AU448024B2 - Phenylaklane derivatives - Google Patents

Description

2-(2,4-Dichloro-5-methylphenoxy)-5-chlorophenylthioacetmorpholide (14.Og, 0.032 mole), potassium hydroxide (14.0g) and methanol (140 ml) were heated under reflux for at least 48 hours (72 hours). The mixture was evaporated, water was added and the mixture was extracted with ether. The aqueous layer was then acidified with con- centrated hydrochloric acid and the product was extracted into ether. The other extracts were washed with water, dried and evaporated. The solid residue (10.5g, 93%) was 8 crystallised from light petroleum (B.p. 0-100 to give 2-(2,4-dichloro-5-methylphenoxy) 0 acid as colourless needles, m.p. 145-148 C. Anal. Calcd. for C15H1C1303 C, 52.1; H, 3.2; C, 30.8

Found C, 52.1; H, 3.25 C1, 30.2o%.

The overall yield of acid from 2, 5- dichloroacetophenone is 32%.

Page 7, lines 15, .18 and page 8 line 1, in each case after "in" insert "the preliminary" and delete appearing after "Example". Page 8, line 9, after "in" insert "the preliminary". Page 8, line 10 delete Page 10, line 14 and page 11, line 19 in each case amend to read Page 12, after line 24 commencing new paragraph insert the following:

The table sets out details of further examples of orthophenoxyphenylacetic acid derivatives which may be substituted at position 5' of the A ring and at positions 2, 3, 4, 5 or 6 of the B ring which were prepared by the procedures of the preliminary example or examples 1 or 2.

Page 13, cancel example 7. Renumber examples 8-27 as examples 7-26. Page 14, Example 10, in the "method" column amend to read Page 14, Example 11, in the "method" column amend to read Page 14, Example 12, in the "method" column amend to read Page 14, Example 13, in the "method" column amend to read'1 Page 14, Example 14, in the "method" column amend to read Page 14, Example 15, in the "method" column amend to read Page 14, Example 16, in the "method" column amend to read Page 14, Example 17, in the "method" column amend to read "Preliminary". Page 15, Example 18, in the "method" column amend to read "Preliminary". Page 15, Example 19, in the "method" column amend to read Page 15, Example 20, in the "method" column amend to read Page 15, Example 21, in the "method" column amend to read Page 15, Example 22, in the "method" column amend "4(r)'to read Page 15, Example 23, in the "method" column amend to read Page 15, Example 24, in the "method" column amend to read 1(f, Page 15, Example 25, in the "method" column amend to read Page 15, Example 26, in the "method" column amend to read Page 16 cancel lines 8, 15 and 18-21. P

Page 16 line 10 amend to read Page 16, line 11 after "of" insert "the Preliminary and delete after "Example". 7 in each case amend "thiomorpholide" to read Page 16, line 22 and Page 19, line "thioacetmorpholide". Page 17 cancel line 6. Page 17 line 12 amend to read

EDWD. WATERS SONS C.P.130

0 ,L~

(11) 448024

PATENT SPECIFICATION(21) 27,505/71 Class (52) 09.10; 87.16; 09.62-441.

Int. CI. (61) C07c; C07d;A61k.

Application Nlumber (21) 27505/71. LLodged (22) 8th April, 1971.

Complete Specification entitled (54) PHENYLALKANE DERIVATIVES.

Lodged (23) 8th April, 1971. Accepted (44) 18th April, 1974. Published (41) 12th October, 1972. Convention Priority (30) 14th April, 1970, Great Britain, 17832/70.

Applicant (71) RECKITT COLMAN PRODUCTS LIMITED.

Actual Inventor (72) KEITH ERNEST GODFREY.

Related Art (56) 26225/71 09.10.

The following statement is a full description of this invention, including the best method of performing it known to us: 19980/73-LX598 -92 -ND -28P. C. F. Atk,., en nt Pnt., Co, n F D t i s n Gv m e t p i t 'cner X598 -92 -ND -28P C.

