CA1060903A - Pharmaceutically useful indanylpropionic acid derivatives - Google Patents
Pharmaceutically useful indanylpropionic acid derivativesInfo
- Publication number
- CA1060903A CA1060903A CA219,910A CA219910A CA1060903A CA 1060903 A CA1060903 A CA 1060903A CA 219910 A CA219910 A CA 219910A CA 1060903 A CA1060903 A CA 1060903A
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- CA
- Canada
- Prior art keywords
- acid
- group
- isopropylindan
- formula
- ethylindan
- 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
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Classifications
-
- 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
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Abstract
ABSTRACT
Indanylpropionic acid derivatives having formula:
(I) (wherein R represents and ethyl group or and isopropyl group) and pharmaceutically acceptable salts thereof are useful medically as anti-inflammatory, analgesic and antipyretic agents. They can be prepared by hydrolysing a compound having the formula:
Indanylpropionic acid derivatives having formula:
(I) (wherein R represents and ethyl group or and isopropyl group) and pharmaceutically acceptable salts thereof are useful medically as anti-inflammatory, analgesic and antipyretic agents. They can be prepared by hydrolysing a compound having the formula:
Description
10609~)3 This invention relal;es to novel indanylpropionic acid derivatives, which are useful pharmaceutically by virtue of exhibiting anti-inflammatory, analgesic and antipyretic activities, and to the ir preparation The invention provides compounds having the formula:
~ CH3 (wherein R represents an ethyl group or an isopropyl group) and pharmaceutically acceptable salts thereof.
The compounds of formula (I) and their pharmaceutically acceptable salts can exist in the form of optical isomers. The individual isomers, as well as mixtures thereof, are included within the scope of the invention.
In accordance with the invention, the compounds of formula (I) and their pharmaceutically acceptable salts are prepared by hydrolysing an indan derivative of formula:
R ~ I H - Y (II) (wherein R has the meaning previously given; and Y represents an alkoxycarbonyl group ha~ing from 1 to 4 carbon atoms in the alkoxy moiety, a cyano group or a carbamoyl group ) to obtain a compound of said formula (I) and, if appropriate, q~
~ ~ . . "
~:. ' ' ' " - ~ ~
, ~6~9~3 salifying said compound of formula (I) to obtain a pharmaceutically acceptable salt thereof.
The hydrolysis is suitably performed by treating the indan derivative of formula (II) with a mineral acid, or with an alkali or alkaline earth metal base. It is generally convenient to use an aqueous solution of the acid or base, optionally in the presence of a water-miscible organic solvent, The mineral acid may be, for example, hydrochloric, hydrobromic, sulphuric or phosphoric acid, and is preferably hydrochloric or hydrobromic acid. The base may be a hydroxide, carbonate or bicarbonate of an alkali or alkaline earth metal, and is preferably a hydroxide of an alkali metal, for example potassium hydroxide or sodium hydroxide. If the reaction is carried out in the presence of a water-miscible organic solvent, this may suitably be a carboxylic acid (e. g. acetic or propionic acid), an alcohol, (e. g. methanol, ethanol, isopropanol or n-propanol), a glycol (e, g. ethylene glycol or diethylene glycol), a dialkylformamide (e. g. dimethylformamide)9 or a dialkylacetamide (e. g, dimethyl-acetamide). It is preferred to use an aqueous mixture of such an organic solvent.
The hydrolysis reaction is preferably carried out with heating to a temperature of from 70 to 150C. The reaction period will vary, depending mainly on the reaction temperature
~ CH3 (wherein R represents an ethyl group or an isopropyl group) and pharmaceutically acceptable salts thereof.
The compounds of formula (I) and their pharmaceutically acceptable salts can exist in the form of optical isomers. The individual isomers, as well as mixtures thereof, are included within the scope of the invention.
In accordance with the invention, the compounds of formula (I) and their pharmaceutically acceptable salts are prepared by hydrolysing an indan derivative of formula:
R ~ I H - Y (II) (wherein R has the meaning previously given; and Y represents an alkoxycarbonyl group ha~ing from 1 to 4 carbon atoms in the alkoxy moiety, a cyano group or a carbamoyl group ) to obtain a compound of said formula (I) and, if appropriate, q~
~ ~ . . "
~:. ' ' ' " - ~ ~
, ~6~9~3 salifying said compound of formula (I) to obtain a pharmaceutically acceptable salt thereof.
The hydrolysis is suitably performed by treating the indan derivative of formula (II) with a mineral acid, or with an alkali or alkaline earth metal base. It is generally convenient to use an aqueous solution of the acid or base, optionally in the presence of a water-miscible organic solvent, The mineral acid may be, for example, hydrochloric, hydrobromic, sulphuric or phosphoric acid, and is preferably hydrochloric or hydrobromic acid. The base may be a hydroxide, carbonate or bicarbonate of an alkali or alkaline earth metal, and is preferably a hydroxide of an alkali metal, for example potassium hydroxide or sodium hydroxide. If the reaction is carried out in the presence of a water-miscible organic solvent, this may suitably be a carboxylic acid (e. g. acetic or propionic acid), an alcohol, (e. g. methanol, ethanol, isopropanol or n-propanol), a glycol (e, g. ethylene glycol or diethylene glycol), a dialkylformamide (e. g. dimethylformamide)9 or a dialkylacetamide (e. g, dimethyl-acetamide). It is preferred to use an aqueous mixture of such an organic solvent.
The hydrolysis reaction is preferably carried out with heating to a temperature of from 70 to 150C. The reaction period will vary, depending mainly on the reaction temperature
2, ~0609103 and the nature of the starting material, but it is generally in the range of from 3 to 18 hours.
After completion of the reaction, the desired product can be re covered from the reaction mixture by conventional techniques. For example, if a mineral acid is employed for the hydrolysis, the reaction mixture can be poured into ice -water and extracted with an appropriate organic solvent (e. g.
ether), the extract shaken with a dilute aqueous alkaline solution, the aqueous layer acidified and re-extracted with an lû appropriate organic solvent, the resulting extract washed and dried, and the solvent distilled off to give the desired product.
On the other hand, if an alkali or alkaline earth metal base is employed for the hydrolysis, the product can be recovered by distilling off the solvent from the reaction mixture, diluting the residue with water, shaking the resulting aqueous solution with a water-immiscible organic solvent (e. g. ether), acidiying it and extracting it with an appropriate organic solvent (e. g.
ether), washing the extract with water and drying it, and then distilling off the solvent from the extract to give the desired product. If necessary, the product thus obtained can be purified by conventional methods, such as recrystallisation, distillation under reduced pressure, or column chromatography.
The indanylpropionic acid derivative of formula (I) thus . . , : , ' , ~ : ' ' ' ~ : . ' . , 106()903 obtained can, if appropriate, be converted into a pharmaceutically acceptable salt thereof by neutralisation in the conventional manner, Such pharmaceutically acceptable salts include alkali or alkaline earth metal salts such as the sodium, potassium, calcium and aluminium salts, the ammonium salt, and organic amine salts such as the triethylamine, dicyclohexylamine, procaine, dibenzyl-amine, piperidine and N-ethylpiperidine salts.
The starting materials of formula (II), used in the process of the invention, are themselves new compounds and can be prepared by the process summarised in the followmg reaction scheme: - .
l060sa3 1st step ~ {~CH2 (III) (IV) 2nd step ~CH2CN 3rd step (~) /~ 4th step ~5H-COOR
R ~d (lIa) (IIb) .
