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CA1063618A - Indane derivatives - Google Patents

Indane derivatives

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Publication number
CA1063618A
CA1063618A CA219,396A CA219396A CA1063618A CA 1063618 A CA1063618 A CA 1063618A CA 219396 A CA219396 A CA 219396A CA 1063618 A CA1063618 A CA 1063618A
Authority
CA
Canada
Prior art keywords
formula
compound
indanyl
acetic acid
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA219,396A
Other languages
French (fr)
Inventor
Jean-Marie Teulon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hexachimie SA
Original Assignee
Hexachimie SA
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Filing date
Publication date
Priority claimed from GB5726/74A external-priority patent/GB1492175A/en
Application filed by Hexachimie SA filed Critical Hexachimie SA
Application granted granted Critical
Publication of CA1063618A publication Critical patent/CA1063618A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/194—Radicals derived from thio- or thiono carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/34—Monohydroxylic alcohols containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/50—Halogenated unsaturated alcohols containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/782—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic
    • C07C49/792—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A B S T R A C T
The present invention relates to processes for preparing indane derivatives of general formula (I) in which:
X represents a hydrogen or halogen atom; R1 and R2, which may be identical or different, each represents a hydrogen atom, an alkyl group containing 3 to 5 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms; R3 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms; and Y represents -CH2OH or a group of formula -COOR4 in which R4 represents a hydrogen atom, 1/v(M) where M is a metal of valency v, or a group of formula -(CH2)n-NR5R6 wherein n is an integer of 1 to 5 and -NR5R6 is selected from the group consisting of di-(lower alkyl) amino, morpholino-lower alkyl, pyrrolidino-lower alkyl and piperidino-lower alkyl, and their pharmaceutically acceptable addition salts. The compounds of formula (I) and their salts are useful for the treatment of inflammations, algias, rheumatisms or pain syn-dromes in animals.

Description

i3618 The present invention relates to certain indane derivativ2s~ to processes for their preparation and to their use in therapy.
The present invention provides a compound of 5general fonmula: R
:. 13 :
Rl CH - Y

(I) . . . .
;. . in which: :
X represents a hydrogen or-halogen atom; Rl and R2, which :
.i may be identical or different, each represents a hydrogen : lO atom an alkyl group containing l to 5 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms; R3 ,..................................................................... - : .
.; represents a hydrogen atom or an al~yl group containing ~ ~ .
l to 5 carbon atoms; and Y represents -CH20H or a group . :::
of formula -COOR4 in which R4 represents a hydrogen atom, l/v (M) where M is a metal of valency v, or a group of "~ ~ fonmula: :
~,, :: .
`~ ~(CH2)n~NR5R6 . .~ .
~ wherein D iS an integer of l to S and -NR5R6 is selected from ~.
the group co~sisting of di-(lower alkyl) amino, morpholino-~ lower alkyl, pyrrolidino lower alkyl and piperidino-lower alkyl~ ~ .

'J:
.~ . .
, ~
~ .

: Ç, ~ - 2 -. ,- ",~ .

~C~6361~
or a phannaceutically acceptable addition salt of a compound of formula (I)~
The aforesaid alkyl groups of 1 to 5 carbon atomi~i may be straight or branched; similarly, the group -(CH2)n may be straight or branched. The cycloalkyl groups of 3 to 7 carbon atoms may be, for ~iample~
cyclopropyl~ cyclobutyl, cyclopentyl, cyclohe~cyl, or ~- cycloheptyl, cyclohexyl being preferred. The sub~
stituents Rl and R2 may be on the sama or different 1~ carbon atoms of the indane nucleus.
The metal M is preferably from group I, II or III of the periodic classi~icat~on; sodium, potassium, calcium and aluminium are eisipecially suitable~ -.. .. .
Suitable N-heterocyclic groups -l~R5R6 include, more e5pecially, pyrrolidino9 morpholino, thiomorpholino9 3,5~dimethyl-morpholino, piperidino, 4'-methyl-piperidino, piperazino9 4~ hydro~yethyl)-piperazino, 4-~-chlorophenyl-.: . . .
piperazino and azepino ri~en R4 is an aryl group, it may be, for e~ample, 20 phenyl, and when it is aralkyl, it may be, e.g.
~ .
a-phenylethyl, ~-phenylethyl, or benzyl.
The invention includes the addition salts of the compounds of the formula I, especially the addition salts with amines when R~ is hydrogen and the addition 25 salts with acids or quaternary ammonium salts when R4 ~! ~ iS -(CH2)n~R5R6. The addition salts with acids may be i~ produced by reaction of the base with an inorganic or organic acid in manner known p~r se, Suitable acids for this purpose are, more especially, hydrochloric, sulphuric, . i, .
_ 3 _ -: ' ' ,, ' '.: . ,:

. . . .

~L~63~8 phosphoric, o~alic, ~uccinic, methane~ulphonic, cyclohexyl-sulphamic, formic, aspartic, glutamic, N-acetyl-aspartic~
N-acetyl-glutamic, ascorbic, maleic, malic, fumaric, lactic, benzoic, cinnamic and E-toluenesulphonic acids.
Particularly preferred compounds of formula (I) are those in which Rl and R2 each represents a hydrogen-a~om or a methyl, ethyl isopropyl or cycloheKyl group) R3 represents a hydrogen atom or a methyl or ethyl group and X repre~ents a hydrogen atom. If Y represents a group of formula -COOR4, R4 is preferably a hydrogen atom or a group of formula -(CH2) The compounds of formula (I) can be prepared ~ by conventional techniques. In ma~y aase~ an indane `'t' of the formula:
r~ :

Rl ~ (II) R2 ", ~.3 ,, , ,~
in which Rl, R2 and X are as hereinbefore defined, i3 a ~ convenient ~tarting material. Typical proces~es which ; ~ can be used are the following:
A~ A proces~ whiah comprises:
a) reaating a compound of the ~ormula ,::,1,~ ..

~ ~ (II~

. ~ , .
~ 4 ~
~,; ~ :
.j .
. ~ ' ' .
~'", .... .
j, ~, . .
... . . . . . .
,, :' ' ' . " ' .~ , , , ' ' , , ' ' " ' ' ' ' ~ Ç;361~3 in which Rl, R2 and X are as hereinbefore defined with an ethyloxalyl halide and h~drolysing the re~ulting keto-ester of formula:
'.~ :''.

R~ (V) ~ ~

under acidic or basic conditions to obtain a keto~acid of the f ormula:
.'`'.'` .
Rl~ < W CO--COOH ;' R ~ ~VI) ~ . .
.~- and either: .

(b) ~ub~ecting the keto-acid of formula ~VI) to a Wolff-Kishner reduction to obtain a compound o~ ~ormula .. . .
~ (I) in which Y repre~ents a -COOH group and R3 reprP~ents ; ~ ~ a hydrogen at~m~
or c) reacting the keto-acid of foxmula tVI ) with an o~gano-magnesium compou~d of the fon~ula R3MgZ i~
which Z is a halogen atom and R3 is an al~yl group containing 1 to 5 carkon atoms to obtain a comF~und o~
,,: .
: formula:

VII~

.. .
dehydrating the compound of ~ormula (VII) to obtain ~, 20 a cGmpound o ~ormulas : --s~, - 5 ~

,;, .. . .
, .

~L~636~8 R 3 : .
CH
Rl C - COOH

R r (VIII) . ~
2 ~' :
in which ~'3 represents a group of fonmula ~(C~2)x lH
'! where x is the number of carbo~ atoms in R37 and :.
.. , : .
h~drogenating the compound of formula (VIXI) to obtain ; 5 a compound of formula ~I) in which Y represent~ a ~ -COOH group and R3 represents an alkyl group containing :-: 1 ~o 5 carbon atom~; and if deAired, con~erting the ;` compound of formula (I) obtained m step b) or c) into a.~: pharmaceutically acceptable addition salt thereof.
The preferred ethylo~alyl halide for use in :~3~ step a) is ~he chloride and the pre~erred compounds o~ -formula R3MgZ for use in step c) are tho~e in which Z
; is:iodLne, The various ~teps of process A ma~ be carried out u~ing m~thods known in the art; ~or example step a~
~: i5 may be carried out under typical ~riedel-Crafts' xeaction : .
condition~ in ths presence of a L~wis acid such as AlC13 and a solvent such as ethylene chloride and ~tep b) may be carried out usiny hydrazine in a solution : containing 30dium or potas~ium ion3. The Grignard reaction in step c) is suitably carrîed out in an ether solvent, the dehydration of the compound of ~ormula VII
~; may be carried out u~ing a strong acid such a~
c~ncentrated sulphuric acid and the final hydrogenation ::-uitably carried out in the pre~ence of a cataly~t, : :
:: 25 for example Raney nickel, .` '~ , , , i :

~l.. ~.. ~ ... . .. .

~636~
Process A) i9 illustrated by the followingreaction scheme:
PROCESS A) /~ 3~ocooc2H5 R2 ClCOCOOC ~ ~

X R2 ., (II) (V) hydrolysis ¦
~, . . . ~
~l . . .
. .` ~ '~,-,.
... .

~ R COCOOH Rl CH2COO~ ~

(VI) lI~ :

: ~ R3MgI CH
Z ~1 ~ OOH Rl ~ C-COOH ~' ~:~1 (VII) (VIII) : Rl R3 ::
Z~ 2 ~ -COOH

. 7 ~ .

','', ~ ': ' "~

~ - ,.. .:

: ` :
~ ii36~8 ~::

B) Proceq~es for the preparation of compound~ of formula (I~ in which Y represents a -COOH group~ which ; proces es include the s~ep of hydrolysing a nitrile of general formula:

~ H-CN (IVa) ~' R2 in which Rl, R2, R3 and X are as hereinbefore defined under acidic or basic condition~, and, if desired~
~. converting the resulting compound o~ formula lI) into a :~. pharmaceutically acceptable addition salt thereof~
. ' ~t ~10 A nitrile of formula (IVa) in which R3 ., repre~ents an alkyl group containing 1 to 5 carbon atom~
can ke obtained by reacting a nitril~ of formula (IVa~
in which R3 represents a hydrogen atom with a metallating agent such a~ sodium or potassium hydride or amide or .~ 15 potassium tert-butylate and xeacting the resulting compound o~ formulas CHM-CN (XII) ~, in which M is a~ alkali metal atom~ with a halide of formula R3Z in which R3 repre3ent~ an alkyl group containing 1 to 5~carbon atoms and Z is a halogen atom, :, pre~erably bromine or iodine.
~ Further proces6es o~ general type ~) are the :.~ following proce~ses C) and D).
' - 8 - : :
'~ ' `: ~''' . .
, ,j .

i . , , , , . ,, , ~ , .

36~3 C) A process which comprises ~ -; a) chloromethylating in known manner a compound .
of the ~ormula: -;'' ~

(Il) . R
. .
in which Rl, R2 and X are as hereinbefore defined to obtain a cQmpound o~ formula:

: ~.` R
3~H2Cl ( III ) ;
~`: R2 b) reacting the compound of formula~(III) with .~ an alkali me~ yani~e to obtain a compound of formula~
.'', ~ 10 ~1 ~ ~ Cx2CN (IV) ;

:~ R2 and c) hydroly~ing the ccmpound o~ ormula (IV~
. under acidic or ba~ic conditions to obtain a compound :i of ~ormula (I) in which Y represents a -COOH group and : 5~ R3 represent~ a hydrogen atom, and,i~ de6ired, :~
~i 15 converting the compound of ~ormula (I) into a :~ pharmaceutically acceptahle addition salt thereof.
-~ Step a) i8 pre~erably carried out u~ing ~ hydrochloric acid and foxmaldehyde or trioxymethylene~ --- g ~
, ' .