27: 50 5,n phenylalkane This invention relates to for their production. The derivatives and to processes therapeutic compositions invention also relates to ingredient one or more of comprising as the active these phenylalkane derivatives. has-been in use Acetyl salicylic acid (aspirin) relief of pain and the for over 50 years for the In-the late 1950s alleviation of inflammatory states. discovery that stomach there was much interest in the bleeding could-occur in ulceration and gastrointestinal those patients patients taking aspirin, particularly states such as suffering from various inflammatory rheumatic fever rheumatoid arthritis, osteoarthritis, the treatment necessitated and ankylosing spondylitis in-which drug. Arylacetic acids have continued high dosages of the anti-inflammatory activity, been investigated extensively for introduction of Ibuprofen,- and t swork has led: to the- with other drugs such as for example. This drug in common is strongly ulcerogenic in Phenylbutazone and aspirin, now prepared'novel arylacetic animals such as rats. We have ortho phenoxy. phenylacetic acid derivatives, in particular activity-, acid derivati-ves, which possess anti-infl:am'atory a minimal extant only the and certain of whi.ch possess to' with known anti- .ulcerogenic side effects encountered

ifnlamima tory drugs. there are According to the present invention

provided compounds of the formula

4 8.0 2.4 2.

27, o0 /7

(CH 3n

1 R 2 is chlorine; R iis wherein R is hydrogen or methyl;

chlorine at positions 4 or 5, alkyl of from 1 to 6 carbon

atoms at position 4, trifluoromethyl at position 5 or

methyl at position 6; and n is 0, 1 or 2.

3 448,024

27,505i AdditionaLllYiwhen R3is chloxrinLe at position4, one 'or more R2 may also reptesent a methoxy lgrouP; and repl-aced boy chlorine6 'Substitueflts in the .mnofecure 'may bVe brominWe'. ar Pa pric ujAial pr' 'daspect the pres t *irvett-in .2-ch~r~'4~ai~Y p±~~.ide phenoxy )phenyl-

by methyl at :ac'etllc r-C&~id-i- which may -b'e optikdnally isdbti'tutbd. b-of Rinfg A and (,drhhohO thel'c- 'posit4Y'OPs :6t2.c id .v-hbOAch day '.be ii l.sji~bstituted 'ty one or "two -i-n 'Rihg B an4d ffefhtl -a ;-1ti Oh 'afir A.. mreth'.yl gr :m vh'ti!Cn -zalso -prvilas *he6rapeuiti'c c-ompa-sit, oris

;inative Forrhtxla -I 4n f Csociatn With -a phbajrMieutwftlay di l~dh~t 16-r Oie~~db~hd.~i S. ~'e9

the c-lo~fso~f 71?orYfiira T yS ire rrei ''Oy

i-n 'Wh-i-idh 'tgeth., ed-ffp n a± e !P~azs~a5 i 8=TbrMIT

'B~ f~~e bx of~ lesti0C j -h bpr f ~opb~c aY~non Frn

2r~ dIvC-C l

4,4 o 2 4

27, 5 05 nt which is thereafter transformed into a compound of Formula I

by treatment with sulphur and morpholine to form a thioacet-

morpholide of Formula V (CH 3 )n R

R B A V 2 R i CH CS

which is then hydrolysed.

5 4 48,024

Thii cojPer' cact~a1ysV used' in. ti& abdlb VeacV'ion' is'

prra~mb-lrk Coper' ini fiely, div~Ided f~rd-.'

Thie H3 drolys'id of the- thlioaceim6rph&1id6- is4 c6fe' "ufindr- basic'' co nd-l'i6,~ 5dt I but-

whe'tze ~iiereli a trifuoofith- sUbdtffudnt fri: tte;

mh-6'ta'-' idic' c6ndPi'ons may bd- riecessdae~r, for examnie it haiisi ,eeiir fouhd'- that -Methyl jheznylaceil aicid' mUs't, be, hydi-oiy'sed under

