September 1968
~ I U S C LRELAXAXT E ALKYLSULFONYLBENZAMIDES a m -ISOQUIXOLINES
1023
Synthesis and Muscle-Relaxing Activity of 0-, m - , and p-Alkylsulfonylbenzamides and Related Isoquinoline Derivatives 11. s. CHODNEKAR
AXD
J. E. BLUJI
Research Department of F . Hoffmann-La Roche and Conzpany Ltd., Bade, Switzerland Received January 22, 1968
This report is primarily concerned with the synthesis and pharmacological properties of the alkylsulfonylhenzamides and related isoquinoline derivatives. Thirty-three alkylsulfoiiylbenzene derivatives of series A and B were synthesized and screened for possible pharmacological activities. In both series, 13 compounds showed sigiiificaiit niiiscle-relaxant properties. The most active were p-isopropylsulfonyl-X-isopropylbenzamide ( 3 ) belonging to series A, and 3,4-dihydro-l-[p-(isopropylsulfoiiyl)pheiiyl] -6,i-dimethoxyisoquinoline(25) beloiiging to series B. They also possess ariticoiivrilsant’ properties. The muscle-relaxing effect of both compounds is of the same order as that of chloromezarione,l blit much weaker than that of diazepam.*
During the course of studies 011 alkylsulfonylbenzene derivatives, two series of compounds were synthesized arid screened for their pharmacological activity: (i) 24 benznniides of the general formula A (Table 11), and (ii) nine related 1-[p-(alkylsulfonyl)phenyl]isoquinoline derivatives with the skeleton B (Table 111).
CONjR’
R*& :
=?
SCHEME I
3
&SH
&$JR
I
I1
COOH
COCl
&SO2,
A
&S02R
111
w
S02R
A
B
Several members of both series exert more or less pronounced muscle-relaxing and anticonvulsant activity. Two of them, p-isopropylsulfonyl-S-isopropylbenzamide (3, Table 11) and 3,i-dihydro-1- [p-(isopropylsulfonyl)pheriyl]-G,7-dimethoxyisoqui1ioli1ie(25, Table 111) were found to be the most active. Their effect is of the same order as that of chloromezanone and about half of that of chlorodiazepoxide. S o simultaneous sedation is observed. Further investigation has shown 3 and 25 to possess distinct anticonvulsant properties; they do not notably influence blood pressure and have no analgetic effect. The two compounds described earlier, isopropyl phenyl sulfone3 (22) and S-is~propylbenzamide~ (23), were compared with 3 and were found to possess no muscle-relaxing effect, indicating that the presence of both the “isopropylsulfori~,l”and “N-isopropyl” groups is probably responsible for the activity of 3. Chemistry.-Synthesis of the various compounds was effected by using o-, m-. and p-thiocresols (I) as the starting materials (Table I). S-Alkylation6 gave alkylthiocresols (11) which were oxidized by Ictivr claw (EDdu)was t h e clobe nhich caused suficietit rclautioii t o reduce by half the time the ariinial could ni:iiritaiti its position on the “rotating rod.” .\ti c.stini:itv of the lethal doye ( I D j o ) w:is obtainecl u\itrg otic inoilst’ (female or male, 1s 22 g) per dose. T I i ( ~r:ttio I,D,,, EDio gives : L I ~ estimate of the thempeutic raiige i i i thi5 acute test. T ~ x b l c ~IV 5 :itid Y sliou that of the 33 compounds (I, I:% exert :I more or l e s pronounced muscleing actlvitj in the do5e.i tehtetl. The activity is i n i i c ~ l i R c d L ( > rthaii that of diazepam, :itid the themprutic: riiiige i5 w~allcr. In general, the effect \vas oht : i i i i d sifter 30 m i l l :tiid 1:iitetl for about 3 hr. Compouiicl- 3 :itid 25 ncrc’ particularly active; hut because of i t - higher :tc.utc touicit;, the therapeutic range of 25 is wi:ill~r Tlic moic.l(~-rc~lasiiig effect \vas confirmed i i i Thirty minutet l i c , ?:it (fcnialt~:itid m:ili%, 2 3 kg). :iftvr or:d ~ i c l t i i i i i i s t r : t t i ~ iof i 100 mg, kg of preparatioii 3 or 25, muwle whuitioti becnnie :ipp:irent and w:i. lnal~l\ctl:titer 1 hr. (b) Sedative Effect.-- Preparatiotis \iith hypiioticscd:tliv(i propertic. ;I~.(J curtail the time a mouse call r c ~ ~ i i : i i ioi i i the 1vt:itiiig rod. III the t \ \ o compounds. 3 arid 25 producing thc moit marked muscle relaxation. I ~ ~ ( J I c1et:uled V Ytudieh excluded the possibility that :i 4 : i t i v c4’ect ~ \\ :t- re\poii\ible fc i I ~the muscle relaxation tweauhc the\ did iiot potentiate subthreshold doses of tAth:rtiol (T:ible 1-1). Sedation \\as obtained n i t h 3 ( J I I I J 111 thc high ( ~ r adose l of 300 mg kg and nith 25 I l l :I I;)
5llghtlJ l(J\\er
(10-C.