' ,' ! ~ ~ ~ . .
.
, '1 . ' ,.
~".; ' '' ~ ' ''' "; ' . ' ' ' ' ' ' " ,.. : ' ' : ' , .
.. /,~ : , ' - ' :' ' i 1~6~61~
,, .
Process C) is illustrated by the foll~wing reaction scheme:

R` R

R . R;\~<~\
(II~ (III) ~,` ' ' ,, .

CH2 CN R2 m CH2 COOH
~IV) (I) D) A process which comprises a) reacting a cornpound of the formula: ~ -. .,: : .
.~ Rl -tIIa) ~! in which Rl and R2 are as defined in claim 1 in known ~, 10 manner with a ~alide or anhydride of an acid of formula .
: R3 COOH in which R3 represents an alkyl group containing :: :
., 1 to 5 carbon atoms, to obtain a ketone of formula:

R ~3 in whic~ ~, R2 and R3 are as hereinbefore defined ;'~, , .

, , . . .
: , ", , . - .

1C~636113 ;
b~ reducing ~he ketone of forrnula (XIII) in known manner to obtain an alcohol of formula~

R ~ ~ (XIV) c) converting the alcohol o~ ~o~mula (XIV) -~ -:
:: 5 in known manner into a halide of formula: ~
' . :.
R~

Rl ~3/C~ ~ ~ ( XV ) ~: :
^~ . in which Q is chlorine or bromine.
.;. d) reacting ~he halide of formula (,~) with :~
. an alkali metal cyanide to obtain a compound of formula~

.~ Rl CHCN
Rz ~ (IVa) .j . .~ ; and ;~ : e) hydrolysing the compound o~ formula (IVa~
~ under acidic or basic conditions to obtain a compound 1~ :::.
o~ fonnula (I) in whic~ X represents a hydrogen atom, ~;~ 15 R3 repre~ents an alkyl group containing 1 to 5 carbon atoms and Y represen~ a -COOH group, and if desired, ~- converting the compound of formula (I) into a i-:, pharmaceutically acceptable addition salt thereof.
; ¦ ~he variou~ steps of process C~ may be carried ~ 20 out using method known in th~ art; step a) may be carried ~ '"': ' ~" ., 10~;3 '.:
out under typical Friedel-Crafts' reaction conditions, step b) may be carried out using conventional reducing agents suitable for redu~ing a ketone ~oan ~lcohol, for ~xample an alkali metal borohydride or lit~um aluminium hydride, and step c) may be carried out using, for example, phosphorlls tribromide or thionyl chloride~
Process D) is illustrated by the ~ollowing reaction scheme:
PROCESS D) R R3 ~ .
~`3 R~

`:~; 2 (IIa) 2 a~c ... .

R1 CHCN R ~ CHCOOH

R2 R~

'. A~lother process which may be used to prepare compounds of fonmula ~I) in which R3 represents a hydrogen atom and Y representB a -COOH group is the following:

' :

~ 1063618 :
E) A process which comprises reacting a compound of the formula:

R~

R2 (X) . ~ , in which Rl~ R2 and X are a~ hereinbefore defined in :~ -~
~` 5 known manner with sulphur and a primary or secondary ',! amine of formula NHR5R6 wherein ~5 and R6 are as hereinbefore defined with the proviso that at least one of R5 and R6 is other than hydro~en, ~o o~tain a : thioamide of the formula:
R5 :~

~ CH2 C \ R (~

. .~ . . .
in whic~ Rl, R2, R5~ R6 and X are as hereinbefore defined, and hydrolysing the thioamide of formula (XI) ., :
.':.. 3,;~ to obtain a compound of formula (I) in which R3 :~; represents a hydrogen atom and Y repreqents a -C00~ .:
group, and, i~ desired, converting the compound o~
formula (I) into a phanmaceutically acceptable addition : salt thereof.
. ~his process involves a Willgerodt reaction ~ (a ~ariation o~ the Kindler reaction). The ketones .
~;~ 20 of formula (X) in which X repre~ents a hydrogen atom can be obkained by step a) of process D), The ~ hydrolysi~ o~ the thioamide is pr~ferably carried out --~ under acid conditions7 .! :

, ,, '; "' , '-,' ' ` '' '' ,.''~' ' '' ',:', '"; .. . ':'' ' '' ' ,' ;.' " ''' ,',' "' ' .' "' ~ """',' ',' ' :.. ', ,' ' , ,, ', ',, ' ' ` , ', ' , ' ' . ' .,, ', ' "., ' " " . ,', ' `, ' ' .. ,. , ., ',', '. :", "." '', " :' ' ',: ', ' ' ,, ' . ',' ': ', ' ', ' , . ' , : ' 36~

~ The compounds of formula ~I) in which Y
- represents a -CH2GH group can be prepared by method~
including the step of reducing a compound of formula:

~ ~3 Rl CH--COOR ~

R ~ X
~; S in which Rl, R2, R3 and X are as hereinbefore de~ined and R represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atomsO ~he co~pounds of ~ormula (~I) in which R is hydrogen can be prepared by any o~ the proce~se~ A) to E) de3cri~ed above and :::
the compounds in which R is an alkyl group can be ~.
`~; obtained by conventional e~terification o~ the corresponding acid. The reduction can be carried ` ~'~ri .
out by means of a reducing agent, Eor example~ lithium :~ aluminium hydride, in an organic ~ol~ent such a~ ether or tet~ahydr~an.
he canp~und~ o~ ~o~mula (I) in which Y r~
pre~entS a group o:~ ~ormula --COOR4 in which R~
represent~ a group o~ formula -(CH2~nr-NR5R6 can be ; pr2pared by a proce~3 of the ~ollowing type:
, . . .
~: 20 F) A proCess which compri~e~ either a) reacting the halide of an acid o~ foxmula:

2 ~ C~-COO~

':'', : ' .,, -, ' :~', .) - ',' , ~636~8 ~:

in which Rl~ R2, R3 and X ara as hereinbefore defined with an aminoalcohol of the formula:

~-: / 5 :
HO - (CH2)n - N \

in which n, R5 and R6 are as hereinbefore defined or 5b) reacting a salt of an acid of formula (Ia3 with a halide of the ~ormula: ;

` f R5 in which n9 R5 and R6 are as hereinbefore defined and Z is a halogen a~om.
Process F) i~ illustrated by the ~ollowing ~ .
. reac~ion scheme:
PROCESS F) q~ 1 CH-COOH

','' ~(X 3~(x ~
~'~ R2 (Ia) R2 (IXJ
~!~ ~R5 Rl CH~cootcH2) O(cH2)n-N

?,~ ~ Rl f~7H-COOH Rl CH-COOM

. R ~ X R~ ~ X
Ia) ; - 15 -"' '' - :
., ' ~ - ; , , ,, , , : .

~0636~8 . ~ . , R5 1 CH-~00(CH2)n-N \
~ ( 2)n ~\ ~ R6 '.' >
.:: R2 -:: :
,~
. The compounds of the invention and their non-~ toxic addition salts possess valuable pharmacological activities and are u~eful in therapy, especially as analgesic and anti-i~flammatory ag~nts. They can, ;
for example, be used as anti-inflamma~ory agents for counteracting rheumatism.
. .
-x The invention therefore also provides therapeutic compositions which are especially useful ~ ;
in the treatment of inflammations and algias, rheumatisms ~: and pain syndromes which compositions comprise a:
pharmaceutically ef~ective amount of at least one compound of fonmula (Ij ox one of its non-toxic addition salts and a pharm~aceutically accep~able carrier or ; ; 15 diluent, :,,, The compound~ of formula (I) can, for e~ample, ; be administered to man in the ~orm of gelatine-coated pillB containing 50 to 250 mg of active principle at a dose of 2 to 6 gelatine-coated pill~ per day, in the , ,i :
~ç~ 20 ~orm of suppositories containing 100 to 500 mg of active :~ principle at a daily dose o~ 2 ko 5 suppositories per ; t: ,, r3i day, in the ~orm of a potable suspension containing 25 mg ~"f. ~ : ' of active principle per 5 cm3 at a daily dose of 10 to :
40 cm3 or in the form of an injectable solution 3~ 25 containing 50 mg of active principle per 2 ml of solution : ~--. . .

.. ''~': , ', ~''., : ~ .

': ~ ' ' . ':
,,~., : .
,~ . .

,~,, .. . .. : . "", ., , ,, , . ,, , :, ~ . . .
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~ 10~3611!3 at a daily do~e of 2 to 4 injections.
The compounds of formula (I) possess an LD50 in rat~ of approximately 250 mg/kg when adminis~ered orally, have little tendency to cause ulcers, and posse3s . .~ , .
an activity ~o toxicity ratio w~ich is generally higher than that of the ]~own products possessing simular pharmacological properties.
s -~ The invention is illustrated by the following Examples. Examples 2 to 7 and 11 to 18 illustrate process A~, Example 1 illustrates process C), Example 26 ~, illus~rates proces~ D), Example 36 illustra~es process E) and Examples 8~9 and 21 to 32 illustrate process F).
~! Examples 33 to 35 and 37 illustrate the preparation of compound3 in which Y is -CH20H and Examples 19 and 20 illustrate the preparation of addition salts.
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Exampla 1 [1,3-Dimethyl-indanyl-(5)]-acetic acid .
(a) 1,3-Dimethyl-5-chloromethyl-indane Formula III Rl = R2 = CH3 X = H
A mixture of 73 g of 1,3-dimethyl-indane, 28 g of trioxymethylene, 64 ml of acetic acld, 41 ml of 85% strength phosphoric acid and 100 ml of concentrated hydrochloric acid ~ is stirred for 24 hours at between 58 and 60C. The re--- action mixture is taken up in a mixture of water and ice and the organic products arè extracted with ether. The ether ~: 10 phase is washed with water and dried over sodium sulphate.
After evaporation of the ether, the residue obtained iS dis-tilled in vacuo. 44.8 g of 1,3-dimethyl-5-chloromethyl-.. ,,~ .
indane are thus obtained in the form of a colourless liquid.
, . . .
Boiling point 1 mm Hg = 110C.

(b) [1,3-Dimethvl-indanvl-(5)]-acetonitrile .
Formula IV Rl = R2 CH3 X = H

i A solution of 25 g of potassium cyanide-in 30 ml of `~ water is added over the course of 1 hour to a solution of ;! ~ 44.8 g of 1,3-dimethyl-5-chloromethyl-indane in 130 ml of .. . . .
~ 20 ethanol. The reaction mixture is heated under reflux for .;j:
4 hours and i6 then cooled, diluted with a mixture of water and ice and extracted with ether. The ether phase is : 51, . . .
i:! washed carefully with water and dried over sodium sulphate.
;, ~ -, ~ After evaporation of the ether, the residue obtained is dis "I ~ .
tilled in vacuo. 31.8 g of [1,3-dimethyl-indanyl-(5)]-~,~, acetonitrile are thus obtained in the form of a colourless .;., .
liquid.

