LU87648A1 - NOVEL THIOURE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICINES - Google Patents

Description

The present invention relates to new derivatives of thiourea, their preparation and their use as medicaments.

According to a first aspect, the invention relates to the compounds of formula I

(I) in which

R1 signifies halogen or C1-4alkyl / phenyl, benzyl, optionally substituted benzyloxy, nitro, cyano, trifluoromethyl, for-mylamino or C1-6alkoxy, r2 signifies hydrogen or has any of the meanings given for R 1, R 3 signifies hydrogen or a C1-C4 alkyl group, R4 and R5 each signify, independently of one another, hydrogen, a halogen or an optionally substituted C1-C5 alkyl group, optionally aryl substituted, C.OOH, COORg or CONR9Ri0 where R8 signifies a C1-C5 alkyl group and R9 and Rio each signify, independently of one another, hydrogen or a C1-C5 alkyl group,

Rs and R7, independently of each other, have the meanings indicated for R4 and R5 or together form, with the carbon atoms to which they are attached, an optionally substituted C3-C7 cycloalkyl group, R signifies 0 , S or NH and X signifies - (CH2) n- or - (CH2) a-CH »CH- (CH2) r- where n signifies 1, 2 or 3 and each m and r signifies independently of one of l other, 0 or an integer of 1 to 3, and the physiologically hydrolysable and physiologically acceptable esters or amides as well as the pharmaceutically acceptable salts of these compounds.

The compounds of formula I in which X signifies - (CH2) a-CH »CH- (CH2) r- can exist in both cis or trans isomer forms, that is to say in the form of Z and E isomers The invention includes the individual cis and trans isomers and mixtures thereof.

The substituted benzyloxy group represented by R 1 includes the benzyloxy group substituted by a halogen OR by a phenyl group. The substituents can be located for example in position 2 and / or 4 of the benzyloxy group. The benzyloxy group is advantageously monosubstituted. The benzyloxy group is preferably monosubstituted in position 4.

The alkyl groups represented by Rx to R10 as well as the alkyl radicals of the alkoxy groups represented by R1 or R2, may be straight or branched chain. Such alkyl groups and residues are preferably straight chain.

Halogen means fluorine, chlorine, bromine or iodine.

The preferred aryl groups represented by r4 to r7 are the phenyl and naphthyl groups. Such groups can be optionally substituted, for example mono-, di- or trisubstituted. Preferred substituents are selected from halogens and hydroxy, amino and carboxy groups. The especially preferred aryl groups represented by R4 to R7 are phenyl and substituted phenyl.

A group of compounds of formula I includes the compounds in which R1 is as defined above except for a substituted benzyloxy group, and R, R2 to R1 g and X are as defined above.

In the compounds of formula I, the following meanings are preferred individually or in any combination or sub-combination: 1. R 1 denotes a halogen or a C1-C4 alkyl group, C1-Cifi alkoxy or optionally substituted benzyloxy, especially a halogen or a C1-C5 alkoxy or optionally substituted benzyloxy group. When Ri signifies an alkoxy group in

Ci-Ci g, it is advantageously the n-octyloxy group. When Rx signifies a substituted benzyloxy group, it is advantageously a halo- or phenyl-benzyloxy group, especially a 4-halo- or 4-phenyl-benzyloxy group. Ri is preferably located in position 4.

2. R2 means hydrogen, halogen or an alkyl group. in C1-C4, especially hydrogen or halogen. When R2 has a meaning other than hydrogen, it is preferably located in position 2.

3. R3 signifies hydrogen or a methyl group, advantageously a methyl group.

4. R4 to R7 each mean, independently of each other, hydrogen or a methyl, ethyl, C1-C5 alkyl substituted by OH or NH2, phenyl or (C1-C5 alkyl) phenyl. Preferably, at least one of the symbols R4 to R6 signifies hydrogen. More preferably, at least three of the symbols R4 to R7, for example R4, R5 and R6, signify hydrogen.

