WO1993016694A1

WO1993016694A1 - Use of indylpyridylureas to heal the effects of brain or spiral trauma

Info

Publication number: WO1993016694A1
Application number: PCT/GB1993/000360
Authority: WO
Inventors: Thomas Paul Blackburn
Original assignee: Smithkline Beecham Plc
Priority date: 1992-02-19
Filing date: 1993-02-19
Publication date: 1993-09-02
Also published as: AU3638393A; GB9203637D0

Abstract

Indole derivatives of formula (I) having utility for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus are disclosed.

Description

Use of indylpyridylureas to heal the effects of brain or spinal trauma

This invention relates to a method for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus.

PCT Patent Application No. PCT/GB 91/01553 describes a compound of formula (A) or a pharmaceutically acceptable salt thereof:

(A)

wherein:

Rl, R2 and R3 are independently hydrogen or C\.Q alkyl;

R4 is hydrogen, Ci.g alkyl, halogen, hydroxy or NRgRg where Rg and Rg are independently hydrogen or C .g alkyl;

R5 and Rρ are independently hydrogen or C^.g alkyl; and

R7 is hydrogen, Cι.g alkyl or halogen; and wherein the urea moiety is attached at the 4-, 5- or 6-position of the indole ring. These compounds are described as being useful in the treatment of CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse and/or schizophrenia.

It has now been found that these compounds are useful for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus.

Examples of spinal trauma and/or head injuries are those injuries which result through a spinal injury or impact to the head. It is believed that these compounds are of benefit in the restoration of the functional recovery of patients having sustained spinal trauma and for head injury.

Accordingly, the present invention provides use of a compound of formula (I):

(I) or a salt thereof, wherein:

Rj_, R2 and R3 are independently hydrogen or C_.Q alkyl; R4 is hydrogen, Cι_g alkyl, halogen, hydroxy or NRgRg where Rg and Rg are independently hydrogen or Cι_g alkyl; R5 andRg are independently hydrogen or C_.Q alkyl; and R7 is hydrogen, C .g alkyl or halogen; and wherein the urea moiety is attached at the 4-, 5- or 6-position of the indole ring; in the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus in mammals.

Alkyl moieties within the variables R^ to Rg are preferably C_._ alkyl, such as methyl, ethyl, n- and iso-propyl, most preferably methyl, ethyl and n-propyl.

Suitable R4 and R7 halogens include chloro and bromo.

Examples of Ri include hydrogen, methyl, ethyl and n-propyl, preferably methyl. 2 is preferably methyl or hydrogen and R3 is hydrogen, methyl, ethyl, n-propyl, iso-propyl or n-hexyl.

Preferably R4 is hydrogen, chloro, hydroxy or dimethylamino, most preferably hydrogen.

Preferably R5, Rρ and R7 are independently hydrogen or methyl. The urea moiety may be attached at the 2-, 3-, 4-, 5- or 6-position of the pyridine ring, preferably the 3-, 4- or 5-position.

The urea moiety is preferably attached at the 4- or 5-position of the indole ring.

The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes solvates thereof.

When R5 and or Rg are hydrogen or when R4 is 2- or 4-hydroxy or NRgRg and at least one of Rg and Rg are hydrogen the compounds of formula (I) may exist tautomerically in more than one form. The invention extends to each of these forms and mixtures thereof.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.

The process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises

(a) the coupling of a compound of formula (II):

(ID with a compound of formula (III):

wherein B is attached at the 4-, 5- or 6-position of the indole ring and A and B contain the appropriate functional group(s) necessary to form the moiety -NRs'CONRg'- when coupled, wherein R5' and Rg' are R5 and Rg as defined in formula (I) or groups convertible thereto, and the variables Ri', R^, R3', 4 and R7' are Ri, R2, R3, R4 and R7 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R_ , R2', R3^*, R , δ', Rg' and R7^* when other than R _> 2, R3, R4, R5, Rg and R7 respectively to Rχ» R2, R3, R4, R5, Rg and R7, interconverting R ₅ R2, R3, R4, R5, Rg and R7, and forming a pharmaceutically acceptable salt thereof, or

(b) cyclising a compound of formula (IV):

(IV)

wherein R4', R5', Rg' and R7' are as defined in formulae (II) and (HI) and C and D contain the appropriate functional group(s) necessary to form the indole ring substituted by R , R2^* and R3' as defined in formula (III), and thereafter optionally and as necessary in any appropriate order, converting any R^', R2', R3', R4', R5', Rg' and R7' when other than R]_, R2, R3, R4, R5, Rg and R7, to l, 2, R3, R4, R5, Rg and R7, interconverting R^, 2, R3, R4, R5, Rg and R7 and forming a pharmaceutically acceptable salt.

