IE920451A1

IE920451A1 - New pharmaceutical use of fused tetrahydropyridine¹derivitives

Info

Publication number: IE920451A1
Application number: IE045192A
Authority: IE
Inventors: Dr Walter Losel; Rein Andre Roos; Dr Dietrich Arndts; Dr Gunter Schingnitz
Original assignee: Boehringer Ingelheim Int
Priority date: 1991-02-13
Filing date: 1992-02-12
Publication date: 1992-08-12
Also published as: WO1992014465A1; ZA921039B; AU1199092A; IL100927A0; DE4104257A1

Abstract

A compound having general formula (I) or its pharaceutically acceptable salts with an anorganic or organic acid, are used for treating neurological diseases. In general formula (I), A stands for a benzo, thieno or indolo residue; U and V represent each hydrogen or, when A stands for an indolo residue, they represent together a link; whereas R<4> and R<6> stand for independent groups or form together a group having formula (a).

Description

New pharmaceutical use of fused tetrahydropyridine derivatives The present invention relates to the use of fused tetrahydropyridine derivatives for the treatment of neurological diseases.

German Patent Application No. P 38 27 727.1 5 describes fused tetrahydropyridine acetic acid derivatives as compounds having a cardioprotective effect.

We have now found that a range of fused tetrahydropyridine acetic acid derivatives provide useful neuroprotective activity. The present invention thus relates to the use of these compounds for the treatment of neurological disorders.

The present invention relates to the use of a compound of general formula (I) wherein A represents a benzo, thieno or indolo group; R represents a hydrogen or halogen atom, a (C1.4) alkyl, hydroxy, (C.,_4) alkoxy, amino, methylthio, methanesulphonyloxy or methanesulphonamido group; or two adjacent R substituents together represent a group -O-CH2~O- or -O-CH2-CH2-O-; - 2 m represents 1 or 2 and may additionally represent 3 if A is a benzo or indolo group; R5 represents a hydrogen atom, or a (C.,_10) alkyl, phenyl, phenyl(C,^)alkyl, (CV4) alkoxy or -NHCOX group (wherein X represents (CV5) alkyl) ; R4 represents a hydrogen atom or a (CV4) alkyl group; R6 represents a hydroxy, (Ον4) alkoxy or -NR7R8 gr.oup [in which R7 and R8, which may be the same or different, each represent a hydrogen atom, a branched or unbranched (C3.6) alkenyl group, a branched or unbranched (C36)alkynyl group or a branched or unbranched (CV12) alkyl group (in which the alkyl chain may be substituted by one or more of the following substituents: a hydroxy, (CV4) alkoxy, di (CV4)alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl or phenyl group or a phenyl group which is mono- or polysubstituted by hydroxy, methoxy or fluorine); or R7 represents a hydrogen atom and R8 represents a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group; or R7 and R8 together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl ring, the piperazinyl ring being optionally N-substituted by a methyl, unsubstituted phenyl, mono- or di(C,_4) alkyoxyphenyl, pyrimidinyl or phenyl (CV4) alkyl group]; or - 3 R4 and R6 together represent the group [in which R8 represents a hydrogen atom, a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group, a branched or unbranched (C3.6) alkenyl group, a 10 branched or unbranched (C3.6) alkynyl group or a branched or unbranched (CV12) alkyl group (in which the alkyl chain may be substituted by one or more of the following substituents: a hydroxy, (CV4) alkoxy, di(Cv4)alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl or phenyl group or a phenyl group which is mono- or poly-substituted by hydroxy, methoxy or fluorine; and R9 represents a hydrogen atom or a (C^j) alkyl group]; and U and V each represent a hydrogen atom or U and V together represent a bond if either (a) A is an indolo group; R, m and R5 are defined as hereinbefore; R4 represents a (C14)alkyl group; and R6 represents a hydroxy, (C1.4) alkoxy or an -NR7R8 group as hereinbefore defined; or (b) A is an indolo group; R and m are defined as hereinbefore; R4 represents a hydrogen atom; R5 0 represents a hydrogen atom or a (Ο,.,θ) alkyl, phenyl(0^5)alkyl, (Cv4) alkoxy or -NHCOX group (wherein X is (Cv5) alkyl) ; and R6 represents a hydroxy, (CV4) alkoxy or -NR7R8 group as hereinbefore defined; and salts thereof with physiologically acceptable acids for neuroprotection and repair and for the treatment of - 4 neurological disorders.

In the definitions herein, use of the term alkyl indicates an alkyl group which may be branched or unbranched. Similar considerations apply in connection with derived terms such as, for example, alkoxy.

The term halogen atom used herein denotes a fluorine, chlorine, bromine or iodine atom.

Preferred compounds for the use according to the present invention are the compounds of general formula (la) wherein A, R, m and R5 are as defined above; R4 represents a hydrogen atom or a (C14)alkyl group; and R6 represents a hydroxy, (C^^) alkoxy or -NR7R8 group as defined above; and the salts thereof with pharmaceutically acceptable acids .

Further preferred compounds for the use according 30 to the present invention are the compounds of general formula (lb) (lb) wherein A represents an indolo group; and either a) R, m and R5 are defined as hereinbefore; R4 represents a (CV4)alkyl group; and R6 represents a hydroxy, (C14)alkoxy or an -NR7R8 group as hereinbefore defined; or b) R and m are defined as hereinbefore; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a (CV1O) alkyl, phenyl(C15) alkyl, (C^) alkoxy or -NHCOX group (wherein X is (Όν5) alkyl) ; and R6 represents a hydroxy, (C14) alkoxy or -NR7R8 group as hereinbefore defined; and the acids . salts thereof with pharmaceutically acceptable Further preferred compounds for the use according to the present invention are compounds of general formula (Ic), wherein A, R, m, R5, R8 and R9 are defined as for general formula (I), (R9 preferably representing hydrogen); and the salts thereof with pharmaceutically acceptable acids.

Formulae (I), (Ia), (lb) and (Ic) described above should be understood as including all the possible isomeric structures. It should be emphasised in particular that the compounds of general formula (lb) wherein R4 represents a hydrogen atom may also occur in the isomeric forms of general formulae (Id) or (Ie) (Id) (Ie) The above-mentioned definition of general formula (lb) also includes the compounds of general formula (Id) in which R4 represents a hydrogen atom or a (CV4)alkyl group.

Particularly preferred compounds for the use according to the present invention are the compounds of general formula (Ia) wherein A represents a benzo group; m is as defined above; R represents a hydrogen atom, a hydroxy, (C^J alkoxy or 25 methylthio group, preferably a methoxy group, more preferably R represents a methoxy group, m represents 2 and the substituents R are in the 6- and 7-positions; R4 represents a hydrogen atom or a methyl group? R5 represents a hydrogen atom or a (C15)alkyl, phenyl, phenyl(C^j)-alkyl or (C^)alkoxy group, preferably a hydrogen atom, or a (CV5)alkyl, phenyl, phenethyl or methoxy group, more preferably a (C45)alkyl or phenethyl group; and R6 represents a hydroxy, ethoxy or an NR7R8 group in which - 7 R7 and R8, which may be the same or different, each represent a (C15)alkyl group; or R7 represents a hydrogen atom and R8 represents a 5 C3-alkenyl or -alkynyl group, preferably a group -CH2CH=CH2; or R7 represents a hydrogen atom and R8 represents a (C^g) alkyl group; or R7 represents a hydrogen atom and R8 represents a (C13)alkyl group substituted by hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino or phenyl, or by phenyl which is mono15 to tri-substituted by hydroxy or methoxy; or R7 and R8 together with the nitrogen atom to which they are bound represent a pyrrolidinyl, morpholino or piperazinyl group; and the salts thereof with pharmaceutically acceptable acids .

Further particularly preferred compounds for the 25 use according to the present invention are the compounds of general formula (Ia) wherein A represents a thieno group; R represents a hydrogen atom; m is as defined hereinbefore; R4 represents a hydrogen atom or a methyl group; R5 represents a phenyl or phenethyl group; and -δΗ6 represents an -NR7R8 group in which R7 represents a hydrogen atom or a methyl or ethyl group and R8 represents a methyl or ethyl group optionally substituted by a morpholino or thienyl group; or R7 and R8 together with the nitrogen atom to which they are bound represent a morpholino group; and the salts thereof with pharmaceutically acceptable acids.

Further particularly preferred compounds for the use according to the present invention are the compounds of general formulae (Ia) and (lb), wherein A represents an indolo group; R and m are as hereinbefore defined; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a phenyl group; R6 represents a (CV2) alkoxy group; or R6 represents an -NR7R8 group in which R7 represents a hydrogen atom and R8 represents an unsubstituted (C14) alkyl group or a substituted (C12) alkyl group; and the salts thereof with pharmaceutically acceptable acids.

Further particularly preferred compounds for the use according to the present invention are the compounds of general formula (Ic) wherein A represents a benzo group; m is as defined hereinbefore; R represents a hydrogen atom or a hydroxy, (C14)alkoxy or methylthio group, preferably a methoxy group, more - 9 preferably R represents a methoxy group, m represents 2 and the substituents R are in the 6- and 7-positions; R5 represents a hydrogen atom or a (CV5)alkyl, phenyl, phenyl (C,_5) alkyl or (CV4) alkoxy group, preferably a hydrogen atom or a (Cv5) alkyl, phenyl, phenethyl or methoxy group, more preferably a (C4.5) alkyl or phenethyl group; R8 represents a C3-alkenyl or -alkynyl group, preferably a -CH2CH=CH2 group; or R8 represents a (C^g) alkyl group, preferably a (C^g) alkyl group; or R8 represents a (C13) alkyl group substituted by a hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino or phenyl group or a phenyl group which is mono- to tri-substituted by hydroxy or methoxy; and R9 is as defined hereinbefore, but preferably represents a hydrogen atom; and the salts thereof with pharmaceutically acceptable acids .