\th step \~ ','.
R ~3 CH-CONH2 ( IIc) : ,: .
In the reaction scheme, R has the meaning already defined, and R represents an alkyl group having from 1 to 4 carbon atoms.
In the first step of the reaction scheme, the compound (III) is heated with formaldehyde in aqueous hydrochloric acid solution at 50 - 100 C, to give the compound (IV). In the second step, the compound (IV) is refluxed with an alkali metal cyanide (e. g.
potassium cyanide or sodium cyanide) in an appropriate organic solvent, to give the compound (V). In the third step, the compound (V) is refluxed with a methyl halide (e. g. methy~. iodide), in the presence of an alkali metal compound such as sodium amide, sodium hydride or n-butyl lithium, in an appropriate organic solvent, giving the compound (IIa), which is one of the starting materials of formula (II) used in the process of the invention.
If desired, the compound (IIa) can be converted into the compound (IIb), another of the starting materials of formula (II), by refluxing it with an alkanol having from 1 to 4 carbon atoms, in the presence of an acid catalyst (e. g. concentrated sulphuric acid or concentrated hydrochloric acid), Alternatively, the compound (IIa) can be converted into the compound (IIc), which is the third type of the starting materials of formula (II), by reacting it with a mineral acid (e. g. concentrated sulphuric acid or concentrated hydrochloric acid), at a reaction temperature in the range of from room temperature to 9 0C.
~t the end of any of the reaction steps in the preparation of the compounds of formula (II), the desired product can be isolated from the reaction mixture by conventional techniques and, if necessary, purified by one of the usual methods, such as column chromatography or thin-layer chromatography.
The two compounds of formula (III), used as starting materials in the preparation of the compounds of formula (II), are already known. The compound of forrmlla (III) wherein R
is an ethyl group can be prepared by the process described by T. Wagner-lauregg et al. in Chem. Ber. 74, 1522 (1~41); and the compound of formula (III) wherein R is an isopropyl group can be prepared by the process described by Pl. A. Plattner et al, in Helv. ~him. Acta, 30, 689 (1947) When a mixture of optical isomers is obtained in any of the processes described hereinabove, if desired it can be resolved -by conventional techniques at a convenient point in the synthesis.
So far as we are aware, no indanylpropionic acid derivatives have previously been described in the scientific literature. We have discovered that the indanylpropionic acid derivatives of the present invention have potent anti-inflammatory, analgesic and antipyretic activities, in association with extremely low toxicities. By virtue of these properties, the compounds of the invention are useful as pharmaceuticals; and, accordingly, the - invention also provides a pharmaceutical composition, comprising a compound of said formula (I) or pharmaceutically acceptable salt thereof, together with a pha~maceutical carrier or diluent.
The compounds of formula (I) and their pharmaceutically acceptable salts can be administered orally or parenterally, by conventional methods. Accordingly, the pharmaceutical composition of the invention can be formulated for oral or parenteral administration, using solid or liquid pharmaceutical carriers and diluents, and optionally also appropriate pharmaceutical adjuvants, for example as tablets, capsules, injectable liquids and suspensions. The optimum dosage can vary, depending on the age, body weight and clinical condition of the patient, but the total daily dosage for adults would generally be in the range of from 50 mg to 2000 mg of the compound of the invention, conveniently administered in divided doses three or four times a day.
The pharmacological properties of the compounds of the invention are illustrated by the following tests, in which acetyl-salicylic aoid was used for comparative purposes.
I. Anti-inflammatory activity ( 1 ) Carrageenin -Oedema Test in Rats The test compounds shown in Table 1 were administered orally, in aqueous gum tragacanth suspension, to male rats of the Wistar strain having a body weight of 120 - 150 g which had fasted overnight. After 30 minutes, inflammation was induced by the - 8.
; . '' , ... .::
1060'~03 method of Winter et al., Proc. Soc:. Exp. Biol. ~ed. 111 544(1962), by injecting subcutaneously 0. 05 ml of a 1% carrageenin suspension into the plantar tissue of the hind paw. Paw oedema was measured volumetrically, immediately before and also 3 hours after the carrageenin injection, and the response (R) was calculated by the following equatiorl:-~ = (~-Vo) / ~o where Vo and V represent the paw volumes 0 and 3 hours after the carrageenin injection, respectively.
(2) Adjuvant-induced Arthritis Test in Rats (Therapeutic Effect on Established Arthritis).
7 ~ 8 Week old female rats of the Lewis or Sprague Dawley strain were injected intradermally in the hind paw with 0. 5 mg of heat-killed Mycobacterium butyricum in 0. 05 ml of liquid paraffin. Eighteen days after this adjuvant injection, the animals with well-established arthritis were selected and then treated for 7 consecutive days with the test compounds shown in Table 1, administered twice a day orally. The response to this therapy was assessed by measuring the thickness of the injected foot with a micrometer at the beginning (day 18) and at the end (day 25) of the therapy period.
II Analgesic Activity on Inflammatory Pain (1) Yeast-Induced Pain Test in Rats (Randall-Selitto's Method) Male rats of the Wistar slrain, with a body weight of 70 -9.
: . . . ..
106a\903 80 g, were injected in the plantar surface of the hind paw with 0.1 ml of a 5% suspension of dried yeast, to produce inflammation therein. The pain reaction threshold when pressure was applied to the paw was then measured, using the apparatus described by S Randall and Selitto in Archs int. Pharmacodyn. Ther. 111~
409 (1957), and those animals were selected which satisfied the following conditions :-(a) the threshold in the inflamed paw was less than 50 mm Hg; and (b) the difference in thresholds between the non-inflamed and inflamed paws was more than 50 mm Hg.
The test compounds shown in Table 1 were administered orally to these selected animals, 4 hours after the injection of the dried yeast suspension. The pain reaction threshold was determined as before, and the percentage increase in pain threshold (% IPT) of each animal was calculated from the equation:
% IPT=(Pd-Pi/Po-Pi) x 100 where Poand Pi represent the thresholds before medication in the non-inflamed and inflamed paws, respectively, and Pd , _ , represents the threshold in the inflamed paw after medication.
The value of Pd was measured 1 and 3 hours after the administration of the test compounds, and a mean value for the % IPT was calculated from these two measurements.
10.
; ~060~03 (2) Thermal Pain Test in Rats The method described by Y. Ii~uka and K. Tanaka in Folia Pharmacol. Japan, 70, 697 (1974) was used for this test. 5 to 7 Week old male rats of the Wistar strain received a standard heat injury on their hind paw, by dipping it for 5 secondsin water at 57 C. More than 1 hour later, a pain reaction could readily be evoked by further application of heat (5 seconds at 40 C) - that is to sayJ immediately after this treatment the animal raised its injured paw, presumably to avoi~ further pain which might be caused by contact with the wire netting of its cage. The "pain reaction time" was taken as the total time during which this paw-raising behaviour occurred over a period of 30 seconds. The test compounds shown in Table 1 were administered orally to the rats 2 hours after the first application of heat, and the response to the drugs was assessed by calculating the mean value of the pain reaction times measured 1 and 2 hours after drug administration.
III. Antipyretic Activity .
TTG-induced Fever Test in Guinea~pigs : .
Antipyretic activity was determin~ d by a modification of the method described by Kobayashi and Takagi in Jap. J.
