WO1988004169A1

WO1988004169A1 - Drug for nephritis

Info

Publication number: WO1988004169A1
Application number: PCT/JP1987/000932
Authority: WO
Inventors: Shinji Ozawa; Kazuo Sugio; Toshio Wakabayashi; Yasuhiko Iino; Seiitsu Murota
Original assignee: Terumo Kabushiki Kaisha
Priority date: 1986-12-01
Filing date: 1987-12-01
Publication date: 1988-06-16
Also published as: JPH0228566B2; JPS63139124A

Abstract

A drug for nephritis, which comprises an omega-(3,4-dihydroxyphenyl)alkenecarbonyl derivative represented by general formula (I), wherein R1 and R2, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy-lower alkyl group or a hydroxy-protective group, R3 represents a hydrogen atom or a lower alkoxy group, m represents an integer of 1 or 2, and Y represents an alkyl group, an aralkyl group, an alkoxy group, and aralkyloxy group or a group represented by formula (II), wherein n represents an integer of 1 to 5. This drug is particularly effective for treatment of chronic nephritis.

Description

Remedy Nephritis treatment drug technology field

TECHNICAL FIELD The present invention relates to a therapeutic agent for nephritis, and more particularly to a therapeutic agent for nephritis containing a Fuunil derivative.

The agents of the present invention are particularly effective for treating chronic nephritis. Nephritis is a renal disease with hematuria as the main symptom, but the mechanism of its onset and progress remains unknown at present. However, recently, various renal disease models in animals have been increasingly studied and used to evaluate drugs.

Background technology

Currently, steroidal and non-steroidal anti-inflammatory and anticoagulant drugs are used in certain types of nephritis, but no drug has been found that has a definite therapeutic effect on nephritis. Rest and diet are the mainstays of treatment, and the emergence of truly effective therapeutic agents is desired.

The present inventors previously synthesized various novel funil derivatives and studied their pharmacological actions. As a result, they found that they had an excellent inhibitory effect on platelet aggregation, and filed a patent application (Japanese Patent Application No. 61-2682). 61-6091). As a result of further research, the present inventors have found that the below-mentioned funyl derivative has an effect of remarkably suppressing chronic nephritis in rats due to administration of bovine serum albumin (BSA), and completed the present invention. Disclosure of the invention

According to the present invention, the following therapeutic agents for nephritis are provided.

) —General formula (I)

Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkyl group or a protecting group for a hydroxyl group; and R ³ represents a hydrogen atom or a lower alkoxy group. And m represents an integer of 1 or 2, and Y represents an alkyl group, an aralkyl group, an alkoxy group, an aralkyloxy group, or a compound represented by the formula (Π)

(In the formula, n represents an integer of 1 to 5.) A therapeutic agent for nephritis, comprising a funil derivative having the formula:

2) The remedy for nephritis according to item ¹ , wherein in the formula (I), R ¹ is a lower alkyl group.

3) The therapeutic agent for nephritis according to item 1, wherein in the formula (I), R ² is a hydrogen atom or a lower alkoxycarbonyl group.

4) The therapeutic agent for nephritis according to item 1, wherein in the formula (I), Y is a group represented by the formula (Π) (where n is 2).

5) The agent for treating nephritis according to item 1, wherein in the formula (I), Y is an alkyl or alkoxy group having 1 to 20 carbon atoms.

6) The therapeutic agent for nephritis according to claim 1, wherein in the formula (I), Y is a phenylalkyl group having 1 to 5 carbon atoms in the alkyl moiety.

In the substituents R ¹ to R ³ in the above formula (I), the term “lower alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms, preferably methyl or ethyl. , Isopropyl, n-propyl and the like; the term "lower alkoxy" is a straight or branched alkoxy having 1 to 4 carbon atoms, preferably methoxy, ethoxy, isopropoxy, n-means propoxy and the like. The term "hydroxyl protecting group" means a group usually used for protecting a hydroxyl group in the field of synthetic organic chemistry. Preferred examples thereof include a lower alkoxy lower alkyl group, a benzyl group and a tetrahydrofuranyl group. , Toluoyl, and acyl groups. Furthermore, in the definition of the substituent Y, "alkyl group" or "alkoxy group" means a straight-chain or branched alkyl group or alkoxy group having preferably 1 to 20 carbon atoms, more preferably 7 to 15 carbon atoms. "Aralkyl" preferably means a phenylalkyl group having 1 to 5 carbon atoms in the alkyl moiety. The phenyl derivative having the above formula (I) used in the present invention is a novel compound. It is produced by the following method according to the type of the substitution component.

