LU87261A1 - NOVEL THIOURE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICINES - Google Patents

Description

/ y O Û. ) ¾ - GRAND-DUCHÉ-DELUXEMBOURG - _ - - _ _ ....... / ......... L ....., ... M I 1,.

9 λ IliiN 1088 Cgfe Minister of ___________fc O wU <fl lyOO________ r + F! TKi Economy and the Middle Classes, .., Intellectual Property Service

Job title ---- | gp) LUXEMBOURG .........

Patent Application T · _______________ (1) I. Application

La ...... so cle te ..... dit.e.;. „__ SMD.QZ._S., A .., ... Iiich.ta.tras.s. & ..... 3.5 .., ...- CÏÏ-.40û2-Bâlar .-- Am se, __ (2) repre.s.entee ..._ p.ar .... Monsi_eB.r_Lo.ui.s_ÆMRI.ÎIGER ,. ._aY.Q..ca.t., ...... d.emeur.an.t .... l.-i-uxeinb.Qurg.i ______ acting in his capacity as agent_________________________________________ ------ ---------------------------------------------------------- ---------------------------------------------------------- ----- (3) * deposit) this j LLsLyi 1 9 0 0 ~ Q ILCLfcfLQ * - V * VIQ £ ÎtU.'L'C ____ ^ .... hours, at the Ministry of the Economy and the Middle Classes , in Luxembourg: 1. this request for obtaining a patent for an invention concerning: ............................ ............ New derivatives of ...... thiourea, their preparation and their _______ (5) ................... ..................... use as medicine ___________________________________________________________ 2. description in language .................... . „French ...................................... ....... of the invention in triplicate; 3 ................................................. ..drawing plates, in triplicate; · 4. receipt of the fees paid to the Luxembourg Registration Office, on, Aß — .IßJS „J„ 2ÄÄ ______________; 5. the delegation of power, dated _____________ Mis ......................................... ............................... on _____ I ... J.3ÂI1 lîÂl ______; 6. the successor document (authorization); Héiâl ^ HîtlKSigasKaK ^ jiacresisam ^ ihifcdexaittgriédarHtigDsxgisifiÏB ^ kHÎgoibeKgésàastrfeaEcà ·: (6) claims (nt) for the aforementioned patent application the priority of (a) request (s) of (7X): ... _____________________________________: _________________ i_ deposited in (8) -JSrandje-Bx, e.tagn.e__ on (9) June 30, 1987 _________; ______________________ under N ° (10) §7.15357 ______________________________________

SAND0Z Institute for Medical Research, 5, Gower Place, London WClE

in the name of (11) ~ 3 JS7- “Grand'ë ^ rë'0'grie ----------------------------- ïir ~ lTV ~ T7 ^ 77E ~ elect) domicile for him (her) and, if appointed, for his representative, in Luxembourg ....._

Undzn 2652 LuxzmbouAg _______________________________; ______________ (12) requests (s) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, with adjournment of this issue ^ ..... ÎLL? _______________________________ months. (13)

The depositor / agent: ^ ------------------------: _________ — __________________________________________________________ (14) pM (é JEE ^ ërocos-Verbal de Dépôt.

The above application for a patent for invention has been filed with the Ministry of the Economy and the Middle Classes, Property Service InteUgffi * eggLuxembourg, dated: g g jy ^ ggg f; ^ Γ ’^ ™ stre Economy and Middle Classes, \ 'w | vlïH | J The head of the seemingly intellectual property,

OoÎC- ix -, -— Jqy - = - - / EXPLANATIONS RELATING TO the formt îNjafi ngDÉroT. /) / \ A / * - _ 11) if applicable "Request for certificate of addition to the main patent, to the main patent application No /......//. Of .... ........ ”- (2) enter the surname, first name, profession, - f \ I / kjÂ'K ~ - address of the applicant, when the latter is an individual or company name, - legal form , address of si & e socia |, when the applicant is a legal person - (3) enter "i. v \ the surname, first name, address of the professional representative, industrial property attorney, with special powers, if there is yteu: "represents by ........... acting as agent” - = {4) date of filing in full - (5) title of the invention - (6) enter the names -, first names, addresses of the inventors or rmdication ”(see) separate designation (will follow)”, when the designation is made or will be made in a separate document, or the indication ”do not mention”, when the inventor signs or signs a non-mention document to be attached to a separate present or future designation - Key \ patent, certificate of addition, utility model, European patent (EPC), international protection (PCT) - (8) State in which the first filing was made / · (