I 1 I ( IarhP II t3 Lillrsliir ani1 66, l i i l ( 1 ~ 4 i i i
Y
Z
\\ri%Iiaii~
J
4 m C‘hrm
(c) Anticonvulsant Effect.- 111the rlectrchhocb l w t ’ i n the mouse, 3 :tnd 25 showed ariticc~~ivuli:ttitpropc’i ties both for threshold corivulsioiih (minimal shock) n i i d maximal convulk)iii (niuximnl .hock). T a h k VI I \lio\vs that the relatively potoiit ctffect of 3 againqt m:n]mal electric shock in the nioiiw (indicating cffic:ic~ against grand mal typt izurc5) could be confirmrd i i i the cat. This T\:L\ riot so f ~ i th(. \waker 25. .It L: tiosc. of 300 mg ILg p o preparation 3 g:iv(~ f i d l protection :ig:rinqt coiiviilsioii- produced ti) i i i t r:ivenous injectioii of p c w ~leirrtc~trnzolc~;“ ,~ I I O tonic. ntension of the h i d limb\ occurrc~l111 ten niiccl ( f ( m : i l ( ~ , 19-21 g) ; with 100 mg lLgP O , : h o s t twice the p e i i t ~1rnetetrnzole dose h:id to hr infuwl. ;\ccortliiig to th(> classical nwthod, i after i~itrayritoiie:iIiiijcctioir of :i lethal conceiitr:itioti of pent!-leric.tetrazole i i i h:ttchc- 01 tell mice prr (lose (female :uid mnle, %-2h g), .io% suiviva1 \v:is :ttt:iiti(d with kh0 mg hg PO of 3. Thii. :I clear aiit:igoni.m agai tist pen( ylciietetr:u”~ cffec t \ \\ : i i ohtained 01113 at sctiatiw dosoh :I\ referrcd t o :it i o v ~ . g hg p o of 25, twice the pent\ leiic>required to produce tonic exteiisioti I’sitig tlic classical method of intraI)eritonenl iiijcctioti of i t Icthal c~)iicentrationof p c ~ t i t ~ ~ l twctetrazolc iteii iiiicc per c l o ~ t ~ )507/, , Yiirvival \\:I. kg. ?’hi\ c1o.e i- :11-o i i r t ssure. Alpart ti.oiii :t 4iglit initial hypoteiisivc txffe>ct uf 3 mg kg iv of 25 i i i : t i i c + thetized c:ith (femiile :ind male, 2-3 kg) :uid :I h i i l a i effect :it :HI oral (lost>of 30 mg kg in the noti:iiiestli~~tiz~~~l hypertensive rat t11(1hloiid prcshure I\ as not iiotic(>:thl> affected by oral do [ i f up t o 50 mg kg of 3 :itid lip t o 100 mg kg of 25. cithc>runder the :iboVe-IIieiitioii(~d coiiditiony o r iri t h c , uti:iiie.tlit~tized cat nith c.:irot itl artery loop (van I,c~r.uim) ~
1023 TABLE I1 a-, m-, AND ~-ALKYLSULFONYLRENZ.IMIDES
XO.
