GB2054593A - 6-Alkyl-7-phenyl-1,6-naphthyridine- 5(6H)-one derivatives - Google Patents

Abstract

6-Alkyl-7-phenyl-1,6-naphthyridine- 5(6H)-one derivatives having the formula I <IMAGE> wherein R1 represents C1-4alkyl, R2 represents hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl, C1-4alkylthio or -NR5R6, wherein each of R5 and R6 represents independently hydrogen or C1-3 alkyl, R3 represents hydrogen, C1-3alkyl, C1-3alkoxy, halogen or trifluoromethyl, and R4 represents hydrogen, C1-3alkyl, C1-3alkoxy or halogen, and acid addition salts thereof have muscle relaxant and anti-inflammatory activity and can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION 6-Alkyl-7-phenyl-1 ,6-naphthyridine-5(6H)-one derivatives This application relates to novel 6-alkyl-7-phenyl-1 ,6-naphthyridine-5(6H)-one derivatives, their acid addition salts, processes for their production and their use as muscle relaxants and anti-inflammatories.

In particular the invention relates to compounds of formula I

wherein R, represents C1-4alkyl, R2 represents hydrogen, C1-4alkyl, C, 4alkoxy, halogen, trifluoromethyl, C, 4alkylthio or -NR5R8, wherein each of R5 and R6 represents independently hydrogen or C, 3 alkyl, R3 represents hydrogen, C1alkyl, C, 3alkoxy, halogen or trifluoromethyl, and R4 represents hydrogen, C1-3alkyl, C, 3alkoxy or halogen.

The following meanings for the substituents R, to R4 and combinations thereof are preferred; For R1 = a) C, 3alkyl; b) C1 2alkyl; c) methyl.

For R2 = a) H, C1-3alkyl, halogen, C, 2alkylthio, tri fluoromethyl or 2- or 3-dimethylamino; b) H, C1-2alkyl, fluoro, chloro or 2- or 3-di methylamino; c) C, 2alkyl, fluoro, chloro or 3-dimethylamino; or d) 2-methyl or 2-chloro.

For R3 = a) H, Alkyl or halogen; = b) H, C1-2alkyl, fluoro or chloro; or =c) H.

For R4 = H.

Examples of preferred compound groups are thus those for formula I wherein R, represents C1-3alkyl, R2 represents hydrogen, C1-2alkyl, fluoro, chloro, or 2- or 3-dimethylamino, R3 represents hydrogen, C1-2alkyl, fluoro or chloro and R4 represents hydrogen; or those of formula I wherein R, represents C1-2alkyl, R2 represents C, 2alkyl, fluoro, chloro or 3-dimethylamino and R3 and R4 represent hydrogen; or those of formula I wherein R, represents methyl, R2 represents C, 2alkyl, fluoro, chloro or 3-dimethylamino and R3 and R4 represent hydrogen.

Another preferred group of compounds within the aforementioned is that of the formula I wherein at least one ortho-position in the phenyl ring is occupied by hydrogen or fluoro.

In the definitions of R, to R4 halogen stands for fluorine, chlorine or bromine.

A further interesting group of compounds of formula I is that wherein R, represents C1-4alkyl, R2 represents hydrogen, C1-4alkyl, C, 4alkoxy, halogen, trifluoromethyl or -NR5R6, with the proviso that when R2 is -NR5R6 it is in ortho- or meta-position, wherein each of R5 and R8 represents independently hydrogen or C1-3alkyl, R3 represents hydrogen, C1-3alkyl, C1-3alkoxy, halogen or trifluoromethyl, and R4 represents hydrogen, C1-3alkyl, C, 3alkoxy or halogen.

US Patent 4,154,837 discloses a wide range of 6-alkyl-7-bis-methoxyphenyl and benzyl-iso quinoline-1 (2H)-one- and -naphthyridine-5(6H)-one derivatives as intermeidates only, without disclosing compounds of the present invention or their use.

The present invention further provides a process for the production of compounds of formula I which comprises dehydrating a compound of formula VID or formula VIII

or a mixture thereof.

