AU628902B2

AU628902B2 - N-(3,4-Dioxy-and N-(4-oxy-3-thio-benzyl)-thioureas

Info

Publication number: AU628902B2
Application number: AU47170/89A
Authority: AU
Inventors: Derek J. Reid; Christopher S.J. Walpole; Roger Wrigglesworth
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1988-12-23
Filing date: 1989-12-21
Publication date: 1992-09-24
Anticipated expiration: 2009-12-21
Also published as: FR2640971B1; IT8948682A0; GB8928581D0; GB2226313A; NZ231965A; HU896479D0; FI896192A0; LU87648A1; IL92830A; PT92674A; GR890100859A; DE3942729A1; DK657089A; JPH0764803B2; ATA290289A; ES2021182A6; CH678621A5; BE1003848A3; HUT56342A; GR1000460B

Description

1 i 1 i /i t t 628902 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: Sandoz Ltd.

Lichtstrasse CH-4002 Basle Switzerland NAME(S) OF INVENTOR(S): Derek Jon REID Christopher Simon John WALPOLE Roger WRIGGLESWORTH ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

b: i' U lb COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: *N-[3,4-Dioxy- and N-[4-oxy-3-thio-benzyl]-thioureas The following statement is a full description of this invention, including the best method of performing it known to me/us:- ,1 V1,.

1A The present invention relates to novel compounds having pharmaceutical properties, to processes for their production, pharmaceutical compositions comprising them and their use as pharmaceuticals.

The present invention provides in one aspect compounds of formula I

S

II Q R

CH

2 -NH-C-NH-X

I

R2

OR

3

R

4

R

R C C NH 2

R

6

R

7 wherein: i

R

1 is halogen, Cl_4alkyl, phenyl, benzyl, benzyloxy or halo- or phenyl-substituted benzyloxy, nitro, cyano, trifluoromethyl, formylamino or C 1 l 16 alkoxy,

R

2 is hydrogen or has any one of the meanings given for

R

1

SR

3 is hydrogen or C 1 _4alkyl,

R

4 and R 5 independently, are hydrogen, halogen, S C1_5alkyl, substituted Cl-5alkyl, aryl, COOH, COOR 8 or CONRgR 10 wherein R 8 is C 1 5 alkyl, and each of R 9 and R 10 independently is hydrogen or C 1 Rg and R 7 independently have the meanings given for R 4 and R 5 or, together with the carbon atoms to which they are attached form a C 3 7 cycloalkyl group, R is O, S or NH and 920506,dbdat119,47170.res,1 -2- X is -(CH2)n or -(CH 2 )m-CH=CH-(CH 2 wherein n is 1, 2 or 3 and each of m and r is independently zero or an integer of from 1 to 3, and physiologically hydrolysable and acceptable esters or amides and pharmaceutically acceptable salts thereof.

The compounds of formula I wherein X is -(CH2)m-

CH=CH-(CH

2 r may exist in both cis or trans isomeric forms, i.e. as Z and E isomers. The present invention is to be understood as embracing both the individual cis and trans isomers as well as mixtures thereof.

Substituted benzyloxy groups as R1 are benzyloxy substituted by halogen or phenyl. Substitutions may be, e.g. at the 2- and/or the 4-position of the benzyloxy group. Suitably the benzyloxy group is mono-substituted.

a 20 Preferably the benzyloxy group is mono-substituted at the o a 4-position.

0 S" Alkyl groups as R 1 through R 10 as well as the alkyl moiety of alkoxy groups as R1 or R 2 may be branched or straight chain. Preferably such alkyl groups and 4, moieties are straight chain.

4 *1 I4 By halogen is meant fluorine, chlorine, bromine or iodine.

Preferred aryl groups as R 4 to R7 are phenyl or napthyl.

A group of compounds of formula I comprises those compounds in which R 1 is as defined above but excluding substituted benzyloxy and R, R 2 to R 10 and X are as defined above.

11 Y920506,dbdat.119,47170.res,2 V~ i _lil_ I -3- In the compounds of formula I, the following significances are preferred either individually or in any combination or sub-combination: 1. R1 is halogen, Cl_ 4 alkyl C 1 l 1 6 alkoxy, benzyloxy or halo- or phenyl-substituted benzyloxy, especially halogen, C 1 l 1 6 alkoxy, benzyloxy or halo- or phenylsubstituted benzyloxy. When R 1 is C 1 1 6 alkoxy this is suitably n-octyloxy. When R 1 is halo- or phenylbenzyloxy this is especially 4-halo- or 4-phenylbenzyloxy. R 1 is preferably in the 4-position.

