FR2640971A1 - - Google Patents

Abstract

The subject of the invention is the thiourea derivatives of formula I (CF DRAWING IN BOPI) in which R, R1 to R7 and X have various meanings. These compounds can be used as drugs.

Description

The subject of the present invention is new derivatives of thiourea,

their preparation and

  their use as medicines.

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

CH2 -NH --- XC_

R2 OR3 R4 R5 II I

R - C - C - NE2

  Wherein R is halogen or C 1 -C 4 alkyl, phenyl, benzyl, optionally benzyloxy;

  substituted, nitro, cyano, trifluoromethyl,

  m-amino or C 1 -C -alkoxy, R 2 is hydrogen or any of the meanings given for R 1, R 3 is hydrogen or an alkyl group

C -C4,

  R4 and R5 each independently of one another is hydrogen, halogen, optionally substituted C1-C5 alkyl, optionally substituted aryl, COOH, COOR5 or CONR9RI0; R8 is C1-C6alkyl; Cs and R9 and R10 are each independently of one another hydrogen or C1-C5alkyl, R6 and R7, independently of one another, have the meanings indicated for R4 and R5 or together with the carbon atoms to which they are attached form an optionally substituted C3-C3 cycloalkyl group, R is O, S or NH and X is - (CH2) .- or - (CH2) o- CH-CH- (CH 2) n is 1, 2 or 3 and each m and r is, independently of each other, O or an integer of 1 to 3, and the esters or amides are physiologically hydrolysable and physiologically acceptable salts

  pharmaceutically acceptable compounds of these compounds.

  Compounds of formula I wherein x is - (CH2) .CH = CH- (CH2) can exist in both cis and trans isomeric forms, i.e. as Z and E isomers. The invention comprises the individual cis and trans isomers and mixtures thereof. The substituted benzyloxy group represented by R 1 comprises the benzyloxy group substituted with a halogen or with a phenyl group. The substituents may be located for example in position 2 and / or 4 of the benzyloxy group. The benzyloxy group is advantageously monosubstituted. The benzyloxy group is monosubstituted from

preferably in position 4.

  The alkyl groups represented by R1 to RO10

  as well as the alkyl residues of the alkoxy groups

  R1 or R2 may be straight-chain or branched. Such groups and alkyl residues are of

preferably straight chain.

  Halogen means fluorine,

chlorine, bromine or iodine.

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

  phenyl and substituted phenyl groups.

  A group of compounds of formula I include the compounds wherein R [is as defined above except for a substituted benzyloxy group, and R, R2 to

  Rj0 and X are as defined above.

  In the compounds of formula I, the

  The following are preferred individually or in any combination or sub-combination: 1. R1 is halogen or C1-C4 alkyl, C1-C6 alkoxy or optionally substituted benzyloxy, especially halogen or group

  C1-C16 alkoxy or optionally benzyloxy

  stitutes. When R 1 is C 1 -C 6 alkoxy, it is advantageously n-octyloxy. When R 1 is a substituted benzyloxy group, it is preferably a halo or phenylbenzyloxy group, especially a 4-halo or 4-phenylbenzyloxy group. R1 is located

preferably in position 4.

  2. R2 is hydrogen, halogen or C1-C4 alkyl, especially hydrogen or halogen. When R2 has a meaning other than hydrogen, it is preferably located in position 2. 3. R3 is hydrogen or methyl,

advantageously a methyl group.

  4. R4 to R7 mean each, independently of each other, hydrogen, methyl, ethyl, C1-C5 alkyl substituted with OH or NH2, phenyl or (C1-C8) alkyl phenyl. Preferably,

  at least one of R4 to R6 signifies hydro-

  gene. More preferably, at least three of the

  symbols R4 to R7, for example R4, R5 and R6, signify

have hydrogen.

5. R means -O-.

  6. X means - (CH2) n- has a significance

  diqué above. n preferably means 1 or 2,

especially 2.

