HYDROXYAMINOMETHYL DERIVATIVES OF BENZOYL DI-SUBSTITUTED .alpha.-PHENOXY ALKANOYL ESTERS

DERIVES HYDROXYAMINOMETHYLES D'ESTERS DE BENZOYLE .alpha.-PHENOXYALCANOYLE DISUBSTITUE

English Abstract

Abstract of the Disclosure
Described are compounds of the formula
<IMG>
wherein R1 is <IMG> wherein R5 and R6 are hydrogen,
loweralkyl or together are alkylene of 4 or 5 carbon atoms,
R2 is hydrogen, halo, haloloweralkyl, loweralkyl,
loweralkoxy, loweralkylthio or <IMG> wherein R5 and
R6 are as previously defined,
R3 is hydroxy, alkoxy, branched alkoxy,
adamantyloxy, morpholino, amino or amino substituted by
loweralkyl or alkylene of 4 or 5 carbon atoms,
R4 is hydrogen or loweralkyl, and
X1 and X2 are hydrogen, loweralkyl, halo or when
substituted on adjacent carbon atoms of the benzene ring
form a 1,3-butadienylene linkage, with the proviso that
X1 and X2 are not both hydrogen, and pharmaceutically
acceptable salts thereof, the compounds are effective as
diuretic agents in increasing urinary excretion.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of
the general formula:
<IMG> IV
wherein R1 represents CH2NR5R6, R2 represents a group
selected from hydrogen, halo, loweralkyl and CH2NR5R6, R3
represents a group selected from hydroxy, alkoxy, branched
alkoxy and adamantyloxy, R4 represents a group selected
from hydrogen and loweralkyl, and X1 and X2 represent a
group selected from loweralkyl, halo and when substituted
on adjacent carbon atoms of the benzene ring form a 1,3-
butadienylene linkage, and wherein R5 and R6 represent a
group selected from hydrogen, loweralkyl and together
alkylene of 4 to 5 carbon atoms; said process comprising:
(a) when R5 and R6, as defined above, are hydrogen,
amidoalkylating a compound of the general formula:
<IMG> V
wherein R2, R4, X1 and X2 are as defined above, with an
amidoalkylating agent, including 2-chloro-N-(hydroxy-
methyl)acetamide, hydrolyzing the amido group of the
amidoalkylated product and, if R3, as defined above, is
not hydroxy, esterifying the hydrolyzed product;
(b) when R5 and R6, as defined above, are not
hydrogen, reacting a compound of the general formula:
49

<IMG> V
wherein R2, R4, X1 and X2 are as defined above, with a
secondary amine of the general formula: R5R6NH and
formaldehyde, and, if R3, as defined above, is not hydroxy,
esterifying the product.
2. A compound of the general formula:
<IMG> VI
wherein R2 represents a group selected from hydrogen, halo,
loweralkyl and CH2NH2, R3 represents a group selected from
hydroxy, alkoxy, branched alkoxy and adamantyloxy, R4 represents
a group selected from hydrogen and loweralkyl, and X1 and X2
represent a group selected from loweralkyl, halo and when
substituted on adjacent carbon atoms of the benzene ring
form a 1,3-butadienylene linkage, and a pharmaceutically
acceptable salt thereof, when prepared by the process defined
in claim 1(a), or an obvious chemical equivalent thereof.
3. A compound of the general formula:
<IMG> VII
wherein R1 represents CH2NR5R6, R2 represents a group selected

from hydrogen, halo, loweralkyl and CH2NR5R6, R3 represents
a group selected from hydroxy, alkoxy, branched alkoxy and
adamantyloxy, R4 represents a group selected from hydrogen
and loweralkyl, and X1 and X2 represent a group selected
from loweralkyl, halo and when substituted on adjacent
carbon atoms of the benzene ring form a 1,3-butadienylene
linkage, and wherein R5 and R6 represent a group selected
from loweralkyl and together alkylene of 4 to 5 carbon
atoms, and a pharmaceutically acceptable salt thereof,
when prepared by the process defined in claim 1(b), or an
obvious chemical equivalent thereof.
4. A process for the preparation of a compound of
the general formula:
<IMG> VIII
wherein R2 represents a group selected from hydrogen, halo,
loweralkyl and CH2NH2, R3 represents a group selected from
hydroxy, alkoxy, branched alkoxy and adamantyloxy, R4 represents
a group selected from hydrogen and loweralkyl, and X1 and X2 represent a
group selected from loweralkyl, halo and when substituted on adjacent car-
bon atoms of the benzene ring form a 1,3-butadienylene linkage; said process
comprising: amidoalkylating a compound of the general formula:
<IMG> IX
wherein R2, R4, X1 and X2 are as defined above, with an
amidoalkylating agent, including 2-chloro-N-(hydroxymethyl)acetamide,
hydrolyzing the amido group of the amidoalkylated product and,
51

?f R3, as defined above, is not hydroxy, esterifying the
hydrolyzed product.
5. A process as defined in claim 4, wherein R2
represents CH2NH2, R3 represents ethoxy, R4 represents
hydrogen, and X1 and X2 represent chloro.
6. A process as defined in claim 4, wherein R2 and
R4 represent hydrogen, R3 represents a group selected from
hydroxy, ethoxy and isopropoxy, and X1 and X2 represent
chloro.
7. A process as defined in claim 4, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, and X1 and X2
represent methyl.
8. A process as defined in claim 4, wherein R2
represents methyl, R3 represents ethoxy, R4 represents
hydrogen, and X1 and X2 represent chloro.
9. A process as defined in claim 4, wherein R2
represents chloro, R3 represents ethoxy, R4 represents
hydrogen, and X1 and X2 represent chloro.
10. A process as defined in claim 4, wherein R2
represents iodo, R3 represents ethoxy, R4 represents hydrogen,
and X1 and X2 represent chloro.
11. A process as defined in claim 4, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, and X1 and X2
represent chloro.
12. A process as defined in claim 4, wherein R2 and
R4 represent hydrogen, R3 represents hydroxy, and X1 and X2
represent chloro.
13. A compound of the general formula:
<IMG> VIII
52

wherein R2 represents a group selected from hydrogen, halo,
loweralkyl and CH2NH2, R3 represents a group selected from
hydroxy, alkoxy, branched alkoxy and adamantyloxy, R4 represents
a group selected from hydrogen and loweralkyl, and X1 and X2
represent a group selected From loweralkyl, halo and when
substituted on adjacent carbon atoms of the benzene ring form
a 1,3-butadienylene linkage, and a pharmaceutically acceptable
salt thereof, when prepared by the process defined in claim 4,
or an obvious chemical equivalent thereof.
14. A compound as defined in claim 13, wherein R2
represents CH2NH2, R3 represents ethoxy, R4 represents
hydrogen, and X1 and X2 represent chloro, and a pharmaceutically
acceptable salt thereof, when prepared by the process defined
in claim 5, or an obvious chemical equivalent thereof.
15. A compound as defined in claim 13, wherein R2 and
R4 represent hydrogen, R3 represents a group selected from
hydroxy, ethoxy and isopropoxy, and X1 and X2 represent
chloro, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 6, or an obvious
chemical equivalent thereof.
16. A compound as defined in claim 13, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, and X1 and X2
represent methyl, and a pharmaceutically acceptable salt
thereof, when prepared by the process defined in claim 7,
or an obvious chemical equivalent thereof.
17. A compound as defined in claim 13, wherein R2 represents
methyl, R3 represents ethoxy, R4 represents hydrogen, and X1
and X2 represent chloro, and a pharmaceutically acceptable
salt thereof, when prepared by the process defined in
claim 8, or an obvious chemical equivalent thereof.
18. A compound as defined in claim 13, wherein R2
represents chloro, R3 represents ethoxy, R4 represents hydrogen,
and X1 and X2 represent chloro, and a pharmaceutically acceptable
53

salt thereof, when prepared by the process defined in claim
9, or an obvious chemical equivalent thereof.
19. A compound as defined in claim 13, wherein R2
represents iodo, R3 represents ethoxy, R4 represents hydrogen,
and X1 and X2 represent chloro, and a pharmaceutically accept-
able salt thereof, when prepared by the process defined in
claim 10, or an obvious chemical equivalent thereof.
20. A compound as defined in claim 13, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, and X1 and X2
represent chloro, and a pharmaceutically acceptable salt
thereof, when prepared by the process defined in claim 11,
or an obvious chemical equivalent thereof.
21. A compound as defined in claim 13, wherein R2 and
R4 represent hydrogen, R3 represents hydroxy, and X1 and X2
represent chloro, and a pharmaceutically acceptable salt
thereof, when prepared by the process defined in claim 12,
or an obvious chemical equivalent thereof.
22. A process for the preparation of a compound of the
general formula:
<IMG> X
wherein R2 represents a group selected from hydrogen, halo,
loweralkyl and CH2NR5R6, R3 represents a group selected from
hydroxy, alkoxy, branched alkoxy and adamantyloxy, R4 represents
a group selected from hydrogen and loweralkyl, R5 and R6
represent a group selected from loweralkyl and together
alkylene of 4 to 5 carbon atoms, and X1 and X2 represent a
group selected from loweralkyl, halo and when substituted on
adjacent carbon atoms of the benzene ring form a 1,3-butadienylene
54

linkage; said process comprising: reacting a compound of the
general formula:
<IMG> IX
wherein R2, R4, X1 and X2 are as defined above, with a secondary
amine of the general formula: R5R6NH and formaldehyde, and,
if R3, as defined above, is not hydroxy, esterifying the product.
23. A process as defined in claim 22, wherein R2
represents CH2N(CH3)2, R3 represents a group selected from
ethoxy and isopropoxy, R4 represents hydrogen, R5 and R6
represent methyl, and X1 and X2 represent chloro.
24. A process as defined in claim 22, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, R5 and R6 represent
methyl, and X1 and X2 represent chloro.
25. A process as defined in claim 22, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, R5 and R6 represent
ethyl, and X1 and X2 represent chloro.
26. A process as defined in claim 22, wherein R2 represents
chloro, R3 represents ethoxy, R4 represents hydrogen, R5 and
R6 represent methyl, and X1 and X2 represent chloro.
27. A process as defined in claim 22, wherein R2 represents
CH2N(CH3)2, R3 represents methoxy, R4 represents hydrogen,
R5 and R6 represent methyl and X1 and X2 represent chloro.
28. A process as defined in claim 22, wherein R2 represents
CH2N(CH3)2, R3 represents octyloxy, R4 represents hydrogen,
R5 and R6 represent methyl, and X1 and X2 represent chloro.
29. A process as defined in claim 22, wherein R2 represents
CH2N(CH3)2, R3 represents pentoxy, R4 represents hydrogen, R5
and R6 represent methyl and X1 and X2 represent chloro.