2. R 2 is hydrogen, halogen or Cl_ 4 alkyl especially hydrogen or halogen. When R 2 is other than hydrogen it is preferably in the 2-position.

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

4. R 4 to R 7 independently are hydrogen, methyl, ethyl, 20 C 1 _5alkyl substituted by OH or NH 2 phenyl or

C

1 _5alkyl-phenyl. More preferably at least one of

R

4 to R 6 is hydrogen. Yet more preferably at least three of R 4 to R 7 e.g. R 4

R

5 and Rg are hydrogen.

Most preferably all of R 4 to R7 are hydrogen.

5. R is -0t 6. X is wherein n has the meanings given above. Preferably n is 1 or 2, especially 2.

C 920506,dbdat119,47170.res,3 700-0062 7. X is -(CH 2 )m-CH=CH-(CH 2 in which one of m and r is zero and the other is 1. More preferably both m and r are zero. Most preferably such groups X are in Z isomeric form.

An especially preferred group of compounds of formula I are those wherein X has the meanings given under 6 above and especially such compounds wherein RI and R 2 are as defined under 1 and 2 above. A further preferred group of compounds of formula I are those wherein X has the meanings given under 6 above and each of R 4 to R 7 is hydrogen, especially such compounds wherein Ri and R 2 are as defined under 1 and 2 above.

9" 9By the term "physiologically-hydrolysable and -acceptable esters or amides" as used herein is meant esters compounds of formula I wherein one or more of R 4 to R 7 is -COOH and/or R 3 is hydrogen) or amides which are hydrolysable under physiological conditions to produce acids or alcohols which are themselves non-toxic, i.e. have no significant undesirable side effects at desired dosage levels. Such esters include esters with mono- and di-carboxylic acids, e.g. esters of the compounds of formula I in which the 3-hydroxy group is acetylated and esters with lower, e.g. C1-4 alkanols. Such amides include those deri- S ved from organic carboxylic acids e.g. acetic acid amides including S amino acids e.g. glycine amides.

i The present invention also provides a process for the production of the compounds, amides, esters and salts of the invention which process comprises: Sa) for the production of a compound of formula I reacting a compound of "formula II -4-

S

CR2-NH-C _NH_ R R2

(II)

OR

3

R

4

R

I I R- C-C-N

R

6

R

7 eso a a o o a e o*o 0' 6 0 0 0 So 0 *o a r o oo o a o o 0, a o a o o a +4 o oa oa a a wherein R, R 1 to R 7 and X are as defined above, with hydrazine; b) for the production of a physiologically-hydrolysable and -acceptable ester or amide of a compound of formula I, esterifying or amidating a compound of formula I, for example in which R 3 is hydrogen, by reaction with an appropriate acylating or amidating agent, respectively; c) for the production of a compound of formula I wherein X is -(CH 2 )m-CH=CH-(CH 2 in Z-isomeric form isomerising a compound of formula I wherein X 25 is -(CH 2 )m-CH=CH-(CH 2 in E-isomeric form; and recovering a compound of formula I thus obtained in free or salt form.

30 Process step a) may be carried in analogy with known methods, for example by reaction of the compound of formula II with hydrazine hydrate in an inert solvent or diluent, e.g. alkane/alkanol, at ambient or elevated temperatures, e.g. at a temperature of from 0 C to reflux.

t9,4 s, I 920723,dblet;29,47170.res,5 r :c 700-0062 for the removal of amino protecting s own in the art. Suitable amino protecti oups include p-toluene sulphonyl, benzyl, ~f y. t::'rfl roaoetyl.

Process step b)may also be performed employing conventional acylation or amidation methods e.g. by reaction with an appropriate e.g.

C1-4 acyl halide or anhydride.

The trans isomers of compounds of formula I wherein X is

-(CH

2 )m-CH=CH-(CH 2 may be converted into the cis isomers in conventional manner, e.g. by irradiation. Individual cis and trans isomers S may be obtained in accordance with techniques known in the art, e.g.

separation of cis/trans isomer mixtures, for example by chromatography.