  7. x means - (CH2)> - CH-CH- (CH2) r- o one of the

  symbols m and r means 0 and the other means 1.

  The two symbols m and r are preferably 0. More preferably, such groups represented by X are in the Z isomer form. A particularly preferred group of compounds

  Formula I includes those in which X has the meanings

  mentioned in 6 above and especially

  compounds in which R1 and R2 are such that

  terminated above under 1 and 2. Another preferred group of compounds of formula I include those wherein X has the meanings given in 6 above and each R4 to R7 signifies hydrogen, especially those compounds in which R1 and R2 are as defined

under 1 and 2 above.

  By the term "physiological esters or amides"

  hydrolyzable and physiologically acceptable

  "Esters" means esters (eg compounds of formula I in which one or more of R4 to R7 means -COOH and / or R3 is hydrogen)

  or amides which are hydrolyzable under conditions

  physiologically to give acids or alcohols which are themselves non-toxic, that is to say which do not give really undesirable side effects at the doses administered. Such esters

  include esters with mono- and di-

  carboxylic acids, for example the esters of the compounds of formula I wherein the 3-hydroxy group is acetylated and the esters with lower alkanols, for example the C1-C4 alkanols. Such amides include those derived from organic carboxylic acids, for example

  amides of acetic acid, including amino

  acids, for example amides of glycine.

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

CR2-DO-DO-C-X

  Wherein R, R 1 to R 7 and X are as defined above, with hydrazine; b) removing at least one protecting 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, esterifies or amides a compound of formula I, for example wherein R3 is hydrogen, by reaction

  with respectively an acylating agent or a

  d) for the preparation of a compound of the formula I wherein X is - (CH2), - CH-CH- (CH2) r- in Z-isomeric form, isomerized a compound of the formula I wherein X is - (CH2), - CH-CH- (CH2) r- in isomeric form E, and recovering the compound of formula I thus obtained,

  in free form or in the form of a salt.

  Step a) of the process may be carried out analogously to known methods, for example by reacting a compound of formula II with hydrazine hydrate in an inert solvent or diluent, for example an alkane / alkanol, at room temperature or

  at high temperatures, for example at a temperature of

  temperature between 0 C and the reflux temperature.

  Step b) of the process can be carried out according to the conventional techniques known in the prior art to remove the protecting groups of the amino groups. As appropriate protective groups of

  amino groups, mention may be made of the p-toluene groups

  sulfonyl, benzyl, formyl and trifluoroacetyl.

  Step c) of the process can also be carried out according to the usual methods of acylation or

  amidation, by reaction with, for example, a halogenated

  genius or an appropriate acid anhydride.

  The trans isomers of the compounds of formula I wherein X is (CH 2) C-CHCH- (CH 2) r- may be converted to cis (Z) isomers by the usual methods, for example by irradiation. The cis and trans individual isomers can be obtained according to techniques known in the state of the art, for example by separation of the mixtures of isomers

  cis / trans, for example by chromatography.

  The compounds of formula II used as starting products in step a) of the process may be prepared according to one of the following reaction schemes A and B:

REACTION SCHEME A

S R1

CH 2 -NH-C-NH-X-C 'R (VIII)

aR R2

I OR3 R4 R5

R '^ H to -c-C Y (IX)

R6 R.,

tetrabutylammonium droxide

--- S R1

CH2-NH-C-NH-X - \

"\ 7R2

DMF: dimethylformamide

OR3 (X)

R4 Rs

/ R R

/ a) DMF b) potassium phthaliride

S R

CH2 -NH-C-NH-XC

1 R2

OR3 O

R-C-C-N I I

  Wherein R, R 1 to R 7 are as defined above, Y is halogen, for example bromine, and R 'is O or S. The compounds of formula VIII, wherein R is O, are described. as well as their preparation methods for example in British Patent Application 2 206 347A. Other compounds of formula VIII may be prepared in a similar manner or

analogous to the known compounds.

  In reaction scheme B of the following page, R, R1 to R7 and X are as defined above

  high and Y means a halogen, for example bromine.

