PREPARATION OF NOVEL 1-[2-CARBETHOXY 4- BENZALKYLAMIDO PHENOXY]3-AMINO 2-PROPANOLS USEFUL IN THERAPEUTICS

PREPARATION DE NOUVEAUX 1-[2-CARBETHOXY 4- BENZALCOYLAMIDO PHENOXY]3-AMINO 2-PROPANOLS UTILES DANS DES COMPOSES THERAPEUTIQUES

English Abstract

PATENT APPLICATION
entitled: Preparation of novel 1-[2-carbethoxy 4-benzalkylamido phenoxy]
3-amino 2-propanols useful in therapeutics
ABSTRACT OF THE DISCLOSURE
Process for preparing compounds of formula:
<IMG>
These compounds are endowed with pharmacological properties.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the for-
mula
<IMG>
(I)
in which: R and R' each designate a hydrogen atom, a halo-
gen atom, a nitro group or an alkyl or an alkoxy radical
with 1 to 5 carbon atoms, or an-SCH3 or-CF3 group, R1 repre-
sents a lower alkyl radical with 1 to 5 carbon atoms, R2
represents a lower alkyl radical with 1 to 5 carbon atoms,
and n is an integer less than 5, or a pharmeceutically acceptable
acid addition salt thereof said process comprising reacting
a base of formula
NH2-R2
where R2 is as above with a compound of formula (II)
<IMG>
(II)
wherein R, R', R1 and n are as defined above at a tempera-
ture of between 20°C and 150°C, and where the salt is re-
k reacting the free base obtained with a suitable acid.
2. A process according to claim 1, in which the
reaction is effected in the presence of a solvent.
3. The process of claim 1, wherein the compounds
of formula II are obtained by reaction of a phenol of gen-
22

eral formula (III)
<IMG>
(III)
R, R' and R1 being as defined in claim 1 with an excess of an
epihalohydrin in the presence of a catalyst at a temperature
of from 110°C to 130°C.
4. The process of claim 1, wherein R1 represents
the ethyl group.
5. The process of claim 4, wherein R2 represents
the isopropyl or tertbutyl radical.
6. The process of claim 5, wherein n is equal to
0 or 1.
7. A process of claim 6, wherein R is H and R' is
F or R and R' are both F.
8. A compound of formula I given in claim 1, or a
pharmaceutically acceptable acid addition salt thereof wherein
R, R', R1, R2 and n are as in claim 1 whenever prepared
or produced by the process claimed in claim 1, 2 or 3 or an
obvious chemical equivalent thereof.
9. A compound of formula I given in claim 1,
or a pharmaceutically acceptable acid addition salt thereof
wherein R, R', R2 and n are as in claim 1 and R1 is ethyl
whenever prepared or produced by the process claimed in
claim 4, or an obvious chemical equivalent thereof.
10. A compound of formula I given in claim 1,
or a pharmaceutically acceptable acid addition salt thereof
wherein R, R' and n are as in claim 1, R1 is ethyl and R2
is isopropyl or tert-butyl whenever prepared or produced by
23

the process claimed in claim 5, or an obvious chemical equi-
valent thereof.
11. A compound of formula I given in claim 1,
or a pharmaceutically acceptable acid addition salt thereof
wherein R and R' are as in claim 1, n is 0 or 1, R1 is
ethyl and R2 is isopropyl or tert-butyl whenever prepared
or produced by the process claimed in claim 6 or an obvious
chemical equivalent thereof.
12. A compound of formula I given in claim 1,
or a pharmaceutically acceptable acid addition salt thereof
wherein R1 is ethyl, R2 is isopropyl or tert-butyl, n is 0
or 1 and R and R' are as in claim 7 whenever prepared
or produced by the process claimed in claim 7 or an obvious
chemical equivalent thereof.
13. A process according to claim 1, in which R is
fluorine in the 4-position, R1 is ethyl, R' is hydrogen, n
is 0 and R2 is tert-butyl.
14. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2 car-
bethoxy 4-(4-fluoro benzamido) phenoxy]2,3-epoxy propane.
15. 1-[2-carbethoxy 4-(4-fluoro benzamido)
phenoxy] 3-terbutylamino 2-propanol whenever prepared by the
process claimed in claim 13 or 14 or an obvious chemical
equivalent thereof.
16. A process according to claim 1, in which R is
fluorine in the 4-position, R1 is ethyl, R' is hydrogen, n is
0 and R2 is isopropyl.
17. A process according to claim 1, which com-
prises heating isopropyl amine in ethanol with l-[2-car-
bethoxy 4-(4-fluoro benzamido) phenoxy]2,3-empoxy propane.
24

18. 1-[2-carbethoxy 4-(4-fluoro benzamido)
phenoxy] 3-isopropylamino 2-propanol whenever prepared or
produced by the process claimed in claim 16 or 17 or an
obvious chemical equivalent thereof.
19. A process according to claim 1, in which R is
fluorine in the 3-position, R1 is ethyl, R' is hydrogen, n
is 0 and R2 is tert-butyl.
20. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane.
21. 1-[2-carbethoxy 4-(3-fluoro benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or
produced by the process claimed in claim 19 or 20 or an
obvious chemical equivalent thereof.
22. A process according to claim 1, which com-
prises heating isopropyl amine in ethanol with 1-[2-car-
bethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane
and the product obtained is treated with hydrochloric ether.
23. Hydrochloride of 1-[2-carbethoxy 4-(3-fluoro
benzamido) phenoxy] 3-isopropylamino 2-propanol whenever
prepared or produced by the process claimed in claim 22 or
an obvious chemical equivalent thereof.
24. A process according to claim 1, in which R is
fluorine in the 2-position, R1 is ethyl, R' is hydrogen, n
is 0 and R2 is tert-butyl.
25. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(2-fluoro benzamido) phenoxy] 2,3-epoxy propane.