44"4 Compounds of formula II used as starting materials in process step may be produced by either of the following Reaction schemes, A or B 4 t d t t -6t At\ <v J\

I

700-0062 REACTION SCHEME A S R

CH

2 -NH-C-NH-X- a

R

I OR3

R'H

(VIII)

R

4

R

Y -C -C -Y (IX) k 6 k7 tetrabutylammonium hydroxide S R

OR

3

(X)

B

4

R

R Y a) DMFk6k b) potassium phthalimide at t*a~ a at tat.

a, t

CH

2

-NH-C-NB.

OR

3 4 k 6

R

7

(II)

0 0 t Ct wherein R, R, to R7 and X are as defined above, Y is halogen, e.g.

bromine and R' is 0 or S.

Compounds of formula VIII, in which R is 0, are described, along -7- 700-0062 with processes for their production in, for example, published GB patent application 2,206,347A. Other compounds of formula VIII may be produced in similar or analogous fashion to the known compounds.

In Reaction Scheme B, on the following page, R, Ri to R 7 and X are as defined above and Y is halogen, e.g. bromine.

The intermediates in Reaction Schemes A and B of formulae X, VIII, VI, V, II and III are new and also form part of the present invention per se.

I

L -8-

-I

700-0062

NH

3 +cl-

IOR

3

RH

(VII)

Et 3

N

di-t-butyldicarbonate

H

N 0- -C (CH 3 3 0 (V

OR

3

I)

RH

REACTION SCHEME B

R

4

R

Y -C C Y, KOH

R

6

R

7 tet rabu tylammoniumhydroxide

H

N 0-C(CH 3 3 0

OR

3

(V

R-C--C-

a) potassium phthalimide,

DMF

NH

3 +TFA- k6 k7 b) TFA, CH 2 C1 2

I

$1~I R4 1 6 C N,

R

6 R-1 t

(III)

b) N-X 11 (IV)

S

a) Et 3

N

S

CH2NHC-NH-X-c/Z< N 0

OR

3 4 R C -N k 6 k 7 (nI) 9- __7 1i 700-0062 Insofar as the production of the starting materials is not particularly described, the compounds may be prepared by analogy with known methods.

The compounds of formula I as defined above may exist in free or salt form. Suitable pharmaceutically acceptable salts of compounds of formula I, e.g. wherein one or more of R 4 to R 7 is -COOH for use in accordance with the present invention include for example the sodium, potassium and calcium salts as well as quaternary ammonium, e.g. triethylammonium salts. Such salts also include pharmaceutically acceptable acid addition salts, e.g. salts with inorganic or organic acids such as hydrochloric acid, acetic acid, fumaric acid, citric acid and benzoic acid.

The following Examples are illustrative of the process of the present invention.

The following abbreviations are used: DMF dimethylformamide TLC thin layer chromatography EXAMPLE 1: N-[4-(2-Aminoethoxy)-3-Methoxy-Benzyl]-N'-12-(4-Chlorophenyl)-Ethyl]Thiourea g N-[4-(2-Phthalimidoethoxy)-3-methoxybenzyl]-N'-[2-(4-chlorophenyl)ethyl]thiourea (0.0038 mole) is suspended in 10 ml ethanol in a round bottomed flask and heated to 600 C until the solution becomes homogeneous. 0.10 ml 1-Hexene and 0.95 ml of a 64% aqueous solution of hydrazine hydrate is added and the mixture heated for 90 minutes. After 15 minutes a white precipitate begins to form and a small amount of ethanol is added to keep the mixture mobile. The reaction is cooled, transferred to a separating 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 10 i 700-0062 is shaken thoroughly and the organic layer extracted twice as above, then washed with brine. The organic layer is dried over Na 2

SO

4 filtered and the solvent removed by evaporation. The residue is purified via flash column chromatography, eluting first with CH 2 C1 2 MeOH (10:1) and then with MeOH. The product fractions are evaporated and dried in vacuo (300 C, 0.1 mm Hg) to give the title compound as a solid colourless glass.