, Boiling point 0.7 mm Hg = 125~132C.
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(c) [1,3-Dimethyl-indanyl-(5)]-acetic acid Formula I R1 = R2 CH3 R3 = R4 = X = H
A solution of 31 8 g of [1,3-dimethyl-indanyl-(5)]-`~- acetonitrile in 175 ml of ethanol containing a solution of 62 g of potassium hydroxide in 100 ml of water is heated under reflux for 16 hours.
After evaporation of the ethanol in vacuo, the re-; action mixture is diluted with 200 ml of water and then filter-ed. The filtrate is acidified at 0 by means of 10% strength hydrochloric acid and the precipitate formed is filtered off, washed with water and dried. After recrystallisation from ~`l toluene, 20 g of [1,3-dimethyl-indanyl-(5)]-acetic acid are ~A~ obtained in the form of white crystals.
Melting point = 115-117C.
Example 2 [1,3-Dimethyl indanyl-(5)]-acetic acid ;~i (a) Ethyl [1,3-dimethyl-indan~1-(5) ~
. ~. .
; Formula V Rl = R2 = CH3 X = H
A solution of 78 g of 1,3-dimethyl-indane and 83.5 g of ethyloxalyl chloride in 300 ml of methylene chloride is ~; 20 added, over the course of 1 hour, to a stirred suspension of ~;:d :~ 125 g of aluminium chloride in 300 ml of methylene chloride, -~`~s;~ whilst cooling in such a way that the temperature of the :.~1 - , : .
reaction mixture remains below 5. The mixture is then stirred for 2 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified ta pH 3 ay means of hydrochloric acid. The methylene chloride phase is isolated and the mother liquors are extracted with methylene . ~ .

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chloride. The methylene chloride phases are combined, washed with water saturated with sodium chloride and dried over sodium sulphate. After evaporation of the solvent, 119 g of ethyl [1,3-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
(b) [1,3~Dimethyl-indanyl-(5)]~glyox~1ic acid Formula VI Rl = R2 = CH3 X = H
A solution of 119 g of ethyl [1,3-dimethyl-indanyl-
(5)]-glyoxylate in 600 ml of ethanol is treated with a solution .
of 20,5 g of sodium hydroxide in 600 ml of water and is heated under reflux for 2 hours. The mixture is then cooled, diluted with 300 ml of water and acidified at 0 by means of 10~ strength hydrochloric acid. The mixture is extracted -;` with chloroform which is then washed with water saturated with .,~ .
sodium chloride, dried over sodium sulphate and evaporated.
. ~
~` After vacuum distillation of the residue obtained, 77 g of ~` [1,3-dimethyl-indanyl-(5)]-glyoxylic acid are isolated.

Boiling point 1.5 mm Hg = 170C.
`I , . . . ., 20 (c)[1,3-Dimethyl-indanyl-(5?]-acetic acid Formula I R = R = CH R3 = R~ = X ~ H
` A mixture of 12 g of [1,3-dimethyl-indanyl-(5)]-gly-oxylic acid and 25 ml of hydrazine hydrate is heated under ~Z reflux for 30 minutes. The mixture is cooled to 70C
~' and 15 g of potassium hydroxide pellets are added in small portions. After the end of the addition, the mixture is 20 - ~

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heated under reflux for 1 hour 30 minutes and then the:excess hydrazine hydrate is evaporated in vacuo, The solution is then cooled and acidified at 0C by means of 10% strength hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried. After recrystallisation from toluene, 7.7 g of [1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 116-117C. -Example 3 [6-Chloro-1,3-dimeth~l-indanyl- (5? ]-acetic acid , - ,.
~ 10 (a) Ethyl [6-chloro-1,3-dimethyl-indanyl-(5?]-glyoxylate .; .
Formula V Rl 2 3 X - Cl Following the procedure of Example 2~a) but usi~g 50 g - of 1,3-dimethyl-6-chloro-indane and 43 g of ethyloxalyl ;.~,1 ' chloride, 80 g of ethyl [6-chloro-1,3-dimethyl-indanyl-(5)]-~ glyoxylate are obtained in the form of an oil which is used `,i! in crude form for the remainder of the operations.

i (b) [6-Chloro-1,3-dimethyl-indan~l-(5) ]-gl~oxylic acid -~ Formula VI Rl = R2 CH3 X = Cl Following the procedure of Example 2(b) but starting ~i 20 from 80 g of ethyl [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxy-late, 61 g of [6-chloro-1,3-dimethyl-indanyl-(5) ]-glyoxylic :

l acid are obtained in the form of pale yellow crystals.

l Melting point 170-173C.

! (c) [6-Chloro-1,3-dimethyl-indanyl~(5)]-acetic acid 'i~ Formula I Rl = R2 = CH3 X = Cl R = R4 = H

- 21 - ~ ;
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., .

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.: -:: i , . , : , . .
- : : -: , ~63~8 Following the procedure of Example 2(c) but starting from 20 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-glyoxylic acid, 10.5 g of [6-chloro-1,3-dimethyl-indanyl-(5)]-acetic ~ acid are obtained in the form of white crystals, after re-: crystallisation from toluene.
Melting point 158-160C.
: Example 4 [2-Isopropyl-indanyl-(5)]-acetic acid ta) Ethyl ~2-isopr_pyl-indanyl-(5)]-glyoxylate . Formula V Rl = X = H R = isopropyl ; 10 Following the procedure of Example 2(a) but using 43g of 2-isopxopyl-indane and 42.2 g of ethyloxalyl chloride, 69 g ; ~ .
of ethyl [2-isopropyl-indanyl-(5)]-glyoxylate are obtained in . the form of an oil which is used in crude form for ths ~-remainder of the operations . -~ (b) 2-[2-Isopropyl-indanyl-(5)]-glyoxylic acid ~^, .- . . ~
~;~ Formula VI Rl - X = H : R2 = isopropyl Following the procedure of Example 2(b) but starting ;~i from 69 g of ethyl [2-isopropyl-indanyl-~5)]-glyoxylate, 58 g of 2-[2-isopropyl-indanyl-(5)]-glyoxylic acid are obtained in the form of pale yellow crystals, rPcrystallised from a 50/50 j mixture of hexane and cyclohexane.
.i ~i~ Melting point 55-60C, ... ~ ~ .
: ~c) [2-Isopropyl-indanyl-(5)]-acetic acid . .:

Formula I Rl = X = R3 - R4 = H

~ R2 = isopropyl ::~ : Following the procedure of Example 2(c) but startingfLom ' ~ - 22 -' .

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20 g of [2-isopropyl-indanyl-(5)]-ylyoxylic acid, 11 g of [2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from hexane, Melting point 80-81C.
Example 5 [1-Cyclohexyl-lndanyl-(5)]-acetic acid (a) Ethyl [l-cyclohexyl-indanyl-(5)]-glyoxylate .~ .
Formula V R2 = X = H Rl = cyclohexyl Following the procedure of Example 2(a) but using 70 g of l-cyclohexyl-indane and 54 6 g of ethyloxalyl chloride, :
110 g of ethyl [1-cyclohexyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder of the operations.
(b) [1-Cyclohexyl-indanyl-(5)~-glyoxylic acid :
Formula VI R2 = X = H Rl = cyclohexyl ~ Following the procedure of Example 2(b) but starting -7~ from 110 g of ethyl [1-cyclohexyl-indanyl-(5)]-glyoxylate, 90g ;~ of [l-cyclohexyl-indanyl-~5)]-glyoxylic acid are obtained in the form of an oil which is used in crude form for the remaind~r of the operations.

`~ 20 (c) [1-Cyclohexyl-indan~1-(5)]-acetic acid ;

; Formula I R2 = X = R3 = R4 =

Rl = cyclohexyl Following the procedure of Example 2tc~ but starting ~7~ from 30 g of [1-cyclohexyl-indanyl-(5)]-glyoxylic acid, 15.9 g `~ of [1-cyclohexyl-indanyl-(5)]-aceti.c acid are obtained in the ~;; form of white crystals, after recrystallisation from pentane.

Melting point 75-78C.
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~963611!3 Example 6 Sodium salt of 2-methyl-[1,3-dime-thyl~indanyl-(5)]-acetic acid (a) 2-Hydroxy-2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid ormula VII Rl = R2 CH3 X = H
The Grignard reagent, prepared from 34.2 g of magnesium in 75 ml of ether and 105 ml of methyl iodide in 200 ml of ether, is added dropwise to a solution, cooled in ice, of -65.5 of [1,3-dimethyl-indanyl-t5)]-glyoxylic acid in 900 ml - of ether. The addition lasts for 1 hour. The reaction mixture is then stirred at the temperature of the laboratory ~ . .
for 2 hours and is then poured onto 2 kg of ice and acidified by means of 10% strength hydrochloric acid. The mixture ~ ~ .
is extracted with ethyl acetate and the extract is washed with water and dried. After evaporation of the solvent, 53 g of 2-hydroxy~2-methyl-11,3-dimethyl-indanyl-(5)]-acetic acid are obtained and are used in crude form for the remainder of :~ :
~j the operations.
~ .
s~ (b) 2-Methylene-[1,3-dimethyl-indanyl-(5)] acetic acid : ~, Formula VIII Ql = R2 = CH3 X = H
; 20 A solution of 48 g of 2-hydroxy~2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid in 2.1 litres of dioxane and 105 ml . i~ .
of conce~trated sulphuric acid is heated under reflux ~or 2 hours and is then cooled and poured onto 2 kg of ice and il; extracted with chloroform.
The extracts are washed with water and dried over ,l sodium sulphate. After evaporation of the solvent, 42 g ;I of 2-methylene-[1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals~
, :,, ~ ' . : ....

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- ; - . . , . , . , . . . , ,; , ~ . , 36~L 51 Melting point 66-69C after recrystallisation from pentane (c) Sodium salt o 2-meth~l-[1,3-dimethyl-indan~l-(5)]-acetic acid ; Formula I Rl - R2 = R3 = CH
X = H Ra = Na 35.5 g of 2-methylene-[1,3-dimethyl-indanyl-(5)~-acetic acid dissolved in 350 ml of methanol are hydrogenated in the presence of 10 g of Raney nickel at 80C under 40 kg for 7 hours. After cooling, filtration and evaporation of ~, .
the filtrate, a thick white oil is obtained which does not . ::
- crystallise. 21.4 g of this oil are treated with a ` solution of 20 ml of sodium ethylate prepared from 2 g of . . .
sodium dissolved in 20 ml of ethanol, After evaporation . .
~; of the solvent, the residue is taken up in --~ether and 16 g of the sodium salt o 2-methyl-[1,3-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of a white powder which is soluble in water.
~ ~ .
~t Analysis: potentiometric ~etermination ~perchloric æid) ¦ Molecular weight found: 239.6 Molecular weight calculated- 240 ~ Example 7 ~ Isopropyl-indanyl-(5)]-acetic acid `~ (a) 2-Hydroxy-2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid Formula VII Rl = X = H
R2 = isopxopyl Following the procedure of Example 6(a) but starting t from 44 g of [2-isopropyl-indanyl-(5)]-glyoxylic acid, 39 g of 2-hydroxy-2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are '$. :

