Note: Descriptions are shown in the official language in which they were submitted.
QA170/170a/168
N-SUBSTITUI'ED MERCAPTOACYL PROPIONAMIDES
. , _ . _ _ .
Mammalian collagenase is inhibited by compounds
having the formula
I 13 R
1 S C~2-~ C-NH-(cH2) -R
In formula I, and throughout the specification, the
symbols are as defined below.
Rl is hydrogen, alkanoylo~ 2 to 10 ~rbon atcms
(ace~y~ is p~e~erred) or arylcar~ benzoyl is preferred);
NH 1 l4
R2 is ~NH-~ H2, ~ R4, -C-(O-alkyl)2,
~4 ~ - CH2
-C/
~ O - CH2, l-pyrrolidinyl, l-piperidinyl, 4-morpholinyl,
l-piperazinyl, or 4-alkyl-1-piperazinyl; wherein R4 is
hydrogen, alkyl or aryl;
R3 is alkyl of 3 to 8 carbon atoMs, cycloalkyl
of 3 to 7 carbon atoms, aryl or arylalkyl; and
n is an integer of 1 to 20.
The term "aryl", as used throughout the
specification, either individually or as part
of a larger group, re~ers to phenyl or phenyl
substituted with one, two or three alkyl, alkoxy,
halogen, amino, hydroxy, or alkanoyloxy groups.
Phenyl and monosubstituted phenyl are the preferred
aryl groups.
The terms "alkyl" and "alkoxy", as used
throughout the speci~ication (unless otherwise
defined), either individually or as part of a
larger group, refer to groups having 1 to 8
~arbon atoms.
~.
~ Q~170 /l7oa/l68
qhe term halogen, as used throughout -the
specification, either individually or as part
of a larger group, refers to fluorine, chlorine,
bromi.ne and iodine.
The compounds of this invention can be
prepared using as a starting material-a carboxylic
acid having the formula .
II
11
HO-CH2-CH-C-OH.
Heating a carboxylic.acid of formula II with
phosphoric acid yields a compound ha~ing the
formula
III
~3
CH2=C - C- OH,
which can in turn be reacted with a thio acid
having the formula
IV
R -SH,
wherein Rl is alkanoyl or arylcarbonyl, to yield
a product having the formula
~d. `~ 3 ~ ~3 Q~170/170a/16
--3--
, 3 11
Rl-S-CH~-CH-C~OH.
5An acid of formula V, or ester thereoE, can
be coupled with a compound having the formula
VI
10NH2- (CH2) n~R2 ~
or a salt thereof, to yield the compounds of
formula I wherein Rl is other than hydrogen.
The coupling reaction can be effected by first
activating the acid of formula V, ~, by
formation of a mixed or symmetrical anhydride,
acid chloride, or active ester, or by the use
of Woodward reagen~ R, EEDQ (N-ethoxycarbonyl-2-
ethoxy-1,2-dihydroxyquinoline) or the like. A
preferred method of activation comprises first
treating an acid of formula V with an organic
base (e~., tr.iethyl.amine) and then adding ethyl
chloroformate.
Those products of formula I wherein Rl
is hydrogen can be prepared Erom corresponding
compounds of formula I wherein Rl is alkanoyl
or arylcarbony:L by treatment of the acylthio
compound with concentrated ammonium hydroxide.
Alternatively, the compounds of this .
invention can be prepared using as a starting
~ Q~170/170a/168
material a malonic acicl ester derivative having
the formula
VII
O R O
1~ l3 ll
alkyl-O-C-CH-C-O-alkyl.
Hydrolysis of a mak~nic acid ester derivative
of formula VII yields the corresponding compound
having the formula
VIII
O R O
Il l3 11
HO-C-CH-C-OH.
Sequen-tial reaction of a diacid of formula VIII
with a secondary amine (such as dimethylamine)
and formaldehyde yields the corresponding
compound having the formula
~0
~X
O R O
l3 li
HO-C~C - C - OH
CH2
( 3 2
Con~ersion of a compound of formula IX to the
corresponding compound having the formula
III
R O
13 11
CH2=C~C--OH
~ r~ Q~170/170a/16
can be accomplished by melting the precursor
compound. The compounds oE this inven-tion can
be prepared from khe compounds of formula III
using the procedures described above.