Pharmacol. 18, 80 (1968). Fever was induced in female guinea-pigs of the Hartley strain with a body weight of about 300 g, whlch had fasted overnight, by injecting them with 10 jug/ml/kg .
, , . . .
~060'103 of TTG (a polysaccharide elaborated by Pseudomonds luorescens, produced by Fujisawa Pharmaceutical Co., Ltd., Japan). One hour after the injection, those test animals were selected which had a rectal temperature in the range of from 0. 8C to 1. 2 C
above normal. The test compounds shown in Table 1 were administered orally to these selected animals 1. 5 hours after the TTG injection, and the response to the drugs was assessed by calculating the mean value of the rectal temperatures measured 1 and 2 hours after drug administration.
Statistical Analysis The results obtained in the pharmacological tests were analysed. In order to obtain the regression line of H (percentage inhibition of response) over D (dose of the test drug), the H for each animal was calculated from the ratio of the response to the mean response in a non-medicated group. The regression line and ID50 (inhibition dose 50%) were obtained by the method of least squares. Confidence limits for the ID values were calculated by means of Fieller's Equation.
However, in the adjuvant-arthritis test, the ratio (RR) of responses after/before medication was first calculated, the response being assessed by measuring the thickness of the injected foot. The value of EI for each animal was then calculated from the ratio of RR to RRc, where RRc represents the mean value of RR
1 2.
1060~03 for a non-medicated group.
In the test by the Randall-Selitto method, the value of H for each animal was obtained directly from the percentage increase in the pain threshold, after adjusting it by the corresponding mean value for a non-medicated group.
ute Toxicit~
The acute toxicity of the two compounds OI the invention shown in Table 1 was determined by administering a single oral dose to male ICR mice 5 weeks old. The lethal effect was . .
expressed as X/n, in which ~ is the number of animals which were dead one week after administration and n was the total number. .
of animals used in the test.
The data thus obtained rom the pharmacological tests are shown in Table 1. The ranges of values shown in parantheses for ID50 (inhibition dose 50%) are those corresponding to statistical confidence limits of 95%. In the case of the adjuvant-arthritis test, the values given are for ID30 (inhibition dose 30%).
' ' ' ' .
106VC~O~
+~, _~ a Q~
,o ~ 1 ~ ~ c~o ~ ~ ., h ~ ' ~--~ ~i ~1 ~¢ ~ ~ ~i ,_ . --~
~ O~ ~ C~ .' ~ h ~ O-- di 1:- ~
.~ ~ ~3 ~1` t~ ~
~ ~ ol i~ ~ ¦ O~ N ~ N
!~ ¦ I ~ ~ ~
o ~ ol O O oo ~, ~¢~ ~ ~ ~:; l ..
o .~ ~ ~
a = 'o ~: O o ~
_ E~, c~ C~ d ¢~d 1060'~03 The invention is illustrated l~y the following Examples 1 to 7, while the subsequent Preparations 1 to 5 illustrate the synthesis of the starting materials of formula (II) and intermediates therefor.
Example 1 2-(2-Ethylindan-5-yl)propionic acid 5 g of ethyl 2-(2-ethylindan-5-yl)propionate were dissolved in a mixture of 50 ml of 10% aqueous potassium hydroxide solution and 80 ml of ethanol, and the resulting solution was refluxed for 4 hours over a water bath. After completion of the reaction, the reaction mix~ure was poured ir.to ice-water, and the resulting solution was shaken with ether to remove unreacted starting material. The aqueous layer was separated off, acidified to pH 4 - 5 with dilute hydrochloric acid, and extracted with ether.
The ether extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving 3. 2 g of a pale yellow oil. This oil was distilled under reduced pressure, giving the desired product as a colourless oil boiling at 165 - 166C/1. 5 mmHg.
Elemental analysis:
Calculated for C14H18 2 ' %; ' %-Found: C, 76. 93%; H, 8. 53%.
10609()3 Example 2 Piperidine 2-(2-ethylinda_-yl)propionate 200 mg of piperidine were added to a solution of 360 rng of 2-(2-ethylindan-5-yl)propionic acid in 2 ml of benzene, The solvent and excess piper;dine were distilled off under reduced pressure, and the residue was cooled, leaving 300 mg of a colourless powder. This powder was recrystallised from a mixture of chloroform and petroleum ether, giving the desired product as colourless prisms melting at 95 - 96C with decomposition.
Elemental analysis (%):
Calculated for ClgH2902N: C, 75. 20; H, 9. 63; N, 4. 62 Found: C, 74, 72; H, 9. 69; N, 4, 82 Example 3 Sodium 2-(2-ethylindan-5-yl)propionate 2. 2 g of sodium hydroxide and 12. 2 g of 2-(2-ethylindan-5-yl)propionic acid were dissolved in a mixture of 9 ml of water and 21 ml of ethanol, the solvent was distilled off, and ether was added to the residue. The precipitate obtained was collected on a filter and washed with ether, giving 12. 9 g of a white powder.
This powder was recrystallised from a mixture of ethanol and ether, giving the desired product as white needles melting at 178 - 181C, 16.
?
~060903 Elemental analysis(%) Calculated for C14H1~702Na C, 69- 98; H~7 13 Found: C, 7 0. 22; H, 7 . 27 :Example 4 2-(2-Isopropylindan-5-yl)propionic acid 2. 6 g of ethyl 2-~2-isopropylindan-5-yl)propionate were dissolved in a mixture of 20 ml of 10% aqueous potassium hydroxide solution and 80 ml of ethanol, and the resulting solution was refluxed for 3 hours ov~r a water bath. After completion of the reaction, the organic solvent was distilled off from the reaction mixture, and water was added to the residue. The aqueous layer was separated off and shaken with ether, to remsve unreacted starting material, acidified to pH 4 - 5 with dilute hydrochloric acid, and extracted with ether. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving 2.1 g of colourless crystals. These crystals were recrystallised from a mixture of benzene and n-hexane, giving the desired product as colourless prisms melting at 90 - 91. 5 C.
Elemental analysis(%) Calculated fo 15 20 2 l~ound: C, 77 . 59; H, 8. 65 106~903 Example S
2-(2-Isopropylindan-5-yl)propionic acid 1. 05 g of 2-(2-isopropylindan-5-yl)propionitrile were dissolved in a mixture of 15 ml of concentrated hydrochloric acid and lS ml of dioxane, and -the resulting solution was refluxed for 6 hours over an oil bath. After completion of the reaction, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving 0. 81 g of colourless crystals. These crystals were recrystallised from n-hexane, to give the desired product as colourless prisms melting at 90 - 91. 5C.
, This product was shown to be identical with the one obtained in Example 4, by means of a mixed melting point determination and their infrared spectra.
Example 6 2-(2-Isopropylindan-5-yl)propionic acid 15 ml of concentrated hydrochloric acid were added to 2. 3 g of 2-(2-isopropylindan-5-yl)propionic acid amide and the resulting mixture was refluxed for 1. 5 hours. After completion of the reaction, the reaction mixture was worked up in the same way as in Example 5, giving 2.1 g of the desired product as colourless prisms melting at 90 - 91. 5C.
18.
.:
10t~0903 This product was shown to be identical with the one obtained in Example 4 by means of a mixed melting point determination and their infrared spectra.