Case 700-0007 "CLAIMING THE PRIORITY of the patent application In Great Britain From June 30, 1987 DESCRIPTIVE MEMORY filed in support of an application for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: New derivatives of thiourea, their preparation and their use as medicines «

The subject of the present invention is new derivatives of thiourea, their preparation and their use in therapy as medicaments.

The invention relates in particular to the compounds of formula I

S Rl I rv CH2 - NH - C - NH - (CH2) n) (I)

(X Y

in which

Ri means halogen or C1-C4 alkyl, phenyl, benzyl, benzyloxy, nitro, cyano, tri-fluoromethyl, formylamino or C1-C16 alkoxy, R2 means hydrogen or has one of the meanings indicated for Ri , R3 signifies hydrogen or a C1-C4 alkyl group and n signifies 1 or 2, their physiologically hydrolysable and physiologically acceptable esters and their salts.

The alkyl groups represented by Rx, r2 and R3 as well as the alkyl residues of the alkoxy groups re-presented by R1 or R2 can be linear or branched. The alkyl radicals of the alkoxy groups are preferably linear. Halogen means fluorine, chlorine, bromine or iodine.

In the compounds of formula I, the following meanings are preferred, either individually or in combination with one another:

R 1 signifies a halogen or a C1-C4 alkyl group, especially a halogen.

î 2

Ri is located in position 4.

R2 means hydrogen, halogen or a C1-C4 alkyl group, especially hydrogen.

When R2 is other than hydrogen, it is preferably located in position 2.

R3 signifies hydrogen or a methyl group.

By the expression "physiologically hydrolysable and physiologically acceptable esters" is meant esters which are hydrolyzable under physiological conditions to give acids which are themselves non-toxic, that is to say that they do not exhibit important side effects at the desired doses. Such esters include the esters of mono- and dicarboxylic acids, for example the esters of the compounds of formula I in which the 4-hydroxy group is acetylated.

The invention also relates to a process for preparing the compounds of formula I, their esters and their salts, process according to which a) to prepare a compound of formula I, a compound of formula II is reacted, .u LH2 - x 0- 1

L

in which R3 has the meaning indicated above,

with a compound of formula III

Ri ’Ç) · fflW.

R2 4 »3 in which Ri, r2 and n have the meanings indicated above and either X signifies an amino group ec Y sign -N = C = S, or where X signifies -N = C = S and Y signifies an amino group , b) to prepare a physiologically hydrolysable and physiologically acceptable ester of a compound of formula I, a compound of formula I is esterified by reaction with an appropriate acylating agent, and the resulting compound of formula I is recovered in the form free or in salt form.

Step a) of the process can be carried out according to the usual methods, for example by reaction of a compound of formula II, advantageously in the form of an acid addition salt when X signifies an amino group and Y signifies - N = * C = S, for example in the form of the hydrochloride, with a compound of formula III in a suitable inert solvent or diluent such as dimethylformamide, and under basic conditions, for example in the presence of an alkali metal hydroxide. The reaction is suitably carried out at a temperature of, for example, between -20 ° C and 90 ° C.

Step b) of the process can also be carried out according to the usual acylation methods, for example by reaction with an appropriate acid halide or acid anhydride, for example C1-C4.

The starting materials of formula II or III are known or can be prepared in a similar manner to that described for the known compounds.

The compounds of formula I as defined above can be in free form or in the form of a salt. Examples of suitable pharmaceutically acceptable salts of the compounds of formula I for use according to the invention include, for example, the sodium and potassium salts.

Λ i 4 ί

The following examples illustrate the present invention without in any way limiting its scope. In these examples the temperatures are indicated in degrees Celsius.