26. 1-[2-carbethoxy 4-(2-fluoro benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared
or produced by the process claimed in claim 24 or 25 or
an obvious chemical equivalent thereof.
27. A process according to claim 1, which com-
prises heating isopropyl amine in ethanol with hydro-
chloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-isopropylamino 2-propanol and the product obtained is
treated with hydrochloric ether.
28. Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro
benzamido) phenoxy] 3-isopropylamino 2-propanol whenever
prepared or produced by -the process claimed in claim
27 or an obvious chemical equivalent thereof.
29. A process according to claim 1, in which R
and R' are hydrogen, R1 is ethyl, n is 0 and R2 is tert-
butyl.
30. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-benzamido phenoxy] 2,3-epoxy propane.
31. 1-[2-carbethoxy 4-(4-methyl benzamido)
phenoxy] 2,3-epoxy propane whenever prepared or produced
by the process claimed in claim 29 or 30 or an obvious
chemical equivalent thereof.
32. A process according to claim 1, in which R is
methyl in the 4-position, R1 is ethyl, R' is hydrogen, n is
0 and R2 is tert-butyl.
33. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane.
26

34. 1-[2-carbethoxy 4-(4-methyl benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared
or produced by the process claimed in claim 32 or 33 or
an obvious chemical equivalent thereof.
35. A process according to claim 1, in which R is
methyl in the 4-position, R1 is ethyl, R' is hydrogen, n is
0 and R2 is isopropyl.
36. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane.
37. 1-[2-carbethoxy 4-(4-methyl benzamido)
phenoxy] 3-isopropylamino 2-propanol whenever prepared or
produced by the process claimed in claim 35 or 36 or an
obvious chemical equivalent thereof.
38. A process according to claim 1, in which R is
methoxy in the 4-position, R1 is ethyl, R' is hydrogen, n is
0 and R2 is tert-butyl.
39. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane.
40. 1-[2-carbethoxy 4-(4-methoxy benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared
or produced by the process claimed in claim 38 or 39 or
an obvious chemical equivalent thereof.
41. A process according to claim 1, in which R is
fluorine in the 2-position, R' is fluorine in the 4-position,
R1 is ethyl, n is 0 and R2 is tert-butyl.
42. A process according to claim 1, which com-
27

prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(2,4-difluoro benzamido) phenoxy] 2,3-epoxy pro-
pane.
43. 1-[2-carbethoxy 4-(2,4-difluoro benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared
or produced by the process claimed in claim 41 or 42 or
an obvious chemical equivalent thereof.
44. A process according to claim 1, in which R is
fluorine in the 4-position, R1 is ethyl, R' is hydrogen, n
is 0 and R2 is tert-butyl.
45. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-fluoro benzacetamido) phenoxy] 2,3-epoxy pro-
pane.
46. 1-[2-carbethoxy 4-(4-fluoro benzacetamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the
process claimed in claim 44 or 45 or an obvious chemical
equivalent thereof.
47. A process according to claim 1, in which R is
chlorine in the 4-position, R1 is ethyl, R2 is tert-butyl,
R' is hydrogen and n is 0.
48. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-chloro benzamido) phenoxy] 2,3-epoxy propane.
49. 1-[2-carbethoxy 4-(4-chloro benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the
process claimed in claim 47 or 48 or an obvious chemical
equivalent thereof.
28

50. A process according to claim 1, in which R is
methyl in the 3-position, R1 is ethyl, R2 is tert-butyl R'
is hydrogen and n is 0.
51. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(3-methyl benzamido) phenoxy] 2,3-epoxy propane.
52. 1-[2-carbethoxy 4-(3-methyl benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the
process claimed in claim 50 and 51 or an obvious chemical
equivalent thereof.
53. A process according to claim 1, in which R is
methoxy in the 3-position, R1 is ethyl, R2 is tert-butyl, R'
is hydrogen and n is 0.
54. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(3-methoxy benzamido) phenoxy] 2,3-epoxy propane.
55. 1-[2-carbethoxy 4-(3-methoxy benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the
process claimed in claim 53 or 54 or an obvious chemical
equivalent thereof.
56. A process according to claim 1, in which R is
methyl in the 2-position, R1 is ethyl, R2 tert-butyl, R' is
hydrogen and n is 0.
57. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane.
58. 1-[2-carbethoxy 4-(2-methyl benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or
29

produced by the process claimed in claim 56 or 57 or an
obvious chemical equivalent thereof.
59. A process according to claim 1, in which R is
CH3S-in the 4-position, R1 is ethyl, R2 is tert-butyl, R' is
hydrogen and n is 0.
60. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy
propane.
61. 1-[2-carbethoxy 4-(4-methylthio benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared or
produced by the process claimed in claim 59 or 60 or an
obvious chemical equivalent thereof.
62. A process according to claim 1, in which R is
chlorine in the 3-position, R1 is ethyl, R2 is tert-butyl,
R' is hydrogen and n is 0.
63. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(3-chloro benzamido) phenoxy] 2,3-epoxy propane.
64. 1-[2-carbethoxy 4-(3-chloro benzamido)
phenoxy] 3-tertbutylamino 2 propanol whenever prepared or
produced by the process claimed in claim 62 or 63 or an
obvious chemical equivalent thereof.
65. A process according to claim claim 25, in
which the 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-
tertbutylamino 2-propanol obtained in absolute ethanol is
acidified with hydrochloric ether.
66. Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro

benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever
prepared or produced by the process claimed in claim 65 or
an obvious chemical equivalent thereof.
67. A process according to claim 1, in which R is
-CF3 in the 4-position, R1 is ethyl, R' is hydrogen, n is 0
and R2 is tert-butyl.
68. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 2,3-epoxy
propane.
69. 1-[2-carbethoxy 4-(4-trifluoromethyl ben-
zamido) phenoxy] 3-tertbutylamino 2-propanol whenever
prepared or produced by the process claimed in claim 67 or
68 or an obvious chemical equivalent thereof.
70. A process according to claim 1, in which R is
methoxy in the 2-position, R1 is ethyl, R' is hydrogen, n is
0 and R2 is tert-butyl.
71. A process according to claim 1, which com-
prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane.
72. 1-[2-carbethoxy 4-(2-methoxy benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared
or produced by the process claimed in claim 70 or 71 or
an obvious chemical equivalent thereof.
73. A process according to claim 1, in which R is
chlorine in the 2-position, R1 is ethyl, R' is hydrogen, n
is 0 and R2 is tert-butyl.
74. A process according to claim 1, which com-
31

prises heating tert-butyl amine in ethanol with 1-[2-car-
bethoxy 4-(2-chloro benzamido) phenoxy] 2,3-epoxy propane.
75. 1-[2-carbethoxy 4-(2-chloro benzamido)
phenoxy] 3-tertbutylamino 2-propanol whenever prepared
or produced by the process claimed in claim 73 or 74 or
an obvious chemical equivalent thereof.
76. A process according to claim 74, in which the
1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-tertbutyl-
amino 2-propanol obtained, is disolved in acetone and the
solution acidified by hydrochloric ether.
77. The hydrochloride of 1-[2-carbethoxy 4-(2-
chloro benzamido) phenoxy] 3-tertbutylamino 2-propanol
whenever prepared or produced by the process claimed in
claim 76 or an obvious chemical equivalent thereof.
78. A process according to claim 42, in which the
1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-tert-
butylamino 2-propanol obtained in ethanol is acidified with
hydrochloric ether.
79. The hydrochloride of 1-[2-carbethoxy 4-(2,4-
difluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol
whenever prepared or produced by the process claimed in
claim 78 or an obvious chemical equivalent thereof.
32

Description

378
--I--
The present invention relates to the preparation of novel derivatives
of ~-benzalkylamido 2-carbalkoxy phenoxy amino-propanol of general forrnula
(I) and ~o their acid addition salts. The derivatives in question present a
highly original and very surprizing pharmacological profile since they are
5 endowed with diuretic properties associated, for certain, with ,B ~ blocking
properties.
The present invention also relates to the process for preparing the
novel intermediate compounds allowing synthesis of said products.
The novel compounds according to the invention belong to the group
10 constituted by the products of general formula (1) and their non-toxic acid
addition salts
COO Rl
R ~ 2)n CONH~OCH2_1CH-CH2-NH R2
R'
(I)
In formula (1):
20 - R and R' may each designate an atom of hydrogen, an atom of halogen
for examPle fluorine, a nitro group or alkyl or alkoxy radicals with Cl-C5,
branched or not, or a SCH3 or ~3 grouF~;
- Rl represents a lower alkyl radical with I to 5 carbon atoms, branched
or not, advantageously the ethyl radical;
25 - R2 represents a lower alkyl radical with I to 5 carbon atoms, straight or
branched, and preferably the isopropyl radical or the terbutyl radical;
- n designates an integer less than 5, and preferably equal to 0 or 1.
The compounds according to the invention are synthesized by action
of an NH2-R2 base (R2 being defined as hereinabove) on a compound of
30 formula (Il) without solvent or in a conventional organic solvent such as
alcohols, at a temperature of between 20C and 150C.

8~78
--2--
,COO ~
R ~3 (CH2~--CONH~ ~oc~2--C~H2
R'
(Il)
In formula (Il), R, R', Rl and n are defined as hereinabove.
The compounds of formula (Il) are generally obtained by reaction
of a phenol of general formula (111) with an excess of epihalohydrin, particularly
10 epichlorohydrin or epibrornohydrin, in the presence of a catalyst such as
benzyltrimethylammonium chloride, at a temperature ranging from ilOC
to 130C. This process yields perfectly crystallized compounds with better
yields than the processes evoked hereinafter. The compounds of formula
(Il) may also be obtained by reaction of the phenol of general formula (III)
15 with any epihalohydrin according to the conventional processes. The phenol
of formula (111) will then be metalled by conventional metallation agents
such as potassium hydroxide, sodium hydroxide, an alcoholate or sodium hydride
in a dilute alcoholic, alcohoîic solvent or dimethylformamide (DMF) at a
temperature of between 20C and 150C. However, these processes yield
20 products which are less well defined.
COO Rl
R~(C~2) -- CO~H ~ OH
R'
(111)
In formula (III), R, R', Rl and n are defined as hereinabove.
The compounds of formula (III) are obtained in accordance with
known processes of preparation consisting either in reacting the chloride
30 of the corresponding arylalkanoic acid with a 4-amino 2-carbalkoxy phenol
in the presence of a base such as triethylamine in a solvent such as acetone
or benzene, or in esterifying the corresponding acid (IV) in a sulfuric acid-
alcohol medium.
.