30. A process as defined in claim 22, wherein R2
represents CH2N(CH3)2, R3 represents isobutoxy, R4 represents
hydrogen, R5 and R6 represent methyl and X1 and X2 represent
chloro.
31. A compound of the general formula:
<IMG> X
wherein R2 represents a group selected from hydrogen, halo,
loweralkyl and CH2NR5R6, R3 represents a group selected from
hydroxy, alkoxy, branched alkoxy and adamantyloxy, R4 represents
a group selected from hydrogen and loweralkyl, R5 and R6
represent a group selected from loweralkyl and together
alkylene of 4 to 5 carbon atoms, and X1 and X2 represent a
group selected from loweralkyl, halo and when substituted on
adjacent carbon atoms of the benzene ring form a 1,3-butadienylene
linkage, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 22, or an obvious
chemical equivalent thereof.
32. A compound as defined in claim 31, wherein R2 represents
CH2N(CH3)2, R3 represents a group selected from ethoxy and
isopropoxy, R4 represents hydrogen, R5 and R6 represent methyl,
and X1 and X2 represent chloro, and a pharmaceutically accept-
able salt thereof, when prepared by the process defined in
claim 23, or an obvious chemical equivalent thereof.
33. A compound as defined in claim 31, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, R5 and R6
represent methyl, and X1 and X2 represent chloro, and a
pharmaceutically acceptable salt thereof, when prepared by
the process defined in claim 24, or an obvious chemical
56

equivalent thereof.
34. A compound as defined in claim 31, wherein R2 and
R4 represent hydrogen, R3 represents ethoxy, R5 and R6
represent ethyl, and X1 and X2 represent chloro, and a
pharmaceutically acceptable salt thereof, when prepared by
the process defined in claim 25, or an obvious chemical
equivalent thereof.
35. A process as defined in claim 31, wherein R2
represents chloro, R3 represents ethoxy, R4 represents
hydrogen, R5 and R6 represent methyl, and X1 and X2 represent
chloro, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 26, or an obvious
chemical equivalent thereof.
36. A compound as defined in claim 31, wherein R2
represents CH2N(CH3)2, R3 represents methoxy, R4 represents
hydrogen, R5 and R6 represent methyl, and X1 and X2 represent
chloro, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 27, or an obvious
chemical equivalent thereof.
37. A compound as defined in claim 31, wherein R2
represents CH2N(CH3)2, R3 represents octyloxy, R4 represents
hydrogen, R5 and R6 represent methyl, and X1 and X2 represent
chloro, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 28, or an obvious
chemical equivalent thereof.
38. A process as defined in claim 31, wherein R2
represents CH2N(CH3)2, R3 represents pentoxy, R4 represents
hydrogen, R5 and R6 represent methyl, and X1 and X2 represent
chloro, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 29, or an obvious
chemical equivalent thereof.
39. A compound as defined in claim 31, wherein R2
represents CH2N(CH3)2, R3 represents isobutoxy, R4 represents
57

hydrogen, R5 and R6 represent methyl, and X1 and X2 represent
chloro, and a pharmaceutically acceptable salt thereof, when
prepared by the process defined in claim 30, or an obvious
chemical equivalent thereof.
58

Description

~g~3
--1 .
Detailed Description of the Invention
The present invention is directed to compounds
of the formula
X X
2 1 2
/R5
wherein Rl is CH2N \ wherein R5 and R6 are hydrogen,
loweralkyl or together are alkylene of 4 or 5 carbon atoms,
R2 is hydrogen, halo, haloloweralkyl, loweralkylt
/R5
loweralkoxy, loweralkylthio or C~2N \ wherein R5 and R6
are as previously defined~
R3 is hydroxy, alkoxy, branched alkoxy,
adamantyloxy, morpholino, amino or amino substituted by
loweralkyl or alkylene of 4 or 5 carbon atoms,
R4 is hydrogen or loweralkyl, and
Xl and X2 are hydrogen, loweralkyl, halo or when
substituted on adjacent carbon atoms of the benzene ring.
form a 1,3-butadienylene linkage, with the proviso that
Xl and X2 are not both hydrogen, and pharmaceutically
acceptable salts tnereof. The compounds are useful in.
increasing diuresis in warmblooded animalsO
The compounds of formula I may be further
classified as having the formula
5 ~ N - 2
~O- ~ C ~ - OCHCR3 II
R2 Xl X2

wherein R2 is hydrogen, halo, haloloweralkyl, loweralkyl,
loweralkoxy or loweralkylthio,
R3 is hydroxy, loweralkoxy, branched loweralkoxy,
adamantyloxy~ morpholino, amino or amlno substituted by
loweralkyl or alkylene of 4 or 5 carbon atoms,
R4 is hydrogen or loweralkyl,
R5 and R6 are hydrogen, loweralkyl or together are
a].kylene of 4 or 5 carbon atoms, and
Xl and X2 are hydrogen, loweralkyl, halo or when
substituted on adjacent carbon atoms of the benzene ring
form a 1,3-butadienylene linkage, with the proviso that
Xl and X2 are not both hydrogen or of the formula
R~' ~ ~ C ~ OCHCR3 III
5 \ ~
~- - H Xl ~2
. wherein R3 is hydroxy, alkoxy, branched alkoxy,
adamantyloxy, morpholino, amino or amino substituted by .
loweralkyl or alkylene of 4 or 5 carbon atoms,
R4 is hydrogen or loweralkyl,
R5 and R6 are hydrogen, loweralkyl or together are
alkylene o~ 4 or 5 carbon atoms, and
Xl and X2 are hydrogen, loweralkyl, halo or when
substituted on adjacent carbon atoms of the benzene ring
form a l,3-butadienylene linkage, ~ith the proviso that
Xl and X2 are not both hydrogen.
The term "loweralkyl" as used herein refers to
straight or branched chain alkyl radicals containing from
1 to 6 carbon atoms including but not limited to methyl,
ethyl, _-propyl, iso-propyl, n-butyl, sec-butyl,
2-methyhexyl r _-pentyl, l-methylbutyl, 2,2-dimethylbutyl,
2-methylpentyl, 2,2-dimethylpropyl, _-hexyl and the likeO
.
.

g~3
--3--
The term "loweralkoxy" as used herein refers
to straight or branched chain alkyl radicals containing
from 1 to 6 carbon atoms, attached to an oxygen atom.
The term "halo" as used herein refers to chloro,
bromo, fluoro and iodo.
The term "pharmaceutically acceptable salts"
includes non-toxic acid addition salts of the compounds of
Formulas II or III which are generally prepared by reacting
the free base with a suitable organic or inorganic acid.
Representative salts include the hydrochloride~
hydrobromide, sulfate, b~sulfate, acetate,
oxalate, valerate, oleate, palmitate, stearate,
laurate, bora~e, benzoate, lactate, phosphate, tosylate,
citrate, maleate, fumarate, succinate, tartrate, napsylate,
and like salts. Also included are metallic salts such
as the sodiu~ or potassium salt of the acid.
The present compounds may be administered to
warm-blooded animals orally or parenterally. They can
generally be adminiskered with a pharmaceutical carrier.
The term "pharmaceutical carrier, 1I for the purpose of the
present invention, is intended to refer to any medium that
is suitable for the preparation of a dosage unit form,
and thus includes the tablet medium or a pharmaceutically
acceptable vehicle or solvent such as is ordinarily used in
the preparation of intravenous or intramuscular solutions.
A pharmaceutical composition containing the com-
pound can be administered to warm-blooded animals in
parenteral or oral dosage form. For oral administration,
amounts of from about 0.1 to 200 mg/kg per day per patient
are useful, with the total dose of about 3 gms. per day
being a suitable range for large animals, including humans.
The whole dosage range described increases the total
urinary excretion from about 2 to about 10 fold in most
animals. From these figures, it is apparent that the new
diuretic compounds are particularly effective in increasing
urinary excretion in most animals.

_4_
For all dosage forms, the above exemplified
compounds can be placed in capsules, formulated into
pills, wafers or tablets in conventional fashion together
with pharmaceutical carriers well known in the art
Tablets may be prepared for immediate release of the
active compound or they may be made enteric, i.e.,
whereby the active ingredient is released slowly over
a period of several hours from within the intestinal
tract.
In order to illustrate the manner in which the
above compounds may be prepared and the properties of the
compounds, reference is made to the followin~ examples,
which, however, are not meant to limit or restrict the
scope of the invention in any respect
The following is a general procedure for the
preparation of mono and bis dialkylaminomethyl derivatives of
2,3-dichloro-4-(4'-hydroxybenzoyl)phenoxyacetic acid.
2,3-Dichloro-4~4'-hydroxybenzoyl)phenoxyacetic
acid, prepared as described in U.S. Patent 4,058,559,
issued November 15~ 1~77, is slurried with ethanol
(l.l /mole of acid). 2 Moles of secondary amine is added
to the slurry in one portion. The reaction mixture is
stirred to give a solution to which is added a mixture
of 1 mole formaldehyde and 2 moles secondary amine if
"mono" product is desired. 2.5 Moles formaldehyde and
3 moles secondary amine is added if the "bis" product is
desired. The reaction mixture is heated to reflux for 16
to 24 hours, cooled to give product. If product does not
precipitate, the reaction solution is concentrated in vacuo
to give a glass. The glass is taken up in water, made acid
(pH about 4), to give a solid on standing. The crude solid
- is recrystallized from a suitable solvent to give product.
~ .