A suitable dehydrating agent is a strong organic or mineral acid such as trifluoroacetic acid, ptoluenesulphonic acid, methanesulfonic acid, sulfuric acid, perchloric acid and preferably hydrochloric or trifluoromethane sulfonic acid. The process may be carried out in an inert solvent such as an alcohol e.g. methanol or ethanol, tetrahydrofuran, methylene chloride or chloroform.

The process is conveniently effected at a temperature of from 0 C to reflux of the reaction mixture in particular 50 C to reflux (preferably < 1 00 C) more particular 70-80'C.

The compounds of formulae Vll and Vlil may be prepared by treating a compound of formula V

with a strong base to produce a dianion and reacting the resulting dianion with a compound of formula VI

whereby in formulae V and VI R1 to R4 have the meanings given above and X represents CN or COOR7 wherein R7 represents n-C13aIkyI, preferably ethyl and in the case when X = CN hydrolysing the compound thus obtained.

Examples of strong bases suitable for treatment of the compound of formula V to form its dianion are very strong, bulky bases such as lithium di-(C14alkyI)amides, dicyclohexylamide or N-(C1 4alkyl)-sl-cyclohexylamides e.g. lithium diethylamide, lithium dicyclohexylamide, lithium-N cyclohexyl-N-isopropyarnide and especially lithium diisopropyl amide.

This reaction may be carried out in a dry aprotic solvent e.g. toluene, 1,2-dimethoxyethane, diglycol methyl ether (diglyme) or especially tetrahydrofuran. Reaction temperatures conveni ently lie between - 60" and 25 C preferably - 30' and - 5"C and the reaction is carried out in an inert atmosphere e.g. under nitrogen. The subsequent reaction with a compound of formula VB may be carried out without prior isolation of the dianion and in similar suitable solvents and under similar conditions.

When using a compound of formula VI wherein X = COOR7 mixtures of the compounds of formulae VII and Vll may be obtained.

When using a compound of formula VI wherein X = CN an intermediate compound of formula X results

which can be converted to a compound of formula VIII by hydrolysis.

This hydrolysis can be effected using an aqueous acid. Use of a- weak acid will produce a compound of the formula VII whereas the use of a strong acid will result in at least partial conversion to a compound of formula I. The hydrolysis may be carried out in an inert solvent such as tetrahydrofuran or ethanol and at temperatures of between 25 and 75"C.

The compounds of the formulae VII, VIII and X obtained in the above processes can either be isolated and purified in conventional manner as such or further reacted without isolation.

The compounds of formulae VII, VIII and X are new and also form part of the invention.

Preferred compounds of formulae VII, VIII and X are equivalent to those defined for formula I.

Isolation and purification of the compounds of formula I takes place in conventional manner.

Depending on the conditions employed the compounds of formula I may be obtained either in free base form or as acid addition salts. The acid addition salts of the compounds of formula I also form part of the invention.

Free base forms of formula I may be converted into acid addition salt forms in conventional manner and vice versa.

Examples of suitable salt forming acids are hydrochloric, hydrobromic, hydroiodic, phosphorous, sulfuric, perchloric, methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic.

The compounds of formula V may be prepared e.g. according to the following scheme:

The compounds of formulae II, IV and VI are either known or may be prepared in conventional manner from available materials.

The compounds of formula I possess pharmacological activity. In particular, they possess muscle relaxant activity as indicated 1) by their activity in a modification of the rotarod test as described by Dunham and Miya [J. Am. Pharm. Assoc., 45, 208, (1957)1 and 2) by their ability to depress spinal reflexes measured by flexor and patellar responses using force displacement transducers in male cats given 0.5-50 mg/kg of animal body weight, i.v. of the test compound and optionally in a second test procedure having their spinal cord cut at C-1; and an anti-inflammatory activity as indicated in the acute carrageen-induced edema test in rats cf. Winter Proc. Soc. Exp. Biol., 111, 544 (1962), on oral administration of 10-200 mg/kg body weight of the test substance.