That is, in the above formula (I), a compound in which Υ represents an alkyl group or an aralkyl group is represented by the formula:

[Wherein R ¹ , R ² , R ³ and m have the meanings given above]

An aldehyde derivative represented by

Formula (IV)

0 0

t

(CH ₃₀ ) P-CH-C-Y '(IV) [Wherein Y 'represents an alkyl group or an aralkyl group]. The above reaction is suitably carried out using tetrahydrofuran, 1,2-dimethoxetane, benzene or the like as a solvent in the presence of a base such as sodium hydride or potassium butoxide.

In the above formula (I), the compound wherein Υ is an alkoxy group, an aralkyloxy group or a group represented by the above formula (Π) is represented by the formula (V)

(Wherein R ¹ , R ² , R ³ and m have the same meaning as described above)

And a carboxylic acid derivative represented by the formula (VI)

H — Y "(VI) [wherein Y * represents an alkoxy group, an aralkyl group or a group represented by the above formula (Π)]

_{N The} above reaction is produced by reacting with an alcohol or amine derivative represented by It is preferably carried out in a suitable solvent in the presence of a condensing agent such as ethyl carbonate chloride or N, If-dicyclohexylcarpoimide.

The phenyl derivative (I) of the present invention is effectively used for the treatment of nephritis, particularly chronic nephritis, and the dose varies depending on the symptoms. In general, the daily dose for adults 1 to: LOO Omg, preferably 10 to 500 It is recommended to be administered in 1 to 3 divided doses as needed, depending on the symptoms. The administration method can be in any form suitable for administration. In particular, oral administration is desirable, but intravenous injection is also possible. The compound of the present invention is used alone or as an active ingredient, alone or mixed with a pharmaceutical carrier or excipient in a usual manner, to prepare tablets, dragees, powders, capsules, granules, suspensions, It can be applied in various forms formulated into emulsions and injection solutions. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate and the like.

Next, the present invention will be described more specifically with reference to Production Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.

Manufacturing example 1

Dissolve 15 g (68.1 ram I) of 5- (3-methoxy-4 -hydroxyphenyl) -2,4-pentagenenoic acid in 400 ml of dichloromethane and cool to 0 ° C. Add 21 ml (150 ol ol) of Lethylamine, then 14.3 ml of ethyl carbonate chloride (150 mmol) and stirred at 0 ° C. for 1 hour.

On the other hand, 4.26 g (68.1 ramol) of 80% hydrazine hydrate was added to an ethanol solution (400 ml) of 30 g (68.lramol) of 1- (2-phthaloylaminoaminoethyl) -4-benzhydroxybiperidine. The mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 400 ml of dichloromethane was added to the obtained residue, and the mixture was added to the reaction solution prepared above and stirred at room temperature for 14 hours.

The reaction solution was filtered, and the filtrate was sequentially washed with 1N-hydrochloric acid, water, and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give 1- [2- [5- (3-methoxy-4-carbonylethoxycarbonyl) -2,4-pentadienyl] aminoethyl] -4-benzhydroxypiperidine. 27.8 s:

(47.7 ramol). Its spectroscopic data supports the structure (W) of the following formula:

0 (VE)

(Hereinafter the margin) PHR (CD Ci 3) δ:

1.33 (3H, t, J-8Hz), 1 ■ 52 ~ 3.0 (lOH, m), 3.16- 3.78 (3H, ni), 3.78 (3H, s), 4.22 (2H, q, J-8Hz), 5.42 (lH, s), 5.88 (lH.d, J-15Hz), 6.55-7.87— (16H.ni)

1 R: ³ (cm ^-1 ): 3400, 1762, 1660,

1615, 1510, 1255

Manufacturing example 2

Under an argon atmosphere, a mixed solvent of 7.00 g of 3- (3-methoxy-4-methoxymethyloxyphenyl) propenal and 12.50 g of 2-tridecane, 120 ml of tetrahydrofuran, 30 ml of water and 30 ml of ethanol And 15 l of a 10% aqueous sodium hydroxide solution was added at room temperature. After reacting at room temperature for .16 hours, 37 ml of 1N hydrochloric acid was added under ice cooling. After the reaction mixture was concentrated under reduced pressure, the residue was poured into ice-cooling, and extracted three times with ethyl acetate. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 19.4 g of an extraction residue.

