JPH0764803B2 - Capsaicin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to novel compounds having medicinal properties, a method for producing them, a pharmaceutical composition containing them, and their use as a medicine.

[Configuration of the Invention] Wherein, R ₁ is halogen, C _1-4 alkyl, C _1-16 alkoxy, and benzyloxy substituted with benzyloxy or halogen or phenyl, R ₂ is hydrogen or a R ₁ Has any one of the meanings given for R ₃ , R ₃ is hydrogen or C _1-4 alkyl, X is — (CH ₂ ) n-, where n is 1, 2 or 3 And a physiologically hydrolyzable and acceptable ester or amide thereof and a pharmaceutically acceptable salt thereof.

Substituted benzyloxy groups for R ₁ include benzyloxy substituted with halogen or phenyl.
The substitution can be at the 2- and / or 4-position of the benzyloxy group, for example. Suitably the benzyloxy group is mono-substituted. Preferably, the benzyloxy group is mono-substituted at the 4-position.

Alkyl moiety of the alkyl group and alkoxy group as R ₁ or R ₂ as to no R ₁ R ₃ may be a molecular chain or straight chain. Preferably, those alkyl groups and moieties are straight chain.

The term halogen includes fluorine, chlorine, bromine or iodine.

_One group of compounds of formula (I) includes those compounds in which R ₁ is as defined above other than substituted benzyloxy and R, R _{2 to} R ₃ and X are as defined above.

In the compound represented by the formula (I), it is preferable to have the following meanings individually or to have some combinations or partial combinations.

1. R ₁ is halogen, C _1-4 alkyl, C _1-16 alkoxy or substituted or unsubstituted benzyloxy, especially halogen, C _1-16 alkoxy or substituted or unsubstituted benzyloxy. When R ₁ is C _1-16 alkoxy it is preferably n-octyloxy. When R ₁ is substituted benzyloxy, this is preferably halo- or phenyl-benzyloxy, especially 4-halo- or 4-phenyl-benzyloxy. R ₁ is preferably located in the 4-position.

2. R ₂ is hydrogen, halogen or C _1-4 alkyl, especially hydrogen or halogen. If R ₂ is other than hydrogen, it is preferably located in the 2 position.

3. R ₃ is hydrogen or methyl, preferably methyl.

The 4.X - (CH ₂₎ n- (wherein, n has the meaning of the)
Is. Preferably n is 1 or 2, especially 2.

A particularly preferred group of compounds of formula (I) are compounds in which X has the meanings given under 4 above, and in particular R ₁ and
R ₂ is the above compound having the meaning described in 1 and 2 above. A further preferred group of compounds of formula (I) are those compounds wherein X has the meaning given in paragraph 4 above, in particular said compounds where R ₁ and R ₂ have the meaning given in paragraphs 1 and 2 above.

As used herein, the term "physiologically hydrolyzable and acceptable ester or amide" is hydrolyzable under physiological conditions and non-toxic per se, i.e. at the desired dose level. Esters capable of forming acids without significant undesired side effects with [eg,
The compound represented by formula (I) (provided that R ₃ is hydrogen)] or amides are included. These esters include esters with mono- and di-carboxylic acids, such as the ester of the compound of formula (I) where the 3-hydroxy group is acetylated.
These amides include amides derived from organic carboxylic acids, such as acetic acid amides, amino acids, such as glycine amides.

The present invention also provides a process for producing the compounds, amides, esters and salts of the present invention, comprising the steps of: a) preparing a compound of the formula (II) (Wherein R, R _{1 to} R ₃ and X are as defined above) are reacted with hydrazine to produce a compound of formula (I) Removing at least one amino acid protecting group present on the amino protected compound of formula c) to produce a physiologically hydrolyzable and acceptable ester or amide of the compound of formula (I): For example, a compound of formula (I) in which R ₃ is hydrogen is esterified or amidated by reacting with a suitable acylating or amidating agent, respectively, to thereby release the compound of formula (I) thus obtained. A method is provided that includes recovering a salt form.

The preparation step a) is carried out in a similar manner to known methods, for example in an inert solvent or diluent, for example an alkane / alkanol, at ambient or elevated temperature, for example 0 ° C. to reflux temperature, with a compound of formula (II) and hydrazine hydrate. Can be carried out by the reaction of
Process step b) may be performed according to standard techniques known in the art for removal of amino protecting groups. Suitable amino protecting groups include p-toluenesulfonyl, benzyl, formyl and trifluoroacetyl.