  Intermediate products of Reaction Schemes A and B of Formula II, III, V, VI, VIII and

  X, are new and are also part of the invention.

tion.

NH3 + C1

/ H

N "O-C (CH3) 3

OR3 Et3N (VI)

I OR3 - (

  RH di-tert-butyl (VII) dicarbonate RH R R

(VII> RH R

Y - C - C - Y, KOH

R6 R7

tetrabutylammonium hydroxide

REACTION SCHEME B H

N O-C (CH3) 3

  / o O a) phthalimide of OR3 (V) potassium, I4 R 5

DMF R - C - C - Y

NH3-TFA-R6 R7

b) TFA, CH2C12 O OR3 R4 R5s

R-C-C-N

R6 R7

(III) -

  O R1 \ a) Et3N b) N-X- \ il \ =. -R2 S c R

|| (IV) CH2-NH-C-NH-X

S R2

DMF: dimethylformamide I OR3

R4 R.5

  TFA: trifluoroacetic acid R - C - C - N residue R7 When the preparation of the starting materials is not described, these can be prepared

  similarly to known methods.

  The compounds of formula I as defined above may be in free form or in salt form. For 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 signify -COOH, include, for example, the sodium,

  potassium and calcium, as well as

  ethylammonium. Such salts also include pharmaceutically acceptable acid addition salts, for example salts with organic or inorganic acids such as hydrochloric acid, acetic acid, fumaric acid, citric acid, and the like.

and benzoic acid.

  The following examples illustrate this

  invention without in any way limiting its scope.

  EXAMPLE 1 N- [4- (2-aminoethoxy) -3-methoxy-benzyl-N '[2- (4-chlorophenyl) ethyl] thiourea In a round-bottomed flask,

  suspended in 10 ml of ethanol 2.0 g of N- [4- (2-

  phthalimidoethoxy) -3-methoxybenzyl] -N '- [2- (4-chloro-

  phenyl) ethyl] thiourea (0.0038 mol) and heated to C until the solution becomes homogeneous. 0.10 ml of 1-hexene and 0.95 ml of a 64% aqueous hydrazine hydrate solution are added and the mixture is heated for 90 minutes. After 15 minutes, a white precipitate is formed 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. The mixture is agitated thoroughly.

  After this, the organic phase is extracted twice as indicated above and then washed with saturated sodium chloride solution. The organic phase is dried over Na 2 SO 4, filtered and the solvent removed by evaporation. The residue is purified by flash chromatography, eluting first with CH 2 Cl 2: MeOH (10: 1) and then with MeOH. The product fractions are evaporated and dried under vacuum (300C, 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 proceeding in an analogous manner: Exemplified R R, R2 R3 PR4 to R7 X

CH 3 H (CH 2) 2

  CH 2 H (CH 2) 2 and also the following compounds of CH 2 -NH-C-NH- (CH 2) n O-R 11 (I)

I OCH3

O-CH2-CH2 -NE2

  EXAMPLE R n 4 benzyl 2 4-bromobenzyl 2 6 n-octyl 2 7 n-octyl] 1 8 4chlorobenzyl 2 9 4 -phenylbenzyl] 2