SThe following compounds of formula I may be obtained analogously: Example R RI R 2 R3 R 4 to R X 2 0 4-F H CH 3 H (CH 2 2 3 0 4-C1 2-Cl CH 3 H (CH 2 2 and also the following compounds of formula I

(I)

II 22 O-R11

OCH

3

O-CH

2

-CH

2

-NH

2 EXAMPLE R11 n 4 benzyl 2 5 4-bromobenzyl 2 6 N-octyl 2 7 N-octyl 1 S8 4-chlorobenzyl 2 9 4-phenylbenzyl 2 11 700-0062 CHARACTERISING DATA 1.H1 NMR data [400 MHz] Example 1: [D 6

DMSO]

822.80(211,t,J.7.21z), 2.99(21, t,J-5.5HZ), 3.61(2H,S,broad), 3.75(3H,s), 4.00(21, t,J=5.5Hz), 5.57(2H,s,broad), 6.79(1H,d,J=1.81z), 6.94(1H,d,J=8.lHz), 6.96(1H,d,J=1.6Hz), 7.26(2H,d,J=8.2Hz), 7.34(2H,d,J=8.lHz), 7.75(1H,s,broad), 7.99(lH,s,Lzoad) Example 2: [ODC1 3 81.55(311,s,broad), 2.84(211,t,J=6.9Hz), 3.10(2H,t,J=5.31z), 3.74(211,s,broad), 3.83(3H-,s), 4.02(211,t,J.5.31z), 4.41(211,s,broad), 5.72(1H,s,broad), 6. 18(111,s,broad), 6.70-6.81(2H,m), 6.93-6.98(21,m), 7.06-7.l0(21,m) Example 3: [CDCl 3 3.75(2H,s,broad), 3.84(3H,s), 4.03(21, t,J=5.3Hz), 4.45(211,s,broad), 5.82(1H,s,broad), 6.17(1H,s,broad), 6.79-6.84(41,m), Example 4: [CD 3

OD]

82.80(21, t,J=7.lHz), 3.09(21, t,J=5.lHz), 3.68(2H,s,broad), 3.83(3H,s), 4.06(2H,t,J=5.lHz), 4.60(211,s,broad), 5.04(2H,s), 6.80-7.13(5H,m), 7.29-7.43(41,m) Example 5: CD 3 0DJ S2.78(211,t,J=7.l5Hz), .13(211,t,J=5.lHz), 3.68(211,s,broad), 3.84(3H,s), 4.08(2H, t,J=5.lHz), 4.60(211,s,broad), 5.01(2H,s), 6.81-7.12(71,m), 7.43(411,dd,J=8.311z,J=64.5Hz) 12 700-0062 Example 6: [CD 3

OD]

80.92(311,m), 1.28-1.38(8H,m), l.46(211,m), 1.75(2H-,m), 3.27(2H,t,J=5.0Hz), 3.83(311.s), 3.94(211,t,J=6.4Hz), 4.16(21, t,J=5.OHz), 4.63(411,s,broad), 6.82-7.90(5H,m), 7.19-7.21(211,m) Example 7: [CD 3

ODI

80.90(3H,m), 1.28-1.35(81,m), 1.46(211,m), l.74(211,m), 2.79(21, t,J=7.2511z), 3.16(21,t,J=5. 15Hz), 3.68(211,s,broad), 3.85(3H,s), 3.92(2H,t,J=6.45Hz), 4.11(21, t,J=5.151z), 4.63(2H,s,broad), 6.70-7.ll(7H,m) Example 8: [CD 3

OD]

3.83(3H,s), 4.03(211,t,J=5.25Hz), 4.59(211,s,broad), 5.03(211,s), 6.80-6.97(51,m), 7.11(2H A.J-8.4'Hz), 7.38(4H,dd,J=8.5Hz,J=13.4z) Example 9: [d 6

DMSO]

82.74(211,t,J=7.31z), 2.94(2H, t,J=5.65Hz), 3.56(211,s,broad), 3.74(311,s), 3.95(211,t,J=5.651z), 4.56(211,s,broad), 5.12(2H,s), 6.78(1H,m), 6.80-6.97(4H,m), 7.15(211,d,J=8.5Hz), 7.37(1H,m), 7.45-7.54(511,m), 7.66-7.69(41,m) The compound of Example 9 has a melting point of 90-921C.