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obtained in the form of white crystals, after recrystalliza-~ tion from isopropanol.
- Melting point 140-143C.
(b) 2-Methylene-[2-isopropyl-indanyl-(5)]-acetic acid :
Formula VIII Rl = X = H
R2 = isopropyl Following the procedure of Example 6(b) but using 21,8 g of 2-hydroxy-2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, 19 g of 2-methylene-[2-isopropyl-indanyl-~5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 145-148C.
(c) 2-Methyl-[2-isopropyl-indanyl-(5)]-acetic acid ` Formula I Rl = X = R4 = H
~ . .. . .
~ R2 = isopropyl 3 3 ;
-- A solution of 19 g of 2-methylene-[2-isopropyl-'~'J indanyl-(5)]-acetic acid in 250 ml of dio~ane containing 1.5 g --of S~ strength Pd/C i5 hydrogenat~d under a pressure of 50 kg for 4 hours. The catalyst is filtered off and the filtrate .-: ~
is concentrated in vacuo. 15 g of 2-methyl-[2-iso-`i~ 20 prop~l-indanyl-(5)]-acetia acid are thus obtained in the form . . .
of white crystals, after recrystallisation from pentaneO
Melting point 81-83C.
Example 8 H~drochlo~ide _f the morpholino-ethyl_es er of [2-isopropyl-indanyl-(s)]-acetic acid (a) [2-Isop_o~ l-indanyl- (5? ]-acetic acid chloride Formula IX Rl = R3 = X = H
R2 = isopropyl : i , :

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~0~3618 A solution of 9 g of [2-isopropyl-indanyl-(5)]-acetic ~ acid and 6 g of thionyl chloride in 50 ml of benzene is heated ; at 80C for 2 hours. The solvent and the excess thionyl chloride are then evaporated in vacuo. The oil obtained ` is used in crude form for the remainder of the operations.
(b) Hydrochloride of the morpholino-ethyl ester of [2-isopropyl-indanvl-(5)]-acetic acid Formula I Rl = R3 = X = H -R2 = isopropyl R4 = CH2 ~ CH2 ~
6 g of morpholino-ethanol are added dropwise at 0C to `' a solution of [2-isopropyl-indanyl-(5)~-acetic acid chloride, prepared from 9 g of acid, in 100 ml of ether. The mixture is stirred for 1 hour at ambient temperature and is then 3 taken up in 100 ml of water containing 5% of hydrochloric acid.
The aqueous phase is isolated and rendered alkaline at 0C by means of a 5% strength solution of sodium hydroxide, and the organic products are extracted with ether. The ether 2~f extracts are washed with water and dried over sodium carbonate.
~' 20 After evaporation of the ether, 7 g of the morpholino-ethyl - ester of t2-isopropyl-indanyl-(5)]-acetic acid are obtained.
On adding a solution of hydrogen chloride in e~her and re-crystallising from acetone, 7 g of the hydrochloride are . ...................................................................... .
~ obtained in the form of white crystals.
l Melting point 153-156C.
~, Example 9 Morpholino-ethyl ester of 2-methyl-[2-isopropyl-~-f indanyl-(5)]-acetic acid ~ ''t,i, (a) 2-Methyl-[2-isopropyl-inda~y~-(5)]-acetic acid chloride .~:'~
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~63f~8 :
Formula IX Rl = X = H
R2 = isopropyl R3 = CH3 Following the procedure of Example 8(a), 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride is prepared from 10 g of acid.
(b) Morpholino-ethyl ester_of 2-methyl-[2-iso~ropyl-indanyl-(5)]-acetic acid ~ .. . .
~;~ Formula I Rl = X = H ~-R2 = isopropyl R8 = CH3 R4 = CH2 - CH2 ~
-~ Following the procedure of Example 8(b) but using i~2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride pre-0~pared from 10 g of acid, 7 y of the morpholino-ethyl ester of ~ --2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid~are obtained.
,.. ~ .
After adding 2.55 g of oxalic acid in acetone and re-crystallising from acetone, 7.3 g of the oxalate are obtained in the form of white crystals.
~, 20 Melting point 135-140C.
~- Example 10 2-Methyl-[2-isopro~yl-indanyl-(5)]-acetic acid ~., .
~ ~a) [2-Isopropyl-indanyl-~5)]-methyl ketone 'j A solution of 100 g of 2-isopropyl-indane and 65 ml of ~
~`~, acetic anhydride in 400 ml of methylene chloride is added over ~ -the course o~ 1 hour to a stirred suspension of 190 g of , aluminium chloride in 400 ml of methylene chloride, whilst .. . .
cooling in such a way that the temperature of the reaction mixture remains below 10C. The mixture is then stirred ''''i ' ' . ' ;'., ~
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J1~636~
for 5 hours at the temperature of the laboratory and is then poured onto 2 kg of i e and acidified to pH 3 by means of ~ hydrochloric acid. The methylene chloride phase is -; isolated and the mother liquors are extracted with methylene chloride. The methylene chloride phases are combined, washed with water and dried over sodium sulphate. After evaporation of the solvent, the residue, weighing 137 g, is distilled in vacuo; 105.5 g of [2-isopropyl-indanyl-(5)]-methyl ketone are thus obtained in the form of white crystals which melt at a very low temperature ( ~40C).
Boiling point 1.5 mm Hg (b) ~-[2-Isoprop~l-indanyl-(5)]-ethanol ~; 25.6 g of potassium borohydride are added in small ~, . .
portions to a solution of 105.5 g of [2-isopropyl-indanyl-(5)]-, methyl ketone in 600 ml of methanol, After the reaction mixture has been stirred magnetlcally at the temperatura of the laboratory for 3 hours, it is concentrated in vacuo, ice is added to it, and the organic products are extracted with ether. After washing with water and drying over medium sulphate, the ether is evaporated. 106 g of a [2-isopropyl-~'A' indanyl-(5)]-ethanol are thus obtained and are used in cruda ' form for the remainder of the operations.
(c) ~-[2-Isopropyl-indanyl-(5)]-ethyl chloride ~Ji~ 70 ml o thionyl chloride are added over the course of 2 hours to a solution of 106 g of d- [2-isopropyl-indanyl-(5)]-j ~ ethanol in 500 ml of benzene, whilst stirring magnetically.
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After stirring for 15 minutes at ambient temperature, the reaction mixture is poured onto ice. The benzene phase is isolated and the mother liquors are extracted with ether.
The combined organic phases are washed with water, with a 5% strength bicarbonate solution and then again with water and are finally dried over sodium sulphate. After the organic solvents have been evaporated in vacuo, the residue `~ obtained is distilled in vacuo. 104.1 g of a-[2-iso-propyl-indanyl-(5)]-ethyl chloride are thus isolated in the form of an oil.
; Boiling point 1 5 mm ~g = 132-136C- ;~
(d) [2-Isopropyl-indanyl-(5)]-2-methyl-acetonitrile A solution of 104.1 g of~-[2-isopropyl-indanyl-(5)]-ethyl chluride in 70 ml of dimethylsulphoxide is added drop-'''f wise to a solution of 24.3 g of sodium cyanide in 210 ml of ~ dimethylsulphoxide. After the end of the addition, the : . : . .
reactIon mixture is heated at 70-80C for 4 hours 30 minutes.
i The reaction mixture is then cooled, taken up in a mixture of water and ice and extracted with ether. The ether extracts j 20 are washed carefully with water and dried over sodium sulphate.
After evaporation of the ether, the residue is distilled in ;, vacuo; 74,1 g of [2-isopropyl-indanyl-(5)]-2-methyl-acetonitrile are thus obtained in the form of an oil.
Boiling point 1.5 mm Hy ~! (e) 2-Meth 1-[2-iso~ro~vl-indanYl (5)]-acetic acid ' A solution of 74.1 g of [2-isopropyl-indanyl-(5)]-;,)j ' '.

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2-methyl-acetonitrile in 185 ml of ethanol containing 185 ml of water and 74 g of potassium hydroxide is heated under reflux for 12 hours.
Ice and water are added to the reaction mixture and the neutral products are extracted with ether.
After acidifying the cold mother liquors, the acid is extracted with ether. The ether phase is washed with water and dried over sodium sulphate.
After evaporation of the ether and recrystallisation (of the residue) from petroleum ether, 50.6 g of 2-methyl-[2-isopropyl-indan~l-(5)]-acetic acid are obtained in the form of white crystals. -Melting point 81-83C.
Example 11 [2-Cyclohexyl~indanyl~(5~]-acetic acid ~-~- (a) Ethyl [2-cyclohexyl-i_danyl-(5)]-ylyoxylate ,~ Formula V Rl = X - H R2 = cyclohexyl A solution of 110.3 g of 2-cyclohexyl-indane and 86 g of ethyloxalyl choride in 400 ml of methylene chloride is ~;
~`l added over the course of 1 hour to a stirred suspension of ., 20 128 g of aluminium chloride in 400 ml of methylene chloride, ~; whilst cooling in such a way that the temperature of the -` reaction mixture remains below 5C. The mixture is then stirred for 2 hours at the temperature of the laboratory and is then poured onto 2 kg of ice and acidified to pH 3 by means ~1 of hydrochloric acid. The methylene chloride phase is isolated and the mother liquors are extracted with methylene .~ .
~`, chloride. The methylene chloride phases are combined, washed with water saturated with sodium chloride and dried ~'.JZ ~' ' j 31 ~- "
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over sodium sulphate.
After evaporation of the solvent, 156.3 g of ethyl [2-cyclohexyl-indanyl-(5)]-glyoxylate are obtained and are used in crude form for the remainder of the operations (b) [2-Cyclohexyl-indanyl-(5)]-glyoxylic acid Formula VI Rl = X = H R2 = cyclohexyl A solution of 156 3 g of ethyl [2-cyclohexyl-indanyl-(5~]-glyoxylate in 700 ml of ethanol, which has been treated with a solution of 30 g of sodium hydroxide in 700 ml of water, is heated under reflux for 2 hours. The mixture is then ;:, . ~:
cooled, diluted with 350 ml of water and acidified at ooC by ~--means of 10% strength hydrochloric acid. The mixture is extracted with ether which is washed with water, dried over sodium suIphate and evaporated. 136 g of ~2-cyclohexyl- -indanyl-(5)]-glyoxylic acid are thus obtained in the orm oE
pale yellow crystals, after washing with a mixture of pentane and petroleum ether. -~
,! Melting point 117-121C.
., : . , ~r, ( C~ ~ ~ ~ ~ ~
' ,~i :. ' ' , -`i 20 Formula I Rl = R3 = X = H
R2 = cyclohexyl A mixture of 40 g o [2-cyclohexyl-indanyl-(5)]-, :!,~ glyoxylic acid and 100 ml of hydrazine hydrate is heated under reflux for ~5 minutes. The mixture is cooled to 70C
and 50 g of potassium hydroxide pellets are added in small . ~ . , ~: .3 ~ 2 - ~ -, " ' , : J
', : . .

1~3636:1~8 portions. After the end of the addition, the mixture is heated under reflux for 1 hour 30 minutes and then the excess hydrazine hydrate is evaporated in vacuo; the solution is then cooled and diluted with distilled water, and the neutral products are extracted with chloroform.
- The mother liquors are acidified at 0C by means of 10% strength hydrochloric acid and the acid is extracted with ether which is washed with water, dried and evaporated~ -After recrystallisation from a 50/50 mixture of cyclohexane - 10 and hexane, 29 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid are obtained in the form of white crystals.
Melting point 126-132C.
Example 12 [2-Methyl-lndanyl-(5)]-acetic acid ..
~`! (a) Ethyl t2-methyl-indanyl-(5 ~ 1ate Formula V Rl = X = H R2 = methYl ~`! - Following the procedure of Example ll(a) but using 66 g of 2-methyl-indane and 78.5 g of ethyloxalyl chloride, ~1 i ~;~ 110 g of ethyl ~2-methyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the , . , remainder of the operations.
~.;i:
~b) [2-Methyl-indanyl-(5)]-glyox~lic acid Formula VI Rl = X = H R2 = CH3 Following the procedure of Example ll(b) but starting ,^l from 110 g o~ ethyl [2-methyl-indanyl-(5)]-glyoxylate, 98 g of -~l [2-methyl~indanyl-(5)]-glyoxylic acid are obtained and are ~ used in crude form for the remainder of the operations.