1 2
NRIR?
R
CH( CIIa), CH(CI13)2
N IIZ KHCH,
Position of alkylsulfonyl Yield, group 7%
P P
P
3 4
in
63 70
168-170 128-1 32
82 41
136-138 122-124 113-1 17
SHCH(CH3h
NHCII&H=CH:! SHCHzCHtOH 10 I1
13 14
CHI CI&
NHCII(CH?)z ?;(CJI,)2
21
CH(CHa)z
NHSHCH(CHr)z
22 23
CH(CII3)z
(COSRiRz = H) S H C H (CH,),
(SOzR
=
H) 24 C1 SHCII(CH3)z a The reartion was carried out below 0".
Crystn solvent
EtOB EtOIIEt& EtOH Et &pe t I' ether CsH-petr ether EtOIl EtrO-pet,r ether CsH6 EtOIlEtrO EtOIl
Method
Formula
.Inals?ies
C,~H,~NO~S CiiII,,NOaS
c, 11, N, d c, ir, s
1)
CIIII1',XO,d ClrHl,,XOrS
c, II, s c, IJ, s
I)
C13H,!,N08S
c, Ir, s
u
C,,II,I?U'OIS CIJT,INOIS
C, €I, N, S II, S
CuIInN03S CisHi,SO&
c, €Ij s c, Ir, s,s
1)
C1,H,1SO:3S clsII,6?\T,o,Y
c, Ir, s c, rr, s,s c, 11, T,s c, Ir, N , s
1)''
1)
0
62 35
129-131 88-90
P P
71 61
126-127 106-10T
P
P
68 44
149-131 207.9 (0.04)
P
5,5
150-152
EtOIl
L,
Clr,II,,NO1S
P P
84 61
185-187 67-69
EtOH EtSO-petr ether
u
C1lIII,?;O~S CIJ~I~NO~S
P
49
98-99
i-PrOHi-PrzO
C, H, S
P
44
145-147
EtOH
c, 11, N, s
P P P
6.5
P
75
120-122
P
81
119-121
EtOH MenCO H20EtOH CsHs-petr ether CtiHs-petr ether
C, II, e, Ir,
98
203-206 244-246 182-184
70 62
133-155 (14) 98-101
H,O
40
142-145
CtiHs
P
6 7
Bp (mm) or mp, OC
P
54
* The reaction solvent mas CtiH6.
(e) Analgetic Effect.-'(Writhing" (pain produced in the mouse by intraperitoneal injection of dilute AcOH) was not significantly reduced by either 3 or 25, in groups of four animals at various dose levels, Experimental Section Melting points and boiling points are uncorrected. Where analyses are indicated only by symbols of the elements or functions, analytical results obtained for those elements or functions were within f 0 . 4 7 , of the theoretical valiies. Analyses, yields, melting points, boiling points, and other relevant data are recorded in Tables 1-111. Method A. p-Isopropylthiocresol or p-Thiocresol Isopropyl Ether (a).-To an EtOH solution of KaOEt prepared from 4 a (23 g, 1 g-atom) and absoliite EtOH (600 ml) was added dropwise with stirring p-thiocresol(124 g, 1 mole). The mixture was stirred for 1 hr at room temperatiire and then i-PrI (170 g, 1 mole) was
U
u E
ll
c,
c, Ir, s
c1, s ci, IU, J c, 11, s,s
c, 11, s c , €1,
CJI,,02S ClOHiINO
s
c, I€, s c, 11, s
c, 11, e1
added drop by drop with stirring and maintaining the temperature of the reaction below 30" during addition. After refluxing the mixture for 5 hr, the solvent was distilled off under reduced pressure. The resulting residue was decomposed with H20 (300 ml) and extracted (EtkO, three 150-ml portions). The combined etheral extract was washed (HzO, lOyc S a O H , HsO, 10% H*SOa, HzO). After drying ( NapSOa)the ether was evaporated to dryness to give a yellowish oil which was distilled in a high vacuum. Method B. p-IsopropylsulfonylbenzoicAcid (e).--4 mixture of p-isopropylthiocresol (49.8 g, 0.3 mole), KlInO4 (190 g, 1.2 moles), 10% NaOH (30 ml), and H2O (1.5 1.) was refluxed on an oil bath for 3 hr. After cooling, the reaction niixtiire was decolorized with 407, aqueous NaHSO3 (1.3 l.) and filtered. The residue was washed (HzO) and the washings were combined with the filtrate, which on acidification wit.h concentrated HCI gave a white crystalline precipitate. Method C. p-Isopropylsulfonylbenzoyl Chloride (i).-pIsoprop~lsiilfon~lhenxoic acid (10 g) was mixed with dry T H F
Nu.