Preparation step c) can also be carried out using conventional acylation or amidation methods, for example by reaction with a suitable eg C _1-4 acyl halide or anhydride.

The formula (I) used as a starting material in the manufacturing process (a)
The compound of I) can be produced by the following reaction scheme A or B.

(Wherein R, R _{1 to} R ₃ and X are as defined above, and Y is halogen such as bromine). The compounds of formula (VIII) are disclosed, for example, in published British Patent Application No. 2206347A, It is described together with their manufacturing method. The other compound represented by the formula (VIII) can be produced by a method similar to or similar to the known compound.

In reaction formula B on the next page, R, R _{1 to} R ₃ and X are as defined above, and Y is halogen such as bromine.

The intermediates in the reaction schemes A and B of formulas (X), (VIII), (VI), (V), (II) and (III) are novel and as such form part of this invention. To do.

Unless stated otherwise for the preparation of the starting materials, the compounds may be prepared in analogy to known methods.

The compounds of formula (I) may exist in free or salt form. The salts also include pharmaceutically acceptable acid addition salts, such as salts with inorganic or organic acids such as hydrochloric acid, acetic acid, fumaric acid, citric acid and benzoic acid.

[Examples] Hereinafter, the method of the present invention will be described with reference to Examples.

Use the following abbreviations.

DMF = dimethylformamide TLC = thin layer chromatography.

Example 1 N- [4- (2-aminoethoxy) -3-methoxy-benzyl] -N '-[2- (4-chlorophenyl-ethyl] thiourea.

2.0 g of N- [4- (2-phthalimidoethoxy) -3-methoxybenzyl] -N '-[2- (4
-Chlorophenyl) ethyl] thiourea (0.0038 mol)
Suspend in 10 ml of ethanol, 60 ℃ until the solution becomes uniform.
Heat to. 0.10 ml 1-hexene and 0.95 ml hydrazine hydrate 64% aqueous solution are added and the mixture is heated for 90 minutes. After 15 minutes, a white precipitate begins to form. The mixture is kept fluid by adding a small amount of ethanol. The reaction is quenched and transferred to a separatory funnel and 10 ml methyl-butyl ether, 5 ml water, 5 ml 1N-NaOH and 0.5 ml 50% NaOH are added. The resulting mixture is shaken thoroughly, the organic layer is extracted twice as above and then washed with brine. The organic layer is dried over Na ₂ SO ₄ , filtered and evaporated. The residue is purified by flash column chromatography eluting first with CH ₂ Cl ₂ : MeOH (10: 1) then MeOH. Product fractions were concentrated and dried under vacuum (30
C., 0.1 mmHg) to give the title compound as a solid colorless glass.

The following compound represented by the formula (I) is also obtained by the same method.

The same applies to the following compound represented by the formula (I).

Example R ₁₁ n 4-benzyl-2 5 4-bromobenzyl 2 6 N-octyl 2 7 N-octyl 1 8 4-chlorobenzyl 2 9 4-phenylbenzyl 2 characteristic data 1. ¹ HNMR Data [400 MHz] Example 1: [D ₆ DMSO] δ2.80 (2H, t, J = 7.2Hz), 2.99 (2H, t, J = 5.5Hz), 3.
61 (2H, S, wide), 3.75 (3H, s), 4.00 (2H, t, J = 5.5H
z), 5.57 (2H, s, wide), 6.79 (1H, d, J = 1.8Hz), 6.9
4 (1H, d, J = 8.1Hz), 6.96 (1H, d, J = 1.6Hz), 7.26 (2
H, d, J = 8.2Hz), 7.34 (2H, d, J = 8.1Hz), 7.75 (1H, s,
Wide), 7.99 (1H, s, wide).

Example 2: [CDCl ₃ ] δ1.55 (3H, s, wide), 2.84 (2H, t, J = 6.9Hz), 3.10
(2H, t, J = 5.3Hz), 3.74 (2H, s, wide), 3.83 (3H,
s), 4.02 (2H, t, J = 5.3Hz), 4.41 (2H, s, wide), 5.7
2 (1H, s, wide), 6.18 (1H, s, wide), 6.70−6.81 (2H, s
m), 6.93-6.98 (2H, m), 7.06-7.10 (2H, m).

