Antihypertensive dihydropyridine derivatives

Claim 2

A compound of formula 1; or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -NO 2 , -CF 3 , or halo; and R 5 is lower alkyl or -CN 2 CH 2 OCH 3 .

Claim 3

The compound of Claim 1 wherein R 4 is meta nitro, R 5 is methyl, Y is para -0-, R 1 is A 1 , m is 1, p is 1, and n is 2, i.e., the compound 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,3-dihydroxypropoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine.

Claim 4

The compound of Claim 2 wherein said 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,3-dihydroxypropoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine is racemic.

Claim 5

The compound of Claim 2 which is (b+)-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,3-dihydroxypropoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine.

Claim 6

The compound of Claim 2 which is (b-)-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,3-dihydroxypropoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine.

Claim 7

A pharmaceutical composition which comprises a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(0) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -N0 2 , -CF 3 , or halo; and R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 8

A pharmaceutical composition which comprises a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(0) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -N0 2 , -CF 3 , or halo; and R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 9

A compound of formula 1: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A l is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CN 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -NO 2 -CF 3 , or halo; and R 5 is lower alkyl or -CH 2 CH 2 OCH 3 for use in treating cardiovascular disorders susceptible to treatment with calcium entry blockers.

Claim 10

A compound of formula 1: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A l is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CN 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -NO 2 -CF 3 , or halo; and R 5 is lower alkyl or -CH 2 CH 2 OCH 3 for use in treating cardiovascular disorders susceptible to treatment with calcium entry blockers.

Claim 11

A compound represented by the formula or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOG 1 )pCH 2 OG 2 ; A 2 is -(CH 2 ) q CH (3-r) [C(CH 2 ) s OG 1 ] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p C00R 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and G 1 and G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(R a )(R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -N0 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 12

A compound represented by the formula or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOG 1 )pCH 2 OG 2 ; A 2 is -(CH 2 ) q CH (3-r) [C(CH 2 ) s OG 1 ] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p C00R 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and G 1 and G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(R a )(R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -N0 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 13

The compound of Claim 1 wherein n is 1, i.e., the compound 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-[4-(2,3-dihydroxypropoxy)phenyl]methoxycarbonyl)-1,4-dihydropyridine.

Claim 14

The compound of Claim 1 wherein n is 3, i.e., the compound 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(3-[4-(2,3-dihydroxypropoxy)phenyl]propoxycarbonyl)-1,4-dihydropyridine.

Claim 15

The compound of Claim 1 wherein n is 2, Y is para -0 and R 1 is A 2 .

Claim 16

The compound of Claim 11 wherein q is 1, r is 2, and s is 1, i.e., the compound 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(1,3-dihydroxyprop-2- oxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine.

Claim 17

The compound of Claim 1 wherein n is 2, Y is para -NH and R 1 is A 1 .

Claim 18

The compound of Claim 13 wherein m is 2, and p is 0, i.e., the compound 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethylamino)phenyl]-ethoxycarbonyl)-1,4-dihydropyridine hydrochloride.

Claim 19

The compound of Claim 1 wherein, n is 2, Y is para -NR 2 , and R 1 and R 2 are A 1 .

Claim 20

The compound of Claim 15 wherein m is 2, and p is 0, i.e., the compound 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-N,N-(2-hydroxyethyl)aminophenyl]-ethoxycarbonyl)-1,4-dihydropyridine hydrochloride.

Claim 21

The use of a compound to form a pharmaceutical composition useful for treating congestive heart failure, angina, hypertension, or other cardiovascular disorders susceptible to treatment with calcium entry blockers, such as migraine or vasospastic disorders, wherein said compound is of formula 1: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(0) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A l is -(CH 2 ) m (CHOG 1 ) p CH 2 OG 2 ; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OG 1 ] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and G 1 and G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(R a )(R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -NO 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 22

The use of a compound to form a pharmaceutical composition useful for treating congestive heart failure, angina, hypertension, or other cardiovascular disorders susceptible to treatment with calcium entry blockers, such as migraine or vasospastic disorders, wherein said compound is of formula 1: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(0) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A l is -(CH 2 ) m (CHOG 1 ) p CH 2 OG 2 ; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OG 1 ] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and G 1 and G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(R a )(R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -NO 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 23