~2~ 37~
~C~OH
R~_(CH2) -- CO~ OH
~,
(IV)
In formula (IV), R, R' and n are defined as hereinabove.
The addition salts of the compounds of formula (I) may be obtained
by reaction of these compounds with an inorganic or organic acid in accordance
10 with a method known per se. Among the acids which may be used to this
end, particular mention will be made of hydrochloric, hydrobromic, acetic,
p-toluene sulfonic, methane sulfonic, oxalic, succinic, maleic, fumaric, cinna-
mic, malic, aspartic, glutamic, ascorbic, N-acetyl aspartic, N-acetyl glutamic
acids.
The novel compounds according to the invention are endowed with
remarkable pharmacological properties and may be used in therapeutics for
the treatment of hypertension since, most surprizingly, they present diuretic
properties with, for certain of the products, /~1 blocking properties, and
low toxicity. These remarkable characteristics seem to be due to the presence
20 in the molecules of the ester function in ortho position and of the amide
function in para position.
In human therapeutics, the compounds of formula (I) and their non-
toxic acid addition salts may be administered in particular by the oral route.
In that case, the use of gelatin-capsules or of tablets containing from 50
25 to 300 mg of active ingredient in association with a physiologically acceptable
excipient is recommended. The compounds claimed present -the advantage
of rendering treatment easier. On the other hand, with respect to the l3_
blocking/diuretic associations used in the treatment of hypertension~ the
cornpounds of formula (I) have the advantage of single pharmacokinetics.
30 Angor pectoris and arrhythmia will be mentioned as other possible examples
of indications.
Other features and advantages of the invention will appear more
clearly on reading the following non-limiting examples of preparation given
by way of illustration.

~ 8;37~3
The forrnulae corresponding to the Examples are given in the single
Table at the end of the specification.
Example 1: 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 2,3-epoxy propane
Formula ll R = Fluorine in 4 position Rl C2H5
R' = H n = 0
In a flask, the rnixture of 34 g of 2-carbethoxy 4-(4-fluoro benzamido)
phenol and 150 ml of epic:hlorohydrin is heated to 110C. 2.7 g of benzyltrimethyl
ammonium chloride are then introduced. The reaction mixture is heated to
reflux for 1/2 hr. then cooled. Once the temperature has dropped to 50C,
150 ml of water are added and the mixture is stirred well. The organic phase
is decanted and the aqueous phase extracted twice with 50 ml ether. The
organic phases are dried over magnesium sulfate then concentrated in vacuo.
The crude residue obtained crystallizes in 200 ml of ether to yield 22 g of
1-[2-carbethoxy 4-~4-fluoro benzamido) phenoxyi 2,3-epoxy propane melting
at 115C.
Example 2: 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane
Formula 11 R = Fluorine in 3 position Rl C2H5
R' = H n = 0
The rnodus operandi is identical to the one described in Example
1. From 50 g of 2-carbethoxy 4-(3-fluoro benzamido) phenol, 4 g of benzyltri-
methylammonium chloride and 250 ml of epichlorohydrin, 24 g of 1-[2-carb-
ethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane melting at 100C
are obtained.
Example 3: 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 2,3-epoxy propane
Formula 11 R = fluorine in 2 position Rl C2H5
R' = H n = 0
The modus operandi is the same as the one described in Example
1. From 36 g of 2-carbethoxy 4-(2-fluoro benzamido~ phenol, 3 g of benzyltri-
methylammonium chloride and 185 ml of epichlorohydrin, 14 g of 1-[2-carbethoxy
4-(2-fluoro benzarnido) phenoxy] 2,3-epoxy propane melting at 89C are
obtained.
Example 4: 1-[2-carbethoxy 4-~4-fluoro benzamido) phenoxy] 3-terbutylamino
_.
2-propanol

~21~33~
CH3
Formula I R = fluorine in 4 position Rl = C2H5 R2=-C-CH3
1~3
R' = H n = 0
T~le mixture of 11 g of the product of Example 1, 20 ml of terbutyl-
amine and 60 ml of ethanol is heated to 60C for 8 hrs., then concentrated
5 in vacuo. The residue is taken up in 3 ml of acetic acid in 200 ml of water
and 200 ml of isopropyl acetate. The mixture is stirred well and the isopropyl
acetate eliminated by decantation. The aqueous phase is then neutralized
by ammonia then extracted 3 times with 50 ml of methylene chloride. After
drying over magnesium sulfate and concentration in vacuo oI the organic
- 10 phase, a residue is obtained which crystallizes in ether. Recrystallization in
isopropyl acetate yields 8 g of 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol in the form of white crystals melting at 130C.
Example 5: 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-isopropylamino
2-propanol
/ CH3
15 Formula I R = fluorine in 4 position Rl=C2H5 R2= -CH
CH3
R' = H n = 0
The modus operandi is identical to the one described in Example
4 but using isopropylamine in place of terbutylamine. From 11 g of the product
of Example 1, a crude product is obtained whichSrecrystallized in isopropyl
20 acetate, yields 6 g of 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-iso-propylamino 2-propanol in the form of white crystals melting at 117C.
Example 6: 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-terbutylamino
2-propanol
ICH3
Formula I R = fluorine in 3 position Rl=C2H5 R2=-C-CH3
H3
R' = H n = 0
The modus operandi is the same as the one described in Example
4. From 14 g of the product of Example 2 and from 80 ml of terbutylamine,
7 g of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-terbutylamino 2-
propanol in the form of white crystals melting at 114C are obtained after

