(Substituted) Phenyl-aliphatic-isoxazoles useful as antiviral agents and preparation thereof

Claim 2

A compound having the formula or wherein: R, R 1 , R 2 , R 3 and R 4 are each hydrogen or alkyl of 1 to 3 carbon atoms optionally substituted by hydroxy, lower-alkanoyloxy, lower-alkoxy, chloro, or N=Z, wherein N=Z is amino, lower-alkanoylamino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl; with the proviso that R is other than hydrogen; R 5 is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl; R 6 is alkyl of 1 to 3 carbon atoms; X is O or a single bond; and n is an integer from 3 to 9; or a pharmaceutically acceptableacid-addition salt thereof.

Claim 3

5-{7-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 4

5-{7-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 5

5-{7-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy] heptyl}-3-methylisoxazole, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 6

5-{7-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy] heptyl}-3-methylisoxazole, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 7

5-{5-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy] pentyl}-3-methylisoxazole, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 8

5-{5-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy] pentyl}-3-methylisoxazole, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 9

A compound having the formula or wherein R 5 is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl and n is an integer from 3 to 9, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 10

A compound having the formula or wherein R 5 is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl and n is an integer from 3 to 9, or a pharmaceutically acceptable acid-addition salt thereof.

Claim 11

A process for preparing a compound according to claim 1, which comprises: a. reacting a compound of the formula or with a lower-alkanol in the presence of a strong acid, and heating the resulting imino ester with a compound of the formula wherein R is alkyl or hydroxyalkyl of 1 to 3 carbon atoms, and R ' 1 , R ' 2 , R 3 and R 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms, so as to prepare the corresponding compound of Formula I or II or b. reacting a compound of the formula wherein Hal is bromine or iodine, and m = n-1, with an alkali metal derivative of 3-R'-4-R' 4 -5-methylisoxazole; wherein R' is alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R' 1 , R' 2 , R' 3 and R' 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms so as to prepare the corresponding compound of Formula I where X'is O or c. reacting a compound of the formula with an alkali metal salt of a compound of the formula wherein R' is alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R 1 , R ' 2 , R 3 and R 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms so as to prepare the corresponding compound of Formula I where X is 0, if desired, converting a compound of Formula I or II obtained where one or more of R, R 1 , R 2 , R 3 or R 4 is hydroxyalkyl as follows: d. esterifying said compound to prepare the corresponding compound where said one or more radicals is lower- alkanoyloxyalkyl, e. etherifying said compound to prepare the corresponding compound where said one or more radicals is lower-alkoxyalkyl, f. subjecting said compound to the action of a reagent capable of replacing aliphatic hydroxyl groups by chlorine to prepare the corresponding compound where said one or more radicals is chloroalkyl, g. subjecting a compound thus obtained where one or more of R, R l , R 2 , R 3 or R 4 is chloroalkyl to reaction with ammonia or an amine, HN=Z, to prepare the corresponding compound where said radical or radicals is alkyl-N=Z, wherein N=Z is.amino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, h. reacting a compound thus obtained where said one or more radicals is aminoalkyl with a lower-alkanoyl halide or anhydride to prepare the corresponding compound where said one or more radicals is lower-alkanoylaminoalkyl, and, if desired, converting a free base obtained to a pharmaceutically acceptable acid addition salt thereof. 7. A process for preparing a compound according to claim 5, which comprises subjecting to suitable fermentative enzymatic action for example using Aspergillus niger (A l ) or Trichotecium roseum (T 1 ), a compound of Formula I according to claim 1, wherein R is CH 3 , R 1 , R2, R3 and R4 are H, X is O, the dihydro-oxazole moiety is in the 4-position of the phenylene ring, and, if desired, converting a free base obtained to a pharmaceutically acceptable acid-addition salt thereof. 8. A compound having the formula IX or VII wherein R ' 1 , R ' 2 and R ' 3 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R 5 is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl; Hal is bromine or iodine; and m is an integer from 2 to 8. 9. A process for preparing a compound according to claim 8, which comprises cyclizing a compound of the formula to prepare a compound of the Formula IX, if desired, etherifying a compound of the Formula IX obtained with an alkylene dibromide to obtain a compound of the Formula VII . where Hal is bromine, and, if desired, replacing the bromide with an iodide to obtain the compound of Formula VII where Hal is iodine. 10. A composition for combatting viruses which comprises an antivirally effective amount of a compound according to any one of claims 1-5 in admixture with a suitable carrier or diluent.