Further particularly preferred compounds for the use according to the present invention are the compounds of general formula (Ic), wherein A represents a thieno group; R represents a hydrogen atom; m is as defined hereinbefore; - 10 R5 represents a phenyl or phenethyl group; R8 represents a methyl or ethyl group optionally substituted by a morpholino or thienyl group; R9 is as defined hereinbefore, but preferably represents a hydrogen atom; and the salts thereof with pharmaceutically acceptable 10 acids.

The following Tables (Tables 1 to 8) show examples of compounds of general formula (I). - 11 e o Ή 4J —I Π3 ω to Οί o to o ZE CO ZC si co ( I O CO Kt UO —< CN T—< CN I I co co o •—4 C\J CO GO CO CO <_> CO CO ZE CO CO CO CO co o CO ze O ^3* τ—« *~4 CN I I to co CN *—I CN ·—< I I tO CN τ—t CN —< CN CJ> CJ> O -—· vr co mi ii f* —' ZC CO ZE ZE CN O CN O CO ZE UO CO CN ΖΣΖ CN—' <_> ze ze ze co ze ze — CN O O I Ο O ZE O ZE ZE ZE ZE 3Z ZZ Ο ZZ ZZ ZZ ZZ ZZ 'cr co ω co cn γ1 I I CN CN tO co cn rCN CN — UO co rc nz CN o o co CN «—*< I uo CN CO to I I O O «—4 tO O s ifo O X-2-Χ* O’- 'ΣΤ UO ZE CN o o II II *· II * It It It II II II II CN or co co co co ZE ZE ΖΠ ZE ο ο ο o o o o o co ZE o o co co ze zn o o o o co CO co ZE IX o ο o o o o' co ZE O_ o co co ZE ZC o o o .o Table ze ze ze ze ze ze CN cn k\ - 12 Salt form to ce tn ce xi“ ce co ce CXI ce ce CXI o CXJ I co ΟΊ LO co CO co «—< ΟΊ Xt O CXI Γ~-—♦ CXI I I I Γ--- uo ld CT> CXI to CXI o CXI in O CXI t CXI o CXI CXI CXI CXI CXJ CXI CXI o nr CM CTi co co co co co co co co Ο O CM CX CXI CXJ CX CXI csj xj r: x τ τ x nr nr nr ο ο ο o <_> o O O ’ I x x x rx ζ ζ η ζ ζ ζ n rz co co co co co co co co nr re rc nr re nr nr re 0000000 0 CO co CO co co co co co re nr re nr re nr nr rc <0 0000000 0 co co co co co co co nr CO f\ 000 000 co nr co 0 0 «—I *—I CXI o c_> o rc nr nr CXI I to o CXJ I co xr cn o CXJ co σ> to o CXI I o CXI co nr cj co nr co rc co rc CM CM co nr co nr co re co nr ro CM co nr cj> co nr co nr co re re co co co nr nr re 000 000 co co co nr nr_ nr 0 0 000 nr rc CM CM CM Salt form LO CC CO or co cx: cx ΖΣΣ OO co cx cx cx X X T cx cx zc x co to I LO O O I cn ΟΊ CM CM co CM LO cn cn CO LO o CM I o CM t co co on LO LO cn CM cn CO CO I LO co Γco Ό CM I LO o CM LO o CM I IO o CM CM CO CX CX CM CM co co X X cx cx CX CM CM X X cx cx —CO ZC cx co zc cx co zc cx co co c' ZO XX <_> CX CX co co co co O X XXX X cx cx cx cx cx CO CO c” XXX cx cx cx co X cx cx o cx o co zc cx o co cx o cx o cx o cx o CO co XXX cx cx cx o o o co co X cx o co X cx co X cx co X cx o co X cx CO X cx CO cx o co X cx o co zc cx o co zc cx o cx o CO ΟΧ zc cx cx o o cx o CO CO O' XXX cx cx cx o o o co X cx o co X cx o ΓCM co CM cn CM o rO CM ?O ro ro ro uo ro LO ro ΓΓΟ co ro lo cn X X CM CM cx cx co co cx cx o o co co <*· ,X XX CX - cx cx Ό Ο O cn ro Ο -H LO ce •*4 ce co ce CC ce un t_n i_n co XXX X CM CM CM CM ο ο o CJ CD LO LO XX X OJ CM cj cj cj cj CJ LO CO LO LO LO LO X X X X X X 04 04 CM 04 04 CJ CJ O CJ CJ CJ zc CO CO CO XX x X X X X (J ο CJ CJ CJ CJ o o o CJ o co ro zc zc CJ CJ o o CO X CJ o co co ZC X CJ CJ o o CO CO CO CJ o CJ CJ CJ O O O CJ o CJ o co co co co ZC ZC ZE ZC CJ CJ CJ CJ o o o o co co co ZC ZC ZC CJ CJ CJ o o o co co ΣΓΖ X CJ CJ o o co X CJ o co co co co ZC X X X CJ CJ CJ CJ o o o o co X CJ o ΓΟ tf\ Lf\ lO lO MJ Lf\ - 15 ε Μ ο Μ-Ι +J I—'I ίθ ω ο ο ο οο ο ΊΣΖ X X CO X cj ο ο ο X X X X CJ CJ X ΣΕ CJ X α. cn <0 cn to co co VO vo cc VO r-lo CV4 co xT VO XT o CJ f co o CJ xT CO CO co CO o-. «—Ί I co co CJ cn cn cn VO co co cn vo co co co o cn to CO • 1 I O co cn co Γ-*. vo cO LO OZ χτ cc co or CJ az LO X CJ CJ co X CJ CJ o CJ o olT\ LO LO CJ CJ CJ cj co co co co co co x x x x x x co co co coco CJ CJ CJ CJ CJ CJ X X X X X I I I I I I CJ CJ CJ CJ CJ cocorococococococococo LO CJCJCJCJCJCJCJCJCJCJCJ xxxxxxxxxxxx OJCJCJCJCJCJCJCJCJCJOCJ rc CJ rc X CJ co X CJ co X CJ COCOCOCOCOCOCOCOCOCO CJ o co Lf\ CJ o CJ o CJ CJ o o CJ o CJ o CJ CJ o o CJ o CJ CJ o o CO CO X X CJ CJ o o co COCOCOCOCOCOCOCOCOCOCOCO x xxxxxxxxxxxx CJ OOOCJCJCJCJOCJCJCJO O OOOOOOOOOOQO Cn LC o vO vO Ol VO rc vO lC VO v0 vO Ονο co VO cn σ vo Γ-ro X CJ rc Ol X CJ rc fMX x CJ CJ o o rc x =c O CJ o O co CJ Ο Γ-IE 920451 Salt form LD OE CO OE OE co co zc ZC CJ o CO CO 04 ZC zc CJ CJ CJ CJ cj o CJ CJ o o CJ co CJ CO ZC CJ zc CJ CJ CO zc CJ CJ co zc CJ CJ co zc CJ co CJ o CJ o CJ o CJ o CJ o LP\ CO □z CJ CJ CJ o CJ o CJ o o rθ’co Γσ\ Γco co co co zc zc zc zc CJ CJ CJ o co co co co 04 04 τ τ x τ CJ CJ CJ CJ CJ co zc CJ CJ co zc CJ co co CO co ZC ZZ ZC ZC CJ CJ CJ CJ o o o o co co co o' zc zc zc zc CJ CJ CJ CJ ο ο ο o σ co co fO co ro zc CJ o co zc o o CJ -o co zc cj o ο M-l Π3 ω o o 2C 32 O O O 32 32 CO o CO 32 co co co co co co CO o ’d· o co LO co LO o xo CO Γ-- CO o oo o OX Γ- co co Cd Ox co OX r^. LO xo Kj- —1 Cd « < » 4 r· < —‘ « 4 · y 1 Cd 1 o co CXJ co xo LO Cd ^J· ox •Xj· xo kO co co .-1 co Ox XD co r-·- Cd ox Ox r^. LO xo co . 4 —< —· '—t —· —« ΧΟ or LO Cd or co Cd CJ CJ o CJ o co CJ o <_j o co r·'c? co co 32 232 32 CJ CJ CJ co co co CJ Cd CJ 32 32 32 CJ CJ CJ co CJ co Cd 2C CJ co co co co co 32 32 32 32 CJ CJ CJ CJ CJ co co CO CO co Cd Cd Cd Cd Cd 212 32 232 212 32 CJ CJ CJ CJ CJ co 212 CJ CO CJ co co co CJ o CJ o CJ o co CJ o co CJ o co 212 CJ o CJ o CJ o CJ co CO CJ CO CJ O CO co O' 32 32 2C O CJ o o o o co 232 CJ o co co co co O O CJ O co co CJ o co 232 CJ CJ CO 232 CJ o CO CJ CJ co co Ox co CJ ox Cd Ox Ox XO οχ Γ*Ox co crx co CJ co Cd 212 CJ CJ co cd CJ CO CJ co CJ CJ o CJ o' Ox οχ CJ σ CO 212 CJ o - 19 Ε ο Ψ-ι +J f—-4 (0 cn CO co VO O O CM O VO ΟΊ I f 1 ro VO CO m vo co co co co co <_> CO X co CM co CO cn μ- V<—<*—< I I ΓΜ θ o — VO «ςτ co r-t ro CO CO co co co co <3 cn VO --( co co ι cn w—4 ΓΟ ·—< cn co CJ co CO X CQ O vo co CM co vo cn cn jo Π3 GJ ΓΜ CM VO - 20 ε Μ ο u-i +J ι—I ω Cb i t CO CJ zc CJ CO CJ zc co zr cn co cn co CJ CJ co zr zc CO co CO CQ C9 cn GO cn C4 co I o co « o-.cn r-- 04 γ-co co cn oj 04 r-> I O on cr> co co tr cn on ι co co ro co co co cn CO cn OE OE on OE OE OE co CJ on zc CJ o on zc CJ o on CJ o <—I to cn zz co CJ cn cn cn cn zz zz zz zc co co CO co CJ CJ CJ CJ rn CJ o on CJ o C4 m cn cn on on on on CJ CJ CJ CJ o o o o on on on on CJ o co CJ co CJ cn zz co CJ 04 04 04 04 04 04 ZZ ZZ ZC ZZ CJ CJ CJ CJ cn ZZ CJ cn cn cn cn cn ZC ZZ zc ZC zc CO co CO co CO VO CJ CJ CJ CJ CJ CJ zc zc m m zc zc CJ CJ zc zz zz on CJ O on CJ o on on on zz zc zz CJ CJ CJ o o o on on zz zc CJ CJ o o zc CJ o CJ CJ CJ o o o on zc CJ σ on zz CJ o on zc CJ o cn co ra co ZC ZC ZZ ZZ CJ CJ CJ CJ o o __o o on zc CJ Ό on ZC CJ o zz zz zz zc zz zz lT\ m m rco m cr\ ro ε ε ο y-i 4-1 r—( cn tn ce co CXI az co co co co co co to re to co co CD CO co co co co co co co co co to -ΤΓ to co xr XT uo co O XT I <33 CO CM I CO o CM CM co I <73 CXJ XT to »—4 I CXI to xr t xt cn to I to uo cxi to CXI I xt CXJ CM f*X □r CO CM CM ne co to nr to to co nr o o to o ux CXI CXI nr to to n: to to CXI CM nr to to ne to to CXJ CM nr to LO nr to to CM CM CXI CM CM CXJ rc re nr to to to LO to to ne re nr to to to to to to CM CM re to uo nr to to to o to o to co rc to o to o co co co ir ne rc to o to o to o to o to o co nr to o CO CO CO ae nr ne to o to o to o to o UX CM UX to I re CM CXJ re to tn rc to to CM CM nr to uo rc to to CM ne to uo nr Ό to to o to o to o to o r-x UX CO ne to o CO nc to o ux LfX MX - 22 4-> γ-—I ίϋ ω ΟΟ CO co co co co o o cn co o o CM « ’CT ο ο ο XXX CO CM CM —< CO I Γ—< CM «—« CM Ο γγο co co o cn I cn co 1Ζ) Ο co CO X CD LO Γ— I Γ— GO I CM co O cn ι cn cn CO co Γ— I LO Γ- ΙΟ CC co (X CM CM X cx LO X co cx CM CM cx LO X co cx cx o COCOCOCOCOC'· X X X X X X cx cx cx cx cx cx o o o cx o o cx o co X cx o co X cx o ro CJ ro cj ro CM X CJ co X cx CO X cx rO X CJ cx o co un cx o cx o cx o co LT\ CO co CO CO CO o X X X X X x cx cx cx cx cx cx ΟΟΟΟΟΟ co co XXX cx cx cx o o o cn o un co co co co co cx o cx o cx o cm ro CO co CO co X o o co X cx o lO co cx o cx o CJ o CJ o CO X cx o cx o CJ o CJ o co cC Γ— co CD co cn CO .X - 23 Table 2: No.R4R5R6 170 HC6H5 171CH3C6H5 172 HC6H5 nh(ch2)2~no 173 HC6H5 174 H c6h5(ch2)2 n(c2h5)2 175 H CHc(CHo)o N 0 M.p. Salt form 171-172 HCI 101-105 BS 128 ( Decomp. ) BS 210-215 HCI 191-193 HCI 145 ( Decomp.) HCI 176 H C6H5 177 H C6H5 178 H C6H5 175 HCI ( Decomp. ) - NH-Q-CH2-C6H5 195 ( Decomp. ) HCI NH-(CH2)2~N 0 90 ( Decomp. ) HCI - 24 Table 4: 180 H H nh(ch2)2-n_0 262-265 HC1 181 H H nh-ch2ch(chJ 165-168 BS 182 H H 0CoHc 128-130 BS - 25 Table 5: No. e R R5 M.p. (°C) Salt form 183 ch3-ch2-ch2- H 95-96 BS 184CH3- H 96-100 BS 185 CH =CH-CH 2 2 H 67-9 1 BS 186 CH O-CH -CH 3 2 2 H Oil 187CH3-2’4- H 87-90 BS' 188 ch3-(ch2)3- H 74-75 BS 189 (CH^N-'cnpa- H 170-190 (Decomposition ) HCl 190 (CH3)2CH-CH2- H 84-90 BS 191 (ch3)2ch- H 144-145 BS 192 ch3o-(ch2)3- H 71-75 BS 193 ch -ch -ch 3 2 2 CH 3 119-124 ELS 194 Q_CH2-CH2- CH 3 96-102 BS 195CH3-<CH2VC2H5 c 3 _ o 5 BS 196 V-ch2-ch2-C2H5 86-89 BS 197 (CH3)2CH-CH2-C2H5 110-112 BS 198 aC5H11 123-125 BS - 26 Table 6: No.