5. R means -0-.

6. X means - (CH2) „- where n has the meaning indicated above, n preferably means 1 or 2, especially 2.

7. X signifies - (CH2) a-CH »CH- (CH2) r- where one of the symbols m and r signifies 0 and the other signifies 1. The two symbols m and r preferably signify • 0. More preferably, such groups represented by X are in the Z isomer form.

A specially preferred group of compounds of formula I includes those in which X has the meanings indicated under 6 above and especially the compounds in which R1 and R2 are as defined above in 1 and 2. Another preferred group of compounds of formula I includes those in which X has the meanings indicated under 6 above and each symbol R4 to R7 signifies hydrogen, especially the compounds in which R2 and R2 are as defined in 1 and 2 above.

The expression "physiologically hydrolysable and physiologically acceptable esters or amides" means esters (for example the compounds of formula I in which one or more of the symbols R4 to R7 signifies -COOH and / or R3 signifies hydrogen) or amides which are hydrolyzable under physiological conditions to give acids or alcohols which are themselves non-toxic, that is to say which do not give genuinely undesirable side effects at the doses administered. Such esters include esters with mono- and dicarboxylic acids, for example esters of compounds of formula I where the 3-hydroxy group is acetylated and esters with lower alkanols, for example C1-C4 alkanols. Such amides include those derived from organic carboxylic acids, for example amides of acetic acid, including amino acids, for example glycine amides.

The invention also relates to a process for the preparation of the compounds, amides, esters and salts of the invention, process according to which a) a compound of formula il is reacted

(II) in which R, R 1 to R 7 and X are as defined above, with hydrazine; b) removing at least one protective group present in a compound of formula I having a protected amino group, c) for the preparation of a physiologically hydrolyzable and physiologically acceptable ester or amide of a compound of formula I, esterify or amide a compound of formula I, for example in which R3 signifies hydrogen, by reaction with an appropriate acylation or amidation agent respectively, d) for the preparation of a compound of formula I where X signifies - (CH2) a-CH = CH- (CH2) r- in the Z isomer form, a compound of formula I is isomerized in which X signifies - (CH2) „- CH» CH- (CH2) e- in the E isomer form , and the compound of formula I thus obtained is recovered, in free form or in the form of a salt.

Step a) of the process can be carried out in a manner analogous to known methods, for example by reaction of a compound of formula II with hydrazine hydrate in an inert solvent or diluent, for example an alkane / alkanol, at ambient temperature or at elevated temperatures, for example at a temperature between 0 ° C. and the reflux temperature.

Step b) of the process can be carried out according to conventional techniques known in the state of the art to remove the protective groups from the amino groups. As suitable protective groups for amino groups, mention may be made of p-toluene-sulfonyl, benzyl, formyl and trifluoroacetyl groups.

Step c) of the process can also be carried out according to the usual acylation or amidation methods, by reaction with, for example, a halogenide or an appropriate acid anhydride.

The trans isomers of the compounds of formula I in which X signifies - (CH2) a-CH »CH- (CH2) r- can be transformed into cis isomers (Z) according to the usual methods, for example by irradiation. The individual cis and trans isomers can be obtained according to techniques known in the state of the art, for example by separation of the mixtures of cis / trans isomers, for example by chromatography.

The compounds of formula II used as starting materials in stage a) of the process can be prepared according to one of the following 2 reaction schemes A and b:

REACTIONAL DIAGRAM · A

in which R, Rx to R7 are as defined above, Y means a halogen, for example bromine, and R 'signifies O or S.

The compounds of formula VIII, in which R signifies O, are described as well as their methods of preparation, for example in British patent application 2 206 347A. Other compounds of formula VIII can be prepared in a similar or analogous manner to the known compounds.

In reaction scheme B on the following page, R, R 1 to R 7 and X are as defined above and Y signifies a halogen, for example bromine.

The intermediate products of reaction schemes A and B of formula II, III, V, VI, VIII and X, are new and also form part of the invention.

When the preparation of the starting materials is not described, these can be prepared in a similar manner to known methods.