9~6~3
-5-
EX~MPLE 1
Ethyl 2,3-Dichloro-4-(4'-hydroxybenzoyl)phenoxyacetate
85.38 g. (0.~5 mole) of 2,3-dichloro 4-(4'-
hydroxybenzoyl)-phenoxyacetic acid, 34.5 g. (0.75 mole)
S of ethanol, and lO0 ml. of ethylene dichloride, using
3.5 ml. of sulfuric acid as the catalyst were mixed and
refluxed with stirring overnight according to the pro-
cedure of Clinton and Laskowski, J.A.C.S. 70 3135, 1948.
The acid gradually went into solution. The reaction
layer was cooled, separated and the organic layer washed
successively with water, twice with KHCO3 solution and
finally with water. The dried ethylene dichloride was
evaporated to dryness to give an oil which solidified to
give 86 g. crude ester on trituration with pentane ana
filtering; m.p. 127-9 (93~ yield). This material was
used without further purification in subsequent experi-
ments.
EXAMPLE 2
Ethyl 2,3-dichloro-4-~(3'-chloro-4'-hydroxy)benzoyl~-
_ phenoxyacetate
A mixture of 50 ml. ethylene dichloride and
9.2 g. (Q.025 mole) of ethyl 2,3-dichloro-4-(4'-hydroxybenzoyl)~
phenoxyacetate was treated with 2.5 g. (0.03 mole)
of SO2C12. The mixture was heated on a steam bath at
reflux for 6 hours. The solvent was removed to give a
white solid. This was collected with the aid of ether to
give 8.5 g. of a solid; m.p. 135-40. Recrystallization
with tolene with Darco* gave 4.5 g of the product; m.pO
15~-155.
Analysis Calcd. for: C17Hl3C13O5 = 403-65
C, 50.59; H, 3.24; Cl, 26.35
Found: C, 50.55; H, 3.12; C1, 25.80
EXAMP~E 3
2~3-Dichloro-4-[l~3'-chloro-4'-hydroxy)benzoyl]phenoxy-
acetic acid
.. _
A solu~ion of 10.09 g. (0.025 mole) of ethyl
2,3-dichloro-4-[~3'-chloro-4'-hydroxy)benzoyl]phenoxyacetate
* trade mark

--6--
in 37.5 ml. of 2N NaOH (3 g. in 37.5 ml. H20) was stirred
and heated at 90-98 for 1-1/4 hours. The solution was
cooled to about 50 and acidified with 6N HCl. A white
solid precipitated which was filtered, washed with water
and dried to give 9.0 g.; m.p. 104-111 (dec.) Recrystal-
ization with hot acetic acid and adding water to cloudy
point. Cooling gave product, m.p. 190-191, 8.69 g.
(92.5~).
EXAMPLE 40 Ethyl-2,3-dichloro-4-(4'-methoxybenzoyl)phenoxy-a-methyl-
_ _ acetate
A solution of 9.96 (0.055 mole) of ethyl 2-bromo-
propionate in 12 ml. of acetone was added over a period of
2 hours to a stirred, refluxing mixture of 14.85 g. (0.05
mole) of 2,3-dichloro-4-(4-methoxybenzoyl)phenol and
7.60 g. (0.055 mole) of powdered anhydrous potassium car-
bonate in 200 ml. of acetone. After the addition, the mix-
ture was refluxed for 20 hours and the hot mixture was
filtered. The filtrate was evaporated ln vacuo and the
residue was taken up in 250 ml. of chloroform. The
chloroform solution was washed with 10~ aqueous potassium
carbonate, water, dried over anhydrous sodium carbonate
and evaporated in vacuo to give the product.
2,3-Dichloro-4-(4'-hydroxybenzoyl)phenoxy-~-methylacetic
acid _ _
A mixture of 19.34 g. of ethyl 2,3-dichloro-
4-(4'-methoxybenzoyl)phenoxy-~-methylacetate and 330 ml.
of 48~ hydrogen bromide was rapidly stirred and refluxed
for 21 1/2 hours. The mixture was cooled in an ice bath
and diluted with 415 ml. of water, wi-th stirring. The
product was filtered and washed with ice water; m.p.
208-212.

--7--
EXAM2LE 6
Ethyl 2,3-dichloro-4-[(3'-dimethylaminomethyl-4'-hydroxy)
benzoyl]phenoxyacetate hydrochloride _ _ -
A suspension of 2,3-dichloro 4-(4'-hydroxy-
benzoyl)phenoxyacetic acid, 34 g. (0.1 mole) was takeninto solution by adding 20 ml. of 40% aqueous dimethyl-
amine (0.2 mole). This solution was treated dropwise with
a mixture of 20 ml. of dimethylamine and 10 ml. of 37%
formaldehyde. The reaction solution was heated at reflux
overnight. The reaction was co;ncentrated to give a glass.
This was taken up in DMF but no product precipitated. The
DMF was removed _ vacuo and the residue taken up in water.
The water solution deposited an off-white solid. Yield
of crude solid was 22.5 g., m.p. 250-4 dec. The crude
solid was triturated with hot DMF and cooled. The product
was vacuum dried to give 17 g., m.p. 265-268 dec. This
material was converted to the ethyl ester by suspending
in 300 ml. ethanol and adding 20 ml. (excess) thionyl
chlor,ide dropwise. This was refluxed overnight. The
solution was concentrated in vacuo to give a solid which
was recrystallized from ethanol to yield 19.0 g. product,
m.p. 186-188, 41% of theory.
Analysis Calcd. for C20H22C13No5
C, 51.92; H, 4.79; N, 3.02
25Found: C, 51.67; H, 5.00; N, 3.01
EXAMPLE 7
2,3-Dichloro-4[(3'-dimethylaminomethyl-4'-hydroxy)benzoyl]
~henoxYacetic acid
7,~
To a solution of ethyl 2,3-dichloro-4-~(3'-dimethyl-
aminomethyl-4'-hydroxy)benzoyl]phenoxyacetate hydrochloride
(13 g., 0.028 mole) in 150 ml. formic acid 88%,was added 6.0 g.
(0.061 mole) of methanesulfonic acid. This resulting solu-
tion was heated on a steam bath for about 16 hours. The
solution was concentrated to give a glass. This glass
was taken up in water and treated with NaHCO3 solution
(2~) until the solution became cloudy. Standing gave a
white solid. Yield was 10.5 g. (91~) m.p. 268-70 dec.

-8-
y C18 17Cl2NO5 398.25
c, 54.29; H, 4.30; N, 3.52
Found:C, 5~.55; H, 4.30; N, 3.56
Ethyl 2,3-dichloro-4-[(3'-diethylaminomethyl-4'-hydroxy)
benzo~l]phenoxyac'etate ' ' ' - _
A solution of 18.1 g. (0.03 mole) of ethyl
2,3-dichloro-4-(4'-hydroxy~enzoyl)phenoxyacetate and
4.3 g ~0.033 mole) of N-ethoxymethyl diethylamine in
40 cc. of 1,2-aimethoxyethane (monoglyme) was refluxed
for 4 hours. At the end of this time, the reaction mix-
ture was concentrated and the resulting gum was taken up
in ether and filtered. The ether solution was treated
with ethereal HCl and after filtering and drying 14 g. of
a slightly hygroscopic hydrochloride salt was obtainedO
The product was recrystallized from acetonitrile and
ether mixture, m.p. 115-120.
Analysis Calcd. for C22H25C12NO5 H
C, 53.84; H, 5.34; N, 2.85
20Found: C, 53 35i H, 5.54; N, 3.05
EX~MP~E 9
Ethyl 2,3-dichloro-4-{t3'-(1-pyrrolidinylmethyl)-4'-
hydroxy]benzoyl}phenoxyacetate hydrochloride
To a stirred solution of 11.07 g. (0.03 mole)
~5 of ethyl 2,3-dichloro-4-(4'-hyd.roxybenzoyl)phenoxyacetate
in 50 ml. of etha~ol, cooled in an ice bath, there was
added dropwise of a previously'prepared solution (made by
adding slowly 2.5 ml. tO~033 mole) of 37% formaldehyde
- solution to a stirred solution of 2.14 g. (0.03 mole) of
pyrrolidine in 10 ml. o ethanol, cooled in an ice bath)~
After the addition, the m1xture was refluxed for 4 1/2
hours and'evaporated in vacuo. The residue was extracted
with ether. The ether extract was evaporated in vacuo
and the residue was purified by chromatography on a Florisil*
column (100-200 mesh) and eluted with chloro~orm and then
graded chloroform-ethanol mixtures~ The produce was
,l trade mark

~g8~
isolated as a hydrochloride, m.p 149-152 (from ethanol-
ether).
Analysis Calcd. for C22H~3C12NO5 HCl
C, 54.06; H, 4.95; N, 2.87
5Found: C, 54.18; H, 5.~1; N, 2.84
E~YAMPLE 10
Ethyl 2,3-dichloro-4-[(3'-piperid:inomethyl-4'-hydroxy)
benzoyl]Phenoxyacetate hydrochloride
37% Formaldehyde solution (2.5 ml., 0.33 mole)
was added to a solution of 2.55 g. (0.03 mole) of piperi-
dine in 40 ml. ethanol. To this solution was added 11.07 g.
(0.03 mole) of ethyl 2,3-dichloro-4-(4'-hydroxybenzoyl)-
phenoxyacetate and 20 ml. of ethanol. The mixture was
refluxed for 13 hours and evaporated in vacuo. The
residue was extracted with ethèr. The ether extract was
evaporated and the residue was purified by chromatography
on a Florisil column ~100-200 mesh) and eluted with graded
chloroform-ethanol mixtures. The product was isolated as
a hydrochloride, m.p. 109-111 (dec) (from ethanol-ether)O
Analysis Calcd. for C23H25C12NO5 HCl
- C, 54.94; H, 5.21; N, 2.79
Found: C, 54.97; H, 5.86; N, 2.43
EXAMPLE 11
2,3-Dichloro-4-[(4l-hydroxy-3'-morpholinomethyl)benzoyl]
phenoxyacetic acid
A mixture of morpholine (0.1 mole, 9.0 mI.) and
paraformaldehyde ~0.05 mole, 1.5 g.~ was suspended in 100
ml. of cyclohexane and t-butanol (l:l)u T~e mixture was
heated fox two hours and the water formed was removed
by a D~an-Stark trap. The mixture was treated with 17 g.
l0.05 mole) of 2,3-dichloro 4-(4~-hydroxybenzoyl)phenoxy-
acetic acid dissolved in 50 ml. DMF. After refluxing for
- 16 hours, the solvents were removed in vacuo to give a
solid. This solid was collected with the aid of ethanol
to give 7.5 g~ white tan solid, m.p. 263-265 (dec.) A
second crop of solid was obtained by concentrating the
* trade mark

--10--
mother liquor to dryness. The residue was taken up in
water and neutralized with lN HCl to give 4.5 g. white
solid, m.p. 259-260 dec. The two fractions were combined
and recrystallized from minimum amount of DMF (250 ml.)
and adding water to cloudy point. Yield of solid was
9.o g., m.p. 274-6 dec. Yield was 41% of theory.
y20 1gCl2NO6 440.283
~, 54.56; H, 4.35; N, 3.18
Found: C, 54.33; ~ 4.07; N, 3.71
EXAMPLE 12
Ethyl 2,3-dichloro-4-[(4'-hydro~y-3'-thiomorpholinomethyl)
benzoyl]pheno~_cetate, S,S-dioxide
11.1 g.(0.03 mole) of the ethyl 2,3-dichloro
4-(4'-hydroxybenzoyl)phenoxyacetate 4.056 g. (0.03 mole)
of thiomorpholine sulfone,2.5 g. (0.033 mole) 37~ formalin
and 60 ml. of 3A alcohol were refluxed for 20 hours and
then allowed to set and cool. A gum separated, which was
triturated with ether to give 7 g. of colorless solid,
softened 1~0C, melted at 173-177C. The solid was taken
up in 100 ml. boiling acetone and filtered, then concentra-
ted to 50 ml. and ether was added to cloudiness to yield
6 g. of product, m.p. 184-185C.
Analysis Calcd. for C22H23C12NO7S
C, 50.78; H, 5.23; N, 2.69
25Found: C, 50.50; H, 4.71; N, 3.14
EXAMPLE 13
Ethyl 2,3-dichloro-4-[(4'-hydroxy-3'-morpholinomethyl)
benzoyl3~henoxyacetate, hydrochloride
A suspension of 2,3-dichloro-4~(4'-hydroxy-
3'-morpholinomethyl)benzoyl]phenoxyacetic acid (0.02
mole, 9.0 g.) in ethanol was treated dropwise with 10 ml.
of thionyl chloride. This solution was heated at reflux
for 2 houxs, cooled overnight and concentrated ln vacuo
to give a glass. This glass could not be made to solidify.
The yield of glass was 9.3 g. Yield was 93~ of theory.