HPLC Retention time The retention times of the compounds of Examples 1 to 9 were measured on a 0-18 MicrobondapakR reverse phase column using the following gradient and conditions: 13 700-0062 Solution Solution

TIME

(min) 0 2 6 22 29 31 1: 0.1% trifluoroacetic acid 1: acetonitrile FLOW PATE %A %B (ml/min) 2.25 90 2.25 90 2.25 45 2.25 40 2.25 0 100 2.25 90 The following results were 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 may be prepared as follows: r x;"jll:-

"R

14

~P"I

700-0062 a) t-Boc-vanillylamine 18.0g Vanillylamine hydrochloride (0.095 mole) and 10.6g triethylamine (0.11 mole) are dissolved in 250ml water and placed in a 1L round bottomed flask. 20.5g di-tert-butyldicarbonate (0.095 mole) in 200ml dioxan is added with stirring, over a period of 15 minutes. The resulting mixture is stirred overnight at room temperature.

The dioxan is removed in vacuo and the aqueous residue extracted with CHC13 (5xl0ml). The combined extracts are dried over MgS04, filtered and the solvent removed in vacuo to leave a brown oil which is purified via flash column chromatography (cyclohexane EtOAc 5:2) to give a colourless oil which crystallises on standing. cyclohexane EtOAc 1:1; r.f. Sb) t-Boc-(4-(2-bromoethoxy)-3-methoxybenzylamine 21.Og t-Boc-vanillylamine (0.083 mole), 250ml 1,2.dibromoethane, 66ml 40% KOH and 6.6ml 40% tetrabutylammonium hydroxide are combined in j a 500ml round bottomed flask and the resulting mixture is heated at 50 0

C

for 3 hours with rapid stirring.

The mixture is cooled, diluted with 200ml CH 2 C12, washed with water (3x200ml) and the combined aqueous washings extracted once with 600ml

CH

2 C1 2 The combined organic layers are washed with brine, dried over MgS0 4 filtered and the solvent removed in vacuo to leave a white solid which is used without further purification. cyclohexane EtOAc 1:1; r.f. 0.6] "I c) t-Boc-(4-(2-phthalimidoethoxy)-3-methoxybenzylamine 23.0g t-Boc-(4-(2-bromoethoxy)-3-methoxybenzylamine (0.064 mole) and 11.8g potassium phthalimide (0.064 mole) are suspended in 500ml dry DMF 15 a Ij: ji i- 1

I:

700-0062 in a round bottomed flask. The resulting suspension is heated at for 2 hours with rapid stirring. After 30 mins of this heating/stirring, the mixture becomes homogeneous. The mixture is then cooled and the DMF removed under high vacuum. The resulting solid residue is purified via flash column chromatography (cyclohexane EtOAc 1:1) to give a white solid. (cyclohexane EtOAc 1:1) rf 0.45.

d) 4-(2-phthalimidoethoxy)3-methoxybenzylamine.TFA 26.5g t-Boc-(4-(2-phthalimidoethoxy)-3-methoxybenzylamine (0.062 mole) is dissolved in 200ml CH 2 C12 in a 500ml round bottomed flask.

trifluoroacetic acid is added dropwise with stirring. On completion of the addition, the mixture is stirred for a further 2 hours at room temperature (the reaction is shown to be completed by the loss of staring material (cyclohexane EtOAc The solvent is removed in vacuo, initially on the water pump and then high vacuum. The resulting colourless oil solidifies on standing and is used without further purification.

e) N-[4-(2-phthalimidoethoxy)-3-methoxybenzyl)-N-[2-(4-chlorophenyl)ethyl]thiourea 4-(2-phthalimidoethoxy)-3-methoxybenzylamine.TFA (0.005 mole) and 0.5g Et 3 N (0.005 mole) are suspended in 30 ml dry EtOAc under n, atmosphere of dry nitrogen. 0.9g 2-(4-chlorophenyl)ethylisothiocyana,.e (0.0045 mole) in dry 10ml EtOAc is added dropwise and the mixture stirred at room temperature for 3 hours.

The EtOAc is removed in vacuo, the residue suspended in 50ml water and then extracted with 3x50ml CH 2 C12. The combined organic layers are dried over MgSO 4 filtered and the solvent removed in vacuo to leave a brown oil which is purified via column chromatography [tlc (cyclohexane EtOAc 1:1) rf Melting point 59-61°C.

p.

p- 16 4")-Wn -crwrr~- I 700-0062 The compounds and amides and esters of the invention have pharmacological, in particular analgesic and anti-inflammatory, activity and are therefore indicated to be useful as pharmaceuticals, e.g. for therapy.