Example 3: [CDCl ₃ ] δ1.52 (3H, s, wide), 2.99 (2H, t, J = 7.0Hz), 3.11
(2H, t, J = 5.3Hz), 3.75 (2H, s, wide), 3.84 (3H,
s), 4.03 (2H, t, J = 5.3Hz), 4.45 (2H, s, wide), 5.8
2 (1H, s, wide), 6.17 (1H, s, wide), 6.79-6.84 (4H,
m), 7.10-7.17 (3H, m), 7.35 (2H, d, J = 1.8Hz).

Example 4: [CD ₃ OD] δ 2.80 (2H, t, J = 7.1Hz), 3.09 (2H, t, J = 5.1Hz), 3.
68 (2H, S, wide), 3.83 (3H, s), 4.06 (2H, t, J = 5.1H
z), 4.60 (2H, s, wide), 5.04 (2H, s), 6.80−7.13
(5H, m), 7.29-7.43 (4H, m).

Example 5: [CD ₃ OD] δ2.78 (2H, t, J = 7.15Hz), 3.13 (2H, t, J = 5.1Hz),
3.68 (2H, S, wide), 3.84 (3H, s), 4.08 (2H, t, J = 5.1
Hz), 4.60 (2H, s, wide), 5.01 (2H, s), 6.81-7.12
(7H, m), 7.43 (4H, dd, J = 8.3Hz, J = 64.5Hz).

Example 6: [CD ₃ OD] δ0.92 (3H, m), 1.28-1.38 (8H, m), 1.46 (2H, m),
1.75 (2H, m), 3.27 (2H, t, J = 5.0Hz), 3.83 (3H, m
s), 3.94 (2H, t, J = 6.4Hz), 4.16 (2H, t, J = 5.0H)
z), 4.63 (4H, s, wide), 6.82−7.90 (5H, m), 7.19−
7.21 (2H, m).

Example 7: [CD ₃ OD] δ 0.90 (3H, m), 1.28-1.35 (8H, m), 1.46 (2H, m),
1.74 (2H, m), 2.79 (2H, t, J = 7.25Hz), 3.16 (2H, t, J
= 5.15Hz), 3.68 (2H, s, wide), 3.85 (3H, s), 3.92
(2H, t, J = 6.45Hz), 4.11 (2H, t, J = 5.15Hz), 4.63
(2H, s, wide), 6.70-7.11 (7H, m).

Example 8: [CD ₃ OD] δ2.8 (2H, t, J = 7.15Hz), 3.02 (2H, t, J = 5.25Hz),
3.68 (2H, S, wide), 3.83 (3H, s), 4.03 (2H, t, J = 5.2
5Hz), 4.59 (2H, s, wide), 5.03 (2H, s), 6.80−6.97
(5H, m), 7.11 (2H, d, J = 8.45Hz), 7.38 (4H, dd, J =
8.5Hz, J = 13.4Hz).

Example 9: [d ₆ DMSO] δ2.74 (2H, t, J = 7.3Hz), 2.94 (2H, t, J = 5.65Hz),
3.56 (2H, s, wide), 3.74 (3H, s), 3.95 (2H, t, J = 5.6
5Hz), 4.56 (2H, s, wide), 5.12 (2H, s), 6.78 (1H,
m), 6.80-6.97 (4H, m), 7.15 (2H, d, J = 8.5Hz), 7.
37 (1H, m), 7.45-7.54 (5H, m), 7.66-7.69 (4H, m)
m).

The compound of Example 9 has a melting point of 90-92 ° C.

HPLC Retention Times Retention times of the compounds of Examples 1-9 were measured on a C-18 Microbonderpack ™ reverse phase column using the following gradients and conditions.

Solution A: 0.1% trifluoroacetic acid Solution B: Acetonitrile Time (min) Flow rate (ml / min)% A% B 0 2.25 90 10 2 2.25 90 10 6 2.25 45 55 22 2.25 40 60 29 2.25 0 100 31 2.25 90 10 The following results were obtained.

Example Retention time (min) 1 9.404 2 9.415 3 9.740 4 9.752 5 10.297 6 10.827 7 11.317 8 10.080 9 10.482 According to the process of Reaction formula B, the compound used as a starting material can be prepared in the following manner.

a) t-Boc-vanillylamine 18.0 g of vanillylamine hydrochloride (0.095 mol) and 10.6
g Triethylamine (0.11 mol) is dissolved in 250 ml water and placed in a 1 round bottom flask. 20.5 g di-t-butyl dicarbonate (0.095 mol) in 200 ml dioxane
For 15 minutes with stirring. The resulting mixture is stirred overnight at room temperature.

