IE41538B1 - Spirotetrahydropyrans and spirothiatetrahydropyrans - Google Patents

Abstract

1456955 Spiro-(thia)tetrahydropyrans ROUSSEL UCLAF 8 May 1975 [8 May 1974] 19486/75 Heading C2C Novel compounds I in which X is O or S, R is H or C 1-4 alkyl, n is 2 to 4 and R1 is H or C 1-12 acyl, are prepared by reducing a compound II in which R1 1 is H or C 1-8 alkyl, and, if desired, esterifying the resulting compound I in which R1 is H to obtain a compound I in which R1 is C 1-12 aryl. Pharmaceutical compositions having antiinflammatory and analgesic activity, for oral, rectal, parenteral or topical administration, comprise a compound I together with a pharmaceutical carrier or excipient.

Description

The present invention relates to new spiro heterocyclic compounds having valuable anti-inflammatory and analgesic properties.

According to one feature of the present invention 5 we provide compounds of the general formula: R in which X represents an oxygen or sulphur atom, R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, and R’ represents a hydrogen atom or an acyl radical containing from 1 to 12 carbon atoms, n being an integer of from 2 to 4.

When R in formula I represents an alkyl radical, it preferably represents the methyl or ethyl radical.

When R1 in formula I represents an acyl radical, it preferably represents the acyl radical of a saturated 15 or unsaturated aliphatic acid, in particular an alkanoic acid such as formic, acetic, propionic, butyric, isobutyric or undecylic acid; a cycloalkylcarboxylic or (cycloalkyl) alkanoic acid such as, for example, cyclopropyl-, - 2 41538 cyclopentyl- or -cyclohexyl-carboxyl acid, or cyclopentylor cyclohexyl-acetic or -propionic acid; benzoic acid; or a phenyl alkanoic acid such as phenylacetic Or phenylpropionic acid.

Particularly preferred compounds according to the invention by virtue of their especially favourable pharmacological properties include those compounds of formula I in which X represents an oxygen atom, and/οχ R represents a hydrogen atom or a methyl radical, and/or h represents the number 2, an especially preferred compound being a-methyl 2,3,5,6-tetrahydrospiro [pyran 4(4H)-1'-indane] 5-ethanol.

According to a further feature of the present invention we provide a process for preparing compounds of general formula I as hereinbefore defined which comprises reducing a compound of formula: (in which R, X and n are as hereinbefore defined and R' I Jrepresents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms) to obtain a compound of formula; which is, if desired, esterified to obtain a compound of formula I in which R* represents an acyl radical containing from 1 to 12 carbon atoms.

When R’i represents an alkyl radical, this is preferably an alkyl radical containing 1, Z, 3 or .4 carbon atoms.

The reduction of the compound of formula II may he effected for example using a mixed hydride such as lithium aluminium hydride, or lithium borohydride; alternatively the reduction can be effected using sodium in the presence of an alcohol such as, for example, methanol or ethanol. The reduction reaction is advantageously effected in an organic solvent, preferably an ether such as tetrahydrofuran, diethyl ether or dioxan. In a preferred / method of carrying out the process according to the invention, the reduction is effected using aluminium lithium' hydride in - 4 I tetrahydro furan.' The optional esterification of the initially formed compound of formula 1^ is preferably carried out by means of an acid or a functional derivative thereof, for example an acid anhydride or an acid halide, especially an acid bromide or chloride.

The compounds of formula II, used as starting materials can be prepared for example according to the method described in the French Patent Application 2,101,148.

The above compounds of formula I possess valuable anti-inflammatory and analgesic properties which render them useful in human or veterinary medicine especially for the treatment of for example rheumatic complaints, arthritis, arthroses, muscular, articular or nervous pains, toothache and migraine.

According to a further feature of the present invention we provide pharmaceutical compositions comprising as active ingredient, at least one compound of formula I (as hereinbefore defined) in association with at least one pharmaceutical carrier or excipient.