Example 7 Aluminium bis[ 2 ~2 -isopropylindan- 5 -yl)propionate~
2. 32 g of 2-(2-isopropylindan-S-yl)propionic acid and 1. 02 g of aluminium isopropoxide were added to 30 ml of toluene.
The resulting mixture was refluxed for 3 hours, then 10 ml of water and 2Q ml of isopropanol were added to it, and the mixture was refluxed for a further 1 5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, and 30 ml of ethanol were added to the residue. The precipitate obtained was collected on a filter, giving 2. 2 g of the desired product as a white powder.
Elemental Analysis(%) Calculated for C30H3905Al H20: C, 68. 68; H, 7. 87 Found: C, 68. 92; H, 7. 60 Preparation 1 2-Ethyl-S-~-cyanoethylindan (IIa) (1) 2-Ethyl-5-chloromethylindan (IV) 100 ml. of concentrated hydrochloric acid were added with ætirring to a mixture of 60 g of 2-ethylindan, 30 g of paraformaldehyde, 68 ml of acetic acid and 45 ml of phosphoric acid. The resulting 19.
mixture was heated with stirring for 5 hours at 90 - 95 C, After completion of the reaction, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ether.
The ether extract was washed with water and dried over anhydrous sodium sulphate, Tbe solvent was distilled off from the extract, leaving a pale yellow oil. This oil was subjected to vacuum distillation, giving 46 g of the desired product as a colourless oil boiling at 108 C/2mmHg.
Elemental analysis(%):
Calculated for C12H15Cl: C, 74. 03; H, 7. 77; Cl, 18- 21 Found: C, 73. 59; H, 7. 90; Cl, 17, 67 2) 2-Ethyl-5-cyanomethylindan (V) 30 g of 2-ethyl-5-chloromethylindan and 15 g of potassium cyanide were dissolved in a mixture of 20 ml of water and 80 ml of ethanol, and the resulting solution was refluxed for 5 hours over a water bath. After completion of the reaction, the ethanol was distilled off under reduced pressure, leaving a colourless oil.
This oil was subjected to vacuum distillation, giving 18. 7 g of the desired product as a colourless oil boiling at 130C/3mmHg.
Elemental analysis~%):
Calculated for C13H15N: C, 84. 28; H, 8. 16; N, 7. 56 Found: C, 84. 46; H, 8, 42; N, 7. 34 20, 106(~903
After completion of the reaction, the desired product can be re covered from the reaction mixture by conventional techniques. For example, if a mineral acid is employed for the hydrolysis, the reaction mixture can be poured into ice -water and extracted with an appropriate organic solvent (e. g.
ether), the extract shaken with a dilute aqueous alkaline solution, the aqueous layer acidified and re-extracted with an lû appropriate organic solvent, the resulting extract washed and dried, and the solvent distilled off to give the desired product.
On the other hand, if an alkali or alkaline earth metal base is employed for the hydrolysis, the product can be recovered by distilling off the solvent from the reaction mixture, diluting the residue with water, shaking the resulting aqueous solution with a water-immiscible organic solvent (e. g. ether), acidiying it and extracting it with an appropriate organic solvent (e. g.
ether), washing the extract with water and drying it, and then distilling off the solvent from the extract to give the desired product. If necessary, the product thus obtained can be purified by conventional methods, such as recrystallisation, distillation under reduced pressure, or column chromatography.
The indanylpropionic acid derivative of formula (I) thus . . , : , ' , ~ : ' ' ' ~ : . ' . , 106()903 obtained can, if appropriate, be converted into a pharmaceutically acceptable salt thereof by neutralisation in the conventional manner, Such pharmaceutically acceptable salts include alkali or alkaline earth metal salts such as the sodium, potassium, calcium and aluminium salts, the ammonium salt, and organic amine salts such as the triethylamine, dicyclohexylamine, procaine, dibenzyl-amine, piperidine and N-ethylpiperidine salts.
The starting materials of formula (II), used in the process of the invention, are themselves new compounds and can be prepared by the process summarised in the followmg reaction scheme: - .
l060sa3 1st step ~ {~CH2 (III) (IV) 2nd step ~CH2CN 3rd step (~) /~ 4th step ~5H-COOR
R ~d (lIa) (IIb) .
\th step \~ ','.
R ~3 CH-CONH2 ( IIc) : ,: .
In the reaction scheme, R has the meaning already defined, and R represents an alkyl group having from 1 to 4 carbon atoms.
In the first step of the reaction scheme, the compound (III) is heated with formaldehyde in aqueous hydrochloric acid solution at 50 - 100 C, to give the compound (IV). In the second step, the compound (IV) is refluxed with an alkali metal cyanide (e. g.
potassium cyanide or sodium cyanide) in an appropriate organic solvent, to give the compound (V). In the third step, the compound (V) is refluxed with a methyl halide (e. g. methy~. iodide), in the presence of an alkali metal compound such as sodium amide, sodium hydride or n-butyl lithium, in an appropriate organic solvent, giving the compound (IIa), which is one of the starting materials of formula (II) used in the process of the invention.
If desired, the compound (IIa) can be converted into the compound (IIb), another of the starting materials of formula (II), by refluxing it with an alkanol having from 1 to 4 carbon atoms, in the presence of an acid catalyst (e. g. concentrated sulphuric acid or concentrated hydrochloric acid), Alternatively, the compound (IIa) can be converted into the compound (IIc), which is the third type of the starting materials of formula (II), by reacting it with a mineral acid (e. g. concentrated sulphuric acid or concentrated hydrochloric acid), at a reaction temperature in the range of from room temperature to 9 0C.
~t the end of any of the reaction steps in the preparation of the compounds of formula (II), the desired product can be isolated from the reaction mixture by conventional techniques and, if necessary, purified by one of the usual methods, such as column chromatography or thin-layer chromatography.
The two compounds of formula (III), used as starting materials in the preparation of the compounds of formula (II), are already known. The compound of forrmlla (III) wherein R
is an ethyl group can be prepared by the process described by T. Wagner-lauregg et al. in Chem. Ber. 74, 1522 (1~41); and the compound of formula (III) wherein R is an isopropyl group can be prepared by the process described by Pl. A. Plattner et al, in Helv. ~him. Acta, 30, 689 (1947) When a mixture of optical isomers is obtained in any of the processes described hereinabove, if desired it can be resolved -by conventional techniques at a convenient point in the synthesis.
So far as we are aware, no indanylpropionic acid derivatives have previously been described in the scientific literature. We have discovered that the indanylpropionic acid derivatives of the present invention have potent anti-inflammatory, analgesic and antipyretic activities, in association with extremely low toxicities. By virtue of these properties, the compounds of the invention are useful as pharmaceuticals; and, accordingly, the - invention also provides a pharmaceutical composition, comprising a compound of said formula (I) or pharmaceutically acceptable salt thereof, together with a pha~maceutical carrier or diluent.
The compounds of formula (I) and their pharmaceutically acceptable salts can be administered orally or parenterally, by conventional methods. Accordingly, the pharmaceutical composition of the invention can be formulated for oral or parenteral administration, using solid or liquid pharmaceutical carriers and diluents, and optionally also appropriate pharmaceutical adjuvants, for example as tablets, capsules, injectable liquids and suspensions. The optimum dosage can vary, depending on the age, body weight and clinical condition of the patient, but the total daily dosage for adults would generally be in the range of from 50 mg to 2000 mg of the compound of the invention, conveniently administered in divided doses three or four times a day.