Dioxane was removed in vacuo and the aqueous residue was washed with CHCl ₃ (5 x 10 m
Extract with l). The extracts were combined, dried over MgSO _4, filtered and the solvent was removed in vacuo, a brown oil remains. This was purified by flash column chromatography (cyclohexane: EtOAc / 5: 2) to give a colorless oil which crystallized on standing. [Thin layer chromatography (tlc), cyclohexane: EtOAc / 1: 1, rf =
0.5].

b) t-Boc- (4- (2-bromoethoxy) -3-methoxybenzylamine 21.0 g t-Boc-vanillylamine (0.083 mol), 250 ml
1,2-dibromoethane, 66 ml of 40% KOH and 6.6 ml of 4
Combine 0% tetrabutylammonium hydroxide in a 500 ml round bottom flask and stir the resulting mixture with rapid stirring.
Heat at 50 ° C. for 3 hours.

The mixture is cooled, diluted with 200 ml CH ₂ Cl ₂ , washed with water (3 × 200 ml), the aqueous washings are combined and extracted once with 600 ml CH ₂ Cl ₂ . Combine the organic layers, wash with brine,
Dry over MgSO ₄ , filter and remove the solvent in vacuo to leave a white solid. This is used without further purification. [T.
lc cyclohexane: EtOAc / 1: 1, rf = 0.6].

c) t-Boc- (4- (2-phthalimidoethoxy)-
3-Methoxybenzylamine 23.0 g of t-Boc- (4- (2-bromoethoxy) -3-
Methoxybenzylamine (0.064 mol) and 11.8 g potassium phthalimide (0.064 mol) are suspended in 500 ml dry DMF in a round bottom flask. The resulting suspension is heated at 50 ° C. for 2 hours with rapid stirring. After the heating / stirring for 30 minutes, the mixture becomes homogeneous. The mixture is then cooled and DMF is removed under high vacuum. The resulting solid residue is purified by flash column chromatography (cyclohexane: EtOAc / 1: 1) to give a white solid. [Tlc (cyclohexane: EtOAc / 1: 1) rf = 0.
45].

d) 4- (2-phthalimidoethoxy) -3-methoxybenzylamine. 26.5 g of t-Boc- (4- (2
- dissolved phthalimidoethoxy) -3-methoxybenzyl amine (0.062 mol) of CH ₂ Cl ₂ 200 ml. Add 15 ml of trifluoroacetic acid dropwise with stirring. After completion of dropping
The mixture is stirred for an additional 2 hours at room temperature (the reaction is
Completed by disappearance of starting material (cyclohexane: EtOAc / 1: 1). The solvent is removed under reduced pressure, first by a water pump and then by high vacuum. The colorless oil formed solidifies after standing and is used without further purification.

e) N- [4- (2-phthalimidoethoxy) -3-methoxybenzyl) -N- [2- (4-chlorophenyl)
Ethyl] thiourea 2.0 g 4- (2-phthalimidoethoxy) -3-methoxybenzylamine.TFA (0.005 mol) and 0.5 g Et ₃ N
(0.005 mol) under dry nitrogen atmosphere in 30 ml of dry EtOAc
Suspended in. 0.9 g 2- (4-chlorophenyl) ethyl isothiocyanate (0.0045 mol) in 10 ml dry EtOAc
Is added dropwise and the mixture is stirred at room temperature for 3 hours.

The EtOAc is removed under reduced pressure, the residue is suspended in 50 ml of water and then extracted with 3 × 50 ml of CH ₂ Cl ₂ . Combine the organic layers,
Dry over MgSO ₄ , filter and remove the solvent under reduced pressure to leave a brown oil. It is purified by column chromatography [tlc (cyclohexane: EtOAc / 1: 1) rf = 0.
2]. Melting point = 59-61 ° C.

EFFECTS OF THE INVENTION The compounds and amides and esters of this invention have pharmaceutical applications, especially analgesic and anti-inflammatory applications, as may be demonstrated, for example, in the following standard test model.