EXAMPLE 1 N- (4-hydroxy-3-methoxybenzyl) -Nf- (4-chlorobenzyl) -thiourea To a suspension of 2.5 g of 4-hydroxy-3-methoxybenzylamine hydrochloride in 20 ml of dimethylformamide 5.2 ml of 5N NaOH are added. The resulting solution is cooled in an ice bath and 2.66 g of 4-chloro-benzyl isothiocyanate is added dropwise. The reaction mixture is stirred for 3 hours at room temperature, poured into 250 ml of H 2 O and extracted with 4 successive 100 ml portions of diethyl ether. The ethereal extracts are combined and extracted with 50 ml of IN HCl, 50 ml of a saturated NaHCO3 solution, 50 ml of H2O and 50 ml of a sodium chloride solution. The organic phase is dried over MgSO4, filtered and evaporated. The product is purified in the raw state by rapid chromatography on silica gel with a dichloromethane / methanol mixture (50: 1) as eluent and recrystallized from hot methanol, which gives the title compound: F = 135-138 °.

EXAMPLE 2 N- (4-hydroxy-3-methoxybenzyl) -N '- (4-chlorophenethyl) thiourea

The title compound is obtained by proceeding analogously to that described in Example 1 from 4-chlorophenethyl isothiocyanate: mp 143-144 °.

The following compounds of formula I are obtained by proceeding in a manner analogous to that described in Examples 1 or 2.

5

Examples Ri R2 r3 n F ec 3 4-FH CH3 2 147-150 4 4-benzyloxy H CH3 2 97-101 5 4-N02 H CH3 2 161-165 6 4-C1 2-C1 CH3 2 136-138 7 4 -0CH3 2-0CH3 CH3 2 124-128 8 4-FH CH3 1 145-147 9 4-octyloxy H CH3 1 110-112

The compounds of formula I, their esters and their pharmaceutically acceptable salts, hereinafter referred to as "the compounds of the invention", have interesting pharmacological properties and can therefore be used in therapy as medicaments. They exert in particular an analgesic and anti-inflammatory activity as it appears from the following tests î

1. TAIL REMOVAL FROM THE MOUSE

This trial is based on the protocol of D'Amour et al., J. Pharmacol. Exp. Ther. 12, 74-79 (1941). The animals (20-25 g females) are fasted for 18-24 hours and 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 harmful radiant heat (55 °) and the latent period until the tail is removed is determined. The test substance is administered subcutaneously 30 minutes before the test. Groups of 15 animals are used. The latent periods determined with the control animals and the test animals are statistically compared according to the Litchfield-Wilcoxon method, and the statistically lowest significant dose is taken as the effective dose (ED) "6 (p <0.05). . The compounds of the invention are active in this test at doses of between approximately 0.5 and 120 mg / kg after administration by the subcutaneous route.

2. PROPOSED INFLAMMATION TEST! BY YEAST IN THE MOUSE

50 μΐ of a 20% fresh yeast suspension are injected into the plantar region of one of the hind legs and the vehicle is injected into the other. The degree of inflammation is evaluated by the relative increase in the weight of the paw (yeast injection / sodium chloride solution) 2 hours after the injection. The test substance is administered subcutaneously in various doses at the time of treatment (yeast / sodium chloride solution). 10-20 animals are used for each dose and the control and test values are statistically compared as described above, the effective dose (ED) being the lowest dose necessary to produce a statistically significant reduction in l inflammation (as measured by the weight of the paw). The compounds of the invention are active in this test at doses of between approximately 0.5 and 50 mg / kg after administration by the subcutaneous route.

The compounds of the invention are therefore useful as medicaments, for example as analgesics for the treatment of pain of various origins or ethiolgia, for example for pain in the head and headache, in particular 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 inflammatory diseases or conditions, for example for the treatment of arthritis and "7 rheumatism, Raynaud's disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders, psoriasis and 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, of severe chronic pain, for example for the treatment of pain of deafferentation in order to avoid surgical interventions.