9~.;~
--11--`
.
Y C22H24C13N6 504.798
C, 52.35; H, 4.79; N, 2.77
Found: C, 52.22; H, 4.90; N, 2.8g
EXAMPLE 14 2,3-Dichloro-4-[(4'-hydroxy-3' --sarcosylmethyl)benzoyl]-
phenoxyacetic acid
A mixture of sarcosine (0.22 mole, 19.6 g.)
paraformaldehyde (0.11 mole, 3.3 g.), and 100 ml. of
cyclohexane/t-butanol was heated to reflux. To this
mixture was added 2,3-dichloro-4-(4'-hydroxykenzoyl)-
phenoxyacetic acid (O.OS mole, 17 g.) dissolved in 50 ml.
D~. The reaction mixture was refluxed overnight (16 hours)
and the solvents were removed in vacuo to give a gum. This
gum was taken up in water and the solution was made acid
with 6~ HCl to cause precipitation of a solid. This solid
could not be recrystallized from any suitable solvent~
The yield of solid was 3.5 g. (16%), m.p. 230-235dec.
Because of its insolubility, this compound was converted to
its diethyl ester hydrochloride salt in the next step.
EXAMPLE 15
Ethyl 2,3-dichloro-4-[(3'-ethylsarcosylmethyl-4'-hydroxy)-
benzoyl]phenoxvacetate, hydrochloride
A suspension of 2,3-dichloro-4-[(4'-hydroxy-3'-
sarcosylmethyl)benzoyl]phenoxyacetic acid, (3.5 g., 0.008
mole) in 100 ml. ethanol was treated dropwise with 10 ml.
of thionyl chloride. This mixture was heated at reflux
for 16 hours, cooled, concentrated ln vacuo to give a glass
which on drying overniyht ln vacuo at 80 gave a solid.
Yield was 3.6 g., m.p. 198-201rdec.). The solid was
recrystallized by dissolving in ethanol, concentrating to
give a glass and then triturating with hot ethyl acetate
to give 3.0 g. product, m.p. 200-202(dec.).
y c fo~ C23H26C13N7 534.325
C, 51.65; H, 4.90; N, 2.62
Found: C, 51.76i H, 4.93; N, 2.66

~,q~
-12-
Example 16
2,3-Dichloro-4- E (3~-chloro-5'-dimethylaminomethyl-4'-
hydroxy)benzoyll~heno:~y~cetic acid
A mixture of paraforma.ldehyde ~0.05 mol, 1.5 g.)
and 20 ml. (0.2 mole) of 40% aqueous dimethylamine and
~0 ml. each of t-butanol and cyclohexane were refluxed and
water removed with a Dean-Stark trap. This resulting solution
was treated wi~h 8.0 g. (0.02 mole) of 2,3-dichloro-4-~(3'-chloro-
4'-hydroxy)benzoyl]-phenoxyacetic acid and 50 ml. of DMF. This
mixture was refluxed overnight. The solution was concentrated
_ vacuo to give a solid. This solid was col~ected with aid of
ethanol to give 3.0 g. product, m.p. 225-228(dec.). A
second crop was obtained from the ethanol mother liquor,
yield was 5.0 g., m.p. 75-100~dec,l. Secon~ crop solid was
15 dissolved in water and heated to give a cloudy solution. To
this solution was added glacial acetic acid. A white solid
precipitated. This solid was collected and washed with
ethanol and finally with ether to give 4. 0 g. product,
m.p. 221-223~dec.). This solid was recrystallized by dis-
20 solving in aqueous 2% ~HCO3 and precipitating by adding
glacial acetic acid. This solid melted 223-225(dec.) and
gave 2.7 g.
Analysis Calcd~. for C18X16C13N05 = 432.69
C, 49.97; H, 3.73; N, 3.23
Fou~d: C, 49.64; H, 3.79; N, 3.20
.

-13-
Example 17
Ethyl 2,3-dichloro-4-~ (3 ' -ch:Loro-5 '-dimethylaminomethyl-
4'-hydroxybenzoyl]phenoxyacetate, hydrochloride
To a mixture of 3 g. of 2,3-dichloro-4-~(3'-
S chloro-5'-dimethylaminomethyl-4'-hydroxy)benzoyl~phenoxyacetic
acid in 50 ml. of ethanol was added dropwise 6 ml. ~excess~
thionyl chloride. After the addition the mixture was heated
on the ste~m bath to give a solution. The solvent was
removed in vacuo to give a white solid. This was rPcrystallized0 from acetone-ether ~1:1) to give product, m.p. 178-179.5(dec.).
ysis C ~cd.for C~oH21C14~O5 497.~06
C, 48.31; H, 4.26; N, 2.82
Found: C, 48.63; H, 4.38; N, 2.92

-14-
Example 18
2,3-Dichloro-4-{~3',5'-bis(dimethylaminomethyl)-4'-
hydroxy]benzoyl}~henoxyacetic acid! dihydrochloride
A solution of 40~ aqueous dimethylamine ~0.4 mole),
40 ml. and 37% formaldehyde solution (0.2 mo'e) 20 ml. was
treated with 2,3-dichloro-4~4~-hydroxyhe~zoyl)phenoxyacetic
acid tO.05 mole) 17 g. This mixture was heated on a st~am
bath to give a light amber solution. This solution was
heated on a steam bath overniyht. The amber .solution was
concentrated in vacuo an~ azeotroped with toluene (50 ml.)
to give a grey-brown solid. Thi~ crude solid was triturated
with ethanol lhot) and ~ollected on a Bucher funnel to give
yellow solid. This was air dried to give 23.5 g., m.p. 165-
170(dec.). Recrystallizing first from DMF and then from
ethanol-water (1:1~ and finally from DMF gave 13.~ g.,
m.p. 215-217(dec.).
Analysis Calcd- for ~21H24C12N2O5-1-5 H20 = 411-457
C, 52.29; ~, 5.64; ~, 5.80
Found: C, 52.07; H, 5.53; N, 5O95
The base above (2 g.) was converted to the dihydro-
chloride salt as follows: The base (2 g.~ was dissol~ed in
glacial acetic acid and etheral HCl was added in excess.
The flask was warmed on steam bath to drive off excess HC1
and the dihydrochloride salt was precipitated by adding
ether to give a gum. This gum was take~ up in acetonitrile
to give on cooling a white solid, m.p. 221-223~dec.).
Yield was 2.3 g.
Analysis Calcd- for C21X26C14N25 528-263
C, 47.75; H, 4.96; N, 5.30;
Cl, 26.85
Found~ C, 47.89; H, 5.09; N, 5.19;
C1, 27.11

Example 19
Ethyl 2,3-dichloro-4~[3',5'-bls-(dimethylaminomethyl)-
2,3-Dichloro-4{~3',5'-bis-(dimethylaminomethyl)
4'-hydroxy]benzoyl}phenoxyacetic acid (54 g., 0.13 mole) was
placed into a 1 liter round bottom, three-necked ~lask,
equipped with a mechanical stirrer, an additional funnel and
a reflux condenser. To this flask was introduced 500 ml. of
absolute N.F. ethanol. The stirred suspension was treated
with 50 ml. (0.7 mole) thionyl chloride in a slow steam over
a 15 minute period. The heat of reaction caused refluxing
and reflux was maintained by heating on a steam bat~.
Reflux was continued for 2-1/2 hours. Th~ mixture was
cooled in an ice water bath to give on collection and washing
first with ethanol and finally with ethyl ether a white
solid ~platelets). These were dried in vacuo to give 59 g.
(8-2%) product, m.p. 208-210~(dec.). Recrystallizing with
1 liter ethanol containing 10 ml. of thionyl chloride two
additional times gave product, m.p. 222-224(dec.). Yield0 of final purified product was 23.5 g. (33~).
Analysis Calcd. or C23H28C12N2O5
C, 49.66; H, 5.44; N, 5.05
Found: C, 49.74, H, 5.68; N, 5.08

-16-
Example 20
Ethyl 2,3-dichloro-4-{~3',5'-bis-(dimorpholi~omethyl)-
4'-hydroxy]benzoyl}phenoxy
A mixture of morpholine ~about 0.4 mole, 36 ml.)
and paraformaldehyde (O.22 mole, 6.6 g.) in a solution of
100 ml. cyclohexane and 100 ml. t-butanol was heated to
reflux on an oil bath. The water formed was removed by a
Dean-Stark trap. After the theoretical amount of water had
been removed (about 2 hours), the flask was allowed to cool
and a solution of 17 g. (0.05 mole~ of 2,3-dichloro-~(4'-
hydroxy)be~zoyl]phenoxyacetic acid in 50 ml. of DMF was
added. The reaction mixtu-re was refluxed overnight. The
reaction was ~ooled in an ice bath to give 12.0 g. (44%) o
product, m.p. 175-185(dec.). This product was recrystal-
liæed ~rom absolute ethanol to give 9 g. produc~, m.p. 188-
l91~tdec.). This solid was suspended in ethanol and 10 ml.
~excess) of thionyl chloride was added dropwise with stirring.
The solu~ion was re~luxed for ~ hours, cooled and concentrated
in vacuo to give a glass. This glass could not be made to
crystallize. Yield of glass was 10 g. (93%).
Analysis Calcd- for C27~34C14N~7 = 640.39
C, 50.64; H, 5.35; N, 4.38
Found: C, 50.45; H, 5.50; N, 4.27

~L4gB~
Example :21
2, 3-Dichloro-4-{ ~3 ', 5 ' -bis (l-pyrrolidir~ylmethyl) -
4 ' -hydro~] ben~ox~ }~-~
37% Formaldehyde solution (7.5 ml., 0.1 mole) was
added dropwise to a stirred sulution of 17.05 g. ~0.05 mole)
of 2,3-dichloro-4-(4'-hydroxybenzoyl)phenox~acetic acid and
14.22 g. (0.2 mole) of pyrrolidine in 80 ml. o ethanol.
The mixture was stirred and refluxed ~or 6 hours and more
37~ ~ormaldehyde solution (3.75 ml.) wa added dropwise a~d
the mixture was refluxed for 18-1/2 hours. After evaporation
~n vacuo~ the residue was triturated with ether and recrystal-
li~ed from 2-butanone-ethanol, m.p. 233-236.