1. Tail-flick test in mice.

This method is described by Damour et al., “Journal of Pharmacology and Experimental Therapeutics” (J.Pharmacol.Exp.Ther.), 72, 74-79.
Page (1941), but using non-fasted mice (o + o, 16-25g). Animals are divided into control and test groups, control animals receive only vehicle injections. By placing each test animal in a separate perspex cylinder, movement of the tail protruding along a narrow groove is suppressed. The tail of each animal is exposed to a beam of radiant heat approximately 35 mm from the base of the tail by a lamp of known power and temperature placed directly under the tail. 30 in the cylinder introduction
Minutes later, the test substance is administered orally or subcutaneously. The time (in seconds) it takes for the mouse to flick its tail from the light beam 30-15 minutes prior to test substance administration is recorded. Animals with different reaction times greater than 25% are excluded. The reaction time is remeasured 15 and 30 minutes after administration. Prolonged reaction time> 75% above the mean pretreatment value in the same animal is an indicator of analgesic response. 3 doses per test substance and 10 animals per dose are used. ED ₅₀ values (95% confidence limits) are evaluated according to the method of Litchfield and Wilcoxon. These represent doses that extend the treatment reaction time by a rate of> 75% in 50% of the test animals.

The compounds and amides and esters of this invention are active in the above test models at doses of the order of about 1.0 to about 120.0 μm / kg (subcutaneous).

2. Yeast-induced inflammation test in mice.

20 μl of fresh 20% yeast suspension is injected into the plantar region of one hind paw and the other with saline. Two hours after injection, the degree of inflammation is assessed by the relative increase in paw weight (yeast vs saline injection). The test substances are administered subcutaneously at different doses simultaneously with the yeast / saline treatment. 5 per dose
Animals are used and the test at each dose is repeated 2-3 times, and control and test values are statistically compared as above. The dose required to achieve 50% inhibition of inflammation compared to control animals receiving no test substance is taken as the ED ₅₀ value and is established from a dose response curve plotting% inflammation versus dose. The compounds and esters of this invention have about 2.5 to 1 in the above test model.
It exhibits activity at a subcutaneous dose of about 00 μmol / kg.

Thus, the compounds, esters, amides and pharmaceutically acceptable salts of this invention are useful as pharmaceuticals, eg, in pains of various origins or etiologies, such as toothache and headache,
Analgesics, especially for the treatment of vascular headaches, such as migraine, cluster headaches and mixed vascular syndrome and non-vascular tension headache, and treatment of inflammatory diseases or conditions, such as arthritis and rheumatic diseases, Raynaud's disease, Inflammatory bowel disease, trigeminal neuralgia or herpetic neuralgia, inflammatory eye disease,
For example, they are useful as anti-inflammatory agents for the treatment of uveitis, psoriasis, cystitis and other chronic inflammatory conditions.

In connection with their analgesic / anti-inflammatory profile, they are treated as an alternative to inflammatory pain, hyperalgesia and particularly important chronic pain treatments, eg as an alternative to surgical methods. It is especially useful for treating pain.

According to another embodiment, the compounds of formula (I), their esters, amides and pharmaceutically acceptable salts are also used for the prophylactic or therapeutic treatment of epithelial tissue damage or dysfunction, eg spontaneous lesions, and Control of visceral motility disorders at the respiratory, genitourinary, gastrointestinal and vascular levels, such as the treatment of trauma, burns, cutaneous allergic reactions, itching and vitiligo, the prevention or treatment of gastrointestinal disorders such as gastric ulcer, duodenal ulcer and diarrhea. It is useful for treatment, prophylaxis or therapeutic treatment of gastric lesions induced by necrotizing agents such as ethanol, treatment of vasomotor or allergic rhinitis and treatment of bronchial or bladder diseases. Utility in treating epithelial tissue damage or dysfunction can be demonstrated, for example, in the standard tests described below.

Ethanol-induced gastric lesions Male rats (200-250) fed water ad libitum but fasted overnight.
Perform the test using g). The test substance is administered subcutaneously or orally by means of a metal gastric tube. Thirty minutes after administration of the test substance, absolute ethanol is orally administered and 1 hour later, the animals are killed. Open the abdomen along the bay and pin it flat. Hemorrhagic erosion is quantified by two methods: erosion area and length.

When the compound of formula (I) was administered as the test compound at a dose of about 0.1 to 20 mg / kg, ethanol-induced gastric disease was compared to the results obtained by the control group which received placebo instead of the test compound. A considerable inhibition of the weirdness is observed.