3i ~ .

,~ . .

'~ .
., :
:,,, , ~ , , ' : .. ' ' " .; ' ., .. . . . . . . .

~0636~8 -(c) [2-Methyl-indanyl-(5)]-acetic acid Formula I Rl 3 Following the procedure of Example ll(c) but starting ~ from 40 g of [2-methyl-indanyl-(5)]-glyoxylic acid, 26 g of ; [2-methyl-indanyl-(5)]-acetic acid axe obtained in the form of white crystals, after recrystallisation from pentane Melting point 57-58C. - -~ [2,_-Dlmethyl-indanyl-(5)]-acetic acid (a) Ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate :
~, 10 Formula V X = H R R CH ~-Following the procedure of Example ll(a) but using 68 g of~2,2-dimethyl-indane and 73.5 g of ethyloxalyl chloride, 110 g of ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude orm for ~-the remainder of the operations. ~
(b) [2,2-Dimethyl-indanyl-(5)]-glyoxylic acid `
~ ~ .
Formula VI X - H Rl = R2 = CH3 -~; Following the procedure of Example ll(b) but starting from 110 g-of ethyl [2,2-dimethyl-indanyl-(5)]-glyoxylate, 92 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid are obtained .
~ and are used in crude form for the remainder of the operations. ~ -, !,` : .
(c) [2,2-Dimeth~l-indanyl-(5)]-acetic acid, Formula I R3 = X - H Rl = R2 = CH3 Following the procedure of Example ll(c) but starting from 35 g o~ [2,2-dimethyl-indanyl-(5)]-glyoxylic acid, 24.7 g ~3 .
-~ 3~ ~
.i ~ , .

, J~ . .
~''~ ' .
'.~ ' . ' , :-, . : .. ~ . : .
, ",, .,-" , ", , ,, , :, .... .. . .. .. . . . . . .
.~ ., ,.. -.,, ., ., .. ,,, .. , . ,, .. .,., . . ., , ~ . .

6361~

of [2,2-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from pentane.
Melting point ~40C.
Example 14 2-Methyl-L2-cyclohexyl-indanyl-(5)]-acetic acid .
(a) 2-Hydroxy-2-methyl-[2-cyclohexyl-indanyl-(5~]-acetic acid Formula VII Rl = X = H R2 = cyclohexyl R3 = CH3 The Grignard reagent prepared from 42.3 g of magnesium and 135 ml of methyl iodide in 850 ml of anhydrous ether is ` added dropwise to a solution, cooled in ice, of 100 g of [2-cyclohexyl-indanyl-(5)]-glyoxylic acid in 850 ml of anhydrous ether. The addition lasts for 1 hour. The ; reaction mixture is then stirred at the temperature of the laboratory for 2 hours and is then poured onto kg (sic) of ice -.:' and acidlfied by means of 10% strength hydrochloric acid.
The mixture is extracted with ethyl acetate which is washed .::
;~ with water and dried. After evaporation of the solvent and washing the crystals obtained with petroleum ether, 80.2 g , of 2-hydroxy-2-methyl-[2-cyclohexyl-indanyl-(5)~-acetic acid ' "i are obtained in the form of white crystals.
'''~!~: ' Melting point 142--144C.
(b) 2-Methylene-[2-cyclohexyl-indanyl-(5)]-acetic acid Formula VIII Rl = X = H R2 = cyclohexyl ~j ~'3 = H
~1 A solution of 80.2 g of 2-hydroxy-2-methyl [2-cyclo-hexyl-indanyl-(5)]-acetic acid in l.9S0 1 of dioxane and 106 ml of concentrated sulphuric acid is heated under reflux for 2 hours and is then cooled and poured onto 2 kg of ice.
~ ~ .

~ ~ 35 ~

`1 . ~ . . .

-! `- :

, The precipitate obtained is washed with water and drled. 72 g of 2-methylene-[2-cyclohexyl-indanyl-(5)]-acetic acid are ~ -~ thus obtained in the form of light beige crystals.
`~ Melting point 179-182C.
(c) 2-Methyl-[ cyclohex~l-indanyl-(5)]-acetic acid -Formula I Rl = X = H R2 = cyclohexyl R = CH
72 g of 2-methylene-[2-cyclohexyl-indanyl~(5)]-acetic acid dissolved in 600 ml of dioxane are hydrogenated in the presence of 10 g of Raney nickel at 80C under 50 kg for 7 1-hours. After cooling, filtration and evaporation of the filtrate, the crystals obtained are recrystallised from a ,'f" 10/90 mixture of toluene and petroleum ether; 48 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid are thus obtained ~-in the form of white crystals.
~! .:
:,' ' : :~ ' ,, .
' Melting point 119-121C.
. .I .
'i Example 15 Sodium salt of 2-methyl-[2-methyl-indanyl-(5)]-:~ . ... ..
;1 acetic acid J~ (a) 2-H drox -2-methyl-[2-meth l-indan 1-(5)]-acetic acid i j Y Y Y Y _ _ , ~, 20 Formula VII Rl = X = H R2 = R3 = C~3 Following the procedure of Example 14ta) but starting ~;i from 63 g of [2-methyl-indanyl-~5)]-glyoxylic acid, 48 g o ~i 2-~ydroxy-2-methyl-~2-methyl-indanyl-(5)]-acetic acid are !~ ~ obtained in the form of white crystals.

~,~ Melting point 97-100C.

(b) 2-Methylené-~2-methyl-indanyl-(5)]-acetic acid i Formula VIII Rl = X = H R2 ~ CH3 f R'3 = H

,i , ,. ~ , . .

i ' .. . '' 'f' . :
` '' ' ' ' ' f '~ : ' ':' ~,. ' :' f ::

Following the procedure of Example 14(b) but starting from 33 g of 2-hydroxy-2-methyl-[2-methyl-indanyl-(5)]-acetic acid, 29 g of 2-methylene-[2-methyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
Melting point 119C.
(c) Sodium salt o~ 2-methyl-[2-methY~l-indanyl-(5)]-acetic acid Formula I Rl = X = H R2 = R3 = CH3 R4 = Na 29 g of 2-methylene-[2-methyl-indanyl-~5)]-acetic acid dissolved in 200 ml of methanol are hydrogenated in the presence of 10 g of Raney nickel at 80C under 50 kg for 7 hours. After cooling, filtration and evaporation of the . ,;~ . .
filtrate, an oil is obtained which does not crystallise.
.~ 14.6 g of this oil are treated with a solution of 20 ml of sodium ethylate prepared from 1.65 g of sodium dissolved in 20 ml of ethanol. After evaporation of the solvent, the -residue is taken up in ether and 13 g of the sodium salt of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid are obtained in ,~ .
the form of a white powder which is soluble in water.
Melting point 127-130C.
Exam~le 16 2-Methyl-[2~2~d~m~t~5~l=L~a~ -(5)]-ac~tlc acid (a) 2-HvdroxY-2-methYl-[2,2-dimethYl-~indanyl-(5)]-acetic acid Formula VII X = H Rl = R2 = R3 CH3 Following the procedure of Example 14(a) but starting ~-from 62 g of [2,2-dimethyl-indanyl-(5)]-glyoxylic acid, 37.3 g of 2-hydroxy-2-methyl-[2,2-dimethyl-indanyl(5)]-acetic acid i~ are obtained in the form of white crystals.
i Melting point 99-103C.
'~i ' ' ' '" '. .

; _ 37 _ ' :
~: .

, ' ' , . .
- . : : :, . ' :.: :

, . . . . . . .. . . .. . .

1(~63~18 (b) 2-Methylene-[2,2-dimeth~l-indanyl-(5)]-acetic acid Formula VIII X = H Rl = R2 = CH3 R 3 = H
Following the method of Example 14(b~ but starting from 37.3 g of 2-hydroxy-2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid, 39 7 g of 2-methylene-[2,2-dimethyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
.~ Melting point 115C, ~ (c) 2-Meth 1-[2 2-dimethvl-indanYl-(5)]-acetic acid Y ~ ~ . _ . , Formula I X = H R1 = R2 = R3 = CH3 ~`~ 10Following the procedure of Example 15(c) but starting from 30.7 g of 2-methylene-[2,2-dimethyl-indanyl-~5)]-acetic , .
` acid, 22 5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)~-acetic acid are obtained in the form of white crystals, after re-crystallisation from pentane.
:~ .
~; Melting point 64-65C.
Example ~ 2 Ethyl-[2-isopropyl-indanyl-(5)]-acetic acid l (a~ 2-Hydrox~-2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid ;1 Formula VII Rl = H R2 = isopropyl ~, R3 ~ C2H5 Following the procedure of Example 14(a) but starting from 64~5 g of ~2-isopropyl-indanyl-~5)]-glyoxylic acid (des-cribed above) and 207 g of ethyl bromide, 70.9 g of 2-hydroxy-2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained -,';i: :
l in the form of white crystals.

:JI Melting point 113~116C. ~
'., ,. :
: J : ':

, ~, .

, ~:
'~. ' ' .
;''i ~ :
. ' ' :, - '~'' '. ' ' ' , ~ , ~ , , ' , ', :, ~3618 (b) 2-Ethylene-[2-isopropyl-indanyl-~5)]-acetic acid Formula VIII 1 R2 = isopropyl R'3 = CH3 Eollowing the procedure of Example 14(b) but starting from 70.9 g of 2-hydroxy-2-ethyl-[2-isopropyl-indanyl-(5)~-acetic acid, 60.7 g of 2-ethylene-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of light beige crystals.
.r' Melting point 118-123C.
' (c) 2-Ethyl-[2-isopropyl-indanyl-(5)]-acetic acid ; 1 Formula I Rl = X = H R2 = isopropyl R3 = C2H5 Following the procedure of Example 15(c) but starting from 60.7 g of 2-ethylene-[2-isopropyl-indanyl-(5)]-acetic acid, 40 g of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrys~allisation - -from pentane.
l Melting point 78-80C, .~Ji Example_18 2-Methyl-[2-ethyl-indanyl-(5)]-acetic acid (a) ~
Formula V Rl = X = H R2 C2H5 Following the procedure of Example ll(a) but using 77 g of 2-ethyl-indane and 83 g of ethyloxalyl chloride, 116,3 g , . . .
of ethyl [2-ethyl-indanyl-(5)]-glyoxylate are obtained in the form of an oil which is used in crude form for the remainder -,~ of the operations.

~3 ;, - 39 -.:
.' :

~, , . : ' ~, .
,~ , .
": , - . . : .

` ~ ;3618 . .
` ~b~ 12-Ethyl-indanyl-(5)]-glyoxylic acid Formula VI Rl - X = H 2 2 5 Following the procedure of Example ll(b) but using 116.3 g of ethyl [2-ethyl-indanyl-(5)]-glyoxylate, 93.6 g of [2-ethyl-indanyl-(5)]-glyoxylic acid are obtained and are used in crude form for the remainder of the operationsO
(c) 2-Hydroxy-2-methyl-[2-ethyl-indanyl-(5)~-acetic acid Formula VII Rl = X = H R2 = C2H5 Following the procedure of Example 14(a) but starting from 93.6 g of [2-ethyl-indanyl-(5)]-glyoxylic acid, 100 g of 2-hydroxy-2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are' obtained and are used in crude form for the remainder of the , ` operations.