2 .5
:IO-liO
2
fi0
:io '00 >::00 >:~Oo >::I10
120 >:300
> 100 300 230 >YO0
> 100 100
'I
September 1968
I I U S C L E RELAXANT .ALKPLSULFONYLBENZhMIDES A S D -1SOQUIKOLISES
Method ii.-p-Isopropylsulfonylbenzoic acid (30 g), EtOH (200 ml), and concentrated H2SOd (15 ml) were refluxed together for 5 hr. After distilling the solvent under reduced pressure, the residue was treated with a mixture of C H d X (100 ml) and H 2 0 (50 ml). The CHzClz solution was once again washed (HzO) and dried (NaZSOA), and the solvent was removed by distillation. The residual oil was distilled in a high vacuum, giving a product identical with the above; yield 28 g. Anal. (CizHi~Od3)C, H, S. p-Isopropylsulfonylbenzamide (1 ).-p-Isopropylsulfonylbenzoyl chloride (crude) prepared from p-isopropylsulfonylbenzoic acid (20 g ) was mixed with 28% NHlOII (50 ml) and the mixture warmed on a water bath for 30 min. The reaction mixture was then diluted (IISO, 200 ml) and the resulting solid was collected by filtration. I t was dissolved in EtOH, treat,ed wit,h charcoal, and filtered. The filtrate on cooling gave needles. Method D. p-Isopropylsulfonyl-N-isopropylbenzamide ( 3 ) ~ To a solution of p-isopropylsulfonylbenzoyl chloride (37 g, 0.15 mole) in dry Et20 (250 ml), was added with stirring a solution of isopropylamine (120 g, 0.75 mole) in dry Et20 (200 ml) drop by drop, maint,aining the temperature of the reaction mixture during addition below 15'. After the addition was complete, st,irring was continued for another 2-3 hr below 20' and then the solution stood at, room temperature overnight. The white solid was collected by filtration, washed (EtzO), and dried. It was then mixed with H,O (800 ml), thoroughly stirred, filtered, and recrystallized. Method E. N-(2-Hydroxyethyl)-p-(isopropylsulfonyl)benzamide (I)).-This reaction was carried out in T H F instead of ether under identical conditions as for 3. T H F was removed and the gummy residue was treated wit,h CHzCl, (200 ml), t'he CH&!2 soliition was washed with dilute HC1 (25 ml 1 dried (Na?SO4), and evaporated to dryness, and the gummy product crystallized. N-[ 2 4 Diethy1amino)ethyll -p-( isopropylsu1fonyl)benzamide (11).-.4t the end of t,he reaction of p-isopropylsulfonylbenzoyl chloride and diethylaminoethylamine carried out in Et20 under identical conditions as for 3, ether was evaporated to dryness. The residue was t,reated with 1 S HC1 and EtzO. The acidic soliit,ion F a s separated, made alkaline with 28% NH*OK, and extracted (EtsO). After washing (HZO) and drying (NazSO4) ether was evaporated to give a thick oil, which was distilled under high vacuum. The oxalate prepared in ethereal solution was recrystallized from EtOH-EtZO, mp 116-118". Anal. ( C ~ G H Z ~ N ~ O ~ S .C,H H, ~ CN, ~ OS. ~) p-(1sopropylsulfonyl)benzhydrazide (19).--A mixture of the stoichionietric proportions of ethyl p-isopropylsulfonylbenzoate (44.0 g) and hydrazine hydrate (44.0 g ) was heated on a water bath at, 80-100" for 2 hr. Then the reaction mixture was cooled, diluted with H 2 0 (50 ml), and filtered. The solid was washed (H?O), dried, and recrystallized. p - ( Isopropylsulfonyl)-N'-methylbenzhydrazide( 20).