:~Z~8~371~
recrystallization in isopropyl acetate.
Example 7: Hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy~
3-isopropylamino 2-propanol
~ C H 3
Formula I R = fluorine in 3 position Rl=C2~15 R2=-CH
CH3
R' = H n = 0
The modus operandi is the same as the one described in Example
4 but from 8 g of the product of Example 2 and 30 ml of isopropylamine,
and a white product is obtained which crystallizes in ether. By dissolving
this product in acetone (200 ml) and by adding hydrochloric ether up to pil
10 2, the expected hydrochloride precipitates. After washing with acetone and
drying, 3 g of hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxyl
3-isopropylamine 2-propanol in the form of white crystals meltin~ at 182C
are thus obtained.
Example 8: 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino
15 2-propanol
~H3
Formula I R = fluorine in 2 position Rl=C2H5 R2=-C-CH3
H3
R' = H n = 0
The modus operandi is the same as the one described in Exannple
4. Starting frorn 12 g of the product of Example 3, 3.5 g of 1-[2-carbethoxy
20 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained,
in the form of white crystals melting at 124C.
Example 9: Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido~ pllenoxy]
3-isopropylamino 2-propanol
,CH3
Formula I R = fluorine in 2 position Rl=C2H5 R2=-CH~
CH3
R' = H n = 0
The modus operandi is the same as the one described in Example
7 but from 14 g of the product of Example 3. 2 g of hydrochloride of 1-[2-carb-
ethoxy 4-12-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol are thus
obtained, in the form of white crystals melting at 188~C.

~L2~83~
7_
_xample 10 ~ 2-carbethoxy 4-benzamido phenoxy] 2,3-epoxy propane
~orrnul~ 11 R - R' = H Rl C2 5
n = 0
The modus operandi is identical to that described in Example I but
from 42 g-of 2-carbethoxy 4-benzamido phenol, 257 ml of epichlorohydrin
and 3.5 g of benzyltrimethylarnmonium chloride; 23 g of 1-(2-carbethoxy
4-benzamido phenoxy) 2,3-epoxy propane are obtained in the form of white
crystals melting at 12~C.
r ~ple 11: 1-[2-carbethoxy 4-benzamido phenoxy] 3-terbutylamino 2-propanol
10 l~ormula I R = R' = H Rl C2H5
C,H3
n = 0 R = -C-CH3
~H3
The modus operandi is the same as that described in Example 4.
Starting from 10 g of the product of Example 10 and 50 ml of terbutylamine,
3.5 g of 1-[2-carbethoxy 4-benzamido phenoxy] 3-terbutylamino 2-propanol
15 are obtained, in the form of white crystals melting at 120C.
Example 12: 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy
propane
Formula 11 R = CH3 in 4 position R' = H
Rl 2 5 n = 0
The modus operandi is identical to that described in Example 1.
From 27 g of 2-carbethoxy 4-(4-methyl benzamido) phenol, 40 ml of epichloro-
hydrin and 2.3 g of benzyltrimethylammonium chloride, 13.1 g of 1-[2-carbethoxy
4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form
of white crystals melting at 117C.
25 Example 13: 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-terbutylamino
2-propanol
Formula I R = CH3 in 4 position Rl C2H5
Cl H3
R' = H R2 = -C-CH3
CH3
n = 0
The modus operandi is the same as that described in Example 4,
but starting from 11 g of the product of Example 12 and 60 ml of terbutylamine;

~2~837~3
6.6 g of 1-~2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-terbutylamino
2-propanol are obtained in the form of ~vhite crystals melting at 140C.
_xam le 14: !-L2-carbethoxy 4-~4-methyl benzamiclo) phenoxy] 3-isopropylamino
2-propanol
Formula I R = CH3 in 4 position Rl 2 5
R' = H R2 = -CH C~3
n = 0 CH3
The modus operandi is the same as the one described in Example
4, bu~ replacing the -terbutylamine by isopropylarmine. Starting frorrl 15 g
of the product of Example 12 and 70 ml of isopropylamine, ~ ~ of 1-[2-carb-
ethoxy 4-(4-methyl benzamido phenoxy] 3-isopropylamino 2-propanol are ob-
tained in the form of white crystals melting at 114C.
Exampl_: 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy
propane
Formula 11 R = OCH3 in 4 position Rl C2H5
R' = H n = 0
The modus operandi is identical to that described in Example 1,
but from 13.1 g of 2-carbethoxy 4-(4-methoxy benzoamido~ phenol, 66 ml
of epichlorohydrin and I g of benzyltrimethylammonium chloride; 8.6 g of
1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane are
obtained in the forrn of white crystals melting at 126C.
Example 16: 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxyl 3-terbutylamino
2-propanol
Formula I R = OCH3 in 4 position Rl C2H5
$H3
R' = H R2 = -C-CH3
n = 0 CH3
The modus operandi is the same as the one described in Example
4. From 8~6 g of the product of Example 15 and 20 ml of terbutylamine,
5.2 g of 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 3-terbutylamino
2-propanol are obtained, in the form of white crystals melting at 124C.
30 Exam~: 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutyl-
amino 2-propanol