In particular the compounds exhibit pharmacological activity as indicated in standard test models, for example as follows: 1. TAIL-FLICK TEST IN THE MOUSE The method is based on that of D'Amour et al. J. Pharmacol. Exp.

Ther. 72, 74-79 (1941), but employing unstarved mice (o o, 16-25 g).

S Animals are divided into control and test groups, control animals receiving a vehicle injection only. Each test animal is placed in an individual perspex cylinder to prevent movement with its tail protruding along a narrow groove. The tail of each animal is exposed to a beam of radiant heat at ca. 35 mm from the tail root, from a lamp of known output and temperature, place directly under the tail. Test substance is administered p.o. or s.c. 30 mins. post introduction into the cylinder.

The time in seconds taken by the mouse to flick its tail out of the light beam is recorded 30 to 15 mins prior to administration of test substance. Animals whose reaction times differ by more than 25 are discarded. Reaction time is re-determined 15 and 30 mins post administration. Extension of reaction time by 75 over mean pre-treatment values in the same animal are taken as indicative of analgesic response.

Three doses are employed per test substance and 10 animals per dose.

ED

50 values (95 confidence limits) are estimated in accordance with ,c the method of Litchfield and Wilcoxon and represent the dose prolonging t treatment reactioii time by 75 in 50 of test animals.

Compounds and amides and esters of the invention are active in the above test model at dosages of the order of from about 1.0 to about 120.0 um/kg, s.c.

17 l ~I i 700-0062 2. YEAST INDUCED INFLAMMATION TEST IN THE MOUSE lI, 20 fresh yeast suspension is injected into the plantar region of one hind paw and saline is injected into the other. Degree of inflammation is estimated by the relative increase in paw weight (yeast injected v.s.saline) 2 hrs. post-injection. Test substance is administered s.c. at varying dosage at the same time as yeast/saline treatment. 5 animals are used/dose and testing at each dose is repeated 2 3 times, control and test values being compared statistically as above.

ED

50 values are taken as the dosage required to effect 50 inhibition of inflammation as compared with control animals not receiving test substance, and are established from dose response curves plotting inflammation vs. dose. Compounds and esters of the invention are active in the above test model at dosages of the order of from about 2.5 to 100 uM/kg, s.c.

The compounds, esters, amides and pharmaceutically acceptable salts of the invention are accordingly useful as pharmaceuticals, e.g. as analgesics for the treatment of pain of various genesis or aetiology, for example dental pain and headache, particularly vascular headache, such as migraine, cluster, and mixed vascular syndromes as well as nonvascular, tension headache, and as anti-inflammatory agents for the treatment of inflammatory diseases or conditions, for example the treatment of arthritis and rheumatic diseases, Raynaud's disease, inflammatory bowel disorders, trigeminal or herpetic neuralgia, inflammatory eye disorders e.g. uveitis, psoriasis, cystitis as well as other chronic inflammatory conditions.

Having regard to their analgesic/anti-inflammatory profile they are, in particular, useful for the treatment of inflammatory pain, for the treatment of hyperalgesia and, in particular, the treatment of severe chronic pain, e.g. for the treatment of deafferentation pain as an alternative to surgical procedures.

Ii I. i i' 18 700-0062 According to a further embodiment, the compounds of formula I, their esters, amides and pharmaceutically acceptable salts are also useful for the prophylactic or curative treatment of epithelial tissue damages or dysfunction, e.g. spontaneous lesions, and for the control of disturbances of visceral motility at respiratory, genitourinary, gastrointestinal and vascular level, e.g. for treating wounds, burns, skin allergic reactions, pruritus and vitiligo, for the prophylactic or curative treatment of gastrointestinal disorders such as gastric ulceration, duodenal ulcers and diarrhoea, for the prophylactic or curative treatment of gastric lesions induced by necrotising agents, for example ethanol, for the treatment of vasomotor or allergic rhinitis and for the treatment of bronchial disorders or bladder disorders. The utility in treating as rtt epithelial tissue damages or dysfunction may be shown in standard test models, for example as follows: ETHANOL-INDUCED GASTRIC LESIONS 0 «to *tot The tests are carried out employing male rats (200-250g) fasted overnight but with free access to water. The test substance is administered s.c. or orally by a metal stomach tube. Absolute ethanol is given orally 30 min after the administration of the test substance and the animals are killed 1 hour later. The stomach is cut open along the greater curvature and pinned flat. Haemorrhagic erosions are quantified in two ways: area and length of the erosions.

