (0°0037M) maintained at This was repeated five times to accumulate the monomolecular film formed on the water surface to obtain LB pus.

When the FT-IR (RAS method) spectrum of the obtained LB film was measured, as shown in FIG. 2, absorption was observed at 1653 cm-' and 1602 cm-' due to adenosine. This shows that adenosine is immobilized on the obtained LB.

[Effects of the Invention] As explained above, when the urea derivative of the present invention is used, the urea derivative of the present invention can be used as a nucleoside or nucleobase derivative.

It becomes possible to produce thin films such as liposomes, LB films, monomolecular films, and cast films in which water-soluble peptides, ATP, etc. are regularly incorporated between the layers of the membrane structure at the molecular level.

In addition, the urea unit can be used as a sensor for various substances by using a self-organizing compound alone or by urea units regularly arranged on a thin film by molecular organization.

Furthermore, the substrate incorporated into the membrane is subjected to solvent extraction, pH adjustment,
Since it can be dissociated by heat treatment, it is also useful as a carrier for extraction, transportation, storage, etc. In addition, it is a promising means for preparing drugs because it allows physiologically active substances to be effectively and effectively released locally over a long period of time.

As described above, the urea derivative of the present invention and the functional thin film made from the derivative can be used in a wide range of fields.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the surface pressure-molecular occupied area curve of the monomolecular film obtained in Example 3, and FIG. 2 shows the FT-IR spectrum of the LB film obtained in Example 5. Ic^- Funeral map occupied area (nm2/molecule) ~ ~ °1 Wavenumber (cm゛')

Claims (4)

[Claims] (1) A urea derivative characterized in that at least one of the aryl groups of N,N'-diarylurea is substituted with a long-chain alkyl group having 10 to 22 carbon atoms, a long-chain fluoroalkyl group, or a derivative thereof. (2) A urea derivative-containing composition, characterized in that the urea derivative according to claim 1 is contained in a state bound to a nucleoside, a water-soluble peptide, or a water-soluble polymer, or in an clathrate crystal state. (3) The urea derivative according to claim 1 or the urea derivative-containing composition according to claim 2 is formed into a film by the LB method, casting method or dispersion method, and the urea groups are arranged toward the film surface due to molecular organization. A functional thin film characterized by: (4) A functional thin film, characterized in that the functional thin film according to claim 3 is immobilized on a solid surface by physical or chemical adsorption.