ff1e 'j ,iji6ii is iThrifher lilsU§fa-edl by i~i\,

w6§~f wi1 e&yiaaoi

4 48.024

27.5 05/71 in the presence of aluminium chloride by the method of

A.F. Dokukina, et al., Zhur. obshchei Khim, 1956, 26, 1651 (Chem.Abs 1957, 51 1886a). The product was a mixture containing about 70% of the desired methylacetophenone and 30% of the;isomeric 5-chloro-2- methylacetophenone, and'was used without separation of the isomers. This is satisfactory, since the minor component contains an unactivated chlorine atom (in contrast to the major component, the chlorine atom of which is activated by the orthoacetyl group) and is recovered unchanged after reaction of the mixture with a phenoxide. The chloromethylacetophenone mixture described above (33.7g, 0.2 mole) sodium 2-chloro-4-methylphenoxide (66 .Og; 0.4 mole), 2-chloro-4-methylphenol (14.25g, 0.1 mole) and copper catalyst (1,Og prepared as in Example 1 above) were stirred in a nitrogen atmosphere for about 24 hours at an internal temperature of 120-125*. The reaction mixture was worked up as in Example 1. Distillation of the crude product in vacuo afforded 11.2g of forerun, B.p. 60-137°C/0.3 mm (consisting largely of 5-chloro-2-methylacetophenone), followed by the desired 2-(2-chloro-4-methylphenoxy)-5- methylacetophenone (27.3g, 71% yield based on amount of present in the original mixture) B.p. 137-143*C/0.3 mm. Anal. Calcd. for C1 6 H1 5 CI 02: C, 70.0; H, 5.5; Cl, 12.9 Found: C, 69.9; H, 5.8; Cl, 12.7% 2-(2-Chloro-4-methylphenoxy)-5-methylacetophenone (146g, 0.53 mole) was heated with sulphur and morpholine as 07 4 48,0 24

2T75 a-.47Y

in Examp'l6e- Oh. p'ouring., th reaation- mixtune-. into. methanol

there- was-- obtained: I-Tog: ol- yellbwz s'o-.Ud-, CMrYstal i satloryn f~rom:.. me thtanodr af'forded, 2-X<-ehlonvo- -methyl--

Anl.C'a-Id-.. f~or C" fH' C1, NO 6r3'. IF,, gr4;,

2'(2--{a-hrco-4Jb-methy,1pTenox.) ac'etmorpho'lide. 0..05-9. mare w~as' hy-draISfeT as- in'. EkampIe- 1. The, crude. product' CI4 was, an- oijy aamij±, wkhich,-waE, crysatallised- fi-onr aa-rfon tetrachlmnide- toa g9 e: iQa(&8) of- znateriba- of-' m. &1-9-5C- A, sampIer necny,&taIli.sed] fram- lit'.t PreVroaeun ax.e- 1To2~-~r

phenaxy -5 -methylpheny.TaetLc acifd a5'. eoa-a unIess needles-,X,

Aha-2J. CIcdfor C~ 10-15' F3* 66 5 CL,~

a' 48,024,

27. 5

EXAMPLE* 2- acid. A solution of 2-chloro- 14-ni-propylphenol 4

0.29.mole) in methaniol (200 ml) was treated with sodium methoxide in methanol C62.6 ml of 214% w/v solution, 0.28 mole). The solution was evaporated in vacuo to give, the' corresponding phenox-ide containing a slight excess of the phenol. This was then allowed to react with the mixture of 2-chloro-5-metbylacetophenone and its isomer (91 0.56 mole) in the presence of copper as in Exam~ple 2. 2- C2-Chloro-1 J-n-propylphenoxy )-5-methylacetophenone was collected at 155-160 0 C at 0.35 mm (66.1g, Anal. Calcd. for C1 8 H1 9 C10 2 C, 71.3; H, 6.3; Cl, 11.7. Found: C, 71.14; H, 6.3; Cl, 11.7% 2- (2-Chloro-4-ni-propylphenoxy)-5-methylacetophenone (30.3g, 0.1 mole) was heated with morpholine and sulphur as in Example 1. The yield of 2--(2-chloro-14-n-propylphenoxy)- was 28.2g m.p. 89-89'50C from methanol. Anal. Calcd. for C22 H2 6 C1N02 Ss c, 65.14; H, 6.5; Cl, 8.8; N, 3.8; S, 7.9. Found c, 65.3; H, 6.5; Cl, 8.9; N, 3.5; s,