Those compounds of Eorm~la I wherein R2 .is
-C R4 can alternatively be prepared from the
corresponding product o~ formula I wherein R2
j4 l4O - CH
is -C-(O-alkyl)~ or -C~ 1 2
O- CH2 by acid hydrolysis.
The compounds of formula I have at least
one asymmetric carbon atom; the carbon noted
with an asterisk (*) in formula I. The compounds
accordingly exist in stereomeric forms or as
racemic mixtures thereof. All of these are
within the scope of this invention. The above
described synthesis can utilize the starting
compounds in the form of a racemic mixture or
as a stereomer.
In mammals, collagenase is one of the key
enzymes involved in the cartila~e and joint
destruction of rheumatoid arthritis; see, for
example, Arthritis and Rheumatism, ~0 (6):1231
(1977). It is, therefore, desirable to inhibit
the action of the collagenase enzyme.
While not limitin~ the scope of this
invention to a specific theory or mechanism of
operation, it is nevertheless helpful to an
understanding of the invention to revlew the
possible reasons for the activi~y of the compounds
of formula I. The main components of cartilage
are the collagen polypeptide molecules. These
polypeptides are cleaved by mammalian collagenase
at a single site. The compounds of this invention
~ 170/170a~168
resemble the susceptibl~ sequence of the collagen
molecules and, it is theorized, bind to the
mammalian collagenase enzyme and inhibit its activity.
The mammalian collagenase enzyme contains
zinc, which assists in the cleavage o-f a ~lycine-
leucine or glycine-isoleucine bond and contains
an extended cleft which interacts with an extended
portion of the collagen molecule. This molecule
in turn contains arginine as the last homolo~ous
amino acid in the substrate sequence adjacent
to the cleavage site, a sequence showing a high
de~ree oE homology among the various types of
collagen molecules. The inhibitors of this
invention make use of these features of the enzyme
and make modifications to enhance binding to the
mammalian collagenase molecule~
The action of mammalian collagenase has
also been implicated as a causative factor in
several other diseases in mammals. These
diseases include periodontal disease, corneal
ulceration, tumor invasiveness, and epidermolysis
bullosa; see, for example, Amerlcan Journal of
P~tho~y, _ (2):509 (1978) and The New England
Journal of Medicine, 291 (13):652 (1974).
For use in the treatment of rheumatoid
arthritis, the compounds of this invention can
be administered to a mammal in need thereof
either orally or by injection intraarticularly
into the affected joint. The daily dosage for
a 70 kilogram mammal will be in the range of
about 10 milligrams to 1 gram.
The compounds of this invention can be
formulated in compositions such as tablets,
QA170/170a/168
~7
capsules or elixirs for oral administration or
in sterile solutions or suspensions Eor parenteral
administration. About 10 to 500 mg of a compound
of formula I can be formulated with a pharma-
ceutically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, flavor, etc.,
in a unit dosage form as called for by accepted
pharmaceutical practice. The amount of active
substance in these compositions or prepaxations
0 i5 such that a suitable dosage in the ranye
indicated is obtained.
Salts of the compounds of ormula I wherein
~ H
R2 is -NH-C-NH2 are also useful in the inhibition
of mammalian collagenase and can be~used and
formulated followiny the procedures described
above. The compounds of formula I wherein R2
NH
is -NH-C-NH2 form acid-addition salts with organic
and inorganic acids. These acid-addition salts
are not only useful as inhibitors of mammalian
collagenase but also frequently provide useful
means for isolating the products from reaction
mixtures by forming the salt in a medium in
which it is insoluble, isolating the salt and
then neutralizing the salt. Salts of the compounds
NH
of formula I wherein R2 is -NH-C-NH2 can also be
formed by utilizing a salt of a compound of
formula VI as a reactant.
.a~r~3 QA170/170a/168
--8--
Exa~
~-(?,2-Dimethox~ethyl) -?- [(ace~_th:io)met yl~-
4-methylpen_anamide
.