(b) 2-Methylene-[2-ethyl-indanyl-(5)]-acetic acid Formula VIII Rl = X = H 2 2 5 ~ R 3 = H
i~l Following the procedure of Example 14(b) but starting '''! from 100 g of 2-hydroxy~2-methyl-[2-ethyl-indanyl-(5)]-acetic -aci~, 77.5 g of 2-methylene-[2-ethyl-indanyl-(5)]-acetic acid ~ are obtained in the form of crystals.

"t'; ~ Melting point 88-91C.
1: .
"~! ~e) 2=Methyl-[2-ethyl-indanyl-(5)]-acetic acid ~

Formula I Rl - X = H R2 = C2H5 ~, f _ 40 -. .
., ' .

. " ........... ...
.

;36~L8 ; Following the procedure of Example 15(c) but starting from 77.5 g of 2-methylene-[2-ethyl-indanyl-(5)]-acetic acid, a residue weighing 79 g is obtained and is distilled in vacuo.
53.6 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are thus isolated and crystallise from pentane in the form of white crystals.
Melting point 44-46C.
Example l9 Dimethylaminoethanol salt of 2-methyl-[2-isopropyl-indanyl-,;:
~.~ lO (5)]-acetic acid :~;
Formula I Rl = X - H R2 = isopropyl ~ 4.5 g of dimethylaminoethanol are added to 11.6 g of ;~ 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, melting point 81-83C (described above), dissolved in 50 ml o ether.

~' The solution is concentrated in vacuo and the residue is -~ dilted with 50 ml of pentane. 9~8 g of the dimethyl-ji aminoethanol salt of 2-methyl-[2-isopropyl-indanyl-(5)]-, acetic acid are precipitated under cold conditions in the form of white crystals.

~; Melting point 59-60C.

Example 20 : , Dimethylaminoethanol salt of 2-ethyl-[2-isopropyl-indanyl-~5)]-acetic acid Formula I Rl = X a H R2 = isopropyl ' ~3 Following the procedure of Example 19 but starting s from 13.5 g of 2-ethyl-~2-isopropyl-indanyl-(5)]-acetic acid .'s . ~ , , ' s' ,s' ::.

" !

/', ' ' ' - , ' ' , ,' " ' :
..

636~8 .
and 4,9 g of dimethylaminoethanol, 11,2 g of the dimethylamino-ethanol salt of 2-ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals.
Melting point 69-71C.

Example 21 Hydrochloride of the morpholino-ethy1 ester of t2-mëthyl-indanyl-(5)]~acetïc acld (a) [2-Methyl-indanyl-(5)]-acetic acid chloride Formula IX 1 3 H R2 = CH3 A solution of 11 g of [2-methyl-indanyl-(5)]-acetic acid and 7.5 ml of thionyl chloride in 75 ml of benzene is heated at 80C for 2 hours. The solvent and the excess thionyl chloride are then evaporated in vacuo, The residue obtained is fractionated in vacuo to yield 8.6 g of [2-methyl-indanyl-(5)]-acetic acid chloride in the form of a liquid.

'? Boiling point 12 mm Hg = 148-151 C.
, .
~, (b) Hydrochloride of the morpholino-ethyl ester of [2-methyl- ~
-, -- -- :::.
~ indanyl-(5)]-acetic_acid -~ Formula I Rl = R3 - X = H

~` R4 = CH2 CH2 3 ,~; A solution of 8.6 g of ~2-methyl-indanyl-(5)]-acetic , acid chloride in 50 ml of benzene is added dropwise to a solu-tion of 5,4 g of morpholino-ethanol in 150 ml of anhydrous benzene containing ?. 7 ml of triethylamine, whilst keeping the i reaction mixture at 0C. After the end of the addition, . ~
~ the reaction mixture i5 stirred for 2 hours at ambient tempera-;i ture and is then left to stand overnight. The benzene .

~ .
s ~ .

~: - . ,., , ~ , , , ~ P063618 phase is isolated and the mother liquors are extracted with ether, The combined organic phases are washed carefully with water and then dried over sodium sulphate. After concentration in vacuo, the residue is taken up in a mixture of acetone and ether and a solution of hydrogen chloride in either is added thereto to yield 9.4 g of the hydrochloride of the morpholino-ethyl ester of [2-methyl-indanyl-(5)]-acetic ;
acid in khe form of white crystals.
Melting point 107-110C.
: - .
10 Example 22 Oxalate of the morpholino-ethyl ester of 2-methyl- -[2-methyl-indanyl-(5)]-acetic acid :~ .
~; ~a) 2-Methyl-[2-methyl-indanyl-(5)]-acetic acid chloride !" . ~- ---- - ........ .... _. _ __ ...... _ .
, Formula IX Rl = X = H 2 3 3 A solution of 11.3 g of 2-methyl-[2-methyl-indanyl-- (5)]-acetic acid and 7 ml of thionyl chloride in 100 ml of benzene is heated at 80C for 2 hours. The solvent and ,~ the excess thionyl chloride are then evaporated in vacuo.
~` The oil obtained is used in crude form for the remainder of the operations.
... . .
~ 20 (b) Oxalate of the mor~holino-eth~ ester of 2-methyl-[2-methYl- ~
:: .
indanyl-(5)]-acetic acid ~Formula I Rl = X = H R2 R3 3 ?~R4 = CH2 - CH2 - N O
~, .
~, Following the procedure of Example 21(b) but starting from 7 g of 2-methyl-[2-methyl-indanyl-(5)]-acetic acid ~3 chloride, 6.8 g of the morpholino-ethyl ester of 2-methyl-~ ,1 [2-methyl-indanyl-(5)]-acetic acid are obtained in khe form ~'j of an oil. On adding 2.7 g of oxalic acid dissolved in ;1 "

. I .
!
'' .", ;' ' ::
,:, :, '' ':'; ' , ,. . . : .', " ,. ,, ' .. :
.: ,:

1~63~L8 ethanol, 7.1 g of the oxalate of the morpholino-ethyl ester of 2-methyl-[2-methyl-indanyl-~5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from isopropanol.
Melting point 140-145C.
Example 23 Hydrochloride of the morpholino-ethyl ester of [2,2-dimethyl-indanyl-(5)]-acetic acid -(a) [2,2-Dimethyl-indanyl-(5)]-acetic acid chloride `~ Formula IX R3 = X = H Rl = R2 = CH3 -Following the procedure of Example 21(a) but starting from 16g of [2,2-dimethyl-indanyl-(5)]-acetic acid, there ~ are obtained, after distillation of the residue in vacuo, .~,! 14.7 g of [2,2-dimethyl-indanyl-(5)]-acetic acid chloride in -~'~ the form of a liquid.
: . .
~ Boiling point 10 mm Hg ;`1 (b) Hydrochloride of the morpholino-eth~_ester of ~2,2-dimethyl-indanyl-(5)1-acetic acid ~, Formula I R3 = X = H Rl = R2 = CH3 R4 = CH2 - CH2 ~ ~ O
Following the procedure of Example 21(b) but starting ~ from 14,7 g of [2,2-dimethyl-indanyl-(5)]-acetic acid chloride, . ...
a residue is obtained after evaporation of the organic solvents . ,~
in vacuo; this residue is taken up in a mixture of acetone and ather and a solution of yydrogen chloride in ether i5 added thereto to yield 16 g of the hydrochloride of the morpholino-ethyl es~er of t2,2-dimethyl-indanyl-(5)]-acetic ~ acid in the form o~ white crystals.
;~ Melting point 145-150C.

~ - 4~

.'" ' ' , 1~63611~
Example 24 Hydrochloride of the morpholino-ethyl ester of 2-methyl=]2,2-dimethyl-indanyl-(5)-acetic acid (a) 2-Methyl-[2,2-dimethyl-indanyl-(5)]-acetlc acid chloride -Formula IX X = H R = R2 = R3 = CH3 Following the procedure of Example 21(a) but starting from 10.2 g of 2-methy-1-[2,2-dimethyl-indanyl-(5)]-acetic acid, 10.5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic `
acid chloride are obtained ~n the form of an oil which is used in crude form for the remainder of the operations.
(b) Hydrochloride of the morpholino-ethyl ester of 2-methyl-`~ [2,2-dimethyl-indanyl-(5_3-acetic acid ., Formula I X = H Rl = R2 = R3 - CH3 `
R4 CH2 CH2 N~ O
Following the procedure of Example 21(b) but starting from 10.5 g of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid -chloride, there are obtained, after having taken up the resi-duP obtained in a mixture of acetone and ether and after having added a solution of hydrogen chloride in ether there-to, 12 g of the hydrochloride of the morpholino-ethyl ester . i , 20 of 2-methyl-[2,2-dimethyl-indanyl-(5)]-acetic acid in the `
ii form of white crystals.
;i~ Melting point 140-142~C.

2-methyl-[2-cyclohexyl~indanyl-(5)~-acetic acid ~`3~ 2-Methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid chlorlde . " .
; Formula IX X = R2 = H Rl = cyclohexyl Following the procedure of Example 21(a) but starting : ( .
from 10 g of 2-methyl-[2-cyclohexyl-indanyl-(5)] acetic acid, ~..................................................................... -:

~ - 45 -.. ~11, . ~ ' .
", ~' : ,`
:1 : ", : , .:, , : ` ` `, ' , ,. .. ,: : , ' ; ~ , 10636~8 .
... .
` 10~2 g of 2-methyl-[2-cyclohexyl-indanyl-(5)] acetic acid chloride are obtained in the form of an oil which is used in crude form for the remainder of the operations.
(b) Hydrochloride of the morpholino-eth~l ester of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid Formula I X = R2 = H Rl = cyclohexyl -R4 = CH2 - CH2 - N~ O
- Following the procedure of Example 21(b) but starting from 10.2 g of 2-methyl-[2-cyclohexyl-indanyl-(5)]-acetic acid chloride, there are obtained, after having diluted the ~, residue obtained ~ith a mixture of acetone and ether and after having added a solution of hydrogen chloride in ether thereto, 8.9 g of the hydrochloride of the morpholino-ethyl , ester of 2-methy-[2-cyclohexyl-indanyl-(5)]-acetic acid in the form of white crystals.
Melting point 154-156C.
'l Oxalate of the_m rpholi o ~ ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid (a) 2-MethYl-~2-ethy-l--ind-a-n-y-l-(5)J-acetic acid chloride Formula IX R2 = X = H 1 2 5 ~ R3 = CH3 ;','~f Following the procedure of Example 21(a) but starting from 19.2 g of 2-methyl-[2-ethyl-indanyl-~5)]-acetic acid, 18.5 g of 2-methyl-[2-ethyl-indanyl-(S)]-acetic acid chloride , : ', are obtalned, after dis~illation of the residue in vacuo.

Boiling point 10 mm Hg .~, .. :. .
~J :

. ~j .

. :

: ',- , . , . . , , '., ' . ' i ' ,: ' ' ' : ' ` ':
.. ,, . ~ .