~11 83~7~3
Formula I R = fluorine in 2 position ~1'3 ~1 = C2HS
R' = fluorme in 4 position R2 = -C-CH3
n = 0 ~H3
This product is synthesized in the same rnanner. From 1-[2-carbethoxy
5 4-(2,4-difluoro benzamido) phenoxy] 2,3-epoxy propane and terbutylamine,
1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxyJ 3-terbutylamino 2-propanol
is obtained in accordance with the modi operandi previously described ~.P 138-140C.
Example 18: 1-[2-carbethoxy 4-(4-fluoro benzacetamido) phenoxyl 3-terbutyl-
_ _
amino 2-propanol
10 Forrnula I R = fluorine in 4 position Rl C2H5
l H3
R' = H R2 = -C-CH3
n = 0 CH3
In thc same manner, 1-[2-carbethoxy 4-(4-fluoro benzacetamido)
phenoxy] 3-terbutylamino 2-propanol is obtained from 1-[2-carbethoxy 4-(4-
15 fluoro benzacetamido) phenoxy] 2,3-epoxy propane and terbutylamine in accor-
dance with a modus operandi identical to those described previously M.P 109C.
Example 19: 1-[2-carbethoxy 4-(4-chloro benzamido phenoxy] 2,3-epoxy propane
Formula 11 R = Cl in 4 position Rl C2H5
R' = H n = 0
The modus operandi is identical to that described in Example 1.
From 32 g of 2-carbethoxy 4-(4-chloro benzamido~ phenol, 140 ml of epichloro-
hydrin and 3 g of benzyltrimethylammonium chloride, 13.2 g oi 1-[2-carbethoxy
4-(4-chloro benzamido) phenoxy] 2,3-epoxy propane are obtained, used as
such for subsequent synthesis.
25 Example 20: 1-[2-carbethoxy 4-(4-chloro benzamido) phenoxy] 3-terbutylamino
2-propanol
CH3
~ormula I R = Cl in 4 position Rl = C2H5 R2 = -C-CH3
CH3
R' = H n = 0
The modus operandi is the same as that described in Example 4
30 but, from 13 g of 1-[2-carbethoxy 4-(4.-chloro benzamido) phenoxy] 2,3-epoxy
propane prepared in Example 19, 3.6 g of 1-[2-carbethoxy 4-(4-chloro benz-
arnido) phenoxy] 3-terbutylamino 2-propanol in the form of crystals mel~ing

L8~8
-1-
at 134C are obtained aIter recrystallization in isopropanol.
Example 21: 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxyi 2,3-epoxy
propane
Formula 11 R = CH3 in 3 position Rl C2H5
R' = H n = 0
According to the modus operandi of Example 1, hut starting from
Il g of 2-carbethoxy 4-(3-methyl benzamido) phenol, 20 cm2 of epichlorohydrin
and I g of benzyltrimethylammonium chloride, 15 g of 1-[2-carbethoxy 4-(3-
methyl benzarnido) phenoxy] 2,3-epoxy propane are obtained, in the form
of oil, used as such.
Example 22: 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxy] 3-terbutylamino
2-propanol
CH3
Formula I R = CH3 in 3 position Rl=C2H5 R2=~C~CH3
R' = }1 n = 0 CH3
According to the modus operandi of Example 4, from 15 g of the
epoxicle prepared in Example 21, 8.6 g of 1-[2-carbethoxy 4-(3-methyl benzamido)phenoxy] 3--terbutylarnino 2-propanol are obtained, in the form of white
crystals melting at 109C.
Example 23: 1-[2-carbethoxy 4-(3-methoxy benz~rudo ) phenoxy] 2,3-epoxy
20 propane
Formula 11 R = MeO in 3 position Rl C2H5
R' = H n = 0
According to the modus operandi of Example 1, but from 16.4 g
of 2-carbethoxy 4-(3-methoxy benzamido ) phenol, 50 ml of epichlorohydrin
25 and 1.5 g of benzyltrimethylammonium chloride, 14.5 g of 1-[2-carbethoxy
4-(3-methoxy benz~ido) phenoxy] 2.3-epoxy propane are obtained, in the
form of crystals melting at 90C.
_ample 24: 1-[2-carbethoxy 4-(3-methoxy benzalrido ) phenoxy] 3-terbutyl-
arnino 2-propanol
,CH3
30 Formula I E~ = MeO in 3 position Rl=C2H5 R2=-C-CH3
R' = H n = 0 CH3
According to the modus operandi of Example 4, but from 14.5 g
of the epoxide prepared in Example 23, 2.6 g of 1-[2-carbethoxy 4-(3-methoxy

12~8~378
--11
benzamido ) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form
of white crystals melting at 94C.
Example 25: 1-[2-carbethoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy
propane
Formula 11 . R = CH3 in 2 position Rl C2H5
R' = H n = 0
After having prepared the sodium salt of 20 g of 2-carbethoxy 4-(2-
methyl benzamido) phenol in ethanol in the presence of the stoichiometric
quantity of sodium hydroxide in pastille form, 50 ml of epichlorohydrin are
10 added with stirring and the mixture is taken to reflux for 8 hours. The reaction
rnixture is cooled then concentrated in vacuo. The residue obtained is taken
up in methylene chloride and washed with water. The organic solution is
dried over magnesiurn sulfate, filtered, then concentrated in vacuo. The residuehardens in isopropyl ether. By taking up the solid obtained in a mixture of
15 100 ml of ethyl ether and 10 ml of isopropyl acetate, ~, g of 1-[2-carbe~hoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form
of pink crystals melting at 94"C.
Example 26: 1-[2-carbethoxy 4-~2-methyl benzamido) phenoxy] 3-terbutylamino
2-propanol
C, H3
20 Formula I R = CH3 in 2 position R = C2H5 R2 = -C-CH3
CH3
R' = H n = 0
According to the modus operandi of Example 4, starting from 13
g of the epoxide prepared in Example 25, 1.2 g of 1-[2-carbethoxy 4-(2-methyl
benzamido) phenoxy] 3-terbutylamino 2-propanol is obtained, in the form
25 of white crystals melting at 126C.
Example 27: 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy
propane
Formula 11 R = CH3S in 4 position Rl C2H5
R' = H n = 0
According to the modus operandi of Example 25, but from 40 g
of 2-carbethoxy 4-(4-methylthio benzamido phenol and 80 ml of epichloro-
hydrin, 20 g of 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy3 2,3-epoxy
propane are obtained, in the form of white crystals melting at 105C.