4 48,024

-7 5 nil A,mixture. of, 2- Clr-- ~~plhnX--ehlfei~- thioacetnforphollde (25g., 6.06f mc;2e:) anid' pO'tasslium hy'drOxic' ini ime-haniol (2 O&ml), *as' he~a~ed uflder reflu) fror 48' hda's. '1iie Prod-uct* was' workled, flpas i~n- Extamlple 1, to giVe ~acidcf

I'6r A~ia] C~Id~. H 3i c8 6ti~ ffj 64: Cr.,; tit, .O 1.

3,

-2 -5-WhYp nI ir

4 I ~oufi. It Wa thefi- ietkdd dip i~i kx-Aine 1 tO' glV&

f5-,959~(8% df' P:i'&ddt orti6ni wa APpIU'C

cr-ystailisedi twice fi'6r t-ethAboi f~ -(iveld*

as j~hde yell~k ne &i~dj W=12q 6 C,

Fouhi 1 .6i iH, ci 5 8g; N,3.4; 9,7.8

A mikture of 2-2cir= rfufrityLhsix

14 4 8.02 4

27,5 05 n (9.0g, 0.021 mole), acetic acid (60 ml), concentrated sulphuric acid (9 ml)

and water (13 ml) was heated under reflux for 24 hours.

The solution was filtered hot from a residue of sulphur.

Some product crystallised in the cold filtrate and the

remainder was isolated by diluting the filtrate with 6 water. The combined solids .85g) of melting point

about 120°C, were crystallised from light petroleum

80-100 0C) to give 5.5g of 2-(2-chloro-5-tri-

acid as pale

pinkish microcrystals, m.p. 123-124 0 C.

Anal. Calcd. for C1 6 H 1 2 CIF 30 3 C, 55.7; H,

Cl, 10.3; F,16.5

Found: C,55.8; H,3.5; C1,10.1; F,16.6%

4. Example6-

2-(2-chloro-4-n-pentylphenoxy)-5-methylphenylacetic Acid

The crude acid obtained in 52% yield when

2-chloroj'-n-pentylphenol was allowed to react as in Example

4 (foctnotes r aEnd- of thte Table/app-iy) was an oil which

could not be crystallised. It was therefore purified via

its amide. The oily acid (29.4g, 0.085 mole) was dissolved

in methylene chloride (50 thionyl chloride (6.9 ml,

0.095 mole) was added, and the solution was heated under

reflux for 2 hours. Volatile material was distilled in

vacuo, and two portions of dry benzene were added and

similarly removed in vacuo. The crude acid chloride was S1 448,024

0O5 /7

taken up in dry benzene (loo ml) arid added dropwise with stirring to ammonia (d=0.880, 300.mL.). The resulting suspension was shaken with ether, and. filtered. from- undissolved- product.. The organi-c layer- was, separated- from the- filtrate, washed. with water-, dried- over magnesium sulphate and evaporated. The s.olid residue was. combined with the material obtained, by filtration and triturated several times with ether-and then crystallised from methanol to give Il.4g of 2'-(2-chloro-Li-n-pentylphenoxy) 136-137.5'*C. This was heated under-reflux with 20% methanolic potassi-um hydroxide (120 The solution. was filteredthe filtrate was evaporated to dryness and the residue was taken up in water-. The! solutiony was acidified. with hyrdrochloric acid and extracted with ether. The extract was. washed with water, dried over magnesium-sulphate and evaporated to dryness. The residual oil solidified, when triturated with light petroleumr 60-80*C.). Cryz~tallsation from this solvent afforded 2-(2-&loro-'4 -n-pentylIphenoxy)--me thyl1- -phenylacetic acid, m.pD. 75-7'; yield 6.,7g (23% recovery from crude acid, '12 overall, yield.) -Anal-. Calc'd. for' 02 0 H2 3 C103 6.7; Cl,1 10.2 Found: C, 69.3; H, 6.6; Cl,, 1-0.3%

4 4 8.0 2 4

27,5 5ni

-i l C 1 0 LA

CV A (M \i c H C\i cm. Z H C\j C~j t. C

0 O

c CU C\J ko %U H- a\

0 cm H~ c0\ H .4 L C- O

o %I o UD U; U t_

C) 0 0 0U 0

c U U) p C.)