The compounds of formula I as defined above can be in free form or in the form of a salt. For a use according to the invention, the pharmaceutically acceptable and suitable salts of the compounds of formula I, for example where one or more of the symbols R4 to R7 mean -COOH, include for example the sodium, potassium and calcium salts , as well as the tri-ethylammonium salts. Such salts also include the addition salts of pharmaceutically acceptable acids, for example the salts with organic or mineral acids such as hydrochloric acid, acetic acid, fumaric acid, citric acid and benzoic acid.

The following examples illustrate the present invention without in any way limiting its scope.

EXAMPLE 1; N- [4- (2-aminoethoxy) -3-methoxy-benzyl] -Nf [2- (4-chlorophenyl) -ethyl1thiourea

In a round bottom flask, 2.0 g of N- [4- (2-phthalimidoethoxy) -3-methoxybenzyl] -N '- [2- (4-chlorophenyl) ethyl are suspended in 10 ml of ethanol ] thiourea (0.0038 mole) and heated to 60 ° C until the solution becomes homogeneous. 0.10 ml of 1-hexene and 0.95 ml of a 64% aqueous solution of hydrazine hydrate are added and the mixture is heated for 90 minutes. After 15 minutes, a white precipitate forms and a small amount of ethanol is added to keep the mixture fluid. The reaction mixture is cooled, transferred to a separatory funnel and 10 ml of methyl butyl ether, 5 ml of water, 5 ml of 1N NaOH and 0.5 ml of 50% NaOH are added. The resulting mixture is thoroughly stirred, the organic phase is extracted twice as indicated above and then washed with a saturated sodium chloride solution. The organic phase is dried over Na2SO4 / filtered and the solvent is removed by evaporation. The residue is purified by rapid chromatography, eluting first with a CH2Cl2: MeOH mixture (10: 1) and then with MeOH. The product fractions are evaporated and dried under vacuum (30 ° C, 0.1 mm Hg) to obtain the title product in the form of a colorless glassy solid.

The following compounds of formula I can be obtained by analogous procedure:

Example R Ri R2 R3 R <â R? X .2 0 4-F H. CH3 H (CH2) 2 3 0 4-Cl 2-C1 CH3 H (CH2) 2

and also Your following compounds of -formulate I

(I) EXAMPLE Ru n 4 benzyl 2 5 4-bromobenzyl 2 6 n-octyl 2 7 n-octyüâ 1 8 4-chlorobenzyl 2 9 4-phenylbenzyl 2

CHARACTERISTIC DATA

1. SPECTRUM] H NMR (40Q- „HHz)

Example U- [DeDMSO] S2,80 <2H, t, J-7.2Hz), 2.99 (2H, t, J-5.5HZ), 3.61 (2H, S, large), 3.75 (3H, s), 4.00 (2H, t, J "5; 5Hz), 5.57 (2H, s, large), 6.79 <1H, 8Hz), 6.94 <1H, d, J = 8, Hz), 6.96 (1H, d, Jl, 6Hz), 7.26 (2H, d, J = 8.2Hz), 7.34 (2H, d, J = 8, lHz), 7 , 75 (w, s, large), 7.99 (w, s, large)

Example 2: [cdc13] 51.55 (3H, s, Jargé), 2.84 (2H, t, J-6.9Hz), 3.10 <2H, t, J-5.3Hz), 3.74 (2H, s, large) "3.83 (3H, s), 4.02 (2H, t, J-5.3Hz), 4.41 <2H, s;} arge), 5.72 (1H, s, wide), 6.18 (1H, s, wide), 6.70-6.81 (2H, m), 6.93-6.98 (2H, m), 7.06-7.10 ( 2H, m)

Example 3: [CDC13] 51.52 (3H, s, broad), 2.99 (2H, t, H "7.0Hz), 3, ll (2H, t, D-5.3Hz), 3.75 (2H, s, large), 3.84 (3H, s), 4.03 (2H, t, J "5.3Hz), 4.45 (2H, s, large), 5.82 (1H, s, width ^, 6.17 (1H, s, large), 6.79-6.84 (4H, ra), 7.10-7.17 (3H, m), 7.35 (2H, d, J "l, 8Hz)