-Stoichiomet,ric proportions of et,hyl p-isopropylsulfonylbenzoate (10.0 g) and methylhydrazine (10.0 g) were initially warmed together at 80" in the presence of EtOH (10 ml) for 1 hr and then refluxed for 3-4 hr. The pale yellow clear solution was evaporated under reduced pressure, and the residue was dissolved in C6H6 (30 ml), treated with charcoal, and filtered. T o t,he filtrate was added petroleum ether until turbidity developed and on cooling a pale yellow solid was formed. The hydrochloride was prepared in Et,OH; white cryst>alline salt., mp 240-243'. -4nal. (C11HleNzO,S.HCl) C, H, C1, S. N'-Isopropyl-p-( isopropylsulfony1)benzhydrazide ( 21 ).-p(1sopropylsulfonyl)benzhydrazide (30.0 g) in hIezCO (300 ml) and absolute EtOH (300 ml) was hydrogenated (PtO2, 300 mg) until no more Ht was taken up (24 hr). The catalyst was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure, to give a solid residue which after treatment with charcoal in CsH, and addition of petroleum ether t,o turbidity gave colorless crystals. p-Chloro-N-isopropylbenzamide (24).-p-Chlorobenzoyl chloride (crude) obtained from p-chlorobenzoic acid (31.3 g) was dissolved in CsH, (100 ml) and t.o the resulting solution iso-. propylamine (40 g ) in C ~ H (50 G ml) was added dropwise with stirring under 10". After stirring for another 2 hr at room temperature, the solvent was evaporated to dryness. From the residual solid a neutral fraction was isolated by ext,raction as the desired product. 1 [ ( p-Isopropylsulfonyl)phenyl]-6,7-dimethoxy-3,4-dihydroisoquinoline (25).-To a suspension of N-(B,B-dimethoxy-
-
1027
phenethy1)-p(isopropylsulfony1)benzamide (25 g) in CsH, (250 ml) was added cautiously a t room temperature POCh (23 ml) and the mixture was gradually refluxed for 3 hr. From the clear solution, a yellow precipitate separated out. The solvent was removed by distillation under reduced pressure. The residne was carefully dissolved in MeOH and to the methanolic solution Et20 was added until turbidity developed and a yellow crystalline solid wae formed, mp 226-226". Anal. ( C ~ O H Z ~ N O ~ S .C, HC~) H, C1, S. This was dissolved in H,O and made alkaline with NHaOH, when a colorless solid precipitated out. 1,2,3,4-Tetrahydro-l- [( p-isopropylsulfonyl)phenyl]-6J-dimethoxyisoquinoline (26).--NaBHh (.5 g) was added in portions with stirring to 3,4-dihydro-l-(p-isopropylsulfonyl)phenyl-6,7dimethoxyisoquinoline hydrochloride ( 10 g) in AIeOH (100 ml) at a temperature below 10'. After the addition was complete, the reaction mixture was left standing overnight' at room temperature, the solvent was removed by distillation iinder reduced pressure, and the residue was treated with CHQC12 (100 ml) and dilute HCl (150 ml, 1 iV). The acidic solution was separated, made alkaline with 28% NHIOH, and extracted (CHzC1,). A f k r washing ( H 2 0 ) and drying (Na2S04),CHZC1, was removed to give a colorless oil which was recrystallized. The hydrochloride was prepared in EtOH, mp 238-239". Anal. ((& H,,NOaS.HCI) C, H, C1, S. 1,2,3,4-Tetrahydro-l- [ p - (isopropylsulfonyl)phenyl]-6J-dimethoxy-2-methylisoquinoline (27) and Hydrochloride.