A) Isocaproic Acid
Potassium cyanide (28 y) is partly dissolved
in 125 ml of ethanol and 30 ml of water. Amyl
bromide (63.6 g) is added and the reaction mixture
is digested on the steam cone for 24 hours. The
solution is decanted from the potassium bromide
on to 35 g of potassium hydroxide. This is
digested on the steam cone for 20 hours, diluted
with 50 ml of water and concentrated ln vacuo
to remove the ethanol. A 1:1 mixture of sulfuric
acid and water is added to the reaction mixture
and product is extracted with petroleum ether
to yield 60.6 g of crude product. Vacuum
distillation yields 43.4 g of product boiling
at 90-98C/9 mm of Hg.
B) 4-~lethyl-2-(hydroxymethyl)pentanoic acid
Diisopropylamine (20.6 g) is dissolved in
80 ml of dry tetrahydrofuran. This solution is
cooled to -30 C. n-Butyllithium (77 ml of 2.6M
in hexane) is added dropwise in a nitrogen
atmosphere at a rate that maintains the reaction
at -30 to -20C, and this solution is stirred at
-20 C for 30 minutes. Isocaproic acid (11.6 g)
in 10 ml of tetrahydrofuran is added dropwise
at -20 to -10C, then stirred at -10C for 30
minutes. In a separate flask, paraformaldehyde
(28 g) is heated to about 200C and the vapors
~ J~t~ QA170/170a~16
are carried in a stream of nitrogen over the
surface of the tetrahydrofuran solution of the
dilithium salt of isocaproic acid. During this
procedure the temperature is kept between -10
5 and ~10C. After all oE the paraformaldehyde
has vapori~ed the reaction mixture is cooled to
0C and 10~ hydrochloric acid is added dropwise
until the reaction mix-ture becomes acidic.
Produc~ is extracted with 2 portions of et'ner
(400 ml each). The ether is dried with magnesium
sulfate, filtered and concentrated ln vacuo
-to yield 13.2 g of crude material. Product is
vacuum distilled to yield 9.0 g, boiling point
135-142 C/9 mm of Hg.
C) 4-Methyl-2-methylenepentanoic acid
4-Methyl-2-(hydroxymethyl)pentanoic acid
(8.7 g) is heated with 10 drops of 85~ phosphoric
acid in a Wood's metal bath at 220C for 20
minutes. A distillation head is attached and
the pressure is slowly decreased to 60 mm
while the temperature is increased to 270C.
Product starts to distill and the pressure is
further decreased to 10 mm. The vapor temperature
varies between 180 and 190C. The yield of
the title compound as distillate is 7.0 g.
D~ 2-~Acetylthio)methyl~-4-methylpentanoic acid
4-Methyl-2-methylenepentanoic acid (6-.8 ~)
is stirred with 5 ml of thiolacetic acid under
argon for 5 days, concentrated ln vacuo and a
portion is distilled. The product boils at
117-120 C at 9 mm of Hg.
~ .&3 QA170/170a/168
--10--
E) N-(2,2-Dimethoxyethyl)-2-[(acetylthio)methyl]-
4-methylpentanamide
A solution of 2~[(acetylthio~methyl~4~
methylpentanoic acid (2.0 g) and triethyl
amine ~1.0 g) in 50 ml of -tetr~hydrof~ran (THF) is
cooled to -5C. Ethyl chloroformate (1.1 g)
in 5 ml of THF is added dropwise and the reaction
mixture is stirred at -5C for 30 minutes.
Amino acetaldehyde dimethyl acetal (1.1 g) in 20 ml
of THF is added dropwise to the mixed anhydride
solution at -5C. After addition, it is stirred
at 10-20C for 2 hours and stored at 0C for
about 16 hours. Triethylamine hydrochloride
is filtered off and the filtrate is concentrated
in vacuo. The residue (2.1 g) is dissolved in
3 ml of ether. Silica gel (5 g) is added and
ether is evaporated off. I'his is placed on top
of 40 g of dry silica gel and washed through
with pentane, l:l pentane:ether and finally
ether. Product elutes with ether to yield 1.3 g
of product which solidifies to give a low
melting waxy solid.