Example 4: [CD3OD] 52.80 (2H, t, J = 7, lHz), 3.09 (2H, t, J = 5, lHz), 3.68 (2H, s, large), 3.83 (3H, s), 4.06 (2H, t, J = 5.1Hz), 4.60 (2H, s, broad.), 5.04 (2H, s), 6.80- 7.13 (5H, m), 7.29-7.43 (4H, m)

Example 5: [CD3OD] S2 »78 (2H, t, J = 7.15Hz),, 13 (2H, t, J = 5, lHz), 3.68 (2H, s, .large), 3.84 (3H, s), 4.08 (2H, t, J = 5.1Hz), 4.60 (2H, s, large), 5.01 (2H, s), 6.81- 7.12 (7H, m ), 7.43 (4H, dd, J = 8.3Hz, J = 64.5Hz)

Example 6: [CD3OD] 50.92 (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, s), 3.94 (2H, t, J * 6.4Hz), 4.16 (2H, t, J» 5.0Hz), 4.63 (4H, s, larg $, 6.82-7.90 (5H, m), 7.19-7.21 (2H, m)

Example 7: [CD3OD] S0.90 (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, large), 3.85 (3H, s), 3.92 ( 2H, t, J-6.45Hz), 4, ll (2H, t, J "5.15Hz), 4.63 (2H, s, wide), 6.70-7, ll (7H, m)

Example 8: [CD30DJ

52.8 <2H, t, J-7.15Hz), 3.02 (2H, t, J-5.25Hz), 3.68 <2H, s, large), 3.83 (3H, s), 4.03 <2H, t, D-5.25Hz), 4.59 (2H, s, large), 5.03 (2H, s), 6.80-6.97 (5H, m), 7, ll (2H, d, J * 8.45Hz), 7.38 (4H, dd, J-8.5Hz, J-13.4Hz)

Example 9: [dfiDMSO] S2.74 (2H, t, J-7.3Hz), 2.94 <2H, t, J-5.65Hz), 3.56 (2H, s,; width), 3, 74 (3H, s), 3.95 (2H, t, J "5.65Hz), 4.56 (2H, s, large), 5.12 (2H, s), 6.78 (1H, m) , 6.80-6.97 (4H, m), 7.15 (2H, d, D-8.5Hz), 7.37 (1H, m), 7.45-7.54 (5H, m) , 7.66-7.69 (4H, m)

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

Retention time by liquid chromatography (HPLC)

The retention times of the compounds of Examples 1 to 9 were measured by reverse phase chromatography on C-18 Microbondapak R using the following gradients and conditions:

Solution A: trifluoroacetic acid ^ 0.1¾

Solution B: acetonitrile

FLOW TIME * A% B

• (min) (ral / min) 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 are 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 steps of reaction scheme B, the compounds used as starting materials can be prepared in the following manner: a) t-Boc-vanillylamine

In 250 ml of water, 18.0 g of vanillylamine hydrochloride (0.095 mole) and 10.6 g of triethylamine (0.11 mole) are dissolved and the mixture is placed in a 1 liter round bottom flask. With stirring and over the course of 15 minutes, 20.5 g of di-tert-butyl dicarbonate (0.095 mol) in 200 ml of dioxane are added. The resulting mixture is stirred overnight at room temperature.

The dioxane is removed in vacuo and the aqueous residue is extracted with CHCl3 (5x10 ml). The combined extracts are dried over MgSO4, filtered and the solvent is removed under vacuum, which gives a brown oil which is purified by rapid chromatography (cyclohexane: EtOAc / 5: 2)? a colorless oil is thus obtained which crystallizes on standing (thin layer chromatography: cyclohexane: EtOAc / 1: 1; Rf - 0.5 J - b) t-Boc- [4- (2-bromoethoxy)] - 3- methoxybenzylamine

In a 500 ml round bottom flask, 21.0 g of t-Boc-vanillylamine (0.083 mole), 250 ml of 1,2-dibromoethane, 66 ml of 40% KOH and 6.6 ml of 40% tetrabutylammonium hydroxide and the resulting mixture is heated at 50 ° C for 3 hours with rapid stirring.