The compounds of formula I are thus indicated for use as muscle relaxants and/or antiinflammatories. An indicated suitable daily dosage is from about 1.0 to 1 000mg preferably 10 to 1000 mg suitably administered in divided doses of 0.25 to 500 mg, two to four times daily, or in retard form.

The invention therefore also concerns a method of treating muscle spasms or inflammation using a compound of formula I and also compounds of formula I for use as pharmaceuticals e.g.

as muscle relaxant and anti-inflammatory agents and for use in the treatment of the human or animal body by therapy.

The compounds of formula I may be administered in free base form or in the form of pharmaceutically acceptable acid addition salts.

The compounds of formula I or their pharmaceutically acceptable acid addition salts may be administered alone, or in admixture with a pharmaceutically acceptable diluent or carrier, and, optionally other excipients, and administered orally in such forms as tablets, elixirs, capsules or suspensions or parenterally in such forms as injectable solutions or suspensions. The compounds may be micronized if desired.

The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules.

Such compositions also form part of the invention.

The following examples, in which all temperatures are in "C and room temperatures is 20-30", illustrate the invention.

Example 1 a) Ethyl 2-methylnicotinate To a mixture of 800 ml of ethyl 3-amino crotonate, 30 ml of piperidine and 1.41 of isopropanol, stirred at 25-30", 540 ml of acrolein are added slowly over a 2 hour period with stirring. The reaction mixture is then refluxed for 3+ hours and finally evaporated at reduced pressure to dryness. The residue is heated to 100" and 610 g of sulfur added thereto portionwise. The reaction mixture is then heated at 100" for 2 hours and at 1 25' for 1 + hours and subsequently allowed to coo to about room temperature. 1 I of chloroform is added thereto, and the mixture is filtered thorough Celite and the filter cake washed with additional chloroform.The combined chloroform filtrate and washings are extracted three times with 1 I portions of 2Nhydrochloric acid. The aqueous acidic layers are combined and, with cooling, made basic with 2N-sodium hydroxide solution. The obtained aqueous basic solution is extracted three times with 1 I portions of chloroform and the chloroform extracts combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain an oily residue which is distilled under high vacuum to obtain the pure product b.p. 73"-77'/0.7 mb.

b) 2-Methylnicotinic acid N-methylamide 200 g (1.21 mol) of ethyl 2-methyinicotinate and 11 of 40% aqueous methylamine are heated at 40 for 4 hours. The reaction mixture is stripped at reduced pressure to obtain the crude product as a thick oil which was distilled at 121 -133 /0.24 mb. to give the product m.p. 69"-72".

c) 7-(2 '-Chiomphenyl)- 7, & ihydro- 7-hydroxy-6-methyl- 1, 6-naphthyridine-5(6H)-one (compound no. Vlla) 189 ml of 1.6 M. butyl lithium (302.4 mmol) in hexane are added to a solution of 42.3 ml of di-isopropylamine in 30O ml of dry tetrahydrofuran stirred at - 5' to - 10" under nitrogen.

To the resulting solution of lithium di-isopropylamide, 21.5 g (144 mmol) of 2-methyinicotinic acid N-methylamide, dissolved in 1 50 ml of dry tetrahydrofuran, are added slowly at - 20' to - 30" with stirring under nitrogen. The resulting reaction mixture is stirred under nitrogen at - 20" to - 30" for an additional 2 hours. A solution of 26.8 g (145 mmol) of freshly distilled ethyl 2-chlorobenzoate in 1 50 ml of dry tetrahydrofuran is then slowly added to the reaction mixture stirred at - 20" to - 30" under nitrogen and stirring under nitrogen maintained at the same temperature for an additional 1 + hours.The reaction mixture is then quenched with 250 ml of concentrated aqueous sodium chloride solution and extracted three times with ethyl acetate. The obtained ethyl acetate extracts are combined, washed four times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a thick oil. This oil is chromatographed on a silica gel column (eluant methylene chloride followed by 3% methanol/chloroform). The 3% methanol/ chloroform eluant yields the crude product which is crystallized from ether to yield the product m.p. 144 -146 . A second crop, m.p. 144-146 , is also obtained.The two crops are combined and recrystallized from toluene to obtain the product m.p. 143"-145". The mother liquors from the aforementioned second crop and the toluene crystallization are combined and evaporated at reduced pressure. The residue is dissolved in acetone and treated with 0.9 g of gaseous hydrogen chloride to obtain a crystalline material.