Anal- calc'd for C13H25N4S--l5H2
H, 8.67; N/ 4.76; S, 10.90
Found: C, S3.09; H, 8.73; N, 4.67; S, 10.89
Q~170/170a/1~8
f"3
Exam~le 2
N-t2,2-Dimethoxye h~1)~2-(mercaptometh
methylpentanamide
The N-(2,2-dimethoxyethyl)-2-[(ace-tylthio)-
methyl]~4-methylpentanamide obtained in Example 1
is dissolve~ in 15 ml of absolute ethanol and
the atmosphere is purged with axgon. Concentrated
ammonium hydroxide (2 ml) is added and this
solution is stirred at room temperature for 3 hours,
concentrated to dryness ln vacuo and dried at
50 C for 8 hours over phosphorous pentoxide.
The title compound (0.8 g) crystallizes, melting
point 34-37C.
~nal. calc'd for CllH23N3S 25~l2
H, 9.33; N, 5.51; S, 12.63
Found: C, 52.09; H, 9.05; N, 5.64; S, 12.40
Example 3
N-[2-(Merca~_omethyl)-4-methyIpentanoyl]amino
acetaldehyde
The N-(2,2-dimethoxyethyl)-2-(mercaptomethyl)-
4 methylpentanamide obtalned in Example 2 is
- dissolved in 10 ml of water and treated with a
few drops of 10% hydrochloric acid. After
standlng for 1 hour at 25C, the water is removed
ln vacuo and the product is obtained as a powder
by triturating with acetonitrile~
Examples 4-7
Following the procedures of Example 1 and
2 (sequentially), but substituting the compound
listed in column I for amino acetaldehyde dimethyl
acetal, yields the compound listed in column II,
and on hydrolysis as in Example 3, the compound
listed in column III.
d ~ Q~170/170a/168
--12-
U --U O = U
o = u o - ~ u u
N N N N
~ y ~U y Y
H N ~ t :~ N 3:: N ~
~ ~ --Y U--u Il O _ O ~ O _ y
UO U'~ U U--U--y U--U--y U--U--y
X X ~ N N
U U U U
N N
:~ ~ N t`l
t~ U--U ~ ~
U---U
:C~ l I
U N O
~ ~ U \U~
H UU ` ~ U U
N ~ N :~
~ O_U 3~ O=t.) ~ O=U ~ O--U
-- N ¦ `' ~ I -- N I `' ~N I
U U--y U--U--U U--U--y
U U uN t~
~N ~N ~1 ~N
N U--U U_U
U N 1 1 0
U
ol U U~~y y ~U
N ~N N ~
U~ U y U
~N ~N N t'~l
?~ Q~170/170a/1~8
~-13-
2 [(~cetyl~thlo) hyl] 4-me-th~l-N-[4-[(amino-
iminomethyl)amino]butyl~E~anamide~ acetate (1:1)
~) 2-[(Acetylthio)methyl~-4-methylpentanoic
acid, ~-nitrophenyl ester
2-[(Acetylthlo~methyl]-4-methylpentanoic
acid (5.1 g, see Example lD) in 100 ml of
ethyl acetate is cooled to 5C and treated
with ~-nitrophenol (3.5 g) followed by 5.1 g
of dicyclohexylcarbodiimide, in portions.
After stirring for four hours at 5C, the
dicyclohexylurea is filtered and the ethyl
acetate is removed in vacuo. The resulting
.
solid is washed with hexane to give the title
compound, 8.0 g, as an oil.
B) 4-[(Aminoiminomethyl)amlno~butylamine,
acetate (1:1)
A solution of agmatine sulfate (1.4 g)
and sodium acetate (1.0 g) in 10 ml of water
is cone~entrated in vacuo and the residue is
slurried with hot absolute ethanol and filtered.
The filtrate is evaporated and washed with
ethyl acetate to give 1.5 g of the title compound,
melting point 132-136C.
~ 3~ `3 ~A170/170a/16R
C) 2-¦(Ace~yltlllo)m ~ -meth~ o-
imlnomethxl)amino]butyl]pentanamide, acetate (1-1?
The ~-nitrophenyl ester of 2-[(acetylthio)-
methyl]-4-methylpentanoic acid (3.S g) is dissolved
in 75 ml of dimethylformamide, cooled to 5C,
and treated with a solution of the monoacetate
salt of 4-l(aminoiminomethyl)amino~butylamine
(1.6 g) ln 10 ml oE water. The mixture is stirred,
for about 16 hours at 25C, evaporated ln vacuo
leaving an aqueous solution and extracted
thorou~hly with ethyl acetate. The aqueous
layer is lyophilized to a solid, which is washed
with acetonitrile and dried in vacuo to give
2.8 g of the title compound.