~g~
-18-
xample 22
Ethyl ?,3-dichloro-4-{[3',5'-bis(l-pyrrolidinylmethyl)-
4~-hydroxy]benzoyl}phen
Thionyl chloride (5.71 g., 0.048 mole) was added
dropwise to a ~tirred suspension of 4.85 (0.0096 mole) of
2,3-dichloro-4-{~3',5'-bis(l-pyrrolidinylmethyl)-4'-hydro~y]-
~enzoyl~phenoxyacetic acid in lO0 ml. of ethanol, cooled in
an ice bath. After the addition, the mixture was refluxed
for 3 hours and evaporated to dryness in vacuo. The residue
10 was ~riturated with e~her and recrystallized from ethanol~
m.p. 171-173(dec.).
Analysis Calcd. for C27~3~C12N205 2HCl
C, 53.30, ~, 5.63; N, 4.61
Found: C, 52.70; H, 5.75; N, 4.48

--19--
Ex2mple 23
2,3 Dichloro-4-{[3',5'-bis(piperidinomethyl)-4'~
hydroxy]benzoyl}phanoxyacetic acid
37~ Formaldehyde solution (7.5 ml., 0.1 mole) was
added dropwisa to a stirred solution of 17.05 g. (0.05 mole)
of 2,3-dichloro-4-(4'-hydroxybenzoyl)phenoxyace~i~ acid and
17.03 g. (0.2 mole) of piperidine in 80 ml. of ethanol. The
mixture was heated at 95-100 for 2-1/2 hours and more 37%
form~ldehyde solution (3.75 ml.) was addPd and the mixture
10 was kept at 96 for 15 hours. After evaporation in vacuo,
the residue wzs t~iturated with ether and recrystallized
from dimethylformamide; m.p. 201-205.

-20-
EXam~l~ 24
Ethyl 2,3-dichloro-4-{[3',5'-bis~piperidinomethyl)-
4'-hydroxy]benzo~l}~henoxya ~
Thionyl chloride (9.64 g., 0.061 mole) was added
S dropwise to a stirred suspension o~ 8.70 g. (0.0162 mole) of
2,3-dichloro-4-{~3',51-bis~piperidinomethyl~-4'-hydroxy]-
benzoyl}phenoxyacetic acid in 150 ml. of e~hanol, cooled in
an ice bath. The mixture was refluxed for 3-1/2 hours and
evaporated to dryness in vacuo. The residue was triturated
with ether and recrystallized ~rom ethanol, m.p. 185-188(dec.).
Analysis Calcd. for C2~H36C12N205 2HCl
C, 54.72; H, 6~02; N, 4.40
Found: C, 53.99; H, 6.06; N, 4~35
- , ~

;33
Exa~m~le 25
Ethyl 2,3-dichloro-4-{[3',5''-bis(thiomorpholinomethyl)-
A mixture of 8.1 g. (0.06 mole) of thiomorpholine
S sulfone and 1.8 g. (0.06 mole) of formalin (5 g. of a 37%
solution) were mixed while cooling to form the in~ermediate
me~hylol compound. To this mixture was added 5.55 g. (O.15 mole)
of [2,3-dichloro-4-(4'-hydroxybenzoyl)phenoxy]acetic acid
ethyl ester in 30 ml. of 3A alcohol. The mixture was stirred
and refluxed for 23 hours. The reactio~ mixture was filtered
while still hot. The resulting solid was washed well with a
50/50 mixture of alcohol and ether and finally with ether.
8.5 g. was obtained, m.p. 228-230 ~81% yield). The basic
~annich product was recrystalli2ed from 2-bu~anone, m.p`.,228-
230.
Analysis Calcd. for C27~32C12~09S2
C, 48.87; H, 4.86; N, 4.22
Found: C, 48.74; H, 5.02; N, 4.05
.

-22-
Example ~6
Esters of 2,3-dichloro-4-{[3',~ is(dimethylaminomethyl)-
4'-h~droxy]benzoyl~phenoxyacetic acid
The esters are preparecl in the following manner.
Thionyl chloride (0.63 ml.) was added to a slurry o~ 2,3-
dichloro-4-~3',5'-bis(dimethylaminome~hyl)-4'-hydroxybenz~yl]-
phenoxyacetic acid (2 g~) in dry dimethylformamide (15 ml.)
with stirring under a nitrogen atmosphere. The solid dissolved.
After 5 minutes the alcohol (amount specified below~ was added.
The solution was heated at 70-75 for 16 - 18-1/2 hours.
The solution was cooled and concentrated in ~acuo to give ~
white solid. The solid was dissolved in a methanol/dichloro-
methane/concentrated ammoni~n hydroxide solution in the
ratio of ~0/~011. A white precipitant of ammo~ium chloride
formed. The solution was filtered thr~ugh silica gel (10 g.,
80 - 230 mesh) using the same solvent ratio to elute. The
sol~ent was removed in vacuo to yield a gum. The gum was
dissolved in methylene chloride and treated with anhydrous
hydroge~ chloride gas with cooling. The resul~ant white
solid was isolated by filtration. The solid was dried in
vacuo to yield pure ester dihydrochloride sal~.

-23-
Amount
Alcohol Used Yield Melting Point
Octanol 2.77 ml. 1.151 g./40.9~ 205-6 Dec. t
Ben~yl alcohol1.83 ml. 0.928 g./33.9% 202-4 Dec.
n-Pentanol 1.90 ml. 0.950 g./36% 210-12Dec. ~
2,2-Dimethylpropanol 1.547 ~. 0.910 g./34.6~ 226-8 Dec. t
Cyclohexylmethanol 2.16 ml. 2.250 g./81.9~ 230-1 Dec.
Benzhydrol 3.2353 g. 0.897 g./29.4% 206-7 Dec. t
Elemental Analysis: Octyl ester
10Calculated for: C29H42C14N2O5
C, 54.38; H, 6.61; N, 4O37; Cl, 22.14
Found: C, 54.62; H, 6.81; N, 4.37; Cl, 22.50
Elemental Analysis: Benzyl ester
Calculated for: C28H32C14N2O5
15C, 54.38; H, 5.22; ~, 4.53; Cl, 22.93
Found: C, 54.00; H, 5.35; N, 4.44; Cl, 24.30
Elemental Analysis: n-Pentyl ester
Calculated for: C26H36C14N2O5
C, 52.19; H, 6.06; N, 4.68; Cl, 23.70
20Found: C, 52.37; H, 6.28; N, 4.76, Cl, 23.92
Elemental ~nalysis: 2,2-Dimethylpropyl ester
Calculated for: C26H36C14N2O5
C, 52.19; Hl 6.0~; N, 4.68; Cl, 23.70
Found: C, 52.07; H~ 6.31; N~ 4.82; Cl, 23.53
25 El~mental Analysis: Cy~lohexylmethyl ester
Calculated for: C28~38C14N2O5 1~ 2
C, 53.09; H, 6.21; N, 4.42; Cl, 22.39
Fol~nd: C, 52.73; ~, 6.12; N, 4.43; Cl, 21.77
Elemen~al Analy!3is: Benzhydryl es~er
30Calculated for: C34H36C14N2O5
C, 53.80, H, 5.23; N, 4.03; C1, 20.42
Folmd: C, 58.84; H, 5.34; N, 3.96; Cl, 22.02
.

~49~3
-24-
Exam~le 27
Methvl 2,3-dichloro~4-{~3'~5l-bis(dimethylaminomethyl)-
4'-hydroxy]benzoyl~phenoxyacetate dihydrochloride
Thionyl chloride (2.6 ml.) was added dropwise to a
stirred slurry of 2,3-dichloro-4 {~3',5'-bis(dimethylamino-
methyl~4'-hydroxy]benzoyl}phenoxyacetic acid (8 g.) in dry
dimethylformamide (1 ml.) and dry methanol (60 ml.) under a
~itrogen abmosphere. The mixture was heated at reflux for
6 hours. The solution was cooled and the solvent removed in
vacuo to yi~ld a white solid. The solid was recrystallized
from methanol to yield 2.75 g. (28.9%) of the pure methyl
ester dihydrochloride; m.p. 214-215.
Analysis Calcd- for C22H28C14N2o5
C, 48.73; H, 5.20, N, 5.17: Cl, 26.15
Found- C, 48.83; ~, 5.39; N, 5.24; Cl, 26.36

8~
-25-
Example 28
Ethyl 2,3-dichloro-4-{~3',5'-bis(dimethylaminomethyl)-
4'-hydroxy3benzoy~ henoxYacetate dihydrochloride
Thionyl chloride t50 ml.~ was added over 15 minutes
to a stirred slurry of 2,3-dichloro-4-{~3',5'-bis(dimethyl-
aminomethyl)-4'-hydroxy~benzoyl}phenoxyacetic acid (54 g.
in absolutP ethanol (500 ml.). The addition brought the
solution to reflux. The refluxing was maintained by extPrnal
heating for 1-1/2 hours. ~he mixture was cooled in an ice
bath and filtered. The solid was washed with cold ethanol
and aiethyl ether. The crude solid was recrys~allized twice
from ethanol (1 liter) containing thionyl chloride (10 ml.)
to gi~e 23.5 g. (33~) of the pure ethyl ester dihydrochloride;
m.p. 222- 24.
Analysis Calcd. for C23H2~C14N~05
C, 49.66; ~, 5~44; N, 5.05
Found: C, 4~7.74; H7 5.68; N, 5.08
. .