R' M.p. (°C) Salt foriT1 199 'CH2_CH2“CH3 200 -CH3 201 -CH -CH=CH 2 202 -CH2-CH2-OCH3 203 -CH2-CH2-N(CH3)2 204 -CH2-CH2-CH2-CH2-CH3 205 -CH2-CH2-CH2-CH3 206 -CH2-CH2-CH2-N(CH3)2 207 -CH-CH 3 208 -CH2-CH(CH3)2 209 -CH(CH3)2 210 -CH-CH-CH(CH) 2 3 2 211 -CH -CH -CH -OCH 2 2 3 H HCl H 226-228 HCl H 183-186 HCl K 198-203 HCl H 173-176 HCl H 177-179 HCl H 189-191 HCl H 168-172 HCl H 218-222 HCl H 189-194 HCl H 209-211 HCl H 182-185 HCl H 206-208- HCl 212 213 214 215 216 217 218 219 -CH CH CH 2 2 3 OCH.

CH2CH20CH3 -ch2-ch(ch3)2 -CH CH OCH 2 2 3 -CH CH CH CH CH 2 2 2 2 3 -CH CI1 2 2 CH3 HCl CH. J 181-184 HCl ch3 194-195 HCl ch3 17 0-172 .. HCl ch 3 173-17.5 ' HCl CH 3 168-170 KCI ch3 190-194 HCl ch3 197-200 HCl -ch2ch2 jO - 27 No M.p. (°C) Salt form OCH 220 221 222 223 2 4 -CH CH CH CH CH 2 2 2 2 3 CH^CH^fv CH CH OCH 2 2 3 C H 159-164 HC1 C H 124-133 HC1 C H 192-202 HC1 C H 157-162 HC1 Cl!r 171-175 HCL 225 -ch(ch3)ch2ch2ch2ch(ch3)2C2H5 151-159 *HC1 226 -CH2CH2OC2H5 178-184 HC1 227 -c«2™2OC2H5 192-193 HC1 228 -ch2ch(ch3)2C2H5 . 164-167 HC1 229 -CH CH=CH 2 2 n-C H 4 9 76-78 (A)~ . HC1 230 -CH -CH -N(CH ) 2 2 3 2 n-C H 4 9 181 HC1 23 1 -CH CH OCH 2 2 3 n-C H 4 9 47-62(A) HCl 232 -ch2ch2-@ n-C Hn 4 9 111-118 HC1 233 -ch2ch3)2n-C4H9 95-96(A) HCl 234 -CH CH CH CH CH 2 2 2 2 3 n-C H 4 9 - 68-73(A) HC1 235 -CH CH CH 2 2 3 n-C H 4 9 54-57(A) HCl 236 -CHCHCH(CH) 2 2 3 2 -CH CH -IflJ 2 2 ” n-C H 4 9 90-92(A) HCl 237 n-C H 4 9 197-198 HCl 238 -O-F n-C H 4 9 150-152 HCl 239 -G n-C H 5 11 134-138 BS 240 -ch2-Q n-C H 5 11 107-109 BS No . R8 R5 M.p. (°C) Salt form 241 -CH -CH2-N^0 151 24 2 -CH2“O -och3 155 HC1 243 -CH CH -och3 127-128 BS 244 -ch2ch2-N(ch3)2n-C4H9 HC1 (A) : amorphous isomer mixture Compound No. Isomer mixture 229 50 : 50 231 70:30 233 40 : 60 234 90:10 235 6 0:40 236 70:30 - 29 Table 7 No M.p.[°C] salt form 245 -och2ch3 154-156 BS 246 -nh(ch2)2-n3 74-75 (amorph) BS 247 248 -NH-CH2CH(CH3)2 -NH-(CH2)20H 201-203 BS 248 a -NH-(CH-)„0CH, 144-146 BS Table 8 No.