Exam~le 9
2-(Mercaptomethyl)-4-methyl-N-[4-~[(aminoiminomethy-l)
amino]butyl]pentanamide, acetate (1:1)
2-[(Acetylthio)methyl~-4-methyl-N-[4-[(amino-
iminomethyl)amino]butyl]pentanamide, acetate
(1:1) 11 g) is dissolved in 30 ml of water,
cooled in ice, and purged with argon. Concentrated
ammonium hydroxide (4 ml) is added, and the
mixture is allowed to warm to 25C over 2 hours.
The solution is lyophilized, and the resulting
solid is triturated with acetonitrile. Drying
in vacuo at 40 C gives 0.8 g of the -title compound.
~ 3 QA170/170a/168
-15~
~ _0 and 11
Following the p.rocedures of Examples 8
and 9 (sequentially), but substituting the compound
listed in column I for the.monoacetate salt of
s 4-[~aminoiminomethyl)amino~butylamine, yields
the acetate salt o the compound listed in column II.
Column I CD1~nrl II
Cfl(Cfl3)Z
NH ~Cf~2101 NH
10. H2N_CH2_CH2_NH C_NH2 HS~CH ~CH~C~NH~CH ~CH -NH~ ~NH
CH(Cff3)2
NH C~H2l0l NH
2 2 7 2 HS CH~_CH_C_NH_(CH2)7_NH_C_NH2
Exam~ 12
(+)-2-[(Acetylthio)meth ~ l-N-~2-~4-
morpholinyl)ethyl]pentanamide
2-[(Acetylthio)methyl]-4-methyl pentanoic acid
can be prepared as described in Example 1 or as
follows:
3 QAl/0/170a/16
16-
i) 3~_~tanoic acid
. .
A solution of 91ol g of 2-(ethyl-
oxycarbonyl)-4-methylpentanoic acid, ethyl
ester in 300 ml of methanol is treated for
6 hours at 80C with 400 ml of 1096 sodium
hydroxide. The solution is concentrated
in vacuo to 400 ml and acidified with 10%
.
hydrochloric acid. The product is extracted
with ethyl acetate to yield 67.6 g of the title
compound, which crystallizes on standing.
Recrystallization Erom ethyl acetate-hexane yields
the title compound, melting point 102 - 105C.
ii) 2-Carboxy-4-methyl-2~[~di~e~ n~
me~yl]pentanolc acid
2-Carboxy-4-methylpentanoic acid
(67g) is suspended in 400 ml of water and coole~
to 5C~ Aqueous 40% dimethylamine (50 g) is added
2~ to the suspension followed by aqueous 37% formal-
dehyde (3S.7 g). The resulting solution is
stirred for about 16 hours and solid product is
filtered and dried ln vacuo to yield 57.3 g of
the title compound, melting point 134 - 137C
with carbon dioxide and dimethylamine given off~
iii) _-Methyl-2-methylenepentanolc acid
2 Carboxy-4-methyl-2-[(dimethylamino)-
methyl]pentanoic acid (57.3 g) is suspended
melted at 140 - 145C in an oil bath, and held at
this temperature until bubbling ceases. The melt
170/170a/168
-17-
i5 cooled, taken up in water and acidified with
10~ hydrochloric acid. ~xtraction with hexane,
drying and evaporation yields 30.5 g of the
title compound.
B) 2-~(Acetylthio)methyl]-4-met-x~entanoic acid
4-Methyl-2-methylenepentanoic acid (~.8 g)
is stirred with 5 ml of thiolacetic acid for about
16 hours. The reaction mixture i5 concentrated ln
vacuo until crystallization occurs, yielding 3.6 g
of the title compound, melting point 42 - 47C.