The mixture is cooled, diluted with 200 ml of CH2Cl2, washed with water (3x200 ml) and the combined washings are extracted once with 600 ml of CH2Cl2. The combined organic phases are washed with a saturated sodium chloride solution, dried over MgSO4, filtered and the solvent is removed in vacuo to obtain a white solid which is used without further purification for the following reaction, [ thin layer chromatography: cyclohexane: EtOAc / 1: 1; R.f. -0.6].

c) t-Boc- (4- (2-phthalimidoethoxy) —3-methoxybenzylamine

23.0 g of t-Boc- (4- (2-bromoethoxy) -3-methoxybenzylamine (0.064 mole) and 11.8 g of potassium phthalimide (0.064 mole) are suspended in 500 ml of anhydrous dimethylformamide. The resulting suspension is heated at 50 ° C. for 2 hours with rapid stirring, after 30 minutes with heating and stirring, the mixture becomes homogeneous. It is then cooled and the dimethylformamide is removed under high vacuum. The resulting solid residue is purified by rapid chromatography (cyclohexane: EtOAc / 1: 1) to obtain a white solid, [thin layer chromatography (cyclohexane: EtOAc / 1: 1) Rf »0.45], d) 4- (2-phthalimidoethoxy) 3- methoxybenzylamine, trifluoroacetate

In a 500 ml round-bottomed flask, 26.5 g of t-BOC- (4- (2-phthalimidoethoxy) -3-methoxybenzylamine (0.062 mole) are dissolved in 200 ml of CH2Cl2. drop 15 ml of trifluoroacetic acid. When the addition is complete, the mixture is stirred for a further 2 hours at room temperature (the reaction is complete when no starting material remains (cyclohexane: EtOAc, 1: 1 The solvent is removed in vacuo, first under the vacuum of the water pump and then under high vacuum, the resulting colorless oil solidifies on standing and is used without further purification for the next reaction.

e) N- [4- (2-phthalimidoethoxy) -3-methoxybenzyl) -N- [2- (4-chlorophenyl) -ethyl] thiourea

Under an atmosphere of dry nitrogen and in 30 ml of anhydrous EtOAc, 2.0 g of 4- (2-phthalimidoethoxy) -3-methoxybenzylamine, trifluoroacetate (0.005 mole) and 0.5 g of Et2N (0.005 mole) are suspended. ). 0.9 g of 2- (4-chlorophenyl) ethyl isothiocyanate (0.0045 mole) is added dropwise to 10 ml of anhydrous EtOAc and the mixture is stirred at room temperature for 3 hours.

The EtOAc is removed in vacuo, the residue is suspended in 50 ml of water and then extracted with 3 × 50 ml of CH2Cl2. The combined organic phases are dried over MgSO 4, filtered and the solvent is removed under vacuum to obtain a brown oil which is purified by column chromatography [thin layer chromatography (cyclohexane: EtOAc, 1: 1) R.f. - 0.2]. M ”59-61 ° C.

The compounds, amides and esters of the invention have advantageous pharmacological properties and can therefore be used in therapy as medicaments. They exert in particular an analgesic and anti-inflammatory activity as it emerges from the following tests:

1. TAIL REMOVAL FROM THE MOUSE

This trial is based on the protocol of D'Amour et al., J. Pharmacol. Exp. Ther. 72, 74-79 (1941), but using non-fasting mice (o + o, 16-25 g) which are divided into control groups and test groups, the former receiving a single injection of the vehicle. Each animal is placed in a perspex cylinder, the tail protruding into a groove. The tail of each animal is exposed to radiant heat about 35 mm from the base of the tail, using a lamp of known power and temperature which is placed directly under the tail. The test substance is administered orally or subcutaneously 30 minutes after the introduction of each animal into the cylinder. 15 to 30 minutes before the administration of the test substance, the time in seconds is recorded until the mouse removes its tail. Animals whose reaction times differ by more than 25% are excluded from the test. The reaction time is again determined 15 and 30 minutes after administration of the substance. A substance is considered to have a anal analgesic effect when it prolongs the reaction time by more than 75% compared to the average pretreatment values in the same animal. Three doses are used per test substance and 10 animals per dose. The effective dose (ED50) is determined according to the method of Litchfield and Wilcoxon and represents the dose prolonging the reaction time by more than 75% in 50% of the animals subjected to the test.