CHARACTERISTIC DATA

  1. SPECTRUM 1H NMR (400 MHz) Example 1: [D6DMSO] 62.80 (2H, t, J-7.2 Hz), 2.99 (2H, t, J-5.5HZ), 3.61 (2H , S, broad), 3.75 (3H, s), 4.00 (2H, t, Ju5.5Ez), 5, 57 (2H, s, broad), 6.79 (1H, d, J = 1.8Hz ), 6.94 (1H, d, J-8.1Hz), 6.96 (1H, d, J-1.6Hz), 7.26 (2H, d, J = 8.2Hz), 7.34 (2H, d, J = 8.1Hz), 7.75 (1H, s, broad), 7.99 (1Hs, broad) Example 2: [CDCl 3] 61.55 (3H, s, Jarge), 2, 84 (2H, t, J-6.9Hz), 3.10 (2H, t, J-5.3Hz), 3.74 (2H, s, broad), 3.83 (3H, s), 4eO ( 2H, t, J.5,3Hz), 4.41 (2H, s, arge), 72 (1H, s, broad), 6.18 (E 1 H, s, broad), 6.70-6, 81 (2H, m), 6.93-6, 98 (2H, m), 7.06-7.10 (2E, m) Example 3: [CDCl 3] 61.52 (3H, s, broad), 2 , 99 (2H, t, H.7.0Hz), 3.11 (2H, t, J = 5.3Hz), 3.75 (2H, s, broad), 3.84 (3H, s), 4 , 03 (2H, t, J-5 $ 3Hz), 4.45 (2H, slarge),, 82 (1H, s, broad), 6.17 (1E, s, broad, 6.79-6, 84 (4H, m), 7.10-7.17 (3H, m), 7.35 (2H, d, J.1.8Hz) Example 4: [CD30D] 62.80 (2E, t, J = 7) , 1Ez), 3.09 (2H, t, J = 5.1Hz), 3.68 (2E, s, broad, 3.83 (3H, s), 4.06 (2H, t, J5, 1Ez), 4.60 (2H, s, broad), 5.04 (2H, s), 6.80-7.13 (5H, m), 7.29-7.43 (4H, m) Example 5: [CD30D] 62.78 (2H, t, J.7, 15Hz), 13 (2H, t, J.5.1H) z), 3.68 (2H, s, .larg, 3.84 (3H, s), 4.08 (2H, t, J = 5.1Ez), 4.60 (2H, s, broad), , 01 (2E, s), 6.817.12 (7H, m), 7.43 (4E, dd, J.8.3Hz, J.64.5Hz) Example 6: [CD30DI, 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, broad, 6.82-7.90; (5H, m), 7.19-7.21 (2H, m) Example 7: [CD30D], 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). , broad), 3.85 (3H, s), 3.92 (2H, t, Ju6.45Hz), 4.11 (2E, t, J.5.15Hz), 4.63 (2H, s, broad ), 6.70-7.11 (7H, m). EXAMPLE 8 [CD3OD] 62.8 (2H, t, J.7.15Hz), 3.02 (2H, t, J.5, 25Hz), 3.68 (2H, s, broad), 3.83 (3H, s), 4.03 (2H, t, J-5.25Hz), 4.59 (2H, s, broad), 5.03 ( 2H, s), 6.80-6.97 (5H, m), 7.11 (2H, d, J.8.45Hz), 7.38 (4H, dd, J-8.5Hz, J13.4Hz) Example 9: [d6DMSO] 62.74 (2E, t, J.7,39z), 2.94 (2H, t, J-5.65Hz), 3.56 (2H, s.large), 3, 74 (3H, s), 3.95 (2H, t, J-5.65Hz), 4.56 (2H, s, broad), 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) The example of example 9 has a point of

melting of 90-92 C.

  Retention times 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 0.1% Solution B: Acetonitrile

FLOW TIME ZA ZB

(min) (ml / min)

0 2.25 90 10

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

10.297

6 10.827

7 11,317

8 10,080

9 10,482

  Following the steps of Reaction Scheme B, the compounds used as starting materials can be prepared in the following manner: a) t-Bocvanillylamine In 18 ml of vanillylamine hydrochloride (0.095 mole) was dissolved in 250 ml of water and , 6 g of triethylamine (0.11 mol) and the mixture is placed in a 1 liter round bottom flask. With stirring and for 15 minutes, 20.5 g of di-tert.-butyl dicarbonate (0.095 mole) in 200 ml of dioxane are added. The resulting mixture is stirred overnight

at room temperature.