H H7 H=

Un) U0 u C

>A r H C *b I- r 0' 0S4

H HV) C

kD m

14 17; LA U- I

H 0- H H

0.) F"

CO '4 U U U U

4 48.0 24I'

Cu. m Cu' 94 p UNCu

WA i rI C z

0= A

r t Cj LA\ t- Cu (0 0 t0: L' 0 0. t LA J LA L U LA L %D

L)CO CO CO C; cz C Cujr H. 0 Cu Cu u H Cu Cu

1 tL\LA: t LA u Cu Oi H 0 Cuj Olk c H LA'

t a t 4

,0 P'\0 0 pr\ C 0 0IC (U N~ Cu CjNO Cu Cuj C~ 0 14 c cm A r -I '0 N iCu qLA 0 N L 0 0. c. y

LA '0 C q q LA :LA UN U %D %D U W\ U U\ C0 C. 0 N 0 0 U \IV0 00 0 Hr H U U 1. 1

L'.0 r-4 H -I rf IM Hq, Hr I r4' 0n 0t- Cu H N c Hr Cux A' q

N ON M, -1 v

0) C)

HC) H

UwU al) ne H c

448,02

27, 5-0, n/i

H 1~1 LA 0\ 0% (V H- HOI 0 0 0 ON

LA LA LA% %0 1'0 '0 %D r- L

kD %D %D C

cm r-I H1 0 0 0 0 0%

0 LA LA'. 'D0 'D0 0

%D 0 t-4 l 00 '0 '0 CC) %D0 %0 %D0 NO \.0

o 0 0 0 0 0 0 0 H- H- I H- H H4 HH 0 V. U U C. U. C) I LA\ t- a\ H- H LA UH L 1 H- H4 H cm Cuj Cu Cu CM t- co C7 m ON H4 0 00

o b0 0 b

01 (D 0? Co.)c 0

LA

HA m 1' H- 0 Ln '0

-4 LJ- '0o 0: I a I I 0 'A 2 0 0 t\ n '-I H H H co Ln H L- Cu

LA\ x H 0 LAN LM 0 H- Kl t'm CI HCu _u x

r-I zT =Y M

01M0 0 01 0 0 00

448.o~24

27, 5 05 ni

Footnotes to Table I

a Ketone phenoxide :phenol in ratio 2:4:1 b Ketone :phenoxide :phenol in ratio 1 1 1 c Ketone :phenoxide :phenol in ratio 1 2 1 d Ketone phenoxide :phenol in ratio 2 2 1 e Ketone phenoxide phenol in ratio 4 6 3 f Ketone phenoxide phenol in ratio 4 2 1 g Ketone :phenoxide :phenol in ratio 2 1 1 h The phenoxide-phenol mixture was prepared using the proportions and method of Example 4. The subsequent procedure was that of Example 1, using 2 molar proportions of o-ohloroacetophenone to 1 molar proportion of phenoxide. S Ketone phenoxide phenol in ratio 3:1: k Ketone phenoxide phenol in ratio 5:1:0 k Ketone phenoxide phenol in ratio 5:1:0 m large excess of the phenol required to solubilise the reaction mixture n Phenoxide condensation carried out at 140° p Phenoxide condensation carried out at 1600 q The aryloxyketone crystallised directly without having to be distilled first. r The thiomorpholide was not obta.' d as a solid when the hot reaction mixture was poured into methanol. The methanol was evaporated and the resi was dissolved in ether. The solution was washed wi 16 4 8.0 2 4

27, 50 5n

dilute hydrochloric acid to remove morpholine, then with water, dried over

magnesium sulphate and evaporated. The residual oil was then hydrolysed by the procedure.used for solid thiomorpholides. s Thiomorpholide hydrolysed for 24 hours only. t Thiomorpholide hydrolysed. in a mixture of potassium.hydroxide and 20 ml of 2-ethoxyethanol. u 20% potassium hydroxide in methanol was used for

the hydrolysis stage. w The drude acid.was purified via its amide as in

Example 6.