: `
: ~`
6361~

(b) Oxalate of the morpholino-ethyl ester of 2-methyl-[2-ethyl-.
indanyl-(5)]-acetic acid Formula I R2 = X = H 1 C2H5 R3 = CH3 ., / ~ .
4 CH2 CH2 N~____~O
Following the procedure of Example 21(b) but starting from 16.5 g of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid chloride, 15 g of the morpholino-ethyl ester of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of ~
;~ an oil, On adding 5.5 g of oxalic acid dissolved in -ji ethanol, 15.5 g of the oxalate of the morpholino-ethyl ester , ......................................................................... .
of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid are obtained in the form of white crystals, after recrystallisation from .. ~:i . .
ethanol.
Melting point 143-145C.
. . .
Example 27 ~ydrochloride of the dimet ylaminoethyl ester of -methyl-[_ lsopropyl-indanyl-(5)]-acetic acid (a) 2-Meth 1-[2-isoprop 1-indanyl-(5)]-acetic acid chloride , ~I Y _ Y
` Formula IX R2 = X s H Rl 2 isopropyl R3 = CH3 ' !', Following the procedure of Example 21(a) but using ~?, 31.7 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid, - melting point 81-83C, described above, there are obtained, after distillation of the residue in vacuo, 30.1 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride.
~' Boiling point 1 mm Hg 150 C.
(b) Hydrochloride of the dimethylaminoethyl ester of 2-methyl-- - - -- ; . . .

` i. : : -'' .''' ~' ,, : :.

~,', ' '.

: :~LCI 636~8 2-isopropyl-indanyl-(5)]-acetic acid Formula I Rl - X = H
R2 = isopropyl R3 = CH3 .~ R4 = CH2 - CH2N ~.
CH
Following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride .
;~ and 3,6 g of dimethylaminoethanol, a residue is obtained after ;
:~. evaporation of the organic solvents in vacuo; this residue is `l taken up in a mixture of acPtone and ether and a solution of ~i~ hydrogen chloride in ether is added thereto to yield, after ~' recrystallisation of the crystals obtained from acetone,ll.4 g ',.; of the hydrochloride of the dimethylaminoethyl ester of 2~
:i methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of ' "'I
white crystals.
~"'''! Melting point 123-124C. :.
i :
Example 28 `.'~'!'1 O~alate of the diethylaminoethyl ester of 2-methyl-[2-isopropyl-` ,! ~ ' ^indanyl-~S)]-acetic acid 20 Formula I R2 = X = H Rl = isoP~rPYl .;~ R3 CH3 :;.,,," ~C2H5 ' ~
R4 = CH2 - CH2N ~ ~ :
,, , C2H5 ~ Following the procedure of Example 21(b) but using 10 g :~
of 2-methyl-[2-isopropyl-indanyl-(5~]-acetic acid chloride . and 4.1 g of d1ethylaminoethanol, 10 g of the diethylamino~
~ ' .'~. .
~,,:~ .:::
'~ - 48 -.i '., ' ~ ' ' ', .
, " ;~
~ .

106361~3 ~. ethyl ester of 2-~ethyl-[2-isopropyl-indanyl-(5)]-acetic acid are obtained, after evaporation of the organic solvents in vacuo; 3.8 g of oxalic acid dissolved in ethanol are added to the above ester to yield, after recrystallisation from ~ isopropanol, 11 g of the oxalate of the diethylaminoethyl . .
ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in ~ the form of white crystals.
Melting point 135-137C.
. Example 29 - ~
10 Maleate of the dimethylamino- ~-d~methyl-ethyl es.ter of 2--~ methyl-[2-isopropyl-indanyl-(5)]-acetic acid -~ Formula I R2 = X = H
:'! Rl = isopropyl -.

i 3 3 CH3 ~ 3 R4 = CH2 - C - N \

~` CH3 3 . ~: .
. : Following the procedure of Example 21(b) but using 10 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride and ~- 4.1 g of dimethylamino- ~-dimethyl-ethanol, 11 g of the dimethylamino- ~ -dimethyl-ethyl ester of 2-methyl-[2-iso-~, propyl-indanyl-(5)]-acetic acid are obtained; 3.8 g of ;
., maleic acid dissolved in acetone are added to the above ester to yield 11.2 g of the maleate of the dimethylamino- ~-dimethyl-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in the form of white crystals.

.¦ Melting point 92-95C.

.:
.'~j , .

. - 49 ~

~ i .. . .
'.1 . .
'' .' ~

: ~, . , . :

1~636~{3 Example 30 : Oxalate of the piperidino-ethyl ester of 2-methyl-[2-isopro-:
pyl-indanyl-(5)]-acetic acid Formula I R2 = X = H
Rl = isopropyl R4 = CH2 CH2 ~
`. Following the procedure of Example 21(b) but using 14g :~ of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid chloride `''t~' 10 ' and 7.2 g of piperidinoethanol, 15g of ester are obtained;
. ^. . .
5,5 g of oxalic acid dissolved in ethanol are added to the ;. above ester to yield 14 g of the oxalate of the piperidino-ethyl ester of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid -~
:! in the form of white crystals, after recrystallisation from ~.
`~ ethanol.
Melting point 139-141C.
Example 31 , ,~ . .
Sodium salt of 2-methyl-[2-isopropyl-indanyl-(5)]-àcetic acid Formula I R2 ~ X = H - :~ -Rl = isopropyl -~:~ R N
2515 g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid are treated with a solution of sodium methylate prepared :, ~ . , .
'~?;: ~ from 2.5 g of sodium dissolved in 40 ml of methanol, Ater evaporation of the solvent.j the residue is taken up in ether i~ and 23 g of the sodium salt of 2-methyl-[2-isopropyl-lndanyl-.~ (5)]-acetic acid are obtained in the form of a white powder ,~ . -.j '~ ' ; ~ 50 - :

, ....................................................................... . .

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"
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1C~6361~

which is soluble in water.
Example 32 Maleate of the pyrrolidino-ethyl ester of 2-methyl-[2-isopro-pyl-ind-anyl--55)]-acetic acid ; Formula I R2 = X = H
Rl = isopropyl R3 = CH3 , 4 2 2 ~ ~ --~ A solution of 11 g of the sodium salt of 2-methyl-lO [2-isopropyl-indanyl-(5)]-acetic acid and 6.9 g of ~ -chloro- ;

ethylpyrrolidine in lO0 ml of xylene is heated under reflux ' for 7 hours. After cooling the reaction mixture, the organic phase is washed with water and dried over sodium ~ carbonate. After evaporation of the solvent, a residue ,i weighing 14.3 g is obtained to which a solution of 5 g of .~,3 maleic acid in acetone is added. 17.4 g of the maleate of the pyrrolidino-ethyl ester of 2-methyl-[2-isopropyl-indanyl- 1 . ,:; . .
~i (S)]-acetic acid axe thus obtained in the form of white ; crystals.
-~ 20 Melting point 114-116C.
q, xample 33 2-Methyl~ ~-[2-isopropyl-indanyl-(5)]-ethanol Formula I Rl = H R2 ~ isopropyl " R - CH
A solution of lO g of 2-methyl-[2-isopropyl-indanyl-(5)]-acetic acid in 50 ml of anhydrous ether is added drop-wise to a suspension of 3.3 g of lithium aluminium hydride in 50 ml of anhydrous ether. After the end of the :, :-.

: :s , - 51 -.~ ~

~ ' .
,, ~ .

636~l3 addition, the reaction mixture is hea-ted under reflux for 3 hours~
' After cooling, a saturated aqueous solution of sodium sulphate is added dropwise at 0C in order to destroy the l .
excess hydride. As soon as the hydride no longer reacts;
sodium sulphate is added to the reaction and filtration is effec.ted. The precipi-tate is washed carefully with ether the filtrates are combined and the ether is evaporated. ~i 9.5 g of 2-methyl-~-[2-isopropyl-indanyl-(5)1i-ethanol are thus obtained in the form of white crystals. `
Melting point 45C.
EY~ample 34 ~ I
~i: 2-Meth~rl-~=~ 2-ethyl-indanyl-(5~1-ethanol ' ~ ~' ~., , ;,, ~
Formula I Rl = H R2 = C2H5 Following the procedure of Example 33 but using 12~8 g ; of 2-methyl-[2-ethyl-indanyl-(5)]-acetic acid, there are recovered, a~ter vacuum distillation of the residue obtained, 10 g o~ Z-methyl-~-[2-ethyl-indanyl-(5)~-ethanol in the ~orm of a colourless oil.
: "
Boiling pomtl mm Hg 3 Formula I Rl - H R2 CH3 R~ = H
Following the procedure o~ Example 33 but using 3.5 g .,.
o~ ~2-methyl-indanyl-(5)~acetic acid, there are recovered, after vacuum distillation of the residue obtained, 2.6 ~ of ,, . i.~ . .
&~
.1 . . .

.j . , .
.
~ ~., .,; .. . . . . . ..
; . . . :
,. ~ ~ . ``. - . . , . ,. . . ~ . . . . . .

~6361~3 -[2-methyl-indanyl-(5)]-ethanol in the form of a colourless oil.
Boiling point 0,5 mm Hg ; Example 36 [2-Isopropyl-indanyl-(5)]-acetic acid .. . . . .
(a) [2-Isopropyl-indanyl-(5)]-acetic acid morpholinethioamide -N = -N O
: . \
- 6 ~ ~-Formula XI 1 R2 = isopropyl A mixture of 100 g of [2-isopropyl-indanyl-(5)]-methyl ketone, 22,2 g of sulphur and 75 g of morpholine i5 heated at : . . .: . .
~' 140C for 12 hours, Thereafter, the reaction mixture is '':1 .
, concentrated in vacuo and is then taken up in 200 ml of 95 . j . . ..
- strength ethanol. The crystals formed are filtered off , and washed with a small amount of cold 95 strength ethanol.
~-! 95 g of [2-isopropyl-indanyl-(5)]-acetic acid morpholinethio~
amide are thus obtained in the form of light yellow crystals.
Melting point 120C.
(b) [2-Isopropyl-indanyl-(5)]-acetic acid 20~ Formula I Rl = R3 = R4 = H R2 ~ isopropyl ,l~ A solution of 95 g of [2-isopropyl-indanyl-(5)]-acetic acid morpholinethioamide in 125 ml of acetic acid and ~ 175 ml of hydrochloric acid (d = 1.18) is heated under reflux ,';~J for 18 hours.
,l The reaction mixture is then poured onto ice and the organic products are extracted with ether. After the ~1 ether has been washed carefully with water and dried over ~ -,; .

, :;1l ' :, . .

,, .
,.
., .
,. .. . ,. . , , ,. , , , . , ,,, ; .. .: . .. .

~ 636113 sodium sulphatei it is evaporated in vacuo. After re- .
crystallisation of the residue obtained from petrole-~n ether, . 6~ g of [2-isopropyl-indanyl-(5)]-acetic acid are isolated in :~ the ~orm of white crystals.
. Melting point 80-81C. . :
`: ~xample 37 , -- -Formula I .. Rl ~ H R2 = isopropyl ; R~ ~ H
.~. , ~ollowing the procedure of Example 33 but using 25 g of [2-}sopropyl-indanyl-(5)]-acetic acid, 20.5 g of ~-[2-. , .j isopropyl-indanyl-(~)]-ethanol are obtained in the form o~ .
:' , .
..white crystals, after recrystallisation from pentane.
; Melting point 41-42C.
;~ :
The pharmacological properties o~ the products of ~he in-~J~ ~ vention are illustrated by the following e~perim~ntal results~
.~: . Anti.-inflammatory~ y The products to.be tes-ted are:ad~inistered orally to batches of 12 SPF male rats, OFA strain, weighing 120-130 g, 2 hours and 30 minutes (~ dose each time) before the sub-cutaneous planta~ injection of 0~05 ml of a 1% strength . .~ .
~ solution of carraghenine. The volume of the back paw ~
.
which received the phlogogenic agent is measure~ at regular intervals. The 5~/o effective do5e iS calculated at the moment of greatest.swellin~ o~ the controls.
The results are given in Tables I to IV below, in whicch ~: the percentage reduction in the inflan~nation is noted.