The pharmacological properties of the compounds of the invention are illustrated by the following tests, in which acetyl-salicylic aoid was used for comparative purposes.
I. Anti-inflammatory activity ( 1 ) Carrageenin -Oedema Test in Rats The test compounds shown in Table 1 were administered orally, in aqueous gum tragacanth suspension, to male rats of the Wistar strain having a body weight of 120 - 150 g which had fasted overnight. After 30 minutes, inflammation was induced by the - 8.
; . '' , ... .::
1060'~03 method of Winter et al., Proc. Soc:. Exp. Biol. ~ed. 111 544(1962), by injecting subcutaneously 0. 05 ml of a 1% carrageenin suspension into the plantar tissue of the hind paw. Paw oedema was measured volumetrically, immediately before and also 3 hours after the carrageenin injection, and the response (R) was calculated by the following equatiorl:-~ = (~-Vo) / ~o where Vo and V represent the paw volumes 0 and 3 hours after the carrageenin injection, respectively.
(2) Adjuvant-induced Arthritis Test in Rats (Therapeutic Effect on Established Arthritis).
7 ~ 8 Week old female rats of the Lewis or Sprague Dawley strain were injected intradermally in the hind paw with 0. 5 mg of heat-killed Mycobacterium butyricum in 0. 05 ml of liquid paraffin. Eighteen days after this adjuvant injection, the animals with well-established arthritis were selected and then treated for 7 consecutive days with the test compounds shown in Table 1, administered twice a day orally. The response to this therapy was assessed by measuring the thickness of the injected foot with a micrometer at the beginning (day 18) and at the end (day 25) of the therapy period.
II Analgesic Activity on Inflammatory Pain (1) Yeast-Induced Pain Test in Rats (Randall-Selitto's Method) Male rats of the Wistar slrain, with a body weight of 70 -9.
: . . . ..
106a\903 80 g, were injected in the plantar surface of the hind paw with 0.1 ml of a 5% suspension of dried yeast, to produce inflammation therein. The pain reaction threshold when pressure was applied to the paw was then measured, using the apparatus described by S Randall and Selitto in Archs int. Pharmacodyn. Ther. 111~
409 (1957), and those animals were selected which satisfied the following conditions :-(a) the threshold in the inflamed paw was less than 50 mm Hg; and (b) the difference in thresholds between the non-inflamed and inflamed paws was more than 50 mm Hg.
The test compounds shown in Table 1 were administered orally to these selected animals, 4 hours after the injection of the dried yeast suspension. The pain reaction threshold was determined as before, and the percentage increase in pain threshold (% IPT) of each animal was calculated from the equation:
% IPT=(Pd-Pi/Po-Pi) x 100 where Poand Pi represent the thresholds before medication in the non-inflamed and inflamed paws, respectively, and Pd , _ , represents the threshold in the inflamed paw after medication.
The value of Pd was measured 1 and 3 hours after the administration of the test compounds, and a mean value for the % IPT was calculated from these two measurements.
10.
; ~060~03 (2) Thermal Pain Test in Rats The method described by Y. Ii~uka and K. Tanaka in Folia Pharmacol. Japan, 70, 697 (1974) was used for this test. 5 to 7 Week old male rats of the Wistar strain received a standard heat injury on their hind paw, by dipping it for 5 secondsin water at 57 C. More than 1 hour later, a pain reaction could readily be evoked by further application of heat (5 seconds at 40 C) - that is to sayJ immediately after this treatment the animal raised its injured paw, presumably to avoi~ further pain which might be caused by contact with the wire netting of its cage. The "pain reaction time" was taken as the total time during which this paw-raising behaviour occurred over a period of 30 seconds. The test compounds shown in Table 1 were administered orally to the rats 2 hours after the first application of heat, and the response to the drugs was assessed by calculating the mean value of the pain reaction times measured 1 and 2 hours after drug administration.
III. Antipyretic Activity .
TTG-induced Fever Test in Guinea~pigs : .
Antipyretic activity was determin~ d by a modification of the method described by Kobayashi and Takagi in Jap. J.
Pharmacol. 18, 80 (1968). Fever was induced in female guinea-pigs of the Hartley strain with a body weight of about 300 g, whlch had fasted overnight, by injecting them with 10 jug/ml/kg .
, , . . .
~060'103 of TTG (a polysaccharide elaborated by Pseudomonds luorescens, produced by Fujisawa Pharmaceutical Co., Ltd., Japan). One hour after the injection, those test animals were selected which had a rectal temperature in the range of from 0. 8C to 1. 2 C
above normal. The test compounds shown in Table 1 were administered orally to these selected animals 1. 5 hours after the TTG injection, and the response to the drugs was assessed by calculating the mean value of the rectal temperatures measured 1 and 2 hours after drug administration.
Statistical Analysis The results obtained in the pharmacological tests were analysed. In order to obtain the regression line of H (percentage inhibition of response) over D (dose of the test drug), the H for each animal was calculated from the ratio of the response to the mean response in a non-medicated group. The regression line and ID50 (inhibition dose 50%) were obtained by the method of least squares. Confidence limits for the ID values were calculated by means of Fieller's Equation.
However, in the adjuvant-arthritis test, the ratio (RR) of responses after/before medication was first calculated, the response being assessed by measuring the thickness of the injected foot. The value of EI for each animal was then calculated from the ratio of RR to RRc, where RRc represents the mean value of RR
1 2.
1060~03 for a non-medicated group.
In the test by the Randall-Selitto method, the value of H for each animal was obtained directly from the percentage increase in the pain threshold, after adjusting it by the corresponding mean value for a non-medicated group.
ute Toxicit~
The acute toxicity of the two compounds OI the invention shown in Table 1 was determined by administering a single oral dose to male ICR mice 5 weeks old. The lethal effect was . .
expressed as X/n, in which ~ is the number of animals which were dead one week after administration and n was the total number. .
of animals used in the test.
The data thus obtained rom the pharmacological tests are shown in Table 1. The ranges of values shown in parantheses for ID50 (inhibition dose 50%) are those corresponding to statistical confidence limits of 95%. In the case of the adjuvant-arthritis test, the values given are for ID30 (inhibition dose 30%).
' ' ' ' .
106VC~O~
+~, _~ a Q~
,o ~ 1 ~ ~ c~o ~ ~ ., h ~ ' ~--~ ~i ~1 ~¢ ~ ~ ~i ,_ . --~
~ O~ ~ C~ .' ~ h ~ O-- di 1:- ~
.~ ~ ~3 ~1` t~ ~
~ ~ ol i~ ~ ¦ O~ N ~ N
!~ ¦ I ~ ~ ~
o ~ ol O O oo ~, ~¢~ ~ ~ ~:; l ..
o .~ ~ ~
a = 'o ~: O o ~
_ E~, c~ C~ d ¢~d 1060'~03 The invention is illustrated l~y the following Examples 1 to 7, while the subsequent Preparations 1 to 5 illustrate the synthesis of the starting materials of formula (II) and intermediates therefor.
Example 1 2-(2-Ethylindan-5-yl)propionic acid 5 g of ethyl 2-(2-ethylindan-5-yl)propionate were dissolved in a mixture of 50 ml of 10% aqueous potassium hydroxide solution and 80 ml of ethanol, and the resulting solution was refluxed for 4 hours over a water bath. After completion of the reaction, the reaction mix~ure was poured ir.to ice-water, and the resulting solution was shaken with ether to remove unreacted starting material. The aqueous layer was separated off, acidified to pH 4 - 5 with dilute hydrochloric acid, and extracted with ether.