-1,2,3,4Tet'rahgdro - 1- [( p -isopropylsulfonyl)p 11 -6,i-dimethoxyiso), and formaldehyde quinoline (15 g), formic acid ( 1 5 ml, (22.5 ml, 40%) were mixed together and heated at 100" for 3 hr. The mixture was then evaporated under reduced pressure and the resulting residue was treated with dilute HC1 (75 ml, 1 A'). This was washed (EtnO, 50 ml), made alkaline with 28% NHIOH, and extracted(CHzC12). hfkrwashing (HSO) and drying (Xa2SOa), CH&h was removed by distillation under reduced pressure when a yellowish oil was obtained. The hydrochloride was prepared in Et20 and recrystallized. 2-Acetyl-1,2,3,4-tetrahydro-l[ p - (isopropylsulfonyl)phenyl] 6,7-dimethoxyisoquinoline (28).-1,2,3,4-Tetrahydro-l-[p-(isopropylsulfonyl)pheny1]-6,7-dimethoxyisoqninoline (10 g) was dissolved in pyridine (40 ml) and to t'he clear solution Ac20 (40 ml) was added at room temperature. The mixture was allowed to st'and overnight, the excess pyridine and AcnO were removed by distillation, and the residue ( a brown oil) was decomposed with ice-cold H20 (60 ml). It was then extracted (CH2C12)which after washing (H20, dilute HC1, and HsO) again was dried (SaSOa) and evaporated to dryness under reduced pressure. The resulting residue was recryst,allized. 3,4-Dihydro-1- [ p-( isopropylsulfonyl)phenyl]-6,7-isoquinolinediol Hydrobromide (29).-1- [(p-Isopropylsulfonyl)phenyl]4 7 dimethoxy-3,4-dihydroisoquinoline ( 5 g ) was mixed together with glacial AcOH (25 ml) and HBr (20 ml, GOYo) and the mixture was refluxed for 7 hr and then evaporated to dryness under reduced pressure. The residual solid was t,reated wit,h EtOH (25 ml) and filtered. The filtrate was discarded and the solid was recrystallized. 1,2,3,4-Tetrahydro-l- [ p - (isopropylsulfonyl)phenyl]-6,7-isoquinolinediol (30).-1,2,3,4-Tetrahydro-l-[p-(isopropylsulfonyl)phenyl]-6,7-dimethoxyisoquinoline( 11 g) was mixed with glacial AcOH (60 ml) and HBr (80 ml, 60y0) and heated at, 125" (bath temperature) overnight'. It, was then evaporated under reduced pressure and the residue was dissolved in dilute HC1 (75ml, 1 A-), The acidic solution was made alkaline (KHaOH) and extract,ed (CH2C12). After washing (HSO), drying (NaaSOa), and removing the solvent, the residue was recrystallized. The hydrochloride was prepared in EtOH; mp 165-170" dec. A,na(. (C18H9,NOiS.HC1) C . H. C1. N . S. 3,4-Dihydro-l- [ p - (isopropylsulfonyl)phenyl]-6,7-( methylenedioxy )isoquinoline (31).-To a suspension of p - ( isopropylsrilfony1)S-[(3,4-methylenedioxy)phenethyllbenzamide (95 g ) in CGH, (950 ml), POC1, (150 ml) was added at 20" and in about 13 min. The mixtiire was then gradually refluxed for 4 hr, diiring which time a clear solution turned out into a siispension. .4fter cooling, the solid was collect,ed by filt,ration and dissolved in H 2 0 (800 ml) and t,he acid solution was made alkaline with 28% S H a O H and ext,racted (CH2Clz). After washing (H20) and drying (Xa2SOa), CH2Cl2 was removed under reduced pressure t,o give a solid. The hydrochloride was prepared in EtOH; mp 245-248' dec. 1,2,3,4-Tetrahydro-1- [p-(isopropylsulfonyl)phenyl] -6,7-meth-
-
I
,
,