M.p.t°C] Salt form 249 -nhch2ch(ch3)2 223-225 BS 250 * 206-208 BS 251 a -NH(CH2)2O ch3 166-169 BS 251 -NH(CH2)20H - 30 The compounds of formula (I) used according to the present invention are bases and can be converted in the usual way with inorganic or organic acids into any desired physiologically acceptable salts.

Acids suitable for salt formation include for example hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, acetic, propionic, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, cinnamic, ascorbic or methanesulphonic acid.

Some of the compounds covered by the general definition of formula (I) wherein A is a benzo or indolo group are already known, and some of them have been described as tranquillisers: Eur. J. Med. Chem.- Chim. Ther, 14(1), 77-89 Heterocycles, 3(2), 179-82 Synthesis (5), 474-7 J. Med. Pharm. Chem. 3, 505-17 (1961) EP 2 18 57 US 3 021 331 US 3 081 306 Compounds which are structurally close to the compounds of general formula (lb) have been described in European Patent Applications EP-A 288 048 and EP-A 251-194.

As mentioned hereinbefore, the compounds of general formula (I) and the salts thereof have been described as cardioprotective compounds in German Patent Application P 38 27 727.1.

The compounds of general formula (I) used according to the present invention possess, as mentioned hereinbefore, valuable therapeutic properties both in the form of bases and the salts thereof. In particular, these substances have a significant neuroprotective activity and the present invention relates to the-use of the compounds specified as neuroprotective agents. The compounds are valuable in the treatment of degenerative - 31 and necrotic diseases of the brain. It is also possible to provide preventive treatment for patients who are at risk of such diseases. As is shown by the experiments described hereinafter, the effect of the compounds is not based on an improvement in the circulation of blood in the tissues. The substances avert the pathophysiologically significant intracellular Ca2+overload and thereby act directly on the neurone cells. The Ca2+-overload obviously plays a key role in the pathogenesis of numerous neurodegenerative diseases: in epilepsy (E.J. Speckmann et al., Arzneim. Forsch. 39: 149-156, 1989), in Alzheimer's disease (M.P. Matson, Adv. Exp. Med. Biol. 268: 211-220, 1990 and R.A. Nizon, Ann. N.Y. Acad. Sic. 568: 198-208, 1989) and in stroke (W. Young, Centr. Nerv. Syst. Trauma 3: 235-250, 1986; J.A. Zivin and Choi, Scientific American 36-41, July 1991). The compounds are thus suitable for a novel treatment of epilepsy and Alzheimer's disease and particularly for the treatment of patients who have suffered a stroke or are at risk of suffering a stroke. The following test results demonstrate the surprising efficacy of the compounds.

In the hypoxia tolerance test, compounds of general formula (I) and the salts thereof have proved effective.

In tests for the survival of animals in a sealed chamber (hypoxia tolerance test) through which a mixture of gases was piped, consisting of 96.5% nitrogen and 3.5% oxygen, the animals pretreated with the compounds of general formula (I) showed a statistically highly significant superiority in survival compared with the control animals or animals pretreated with diltiazem, nifedipin or verapamil. The cerebroprotective effect tested by this method was frequently outstanding at a dosage of only 5 mg/kg p.o.

Test results are given below for the following compounds (Table 9): - 32 Table 9 No. R5 R6 Salt form Effective dose [mg/kg] 78 n-C4H9 HN-CH-, HCI 30 82 n-C4H9 n(c2h5)2 HCI 5,10,30 89 n-C4H9 n(ch3)2 HCI from 5 90 n-C4H9 nh(ch2)3oh HCI 10,30 106n-C5H11 NH(CH2)2CH ( CH3)2 20,30 112anC5H11 N( (CH2)3CH3)2 HCI 5,10 114 n-C5Hn NH(CH2)2N(CH3)2 30 The following tests on isolated cell cultures further demonstrate the efficacy of the compounds tested. It can also be concluded from these test results that the compounds of general formula (I) can be used for the treatments mentioned hereinbefore.

The direct neuronal attack of the compounds tested was demonstrated on isolated cortical and hippocampal neuron cells from foetal rats brains (dissected according to H.W. Muller and W. Seifert, Proc. Natl. Acad. Sci. USA 81: 1248-1252, 1984; J. Neurosci. Res. 8: 195-204, 1982; and Muller and Seifert in Methods for Serum Free Culture of Neuronal and Lymphoid Cells, p. 67-77, A.R. Liss Inc., 150 Fifth Ave., New York, N.Y. 10011, 1984). The concentration-time curves (calcium transient) of the cytoplasmic [Ca2+]f were recorded in - 33 FURA2-charged single cells (Method: modified from J.A. Connor, Proc. Natl. Acad. Sci. 83: 6179-6183, 1986).

Both after mechanical lesion and after the administration of excitatory amino acids (e.g. EAA, glutamate, cainate, quisqualate and NMDA) a sharp increase in the cytoplasmic calcium concentrations was induced, which could be inhibited by means of administering the compounds of general formula (I).

The mechanism of activity of this inhibition was investigated both on neuronal cell cultures and also on human neutrophilic granulocytes and HL 60-cells and thrombocytes. It was demonstrated that the compounds tested inhibit the transmembranal calcium influx into the cells stimulated by receptor agonists (e.g. EAA, the chemotactic peptide fMLP, leucotrienes, PAF, endothelin etc.). This influx, referred to as receptor mediated Ca2+ entry (RMCE) by T.J. Hallam and T.J. Rink (Tips 10: 8-10, 1989) cannot be inhibited by conventional calcium antagonists. Conventional calcium antagonists cannot prevent the leucocyte and thrombocyte activation since these cells do not have any voltage-dependent Ca2+ channels. The blockade of the transmembranal calcium influx was confirmed electrophysiologically (using the voltage clamp technique) on HL 60-cells and neurone cells.

The test results are shown in the following tables (Tables 10, 11 and 12).

%H - % inhibition of transmembranal Ca2+-influx, caused by a uniform (10'5M) concentration of the test substances. What is inhibited is the stimulating effect of 30 μΜ cainate on the intracellular [Ca2+] in cortical neurone cells. - 34 cr. rcm o CO CM LO lO r-. CO CM CO <0 xj t— CO CD CM r- f— TT <0 O’ u> cn r- co rTable 10 £ !h O U-i +J r—I ω w CJ X NH(CH ) ~N(CH ) SS 43.97 m az QtZ CO X CO t_o ir> cm XXX CM CM CJ CJ C_> — CO X CO CM X o XXX - 35 CQ Ό CO O r~- ·— oo cn co to tD CQ M to OO O M rCM CO CM lO I— CM CM M r*. CM to O CQ CO p- IO CO Γ-r-. id O CM r- o co r-~ No. R R R R R R Salt form cj to cj X co X CQ CO lO CJ CO CD X CO CJ X CQ CJ CD X CQ CQ X X CJ CJ CQ CQ cq cn cn to X CM cj o CQ X CJ CQ CM X cj X cj X CJ CQ X cj m- CM X cj CQ X CJ CM X cj CQ X cj tjCM X CJ CQ X CJ TT CM X o CM CM X CJ to X tD CJ co X X CJ X X X X X X X X CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ X X X X X X X X X X cj CJ CJ CJ CJ CJ CJ CJ CJ CJ o o o o o o o o o o CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ X X X X X X X X X X cj CJ CJ CJ CJ CJ CJ CJ CJ CJ O o . o o O o o o o o X X X X X X X X X X CM IO tD cn o /O CM CQ IO o O O o 1— <— f— ·— M- cn •— •— — * - 36 co cn ld CM XT I- r~- uj co cn uo m χίο cn cn in r*.

CM cn xj- xj· cn cm r-. in cn in r-. ·— XT co co cn co r·-E o W-i +J »—( Π3 ω LO or xr or co or CM O' or O (_> IZ> VO X CD CD oo CD OO OO CD CD CZ) OO OO m m DQ CM CM X CJ uo X LO O CM CM CM CM CM CM CM CM X X CJ CJ uo uo X x CO lO CJ CJ XXX co co co XXX CJ CJ CJ o o o ro co co X X X CJ CJ CJ o o o XXX cm co O’ -9Γ O’ vr CO X CJ o co X CJ o uo -vr co co co XXX CJ CJ CJ o o o co X CJ o co X CJ o co co X X CJ CJ o o cn o 'T in co X CJ o co X CJ o co O' uo uo - 37 Table 11 Salt form %H 179 C6H5 H NH HCl 45.32 Table 12 No. Salt form %H 249 -NHCH2CH(CH3)2 250 -NH(CH2)2T-1^1 BS . 66.77 BS 62.30 - 38 From the test results given above it can be concluded that, in order to prepare neuroprotective agents (particularly agents for treating or preventing epilepsy, Alzheimer's disease and stroke) it is particularly advantageous to use compounds of general formula (I) wherein A represents a benzo group; R represents a hydrogen atom or a hydroxy, methoxy or methylthio group; or two adjacent substituents R together represent a group -O-CH2~O-; m represents 1, 2 or 3; R4 represents a hydrogen atom or a methyl group; R5 represents a hydrogen atom or a (CV5)alkyl, phenyl, phenyl (C15) alkyl or (C,.4) alkoxy group; R6 represents a (C,.4) alkoxy group or an -NR7R8 group, in which R7 and R8, which may be the same or different, each represent a (C15) alkyl group; or R7 represents a hydrogen atom and R8 represents a C3-alkenyl or -alkynyl group, a phenyl or fluorophenyl group, a (C,^)alkyl group or a (C,,3) alkyl group substituted by a hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino or phenyl group or by a phenyl group which is mono- to tri-substituted by hydroxy or methoxy; or R7 and R8 together with the nitrogen atom to which they are bound represent a pyrrolidinyl, morpholino - 39 10 or piperazinyl group; and the salts thereof with pharmaceutically acceptable acids.