C) (-)-2-[(Acetylthio)methyl]-4-methyl-N~
[2-(4-morpholinyl)e-thyl]pentanamide
2-[(~cetylthio)methyl]-4-metllylpentanoic
acid (2.0 g) is dissolved in 40 ml of tetrahydro-
furan (THF) and 1.0 g of triQthylamine. This
solution is cooled to -5C and ethyl chloroformate
in 5 ml of THF is added dropwise. The reaction
mixture is .qtirred at -5C for 20 minutes and
then N-(2-aminoethyl)morpholine [1.3 g] in 20 ml
of THF is added dropwise. lt is stirred at 20C
for 4 hours and stored at 0C for about 16 hours.
Triethylamine hydrochloride is filtered off and the
filtrate is concentrated _n vacuo. This residue is
'a.~3 QA170/170a/168
-18
dissolved in e~her and washed once with aqueous
Na~CO3 and twice with water. The ether is
dried with MySO4 t filtered and concentrated
in vacuo to yield 1.6 g of material. This is
S purified by dissolving 0.6 g in 2 ml of ether
and placing it on top of a pad of alumina
(activity II 10 g). The column is washed
through with 250 ml of ether which is concentrated
ln vacuo. Product crystallizes and is washed
with 1:5 ether-pentane. The remainder of the
crude is seeded with a small crystal and ~len
washed with 1:5 ether-pentane. Total yield
is 1.0 g of the title compound, melting point
54-59C.
15H28N2O3S: C, 56.93; H, 8.92; N, 8 85
S, 10.13
Found: C, 56.76, H, 8.91; N, 9.10; S, 10.01
Example 13,
(~)-2-[(Acetylthio)methyl~-4-meth~l-N-~2 (1-
piperidinyl_e_ yl~pentanamide
A solution of (~)-2~~(acetylthio)me ~yl]-
4-methylpentanoic acid in 40 ml of THF is cooled
to 5 C, followed by the dropwise addition of
triethylamine (1.0 g) in 5 ml of THF. This
solution i~ cooled to -5C and ethyl chloro-
formate in 4 ml of THF is added dropwise at
-5 to 0C. It is stirred for 30 minutes and
N-(2-aminoethyl)piperidine in 30 ml of THF is
added dropwise. The reaction mixture is stirred
~A170/170a/168
-19-
at 20 C for 4 hours and stored at 0 C for about
16 hours. Triethylamine hydrochloride is
filtered of and the filtrate i5 concentrated
_ vacuo. The residue is dissolved in ether
and washed with aqueous NaHCO3. Ether i~ dried
with MgSO4, filtered and concentrated in vacuo
to yield 2.1 g of crude productO This crude
is absorbed on a 20-g pad of alumina act II
and washed through with ether ~o yield 1.4 g of
product which Grystallizes from pen-tane,
melting point 47-50C.
Calc. for C16H30N2O2S: C, 61.11; H, 9.62; N, 8.91;
S, lO.lg
Found: C, 61.04; H, ~.82; N, 8.93; S, 9.91
Example 14
2-(Mercap-tomethyl)-4-methyl-N-~2-(4-morpholinyl)-
ethyl]pentanamide
-
~ 2-[(Acetylthio)methyl]-4-methyl-N-
[2-(4-morpholinyl)ethyl~pentanamide (0.6 g)
is dissolved in 20 ml of 1:1 ethanol:water.
The solution is saturated with argon and 2 ml
of 47% NH40H is added. This is stirred under
argon for 2 hours at room temperature. The
reaction mixture is concentrated in vacuo and
lyophilized for about 16 hours. The residue
is dissolved in ether and stirred with charcoal
to decolorize the product, which i5 then filtered
through diatomaceous earth and concentrated ln
vacuo.
Q~170/170~/168
-20-
The oil is dried at 45C in vacuo for about 16
hours to yield analytical product.