) 7-(2 '-Chlornphenyl)-6-methyl- I, 6-naphthyridine-5(6H)-one (compound no. 1) 7.8 g of the product of c) are suspended in 50 ml of absolute ethanol and 1.1 g of gaseous hydrogen chloride bubbled in. The reaction mixture is then evaporated practically to dryness and the crystalline material obtained after treatment with HCl in c) and 100 ml of absolute ethanol added thereto. The resulting reaction mixture is refluxed for 5 minutes, cooled by addition of ice and water and made basic with sodium hydroxide solution.The basic solution is extracted with methylene chloride and the methylene chloride extract dried over an hydros sodium sulfate, filtered and evaporated at reduced pressure to obtain the crude product which is recrystallized from absolute ethanol to obtain the product m.p. 1 52"-153'.

Example 2 a) 2-(3'-Thmethyiaminobenzoylmethyi)nicodnic acid N-methylamide (compound no. Villa)) 263 ml of 1.6 M. butyl lithium in hexane (420 mmol) are slowly added to a solution of 58.7 ml (420 mmol) of di-isopropylamine in 200 ml of dry tetrahydrofuran stirred at - 10" under nitrogen. To the resulting solution of lithium di-isopropylamide, a solution of 30 g (200 mmol) of 2-methylnicotinic acid N-methylamide in 200 ml of dry tetrahydrofuran is slowly added at - 20" to - 30". The resulting red reaction mixture is stirred under nitrogen at - 20" to - 30" for an additional two hours.Then, a solution of 38.6 g (200 mmol) of ethyl 3-dimethylamino benzoate in 100 ml of dry tetrahydrofuran is slowly added at - 20" to - 30" with stirring under nitrogen which is continued for 1 hour at the same temperature. The reaction mixture is then quenched with 250 ml of saturated sodium chloride solution and extracted three times with ethyl acetate. The ethyl acetate phases are combined, washed four times with water, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to a thick oil which is dissolved in a small amount of isopropanol and chromatographed on silica gel using 5% isopropanol/chloroform as the eluant. The last major fraction to be eluted is rechromatographed on silica gel using 2% isopropanol/ chloroform as the eluant. The largest fraction contains the crude product.

b) 7-(3'-Dimethylaminophenyl)-6-methyl- 1, 6-naphthyridine-5(6H)-one (compound no. 2) The crude product of Example 2a) is dissolved in ethanol and 4.3 g of gaseous hydrogen chloride bubbled in. The reaction mixture is heated for 5 minutes at 70". Two crops of a solid, m.p. 197"-220" (dec.), and m.p. 224"-226" (dec.), are obtained. The two crops are combined and recrystallized from ethanol to obtain a further solid m.p. 221-232" (dec.). The mother liquors from each of the crystallizations and recrystallizations are combined and two additional crops, m.p. 193'-216" (dec.) obtained therefrom.The combined crystalline materials are dissolved in water, excess sodium hydroxide solution is added and the basic solution extracted with methylene chloride. The methylene chloride extract is dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure. The residue is chromatographed on silica gel using ethyl acetate as the eluant. The major fractions are combined and recrystallized from acetone/ pentane to give the end product m.p. 1 18'-120'.