It is more particularly advantageous to use those compounds wherein either a) A represents a benzo group; m represents 2 and the two substituents R are in positions 6- and 7-, the two R substituents, which may be the same or different, representing a hydrogen atom or a methoxy or methylthio group; R4 represents a hydrogen atom or a methyl group; R5 represents a (C2.5) alkyl or phenyl (C15) alkyl group and R6 represents an ethoxy or NR7R8 group in which R7 and R8, which may be the same or different, each represent a (C2.5) alkyl group; or R7 represents a hydrogen atom and R8 represents a (C4 8) alkyl group, a phenyl or fluorophenyl group, or a (C^j)alkyl group substituted by hydroxy, dimethylamino, furyl, phenyl or dimethoxyphenyl; or b) A represents a benzo group; m represents 2 and the two substituents R are in positions 6- and 7-, and either both substituents R represent a methoxy group or one substituent R represents a methylthio group and the other represents a hydrogen atom; R4 represents a hydrogen atom or a methyl group; R! R' and, - 40 represents a (C2.5) alkyl or phenethyl group; and represents an ethoxy or an NR7R8 group in which R7 and R8, which may be the same or different, each represent a (C2.4) alkyl group; or R7 represents a hydrogen atom and R8 represents a (C4_8) alkyl, phenyl or fluorophenyl group or a (C^j)alkyl group substituted by phenyl, dimethoxyphenyl, furyl, dimethylamino or hydroxy; in the case of a) or b) above, especially those wherein R4 represents a hydrogen atom; R5 represents a (C4.5)~ alkyl or phenethyl group; and R6 represents an ethoxy or NR7R8 group (in which R7 and R8 each represent a butyl group or R7 represents a hydrogen atom and R8 represents a (C58) alkyl, phenyl or fluorophenyl group or a (C.,_2) alkylphenyl group, the phenyl ring being optionally substituted by 2 methoxy groups), more especially those wherein R4 represents a hydrogen atom; R5 represents a (C4 5) alkyl or phenethyl group; and R6 represents an ethoxy or NR7R8 group (in which R7 and R8 each represent a butyl group or R7 represents a hydrogen atom and R8 represents a phenyl, pfluorophenyl, benzyl, phenethyl or (C5g)alkyl group), most especially those wherein R4 represents a hydrogen atom; R5 represents a butyl or phenethyl group; and R6 represents an NR7R8 group (in which R7 and R8 each represent a butyl group or R7 represents a hydrogen atom and R8 represents a phenyl, phenethyl or (C5.8) alkyl - 41 group); and the salts thereof with pharmaceutically acceptable salts.

It is most particularly advantageous to use a compound of formula (I) as defined above wherein A represents a benzo group; m represents 2; both R substituents represent methoxy and are located in positions 6- and 7-; R4 and R5 are as defined above; and R6 represents an NR7R8 group in which R7 represents a hydrogen atom and R8 represents a group -CH(CH3) (CH2)3CH(CH3)2; and the salts thereof with pharmaceutically acceptable salts.

It is also most particularly advantageous to use the following compounds: a) a compound of formula wherein R5 represents a group -(CH2)3CH3 and R6 represents an ethoxy or -Ν(H) (CH2)4CH3 group; and b) a compound of formula wherein R5 represents a group ~(CH2)3CH3 and R6 represents a group -NHCH(CH3) (CH2)3CH(CH3)2 or -NH(CH2)2-O> ; or R5 represents a group -(CH2)4CH3 and R6 represents a group R5 represents a group C6H5(CH2)2- and R6 represents a group N[ (CH2) 3CH3]2, -NHCH(CH3) (CH2)3CH(CH3)2, -NH(CH2)2C6H5 or -NHC6H5. and the salts thereof with pharmaceutically acceptable salts .

The active substances are suitable for use in pharmaceutical compositions for oral or parenteral administration. The main preparations used are tablets, coated tablets, ampoules and syrups. The single dose of these preparations is between 1.0 and 200 mg, preferably between 20 and 50 mg per 75 kg of body weight.

Generally, depending on the gravity of the case, 1 to 3 single doses should be administered daily.

The compounds of general formula (I) may be prepared using methods known per se.

A compound of formula (Ia) wherein A, R, m, R4, R5 and R6 are defined as hereinbefore may, for example, be prepared by reducing the corresponding compound of general formula (II) or a tautomer thereof In the compound of formula (II), A, R, m, R4, R5 and R6 are defined as in the desired compound of formula Ia. - 43 (The compounds of formula (II) are thus compounds wherein A is benzo, thieno or indolo).

This method of preparation is preferably used on compounds of formula (II) wherein R4 is hydrogen.

For the preparation of a compound of formula (Ia) wherein R4 is (C,.4) alkyl, one of the following alternative processes may, for example, be used: a) a compound of formula (Ia) wherein R4 is hydrogen is N-alkylated; b) a compound of formula (II) wherein R4 is hydrogen is converted into a quaternary ammonium salt thereof (e.g. by reacting with (C,_4) alkyliodide) and subsequently reduced to form a compound of formula (la) (wherein R4 is (C,.4) alkyl) .

For the reduction of the compounds of formula (II) it is convenient to use complex metal hydrides (such as for example sodium boranate, sodium cyanoborohydride, optionally combined with a noble metal catalyst) or catalytically activated hydrogen.

The reduction is preferably carried out in a solvent such as methanol or ethanol at ambient temperature or, optionally, at elevated temperature up to the reflux temperature of the reaction mixture.

Some of the compounds of general formula (Ia) (shown below as formula (If)) may be prepared by reduction of a corresponding compound of general formula (V) (Ic ) (If) - 44 wherein A represents a benzo, thieno or indolo group; R represents hydrogen, (C1.4) alkyl, halogen (F, Cl, Br, I), hydroxy, (C1.4) alkoxy, amino, methylthio, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R together represent -O-CH2-O or -O-CH2-CH2-O- ; m represents 1, 2 or 3, if A is a benzo or indolo group, and 1 or 2, if A is a thieno group; R9 represents hydrogen or (C^j)alkyl; R5 represents hydrogen, (CV1O) alkyl, phenyl, phenyl (/.5) alkyl, (C14) alkoxy or -NHCOX (wherein X is (C^g) alkyl); R8 represents (a) hydrogen, (b) branched or unbranched alkenyl having 3 to 6 carbon atoms, (c) branched or unbranched alkynyl having 3 to 6 carbon atoms, or 25 (d) branched or unbranched alkyl having 1 to 12 carbon atoms, wherein the alkyl may be substituted by hydroxy, (CV4) alkoxy, di(Cb4)alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl, phenyl or phenyl which is mono- or - 45 polysubstituted by hydroxy, methoxy or fluorine; (e) phenyl, fluorophenyl, pyridyl or Nbenzylpiperidyl.

The reduction may, for example, be carried out with NaBH4 in glacial acetic acid, possibly with the addition of a solvent (as described by C. Djerassi, H.J.

Monteiro, A. Walser, L.H. Durham J. Am. Chem. Soc. 88, (1966) 1792). For this purpose a compound of general formula Ic is dissolved in glacial acetic acid and an excess of sodium boranate is added in batches with cooling and stirring.

The duration of the reaction is determined to a very great extent by the length of the group R5 and may range from 1 to 15 hours at ambient temperature. The reaction times increase in the following sequence: R5 = H < CH3 < C2H5 < C4H9 < CjH,,...

Reaction times are either not influenced or are only insignificantly influenced by the group R8.

The reaction temperature is largely uncritical and may be between 5°C and the boiling temperature of the reaction mixture. For safety reasons, the reaction can be carried out whilst cooling with ice at a temperature ranging between 5 °C and ambient temperature.

The solvents may be, apart from glacial acetic acid, which is simultaneously present as a reactant, mixtures of glacial acetic acid and a suitable inert solvent, such as THF, dioxan, ethanol, etc. It is preferred to carry out the reaction in glacial acetic acid.

A preferred embodiment of the reduction process is as follows: The starting compounds (Ic) are dissolved in glacial acetic acid. With stirring and cooling to 5 °C the finely powdered NaBH4 (4 - 10 fold excess) is added in batches. After the reaction has ended, water is carefully added, the mixture made alkaline with dilute - 46 NaOH and extracted with CH2C12. The organic phase is washed with water, dried over Na2SO4 and concentrated by evaporation. The residue is crystallised, optionally after purification on a silica gel column (eluant: CH2Cl2/MeOH 100:10).

The compounds of formula (Ia) thus obtained may be subjected to one or more of the following subsequent treatments a) a compound of general formula (Ia) wherein R6 is hydroxy or (C,_4) alkoxy may be converted into the corresponding amide wherein R6 is the group NR7R8.

The starting compound (optionally after the basic ring nitrogen has been protected and/or the carboxy or ester group activated) is reacted with the corresponding amine NHR7R8 (III).