On administration of a compound of formula I as test compound at a dosage of from ca. 0.1 to 20 mg/kg, substantial inhibition of the gastric lesions induced by ethanol is observed compared with results for control groups receiving placebo in lieu of the test compound.

For the above uses the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. An indicated daily dosage in the range of from 19 i i700-0062 Sabout 2 to about 1,000 or 2,000 mg e.g. from about 75 to 750 or :1,500 mg p.o. for analgesic use, and of the order of from about 10 to iabout 2,000 mg p.o. e.g. from about 75 to 1,500 mg for anti- Sinflammatory use, conveniently administered once, in divided dosages 2 to 4 times/day, or in sustained release or retard form. Dosage forms suitable for oral administration accordingly comprise from about 0.5 to about 500 or 1,000 mg, e.g. from about 20 to about 375 or 750 mg (analgesic use) or from about 2.5 to about 1,000 mg, e.g. from about 20 to about 750 mg, (anti-inflammatory use) active ingredient compound, ester, amide or pharmaceutically acceptable salt of the invention) admixed with an appropriate solid or liquid, pharmaceutically acceptable, diluent or carrier therefor.

I In accordance with the foregoing the present invention also proi vides a method: :1 A. i) for the treatment of pain of various genesis or aetiology, for Sexample for the treatment of any such disease or conditions as hereinbefore set forth; i Sii) for the treatment of inflammatory diseases and/or inflammatory pain, for example for the treatment of any such disease or conditions as hereinbefore set forth; iii) for the prophylactic or curative treatment of epitheleal tissue damage or dysfunction, gastrointestinal disorders or gastric lesions induced by necrotising agents; iv) for the control of disturbances of visceral motility at respira- Story, genitourinary, gastrointestinal and vascular level; or v) for the treatment of rhinitis and bronchial or bladder disorders, 20 9 700-0062 in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound of formula I or physiologically hydrolysable and acceptable ester or amide thereof as hereinbefore defined, or a pharmaceutically acceptable salt thereof; B. A compound of formula I or physiologically-hydrolysable and -acceptable ester or amide thereof as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, for example for use in a method as defined under any one of A(i) to A(v) above or for use in the preparation of a pharmaceutical composition for use in a method as defined under any one of A(i) to A(v) above; St as well as C. A pharmaceutical composition comprising a compound of formula I or physiologically-hydrolysable and -acceptable ester or amide thereof as hereinbefore defined, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or Icarrier therefor.

