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GB2030140A - Pharmaceutically active indane derivatives - Google Patents

Pharmaceutically active indane derivatives Download PDF

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Publication number
GB2030140A
GB2030140A GB7930747A GB7930747A GB2030140A GB 2030140 A GB2030140 A GB 2030140A GB 7930747 A GB7930747 A GB 7930747A GB 7930747 A GB7930747 A GB 7930747A GB 2030140 A GB2030140 A GB 2030140A
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hydrogen
formula
group
oxo
acid
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GB2030140B (en
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Lilly Industries Ltd
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Lilly Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/88—Unsaturated compounds containing keto groups containing halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Compounds of formula I <IMAGE> wherein either R<1> and R<2> are both hydrogen or R<1> and R<2>, taken together represent a group of formula (a): <IMAGE> in which R<5> is hydrogen, halogen or C1-4 alkyl, R<3> is hydrogen or a group of formula (b): <IMAGE> in which R<6> is hydrogen or C1-4 alkyl, and R<4> is hydrogen or a group of formula -CHR<7>COOH, where R<7> is hydrogen or C1-4 alkyl, provided that: (i) when R<3> is a group of formula (b), then R<1>, R<2> and R<4> are all hydrogen, (ii) when R<3> is hydrogen, then R4 is -CHR<7>COOH, and (iii) when R<1> and R<2>, together, represent a group of formula (a), then R3 is hydrogen; or pharmaceutically acceptable salts or esters thereof possess pharmacological activity, in particular anti-inflammatory activity, and are particularly useful in treatment of rheumatoid arthritis.