The residue was subjected to silica gel column chromatography, and benzene ♦ ethyl acetate (98 to 2) was eluted from the eluted fraction to give 1- (3-methoxy-4-hydroxymethyloxyphenyl) -5-oxo-1 9.15 g of 3,3-hexadecadiene were obtained.

4.75 g of the arsenic compound was dissolved in 10% of an 80% acetic acid aqueous solution, and the mixture was reacted with heating under reflux for 5 hours. The reaction mixture was dried under reduced pressure to obtain 4.80 g of a residue. The residue is dissolved in ether-hexane (1: 1) Further recrystallization yielded 2.15 g of 1- (3-methoxy-4-hydroxyphenyl) -5-oxo-1.3-hexadecadiene, whose spectroscopic data supports the structure of the following formula.

0

¹ E-N MR CC Ό C ΰ _η ) δ (ρρ / π):

2.55 (2H, t.J-7Hz), 3.88 (3H.s), 6.18 (lH.d, J-15Hz)

M S (m / J?): 358 (molecular ion peak)

Manufacturing example 3

Under an argon atmosphere, 2.804 g of dimethyl methyl phosphate was dissolved in 60 ml of dry tetrahydrofuran, cooled in a dry ice / ethanol bath, and 16.0 ml of n-butyllithium-n-hexane solution (1.55M) was added dropwise. did. Five minutes later, 4.073 g of methyl 4-phenylbutanoate was added, and the mixture was reacted for 1.5 hours in a cold bath. After 5 ml of methanol was added to the reaction mixture, the mixture was cooled to room temperature, 30 ml of water was added, and the mixture was extracted three times with a black hole form. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.448 g of an extraction residue. The residue was subjected to silica gel column chromatography and the fraction eluted with methylene chloride (2-oxo-5-phenyl pentyne). 0951) -Dimethyl phosphonate 3.951 g was obtained. 1.081 g of the compound and 0.845 g of 3- (3-methoxy-4-methoxymethylphenyl) propenal are dissolved in 2 ml of methylene salt, and the solution is dissolved in 2.2 ml of 50% aqueous sodium hydroxide solution and 2.2 ml of hydrogen sulfate. A mixture of 65 mg of tetrabutylammonium and 4.4 ml of methylene chloride was dropped and stirred at room temperature. After reaction at room temperature for 20 minutes, 60 ml of water was added, and extraction was performed three times with methylene chloride. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.411 g of an extraction residue. The residue was subjected to silica gel column chromatography. From the elution fraction of benzene / ethyl acetate 19: 1, 1- (3-methoxy-4-methoxymethoxyloxyl unit) -5-oxo-8-phenyl -1.3- Ok-Yu-Jen 0.765 g was obtained. 0.490 g of the compound was dissolved in 10 ml of methanol, and 1.3 g of an acidic ion exchange resin (DOWEX50WX8) was added thereto. After reacting overnight at room temperature, the ion-exchange resin was removed by filtration, and the mother liquor was evaporated to dryness under reduced pressure to give 1- (3-methoxy-4-hydroxyphenyl) -5-oxo-8-phenyl-1. S-Octadien got 0.384 s. The spectroscopic data of the compound supports the structure of the following formula (DO

H 0 IR ^ ³ (cm ^-1 ): 3540, 1670

max

^-NMR C C D Ci s) δ (ρρπι):

3.87 (3H.S), 6.17 (lH.d, J-15Hz) Production example 4

Dissolve 13.lg "(0.329πιο1) in 400 ml of water, add 50 g (0.329 mol) of vanillin and dissolve. 50 g (0.46 mol, 1.4 eq) of ethyl chlorocarbonate is added to this solution at room temperature. ) And the mixture is stirred at room temperature for 3 hours.The formed crystals are collected by filtration, washed well with water, and dried, and 68.8 g (93.3%) of 3-methoxy-4-ethoxycarboxyloxybenzaldehyde is added. Obtained.