~980~
-2~-
E'xample 29
Isopropyl 2,3-dichloro-4-{[3',';'-bis(dimethylaminomethyl)-
4' hydroxy~benzoyl}phenoxyacetate dihydrochloride_ _
Thionyl chloride (10 ml.) was added to a mixture
or 2,3-dichloro-4-{~3',5'-bis(dimehtylaminomethyl)-4'-
hydroxy]benzoyl}phenoxyacetic acid ~3.8 g.) and isopropyl
alcohol (200 ml.). The mixture was heated at reflux for
2 hours. Dimethylformamide (20 ml.) was added. Refluxing
was continued overnight. The solution was cooled (ice ba~h)
and filtered to give 3.8 g. of a solid material. The solid
was recrystallized by dissolving the crystals in hot dimethyl-
formamide (50 ml.), adding isopropyl alcohol (50 ml.),
cool;.ng and adding diethyl ether (50 ml.). Filtration of
the cold mixture yielded 2.5 g. (52.5~) of the pure isopropyl
ester dihydrochloride; m.p. 212-213.
Analysis Calcd. for C24H32C14N2O5
C, 50.54; H, 5.66; N, 4.91
Found: C, 50.49; H, 5.88; N~ 4.95

-27-
Exampie 30
Adamantyl 2,3-dichloro-4-{~3',5'-bis(dimethylaminomethyl)-
_ 4'-hydroxy]benzoy~}phenoxyacetate, dihydrochloride _
Thionyl chloride (0.95 ml.) was added dropwise to
S a slurry of 2,3-dichloro-4-{~3',5'-bis(dimethylaminomethyl)-
4'-hydroxy]benzoyl}phenoxyacetic acid (3 g.) and l-adamantanol
(4.013 g.) in dry dimethylformamide (23 ml.) with stirring
under a nitrogen atmostphere. The slurry was heated to 70C
during which the solids dissolved. The reaction was heated
at 70~+3C for 6 hours, cooled to room temperature and
concentrated in vacuo to yield a white solid. The solid was
taken up in water and extracted with diethyl ether. The
aqueous l~yer was made basic (pH about 10) with concentrated
ammonium hydroride. The basic solution was axtracted with
dichloromethane. The dichloromethane extracts were dried
(MgSO4), fil~ered and concentrated in vacuo to yield a gum~
The gum was dissol~ed in dichloromethane (25 ml.). The
solution was cooled (ice bath) and treated with dry hydrogen
chloride gas. A white solia formed and then dissolved. The
solution was concentrated to dryness to yield 0.~28 g. oi.
the adamantyl ester dihydrochloride as a white powder;
m.p. 243-244(dec.).
Analysis Calcd- for C32H40C14N205 1/2H2O
C, 55.45; H, 6.15; N, 4.17; Cl, 21.12
Found: C, 55.43; H, 6.09; N, 4.06; Cl, 21.67
The aminomethyl derivatives of 4-(hydroxybenzoyl)-
phenoxyacetîc acid are prepared as follows:
These compounds are prepar~d by reaction of 4-
~hydroxybenzoyl)phenoxyacetic acids with 2-chloro-~-(hydroxy-
methyl)acetamide or other amidoalkylating agents in the
presence oi acetic acid and sulfuric acid, sulfuric acid, or
methanesulfonic acid to form amidoalkylated product followed
by hydrolysis oi- the amido group and formation of the esters.

~49190a
-28-
Example 31
Ethyl 2,3-dichloro-4-~(3'-aminomethyl-4'-
hydroxy)benzoyl]phenoxy~ tate h~drochloride
2-Chloro-N-(hydroxymethyl)acetamide (2.72 g.,
0.022 mole) was added, in small portions, to a s~irred
solution of 6.82 g. (0.02 mole) of 2,3-dichloro-4-~4'-
hydroxybenzoyl)phenoxyacetic acid in 135 ml. acetic acid and
15 ml. concentrated sulfuric acid at 57. The mixture wa~
stirred at 57 for 1/2 hour, then at room teperature for
3 hours and poured into ice water. The gummy solid was
separated and refluxed with 50 ml. of ethanol and 10 mlO of
concentrate~ hydrochloride for 6 hours. After evaporation
in vacuo, the- residue was recrystallized from ethanol and
ether. After refrigeration overnight, crystalline solid
separated which was removed by filtration. To the filtrate
was added more ether and the mixture was kept in cold room
for several days. The solid was collected and recrystallized
from ethanol a~d ether; m.p. 200-210.
Analysis Calcd. for C18H17C12N05 HCl
C, 49.73; H, 4.17; N, 3.22
Found: C, 49.50; H, 4.31; N, 3.18

986~
-29-
Exam~e 3?
Ethyl 2,3-dichloro-4-{~3l,5'~bis(aminomethylj-4'-
hydroxy]ben20y~}phenoxyacetate dihydrochloride
2-Chloro-N-(hydroxymethyl)acetamide (5.44 g.,
0.044 mole) was added, in small portions, to a stirred
solution of 6.82 g. (0.02 mole) of 2,3-dichloro-4-(4'-
hydroxybenzoyl)phenoxyacetic acid in 135 ml~ acetic acid and
15 ml. concentrated sulfuric acid at 57. After stirring at
57 for 1~2 hour and at room temperature for 3 hours, th~
mixture was poured into ice water. The gummy solid was
separated and refluxed with 100 ml. of ethanol and 20 ml. of
concentrated hydrochloric acid for 10 hours. After evaporation
in vacuo, the residue was recryst~llized twice from ethanol
and ether; m.p. 225-230(dec.).
y Clg 20Cl2N25 2HCl
C, 45.62; ~, 4.43; N, 5.60
Found: C, 45.92; Hj 4.48; N, 5.58

-30-
Example 33
Ethyl 2,3-dichloro-4-~(3'-~ninomathyl-4'-hydroxy-5'-
chloro)benzoyl]pAeno~yacetate hydrochloride
2-Chloro-N-(hydroxymethyl)acatamide (2.59 g.,
0.021 mole) was added, in small portions, to a stirred
solution of 7.51 g. (0.02 mole) of 2,3-dichloro-4-(3'-
chloro-4'-hydroxybenzoyl)phenoxyacetic acid in 35 ml. methane-
sulfonic acid at 40-50. After the addition, the mixture
was stirred and heated in an oil bath at 95 for 3-3/4 hours.
On cooling, the mixture was poured into water; the solid was
filtered and washed with water. The crude product was
stirred and refluxed with 75 ml. of ethanol and 15 ml. of
concentrated hydrochloric acid for 5 hours. The solid was
filtered and recrystallized twice from ethanol; m.p. 224-
226.
Analysis Calcd. for C18H15C13NO5-HCl
C, 46.08; H, 3.65; N, 2.99
Found: C, 45.90; H, 3.69; M, 2.99

-31-
Exam~le 34
2,3-Dichloro-4~{[3'~(2-chloroacetamido)methyl)-
4'-h~droxy]benzoyl}~æhenoxy~acetic acid
2-Chloro-N-(hydroxymethyl)acetamide (5.44 g.,
0.044 mole) was added, in small portions, to a stirred
solution of 13.64 g. (0.04 mole) of 2,3-dichloro-4-(4'-
hydroxybenzoyl)phenoxyacetic acid in 120 ml. concentrated
sulfuric acid, cooled in an ice bath. The mixture was
stirred at room temperature overnight and poured into 1 liter
of ice water. The crude product was filtered, washed with
ice water and used or the next experiment.

9~
-32-
' Example 35
Ethyl 2,3-dichloro-4-~(3'-aminomethyl-4'-hyd~oxy 5'-
iodo)benzoyl]phenoxYacetate hydrochloride
A solution of 3.57 g. (0.022 mole) of iodine
monochloride in 10 ml. of acetic acid was added dropwise to
a stirred solution of 8.92 g. ~0.02 mole) of crude 2,3-
dichloro-4-{[3'-(2-chloroacetamido)methyl-4'-hydroxy]benzoyl}-
phenoxyacetic acid in 100 ml. ac~tic acid at 75-80. The
mix~ure was stirred at 75-80 for 20 hours and evaporated in
vacuo to dryness. The residue, after trituration with
water, was stirred and refluxed with 100 ml. of ethanol and
~0 ml. of concentrated hydrochloric acid for 7 hours. After
cooling, the product was filtered and recrystallized from
ethanol; m.p. 215-21a(dec.).
Analysis Calcd- for C18H16C12IN05 HCl
C, 38.56; H, 3.06; N, 2.50
Found: C, 38.33; H, 3.03; N, 2.54
.' . '~ ' ,

-33-
Exam~le~A3~
Ethyl 2,3-dichloro-4-[(3'-aminomethyl-4'-
hydroxy)benzoyl]phenxoy-a-me~hylace_ate
2-Chloro-N-(hydxoxymethyl)acetamide (11.11 g.,
0.09 mole) was added, in small portions, to a stirred solution
of 15.98 g. (0.045 mole) of 2,3-dichloro-4 (4'-hydroxybenzoyl)-
phenoxy-a-methylacetic acid in 270 ml. acetic acid and
30 ml. concentrated sulfuric acid at 45-50. The mixt~re
was sitrred at 45 ~or 1/2 hour and at room tsmp~rature for
2 hours and poured into 1.5 liters of ice water. The gummy
solid was separated and refluxed with 200 ml. of e~hanol and
40 ml. of concentrated hydrochloric acid for 18 hours.
After evaporation in vacuo, the residue was crystallized
from ethanol and ether. A~ter refrigeration overnight, the
solid was removed by filtration. To th~ filtrate was added
ether and the solution was kept cold. The solution was
decanted and evaporated in ~acuo. Tha residue was neutrali2ed
with potassium bicarbonate solution and extracted with
methylene chloride. The extract-was washed with water,
dried with anhydrous sodium sulfate and evaporated to dryness.
The residue was recrystallized from ~thanol; m.p. 122-124.
Analysis Calcd. for ClgHlgC12N05
C, 55.35; H, 4.65; N, 3.40
Found: C, 55.57; H, 4.58; N, 3.53

34-
EXAMPLE 37
2,3-Dichloro-4-[(3' -amlnomethyl-4 ' -hydroxy) benzoyl]-
phenox~acetic acid hydrochloride_
2-Chloro-N- ( hydroxymethyl ) acetam~de ( 5 . 4 4 g .,
0.044 mole) was added, in small portions, to a stirred
solution of 13.64 g. (0.04 mole) of 2,3-dichloro-4-(4'-
hydroxybenzoyl)phenoxyacetic acid in 60 ml. methanesul-
fonic acid, cooled in an ice bath. The mixture was
stirred at room temperature for 24 hours and poured
into ice wateru The solid was filtered, washed
thoroughly with water, and hydrolysed by heati~g with
1~5 ml. of 10% aqueous hydrochloric acid for 10 hours.
After cooling, the crude product was collected and re-
crystallized with 2N hydrochloric acid; m.p. 237-240(dec.).
Analysis Calcd. for C16H13C12NO5 HCl
C, 47.25; H, 3.47; N, 3.44
Found: C, 47.49; H, 3.51; N, 3.35
EXAMPLE 38
Ethyl 2,3-dimethyl-4-[~3'-Aminomethyl-4'-hydroxy)benzoyl~
phenoxyacetate hydrochloride
2-Chloro-N-(hydroxymethyl)acetamide (1.23 g.,
O.O1 mole) was added portion~ise to a stirred solution of
3.0 g. (0.01 mole) of 2,3-dimethyl-4-(4'-hydroxybenzoyl)
phenoxyacetic acid in 35 ml. concentrated sulfuric acid,
cooled in an ice bath. The m1xture was sitrred at ice
bath temperature for 2 hours, then at room temperature
for 25 hours, and poured into ice water. The solid was
filtered, washed with water, and recrystallized from 1:1
aqueous acetic acid. The amidoalXylated product (1.24 g.)
was refluxed with 15 ml. of ethanol and 3 ml. of concen-
trated hydrochloric acid for 17 hours. The mixture was
evaporated to dryness ln vacuo and the residue was recry-
stallized tWiCQ from ethanol and ether to give the pure
product; m.p. 204-207 (dec.).
Analysis Calcd. for C20H23NO5.HCl
C, 60.99; H, 6.14; N, 3.56
~ound: C, 60.29; H, 6.19; N, 3.54