The ether extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving 3. 2 g of a pale yellow oil. This oil was distilled under reduced pressure, giving the desired product as a colourless oil boiling at 165 - 166C/1. 5 mmHg.
Elemental analysis:
Calculated for C14H18 2 ' %; ' %-Found: C, 76. 93%; H, 8. 53%.
10609()3 Example 2 Piperidine 2-(2-ethylinda_-yl)propionate 200 mg of piperidine were added to a solution of 360 rng of 2-(2-ethylindan-5-yl)propionic acid in 2 ml of benzene, The solvent and excess piper;dine were distilled off under reduced pressure, and the residue was cooled, leaving 300 mg of a colourless powder. This powder was recrystallised from a mixture of chloroform and petroleum ether, giving the desired product as colourless prisms melting at 95 - 96C with decomposition.
Elemental analysis (%):
Calculated for ClgH2902N: C, 75. 20; H, 9. 63; N, 4. 62 Found: C, 74, 72; H, 9. 69; N, 4, 82 Example 3 Sodium 2-(2-ethylindan-5-yl)propionate 2. 2 g of sodium hydroxide and 12. 2 g of 2-(2-ethylindan-5-yl)propionic acid were dissolved in a mixture of 9 ml of water and 21 ml of ethanol, the solvent was distilled off, and ether was added to the residue. The precipitate obtained was collected on a filter and washed with ether, giving 12. 9 g of a white powder.
This powder was recrystallised from a mixture of ethanol and ether, giving the desired product as white needles melting at 178 - 181C, 16.
?
~060903 Elemental analysis(%) Calculated for C14H1~702Na C, 69- 98; H~7 13 Found: C, 7 0. 22; H, 7 . 27 :Example 4 2-(2-Isopropylindan-5-yl)propionic acid 2. 6 g of ethyl 2-~2-isopropylindan-5-yl)propionate were dissolved in a mixture of 20 ml of 10% aqueous potassium hydroxide solution and 80 ml of ethanol, and the resulting solution was refluxed for 3 hours ov~r a water bath. After completion of the reaction, the organic solvent was distilled off from the reaction mixture, and water was added to the residue. The aqueous layer was separated off and shaken with ether, to remsve unreacted starting material, acidified to pH 4 - 5 with dilute hydrochloric acid, and extracted with ether. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving 2.1 g of colourless crystals. These crystals were recrystallised from a mixture of benzene and n-hexane, giving the desired product as colourless prisms melting at 90 - 91. 5 C.
Elemental analysis(%) Calculated fo 15 20 2 l~ound: C, 77 . 59; H, 8. 65 106~903 Example S
2-(2-Isopropylindan-5-yl)propionic acid 1. 05 g of 2-(2-isopropylindan-5-yl)propionitrile were dissolved in a mixture of 15 ml of concentrated hydrochloric acid and lS ml of dioxane, and -the resulting solution was refluxed for 6 hours over an oil bath. After completion of the reaction, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving 0. 81 g of colourless crystals. These crystals were recrystallised from n-hexane, to give the desired product as colourless prisms melting at 90 - 91. 5C.
, This product was shown to be identical with the one obtained in Example 4, by means of a mixed melting point determination and their infrared spectra.
Example 6 2-(2-Isopropylindan-5-yl)propionic acid 15 ml of concentrated hydrochloric acid were added to 2. 3 g of 2-(2-isopropylindan-5-yl)propionic acid amide and the resulting mixture was refluxed for 1. 5 hours. After completion of the reaction, the reaction mixture was worked up in the same way as in Example 5, giving 2.1 g of the desired product as colourless prisms melting at 90 - 91. 5C.
18.
.:
10t~0903 This product was shown to be identical with the one obtained in Example 4 by means of a mixed melting point determination and their infrared spectra.
Example 7 Aluminium bis[ 2 ~2 -isopropylindan- 5 -yl)propionate~
2. 32 g of 2-(2-isopropylindan-S-yl)propionic acid and 1. 02 g of aluminium isopropoxide were added to 30 ml of toluene.
The resulting mixture was refluxed for 3 hours, then 10 ml of water and 2Q ml of isopropanol were added to it, and the mixture was refluxed for a further 1 5 hours. After completion of the reaction, the solvent was distilled off from the reaction mixture, and 30 ml of ethanol were added to the residue. The precipitate obtained was collected on a filter, giving 2. 2 g of the desired product as a white powder.
Elemental Analysis(%) Calculated for C30H3905Al H20: C, 68. 68; H, 7. 87 Found: C, 68. 92; H, 7. 60 Preparation 1 2-Ethyl-S-~-cyanoethylindan (IIa) (1) 2-Ethyl-5-chloromethylindan (IV) 100 ml. of concentrated hydrochloric acid were added with ætirring to a mixture of 60 g of 2-ethylindan, 30 g of paraformaldehyde, 68 ml of acetic acid and 45 ml of phosphoric acid. The resulting 19.
mixture was heated with stirring for 5 hours at 90 - 95 C, After completion of the reaction, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ether.
The ether extract was washed with water and dried over anhydrous sodium sulphate, Tbe solvent was distilled off from the extract, leaving a pale yellow oil. This oil was subjected to vacuum distillation, giving 46 g of the desired product as a colourless oil boiling at 108 C/2mmHg.
Elemental analysis(%):
Calculated for C12H15Cl: C, 74. 03; H, 7. 77; Cl, 18- 21 Found: C, 73. 59; H, 7. 90; Cl, 17, 67 2) 2-Ethyl-5-cyanomethylindan (V) 30 g of 2-ethyl-5-chloromethylindan and 15 g of potassium cyanide were dissolved in a mixture of 20 ml of water and 80 ml of ethanol, and the resulting solution was refluxed for 5 hours over a water bath. After completion of the reaction, the ethanol was distilled off under reduced pressure, leaving a colourless oil.
This oil was subjected to vacuum distillation, giving 18. 7 g of the desired product as a colourless oil boiling at 130C/3mmHg.
Elemental analysis~%):
Calculated for C13H15N: C, 84. 28; H, 8. 16; N, 7. 56 Found: C, 84. 46; H, 8, 42; N, 7. 34 20, 106(~903
(3) 2-(2-Ethylindan-5-yl)propionitrile (IIa) 0, 8 g of sodium amide and 3, 7 g of 2-ethyl-5-cyanomethylindan in 20 rnl of anhydrous benzene were added to 10 ml of anhydrous ben~ene. The resulting mixture was refluxed for 3 hours, then 4, 3 g of methyl iodide were added to it, and the mixture was heated with stirring for 5 hours at about 70 C
in a pressure vessel. After completion of the reaction, water was added to the reaction mixture. The benzene layer was separated off, washed with water, and dried over anhydrous sodium I0 sulphate. The solvent was distilled off, giving 1. 6 g of the desired product as a colourless oil.
Preparation 2 Ethyl 2-(2-ethylindan-5-yl)propionate (IIb)
in a pressure vessel. After completion of the reaction, water was added to the reaction mixture. The benzene layer was separated off, washed with water, and dried over anhydrous sodium I0 sulphate. The solvent was distilled off, giving 1. 6 g of the desired product as a colourless oil.