  The dioxane was removed in vacuo and the aqueous residue was extracted with CHCl 3 (5 × 10 ml). The combined extracts were dried over MgSO4, filtered and the solvent removed in vacuo to give a brown oil which was purified by flash chromatography (cyclohexane: EtOAc / 5: 2); a colorless oil is thus obtained which crystallizes at rest. [Chromatography

  thin layer: cyclohexane: EtOAc / -1: 1; R.f. - 0.5].

  b) t-Boc- [4- (2-bromoethoxy)] - 3-methoxybenzylamine In a 500 ml round bottom flask, 21.0 g of t-Boc-vanillylamine (0.083 mol), 250 ml of , 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 CH 2 Cl 2, washed with water (3 × 200 mL) and the combined washings are extracted once with 600 mL of CH 2 Cl 2. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO 4, filtered and the solvent removed in vacuo to give a white solid which is used

  without further purification for the next reaction.

  Thin layer chromatography: cyclohexane: EtOAc /

1: 1; R.f. - 0.6].

  c) t-Boc- (4- (2-phthalimidoethoxy) -3-methoxybenzylamine In 500 ml of anhydrous dimethylformamide,

  suspends 23.0 g of t-Boc- (4- (2-bromoethoxy) -3-

  methoxybenzylamine (0.064 mole) and 11.8 g of potassium phthalimide (0.064 mole). The resulting suspension is heated at 50 ° C. for 2 hours with rapid stirring. After 30 minutes under heating and stirring, the mixture becomes homogeneous. It is then cooled and the dimethylformamide removed under high vacuum. The resulting solid residue is purified by flash chromatography (cyclohexane: EtOAc / 1: 1) to obtain a white solid. [layer chromatography

  Thin (cyclohexane: EtOAc / 1: 1) R.f. - 0.45].

  d) 4- (2-phthalimidoethoxy) -3-methoxybenzylamine, trifluoroacetate In a 500 ml round bottom flask,

  dissolves 26.5 g of t-BOC- (4- (2-phthalimidoethoxy) -3-

  methoxybenzylamine (0.062 mole) in 200 ml of CH2Cl2.

  With stirring, 15 ml of trifluoroacetic acid are added dropwise. When the bill is over, we

  stir the mixture for another 2 hours at room temperature.

  The reaction is complete when no more starting material remains (cyclohexane: EtOAc, 1: 1) .The solvent is removed in vacuo, first under water jet vacuum and then under 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 a dry nitrogen atmosphere and in ml of anhydrous EtOAc, 2.0 g of

  4- (2-phthalimidoethoxy) -3-methoxybenzylamine, tri-

  fluoroacetate (0.005 mole) and 0.3 g Et3N (0.005 mole). 0.9 g of 2- (4-chlorophenyl) ethyl isothiocyanate (0.0045 mole) in 10 ml is added dropwise.

  anhydrous EtOAc and the mixture is stirred at room temperature.

room temperature for 3 hours.

  EtOAc was removed in vacuo, the residue was suspended in 50 ml of water and then extracted with CH2Cl2 (3x50 ml). The combined organic phases are dried over MgSO 4, filtered and the solvent removed in vacuo to give a brown oil which is purified by column chromatography (thin layer chromatography (cyclohexane: EtOAc,

1: 1) R.f. - 0.2]. F - 59-61 C.

  The compounds, amides and esters of the invention exhibit pharmacological properties

  interesting and can therefore be used in

  as medicine. They exercise in particular an analgesic and anti-inflammatory activity as is apparent from the following tests:

  1. REMOVING THE TAIL FROM THE MOUSE

  This test 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

  groups, the first receiving a single

  jection of the vehicle. Each animal is placed in a perspex cylinder with the tail protruding into a groove. The tail of each animal is exposed to radiant heat about 35 mm from the base of the animal.

  tail, using a lamp of power and temperature.

  known to be 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 administration of the test substance, the time is recorded in seconds until the mouse withdraws its tail. Animals with reaction times of more than 25% are excluded from the test. The reaction time is determined again

  and 30 minutes after administration of the substance.