Examples of reactive carboxylic acid derivatives include, for example: acid halides, acid azides or mixed acid anhydrides (e.g. with an aromatic or aliphatic carboxylic acid, alkylcarbonic acid or dialkylphosphoric acid, etc.), as well as acid amides (e.g. with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, etc.) or active esters (such as for example cyanomethyl, methoxymethyl, vinyl, propargyl or pnitrophenylesters, etc.) or esters with dimethylhydroxylamine, 1-hydroxysuccinimide, dicyclohexyl urea, etc.; the active imidazolides are preferred.

The amide formation is generally carried out in an inert solvent such as dioxan, acetonitrile, dimethylformamide or a mixture of one or.more of these solvents, optionally in the presence of an organic or inorganic base as the acid acceptor.

However, it is also possible to carry out the reaction without solvents using the amine in excess . - 47 The reaction temperature may be varied within wide limits, depending on the starting materials used, and may be between about 0°C and the boiling temperature of the reaction mixture. b) A compound of general formula (Ia) wherein R4 is hydrogen may be converted by N-alkylation into the corresponding compound of formula (Ia) wherein R4 is (C^Jalkyl.

Theoretically, all known alkylating agents are suitable for the N-alkylation provided that they are sufficiently reactive, e.g. active alkylesters such as dialkylsulphate, alkyl toluenesulphonate or alkyl fluorosulphonate or alkyl halides such as alkyl bromides or alkyl iodides. The reaction may be carried out at temperatures up to the boiling point of the reaction mixture. Alkyl in this case represents (CV4) alkyl. The aminoalkylation may also be carried out according to Leuckart-Wallach (Ber. dtsch. Chem. Ges. 18., (1985), 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; 4 (1950) No. 378). In general, the substance is treated with an approximately 30% aldehyde solution, preferably formalin solution in the presence of formic acid at reflux temperature. The duration of reaction varies between 3 and 18 hours. This reaction is suitable for compounds of formula (I) wherein R6 does not represent NH2 or NHR8. c) A compound of formula (Ia) wherein R6 is hydroxy can be converted into the corresponding ester (R6 = (CV4) alkoxy) . d) A compound of formula (Ia) wherein R6 is (C^/alkoxy or NR7R8 can be hydrolysed to form the corresponding free acid. - 48 e) The separation of diastereoisomers is carried out to some extent spontaneously by crystallisation or by using the usual methods of racemate separation, e.g. column chromatography. f) The conversion of the free base of general formula (Ia) into the acid addition salts thereof is carried out in a manner known per se.

The compounds of formula (II) or (lb) may be prepared using methods known per se. for example by the method described in German Patent Application P 37 18 570.5.

In the presence of a condensing agent, a malonic acid diamide of general formula (IV) H (R) m-θ-CH2-CH2-NHCO C - CO-R6 (IV) R5 wherein R, m, R5 and R6 are as hereinbefore defined and Ar represents a phenyl, 2- or 3-indolyl or 2- or 3thienyl group, may be cyclised to yield the corresponding compounds of formulae (II) and (lb) in which A, m, R, R5 and R6 are as hereinbefore defined, whilst R4 is a hydrogen atom or a (CV4) alkyl group.

The actual procedure adopted will be discussed further hereinafter. If the reaction is carried out, for example, with a mixture of phosphorus pentoxide and (C1.4) alkylsulphonic acid, the analogous compounds wherein R4 is (C14) alkyl will be obtained in addition to the corresponding compounds of formulae (II) and (lb) wherein R4 is hydrogen.

Suitable condensing agents for this process include strong Lewis acids such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron - 49 strong Lewis acids such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride and also inorganic acids such as polyphosphoric, sulphuric, fluorosulphonic and hydrofluoric acid, or mixtures of condensing agents, such as a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C14) alkylsulphonic acid, e.g. containing approximately 10% by weight of P2O5.

If a compound of formula (IV) is cyclised in the presence of the mixture of phosphorus pentoxide and (C1 _4) alkylsulphonic acid, there will be obtained, in addition to the corresponding compounds (II) and (lb) wherein R4 is a hydrogen atom, the analogous compounds (II) and (lb) wherein R4 is a (CV4)alkyl group, as has already been mentioned. Preferably, this alternative process is carried out with methanesulphonic acid.

Cyclisation may be carried out in the presence or absence of a solvent. Any inert solvent is suitable provided that it has sufficient solubility for the reactants and a sufficiently high boiling point, e.g. benzene, alkylbenzenes (e.g. toluene, xylene), chlorobenzenes, chloroform, acetonitrile and decalins.

In a preferred variant of the process, the condensing agent, e.g. phosphorus oxychloride in acetonitrile or amixture of (CV4)alkylsulphonic acid and phosphorus pentoxide without any added solvent, is used.

Preferably, cyclisation is carried out with phosphorus oxychloride in acetonitrile or, in difficult cases, with a mixture of phosphorus pentoxide and (C14)alkylsulphonic acid (preferably methanesulphonic acid). The reaction may be carried out within a wide temperature range, preferably with heating to 50°C up to approximately the boiling point of the reaction mixture.

The reaction time required will be between 2 and 15 hours, depending on the starting compound (IV). - 50 The tautomers of general formulae (II) and (Ib) wherein R4 is a hydrogen atom may be separated by known methods, e.g. by column chromatography.

The compounds of general formula (Ic) can be 5 prepared by reacting a corresponding compound of general formula (Ia) wherein R4 is hydrogen and R6 represents the group -NHR8 and R, m, R5 and R8 are defined as in the desired compound of formula (Ic), with an aldehyde of general formula R9CHO (VI). R9 represents hydrogen or (C^j)alkyl. The reaction is appropriately carried out with a 30% aldehyde solution at elevated temperature. Preferably, the reaction is carried out with formalin solution in the presence of formic acid at reflux temperature.

The compounds of general formulae (Ib) and (Ic) may be subjected to subsequent reactions analogous to those described above for the compounds of general formula (Ia). Compounds of general formula (II) wherein R4 is (C1_4) alkyl may also be prepared from the corresponding compound of formula (II) in which R4 is hydrogen by formation of the quaternary ammonium salt thereof (for example by reaction with a (C14)alkyl iodide) and subsequent treatment with base (for example alkali). - 51 Example 1 2-(1,2,3,4-Tetrahydro-6-methylmercapto-1-isoquinolinyl)N-(1-pentyl)-hexanamide 2.5 g of 2-(3,4-Dihydro-6-methylmercapto-lisoquinolinyl)-N-(1-pentyl)-hexanamide are mixed with 0.5 g of NaBH4 in 100 ml of methanol in batches and the resulting mixture is stirred for 3 hours at ambient temperature. After the reaction has ended, any excess NaBH4 is destroyed, the solvent is removed in vacuo and the residue is distributed between CH2C12 and water.

After the organic phase has been dried over anhydrous sodium sulphate, the mixture is concentrated by evaporation and the residue is crystallised from ethyl acetate/petroleum ether.

M.p. 95°C Example 2 Ethyl 2-(1,2,3,4-tetrahydro-6-methylmercapto-l20 isoquinolinyl)-hexanoate hydrochloride. g of ethyl 2-(3,4-dihydro-6-methylmercapto-lisoquinolinyl)-hexanoate are combined with 5.2 g of solid NaBH4, added in batches, in 200 ml of boiling ethanol and the mixture is stirred at boiling temperature. After the reaction mixture has been worked up the hydrochloride is formed and crystallised from ethanol/ether.

M.p. 123°C Example 3 Ethyl 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-lisoquinolinyl)-hexanoate hydrochloride g of ethyl 2-(3,4-dihydro-6,7-dimethoxy-lisoquinolinyl)-hexanoate are catalytically hydrogenated in 600 ml of ethanol, with the addition of 17 g of - 52 concentrated HC1, in the presence of 6 g of Pto2 at 20 °C and hydrogen at 5 bar. After the catalyst has been removed, the reaction solution is evaporated down and the product is crystallised by the addition of ether.

M.p. 141-145’C Example 4 Ethyl 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methy1-1isoquinolinyl)-hexanoate hydrochloride A mixture of 12 g of ethyl 2-(l,2,3,4-tetrahydro6,7-dimethoxy-l-isoquinolinyl)-hexanoate, 33 g of formalin (30%) and 16 g of formic acid (98%) is heated to boiling for 1 hour. After the reaction mixture has been concentrated by evaporation, it is made alkaline with half-saturated soda solution, then extracted with CH2C12, the organic phase is washed with water, dried over Na2SO4 and evaporated down in vacuo. The reaction product is purified on A12O3 activity stage III (eluant CC14) and converted into the hydrochloride.

M.p. 156—157°C (ethanol/ether) Example 5 2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-l25 isoquinolinyl)-hexanoic acid hydrochloride .5 g of ethyl 2-(1,2,3,4-tetrahydro-6,7dimethoxy-l-isoquinolinyl)-hexanoate are heated to boiling in 100 ml of cone, hydrochloric acid for 1.5 hours. After the reaction has ended, the mixture is substantially concentrated by evaporation in vacuo and a diastereoisomer is crystallised by the addition of acetone (m.p. 180-183 °C) whilst the second diastereoisomer remains in the mother liquor. - 53 Example 6 2-(1,2,3,4-Tetrahydro-6-methylmercapto-l-isoquinolinyl) N-(1-pentyl)-hexanamide 3 g of ethyl 2-(1,2,3,4-tetrahydro-6methylmercapto-l-isoquinolinyl)-hexanoate are heated to boiling in 50 ml of n-pentylamine for about 14 hours. After the reaction has ended (monitored by TLC), any excess amine is removed in vacuo, the residue is taken up in CH2C12, extracted several times with water, the organic phase is dried over anhydrous Na2SO4, concentrated by evaporation and the residue is purified on silica gel (eluant CH2Cl2/MeOH = 100:3).