The compounds, amides and esters of the invention are active in this test at doses of between approximately 1.0 and approximately 120.0 yt / M / kg, after administration by the subcutaneous route.

2. YEAST-INFLAMMATION TEST

20 μΐ of a 20% fresh yeast suspension are injected into the plantar region of one of the hind legs and a physiological solution is injected into the other. The degree of inflammation is evaluated by the relative increase in the weight of the paw (yeast injection / physiological solution) 2 hours after the injection. The test substance is administered subcutaneously at various doses at the time of the yeast / saline treatment. 5 animals are used for each dose, the test being repeated 2 to 3 times for each dose. The control values and the test values are statistically compared as described above. The effective dose (ED) - is the dose necessary to produce a 50% reduction in inflammation compared to control animals and is determined by establishing the dose / response curve of the percentage of inflammation versus dose. The compounds, amides and esters of the invention are active in this test at doses of between approximately 2.5 and 100 yt / M / kg after administration by the subcutaneous route.

The compounds, esters, amides and pharmaceutically acceptable salts of the invention can therefore be used therapeutically as medicaments, for example as analgesics for the treatment of pain of various origin or ethology, for example for pain in the head and headache, particularly vascular headache such as migraine, cluster headache and mixed vascular syndromes, as well as non-vascular headache and tension headache, and as anti-inflammatory agents for the treatment of diseases or inflammatory conditions, for example for the treatment of arthritis and rheumatism, Raynaud's disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders, for example uveitis, psoriasis or cystitis, as well as other chronic inflammatory conditions.

Thanks to their analgesic / anti-inflammatory profile, the compounds of the invention are useful in particular for the treatment of pain of inflammatory origin, the treatment of hyperalgia and, in particular, severe chronic pain, for example for the treatment of pain of deafferentation in order to avoid surgical interventions.

According to another aspect of the invention, the compounds of formula I, their esters, amides and pharmaceutically acceptable salts, are also useful for the prophylactic and curative treatment of lesions or dysfunction of the tissues of the epithelium, for example of spontaneous lesions, and for the control of disorders of visceral motility at the respiratory, genitourinary, gastrointestinal and vascular level, for example for the treatment of wounds, burns, allergic dermal reactions, pruritus and vitiligo, prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers and diarrhea, for the prophylactic or curative treatment of gastric lesions caused by necrotizing agents, for example ethanol, for the treatment of rhinitis vasomotor or allergic and for the treatment of disorders of the bronchi or bladder. The usefulness of the compounds of the invention in ~ the treatment of lesions or dysfunction of the tissues of the epithelium, can be demonstrated for example in the following test:

GASTRIC LESIONS CAUSED BY ETHANOL

The tests are carried out with male rats (200-250 g) which are made to fast overnight, but which have free access to water. The test substance is administered subcutaneously or orally using a metal tube placed in the stomach. Absolute ethanol is administered orally 30 minutes after administration of the test substance and the animals are sacrificed 1 hour later. The stomach is cut along the large curvature and kept flattened using forceps. Hemorrhagic erosions are quantified according to two parameters: the area and the length of the erosions.

After administration of the compounds of formula I at a dose of between approximately 0.1 and 20 mg / kg, a substantial inhibition of the gastric lesions caused by ethanol is obtained, compared with the results obtained with the control groups receiving the placebo at the place of the substance to be tested.