Example 3 a) 2-(4'-Chloro-ssaminostyryl)nicotinic acid N-methylamide (compound no. Xa)) A solution of lithium di-isopropylamide in dry tetrahydrofuran is prepared by slowly adding 292 ml of of 1.6 M. n-butyl lithium in hexane (467.2 mmol) to a solution of 70 ml of diisopropylamine in 400 ml of dry tetrahydrofuran stirred at - 20' under nitrogen. A solution of 35 g (233.3 mmol) of 2-methylnicotinic acid N-methylamide in 400 ml of dry tetrahydrofuran is slowly added, over a 30 minute period, to the lithium di-isopropylamide solution stirred under nitrogen at - 20" and stirring under nitrogen continued at the same temperature for an additional 1+ hours.Then, a solution of 32.1 g (233.4 mmol) of 4-chlorobenzonitrile in dry tetrahydrofuran is slowly added and stirring under nitrogen at - 20" continued for an additional 1+ hours. The reaction mixture is then warmed to room temperature over a 30 minute period and 500 ml of water added. The organic phase is washed with 500 ml of saturated sodium chloride solution and the aqueous phase extracted four times with 100 ml portions of methylene chloride. The washed organic phase and the four methylene chloride extracts are combined, treated with charcoal, dried over an hydros magnesium sulfate and concentrated at reduced pressure to the crude product which is recrystallized from diethyl ether/methylene chloride to give a yellow solid which upon recrystallization from diethyl ether/methylene chloride has m.p.

1 40'-1 45'.

b) 2-(4'-Chlorobenzoylmethyl)nicotinic acid N-methylamide (compound VilIb)) 22 g (76.5 mmol) of 2-(4f-chloro-ss-aminostyryl)-nicotinic acid N-methylamide are dissolved in 80 ml of tetrahydrofuran and 40 ml of ethanol and a mixture of 40 ml of acetic acid and 40 ml of water added. The reaction mixture is stirred at 40 for 4 hours and then made basic to pH 9 with sodium hydroxide solution and extracted with diethyl ether, ethyl acetate and methylene chloride. The three organic extracts are combined, treated with charcoal, dried over an hydros magnesium sulfate and concentrated at reduced pressure to obtain a yellow solid which is recrystallized from ethanol to obtain the product as a yellow green solid, m.p. 162 -163 .

c) Reaction of this product analogously to Example 2b) using trifluoromethane sulfonic acid yields 7-(4'-Chlorophenyl)-6-methyl- 1 , 6-naphthyridine-5-(6 H)-one m.p. 1 39-140' (compound no. 3) The following compounds of formulae VII, VIII and X may be obtained analogously to Examples 1 to 3 or any other method as herein before described.

TABLE I Compound Physical Type/No. R, R2 R3 R4 constant VII b) CH3 2-CH3 H H oil VII c) CH3 3-CF3 H H m.p. 139 VII d) CH3 3-OCH3 4-OCH3 H m.p. 157' VII e) CH3 H H H m.p. 141" (dec.) VII f) CH3 2-OCH3 H H VI g) CH3 2-F H H VII h) CH3 2-F 6-F H VIII c) CH3 4-CH3 H H m.p. 120 -134 (crude) VIII d) CH3 3-Cl H H m.p. 200 -206 VIII e) C2H5 2-Cl H H VIII f) CH3 p-N(CH3)2 H H m.p. 173 Xb) CH3 H H H m.p. 159 -161 Xc) CH3 4-CH3 H H m.p. 88 -116 (crude) Yhe following compounds of formula I may obtained analogously to Examples 1 to 3 or any other method as hereinbefore described.

TABLE II Compound Physical No. R1 R2 R3 R4 constant 4 -CH3 3-OCH3 4-OCH3 H m.p. 136 -137 5 -CH3 H H H m.p. 90 -90.5 6 -CH3 4-CH3 H H m.p. 134' 7 -CH3 3-Cl H H m.p. 143 8 -CH3 3-CF3 H H m.p. 135 9 -CH3 2-OCH3 H H m.p. 154 10 -CH3 2-F H H m.p. 121 -123 11 -CH3 2-F 6-F H m.p. 162'-163' 12 -C2H5 2-Cl H H 13 fC3H7 2-CH3 H H 14 i-C3H7 2-Cl H H 15 n-C4Hg 2-CH3 H H 16 -C2H5 2-CH3 H H 17 -CH3 2-Br H H 18 -CH3 2-CH3 4-CH3 6-CH3 19 -CH3 2-Cl 6-Cl H 20 -CH3 2-N(CH3)2 H H m.p. 135 -136 21 -CH3 2-CH3 H H m.p. 104'-106' 22 -CH3 2-SCH3 H H m.p. 153 -155 23 -CH3 2-Cl H H m.p. 222 -229 (dec.) (hydrochloride) 24 -CH3 2-Cl H H m.p. 210'-220'(dec.) (methanesulfonate) 25 -CH3 4-N(CH3)2 H H m.p. 199'