M.p. 95°C Example 7 2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-lisoquinolinyl)-hexan-N-[2-(2,4-dimethoxyphenyl)-ethyl]amide 2.58 g of 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-Nmethyl-l-isoquinolinyl)-hexanoic acid are stirred in 50 ml of anhydrous DMF with 3.2 g of N,N'-carbonyldiimidazole for 4 hours at ambient temperature. Then 3 ml of 3,4-dimethoxyphenylethylamine are added and after standing for 15 hours at ambient temperature the mixture is worked up. This reaction takes place without any structural change. If an isomer is used as the starting material, the corresponding isomer of the final compound is obtained.

Diastereoisomer 1: m.p. 94-96°C (ethyl acetate/ligroin) Diastereoisomer 2: m.p. 75-78’C (ethyl acetate/ligroin) Example 8 2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-l-isoquinolinyl)hexan-N-(2-phenylethyl)-amide-hydrochloride - 54 a) 2-[1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-(9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl]-hexanoic acid.

At 0°C, over a period of 30 min, a solution of 9.1 g 5 of 9-fluorenylmethyloxycarbonylchloride in 55 ml of dioxan is added dropwise to a mixture of 10.8 g of 2(1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinyl) hexanoic acid, 70 ml of 10% aqueous soda solution and 35 ml of dioxan. After the mixture has been stirred for 1 hour at 0’C it is left to stand for 15 hours at ambient temperature, then poured onto 1000 ml of ice water and extracted 3 times, each time with 100 ml of ether. The aqueous phase is adjusted to pH 2, the solid white precipitate is suction filtered and after being dissolved in CHCl3/MeOH (1:1), it is crystallised by the addition of petroleum ether.

M.p. 169-172°C. b) 2-[1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-(9-fluorenyl20 methyloxycarbonyl)-1-isoquinolinyl]-hexan-N-(2phenylethyl)-amide 2.65 q of 2-[1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-(9fluorenyl-methyloxycarbonyl)-1-isoquinolinyl]25 hexanoic acid are reacted in 15 ml of anhydrous DMF with 1 q of N,N'-carbonyldiimidazole. After 1 hour, an equivalent quantity of 2-phenylethylamine is added; after a further 15 hours at ambient temperature the mixture is worked up, purified over silica gel (eluant CHCl2/MeOH = 100:2) and crystallised from ethyl acetate/petroleum ether.

M.p. 168-170°C. c) 1.5 g of 2-[1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-(935 fluorenylmethyloxycarbonyl)-1-isoquinolinyl]-hexan-N(2-phenylethyl)-amide are stirred in 30 ml of a mixture of trifluoroacetic acid and anisole (1%) for - 55 15 hours at ambient temperature. After the removal of the solvent, the residue is distributed between CH2C12 and a 10% sodium carbonate solution, the organic phase is washed with water, dried over Na2SO4, concentrated by evaporation, the hydrochloride is formed and crystallised from ethanol/ether.

M.p. 154-156°C.

Example 9 Ethyl 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-lisoquinolinyl)-butyrate hydrochloride a) Ethyl 2-(3,4-dihydro-6,7-dimethoxy-l-isoquinolinyl) butyrate methyliodide 0.35 g of 2-(3,4-dihydro-6,7-dimethoxy-lisoquinol inyl) -butyrate and 1 ml of methyliodide are heated to 60°C in 10 ml of an ethanol/nitromethane mixture (1:1) for 1.5 hours. After the reaction has ended (monitored by TLC) the mixture is evaporated down in vacuo and the residue is crystallised from ethanol/petroleum ether.

M.p. 183-185°C. b) 0.5 g of ethyl 2-(3,4-dihydro-6,7-dimethoxy-lisoquinolinyl)-butyrate methyliodide are stirred for 3 hours in 5 ml of ethanol at ambient temperature with 0.1 g of NaBH4. After the reaction has ended (monitored by TLC) the mixture is worked up in the usual way and the hydrochloride is formed.

M.p. 164-166°C Example 10 2—(1H-1,2,3,4-Tetrahydropyrido[3,4-b]indol-l-yl)-N-(235 morpholinoethyl)-acetamide-hydrochloride a) 2-(1H-3,4-Dihydropyrido[3,4-b]indol-l-yl)-N-(2IE 920451 - 56 morpholinoethyl)-acetamide g of 2-(3-indolyl)ethylaminocarbonylacetic acid-N(2-morpholinoethyl)-amide and 45 ml of POC13 are heated to 40-45 °C for 5 hours in 250 ml of an acetonitrile/benzene mixture (1:1). After the removal of the solvent and any excess POC13, the residue is distributed between ice water and chloroform, purified over A12O3 (eluant: CH2Cl2/MeOH=100:3) and crystallised from ethyl acetate/ether with the addition of ligroin 55-75°C. b) The product thus obtained in part (a) is reduced analogously to Example 1, the product is isolated and converted into the hydrochloride (title compound). M.p. 262—265°C - 57 Examples of Pharmaceutical Preparations a) Coated tablets 1 tablet core contains: Active substance of general formula I 30.0 mg Lactose 100.0 mg Corn starch 75.0 mg Gelatine 3.0 mg Magnesium stearate 2.0 mq 210.0 mg Method The mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatine solution through a screen with 1 mm mesh size, then dried at 40°C and passed through a screen again. The granulate thus obtained is mixed with magnesium stearate and compressed. The resulting cores are coated in the usual way with a coating applied by means of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax. b) Tablets Active substance of general formula I 30.0 mg Lactose 100.0 mg Corn starch 70.0 mg Soluble starch 7.0 mg Magnesium stearate 3.0 mg 210.0 mg - 58 Method The active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granulate is dried and intimately mixed with lactose and corn starch. The mixture is then compressed to form tablets weighing 210 mg. c) Capsules Active substance according to formula I 20.0 mg Lactose 230.0 mg Corn starch 40.0 mg 15 Talc 10.0 mcr 300.0 mg Method The active substance, lactose and corn starch are first mixed in a mixer and then in a grinding machine. The mixture is returned to the mixer, thoroughly mixed with the talc and mechanically packed into hard gelatine capsules.

Claims

1. Use of compounds of formula (I)

2. Use as claimed in claim 1 of a compound as defined in claim 1 wherein 3. 0 phenethyl or (C 5 . 8 ) alkyl group. 3 5 R 7 represents a hydrogen atom and R 8 represents a (C 4 _ 8 ) alkyl, phenyl or fluorophenyl group or a (C^j)alkyl group substituted by phenyl, - 64 dimethoxyphenyl, furyl, dimethylamino or hydroxy. 3 0 R 5 represents a (C 2 _ 5 ) alkyl or phenethyl group; and R 6 represents an ethoxy or an NR 7 R 8 group in which R 7 and R 8 , which may be the same or different, each represent a (C 2 . 4 ) alkyl group; or

3. Use as claimed in claim 1 or claim 2 of a c'ompound as defined in claim 2 wherein A represents a benzo group; R represents a hydrogen atom or a hydroxy, methoxy or methylthio group; or two adjacent substituents R together represent a group -O-CH 2 -O- ;

4. Use as claimed in any one of claims 1 to 3 of a compound as defined in claim 3 wherein represents a benzo group; represents 2 and the two substituents R are in positions 6- and 7-, the two R substituents, which - 63 may be the same or different, representing a hydrogen atom or a methoxy or methylthio group; R 4 represents a hydrogen atom or a methyl group; R 5 represents a (C 2 . 5 ) alkyl or phenyl(C,^)alkyl group; and R 6 represents an ethoxy or NR 7 R 8 group in which

5. Use as claimed in any one of claims l to 4 of a compound as defined in claim 4 wherein 5 m represents 1, 2 or 3; R 4 represents a hydrogen atom or a methyl group; R 5 represents a hydrogen atom or a (C 15 )alkyl, phenyl, 5 (a) A is an indolo group; R, ra and R 5 are defined as hereinbefore; R 4 represents a (C,_4) alkyl group; and R 6 represents a hydroxy, (C,.4) alkoxy or an -NR 7 R 8 group as hereinbefore defined; or (b) A is an indolo group; R and m are defined as 10 hereinbefore; R 4 represents a hydrogen atom; R 5 represents a hydrogen atom or a (C,., o ) alkyl, phenyl (C,_ 5 ) alkyl, (C,_ 4 ) alkoxy or -NHCOX group (wherein X is (C,_ 5 ) alkyl) ; and R 6 represents a hydroxy, (C,_ 4 ) alkoxy or -NR 7 R 8 group as

6. Use as claimed in any one of claims 1 to 5 of a compound as defined in claim 5 wherein R 4 represents a hydrogen atom; R 5 represents a (C 45 ) alkyl or phenethyl group; and R 6 represents an ethoxy or NR 7 R 8 group (in which R 7 and R 8 each represent a butyl group or R 7 represents a hydrogen atom and R 8 represents

7. Use as claimed in any one of claims 1 to 6 of a

8. Use as claimed in any one of claims 1 to 7 of a compound as defined in claim 7 wherein R 4 represents a hydrogen atom; R 5 represents a butyl or phenethyl group; and R 6 represents an NR 7 R 8 group (in which R 7 and R 8 each represent a butyl group or R 7 represents a hydrogen atom and R 8 represents a phenyl,

9. Use as claimed in any of the preceding claims of a compound as defined in any one of claims 5 to 87 wherein m represents 2; and both R substituents represent a 35 methoxy group and are located in positions 6- and,7-. 10. Physiologically acceptable acid-addition salt thereof.