A process of the preparation of compounds of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(0) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 O'H; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -NO 2 , -CF 3 , or halo; and R 5 is lower alkyl or -CH 2 CH 2 OCH 3 which comprises (a) deprotecting a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0- , -NH- , -NR 2 -, - S -, -S(O)-, -S(O) 2 -, or a bond; R 1 .and R 2 are each independently A1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOG 1 ) p CH 2 OG 2 ; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OG 1 ] r ; A 3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and Gland G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(R a )( R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -NO 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 . (b) optionally followed by alkylating a compound of formula 1 wherein Y is -NH- to form a compound of formula 1 wherein Y is -NR 2 -; (c) optionally followed by oxidation of a compound of formula 1 wherein Y is -S- or -S(0)- to form a compound of formula 1 wherein Y is -S(0)- or -S(O) 2 -; (d) optionally followed by oxidation of a compound of formula 1 wherein R i is A, or A 2 to form a compound of formula 1 wherein R 1 is A3 or A4, optionally followed by esterification of the resulting compound; (e) optionally followed by converting a compound of formula 1 to its pharmaceutically acceptable salt; (f) optionally followed by converting a pharmaceutically acceptable salt of a compound of formula 1 to a free compound of formula 1; (g) optionally followed by converting a compound of formula 1 to an ester of a compound of formula 1; and (h) optionally followed by converting an ester of a compound of formula 1 to a free compound of formula 1.

Claim 24

A process of the preparation of compounds of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(0) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 O'H; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; R 4 is -NO 2 , -CF 3 , or halo; and R 5 is lower alkyl or -CH 2 CH 2 OCH 3 which comprises (a) deprotecting a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0- , -NH- , -NR 2 -, - S -, -S(O)-, -S(O) 2 -, or a bond; R 1 .and R 2 are each independently A1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOG 1 ) p CH 2 OG 2 ; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OG 1 ] r ; A 3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and Gland G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(R a )( R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -NO 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 . (b) optionally followed by alkylating a compound of formula 1 wherein Y is -NH- to form a compound of formula 1 wherein Y is -NR 2 -; (c) optionally followed by oxidation of a compound of formula 1 wherein Y is -S- or -S(0)- to form a compound of formula 1 wherein Y is -S(0)- or -S(O) 2 -; (d) optionally followed by oxidation of a compound of formula 1 wherein R i is A, or A 2 to form a compound of formula 1 wherein R 1 is A3 or A4, optionally followed by esterification of the resulting compound; (e) optionally followed by converting a compound of formula 1 to its pharmaceutically acceptable salt; (f) optionally followed by converting a pharmaceutically acceptable salt of a compound of formula 1 to a free compound of formula 1; (g) optionally followed by converting a compound of formula 1 to an ester of a compound of formula 1; and (h) optionally followed by converting an ester of a compound of formula 1 to a free compound of formula 1.

Claim 25

A process for the preparation of a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOG 1 ) p CH 2 OG 2 ; A 2 .is -(CH 2 ) q CH (3-r) [(CH 2 ) s OG 1 ] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and G 1 and G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(Ra)(R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -NO 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 which comprises (a) reacting a compound of the formula: wherein Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(O) 2 -, or a bond; R 1 is A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; and * is a protecting group, with a compound of the formula: wherein R 4 is -NO 2 , -CF 3 , or halo; and a compound of the formula: wherein R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .

Claim 26

A process for the preparation of a compound of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein n is an integer from 0 to 8; Y is -0-, -NH-, -NR 2 -, -S-, -S(O)-, -S(O) 2 -, or a bond; R 1 and R 2 are each independently A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOG 1 ) p CH 2 OG 2 ; A 2 .is -(CH 2 ) q CH (3-r) [(CH 2 ) s OG 1 ] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; R 3 is H or alkyl of 1 to 18 carbon atoms; and G 1 and G 2 are each -H or -CH 2 C 6 H 5 , or G 1 and an adjacent G 1 together form -C(Ra)(R b )-, or G 1 and G 2 together form -C(R a )(R b )- where R a and R b are independently lower alkyl, where at least one G 1 or G 2 is not -H; R 4 is -NO 2 , -CF 3 , or halo; R 5 is lower alkyl or -CH 2 CH 2 OCH 3 which comprises (a) reacting a compound of the formula: wherein Y is -0-, -NH-, -NR 2 -, -S-, -S(0)-, -S(O) 2 -, or a bond; R 1 is A 1 , A 2 , A3 or A4 where A 1 is -(CH 2 ) m (CHOH) p CH 2 OH; A 2 is -(CH 2 ) q CH (3-r) [(CH 2 ) s OH] r ; A3 is -(CH 2 ) q CH (3-r) [(CH 2 ) p COOR 3 ] r ; and A4 is -(CH 2 ) m COOR 3 ; where m is an integer from 1 to 8; p is an integer from 0 to 4; q is an integer from 0 to 8; r is 2 or 3; s is an integer from 1 to 4; and R 3 is H or alkyl of 1 to 18 carbon atoms; and * is a protecting group, with a compound of the formula: wherein R 4 is -NO 2 , -CF 3 , or halo; and a compound of the formula: wherein R 5 is lower alkyl or -CH 2 CH 2 OCH 3 .