L.P. refers to light petroleum of the given b.p.range.

Screening for anti-inflammatory activity has been carried out employing the established adjuvant arthritis

test, based on a procedure described by Newbould (Brit.J.Pharmacol.15,487 (1969). The following is a brief description of the method which we use:-

On day O of the test 0.05ml of liquid paraffin

containing 5 mg/ml of dead Mycobacterium tuberculosis is

inje.cted into the plantar surface of the left hind paw of

male rats. On day 21 the animals are weighed and the

arthritis assessed by measurement of the volume of the left

hind (injected) paw. Those animals in which the arthritis has not fully developed are rejected and the remainder

divided into groups so that the mean left hind paw volume

17 448,024

27, 5 0

of each group is approximately the same. The rats

are then dosed orally with the drug under test on days 21

to 27 inclusive. The control.animals receive the same dose

volume (10 rl/kg) of the drug vehicle, 5% acacia. On

day 28 (approximately 24 hours after the final dose) the

animals are weighed and the left hind paw .volume measured.

The results are expressed as the percentage change in

paw volume and body weight following drug treatment.

Antipyretic activity has been assessed in

yeast-fevered rats, using a modification of the method of

Winder et al (J.Pharmac.exp. therap. 133, 117 (1961)).

Screening to determine the extent of gastric ulcera

following acute administration of a drug in rats has been

carried out by a procedure based on that of Martindale et al

(J.Pharm, Pharmacol, 12, 153T 158T (1960)). Ulceration w.

assessed at 4 hours in the case of Phenylbutazone and

Ibuprofen, but at 24 hours in the case of the compounds of

the invention, for which preliminary studies indicated a

greater ulcerogenic effect at 24 hours than at shorter time

intervals. Acetylsalicylic acid was used as a positive

control for the 2' hour studies.

Table II below sets out results we have

obtained on a number of compounds. Calculation of the ratio

of the approximate minimum ulcerogenic dose (MUD) to the

corresponding approximate daily minimum effective (anti-

arthritic) dose (MED) clearly demonstrates the

reduced ulcerogenic potential of our compounds relative

4 4 8,024

27, Ofn to their, therapeut- actIvity- when compared, with. established ant-iflamt:-y agetsi..

4 4 8.0 24

27.5 05 ni

LA 0 Cu

o LA A A A H- H4 H /AA A A o t- t4-\ 0 0

0 o 0 0 o 0 0 LA\ 0 LA 0 LA\ o o 0 LA\ A A A A bO %0 0 r- o 0 co co

o> 0 0 0 0 =r m~ PC\ %D U' Cuj Cu .4 Cui tr%

0 '0 0\0 X.rq 0 H0 0 4'j. 4- 0 -0 .0 0 '0 0 4.> 0 C0 0u 0) 0 0 -H x 0-4

00 1d0 r- 4 0.0 ~0 0,14> 0 4- 0 '0 0I 0 CS 0 co .0

.0 4 4 ,02 C)H Cuj

Cuj

The. unsubst-it-uted- analagwe,- o.-phenoxyphe-nylacetic acid, is- devoid'. of antLinflammatoiy, artivit y and. pro-duces- no ulceration a-f.t:e~r six, hour&~ and only slight- ulceration 2.4 hours; after administra-tion of lg-/kg. Moreover-, with m-phenoxypheny-lacetic acid-(no anti- arthritic actiyvity) there. was, ulcerat-ion 4 hours after- administration: of 100mglkg, witWr p-phenoxyphenylacet:ic acid ulceration 4Jhours. after admiristration of 50mg/kg, abd finally with the anal-ogous.- p.-(2,4-dichlorophenx-y)-- phenylacetic. acidz the-re. was:- severe ulceration 2'4 hours after administratio- QIf lg/kg-.