10. Use as claimed in any of the preceding claims of a - 65 compound as defined in any one of claims 5 to 9, wherein R 6 represents an NR 7 R 8 group in which R 7 represents a hydrogen atom and R 8 represents a group -CH(CH 3 ) (ch 2 ) 3 ch(ch 3 ) 2 . 10 a (C 58 )alkyl, phenyl or fluorophenyl group or a (C V2 )alkylphenyl group, the phenyl ring being optionally substituted by 2 methoxy groups). 10 R 7 and R 8 , which may be the same or different, each represent a (C 2 . 5 ) alkyl group; or R 7 represents a hydrogen atom and R 8 represents a (C 4 8 ) alkyl group, a phenyl or fluorophenyl group, or a (C 13 ) alkyl group substituted by hydroxy, 10 phenyl(Ο ν5 )alkyl or (C V4 ) alkoxy group; R 6 represents a (C,. 4 ) alkoxy group or an -NR 7 R 8 group, in which R 7 and R 8 , which may be the same or different, each represent a (C 15 ) alkyl group; or R 7 represents a hydrogen atom and R 8 represents a C 3 -alkenyl or -alkynyl group, a phenyl or fluorophenyl group, a (C V8 ) alkyl group or a (C^j)alkyl group substituted by a hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino or phenyl group or by a phenyl group which is mono- to tri-substituted by hydroxy or methoxy; or R 7 and R 8 together with the nitrogen atom to which they are bound represent a pyrrolidinyl, morpholino or piperazinyl group. 10 R 7 and R 8 together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl ring, the piperazinyl ring being optionally N-substituted by a methyl, unsubstituted phenyl, mono- or di15 (C 14 ) alkyoxyphenyl, pyrimidinyl or phenyl (C 14 ) alkyl group] ; or 10 wherein A represents a benzo, thieno or indolo group; R represents a hydrogen or halogen atom, a

11. 11. Use as claimed in any one of claims 1 to 5 of a compound of formula CH^S 1 .NH R 6 R 5 0 wherein R 5 represents a group -(CH2)3CH3 and R 6 represents an ethoxy or -N(H) (CH2) 4 CH 3 group.

12. Use as claimed in any one of claims 1 to 5 of a compound of formula wherein R 5 represents a group -(CH 2 ) 3 CH 3 and R 6 represents a group -NHCH(CH 3 ) (CH 2 ) 3 CH (CH 3 ) 2 or -NH(CH 2 ) 2 H^ ; or R 5 represents a group -(CH 2 ) 4 CH 3 and R 6 represents a group - 66 R 5 represents a group C6H5(CH2)2~ and R 6 represents a group N[ (CH2) 3 CH 3 ] 2 , -NHCH(CH 3 ) (CH 2 ) 3 CH(CH 3 ) 2 , -NH(CH 2 ) 2 C 6 H 5 or -NHC 6 H 5 5

13. Use as claimed in claim 1 or claim 2 of a compound as defined in claim 2 wherein A represents a thieno group and R represents a hydrogen atom.

14. Use as claimed in claim 13 of a compound as defined 10 in claim 13, wherein R 4 represents a hydrogen atom or a methyl group. 15. Phenyl or phenethyl group.

15. Use as claimed in claim 13 or claim 14 of a compound as defined in claim 13, wherein R 5 represents a 15 compound as defined in claim 6 wherein R 4 represents a hydrogen atom; R 5 represents a (C 4 . 5 ) alkyl or phenethyl group; and R 6 represents an ethoxy or NR 7 R 8 group (in which R 7 and R 8 each represent a butyl group or 15 dimethylamino, furyl, phenyl or dimethoxyphenyl. 15 hereinbefore defined; and salts thereof with a pharmaceutically acceptable acid in the preparation of a medicament for use as an agent for neuroprotection or repair or as an agent for 15 (C 1 4 )alkyl, hydroxy, (C v4 ) alkoxy, amino, methylthio, methanesulphonyloxy or methanesulphonamido group; or two adjacent R substituents together represent a group -O-CH 2 -O- or -O-CH 2 -CH 2 -O-;

16. Use as claimed in any one of claims 13 to 15 of a compound as defined in claim 13, wherein R 6 represents an -NR 7 R 8 group as defined in claim 2.

17. Use as claimed in any one of claims 13 to 16 of a compound as defined in claim 16, wherein R 7 represents a hydrogen atom or a methyl or ethyl group and R 8 represents a methyl or ethyl group optionally

18. Use as claimed in any one of claims 13 to 16 of a compound as defined in claim 16, wherein R 7 and R 8 together with the nitrogen atom to which they are 30 attached represent a morpholino group.

19. Use as claimed in claim 1 or claim 2 of a compound as defined in claim 2 wherein A represents an indolo group.

20. Use as claimed in claim 19 of a compound as defined in claim 19 wherein R 4 represents a hydrogen atom; R 5 - 67 represents a hydrogen atom or a phenyl group; and R 6 represents a (C 12 ) alkoxy or -NR 7 R 8 group as defined in claim 2. 5 20 R 7 represents a hydrogen atom and R 8 represents a phenyl, p-fluorophenyl, benzyl, phenethyl or (C 5 8 ) alkyl group). 20 A represents a benzo group; m represents 2 and the two substituents R are in positions 6- and 7-, and either both substituents R represent a methoxy group or one substituent R 20 the treatment of neurological disorders. 20 R 4 and R 6 together represent the group 20 m represents 1 or 2 and may additionally represent 3 if A is a benzo or indolo group; R 5 represents a hydrogen atom, or a (^. 10 ) alkyl, phenyl, phenyl(C^g)alkyl, (C V4 )alkoxy or -NHCOX

21. Use as claimed in claim 19 or claim 20 of a compound as defined in claim 20, wherein R 6 represents an -NR 7 R 8 group, in which R 7 represents a hydrogen atom and R 8 represents a unsubstituted (C V4 )alkyl group or a (C 12 )alkyl group substituted as defined in claim 1.

22. Use as claimed in any one of claims 19 to 21 of a compound as defined in any one of claims 19 to 21, wherein U and V each represent a hydrogen atom. 15

23. Use as claimed in claim 19 of a compound as defined in claim 19, wherein U and V together represent a bond, R 5 represents a hydrogen atom and R 6 represents a group -NHCH 2 CH(CH 3 ) 2 or -NH(CH 2 ) 2

24. Use as claimed in claim 1 of a compound as defined in claim 1, wherein R 4 and R 6 together represent a group -R' N•R / R 8 and R 9 are as defined in claim 1; and U and V each represent a hydrogen atom.

25. Use as claimed in claim 24 of a compound as defined 35 in claim 24, wherein A, R, m, R 5 and R 8 are defined as in any one of claims 3, 13, 15 and 17. 25 substituted by a morpholino or thienyl group. 25 represents a methylthio group and the other represents a hydrogen atom; R 4 represents a hydrogen atom or a methyl group; 25 A, R, m, U, V and R 5 are as defined in claim 1; R 4 represents a hydrogen atom or a (C,_ 4 ) alkyl group; and 30 R 6 represents a hydroxy, (C,. 4 ) alkoxy or -NR 7 R 8 group as defined in claim 1. 25 [in which R 8 represents a hydrogen atom, a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group, a branched or unbranched (C 3 . 6 )alkenyl group, a branched or unbranched (C 3 . 6 ) alkynyl group or a 30 branched or unbranched (C V12 )alkyl group (in which the alkyl chain may be substituted by one or more of the following substituents: a hydroxy, (C V4 )alkoxy, di(C V4 )alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl 35 or phenyl group or a phenyl group which is mono- or poly-substituted by hydroxy, methoxy or fluorine; and R 9 represents a hydrogen atom or a (C^j)alkyl - 61 group]; and U and V each represent a hydrogen atom or U and V together represent a bond if either 25 group (wherein X represents (C v5 )alkyl); R 4 represents a hydrogen atom or a (C v4 )alkyl group; R 6 represents a hydroxy, (C V4 ) alkoxy or -NR 7 R 8 group 30 [in which R 7 and R 8 , which may be the same or different, each represent a hydrogen atom, a branched or unbranched (C 3 _ 6 ) alkenyl group, a branched or unbranched (C 36 )alkynyl group or a branched or unbranched 35 (C 1l2 ) alkyl group (in which the alkyl chain may be substituted by one or more of the following substituents; a hydroxy, (C^)alkoxy, - 60 di (C^) alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl or phenyl group or a phenyl group which is mono- or polysubstituted by hydroxy, methoxy or fluorine); or R 7 represents a hydrogen atom and R 8 represents a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group; or

26. Use as claimed in claim 24 or 25 of a compound as defined in claim 24 or claim 25 wherein R 9 represents a hydrogen atom. 5

27. A method of assisting neuroprotection or repair or of treating neurological disorders in a human or nonhuman animal subject which comprises administering to said subject an effective amount of a compound of formula (I) as defined in any one of claims 1 to 26 or a

28. Each and every novel method and use hereinbefore described.