Preparation 2 Ethyl 2-(2-ethylindan-5-yl)propionate (IIb)
4. 4 ml of concentrated sulphuric acid were added to a solution of 4. Og of 2-(2-ethylindan-5-yl)propionitrile in 8 ml of absolute ethanol, and the resulting mixture was refluxed for 12 hours over a water bath. After completion of the reaction, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ether. The ether extract was washed first with water and then with 101/o aque ous sodium carbonate solution, and dried over anhydrous sodium sulphate. The solvent was distilled off from the extract, leaving an oil. This oil was subjected to vacuum distillation, giving 3. 4 g of the desired product as a colourless oil boiling at 120 - 122 C/2mmHg, 21, .
1060'903 Elemental analysis ~%):
Calculated for C16H22O2 Found: C, 78.22; H, 9.08 Preparation 3 .
2-(2-Isopropylindan-5-yl)propionitrile (IIa) (1) 2-Isopropyl-5-chloromethylindan (IV) A mixture of 100 ml of concentrated hydrochloric acid, 70 g of 2-isopropylindan, 30 g of paraformaldehyde, 70 ml of acetic acid and 50 ml of phosphoric acid was heated with stirring for 5 hours at 90 - 95C. The reaction mixture was then worked up in the same way as in Preparation 1(1), giving 53 g of the desired product as a colourless oil.
(2) 2-Isopropyl-5-cyanomethylindan (V) 32 g of 2-isopropyl-5-chloromethylindan and 15 g of potassium cyanide were dissolved in a mixture of 20 ml of water and 80 ml of ethanol, and the resulting solution was refluxed for 5 hours over a water bath. The reaction mixture was then worked up in the same way as in Preparation 1(2), giving 22 g of the desired pro-duct as a colourless oil.
(3) 2-(2-Isopropylindan-5-yl)propionitrile (IIa) 1.0 g of a 50% suspension of sodium hydride in liquid para-ffinand 4.0 g of 2-isopropyl-5-cyanomethylindan in 20 ml of anhydrous benzene were added to 10 ml of anhydrous benzene. The resulting mixture was refluxed for 3 hours, then 4.3 g of - ' `
methyl lodide were added to it, and the resulting mixture was heated with stirring for 5 hours at about 70C in a pressure vessel. The reaction mixture was then worked up in the same way as in Preparation 1(3), giving a pale yellow oil. This oil was subjected to vacuum distillation, giving 2,1 g of the desired product as a colourless oil boiling at 142 - 145C/0, 5 mmHg.
Elemental analysis(%) Calculated for C15H19N: C, 84 45; H, 8 98; N, 6- 57 Found: C, 84 88; H, 9. 01; N, 6. 29 ' 10 Preparation 4 Ethyl 2-(2-isoyropylindan-5-yl)propionate (Ilb) `~ 4. 4 ml of concentrated sulphuric acid were added to a solution of 4, 3 g of 2-(2-isopropylindan-5-yl)propionitrile in 8 ml of absolute ethanol, and the resulting mixture was refluxed for 12 hours over a water bath. The mixture was then worked up in the same way as in Preparation 2, giving a colourless oil.
This oil was subjected to vacuum distillation, giving 3. 5 g of the desired product as a colourless oil boiling at 160 - 163C/2mmHg ( bath tempe rature ).
Elemental analysis(%) ated for C17H242 C~ 78- 42; H~ 9~ 29 . Found: C, 78, 54; H, 9. 33 ~: 23.
D
. ' ' ' : , Preparation 5 2-(2-Isopropylindan-5-yl)propionic acid amide (IIc) 25 ml of concentrated hydrochloric acid were added to 3. 2 g of 2-(2-isopropropylindan-5-yl)propionitrile, and the resulting rmixture was warmed to about 30C with stirring for 1, 5 hours. After completion of the reaction, the reaction mixture . ~ was poured into ice-water. The precipitate produced was collected : ~ on a filter, washed with water and recrystallised from a mixture of : ethyl acetate and n-hexane, giving 3. 0 g of the desired product as colourless plates with a melting point of 112-114C.
Elemental analysis(%):
.:, Calculated for C15H210N: C, 77, 88; H, 9. 15; N, 6- 05 Found: C, 78, 06; H, 8. 99; N, 6. 35 ., .
: .
. , .
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~ , ,, l .
. 24, ~
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1060'903 Elemental analysis ~%):
Calculated for C16H22O2 Found: C, 78.22; H, 9.08 Preparation 3 .
2-(2-Isopropylindan-5-yl)propionitrile (IIa) (1) 2-Isopropyl-5-chloromethylindan (IV) A mixture of 100 ml of concentrated hydrochloric acid, 70 g of 2-isopropylindan, 30 g of paraformaldehyde, 70 ml of acetic acid and 50 ml of phosphoric acid was heated with stirring for 5 hours at 90 - 95C. The reaction mixture was then worked up in the same way as in Preparation 1(1), giving 53 g of the desired product as a colourless oil.
(2) 2-Isopropyl-5-cyanomethylindan (V) 32 g of 2-isopropyl-5-chloromethylindan and 15 g of potassium cyanide were dissolved in a mixture of 20 ml of water and 80 ml of ethanol, and the resulting solution was refluxed for 5 hours over a water bath. The reaction mixture was then worked up in the same way as in Preparation 1(2), giving 22 g of the desired pro-duct as a colourless oil.
(3) 2-(2-Isopropylindan-5-yl)propionitrile (IIa) 1.0 g of a 50% suspension of sodium hydride in liquid para-ffinand 4.0 g of 2-isopropyl-5-cyanomethylindan in 20 ml of anhydrous benzene were added to 10 ml of anhydrous benzene. The resulting mixture was refluxed for 3 hours, then 4.3 g of - ' `
methyl lodide were added to it, and the resulting mixture was heated with stirring for 5 hours at about 70C in a pressure vessel. The reaction mixture was then worked up in the same way as in Preparation 1(3), giving a pale yellow oil. This oil was subjected to vacuum distillation, giving 2,1 g of the desired product as a colourless oil boiling at 142 - 145C/0, 5 mmHg.
Elemental analysis(%) Calculated for C15H19N: C, 84 45; H, 8 98; N, 6- 57 Found: C, 84 88; H, 9. 01; N, 6. 29 ' 10 Preparation 4 Ethyl 2-(2-isoyropylindan-5-yl)propionate (Ilb) `~ 4. 4 ml of concentrated sulphuric acid were added to a solution of 4, 3 g of 2-(2-isopropylindan-5-yl)propionitrile in 8 ml of absolute ethanol, and the resulting mixture was refluxed for 12 hours over a water bath. The mixture was then worked up in the same way as in Preparation 2, giving a colourless oil.
This oil was subjected to vacuum distillation, giving 3. 5 g of the desired product as a colourless oil boiling at 160 - 163C/2mmHg ( bath tempe rature ).
Elemental analysis(%) ated for C17H242 C~ 78- 42; H~ 9~ 29 . Found: C, 78, 54; H, 9. 33 ~: 23.