~4~ 3
-35-
EXAMPLE 39
2,3-Dichloro-4-[(3'-aminomethyl-4'-hydroxy-5'-methyl)
benzoyl]~enox~acetate hyarochloride
2-Chloro-N-~hydroxymethyl)acetamide (1.48 g.,
0.012 mole) was added, in small portions, to 2,3-dichlo~o-
4-[(4'-hydroxy-3'-methyl)ben20yl]-phenoxyacetic acid in
25 ml. of concentrated sulfuric acid, cooled in an ice
bath. The mixture was stirred at room temperature for
17 hours and poured into ice water. The solid was
filtered, washed with water, and hydrolysed by heating
with 30 ml. of 10% hydrochloric acid for 21 hours. After
cooling to room temperature, the product was collected;
yield 3.54 g. The ethyl ester was obtained by passing
hydrogen chloride to a stirred suspension of the above
acid (3.54 g.) in refluxed for 3 hours. After cooling,
the ethyl ester hydrochloride was filtered and recrystal-
lized from ethanol; m.p. 231-233(dec.)
Analysis Calcd. for: ClgHlgCl~N05 HCl
C, 50.85; H, 4.49; N, 3.12
Found: C, 50.72; H, 4.51; N, 3.11

~19~13
-36-
The diuretic activity of the compounds of
the invention was established in normotensive rats. In
this test, male nOrmotensivQ rats (Sprague-Dawley),
weighing 275-375 grams are used. Groups of eight rats
are used for each dose level.
The test drug or contxol (suspension vehicle)
is administered orally ~via gavage) to each animal and
immediately thereafter the animal is administered saline
via oral catheter with 0.9% sal:ine equivalent to 5~ of
the animal's body weight. The animals are then placed in
individual stainless steel met~olism cages, No food or
water is given to the rats during the test. Urine volume
is measured and recorded and a sample is collected at
intervals of 2 hours and six hours after dosing.
When dose ranging studies are done the urine
volume is read and recorded at 1, 2, 3, 4, 5, 6, and 24
hours after administration.
Each test compound, control or dose of test com-
pound is tested in eight animals. As a control, the sus-
pension vehicle is given ~0.5% methylcellulose)in a volume of2 ml./kg. body weight.
Drugs are dissolved or suspended in 0.5~methylcellulose
so that the appropriate dose is present in 2 ml./kg. body
weight. For routine screening a dose of 100 mg.~kg. po
is typically employed.
For convenience, t~e compounds tested are identi-
fied in Table I with the urine volume obtained at each
dose level of compound administered being recorded in
Table II.
R~
HO ~ 3 ~ OCH-C-R3
2 Xl X2
~1 CH2 < R

~4~303
37-
X I O C~ ~ U O C~ ~ ~ U U t~
~ I C C~ U ~ U ~ U C~ U
m ~ m
C~ U U U U C~
~ 3 ~"o
~ P~ x m m P~
~ U U ~ C~ -- ~ U ~-
m m m m m m ~: m m m m m ,,
I
I
H 1~ Is) Il~ Ir~ In Irl 11~ n
~: m ~: m P~ m
o U C~ o C~ U o U U U C~ o o
o o o o o o o o
. ' . .
.
r~
~c m m m
m ~ ^~ ~ V ~ m m ~
o o
~e * ~ * ~ *
Q r~ ` co ~ o ~1
O
U

33
--38--
X I C~ U t ) C~ C,) O O O C.) C.)
_ _ ~ _ _ _
U~
m
~;
C~ C~o--C~
~ ~ O~ C~
// ~
o o
m~ :q
~ _ _ ~ _ _ U C) ~
~ ~ ~ ~ ~ ~ o ~ o C`~
P~ C~ U
o o o o o o oo
m
o o C,~
~I
~;1 1 1 1 ~ I I I I I I
~ * ~ # ~ *
O ~ ~ o~1
C~ .,

~91~
--39--
X I ~ U U U U
X I ~ U O U U ~ ~ U O U U U
_ _ _
U U U U U C) O C~
O O O O
~r; :r: m ~ m m ~ x ;~
-- -- -- U C~ C~ UU ~ U ~- U
m m m x m
N ~ ~
_ ~U
m ~ u
F~ N N N ~ N m :~: u v N N
u u u c~ u u u -- -- eq ~: m
O O o o o o o o o y Ul V
o o o
N N N N N ~ N N
U U U U U U U U
~i Z Z Z Z Z Z Z ~;
~ ~ ~J !~, C~ N N N N N N N N
C~ U ~ U ~ U
P;l I I I II I I I I I I I
:) * ~ * * IC ~C ~ * 1C ~C
O er U'~ o ,~
~ ~ ~ ~ N ~ ~ ~ t) ~) ~ r

L9~
o--
x l u u c~ u c)
x l u c~ ~ u ~ u o ~
~D
m :q ~c m m m 5~ m
X ~C W
~ .
N X
m U U O o ~, ~,
L!~ ~D ~ 3
p; U ~ZN W U ~ U H \ / ~ --
I U 1 U ~
.,~ Ql. Q
~1 C) o ~.
P~ W
*
N ~
.. . .

-41-
TABLE 2
DOSE
COMPOUND MG/KG RTE ~OAD TIME(HRS) VOLUME
1 30 PO SAL 5% 0-2 4.47/
0-6 3.23/
0-24 1.58/
2 100 PO S~L 5% 0-2 4.~2/.00*
0-6 3.29/.00*
0-24 2.15/.00*
2-6 2.00/.00*
6-24 1.05/.61
PO SAL 5~ 0-2 5.05/.00*
0-6 3.47/.00*
0-24 2.15/.00*
2-6 1.66/.01*
6-24 0.88/.Q4*
PO SAL 5% 0-2 4.~1/.00*
0-6 3.25/.00*
0-24 1.~3/.00*
2-6 1.46/.03*
6-24 0.65/.00*
3 PO SAL 5$ 0-2 4.68,'.C0*
0-6 3.22~'.C0*
G-24 1.~6~.00*
2-o 1. J~/ . 02*
6-2~ 0.5'l~.0~*
1 PO SAL 5% Q-2 ~.. li/.00*
~-~ 2.7~/.03*
0-24 ~.57/.0~*
2-~ 1.27/.22
6-24 Q.39/.03*
0.30 PO S-~ 5~ 0-~ 2.~i/.0~*
0-6 2.0~/.0~*
0-2~ 1.27~.01*
2-o 1.6~/.01*
6-24 0.51/.C~*
0.10 PO SAL 5~ 0-2 1.11/.53
3 100 PO SAL 5% 0~2 7.~C/.00*
0-6 3.3~ 0*
~-6 '.12/.~6
100 PO SAL 5% 0-2 5.51~.00*
0-6 3.40/.0n*
0-24 1.7~ 0*
2-~ 1.5~ 2*
6-24 0.~1/.00*
PO S~L 5% 0-2 ~ -/.0~*
0-6 2.92/.00':
0--2~ 1.57/.~37
2~ 3/.~3~
6-2~ 0.~ 3*
PO SAL 5% 0-2 3.23/.00*
0-~ 2.31~ *
0-24 1.~ *
2~o 1.52/.~5
6 2~ 0.`10/.00~
3 PO SAL 5% 0-2 1.~-~/.C3*
C-6 1.57/.~

-42-
COMPOUND M~9~ RTE LOAD TIME(HRS) V~LU~E
0-24 1.10/.18
2-6 1.33/.08
6-24 0~71/.00*
1 PO SAL 5~ 0-2 0.60/.11
~-6 0.8g/.34
0-24 0.96/.58
2-6 1.14/.41
6-24 1.03/.81
4 100 I~ SAL 5~ 0-2 6O16/.00*
0-6 3.79/.00*
2~6 2.15/.00*
100 PO SAL 5% 0-2 1.17/.60
0-6 0.99/.96
2-6 0.83/.39
5 100 PO SAL 5% 0-2 1.64/.13
0-6 1.29/.07
2-6 1.16/.33
6 100 PO SAL 5~ 0-2 4.05/.00*
0-6 3.03/.00*
2-6 1.89/.00*
PO SAL 5% 0-2 5.02/.00*
0-6 2.75/.00*
0-24 1.52/.00*
2-6 1.08/.60
6-24 0.32/.00*
PO SAL 5% 0-2 3.22/.00*
0-6 1.83/.00*
0-24 1.13/.04*
2-6 0.80/.11
6-24 0.46/.00*
3 PO SAL 5% - 0-2 1.78/.01*
0-6 1.41/.01*
0-24 1.03/.62
2-6 1.14/.32
6-24 0.67/.01*
1 PO SAL 5% 0-2 0.77/.30
0-6 0.99/.92
7 1 PO SAL 5% 0-24 0.98/.74
2-6 1.15/.37
6-24 0.98/.85
100 PO SAL 5% 0-2 1.33/.53
0-6 1.52/.02*
2-6 1.61/.00*
8 100 PO SAL 5% 0-2 1.43/.20
0-6 1.45/.03*
2-6 1.44/.03*
9 100 PO SAL 5% 0-2 4.76/.00*
0-6 3.11/.00*
2-6 1.90/.00*
300 PO SAL 5% 0-2 6.59/.00*
0-6 4.07/.00*
0-24 2.38/.00*
2-6 2.74/.00*
6-24 1.11/.20