For the above uses, of course, the required dosage will vary with the mode of administration, the particular condition treated and the effect desired. However, generally for analgesic applications, about 1
An oral dose rate of about 20 mg / kg, for example about 1 mg / kg to about 1 mg / kg,
And for anti-inflammatory applications, oral dose rates of about 1 to about 20 mg / kg give satisfactory results. That is, a suitable daily dose rate in large mammals is conveniently in a single dose form, in a 2-4 dose / day divided dose form or in a sustained or delayed form, for analgesic use about 2 to about a dose.
1000 or 2000 mg (oral), eg about 75-750 or 150
About 0 mg (oral), and for anti-inflammatory use, about 10 to about 2
It is about 000 mg (oral), for example, about 75 to 1500 mg (oral). Accordingly, suitable dosage forms for oral administration are about 0.5 to about 500 or 1000 mg, e.g. about 20 to about, in admixture with a suitable solid or liquid pharmaceutically acceptable diluent or carrier.
About 375 or 750 mg (for analgesic use), or about 2.5 to about 1000 m
g, for example about 20 to about 750 mg (for anti-inflammatory use) of the active ingredient (ie the compound, ester, amide or pharmaceutically acceptable salt of the invention).

From the foregoing, the invention also relates to A. in a subject in need of treatment: i) treatment of pain of various origins or etiologies, such as treatment of the aforementioned diseases or conditions, ii) inflammatory diseases and And / or the treatment of inflammatory pain, eg the treatment of the diseases or conditions mentioned above, iii) the prophylactic or therapeutic treatment of epithelial tissue damage or dysfunction, gastrointestinal disorders, necrosis-induced gastric lesions, iv) respiratory tract, urine In order to control visceral motility disorders at the genital, gastrointestinal and vascular levels, or v) to treat rhinitis and bronchial or bladder diseases, said subject is treated with a compound of formula (I) as defined above or physiologically A method comprising administering an effective amount of a hydrolysable and acceptable ester or amide, or a pharmaceutically acceptable salt thereof, B. Pharmaceutical, eg analgesic and / or anti-inflammatory. Inflammatory agents and /
Or a compound represented by the above formula (I) or a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutically acceptable compound thereof, which is used as a prophylactic or therapeutic agent in the treatment of epithelial tissue damage or dysfunction. Acceptable salts, and C. A compound of the above formula (I) or a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutical thereof together with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition comprising a pharmaceutically acceptable salt.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Roger Rigglesworth Seven Oaks, UK, Chemsing, Pilgrims Way 73 (56) References JP-A-63-295537 (JP, A)

Claims (3)

[Claims] 1. A formula (I) Wherein, R ₁ is halogen, C _1-4 alkyl, C _1-16 alkoxy, and benzyloxy substituted with benzyloxy or halogen or phenyl, R ₂ is hydrogen or a R ₁ Has any one of the meanings given for R ₃ , R ₃ is hydrogen or C _1-4 alkyl, X is — (CH ₂ ) n-, where n is 1, 2 or 3 Or a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutically acceptable salt, ester or amide of said compound. 2. A) N- [4- (2-aminoethoxy)-
3-Methoxybenzyl] -N ′-[2- (4-chlorophenyl) ethyl] thiourea, b) N- [4- (2-aminoethoxy) -3-methoxybenzyl] -N ′-[2- (4 -Fluorophenyl) ethyl] thiourea, c) N- [4- (2-aminoethoxy) -3-methoxybenzyl] -N '-[2- (2,4-dichlorophenyl)
Ethyl] thiourea, d) N- [4- (2-aminoethoxy) -3-methoxybenzyl] -N '-[2- (4-benzyloxyphenyl) ethyl] thiourea, e) N- [4- (2-Aminoethoxy) -3-methoxybenzyl] -N '-[2- (4- (4-bromobenzyloxy) phenyl) ethyl] thiourea, f) N- [4- (2-aminoethoxy)- 3-methoxybenzyl] -N ′-[2- (4- (N-octyloxy) phenyl) ethyl] thiourea, g) N- [4- (2-aminoethoxy) -3-methoxybenzyl] -N ′ -[4-N-octyloxybenzyl] thiourea, h) N- [4- (2-aminoethoxy) -3-methoxybenzyl] -N '-[2- (4- (4-chlorobenzyloxy) phenyl ) Ethyl] urea, and i) N The selected from the group consisting of [4- (2-aminoethoxy) -3-methoxybenzyl] -N '-[2- (4- (4-phenylbenzyloxy) phenyl) ethyl] thiourea. A compound or a physiologically hydrolyzable and acceptable ester or amide thereof or a pharmaceutically acceptable salt of said compound,
Ester or amide. 3. An analgesic comprising, as an active ingredient, a compound represented by the formula (I) according to claim 1, or a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof. Anti-inflammatory agent.