D
. ' ' ' : , Preparation 5 2-(2-Isopropylindan-5-yl)propionic acid amide (IIc) 25 ml of concentrated hydrochloric acid were added to 3. 2 g of 2-(2-isopropropylindan-5-yl)propionitrile, and the resulting rmixture was warmed to about 30C with stirring for 1, 5 hours. After completion of the reaction, the reaction mixture . ~ was poured into ice-water. The precipitate produced was collected : ~ on a filter, washed with water and recrystallised from a mixture of : ethyl acetate and n-hexane, giving 3. 0 g of the desired product as colourless plates with a melting point of 112-114C.
Elemental analysis(%):
.:, Calculated for C15H210N: C, 77, 88; H, 9. 15; N, 6- 05 Found: C, 78, 06; H, 8. 99; N, 6. 35 ., .
: .
. , .
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Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing indanylpropionic acid derivatives having the formula:
(I) wherein R represents an ethyl group or an isopropyl group and pharmaceutically acceptable salts thereof, which comprises hydrolysing an indan derivative of formula:
(II) wherein R has the above meaning; and Y represents an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy moiety, a cyano group or a carbamoyl group by means of a hydrolysing agent selected from the group consisting of mineral acids, and alkali and alkaline earth metal bases and, when the free acid is obtained and the salt is required, salifying the free acid of formula (I) thus obtained.
(I) wherein R represents an ethyl group or an isopropyl group and pharmaceutically acceptable salts thereof, which comprises hydrolysing an indan derivative of formula:
(II) wherein R has the above meaning; and Y represents an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy moiety, a cyano group or a carbamoyl group by means of a hydrolysing agent selected from the group consisting of mineral acids, and alkali and alkaline earth metal bases and, when the free acid is obtained and the salt is required, salifying the free acid of formula (I) thus obtained.
2. A process according to claim 1 wherein the hydrol-ysis is effected by means of a hydrolysing agent selected from the group consisting of hydrochloric acid, hydrobromic acid, potassium hydroxide and sodium hydroxide.
3. A process as claimed in claim 2 in which the hydrolysing agent is used in aqueous solution.
4. A process according to claim 2 wherein said hydrolysing agent is used in aqueous solution in the presence of a water- miscible organic solvent.
5. An indanylpropionic acid derivative having the formula:
(I) wherein R represents an ethyl group or an isopropyl group or a pharmaceutically acceptable salt thereof, when prepared by the process according to claim 1, 2 or 3 or an obvious chemical equivalent thereof.
(I) wherein R represents an ethyl group or an isopropyl group or a pharmaceutically acceptable salt thereof, when prepared by the process according to claim 1, 2 or 3 or an obvious chemical equivalent thereof.
6. A process as claimed in claim 1 which comprises refluxing ethyl 2-(2-ethylindan-5-yl)propionate in methanolic potassium hydroxide and acidifying the product obtained with hydrochloric acid.
7. 2-(2-Ethylindan-5-yl)propionic acid whenever prepared or produced by the process as claimed in claim 6 or an obvious chemical equivalent thereof.
8. A process as claimed in claim 6 in which the 2-(2-ethylindan-5-yl)propionic acid so obtained is reacted in benzene with piperidine.
9. Piperidine 2-(2-ethylindan-5-yl)propionate when-ever prepared or produced by the process as claimed in claim 8 or an obvious chemical equivalent thereof.
10. A process as claimed in claim 6 in which the 2-(2-ethylindan-5-yl)propionic acid so obtained is reacted with sodium hydroxide in ethanolic aqueous solution.
11. Sodium 2-(2-ethylindan-5-yl)propionate whenever prepared or produced by the process as claimed in claim 10 or an obvious chemical equivalent thereof.
12. A process as claimed in claim 1 which comprises refluxing ethyl 2-(2-isopropylindan-5-yl)propionate in methanolic potassium hydroxide and acidifying the product obtained with hydrochloric acid.
13. A process as claimed in claim 1 which comprises refluxing 2-(2-isopropylindan-5-yl)propionitrile in a mixture of concentrated hydrochloric acid and dioxane.
14. A process as claimed in claim 1 which comprises refluxing 2-(2-isopropylindan-5-yl)propionic acid amide with concentrated hydrochloric acid.
15. 2-(2-Isopropylindan-5-yl)propionic acid whenever prepared or produced by the process as claimed in claim 12, 13 or 14 or an obvious chemical equivalent thereof.
16. A process as claimed in claim 12 in which the 2-(2-isopropylindan-5-yl)propionic acid obtained is refluxed in toluene with aluminium isopropoxide and the mixture obtained further refluxed with aqueous isopropanol.
17. Aluminium bis[2-(2-isopropylindan-5-yl)propionate]
whenever prepared or produced by the process as claimed in claim 16 or an obvious chemical equivalent thereof.
whenever prepared or produced by the process as claimed in claim 16 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP49017981A JPS50111057A (en) | 1974-02-14 | 1974-02-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1060903A true CA1060903A (en) | 1979-08-21 |
Family
ID=11958885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA219,910A Expired CA1060903A (en) | 1974-02-14 | 1975-02-12 | Pharmaceutically useful indanylpropionic acid derivatives |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS50111057A (en) |
| BE (1) | BE825582A (en) |
| CA (1) | CA1060903A (en) |
| CH (1) | CH605566A5 (en) |
| DE (1) | DE2501459A1 (en) |
| DK (1) | DK52975A (en) |
| ES (1) | ES434751A1 (en) |
| FR (1) | FR2261003B1 (en) |
| GB (1) | GB1502662A (en) |
| NL (1) | NL7501806A (en) |
| SE (1) | SE7501520L (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2546906A1 (en) * | 1974-10-29 | 1976-09-30 | Sandoz Ag | NEW ARYL ACID ACIDS THEIR PRODUCTION AND USE IN MEDICINAL PRODUCTS |
| JPS56138138A (en) * | 1981-03-04 | 1981-10-28 | Hexachimie | Manufacture of indane derivative |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH592598A5 (en) * | 1973-10-30 | 1977-10-31 | Hexachimie |
-
1974
- 1974-02-14 JP JP49017981A patent/JPS50111057A/ja active Pending
-
1975
- 1975-01-15 DE DE19752501459 patent/DE2501459A1/en not_active Withdrawn
- 1975-01-27 CH CH92475A patent/CH605566A5/xx not_active IP Right Cessation
- 1975-02-05 GB GB4947/75A patent/GB1502662A/en not_active Expired
- 1975-02-11 SE SE7501520A patent/SE7501520L/xx unknown
- 1975-02-12 CA CA219,910A patent/CA1060903A/en not_active Expired
- 1975-02-13 DK DK52975*#A patent/DK52975A/da unknown
- 1975-02-14 FR FR7504755A patent/FR2261003B1/fr not_active Expired
- 1975-02-14 ES ES434751A patent/ES434751A1/en not_active Expired
- 1975-02-14 BE BE153407A patent/BE825582A/en not_active IP Right Cessation
- 1975-02-14 NL NL7501806A patent/NL7501806A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BE825582A (en) | 1975-08-14 |
| FR2261003B1 (en) | 1978-07-21 |
| CH605566A5 (en) | 1978-09-29 |
| GB1502662A (en) | 1978-03-01 |
| DK52975A (en) | 1975-10-13 |
| ES434751A1 (en) | 1977-04-01 |
| JPS50111057A (en) | 1975-09-01 |
| NL7501806A (en) | 1975-08-18 |
| SE7501520L (en) | 1975-08-15 |
| DE2501459A1 (en) | 1975-08-21 |
| FR2261003A1 (en) | 1975-09-12 |
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