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I hour later, 003 ml of a 0 02% strength solution of .¦ phenylbenzoquinone is injected intr~periioneally into each ~¦ mouse and, from the 5th to the IOth minute after the ].atter .
~ treatment, the number of pain reactions (abdominal twistings) -.¦ is counted, . .
~ Table V to VIII below give the percentage inhibition .s of these reactions. . .

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Claims (22)

The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:
1. A process for the preparation of a compound of general formula (I) in which:
X represents a hydrogen or halogen atom; R1 and R2, which may be identical or different, each represents a hydrogen atom, an alkyl group containing 1 to 5 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms; R3 represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms;
and Y represents -CH2OH or a group of formula -COOR4 in which R4 represents a hydrogen atom, 1/v(M) where M is a metal of valency v, or a group of formula -(CH2)n-NR5R6 wherein n is an integer of 1 to 5 and -NR5R6 is selected from the group consisting of di-(lower alkyl) amino, morpholino-lower alkyl, pyrrolidino-lower alkyl and piperidino-lower alkyl, or a pharmaceutically acceptable addition salt of such a com-pound, which process comprises:

a) reacting a compound of the formula (II) in which R1, R2 and X are as hereinbefore defined, with an ethyloxalyl halide and hydrolysing the resulting keto-ester of formula (V) under acidic or basic conditions to obtain a keto-acid of the formula (VI) and either:
(a)(i) subjecting the keto-acid of formula (VI) to a Wolff-Kishner reduction to obtain a compound of formula (I) in which Y represents a -COOH group and R3 represents a hydrogen atom, or a)(ii) reacting the keto-acid of formula (VI) with an organo-magnesium compound of the formula R3MgZ
in which Z is a halogen atom and R3 is an alkyl group containing 1 to 5 carbon atoms to obtain a compound of formula (VII), dehydrating the compound of formula (VII) to obtain a compound of formula (VIII) in which R'3 represents a group of formula -(CH2)x-1H
where x is the number of carbon atoms in R3, and hydrogenating the compound of formula (VIII) to obtain a compound of formula (I) in which Y represents a -COOH group and R3 represents an alkyl group containing 1 to 5 carbon atoms;
or b) reacting a compound of the formula (X) in which R1, R2 and X are as hereinbefore defined in known manner with sulphur and a primary or secondary amine of formula NHR5R6 wherein R5 and R6 are as hereinbefore defined with the proviso that at least one of R5 and R6 is other than hydrogen, to obtain a thioamide of the formula (XI) in which R1, R2, R5, R6 and X are as hereinbefore defined, and hydrolysing the thioamide of formula (XI) to obtain a compound of formula (I) in which R3 represents a hydrogen atom and Y represents a -COOH group;
or c) reducing a compound of general formula (XVI) in which R1, R2, R3 and X are as defined in claim 1 and R
represents a hydrogen atom ox an alkyl group containing 1 to 4 carbon atoms to obtain a compound of formula (I) in which Y represents a -CH2OH group;

d) (i) reacting the halide of an acid of formula (Ia) in which R1, R2, R3 and X are as hereinbefore defined with an amino alcohol of the formula , in which n, R5 and R6 are as hereinbefore defined or d) (ii) reacting a salt of an acid of formula (Ia) with a halide of the formula in which n, R5 and R6 are as hereinbefore defined and Z is a halogen atom, to obtain a compound of formula (I) in which Y represents a group of formula -COOR4 in which R4 represents group of formula -(CH2)n-NR5R6; and, if desired, converting the compound of formula (I) obtained in any one of steps a) to e) into a pharmaceutically acceptable acid additon salt thereof.
2 A process according to claim 1 in which R1 and R2, which may be identical or different, each represents a hydrogen atom or a methyl, ethyl, isopropyl or cyclohexyl group.
3. A process according to claim 1 in which R3 represents a hydrogen atom or a methyl or ethyl group.
4. A process according to claim 1 in which X
represents a hydrogen atom.
5. A process according to claim 1 in which R4 represents a hydrogen or sodium atom or a group of formula .
6. A process according to claim 1 which comprises:
a) reacting a nitrile of general formula (IVa) as defined in claim 1 in which R3 represents a hydrogen atom with a metallating agent to obtain a compound of formula (XII) in which M is an alkali metal atom and R1, R2 and X are as defined in claim 1, b) reacting the compound of formula (XII) with a halide of formula R3Z in which R3 is an alkyl group containing 1 to 5 carbon atoms and Z is a halogen atom to obtain a compound of formula (IVa) as defined in claim 1 in which R3 represents an alkyl group containing 1 to 5 carbon atoms, and c) hydrolysing the compound of formula (IVa) under acidic or basic conditions, and, if desired, converting the resulting compound of formula (I) in which Y represents a -COOH group and R3 represents an alkyl group containing 1 to 5 carbon atoms into a pharmaceutically acceptable addition salt thereof.
7. A process according to claim 6 wherein the metalllating agent used in step a) is sodium or potassium hydride, sodium or potassium amide or potassium tert-butylate and Z is bromine or iodine.
8. A process according to daim 1 which comprises:
a) chloromethylating a compound of the formula (II) in which R1, R2 and X are as hereinbefore defined to obtain a compound of formula (III) b) reacting the compound of formula (III) with an alkali metal cyanide to obtain a compound of formula (IV) and c) hydrolysing the compound of formula (IV) under acidic or basic conditions to obtain a compound of formula (I) in which Y represents a -COOH group and R3 represents a hydrogen atom, and, if desired, converting the compound of formula (I) into a pharmaceutically acceptable addition salt thereof.
9. A process according to claim 8 in which step a) is carried out by reacting the compound of formula (II) with hydrochloric acid and formaldehyde or trioxymethylene.
10. A process according to claim 1 which comprises a) reacting a compound of the formula (IIa) in which R1 and R2 are as hereinbefore defined with a halide or anhydride of an acid of formula R3-COOH
in which R3 represents an alkyl group containing 1 to 5 carbon atoms, to obtain a ketone of formula (XIII) in which R1, R2 and R3 are as hereinbefore defined, b) reducing the ketone of formula (XIII) to obtain an alcohol of formula (XIV) c) converting the alcohol of formula (XIV) into a halide of formula (XV) in which Q is chlorine or bromine, d) reacting the halide of formula (XV) with an alkali metal cyanide to obtain a compound of formula (IVa) and e) hydrolysing the compound of formula (IVa) under acidic or basic conditions to obtain a compound of formula (I) in which X represents a hydrogen atom, R3 represents an alkyl group containing 1 to 5 carbon atoms and Y represents a -COOH group, and, if desired, converting the compound of formula (I) into a pharmaceutically acceptable addition salt thereof.
11. A process according to claim 10 in which step b) is carried out in the presence of an alkali metal borohydride or lithium aluminium hydride and step c) is carried out by reacting the alcohol of formula (XIV) with phosphorus tribromide or thionyl chloride.
12. A compound of formula (I) as defined in claim 1 when obtained by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
13. A compound of formula (I) as defined in claim 1, and in which R1 and R2 are as defined in claim 2, when obtained by a process as claimed in claim 2 or an obvious chemical equivalent thereof.
14. A compound of formula (I) as defined in claim 1, and in which R3 is as defined in claim 3, when obtained by a process as claimed in claim 3 or an obvious chemical equivalent thereof.
15. A compound of formula (I) as defined in claim 1, and in which X is as defined in claim 3, when obtained by a process as claimed in claim 4 or an obvious chemical equivalent thereof.
16. A compound of formula (I) as defined in claim 1, and in which R4 is as defined in claim 5, when obtained by a process as claimed in claim 5 or an obvious chemical equivalent thereof.
17. A compound of formula (I) as defined in claim 1, and in which Y and R3 are as defined in claim 5, when obtained by a process as claimed in claim 6 or an obvious chemical equiva-lent thereof.
18. A compound of formula (I) as defined in claim 1, and in which Y and R3 are as defined in claim 6, when obtained by a process as claimed in claim 7 or an obvious chemical equiva-lent thereof.
19. A compound of formula (I) as defined in claim 1, and in which Y and R3 are as defined in claim 8, when obtained by a process as claimed in claim 8 or an obvious chemical equi-valent thereof.
20. A compound of formula (I) as defined in claim 1, and in which Y and R3 are as defined in claim 8, when obtained by a process as claimed in claim 9 or an obvious chemical equiva-lent thereof.
21. A compound of formula (I) as defined in claim 1, and in which X, R3 and Y are as defined in claim 10, when obtained by a process as claimed in claim 10 or an obvious chemical equivalent thereof.
22. A compound of formula (I) as defined in claim 1, and in which X, R3 and Y are as defined in claim 10, when obtained by a process as claimed in claim 11 or an obvious chemical equivalent thereof.
CA219,396A 1974-02-07 1975-02-05 Indane derivatives Expired CA1063618A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB5726/74A GB1492175A (en) 1974-02-07 1974-02-07 Indane derivatives
GB3722074 1974-08-23
GB5429274 1974-12-16

Publications (1)

Publication Number Publication Date
CA1063618A true CA1063618A (en) 1979-10-02

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JP (2) JPS51125368A (en)
AR (4) AR206619A1 (en)
CA (1) CA1063618A (en)
CH (2) CH603533A5 (en)
DD (3) DD117209A5 (en)
DE (1) DE2504689A1 (en)
DK (2) DK42475A (en)
ES (1) ES434478A1 (en)
FR (1) FR2260334A1 (en)
NL (2) NL7501518A (en)
NO (3) NO750175L (en)
SE (3) SE418395B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI752917A7 (en) * 1974-10-29 1976-04-30 Sandoz Ag
LU77254A1 (en) * 1977-05-04 1979-01-18
GR65999B (en) * 1978-07-24 1981-01-13 Hexachimie
ZA882957B (en) * 1987-04-27 1989-12-27 Syntex Pharma Int Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal anti-inflammatory drugs

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DD117209A5 (en) 1976-01-05
AU7793675A (en) 1976-08-05
DE2504689A1 (en) 1975-08-14
SE7713839L (en) 1977-12-06
SE418177B (en) 1981-05-11
JPS51125367A (en) 1976-11-01
CH603533A5 (en) 1978-08-31
NO146136B (en) 1982-04-26
AR206620A1 (en) 1976-08-06
NO146136C (en) 1982-08-04
FR2260334B1 (en) 1978-08-18
SE7501339L (en) 1975-08-08
JPS5711296B2 (en) 1982-03-03
SE7501338L (en) 1975-08-08
SE418395B (en) 1981-05-25
ES434478A1 (en) 1977-03-16
AR211541A1 (en) 1978-01-30
NO800268L (en) 1975-08-08
DK42575A (en) 1975-10-06
AR206619A1 (en) 1976-08-06
FR2260334A1 (en) 1975-09-05
NL7501519A (en) 1975-08-11
NL7501518A (en) 1975-08-11
JPS5711295B2 (en) 1982-03-03
AR206862A1 (en) 1976-08-23
NO750176L (en) 1975-09-01
DK42475A (en) 1975-10-06
NO750175L (en) 1975-09-01
DD123319A5 (en) 1976-12-12
DD118271A5 (en) 1976-02-20
CH605567A5 (en) 1978-09-29
JPS51125368A (en) 1976-11-01

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