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

i IIl 21

Claims

22- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A compound of formula I S CH2-NH-C-NH-X R2 OR 3 R 4 Rs R C C NH 2 R 6 R 7 wherein R 1 is halogen, Ci- 4 alkyl, phenyl, benzyl, benzyloxy or halo- or phenyl-substituted benzyloxy, nitro, cyano, trifluoromethyl, formylamino or C 1 16 alkoxy, R 2 is hydrogen or has any one of the meanings given for R1, SR 3 is hydrogen or C 1 i 4 alkyl, R 4 and R 5 independently are hydrogen, halogen, C 1 -salkyl, substituted C 1 -_alkyl, 4f. aryl, COOH, COOR 8 or CONRgRio wherein Ra is C 1 -salkyl, and each of R 9 and Rio independently is hydrogen or C1-salkyl, R 6 and R 7 independently have the meanings given for R 4 and R 5 or together with the l "t carbon atom to which they are attached form a C 3 -7cycloalkyl radical, SR is 0, S or NH and X is -(CH 2 or -(CH2).-CH-CH-(CH wherein n is 1, 2 or 3 and each of m and r is independently zero or an integer of from 1 I -I 23 to 3, or physiologically hydrolysable and acceptable ester or amide thereof or pharmaceutically acceptable salt of such compound, ester or amide. 2. A compound, ester, amide or salt according which, in formula I, R 1 is halogen, C1 4alkyl, C1_ 16 alkoxy, halo- or phenyl-substituted benzyloxy. R 2 is hydrogen or halogen, R 3 is hydrogen or methyl, R 4 to R 7 are each hydrogen, R is and X is -(CH 2 wherein n is 1 or 2. 3. A compound, ester, amide or salt according which, in formula I, RI is halogen, C-. 16 alkoxy benzyloxy phenyl-substituted benzyloxy, and R 3 is methyl. 4. A compound, ester, amide or salt according claims 1 to 3 in which, in formula I, R 1 substituted benzyloxy. to claim 1 in benzyloxy or to claim 2 in or halo- or to any one of is other than r I I S *1 &i t I. "ifi N-[4-(2-aminoethoxy)-3-methoxybenzyl]-N'-[2-(4-chloro- phenyl)ethyl]-thiourea, or pharmaceutically acceptable salt thereof. 6. A compound selected from the group consisting of: N-[4-(2-aminoethoxy)-3-methoxybenzyl]-N'-[2-(4-fluoro- 24 phenyl )ethyl] -thiourea, N-f 2-aminoethoxy)-3-methoxybenzyl 2, 4-dichior- ophenyl )-ethyl] thiourea, N-(4-(2-aminoethoxy)-3-methoxybenzyl]--N'-[2-(4-benzyloxy- phenyl )-ethyl Ithiourea, N-f 2-aminoethoxy)-3-methoxybenzyl I-N'-f 4-bromob- enzyloxy)-phenyl )ethyl ]thiourea, N-f 2-aminoethoxy)-3-methoxybenzyl 4-(N-octylo- xy) phenyl )-ethyl] thiourea, N-f 2-aminoethoxy)-3-methoxybenzyl 4-N-octyloxybe nzyl j-thiourea, N-f 2-aminoethoxy)-3-methoxybenzyl 4-chioro- benzyloxy)-phenyl)ethylithiourea, and N-f 2-aminoethoxy)-3-methoxybenzyl 2-C 4-phenyl- benzyloxy )-phenyl )ethyl] thiourea; or pharmaceutically acceptable salt thereof. 7. A process for the preparation of a compound of formula I or an ester, amide or salt thereof, as defined in claim 1 which comprises: a) reacting a compound of formula Ii I a., I a,. II I, *1 I ft a, II, S R CH 2 -NH-C-NH-X-~~R OR 3 0 R 4 R R-C -C -NQ I I R 6 R 7 (II) I If' i i wherein R, R 1 to R7 and X are as defined in claim 1, with hydrazine; b) for the production of a physiologically hydrolysable and ac:ceptable ester or amide of a compound of formula I, esterifying or amidating a compound of formula I by reaction with an appropriate acylating or amidating agent, respectively; c) for the production of a compound of formula I wherein X is -(CH2)m-CH=CH-(CH2)r- in Z isomeric form, isomerising a compound of formula I wherein X is -(CH 2 )m-CHr ,r-(CH2) r in E isomeric form; and recovering a com of formula I thus obtained in free or salt form. 8. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a 0 physiologically hydrolysable and acceptable ester or amide or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier therefor. 9. A composition as defined in claim 8 comprising the Scompound defined in claim 5 or a pharmaceutically Si acceptable salt thereof. A method for the treatment of pain and/or for the treatment of inflammation, for the prophylactic or curative treatment of epitheleal tissue damage or dysfunction or for the control of disturbances of 920723,dblet 129,47170.res,25 r6~ -26- visceral motility at respiratory, genitourinary, gastrointestinal and vascular level, for the prophylactic or curative treatment of gastrointestinal disorders or gastric lesions induced by necrotising agents, for the treatment of allergic rhinitis and for the treatment of bronchial disorders or bladder disorders in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 or a physiologically hydrolysable and acceptable ester or amide thereof or a pharmaceutically acceptable salt thereof. 11. A method as defined in claim 10 which comprises administering the compound defined in claim 5 or a pharmaceutically acceptable salt thereof. 12. Compounds of formula I or processes for their preparation, substantially as hereinbefore described with reference to the Examples. So0 o 0t t6 0 4 SDATED this 6th day of May, 1992 Sandoz Ltd. By Its Patent Attorneys DAVIES COLLISON CAVE 920506,dbdat119,47170.res,26 I tc-