Claim 12

A process for preparing a compound having the formula or wherein: R, R 1 , R 2 , R 3 and R 4 are each hydrogen or alkyl of 1 to 3 carbon atoms optionally substituted by hydroxy, lower-alkanoyloxy, lower-alkoxy, chloro, or N= Z , wherein N=Z is amino, lower-alkanoylamino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl; with the proviso that R is other than hydrogen; R 5 is hydrogen, lower-alkyl, halogen, nitro, lower- alkoxy, lower-alkylthio or trifluoromethyl; R 6 is alkyl of 1 to 3 carbon atoms; X is O or a single bond; and n is an integer from 3 to 9; or a pharmaceutically acceptable acid-addition salt thereof, characterized by; a. reacting a compound of the formula or with a lower-alkanol in the presence of a strong acid, and heating the resulting imino ester with a compound of the formula wherein R is alkyl or hydroxyalkyl of 1 to 3 carbon atoms, and R' 1 , R' 2 , R' 3 and R' 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms, so as to prepare the corresponding compound of Formula I or II or b. reacting a compound of the formula wherein Hal is bromine or iodine, and m = n-1, with an alkali metal derivative of 3-R'-4-R' 4 -5-methylisoxazole; wherein R' is alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R' 1 , R' 2 , R' 3 and R' 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms so as to prepare the corresponding compound of Formula I where X is 0 or c. reacting a compound of the formula with an alkali metal salt of a compound of the formula wherein R' is alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R ' 1 , R ' 2 , R 3 and R 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms so as to prepare the corresponding compound of Formula I where X is O, if desired, converting a compound of Formula I or II obtained where one or more of R, R 1 , R 2 , R 3 or R 4 is hydroxyalkyl as follows: d. esterifying said compound to prepare the corresponding compound where said one or more radicals is lower- alkanoyloxyalkyl, e. etherifying said compound to prepare the corresponding compound where said one or more radicals is lower-alkoxyalkyl, f. subjecting said compound to the action of a reagent capable of replacing aliphatic hydroxyl groups by chlorine to prepare the corresponding compound where said one or more radicals is chloroalkyl, g. subjecting a compound thus obtained where one or more of R, R 1 , R 21 R 3 or R 4 is chloroalkyl to reaction with ammonia or an amine, HN=Z, to prepare the corresponding compound where said radical or radicals is alkyl-N= Z , wherein N-Z is amino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, h. reacting a compound thus obtained where said one or more radicals is aminoalkyl with a lower-alkanoyl halide or anhydride to prepare the corresponding compound where said one or more radicals is lower-alkanoylaminoalkyl, and, if desired, converting a free base obtained to a pharmaceutically acceptable acid addition salt thereof.

Claim 13

A process for preparing a compound having the formula or wherein: R, R 1 , R 2 , R 3 and R 4 are each hydrogen or alkyl of 1 to 3 carbon atoms optionally substituted by hydroxy, lower-alkanoyloxy, lower-alkoxy, chloro, or N= Z , wherein N=Z is amino, lower-alkanoylamino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl; with the proviso that R is other than hydrogen; R 5 is hydrogen, lower-alkyl, halogen, nitro, lower- alkoxy, lower-alkylthio or trifluoromethyl; R 6 is alkyl of 1 to 3 carbon atoms; X is O or a single bond; and n is an integer from 3 to 9; or a pharmaceutically acceptable acid-addition salt thereof, characterized by; a. reacting a compound of the formula or with a lower-alkanol in the presence of a strong acid, and heating the resulting imino ester with a compound of the formula wherein R is alkyl or hydroxyalkyl of 1 to 3 carbon atoms, and R' 1 , R' 2 , R' 3 and R' 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms, so as to prepare the corresponding compound of Formula I or II or b. reacting a compound of the formula wherein Hal is bromine or iodine, and m = n-1, with an alkali metal derivative of 3-R'-4-R' 4 -5-methylisoxazole; wherein R' is alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R' 1 , R' 2 , R' 3 and R' 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms so as to prepare the corresponding compound of Formula I where X is 0 or c. reacting a compound of the formula with an alkali metal salt of a compound of the formula wherein R' is alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R ' 1 , R ' 2 , R 3 and R 4 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms so as to prepare the corresponding compound of Formula I where X is O, if desired, converting a compound of Formula I or II obtained where one or more of R, R 1 , R 2 , R 3 or R 4 is hydroxyalkyl as follows: d. esterifying said compound to prepare the corresponding compound where said one or more radicals is lower- alkanoyloxyalkyl, e. etherifying said compound to prepare the corresponding compound where said one or more radicals is lower-alkoxyalkyl, f. subjecting said compound to the action of a reagent capable of replacing aliphatic hydroxyl groups by chlorine to prepare the corresponding compound where said one or more radicals is chloroalkyl, g. subjecting a compound thus obtained where one or more of R, R 1 , R 21 R 3 or R 4 is chloroalkyl to reaction with ammonia or an amine, HN=Z, to prepare the corresponding compound where said radical or radicals is alkyl-N= Z , wherein N-Z is amino, lower-alkylamino, di-lower-alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, h. reacting a compound thus obtained where said one or more radicals is aminoalkyl with a lower-alkanoyl halide or anhydride to prepare the corresponding compound where said one or more radicals is lower-alkanoylaminoalkyl, and, if desired, converting a free base obtained to a pharmaceutically acceptable acid addition salt thereof.