0-hnxphenylaaetic acid is therefore much less, ulcerogenic: than the in-- and,,,p- isomers. This property is ret-ained- in: the substitt~ted comprouids,, which, also display ant-i-inflammatory activity. Se.veral compoundw, 2-'CZ,)4-dichlorophenoxy)- phenylac~atIc. acid-- and- 2- CZ, 1 1-dic-hloQro-3 phenylace-tic. acid-, in, addition t-o, anti-inflammatory activity pos-sess- antipyretic- activity-. The. former compound also: has analgesi-c. activity,. andy exerts- an ant-i,-oedematous efflect- in- adrerral-ectoiied. rats. The- pharmaceutically acceptable diluents or carriezs. which. may be admixed- wi.th. the actIve compound to form the. comppsiti'ons of this invention are well known. The, compositi'ons-nay be in a-form suitable for oral, topIcal or parenteral use but the preferred method of administration is orally. Such oral. compositions may take the form of capsules,. tablcts, lozenges or granules or liquid preparations such as elixirs, syrups or suspensions.

14 448,024

27, 505 n

The oral compositions, whether in the form of liquid

or solids, may also incorporate flavouring agents,

colouring matter, disintegrating agents, tabletting

aids and other diluents as required.

Tablets or capsules for oral administration contain from 25 to 500 mg of a compound according to the invention as active ingredient. A preferred tablet or capsule contains from 100 to 500 mg of 2-(2,4-

dichlorophenoxy)phenylacetic acid, 2 -(2,4-dichloro-3,5- dimethylphenoxy)phenylacetic acid 2-(2-chloro-4-

acid, 2-(2-methoxy-4-

acid, or 2-(2-chloro-

phenylacetic acid. A suitable oral daily dose of these preferred compounds

for the relief of inflammatory states in human

beings, would be from 250mg to 3 g of the active

ingredient.

The compounds of the invention may also be

incorporated into novel therapeutic compositions with other known therapeutically active compounds such as, for example, codeine.

Examples of the formulation and preparation of tablets and capsules for oral administration are set out below: Tablet

An intimate mixture was prepared of equal weights 2 of -(2,4-dichlorop,henoxy)phenylacetic acid and a tablet

base comprising starch with the addition of 1% magnesium

22 4 48.024 st-earat'e- as,- lubmiaant. Thiar<miXture was cqoTppessed into- tabeteconainng'.0-g. oIf. 2(2 clorophenoxy).

phenylacetVic,: ac-id.. Similarly, table-ts containing: 50 or 200%,Mg. of' 2'-(-2,.4-dichlor.ophenoxy,). phenylacetic acid. were- prepared:.., Capsule- Batches off' soft geiatin capsules, were prepared, each capsule- containing- 50', 1.00 or. 200 jrg. of dich.-orophnoxy)phe.nylacetic acid. Similar, tables. and, capsules, were prepared containing, 100' and, 200. mg.. of 2-(2,L-Dichloro.-3,5- d-imethyrlphenoxy) pheny'iacetic acid 2(-Cor-4l-

acid., 2- (27Methoxy-4- ac6id or. a-1Ch Icr L,-tert.-bttylphenoxy.)-5,-methyl-phenyl1 acetic acid.

4 48,024

Claims (3)

1. 27, 5,0 5ni THE CL! MES DEFINING THE INVMZTION ARE AS FOLLOWS

   1 Compou-nds of the formula

   4j 6 3 I (OH) BI2 A 6
2. 2 R2 CH2CQOH1

   wherein R is hydrogen or methyl; R22 is chlorine; R3 is chlorine at positions 14or 5, alkyl of from I to 6 carbon atons at p-osition 4, trifluoroniethyl at position 5 or methyl at position 6; and n is 0, 1 or 2. 2. Compounds of Formula I as claimed in claim 1 wh( R2 mjy also represent methoxy when R3 is chlorine at posit

   4.
3. 3. Comrpou~nds as claimed in claim 1 or claim 2 wherein one or more chlorine substituents in the compound is/are replaced by bromine. 4. 2-(2-Chloro-4-alkyl(C 1 to 6) phenoxy)phcnylacet'