12.8 g- (0.32ιπο1, 1.2 eq) of 60% NaH. Was washed with dry η-hexane, and dry THF 1.2Q was added. The mixture was cooled to 15 ° C, and while stirring, triethyl phosphono crotonate 80s: (0.32iol, 1.2eq) was added dropwise over 30 minutes, followed by stirring at 110 ° C for 3 hours. 57.9 g (0, 266 to 101, 1 eq) of 3-methoxy-4-ethoxyethoxybenzobenzaldehyde was dissolved in 100 ml of dry THF, and added dropwise to the above reaction solution over 10 minutes. The reaction solution was returned to room temperature, stirred overnight, added with a saturated aqueous ammonium chloride solution, added with water, and extracted with ethyl acetate. The ethyl acetate layer was washed with INH CJ ™ and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from 100 ml of ethanol to give 5-(3-methoxy-4-ethoxycarbonyloxyphenyl)-2,4-pentagenone. 50 g (59%) of the ethyl ester were obtained. 19.0 g of the above product was dissolved in 180 ml of methanol, and 50 ml of 28% aqueous ammonia was added at room temperature. After reacting at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted twice with chloroform. The extracted organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 17.3 g of an extraction residue. The residue was subjected to silica gel column chromatography, and ethyl-5- (3-methoxy-4--4-hydroxy-dihydroxy) -2,4-pentadienoate was obtained from the form-eluted fraction of the mouth. 12.8 g I got Its spectral data supports the following equation (X).

0

NMR (CD CJ? ₃ ) δ (ρριπ)

1.32 (3H.t, J-7Hz), 3.88 (3H, s), 4.03 (2H.q, J-7Hz), 5.87 (lH, d, J-15Hz)

Product example

Formulation Example 1: Powder

Raw material Prescription amount Prescription compound VII 200 mg

Lactose 700 mg Corn starch 100 mg Production method: Compound VII powder passed through a 60-mesh screen, lactose passed through a 50-mesh screen, and corn starch passed through a 120-mesh screen are mixed with a V-type mixer to form a powder.

Formulation Example 2: Granules

Name of raw material Prescription amount Prescription compound VI 200 nig

Lactose 684 mg Maize starch 100 mg Hydroxypropyl cellulose 16 mg Formulation Compound VI powder passed through a 60 mesh sieve and lactose passed through a 50 mesh sieve and corn starch passed through a 120 mesh sieve After mixing with a V-type mixer, an aqueous solution of hydroxypropylcellulose was added, mixed with a twin-screw kneader, extruded and granulated, dried at 60 ° C, sized with an oscillator, and sized at 12 cm. Granules are those that pass through the mesh and do not pass through the 60 mesh.

Formulation Example 3: Capsule

0.1% magnesium stearate is added to the granules of Example 2, mixed, and filled into No. 4 capsule.

(Hereinafter the margin) Formulation Example 4: Compound X soft capsule

Solution formulation

Compound X 20 nig Soybean oil 250 rag Sorbitan sesquioleate 30 mg Gelatin coating solution formulation

Gelatin 220 kg Glycerin 66 kg Methyl paraben 0.4 kg Propyl paraben 0.11 kg Yellow No. 5 0.11 kg Purified water 180 kg Manufacturing method: Dissolve the formulation at 60 ° C, After cooling to ° C, the mixture is filled with a rotary capsule machine, washed and dried to obtain soft capsules.

Formulation Example 5: Tablet

Ingredient name Prescription amount Compound IX 20 nig Lactose 41 mg Corn starch 30 rag Canoleboxixetinocellulose

Potassium 6.5 mg Methinocellulose 25cP 1,5 rag Magnesium stearate 1.0 m Preparation: Mix compound IX, lactose, corn Shidenpun and carboxymethylcellulose calcium V-type mixer, after kneading with methylcellulose aqueous solution, granulated by an extrusion granulator, to Drying at 60 ^e C. Magnesium stearate is added to the dried granules, mixed, and compressed into a tablet using a tableting machine.