The dosage used of the compounds of formula I can range between 50 mg,and 1 g per day in the adult by oral route. - 5 41538 The compounds of formula'1 may be administered by the oral, rectal or transcutaneous route or by the topical route by application to skin and mucous membranes. The • compositions according to the invention can be presented, e.g 5 in the form of suppositories, injectable solutions or suspensions, as well as ointments or creams. These compositions can be prepared in conventional manner. - 6 41538 The following Examples illustrate the present. . invention.

Example 1: «-methyl 2,3,5,6-tetrahydrospiro pyran 4(4H) 1'-indane 51-ethanol: 1. 23 g of lithium aluminium hydride are introduced under agitation and a current of nitrogen into 50 cm3 of tetrahydrofuran. Then, over 30 minutes and at 15°C, a solution of 4.43 g of methyl α-methyl 2,3,5,6-tetrahydrospiro (pyran-4 (4H) 1'-indane) 5-acetate (prepared according to the method indicated in the French Patent Application No. 2 101 148) in 45cm3 of tetrahydrofuran is introduced. The reaction.mixture is maintained for 2 hours under agitation at ambient temperature and then 5 cm3 of isopropanol and 5 cm3 of a saturated solution of ammonium chloride are introduced. The mineral salts are vacuum-filtered off and the filtrate is brought to dryness under reduced pressure. An oil is thus obtained which is taken up in ether, washed and dried andthe solvent is evaporated.

After purification 3[5 g of α-methyl 2,3,5,6tetrahydrospiro [pyran 4 (4H) 1' indane] 5-ethanol arc obtained, (M. Pt. = 75°C). - 7 41538 Example 2: Pharmaceutical compositions: Tablets were prepared, containing 50 mg of the product of Example 1 as active principle, corresponding to the following formula: - product of example 1........................50 mg - excipient (lactose, starch, magnesium stearate, talc) qs for a tablet.

Claims (16)

1. Compounds of general formula: in which X represents an oxygen or sulphur atom, R represents a hydrogen atom or an alkyl radical containing from 1 to 4 5 carbon atoms, and R' represents a hydrogen atom or an acyl radical containing from 1 to 12 carbon atoms, n being an integer of from 2 to 4.

2. Compounds as claimed in claim 1 in which X represents an oxygen atom. lo

3. Compounds as claimed in claim 1 or 2 in which R represents a hydrogen atom or a methyl radical.

4. Compounds as claimed in any of the preceding claims in which n represents the integer 2.

5. Compounds as claimed in any of the preceding claims 15 in which R’ represents a hydrogen atom or the acyl radical of an alkanoic acid, cycloalkyl -carboxylic acid, (cycloalkyl) alkanoic acid, benzoic acid or a phenyl-alkanoic acid. - 9 I »*1

6. a-methyl'2,3,5,6-tcLrahydrospiro [pyran 4 (4H)-1'indane] 5-ethanol.

7. A process for preparing compounds of general formula I (as defined in claim l) which comprises reducing a compound of formula: (II) (in which R, X and n are as defined in claim 1 and R’^ represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms) to obtain a compound of formula: (ip which is, if desired, esterified to obtain a compound of io fromula I in which R’ represents an acyl radical containing from 1 to 12 carbon atoms.

8. A process aq claimed in claim 7 wherein the reduction of the compound of formula II is effected using a mixed - 10 41538 hydride reducing agent.

9. A process as claimed in claim 7 or claim 8 in which the esterification of the compound of formula is effected using a carboxylic acid or a functional 5 derivative thereof.

10. A process for the preparation of compounds of formula I (as defined in claim 1) substantially as herein described.

11. A process for the preparation of compounds of io formula I (as defined in claim 1) substantially as herein described with reference to Example 1.

12. Compounds of formula I (as defined in claim 1) .whenever prepared by a process as claimed in any of the preceding claims. 15

13. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I (as defined in claim 1) in association with at least one pharmaceutical carrier or excipient.

14. Compositions as claimed in claim 13 in the form of 20 tablets, coated tablets, capsules, granules, emulsions, syrups, suppositories, injectable solutions or suspensions, ointments or creams,' I

15. Pharmaceutical compositions substantially as herein described.

16. Pharmaceutical compositions substantially as herein described with reference to Example 2.