   24 24448,024 acids -which mauy be ptionall7 substituted by rnetllyl at po-sition of Xi~ng A- 2- (2.,4-;.ichorohencLxy,)..phexqylaceti c acids which may be optionally sudbatituted by one or two methyls in Ring B anid methyl at positaon 5' -of .Rimg A.. Choro-4-methylphenox,7.)- -methylphenylaceti c acid-. 7T. (.2-Chloro-4-a--ropy-,l~hednoxy')-5-methylphenylaceti c acid.. 2 2- aceti.,c acid-. 9. 2-.(,2-C-hiaro-4-,n-.pemtkyl-jheno-xy methylphenylaceti c acid.. 2-(2,,4-Di cl-,orop-lhenoxy)phenlacetic aa~id-. 11-. (,5-Dich1Qoro'phenoxy)phenya.lacet.c acid,. 12- 2-C.2--.Chloro-.4- methylphenoxy)phenYlaceic acid,. 4=Didhloro-. 5-methylphenoxy)phenylacetic acid. 14-. 5-dimethyJ1phenoxy).phenylacetic acid.. 2-G(-2,,:5-Dichloro.Pheoxy)-5.methylpheniacetic acid. 2- (2.,.4-flidhloro- :5-methyl -phenoxy) 5-methyiphenylace tic a~d- 17. 2-'(2--CHloro-4, acid,. I1&. 4-Dichloro-3,5-dimethyphenoxy)-5-methylphenyl- .acetic acid&. .19. 2-(2,4-Dichlorophenoxy)-5-me-thylphenylacetic acid.. 2 6 -Chloro- -met acid. 21. 2-(2,4-TDibrornophenoxy)phenylaceti.c acid. 25 4 48,024

   27, 5 22. 2-(2-Chloro-4-ethylphenoxy)phenylacetic acid. 23. 2-(2-Chloro-4-ethylphenoxy)-5-methylphelylaceti( acid.

   24. 2-(2-Chloro-4-~ipropylphenoxy)-5-methylphenylacei acid'. 2

   acid.

   26. 2-(2-Chloro-4-i-butylphenoxy)-5-methyiphenylacet acid.

   27._ 2-(2-Chloro-4-s-buty acid.

   28.. 2-(2-Chboro-4-t-butylphenoxy)-5-methylphenylacet acid.

   29. 2-(2-Chloro-4-n-hexylphenoxy) acid.

   2-(2-1'ethoxy-4-chloropheoxy)-5-methylphenylacet: acid.

   31. Compounds of.Formula I as hereinbefore described with reference to any one of the Examples.

   32. A pharmaceutical composition which comprises as active ingredient a compound as claimed in any one of clan 1 to 31 in admixture with a pharmaceutically inactive diluE or carrier.

   33. A pharmaceutical composition as claimed in claim in tablet or capsule form for oral administration which

   contains from 25 to 500 mg of the active ingredient.

   4 4 8O 2 4

   27.5 34- A process for the preparation of compounds of

   Formula I as claimed in claims 1 to 3, which process

   comprises reacting together compounds of Formula II

   and III (CH) 3 n .R 1

   Y X

   R2 COCH 3 1

   in which R R2 R3 and n are as hereinbefore defined in

   claims I to 3, y is Ona or OK and X is chlorine, bromine or

   iodine, at a temperature of at 0 least 120 C in the presence of

   a copper catalyst to produce a compound of Formula IV

   (CH3)n 3n R B .A

   0

   R2 COCH IV.

   which is thereafter transformed into a compound of formula I

   by treatment with sulphur and morpholine to form a thioacet-

   morpholide of Formula V

   (CH3)n R1

   R3 B A

   R2 CHpCSN/

   which is then hydrolysed.

   448,024

   27, 5

   A process for the preparation of compounds of Formula I as hereinbefore defined in claims 1 to 3

   substantially as hereinbefore described with reference

   to any one of the Examples.

   DATED this 12th day of July 1973.

   RECKITT COLMAN PRODUCTS LIMITED

   EDWD. WATERS SONS, Patent Attorneys, Russell Street, Melbourne. Victoria. Australia.

   28 4 4 8,024