Suitable examples of groups A and B are

(i) A is -N=C=0 and B is -NHRg',

(ii) A is -NHR5' and B is -N=C=0, (iii) A is -NR5 COL and B is -NHRg',

(iv) A is -NHR5' and B is -NRg'COL, or

(v) A is halogen and B is -NRg'CONHR₅ ^*,

wherein R5' and Rg' are as defined above and L is a leaving group. Examples of suitable leaving groups L include halogen such as chloro or bromo, imidazole, or phenoxy or phenylthio optionally substituted for example with halogen.

When A is -N=C=0 and B is NHRg' or when A is NHR5' and B is -N=C=O the reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient temperature.

When A is -NR5 COL and B is -NHRg' or when A is -NHR5' and B is -NRg'COL, the reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature.

When A is halogen and B is -NRg'CONHRs', the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.

The cyclisation of the compound of formula (IV) may be effected using standard methodology such as described in Comprehensive Heterocydic Chemistry 19844, 313 et seq. or J. Het. Chem. 1988 25, p.l et seq.

Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis and the Japp-KHngemann variation and the Madelung synthesis. Examples of the groups C and D thus include

(vi) C = NO2 and D = CH=CH-NZ2 where each Z is independently Cι-.g alkyl or together represent C2-7 alkylene;

(viii) C = NH-N=C(CO2X)-CH₂R3' and D = H where X is Cχ.g alkyl; and

(ix) C = N x'COR^ and D = CH2R3'.

In reaction variant (vi) (Leimgruber synthesis) the compound of formula (IV) is prepared from the 2-methylnitrophenyl urea by treatment with a dialkylacetal of the dialkylformamide OHCNZ2 with heating and the product of formula (IV) cyclised by hydrogenation over a suitable catalyst such as palladium and charcoal optionally under pressure to yield the compound of formula d) where Rι=R2=R3=H.

In reaction variant (vii) (Fischer synthesis) the compound of formula (IV) is prepared from the hydrazinophenyl urea by dehydration, preferably by heating, with the appropriate ketone R^COC^Rs' and the product of formula (IV) cyclised by heating with an acid catalyst such as hydrochloric or sulphuric acid.

In reaction variant (viii) (Japp-Klingemann synthesis) the compound of formula (IV) is prepared from the aminophenyl urea by diazotisation followed by treatment for example with CH3COCH(CO2X)-CH2R3' where Xis Cι_6 alkyl under basic conditions in aqueous alcohol as solvent.

The product of formula (IV) may then be cyclised as in the Fischer synthesis above.

In reaction variant (ix) (Madelung synthesis) the compound of formula (IV) is cyclised with base in an inert solvent optionally with heating.

Suitable examples of groups R2', R3^*, R4', and R7' which are convertible to R2, R3, R4, and R7 respectively, include acyl groups which are introduced conventionally and may be converted to the corresponding alkyl group by conventional reduction, such as using sodium borohydride in an inert solvent followed by hydrogenolysis in an inert solvent and alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and decarboxylation. When R4 is hydroxy it is preferably protected in the compound of formula (II) as, for example, an aryloxy group such as benzyloxy which is removed by hydrogenation.

Suitable examples of a group Rj' which is convertible to Rj, include typical N-protectiπg groups such as alkoxycarbonyl, in particular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and para-methoxybenzyl which are converted to Rj hydrogen using conventional conditions.

Suitable examples of groups R5' and Rg' which are convertible to R5 and Rg respectively include alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R5 and/or Rg hydrogen using conventional conditions.

Interconversions of j, R2, R3, R4, R5, Rg and R7 are carried out by conventional procedures. For example, in the case wherein Rj, R2 and R3 are Cι_g alkyl and R5 and Rg are hydrogen it is possible to introduce a Cι_g alkyl group at both the R5 and Rg positions by conventional alkylation using 2 molar equivalents of a C^.g alkyl halide and 2 molar equivalents of a suitable base in an inert solvent. Monoalkylation can be achieved using 1 molar equivalent of a C^.g alkyl halide and base using conventional conditions. Ri Cι_ alkyl groups may also be introduced by conventional alkylation, for example using a Cj.g alkyl halide and base such as sodium hydride.

R4 halo and R7 halo may be introduced by selective halogenation of the pyridine ring or indole ring respectively using conventional conditions.

It should be appreciated that it may be necessary to protect any Rj to R7 hydrogen variables which are not required to be interconverted.

Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981). I is preferable, however, to introduce and interconvert the groups Ri to R7 before coupling compounds of formulae (II) and (HE) together, or cyclisin the compound of formula (IV).

Compounds of formula (II) in which A is NHR5' are known compounds or can be prepared analogously to known compounds. For example, the compounds of formula (II) in which A is 3-amino and R is hydrogen, 2-chloro or 6-chIoro, and A is 2-amino and R4' is 3-benzyloxy are commercially available from the Aldrich Chemical Company in the UK. R5' Cχ.g alkyl groups may be introduced conventionally, for example by reductive alkylation or acylation and reduction.

Compounds of formula (II) in which A is -N=C=0 may be prepared by treating a compound of formula (IE) in which :

i) A is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent.

ii) A is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et al, Helv. Chim. Acta 1987 70 262).

iii) A is CONH2, via the nitrene intermediate using conventional conditions.

Compounds of formula (II) in which A is -NR5OOL may be prepared by reacting a compound of formula (II) in which A is -NHR5' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine.

Compounds of formula (II) in which A is halogen and R4 is hydrogen are commercially available.

Compounds of formula (HE) in which B is NHRg' are known compounds or can be prepared analogously to known compounds, for example by reduction of the corresponding nitroindole by catalytic hydrogenation over Pd/C by the method of P. Fludzinski et al J. Med. Chem., 1986, 29 2415. Specifically, the compound of formula (III) in which Rχ'and R2' are methyl, R3' is ethyl, Rg' and R7' are hydrogen and B is NH2 is prepared using a procedure similar to that described by Fludzinski.

The nitroindoles are commercially available, for example 5-nitroindole, or may be prepared conventionally (Comprehensive Heterocyclic Chemistry Vol. 4, p. 313 et. seq.(Pergamon Press 1984) and J. Het. Chem. 1988 25, p.l et. seq.)

An R2^* alkoxycarbonyl group may be eliminated to give R2' hydrogen, generally under the conditions effecting formation of the nitroindole or as a subsequent step in the process.

Rg' alkyl groups may be introduced conventionally, for example by reductive alkylation or acylation and reduction. R7' Cι_g alkyl groups may be introduced ortho to a nitro substituent by alkylation using a procedure similar to that described in G. Bartoli et. al., J. Org. Chem. 1986 51 3694 and Tetrahedron 1987 43 4221.

Compounds of formula (IH) in which B is -N=C=O may be prepared by treating a compound of formula (HI) in which :

i) B is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent.

ii) B is acylazide (i.e. CON3), via the nitrene, by thermal rearrangement using conventional conditions.

iii) B is CONH2, via the nitrene intermediate using conventional conditions.

Compounds of formula (III) in which B is -NRg'COL may be prepared by reacting a compound of formula (III) in which B is -NHRg' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triet-hylamine.

Compounds of formula (III) in which B is -NRg'CONHR-δ' can be prepared from the corresponding precursor where B is NHRg' by reaction with an R5' isocyanate under conventional conditions. Examples of phosgene equivalents include triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl chlorothioformate.

Compounds of formula (IV) may be prepared from the appropriate aminophenyl derivative analogously to compounds of formula (I).

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus in mammals such as humans.

The present invention also provides a method for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries in mammals which comprises administering an effective amount of a compound of formula (I) to a host in need thereof.

The present invention yet further provides a pharmaceutical composition for use in the treatment and for prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus in mammals such as humans.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are prepared utilising compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than onc a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such tiierapy may extend for a number of weeks or months. When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.

Examples of specific compounds of formula (I), all of which were prepared according to the procedures hereinbefore outlined and described in

PCT/GB 91/01553, and are especially useful in the present invention are hsted below:

N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea, N-(l-methyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l,2,3-trimethyl-lH-indol-5-yl)-N^*-(3-pyridyl)urea,

N-(l-propyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-4-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-6-yl)-N^,-(3-pyridyI)urea, N-(lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-5-yl)-N'-methyl-N'-(3-pyridyl)urea,

N-methyl-N-(l-methyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-methyl-N-(l-methyl-lH-indol-5-yl)-N^*-methyl-N^,-(3- pyridyDurea, N-(l-methyl-lH-indol-5-yl)-N'-(2-pyridyl)uxea,

N-(l,4-dimethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-5-yl)-N'-(2-chloropyrid-3-yl)urea,

N-(l-methyl-lH-indol-5-yl)-N^,-(2-chloropyrid-5-yl)urea,

N-(l-methyl-lH-indol-5-yl)-N^,-(3-hydroxypyrid-2-yl)urea, N-(l,3-diethyl-2-methyl-lH-indol-5-yl)-N-(3-pyridyl)urea,