Description

SPECIFICATION Pharmaceutically active indane derivatives This invention relates to novel indane derivatives which possess useful pharmacological activity, to the use of the new compounds as pharmaceuticals, especially as anti-inflammatories, and to pharmaceutical formulations containing the new indane derivatives as an active ingredient.
According to the invention there are provided indane derivatives of formula (I):
wherein either R1 and R2 are both hydrogen or R1 and R2, taken together, represent a group of formula (a):
in which R5 is hydrogen, halogen or C14 alkyl, R3 is hydrogen or a group of formula (b):
in which R6 is hydrogen or C14 alkyl, and R4 is hydrogen or a group of formula -CHR7COOH, where R7 is hydrogen or C14 alkyl, provided that:: (i) when R3 is a group of formula (b), then R1, R2 and R4 are all hydrogen, (ii) when R3 is hydrogen, then R4 is -CHR7COOH, and (iii) when R1 and R2, together, represent a group of formula (a), then P3 is hydrogen; or a pharmaceutically acceptable salt or ester thereof.
Where P3 is phenyl substituted by -CHR6CO2H, the -CHR6CO2H group is preferably in thepara-position of the phenyl.
Where R1 and R2,together, represent a group of formula (a), the P5 therein is preferably in the para-position of the phenyl radical.
The preferred halogen as P5 is chlorine, the preferred significance of P5 being hydrogen or chlorine.
As examples of pharmaceutically acceptable salt forms of the compounds of formula (I) may be given the alkali-metal and alkaline earth metal salt forms, for example the sodium, calcium and magnesium salt forms.
As examples of pharmaceutically acceptable ester forms of the compounds of formula I may be given the C14 alkyl, e.g. methyl, ethyl and n-butyl, ester forms.
As will be appreciated, where, in the compounds of formula I, R6 or R7 is other than hydrogen, the compounds posess a chiral centre and hence can exist in optically active enantiomeric form, in dl-form or in racemate form. The present invention is not intended to be limited to any particular form.
Compounds of formula (I) in which R3 is a group of formula (b) can be prepared from compounds of formula:
by an internal Friedel-Crafts reaction using polyphosphoric acid at a temperature of approximately 100 C.
The benzylidene compounds of formula:
can be prepared in two ways depending on whether R7 is hydrogen of C1 4 alkyl.
Such compounds in which R7 is hydrogen can be prepared from known starting materials by the following synthesis:
CH3CO + (CH2)2CO2H 1 HOzCCHz (CW2)2CO2H 8 H2CO2H -# where R7 is H.
Reaction A is the well-known Willgerodt-Kindler reaction. Reaction B in an internal Friedel-Crafts reaction which can be carried out with polyphosphoric acid. Reaction C is accomplished by condensation with the appropriate aldehyde of formula:
Benzylidene compounds of formula (II) in which R7 is C1 4 alkyl can be prepared by the following reaction systhesis::
HO2C CH (CH2)2CO2H 1D EtOzC CH1- (CHZ)2Cd2Et E EtO2C CH +(CH2)2C32Et EtOzC EtO2C ;CR7- (CH2)2COZEt EtOZC / \&verbar;, G Eto2C-CHR7--- (cH2)2c02H H Jl ~ CHR7 C O 2Et < l R7 is W Cs The diethyl ester was produced by reaction D by refluxing the corresponding acid in ethanol containing hydrochloric acid. The partial Claisen condensation, reaction E was accomplished using diethylcarbonate in a solution of sodium in ethanol.The alkylation reaction F can be effected using any suitable alkylating agent, preferably the corresponding iodide, by adding the triester to a warm solution of sodium in ethanol and then adding the appropriate alkyl iodide. Reaction G is a standard hydrolysis reaction and the conditions necessary to effect reaction H are similar to those necessary to effect reaction B bove. Reaction J requires the pre-hydrolysis of the ethyl ester under acidic conditions followed by a condensation reaction using a similar reagent to that already specified for C above.
Compounds of formula (I) are pharmacologically active. In particular, they have been shown to have low toxicity and to possess analgesic, antipyretic and anti-inflammatory activity, particularly anti-inflammatory activity, and are particularly indicated for use in the treatment of rheumatoid arthritis.
The foregoing activities have been demonstrated in tests carried out in animals, for example in the well-known Carrageenan Test and the rat adjuvant arthritis test, usually at doses of from 0.1 to 250 mg/kg. In the treatment of humans, the dose administered may be, for example, between 1 and 25 mg/kg. but, of course, doses outside this range may be used at the discretion of the physician treating the patient. The pharmacologically active compounds of formula I may be administered by the enteral or parenteral routes and for this purpose they will normally be formulated into pharmaceutical compositions comprising the active ingredient in association with at least one pgarmaceutically acceptable carrier therefor.Such compositions form a part of this invention and will normally consist of the active ingredient mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by a carrier in the form of a capsule, sachet, cachet or other contained. The carrier may be a solid, semi-solid or liquid material which serves as a vehicle, excipient, coating agent, or medium for the active ingredient. Some examples of the carriers which may be used are lactose, dextrose, suctose, sorbitol, mannitol, starch, gum acacia, calcium photphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, methyl cellulose, polyoxyethylene, sorbitan monolaurate, methyl or propyl hydroxybenzoate, ethyl cellulose acetate phthalate, low viscosity acetyl cellulose acetate, paraffin wax, mineral wax, vegetable wax, vegetable gum, silicone rubbers such as liquid polydimethylsiloxane rubber, plasticised or unplasticised polyvinyl chloride, plasticised polyethylene terephthalate, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol or cross-linked partially hydrolysed polyvinyl acetate.