For the aforementioned uses, the required dose naturally depends on the mode of administration, the particular condition to be treated and the desired effect. The daily dose suitable for oral administration is between about 2 and about 1000 or 2000 mg, for example between about 75 and 750 or 1500 mg for use as an analgesic, and between about 10 and about 2000 mg, for example d '' about 75 to 1500 mg for use as an anti-inflammatory, advantageously administered in divided doses 2 to 4 times a day, or in a prolonged or delayed release form. Unit doses suitable for oral administration therefore include between about 0.5 and about 500 or 1000 mg, for example between about 20 and about 375 or 750 mg (for use as an analgesic) and about 2.5 at about 1000 mg, for example between about 20 and about 750 mg (for use as an anti-inflammatory) of active substance (i.e. a compound, an ester, an amide or a pharmaceutically acceptable salt of the invention), in combination with a suitable solid diluent or carrier or a pharmaceutically acceptable liquid.

As medicaments, the compounds of the invention are advantageously administered in the form of a pharmaceutical composition comprising a compound of formula I or a physiologically hydrolysable and physiologically acceptable ester or amide of this compound or a pharmaceutically acceptable salt of this compound, in combination with a pharmaceutically acceptable diluent or vehicle. Such pharmaceutical compositions, which also form part of the invention, can be prepared according to the usual methods and can be presented, for example, in the form of tablets or capsules.

In accordance with the above, the invention also relates to: A. A compound of formula I or a physiologically hydrolyzable and physiologically acceptable ester or amide of this compound, as defined above, or a pharmaceutically acceptable salt of this compound, for the use as a medicament, for example for the treatment of the diseases and conditions mentioned above, B. A pharmaceutical composition comprising a compound of formula I or a physiologically hydrolyzable and physiologically acceptable ester or amide of this compound as defined above, or a salt pharmaceutically acceptable compound, in combination with a pharmaceutically acceptable diluent or carrier.

Suitable pharmaceutically acceptable salts of the compounds and esters of the invention include, for example, the sodium and potassium salts.

Claims (7)

2. A compound, an ester, an amide or a salt according to claim 1, characterized in that: Ri signifies a halogen, a C1-C6 alkoxy group or an optionally substituted benzyloxy group, R2 signifies hydrogen or a halogen, R3 means hydrogen or a methyl group, R4 to R7 mean hydrogen, R means -0-, and X means - (CH2) n- where n means 1 or 2. 3. A compound, an ester, an amide or a salt according to claim 1 or 2, characterized in that Rx has a meaning other than a substituted benzyloxy group. 4. A compound according to any one of claims 1 to 3, characterized in that it is chosen from: 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] thiourea, and i) N- [4- (2-aminoethoxy) -3-methoxybenzyl] -N '- [2- (4- (4-phenylbenzyloxy) phenyl) ethyl] thiourea. 5. A process for the preparation of a compound of formula X as defined in claim 1 or of an esterV of an amide or of a salt of this compound, characterized in that a) a compound of formula II

(II) in which R, R 1 to R 7 and X are as defined above, with hydrazine; b) removing at least one protective group present in a compound of formula I having a protected amino group, c) for the preparation of a physiologically hydrolyzable and physiologically acceptable ester or amide of a compound of formula I, esterify or amide a compound of formula I by reaction with an appropriate acylation or amidation agent respectively, d) for the preparation of a compound of formula I where X signifies - {CH2) ra-CH = CH- ( CH2) r- in Z-isomer form, a compound of formula I is isomerized in which X signifies - (CH2) n-CH = CH- {CH2) r- in E-isomer form, and the compound of formula I thus obtained is recovered , in free form or in the form of a salt. 6. A compound, an ester, an amide or a salt, as defined in any one of claims 1 to 4, for use as a medicament. 7. A pharmaceutical composition, characterized in that it comprises a compound of formula I as defined in any one of claims 1 to 4, or a physiologically hydrolyzable and physiologically acceptable ester or amide or a pharma-ceutically salt acceptable for this compound, in combination with a pharmaceutically acceptable diluent or vehicle. 8. A compound of formula II, III, V, VIII or X

(II)

in which R, Rx a R7 and X have the meanings indicated in claim 1, Y means a halogen and R 'means 0 or S.