  A substance is considered to have an anal-

  when it prolongs the reaction time of

  more than 75% of the average values of pre-

  treatment in the same animal. Three doses per test substance and 10 animals per dose are used. The effective dose (ED50) is determined according to the method of

  Litchfield and Wilcoxon and represents the dose

  longer than the reaction time of more than 75% in 50%

animals tested.

  Compounds, amides and esters of

  are active in this test at doses from about 1.0 to about 120.0 μM / kg,

  after subcutaneous administration.

  2. INFLAMMATION TEST CAUSED BY YEAST IN THE

MOUSE

  20% of a 20% fresh yeast suspension is injected into the plantar region of one of the

  hind legs and inject a physiological solution

  logic in the other. The degree of inflammation is evaluated

  by the relative increase in the weight of the leg (

  yeast solution / physiological solution) 2 hours after injection. The test substance is administered subcutaneously at various doses at the time of yeast / saline treatment. Five 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 compared statistically by proceeding as described above. The effective dose (ED) is the dose required to produce a 50% reduction in inflammation compared with the control animals and is determined by establishing the dose / response curve of the percentage of inflammation as a function of the dose. The compounds, amides and esters of the invention are active in this test at doses

  between 2.5 and 100 pM / kg after administration.

subcutaneous administration.

  Compounds, esters, amides and pharmaceutical salts

  The pharmaceutically acceptable compounds of the invention can therefore be used therapeutically as medicaments, for example as analgesics for the treatment of pain of various origin or etiology, for example for odontalgic pains and headaches, in particular vascular headaches such as migraine, cluster headaches and mixed vascular syndromes, as well as non-vascular headaches and tension headaches, 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 and other inflammatory conditions

chronicles.

  Thanks to their analgesic / anti-inflammatory profile

  The compounds of the invention are particularly useful for the treatment of pain of inflammatory origin, the treatment of hyperalgesia and, in particular, of severe chronic pain, for example for the treatment of pain of disaffectionation.

  to avoid surgery.

  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 epithelial tissues, e.g. spontaneous lesions, and for the control of visceral motility disorders

  at the respiratory, genitourinary, gastrointestinal

  tinal and vascular, for example for the treatment of

  wounds, burns, dermal reactions go-

  of pruritus and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, ulcers

  duodenum and diarrhea, for prophylaxis

  lactic or curative gastric lesions caused by necrotizing agents, for example ethanol, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial or bladder disorders. The utility 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 fasted overnight but have free access to water. The substance to be tested is administered subcutaneously or by

  oral 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 flattened with forceps. We quantify

  haemorrhagic erosions according to two para-

  meters: the zone and the length of the erosions.

  After administration of the compounds of formula I at a dose of between about 0.1 and 20 mg / kg,

  obtains a substantial inhibition of gastric lesions

  ethanol levels, compared to the results obtained with the control groups receiving the

  placebo instead of the substance to try.

  For the above-mentioned uses, the

  required dose of course depends on the method of

  tion, the particular condition to be treated and the desired effect. The appropriate daily dose for oral administration is from about 2 to about 1000 or 2000 mg, for example, from about 75 to 750 or 1500 mg for use as an analgesic, and from about 10 to about 2000 mg, for example about 75 to 1500 mg for use as an anti-inflammatory, advantageously administered in divided doses 2 to 4 times daily, or in sustained release or delayed release form. Suitable unit doses for oral administration therefore comprise 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 antiinflammatory use) of active substance (i.e., a compound, an ester, an amide or a pharmaceutically acceptable salt of the invention) in combination with a suitable diluent or vehicle

  solid 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 an ester or amidephysiologically hydrolysable and physiologically acceptable thereof or a salt

  pharmaceutically acceptable composition of this compound,

  cation with a pharmaceutically acceptable diluent or carrier. Such pharmaceutical compositions, which are also part of the invention, may be

  prepared according to the usual methods and

  for example in the form of tablets or capsules. In accordance with the foregoing, the invention also relates to: A. A compound of formula I or a physiologically hydrolyzable and physiologically acceptable ester or amide thereof, as defined above, or a pharmaceutically acceptable salt thereof, for the as a medicine, by

264,097;

  example for the treatment of diseases and conditions

mentioned previously,

  B. A pharmaceutical composition comprising a composition

  of formula I or a physiological ester or amide

  hydrolysable and physiologically acceptable composition of this compound as defined above, or a pharmaceutically acceptable salt thereof, in combination with a diluent or a

  pharmaceutically acceptable vehicle.