Claim 14

A process according to claim 1, wherein 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole is prepared by reacting 5-[7-(4-cyanophenoxy)-heptyl]-3-methylisoxazole with a lower-alkanol in the presence of a strong acid, and heating the resulting imino ester with 2-hydroxyethylamine.

Claim 15

A process according to claim 1, wherein 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexyl halide is reacted with an alkali metal derivativeof3,5-dimethylisoxazole to produce 5-{7-14-(4,5-dihydro-2-oxazolyl)-phenoxy]heptyl}-3-methylisoxazole.

Claim 16

A process according to claim 1, wherein 5-(6- halohexyl)-3-methylisoxazole is reacted with an alkali metal salt of 2-(4-hydroxyphenyl)-4,5-dihydrooxazole to produce 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole.

Claim 17

A process for preparing a compound having the formula or wherein R 5 , is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl and n is an integer from 3 to 9, or a pharmaceutically acceptable acid-addition salt thereof, characterized by subjecting to suitable fermentative enzymatic action a compound of Formula I as defined in claim 1, wherein R is C H3 , R 1 , R 2 , R 3 and R 4 are H, X is O, the dihydro-oxazole moiety is in the 4-position of the phenylene ring, and, if desired, converting a free base obtained to a pharmaceutically acceptable acid-addition salt thereof.

Claim 18

A process according to claim 5, in which R 5 is hydrogen and n is 7 is produced using Aspergillus niger (A l ) or Trichotecium roseum (T 1 ).

Claim 19

A process for preparing a compound having the formula IX or VII wherein R' 1 , R' 2 and R' 3 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R 5 is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl; Hal is bromine or iodine; and m is an integer from 2 to 8, characterized by cyclizing a compound of the formula

Claim 20

A process for preparing a compound having the formula IX or VII wherein R' 1 , R' 2 and R' 3 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms; R 5 is hydrogen, lower-alkyl, halogen, nitro, lower-alkoxy, lower-alkylthio or trifluoromethyl; Hal is bromine or iodine; and m is an integer from 2 to 8, characterized by cyclizing a compound of the formula

Claim 21

to prepare a compound of the Formula IX, if desired, etherifying a compound of the Formula IX obtained with an alkylene dibromide to obtain a compound of the Formula VII where Hal is bromine, and, if desired, replacing the bromide with an iodide to obtain the compound of Formula VII where Hal is iodine.

Claim 22

to prepare a compound of the Formula IX, if desired, etherifying a compound of the Formula IX obtained with an alkylene dibromide to obtain a compound of the Formula VII where Hal is bromine, and, if desired, replacing the bromide with an iodide to obtain the compound of Formula VII where Hal is iodine.

Claim 23

A process according to any one of claims 1, 5 and 7, in which the starting compounds are chosen so that in the compound of Formula I produced R and R 6 are each alkyl of 1-3 carbon atoms, R 1 and R 2 are each hydrogen, or alkyl or hydroxyalkyl of 1 to 3 carbon atoms, R 3 , R 4 and R 5 are each hydrogen, n is an integer from 4 to 8 when separated by 0 from the phenylene ring or an integer from 5 to 9 in Formula I when X is a single bond, and the dihydro-oxazole moiety is affixed to the 4-position of the phenylene ring.

Claim 24

A process according to any one of claims 1, 5 and 7, in which the starting compounds are chosen so that in the compound of Formula I produced a compound according to claim 8 is excluded.