Advantageously the compositions of the invention are formulated in a dosage unit form containing from 1 to 1000 mg. (preferably 25 to 500 mg.) of the active ingredient. Examples of suitable dosage unit forms are tablets, hard or soft gelatin capsules, microcapsules and suppositories, as well as drug dispensing systems comprising the active ingredient contained in a flexible, imperforate polymeric material through which the drug may be released slowly by diffusion. More generally, the term "dosage unit form" as used herein means a physically discrete unit containing the active ingredient, generally in admixture with and/or enclosed by a pharmaceutical carrier, the quantity of active ingredient being such that one or more units are normally required for a single therapeutic administration.
In addition to the active ingredient of formula I, the compositions of the present invention may also contain one or more pharmacologically active ingredients, for example, acetysalicylic acid and salts thereof, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and indomethacin.
The compositions of the present invention will, of course be adapted to the particular route of administration. Thus, for oral administration, tablets, pills, capsules, solutions or suspensions may be used; for parenteral administration, sterile injection solutions or suspensions may be used; for rectal administration, suppositories may be used; and for topical administration, creams, lotions or ointments may be used. Any of the foregoing compositions may, of course be formulated in delayed or sustained release form in a manner well known in the art.
The following Examples will further illustrate the preparation of the compounds of formula (I): Example 1 3-Oxo-5-indaneacetic acid Polyphosphoric acid (1 kg) was stirred and heated to 95-100"C and 4-(2-Carboxyethyl)phenylacetic acid (100 g, 0.48 mol) added over 10 minutes. The mixture was stirred for 0.5 hours and poured into ice and H2O; the product was continuously extracted with CHC13, and recrystallised from benzene to give the title product, m.p.133-5 C.
Example 2 2-Benzylidene-3-oxo-5-indaneacetic acid 3-Oxo-5-indaneacetic acid (4.94 g, 0.026 mol) was added to a stirred solution of 85% KOH (3.43 g, 0.052 mol) in EtOH (73 ml) containing benzaldehyde (2.769, 0.026 mol) at 1 O"C and stirred for 40 minutes. The potassium salt of the precipitated product was filtered off, dissolved in H2O (100 ml) and acidified with conc. HCI to give the title product, m.p. 202-4"C (EtoH).
Example 3 Similarly, 2-(p-chlorobenzylidene)-3-oxo-5-indaneacetic acid, m.p. 264-6"C. was prepared.
Example 4 Ethyl 4-g2-carbethoxyethyl)phenylacetate 4-(2-Carboxyethyl)phenylacetic acid (20.82 g, 0.1 mol) was refluxed overnight in EtOH (416 ml) containing conc. HCI (10.8 ml). The solvent was evaporated and the ester distilled.
Example 5 Diethyl 4- (2-carbeth ox ye th yl)phenylmalonate The diester of Example 4 (340 g, 1.29 mol) was stirred in diethyl carbonate (1975.4 g, 16.7 mol) at 80-100 C and treated with a solution of sodium (29.58 g, 1.29 mol) in EtOH (687 ml) and the mixture was stirred and distilled until the distillate temperature reached 123 C. After storage in a refrigerator overnight, the solution was treated with AcOH (142 ml) in H2O (567 ml), extracted with Et2O. The Et2O was washed with saturated NaHCO3 and saturated NaCI solutions, dried (Na2SO4), filtered and evaporated and the residue distilled to give the title product, b.p. 170"C/0.15 mm.
Example 6 Diethyl-4-(2-carboxyethyl)meth ylphen ylmalonate The tricarboxylic ester produced in Example 5 (300 g, 0.89 mol) in EtOH (200 ml) was added to a warm solution of sodium (20.7 g, 0.9 mol) in EtOH (700 ml). Methyl iodide (332.5 g, 2.34 mol) was added, the solution was stirred and refluxed for 40 minutes and further Mel (322.5 g) added and then again (196.1 g, 1.4 mol) after 2 hours. After the total reflux time of 3 hours the solution was evaporated, H2O added and the mixture extracted with Et2O. The Et2O solution was worked up as in Example 5 to give the title product (nD' 1.4920).
Example 7 Ethyl 4-(2-carboxyethyl)-a-methylphenylacetate The tricarboxylic ester of Example 6 (35 g, 0.1 mol) in EtOH (400 ml) was stirred at room temperature with a solution of KOH (13.2 g of 85%, 0.2 mol) in EtOH (100 ml) for 96 hours. The mixture was evaporated to dryness. The solid foam was broken up, treated with Et2O (200 ml) and filtered. The residue was dissolved in H2O (100 ml), acidified with 5N HCI to give an oil which was extracted with Et2O. The Et2O was dried (Na2SO4) filtered and evaporated to give an oily solid.The solid was shaken with a mixture of CHCl3-light petroleum (b.p. 40-60 C) (100 ml of 50:50), filtered, the residue washed with the same solvent mixture (100 ml) and the filtrate evaporated to leave an oil which was distilled to give the title produce, b.p. 175-7 C/0.25 mm.
Example 8 Using the process of Example 1, the ester of Example 7 was converted to ethyl 3-oxo-5--indane-&alpha;-methyl acetate, b.p. 137 C/0.2mm.
Example 9 3-Oxo-5-indane-a-methylacetic acid The Example 8 ester (9 g, 0.038 mol) in AcOH (90 ml) was added to conc. HCI (90 ml)-and-kept at room temperature for 5 days. The solution was -poured into H2O (1 1.) and extracted withEt20. The Et2O was washed with saturated NaCI solution, dried (MgSO4), filtered and evaporated. The product was further purified by dissolving in saturated NaHCO3 solution (100 ml), extracting with Et2O and acidifying the aqueous phase to give the title product, m.p. 11"C.
Example 10 fp-(3-Oxo- 1-indanyl) phenyllacetic acid Polyphosphoric acid (1 kg) was stirred and heated to 95-100 C and ss-phenyl-p-(carboxymethyl)- hydrocinnamic acid (0.48 mol) added over 10 minutes. The mixture was stirred for 1/2 hour and poured into ice and H2O; the title product was continuously extracted with CHCl3 and recrystallised from ether, m.p.
151 C.
Example ii 2-Benzylidene-3-oxo-5-indane-a-methylacetic acid Employing the acid of Example 9 in the procedure of Example 2, above, there is obtained the title product.
Example 12 2-p-ChlorobenzylideneJ-3-oxo-5-indane-a-methylacetic acid Following the procedure of Example 11, above, but employing p-chlorobenzaldehyde in place of the benzaldehyde used therein, there is obtained the title product, m.p. 206-208 C.