Formulation Example 6 _: Ointment

Raw material Prescription amount Compound 1 1 g Butyl paraoxybenzoate 0.05 g Propylene glycol 2.5 gr Polysorbate 80 2.5 g White petrolatum 93.45 s: Production method: Dissolve components other than white petrolatum at 60 ° C. Separately, dissolve white petrolatum at 70 ° C and cool both dissolving solutions while mixing them gradually to obtain an ointment.

Formulation Example 7: Suppository

Raw material Prescription amount Compound W 50mg Witepsol 1650mg Production method-Melt at 60 C, stir with cooling, fill into aluminum foil using servac to make suppositories.

(Hereinafter the margin) Formulation Example 8: Injection

Raw material Prescription amount Compound IX 5 mg Polysorbate 80 50 mg Water for injection 1 ml Production method Compound X is dissolved in Polysorbate 80, and then distilled water for injection is added to dissolve and disinfect. Aseptically fill the sample into an injection.

Test example

According to the method of Kihara et al. (Acta Pathologia Japoniea. 28, 859-866 (1978)), the nephritis-inhibitory effect of the fuunyl derivative (I) of the present invention was tested.

That is, a physiological saline containing bovine serum albumin (BSA) 2ing is administered subcutaneously to the neck of a 3-week-old male Fisher rat. Once a day for 3 weeks from 6 weeks later, orally (50 mgZkg) orally with the Huunil derivative of the present invention suspended in 5% CMC-Na 1 hour later, intravenous administration of saline containing BSA 2ing . After collecting urine excreted on a single day and removing insoluble matter by centrifugation, the amount of urine and the amount of protein in the urine are measured with an absorptiometer using a urine protein measurement kit. The results are shown in Table 1.

(Hereinafter the margin) Administered drug protein mg / day

Production example No. 3 weeks before drug administration Blank 14.5 ± 1.4 297.3 ± 84.5

1 15.2 ± 1.8 82.3 ± 22.8

2 13.8 Sat 1.6 66.5 ± 23.5

3 14.9 ± 1.5 65.3 ± 23.2 As shown in Table 1, the Fuunil derivative (I) of the present invention showed a marked inhibitory effect on proteinuria, and an inhibitory effect on nephritis was also observed in pathological specimens. Further, it was confirmed that the Fuunyl derivative (I) according to the present invention, which is not shown in Table 1, also has a similar nephritis inhibitory effect.

Sudden poisonous

Acute toxicity tests were performed by oral administration using ICR male mice (5 weeks old). LD _5Q values Fuyuniru derivative (I) of the present invention is any even lOOOfflg / kg or more, high safety in comparison with effective amount was confirmed.

Industrial applicability

The phenyl derivative of the present invention is effectively used as a therapeutic agent for nephritis and used in the pharmaceutical industry.

Claims

) General formula (I)

. One-one blue of

Wherein R ¹ and R are the same or different from each other and represent a hydrogen atom; a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxy lower alkyl group or a hydroxyl-protecting group; and R ³ represents a hydrogen atom or a lower alkoxy group. And m represents an integer of 1 or 2, and Y represents an alkyl group, an aralkyl group, an alkoxy group, an aralkyloxy group or a formula (Π)

2) The therapeutic agent for nephritis according to claim ¹ , wherein in the formula (I), R ¹ is a lower alkyl group.

3) The therapeutic agent for nephritis according to claim 1, wherein in the formula (I), R ² is a hydrogen atom or a lower alkoxycarbonyl group.

4) The therapeutic agent for nephritis according to claim 1, wherein in the formula (I), Y is a group represented by the formula (H) (where n is 2).

5) The therapeutic agent for nephritis according to claim 1, wherein in the formula (I), Y is an alkyl or alkoxy group having 1 to 20 carbon atoms.

6) The therapeutic agent for nephritis according to claim 1, wherein in the formula (I), Y is a fuunylalkyl group having 1 to 5 carbon atoms in the alkyl moiety.