N-(l,2-dimethyl-3-propyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l,2-dimethyl-3-n-hexyl-lH-indol-5-yl)-N^*-(3-pyridyl)urea,

N-(l-methyl-lH-indol-4-yl)-N'-(4-pyridyl)urea,

N-(3-ethyl-l-methyl-lH-indol-5-yl)-N-(3-pyridyl)urea, N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-N-(2-pyridyl)urea,

N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-N-(4-pyridyl)urea,

N-(l-methyl-lH-indol-5-yl)-N'-(2-dimeth^ylamino-5-pyridyl)urea,

N-(l,2-dimethyl-3-isopropyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l,3-diethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea, N-(3-isopropyl-l-methyl-lH-indol-5-yl)-N'-(3-pyridyl)urea, or

N-(l,3-dimethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

or a pharmaceutically acceptable salt thereof.

Claims

Claims:

1. Use of a compound of formula (I):

(I) or a salt thereof, wherein:

Rj, R2 and R3 are independently hydrogen or Cj. alkyl;

R4 is hydrogen, Cj_g alkyl, halogen, hydroxy or NRgRg where Rg and Rg are independently hydrogen or Cι_g alkyl;

R5 and Rg are independently hydrogen or Cι_g alkyl; and

R7 is hydrogen, Cj.g alkyl or halogen; and wherein the urea moiety is attached at the 4-, 5- or 6-position of the indole ring; in the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries such as hydrocephalus in mammals.

2. Use according to claim 1 wherein Rj is methyl.

3. Use according to claim 2 wherein R2 is methyl or hydrogen.

4. Use according to claim 3 wherein R4 is hydrogen.

5. Use according to claim 4 wherein R5, Rg and R7 are independently hydrogen or methyl.

6. Use according to claim 5 wherein the urea moiety is attached to the 4- or 5-position of the indole ring.

7. Use according to claim 1 wherein the compound of formula (I) is selected from:

N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea, N-(l-methyl-lH-indol-5-yl)-N'-(3-pyridyl)urea, N-(l,2,3-trimethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-propyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-4-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-6-yl)-N'-(3-pyridyl)urea,

N-(lH-indol-5-yl)-N'-(3-pyridyl)urea, N-(l-methyl-lH-indol-5-yl)-N'-methyl-N'-(3-pyridyl)urea,

N-methyI-N-(l-methyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-methyl-N-(l-methyl-lH-indol-5-yl)-N'-methyl-N'-(3- pyridyl)urea,

N-(l-methyl-lH-indol-5-yl)-N'-(2-pyridyl)urea, N-(l,4-dimethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-5-yl)-N'-(2-c-hloropyrid-3-yl)urea,

N-(l-methyl-lH-indol-5-yl)-N'-(2-chloropyrid-5-yl)urea,

N-(l-methyl-lH-indol-5-yl)-N^,-(3-hydroxypyrid-2-yl)urea,

N-(l,3-diethyl-2-methyl-lH-indol-5-yl)-N^,-(3-pyridyl)urea, N-(l,2-dimethyI-3-propyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l,2-dimethyl-3-n-hexyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(l-methyl-lH-indol-4-yl)-N'-(4-pyridyl)urea,

N-(3-ethyl-l-methyl-lH-indol-5-yl)-N-(3-pyridyl)urea,

N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-lSr-(2-pyridyl)urea, N-(l,2-dimethyl-3-ethyl-lH-indol-5-yl)-N^,-(4-pyridyl)urea,

N-(l-metiιyl-lH-indol-5-yl)-N^,-(2-dimet-hylamino-5-pyridyl)urea,

N-(l,2-dimethyl-3-isopropyl-lH-indol-5-yl)-N^,-(3-pyridyl)urea,

N-(l,3-diethyl-lH-indol-5-yl)-N'-(3-pyridyl)urea,

N-(3-isopropyl-l-methyl-lH-indol-5-yl)-N'-(3-pyridyl)urea, or N-(l,3-dimethyl-lH-indol-5-yl)-N^,-(3-pyridyl)urea.

or a pharmaceutically acceptable salt thereof.

8. A method for the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries in mammals which comprises administering an effective amount of a compound of formula (D as defined in any one of claims 1-7 to a host in need thereof.

9. A pharmaceutical composition for use in the treatment and/or prophylaxis of disorders associated with spinal trauma and/or head injuries in mammals which comprises a compound of formula (I) as defined in any one of claims 1-7 and a pharmaceutically acceptable carrier or excipient.