Claims (19)

1. Acompoundofformula (I)
wherein either P1 and R2 are both hydrogen or R1 and R, taken together, represent a group of formula (a):
in which R5 is hydrogen, halogen or C1 4 alkyl, R3 is hydrogen or a group of formula (b):
in which R6 is hydrogen or C1-4 alkyl, and R4 is hydrogen or a group of formula -CHR7COOH, where R7 is hydrogen or 01.4 alkyl, provided that:: (i) when R3 is a group of formula (b), then R', R2 and R4 are all hydrogen, (ii) when R3 is hydrogen, then R4 is -CHR7COOH, and (iii) when R1 and R2, together, represent a group pf formula (a), then P3 is hydrogen; or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein P3 is a group of formula (b), stated in claim 1.
3. A compound according to claim 1 or claim 2, wherein, in the group of formula (b), the -CHR6-COOH group is in thepara-position of the phenyl to which it is attached.
4. A compound according to any one of claims 1 to 3, wherein R6 is hydrogen or methyl.
5. A compound according to claim 4, wherin R6 is hydrogen.
6. A compound according to claim 1, wherein P3 is hydrogen.
7. A compound according to claim 1, wherein R1 and R22, together, represent a group of formula (a).
8. A compound according to claim 7, wherein, in the group of formula (a),R5 is in the para position of the phenyl to which it is attached.
9. A compound according to claim 7 or 8, wherein R5, in the group of formula (a), is hydrogen or chlorine.
10. A compound according to claim 1, wherein R' and R2 are both hydrogen.
11. 3-Oxo-5-indaneacetic acid.
12. 2-Benzylidene-2-oxo-5-indaneacetic acid.
13. 2-(p-chlorobenzylidene)-3-oxo-5-indaneacetic acid.
14. 3-Oxo-5-indane-a-methylacetic acid.
15. [p-(3-Oxo-1 -indanyl)phenyl] acetic acid.
16. 2-Benzylidene-3-oxo-5-indane-a-methylacetic acid.
17. 2-(p-Chlorobenzylidene)-3-oxo-5-indane-a-methylacetic acid.
18. A dor 1-enantiomer of an indane of formula (I), claimed in claim 1, wherein P6 or R7 is other than hydrogen.
19. A pharmaceutical composition comprising, as an active ingredient, a compound of any one of the preceding claims.
GB7930747A 1978-09-16 1979-09-05 Pharmaceutically active indane derivatives Expired GB2030140B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182263A (en) * 1988-04-25 1993-01-26 Hoffmann-La Roche Inc. Analogs of tyrosine sulfate or tyrosine phosphate containing peptides
WO2016056726A1 (en) * 2014-10-08 2016-04-14 영남대학교 산학협력단 Composition comprising indeno pyridium-derived compound as active ingredient for preventing or treating inflammatory bowel diseases

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5182263A (en) * 1988-04-25 1993-01-26 Hoffmann-La Roche Inc. Analogs of tyrosine sulfate or tyrosine phosphate containing peptides
WO2016056726A1 (en) * 2014-10-08 2016-04-14 영남대학교 산학협력단 Composition comprising indeno pyridium-derived compound as active ingredient for preventing or treating inflammatory bowel diseases

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