CalC- for C13H26N22S 1/4 2
N, 10.04; S, 11.49
Found: C, 55.78; ~i, 9.48; N, 10.33; S, 11.41
E ~ 15
2-(Mercaptomethyl)-4-methyl-N-[2~ eridinyl)~
eth ~
(~)-2-[(Acetylthio)methyl]--4-methyl-N-
[2~ piperidinyl~ethyl]pentanamide (0.8 g) is
dissolved in 3 ml of water and 5 ml o~ absolute
ethanol. After this solution is purged with
argon, 2 ml of 56~ NH4OH is added and the reaction
mixture is stirred at room temperature for 2.5
hours. It is first concentrated ln vacuo to
get rid of excess ammonia and ethanol and then
lyophilized for about 16 hours. The dark brown
oil is dissol~ed in ether and stirred with a
scoop of charcoal for 20 minutes. It is filtered
through Celite and concentrated ln vacuo to
yield an oil. ~rying in vacuo for 4 hours
at 40C yields the analytical productO
cal~- for C14H28N2S 0-25 H2 ;
N, 10.12; S, 11.58
Found: C, 60.52; H, 10.38; N, 10.51; S, 11.20
~a ~
QA170/170a/168
-21-
Examples 16 - 18
Followiny the procedure of Example 13,but
substituting the compound lis-ted in column I for
N-(2-aminoethyl)piperidine, yields the compound
listed in column II
Column I Column II
5 N-(3-aminopropyl)- (-)-2-[(acetylthio)methyl]
piperaæinyl -4-methyl-N-[3-(l~piper-
azinyl)propyl]pentanamide
6 1-(4-aminobutyl)-4- ~-)-2-[(acetylthio)methyl]
methyl-piperazinyl -4-methyl-N-[4-(4-methyl-
l-piperazinyl)butyl]pen-
tanamide
7 N~2-aminoethyl)pyr- (~)-2-[(acetylthio)methyl]-
rolidinyl 4-methyl-N-[2-(1-pyrroli-
dinyl)ethyl]pentanamide
3-(Acetylthio)--N-[2-(1-piperi n ~ hyl]-2-(phenyl-
methyl)propionarnide
A) 2-Carboxyl-3-~dimethy_ mino)-2-(phenylmethyl3-
pro~ionic acid
. . . _
Benzyl malonic acid (13 g) is mixed wi-th 7.6
g of 40% aqueous dimethylamine and 5.4 g of 37~
for~alin in 150 ml of water. After 2 hours, the
resulting solid is filtered, washed with water and
partially dried in air to yield 2008 g of material.
B) Benzylacrylic acid
The above material is melted in a 170C oil
Q~170/170a/168
-22-
bath and heated for 10 minutes, until amine evolution
stops and bubbling has vlrtually ceased. The cooled
product, a mobile liquid, is acidified with 10~ pot~
assium bisulfate, extracted with hexane, dried (Na2SO4)
S and evaporated to give 6.3 g of solid. The aqueous
filtra-tes from the Mannich reaction of part A are
allowed to stand for about 16 hours and then heated
at 100C on a steam cone until bubbling ceases.
Cooling, acidification and extraction as above give
an additi.onal 1.2 g of solid for a total yield of
7.5 g of benzyl acrylic acid.
C) 3-(Acetylthio)-2-(phenylmethyl)propionic acid
___ _ .
Following the procedure of Example lB, but
substituting benzylacrylic acid for 4-methyl-2-methyl-
enepentanoic acid~ yields the -title compound.
D) 3-(Acetylthio)-N-[2-(1-piperidinyl)ethyl]-2-
. . . ~ . . _ _ . . . _ _ . .
(phenylmethyl)propionic acld
2~ Following the procedure of Example lC, but
substituting 3-(acetylthio) -2-(phenylmethyl)pro-
pionic acid for 2-[(acetyl-thio)me-thyl]-4-methylpentan-
oic acid and N-(2-aminoethyl)piperidine for N-(2-
aminoethyl)morpholine, yields the title compound.
Example 20 - 22
Following the procedure of Example 19, but
substituting the compound listed in column I for
benzyl malonic acid and the compound listed in column
II for N-(2-aminoethyl)morpholine, yields the compound
listed in column III.
- 2 2 a ~ r~
~ 1--
~ ~ ~ n
X 0 3 H
E.
, PJ ,
o
o
n ~. n
~.
Z z z g
3 3 3 H
O r~ O
(D ~<: 1'-
-- g
O ~. ~
O
~.
(D ~,
w ~ ~ ~ w ~ w n
3 ~ ~
O ~ ~ O Q~ ~ H
~ ~ O ~ :~ ~ 5' H
1--~ 0 h~--O ~ ~ O
~ ~ æ' ~t z @ w æ
o n~:~ 3 n
.1 ~