-43-
COMPOUND M~9~ RTE LOAD TIME(HRS) VOLUME
100 PO SAL 5% 0-2 7.57/.O0*
0-6 4.22/.00*
0-24 2.17/.00*
2-6 2.45/.00*
6-24 0.64/.0Q*
PO SAL 5% 0-2 6.71/.00*
0-6 3.60/.00*
0-24 1.81/.0Q*
2-6 i.~6/.00*
6-24 0.48/.00*
PO SAL 5% 0-2 4.62/.00*
0-6 2.54/.00*
0-24 1~36/.00*
2-6 1.43/.05*
6-24 0.49/.00*
3 PO SAL 5% 0-2 3.56/.00~
0-6 1.92/.00*
0-24 1.11/.0~*
2-6 1.05/.74
6-24 0.50/.00*
10 100 PO SAL 5% 0-2 0.71/.07
0-6 Q.67/.02*
2-6 0.65/.05*
11 100 PO SAL 5% 0-2 0.62/.03*
0-6 0.63/.00*
2-6 0.64/.03*
12 100 PO SAL 5% 0-2 1.19/.36
0-6 1.23/.06
2-6 1.26/.09
13 100 PO SAL 5% 0-2 0.91/.66
0-6 0.85/.20
2-6 0.81/.35
14 100 PO SAL 5% 0-2 1.09/.73
0-6 1.16/.41
2-6 1.19/.42
15 100 PO SAL 5% 0-2 1.38.14
0-6 1.23/.17
2-6 1.15/.48
16 100 PO SAL 5% 0-2 5.71/.00*
0-6 3.43/.00*
2-6 1.86/.00*
300 PO SAL 5% 0-2 5.59/.00*
0-6 3.36/.00*
0-24 1.89/.00*
2-6 1.74/.00*
6-24 0.59/.01*
100 PO SAL 5% 0-2 5.58/.00*
0-6 3.11/.~0*
0-24 1.71/.00*
2-6 1.33/.05*
6-24 0.47/.00*
PO SAL 5% G-2 3.30/.00*
0~6 2.22/.00*
0-24 1.26/.00*

~4~
- 44 -
COMæOUND M~ RTE LOAD TIME (HRS~ VOLUME
:
2-6 1.43/.03*
6-2~ 0. ~2/ .00*
PO SAL 5% 0 - 2 1.34~.45
0-6 1. ~8/ .01*
0-24 1.11/.13
2-6 1.5~/ .00*
6-24 0.77/.09
3 PO SAL 5% 0-2 1.00/ .9g
0-6 1.04/.76
0-24 1.06/.38
2-6 1.07/ .68
6-24 1.08/.53
17 100 PO SAL 5~ 0-2 4.33/.00*
0-6 3.06/.00*
2-6 1.96/.00*
18 100 PO SAL 5% 0-2 0.83/.35
0-6 1.00/.99
2-6 1.08/.69
19 100 PO SAL 5% 0-2 0.72/.13
0-6 0.78/.13
2-6 0.84/. ~6
20 100 PO SAL 5% 0-2 5.26/.00*
0-6 3.39/.00*
2-6 1.99/ .00*
21 100 PO SAL 5% 0-2 0.96/.82
0-6 1.35~ .02*
2-6 1.64/ .01*
22 100 PO SAL 5% 0-2 0.90/.56
0-6 1.31/.00*
2-6 1.61/.00*
23 100 PO SAL 5% 0-2 0.97/.83
0-6 1.23/ .02*
2-6 1.43/.04*
2~ 100 PO SAL 5% 0-2 0.81/ .23
0-6 0.98/.88
2-6 1.13/ .62
25 100 PO SAL 5% 0-2 0.50/ .00*
0-6 0.80/.12
2-6 1.06/.75
26 100 PO SAL 5% 0-2 5.07/.00*
0-6 3.68/.00*
2-6 2.23/ .00*
27 100 PO SAL 5% 0-2 4.94/.00*
0-6 3.63/.00*
2-6 2.26/ .00*
28 100 PO SAL 5% 0-2 3.~9/.00*
0-6 2.10/.00*
~ 2-6 0.92/.63
PO SAL 5% 0-2 1.59/.02*
0-6 1.45/ .01*
2-6 1.35/ .10
29 100 PO SAL 5% 0-2 6.19/.00*
0-6 3.28/ .00*
2-6 1.53/.01*
, , : ' ' :

45-
COMPO~ND M~9~ RTE LOAD TIMEt~RS) VOLUME
300 PO SAL 5% 0-2 5.09/.00*
0-6 3.57/.00*
0-24 2.12/.00*
2-6 2.22/.00*
6-24 0.89/ 47
100 PO SAL 5% 0-2 5.72/ 00*
0-6 3.53/.00*
0-24 1.78/.00*
2-6 1.55/.06
6-24 0.~1/.0Q*
PO SAL 5% 0-2 4.07/.00*
0-6 2.71/.00*
0-24 1.42/.00*
2-6 1.49/.09
6-24 0.32/.00*
PO SAL 5% 0-2 2.22/.01*
0-6 2.04/.00*
0-24 1.21/.04*
2-6 1.87/.02*
6-24 0.51/.00*
3 PO SAL 5~ 0-2 1.06/.86
0-6 1.42/.05*
0-24 1.05/.57
2-6 ~.74/.02*
6-24 0.74/.01*
30 100 PO SAL 5% 0-2 8.21/.00*
0-6 4~57/.00*
2-6 2~3/o00*
PO SAL 5% 0-2 5.].9/.00*
0-6 3.12~.00*
0-24 1. 39/. 00*
2-6 1.48/.07
6-24 0.30/,00*
PO SAL 5% 0-2 3.04/.~0*
0-5 2.26/.00*
0-24 1~10/.16
2-6 1.64/.~0*
6-24 0.38/.00*
3 PO SAL 5% 0-2 1.46j.13
0-6 1.37,~.02*
0-24 0.94/.39
2-6 1.~9/.12
6-24 0.57/.~0*
1 PO SAL 5% 0-2 1.27/.50
0-6 1.?5/. 30
0-24 1.02/.80
2-6 1.24/.25
6-24 0.8~/.22
31 lG0 PO SAL 5% 0-2 8.7;/.00*
0-6 4.28/.00*
2-~ 1.87~.01*
PO SAL 5% 0-2 5.34/.~0*
0-6 3.2~/.00*
0-2a 1.42/.00

-46-
COMPOUND M~9~ RTE LOAD TIME(HRS) VOLUME
2-6 1.88/.04*
6-240~ 31/~ 00*
PO S~L 5% 0-23 ~ 52/ ~ 00*
0-62~ 00*
0-241~ 17/~ 01*
2-6 1.16/.35
6-240 ~ 60/~ 00*
3 PO SAL 5% 0-21 ~ 77/~ 01*
0-61~ 66/~ 00*
0-241~ 20/~ 00*
2-6 1.59/.01*
6-240 ~ 92/~ 29
1 PO SAL 5~ 0-21~ 43/~ 25
0-6 1.56/.02*
0-241 ~ lZ/. 04*
2-61~ 65/~ 00*
6-240 ~ 86/o 15
100 PO SAL 5% 0-28~ 31/~ 00*
0-64 ~ 22/~ 00*
2-62 ~ 01/~ 00*
32 30 PO SAL 5~ 0-27~ 15/~ 00*
0-63~48/~00*
0-241 ~ 49/~ 00*
2-61~ 00/~ 99
6-2~0 ~ 30/~ 00*
PO SAL 5% 0-24 ~ 53/~ 00*
0-62 ~ 25/~ 00*
0-24 1.13/.04*
2-60 ~ 70/~ 01*
6-240~ 46/~ 00*
3 PO SAL 5% 0-2 1.68/.04*
0-61 ~ 51/~ 01*
0-24 1.12/.14
2-6 1.38/ ~ 03*
6-240~ 8g/~ 37
1 PO SAL 5~ 0-21~08/~75
0-6 1.23/.16
0-241~ 08
2-61~34/~06
6-24 1.04~.62
33 100 PO SAL 5% 0 - 2 10.40/.00*
0-64 ~ 13/~ 00*
2-60~ 84/~ 35
PO SAL 5% 0-25 ~ 62/~ 00*
0-63~ 12/~ 00*
0-241 ~ 35/~ 00*
2-61~14~45
6-240 ~ 23/~ 00*
PO SAL 5~ 0-23 ~ 45/ ~ 00*
0-61~ ~5/ ~ 00*
0-24 1.02/.82
2-60~76/~17
6-240 ~ 43/~ 00*
3 PO SAL 5% 0-2 1. 92/~ 00*

-47-
COMPOUND M~9~ RTE LOAD TIME(HRS) VOLUME
0-6 1.71/.00*
0-24 1.09/.21
2-6 1.54/.01*
6-~ 0.70/.00*
1 PO SAL 5% 0-2 1.15/.50
0-6 1.16/.29
0-24 0.99/.91
2-6 1.16/.46
6-24 0 89/ 14
100 PO SAL 5% 0-2 6 11/ 00*
0-6 3.65/.00*
2-6 1.52/.04*
35 100 PO SAL 5% 0-2 9.06/.00*
0-6 3.08/.00*
2-6 0.80/.02*
36 100 PO SAL 5~ 0-2 5.16/.00*
0-6 3.07/.00*
2-6 1 17/ 43
300 PO SAL 5% 0-2 3 98/ 00*
0 6 2.83/.00*
0-24 1.73/.00*
2-6 1.83/.00*
6-24 0 80/ 03*
100 PO SAL 5% 0-2 4 51/ 00*
0-6 2.61/.00*
0-24 1.36/.00*
2-6 0.96/.59
6-24 0.31/.00*
PO SAL 5~ 0-2 3.03/.00*
0-6 1.81/.01*
0-24 1.00/.99
2-6 0.75/.13
6-2~ 0.32~.00*
PO SAL 5% 0-2 1.10/.60
0-6 1.25/.05*
0-24 1.04/.33
2-6 1.38/.01*
6-24 0.86/.05*
3 PO SAL S% 0-2 0.81/.29
0-6 0.98/.79
0-24 1.00/.99
2-6 1.13/.08
6 24 1.02/.82
37 30 PO SAL 5~ 0-2 4.49/.00*
0-6 2.63/.00*
2-6 1.46/.00*
PO SAL 5~ 0-2 5.67/.00*
0-6 3.32/.00*
0-24 ~.65/.01*
2-6 1.94/.00*
6-24 0.35/.01*
PO SA~ 5% 0-2 2.96/.00*
0-6 2.30/.00*
0-24 1.38/.09
2-6 1.92/.00*

-48-
CO~OUND M~9~ RTE LOAD TIME(HRS) VOLUME
6-24 0.65/.15
3 PO SAL 5% 0-2 1.~7/.01*
0-~ 1.98/.00*
0-24 1.20/.34
2-6 2.04/.00*
6-24 0.60/.09
1 PO SAL 5~ 0-2 2.13/.01*
0-6 1.75/.01*
0-24 1.30/.17
2-6 1.52/.08
6-24 0.95/.82
Note: * Statistically significant P-values
(0.05 or less).