~2~ 378
-I 2-
Example 2~ [2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-terbutyl-
amino 2-propanol
ICH3
Fornlula I R = CH3S in 4 position Rl = C2H5 R2 = -C-CH3
CH3
R' = H n = 0
~ccording to the modus operandi of Example 4, starting from 12
g of the epoxide prepared in Example 27 and terbutylamine, 6 g of a crude
product are obtained which, recrystallized in isopropyl acetate, yields 3.5
g of 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-terbutylamino
2-propanol in the form of white crystals melting at 142C.
10 Example 29: 1-[2-carbethoxy 4-~3-chloro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = Cl in 3 position Rl C2H5
R' = H n = 0
The modus operandi is identical to that of Example 1. From 7 g
of 2-carbethoxy 4-(3-chloro benzamido) phenol, 30 ml of epichlorohydlin
15 and 0.7 g of benzyltrimethylammonium chloride, 4 g of 1-[2-carbethoxy 4-(3-
chloro benzamido~ phenoxy] 2,3-epoxy propane are obtained in the form of
white crystals melting at 95~C.
Example 30: 1-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-terbutylamino
2-propanol
Cl H3
20 Formula I R = Cl in 3 position Rl = C2H5 R2 = -C-CH3
CH3
R' = H n = 0
According to the modus operandi described in Example 4, 13 g of
the epoxide of Example 29 yield 2 g of 1-[2-carbethoxy 4-(3-chloro benzamido)
phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting
25 at 107C.
Example 31: Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol
Formula R = fluorine in 2 position Rl C2H5
R' = H . CH3
n = 0 R2 =-C-CH3
hydrochloride CH3

~Z1~33 ,7~3
f\ solution oi 4.5 g of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol prepared in Example 8~ In 50 ml of absolute ethanol,
is acidified to pll 2 by hydrochloric ether. The solvent is evaporated to
dryness in vacuo, and the residue is taken up in ether.
After draining of the precipitate obtained and washing with ether,
4.6 g of hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylarnirlo 2-propanol, melting at 168C, are obtained in this way.
Example 32: 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxyl 2,3-
epoxy propane
Formula 11: R = CF3 in 4 position Rl C2H5
R' = H n = 0
According to the modus operandi described in Example 25 but from
20 g of 2-carbethoxy 4-(4-trifluoromethyl benzamido) phenol and 50 ml of
epichlorohydrirl, 7 g of 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido)
phenoxy] 2,3-epoxy propane in the forrn of an oil are obtained, used as such
for the following.
Example 33: 1-L2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 3-
terbutylamino 2-propanol
Formula 1: R = CF3 in 4 position Rl C2H5
CH3
2 0 R ' = H 2 ~ 3
n = 0 CH3
According to the modus operandi described in Example 4, starting
from 13 g of the epoxide prepared in Example 32, and 50 ml of terbutylamine,
1.5 g of 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 3-terbutyl-
amino 2-propanol melting at 155C is obtained a~ter crystallization in ether
and washing with isopropyl acetate.
Example 34: 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy
propane
Formula 11: R = OCH3 in 2 position Rl = C2H5
R' = H n = 0
According to the modus operandi described in Example 1, but from
8.5 g of 2-carbethoxy 4-(4-methoxy benzamido phenol, 50 ml of epichlorohydrin
and 600 mg of benzyltrimethyl ammonium chloride, 3.5 g of 1-[2-carbethoxy
4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane, crystallized in isopropyl

1~3L8~78
--14--
ether and melting at 70C are obtained.
Example 35: 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-terbutyl-
amino 2-propanol
Formula 1: R = OCH3 in 2 position Rl C2~5
R'. = H ICH3
N = 0 R2 = -C-CH3
CH3
According to the modus operandi described in Example 4, but from
3.5 g of the epoxide prepared in Example 34 and 50 ml of terbutylamine,
1.2 g of 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-terbutylamino
10 2-propanol, crystallized in pentane and melting at 107C, is obtained.
Example 36: 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 2,3-epoxy propane
Forrmula 11: R = Cl in 2 position Rl C2H5
R' = H n = 0
A solution of 10 g (0.03 mole) of 2-carbethoxy 4-(2-chloro benzamido)
15 phenol and 2 g of ~5/O potassium hydroxide (0.03 mole), in 200 ml oi ethanol
and 30 ml of DMF, is added dropwise over 4.7 crn3 (0.06 mole) of epichloro-
hydrin in 50 ml of ethanol.
This solution is stirred for 3 hrs. at ambient temperature, then for
I hour at 50, and allowed to stand overnight. It is then concentrated, diluted
20 with water and extracted with ether. After drying and evaporation of the
ether, 4 g of an oil are obtained, used as such for the following.
Example 37: 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-terbutylamino
2-propanol and hydrochloride
Formula I = R = Cl in 2 posi-tion Rl C2H5
~' = H ICH3
n = 0 R2 = -C-CH3
CH3
According to the modus operandi described in Example 4, but starting
from 4 g of the epoxide prepared in Example 36, 2.5 g of 1-12-carbethoxy
4-(2-chloro benzamido) phenoxy3 3-terbutylamino 2-propanol, crystallized
30 in an acetone-ether mixture and melting at 113-115C, are obtained.
Preparation of the hydrochloride
6 g of 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-terbutyl-