For the above indications the dose will naturally depend on the mode of administration, the particular conditions to be treated and the desired effect. A suitable daily dose is between about 10 to about 1,000 or 2,000 mg orally, for example about 75 to 750 or 1,500 mg orally for use as an analgesic, and about 10 to about 2 000 mg orally, for example about 75 to 1500 mg orally for use as an anti-inflammatory, preferably administered in divided doses 2 to 4 times a day, or in a sustained release form. Unit doses suitable for oral administration include, for example, from about 2.5 to about 500 or 1000 mg, for example from about 20 to about 375 or 750 mg (for use as an analgesic) and from about 2.5 to about 1000 mg, for example from about 20 to about 750 mg (for use as an anti-inflammatory) of active substance (i.e., compound, ester or pharmaceutically acceptable salt ) in combination with a suitable solid or liquid and pharmaceutically acceptable carrier or diluent.

"* 8

The compound of Example 2 is the preferred compound for use as an analgesic and anti-inflammatory agent.

In accordance with the above, the invention relates to a compound of formula I or a physiologically hydrolyzable and physiologically acceptable ester of this compound or a pharmaceutically acceptable salt of this compound, for use as a medicament, for example as an analgesic and / or agent anti-inflammatory.

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 hydrolyzable and physiologically acceptable ester 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.

Claims (8)

1. The compounds of formula IS "1 CH2 - NH - C - NH - (CH2) n ^ XV R2 y ^ 3 in which Ri signifies a halogen or a C1-C4 alkyl group, phenyl, benzyl, benzyloxy, nitro, cyano, tri-fluoromethyl, formylamino or CX-CX6 alkoxy, R2 means hydrogen or has one of the meanings indicated for Rx, R3 signifies hydrogen or a C1-C4 alkyl group and n signifies 1 or 2, their physiologically hydrolysable and physiologically acceptable esters and their salts. 2. A compound according to claim 1, characterized in that Rx is located in position 4. 3. A compound according to claim 1 or 2, characterized in that R2 signifies hydrogen, a halogen or a Cx-C4 alkyl group. 4. N- (4-hydroxy-3-methoxybenzyl) -N '- (4-chlorophenethyl) thiourea, in free form or in the form of a pharmaceutically acceptable salt. • ψ 10 5. a compound chosen from N- (4-hydroxy-3-methoxy-benzyl) -N '- (4-chlorobenzyl) -thiouree, N- (4-hydroxy-3-methoxy-benzyl) - N '- (4-fluorophenethyl) thiourea 1 a N- (4-hydroxy-3-methoxy-benzyl) -N' - (4-benzyloxyphenethyl) thiourea la N- (4-hydroxy-3-methoxy-benzy1) -N '- (4-nitrophenated thy1) thiourea N- (4-hydroxy-3-methoxy-benzyl) -N' - (2,4-dichlorophenethyl) thiourea 1 to N- (4-hydroxy-3-methoxy-benzy1) -N '- (2,4-dimé thoxyphénéty1) thiourée la N- (4-hydroxy-3-méthoxy-benzyl) -N' - (4-fluorobenzyl) thiourée et 1 a N- (4-hydroxy-3-methoxy -benzyl) -N '- (4-octyloxybenzy1) thiourea in free form or in the form of a pharmaceutically acceptable salt. 6. A process for the preparation of the compounds of formula I specified in claim 1, of their physiologically hydrolysable and physiologically acceptable esters and of their salts, characterized in that a) to prepare a compound of formula I, a compound of formula II CH2 - X cV OH in which R3 is as specified in claim 1, with a compound of formula III Q “* 'h in which R1, R2 and n are as specified in claim 1 and either X signifies a amino group and Y means -N = C = S, either where X means € 11 r. v-'= N = C = S and Y signifies an amino group, b) to prepare a physiologically hydrolysable and physiologically acceptable ester of a compound of formula I, a compound of formula I is esterified by reaction with an agent of appropriate acylation, and the resulting compound of formula I is recovered in free form or in salt form. 7. A compound as specified in any one of claims 1 to 5 or a physiologically hydrolyzable and physiologically acceptable ester of this compound or a pharmaceutically acceptable salt of this compound, for use as a medicament. 8. A compound according to claim 7, for use as an analgesic or as an anti-inflammatory agent. 9. A pharmaceutical composition, characterized in that it comprises, as active substance, a compound as specified in any one of claims 1 to 5 - or a physiologically hydrolysable and physiologically acceptable ester of this compound or a pharmaceutically acceptable salt of this compound, in combination with a pharmaceutically acceptable diluent or vehicle.