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

Claims (8)

1. Compounds of formula I CH2 -NH-C-NH-X I R2 OR3 R4 Rs II I R - C - C - NH2   Wherein R 1 is halogen or C 1 -C 4 alkyl, phenyl, benzyl, optionally benzyloxy   substituted, nitro, cyano, trifluoromethyl,   or R 1, R 2 is hydrogen or C 1 -C 4 alkyl, R 4 and R 5 are each independently of one of the other, hydrogen, halogen, optionally substituted C1-C5alkyl, optionally substituted aryl, COOH, COOR3 or CONRgR10O where Ra is C1-C5alkyl and R9 and R10o each signify, independently, each other, hydrogen or a C 1 -C 5 alkyl group, R 6 and R 7, independently of one another, have the meanings indicated for R 4 and R 5 or together with the carbon atoms to which they are attached, an optionally substituted C3-C7 cycloalkyl group, R is O, S or NH and X is - (CH2) n0- (CH2), - CH = CH- (CH2) n- means 1, 2 or 3 and each m and r is, independently of each other, 0 or an integer of 1 to 3, and the physiologically hydrolysable esters and amides and physiologic ically acceptable as well as salts   pharmaceutically acceptable compounds of these compounds.   2. A compound, an ester, an amide or a salt according to claim 1, characterized in that R1 is a halogen, a C1-C16 alkoxy group or an optionally substituted benzyloxy group, R2 is hydrogen or halogen, R3 is hydrogen or methyl, R4 to R7 are hydrogen, R is -O-, and   X means - (CH2) n- where n is 1 or 2.   3. A compound, an ester, an amide or a salt according to claim 1 or 2, characterized in that R1 has a meaning other than a substituted benzyloxy group. 4. A compound according to any 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-phénylbenzyloxy) phenyl) ethyl] thiourea. 5. A process for preparing a compound of formula I as defined in claim 1 or an ester, an amide or a salt thereof, characterized in that a) a compound is reacted with of formula II s R il S'.Rl CH2-NH-C-NH-X R2 a (II) OR3 O0 R4 R 2 R -C-C-N He -   R6 R7 wherein R, R1 to R7 and X are as defined above, with hydrazine; b) removing at least one protecting 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 respectively an acylating agent or a   d) for the preparation of a compound of formula I wherein X is - (CH2) m, -CH = CH- (CH2) n- isomeric Z isomerized a compound of formula I wherein X is - (CH2), - CH = CH- (CH2) r- in isomeric form E, and recovering the compound of formula I thus obtained,   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   at 4, for use as a medicine.   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 hydrolytic ester or amide   sand and physiologically acceptable or a pharma-   of this compound, in combination with a pharmaceutically acceptable diluent or vehicle acceptable.   8. A compound of formula II, III, V, VIII or X S he R CH2-NH-C-NH-X 47 OR3 0 R4 Rs I R C -C-N I I R6 R7 NH2 O OR3 R4 R, 5 R-C-C-N R6 R7 (III) H H, N, O-C (CH3> 3 l O OR3 (V) R-C-C-y I R4 R, 5 R-C - c- y R6 R7 S R1 he CH2-NH-C-NH-X-R (VIII) I k3 "R2 I OR3 R'H t2640971 S Ri CE2 -NH-C-NE-X C OR3 (X) R4 R R-C-C - Y   Wherein R, R 1 to R 7 and X have the meanings given in claim 1, Y is halogen and R 'is O or S.