~2~837i~3
-15 -
amino 2-propanol are dissolved in 50 ml of acetone, and the solution is acidi-
fied to pH 2 by hydrochloric ether.
4.5 g of hydrochloride of 1-[2-carbethoxy (4-(2-chloro benzamido)
phenoxy] 3-terbutylamino 2 propanol in the form of crystals melting at 158-161
5 are obtained in this way.
Example 38: Hydrochloride of 1-[2-carbethoxy 4-(2,4-difluoro benzamido)
phenoxy] 3-terbutylamino 2-propanol
Formula I = R = fluorine in 2 position Rl C2H5
R' = fluorine in 4 position CH3
n = O R2 = -C-CH3
hydrochloride CH3
A solution of 25 g of 1-[2-carbethoxy 4-(2,4-difluoro benzamido)
phenoxy] 3-terbutylamino 2-propanol prepared in Example 17 in 100 ml of
ethanol is acidified to pH 2 by hydrochloric ether. The precipitate formed
15 is drained, washed with ether.
24 g of crude hydrochloride are thus obtained, which, crystallized
in acetonitrile, yield 22 g of hydrochloride of 1-t2-carbethoxy 4-(2,4-difluoro
benzamido) phenoxy~ 3-terbutylamino 2-propanol in the form of white crystals
melting at 151-152~C.

1~8378
T A B L E
COO C2H5
Example 1 : F_ ~ CONH ~ \ T
F COO C2H5
Example 2 : ~ CONH_ ~ OCH2-CH-CH2
F /COO C2H5
Example 3 : ~ CONH_ ~ _OCH2-C\ /H2
COO C2H5 ICH3
Example 4 : F ~ CONH_ ~ CH2 ICH 2 j 3
OH CH3
Example 5 : F ~ CONH ~ OCII2-~U-CH2-NH-CU
Example 6 : ~ CONH ~ 2 1 2 1 3
F OH CH3
COO C2H5
Example 7 : ~ CONH. ~ CH2-CH-CH2-NH-CH-CH3, HCl
OH CH3
~ COO C2H5 7H3
Example 8 : ~ ~ _ CONH _ ~ OCH2-CIH CH2 NH I 3
F COO C2H5
Example 9 : ~ CONH ~ OCH2-CH-CH2-NH-CH;CH3, HCl

378
_l7 _
COO C2H5
Exanple 10 ~ CON~H ~OC~12-CH-CH2
COO C2H5 CH3
Ex~mple 11 : ~ CO~ 2 1 2 1 3
COO C2H5
Exa,npLe 12 : CH3 ~ CONH_ ~ 2 \ 5 2
COO C2H5 CH3
Example 13 : CH3 ~ ~ CONH_ ~ 2 1 2 1 3
COO C2H5
Example14 : CH3 ~ CONH_~ 2 1 2 f 3
OH CH3
COO C2HS
ExamplelS : CH30- ~ CONH ~ 2 \O/ 2
COO C2H5 CH3
Exanplel6 : CH30 ~ CONH ~ OCH2-CH-cH2 NH l C 3
COO C2H5 CH3
Example 17 : F~ CONH~ 2 1 2 1 3
OH CH3
2 5 COO C2H5 CH3
Exa,nplel8 :F ~ CH2 _ CONH _ ~ _OCH2-1H-CH2-NH I CH3

~2~83t~8
CO0 - C H
Ex ~ple 19 C1~3COl~T.l--(~O-CH2 CH--CH2
COO-C2H5 CIH
Example 20 C1~CONH~ -CH2--ICH-CH~l--Cl--CH3
CH3 COO-~2~5
Ex ample 21 ~CONH~O-CH2--CH--C~H2
CH3 COO-C H fH3
Ex ample 22 ~ ONH-- ~ -C~2--1CH-CH2 Nl~~~Cl~~CH3
CH COO-C~H5
Example 23 ~ ONH- ~ -CH2 CH~-CH2
CH3 C00-C2H- fH3
~ CO~H_ ~ O-CH2 ,CH-CH ~N~--G--CH3
Example 24 \~/ \J OH C~3

:~Z~378
- 19-
CH3 COO-CH2H5
Example 25 ~ CO~H~_O-CH2 C~a~CH2
CH3 COO-CH2H5 CH
~xa~ple 26 ~CONH~ O c,~ ~ 3
CO~-C2H5
E:~ample 27 Cll3 S { ~ COli'.~ O-CH2 C\ ~CH2
CO~-C2H5 3
Example 28 C113 S~ CO.NI~ CH--CH----CH~H_ ~3CH3
C ,COO-C H5
Example 29 ~3 CONH~30-C'.12 CE~\ /C. 2
Cl~ COO-C2H5 1~11,3
Ex anple 30 ~CO~IH ~ ~f ~ 1 3

~83~7~3
-20-
F ÇOO~t
ample 31 ~ CONH ~ ~ O C!l ~ H-CH ~.~ ~ CH3, HCl
COOEt
Example 32 F3C ~ CONH ~ O CH2 C - CH2
Ex ample 33 F3C ~ ONH ~ o~ CH3
O~e COO_t
Example 34 ~ONH ~ O-CH2--C\~CH2
O!le COOE t
Exa.nple 35 ~ ONH ~ ~H2 b~-CH2 ~ CH3
Cl ,COOE t
Ex aDple 36 ~ C-NH ~ O C~,~2-CH-CH2 .

~83~8
C 1 COOEt
Exa~ple 37 : ~C_NH~O-CH2-CH-CH2-NH +, HCl
F ÇOOE t
Exa~ple 38: F~C-~H~O-CH2-CH CH2-NH+, HCl