Claims (23)

1. A compound of formula I

wherein R, represents C, 4alkyl, R2 represents hydrogen, C, 4alkyl, C, 4alkoxy, halogen, trifluoromethyl, C, 4alkylthio or -NR5R6, wherein each of R5 and R8 represents independently hydrogen or C13 alkyl, R3 represents hydrogen, C, 3alkyl, C, 3alkoxy, halogen or trifluoromethyl, and R4 represents hydrogen, C, 3alkyl, C, 3alkoxy or halogen.

2. A compound as claimed in Claim 1 wherein R, represents C, 3alkyl, R2 represents hydrogen, C, 2alkyl, fluoro, chloro, or 2- or 3-dimethylamino, R3 represents hydrogen, C, 2alkyl, fluoro or chloro and R4 represents hydrogen.

3. A compound as claimed in Claim 1 wherein R, represents C, 2alkyl, R2 represents C, 2alkyl, fluoro, chloro or 3-dimethylamino and R3 and R4 represent hydrogen.

4. A compound as claimed in Claim 1 wherein R, represents methyl, R2 represents C, 2alkyl, fluoro, chloro or 3-dimethylamino and R3 and R4 represent hydrogen.

5. A compound as claimed in Claim 1 wherein R, represents C1-4alkyl, R2 represents hydrogen, C1-4alkyl, C, 4alkoxy, halogen, trifluoromethyl or -NR5R6, with the proviso that when R2 is -NR5R6 it is in ortho- or meta-position, wherein each of R5 and R6 represents independently hydrogen or C1-3alkyl, R3 represents hydrogen, C1-3alkyl, C, 3alkoxy, halogen or trifluoromethyl, and R4 represents hydrogen, C1-3alkyl, C, 3alkoxy or halogen.

6. A compound as claimed in any one of Claims 1 to 5 wherein at least one ortho-position of the phenyl ring is occupied by hydrogen or fluoro.

6. 7-(2'-Chlorophenyl)-6-methyl- 1 ,6-naphthyridine-5(6 H)-one.

7. 7-(2'-Fluorophenyl)-6-methyl-1,6-naphthyridine-5(6H)-one.

8. 7-(2',6'-Difluorophenyl)-6-methyl-1,6-naphthyridine-5(6H)-one.

9. 7-(2'-Methylphenyl)-6-methyl-1 , 6-naphthyridine-5(6 H)-one.

10. A compound as claimed in Claim 1 substantially as hereinbefore described with reference to Examples 1 to 3 and Table II.

11. A compound as claimed in any one of Claims 1 to 10 in free base form.

12. A compound as claimed in any one of Claims 1 to 10 in the form of an acid addition salt thereof.

13. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 10 or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

14. A compound as claimed in any one of Claims 1 to 12 for use as a pharmaceutical.

15. A compound as claimed in any one of Claims 1 to 12 for use as a muscle relaxant.

16. A compound as claimed in any one of Claims 1 to 12 for use as an anti-inflammatory agent.

17. A compound as claimed in any one of Claims 1 to 12 for use in the treatment of the human or animal body by therapy.

18. A process for the production of compounds of formula I which comprises dehydrating a compound of formula VII or formula VIII

or a mixture thereof whereby R,. R2, R3 and R4 are as defined in Claim 1.

1 9. A process as claimed in Claim 18 wherein the dehydrating agent is a strong acid.

20. A process as described in Claim 18 substantially as hereinbefore described with reference to Examples 1 to 3.

21. Compounds of formula VII

wherein R1, R2, R3 and R4 are as defined in any of Claims 1 to 6.

22. Compounds of formula VIII

wherein R1, R2, R3 and R4 are as defined in any of Claims 1 to 6.

23. Compounds of formula X

wherein R1, R2, R3 and R4 are as defined in any of Claims 1 to 6.