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Патент USA US3093643

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3,093,633
United States Patent O?ice
a Patented June -1l,=1>963.
1
available penicillins. The novel ‘compounds of- this in
vention have, in theacid, form, the formula:
3,093,633
NOVEL PENICILLIN COMPOUNDS‘
Donald C. Hobbs, East Lyme, C0nn., assignor to Chas.
P?zer & Co., Inc., New York, N.Y., a corporation of .
Delaware
No Drawing. Filed June 29, 1960, Ser. No. 39,456
13
I (Cl. 260—‘239.1)
whereinM is selected ‘from the group'consisting of hy
' .This invention relates to new ‘antibiotic compounds and‘
their salts and, more particularly,‘ to novel 6-aminopeni-' 10 droxy‘,alkoxy containing 1 to 4 carbon atoms, amidoycara
: boxymethylimido, carboxyethylimido and carboxyethvl—_
cillanic acid derivatives and their salts which are antago
ideneimido; R1 is selected from they group. consistingof
methylene and ethylidene; R2 is selected from the group"
consisting of cycloalkylene containing 4 to 6 carbon atoms,
nistic toward gram-positive and gram-negative micro
organisms.
‘I f” includes‘a numberof iacyl deriv
atives of .6-amino-penicillanic acid which differ only in 15 phenylene, 2,5 -thienylene, 2- carboxy - ‘3,4, .-thienylene,,
i1 methylene and substituted methylene whereinthe sub
the nature of the R group and possess‘ the general formula:
stituent is selected from the group consisting of car-boxy,
and halogen; ralkylene containing 2 tog4, carbon atoms
20 which may be unsaturated and .substitutedderivatives
thereof wherein the substituent is selected from the, group
(I)
\ I consisting. of hydroxy, carboxy, halogen andalkanoyloxy’
radical of a hydrocarbon carboxylic acid containing 1 to 4
carbon atoms. Many of these novel compounds can, by‘
. The propertiesof a particular penicillin are ‘determined 25 virtue of'the asymmetric centers present in the side chain,
exist in diastereoisomeric £orms,‘and mixtures thereof,’
by the R group. ‘The best known and most widely used
derived respectively from the isomeric precursor acids.
penicillins ‘are benzylpenicillin and phenoxymethylpeni
Whenthe dl-precursor acid is used, a mixture of the di
cillin wherein R (Formula ‘1) represents the lbenzyl-v and‘
astereois‘omers will be produced. Moreover, when R; is
phenoxymethyl- radicals. Both compounds are e?ective.
via both parenteral and oral administration in the‘treat 30 asymmetrical, two isomeric. structures are possible for a
given value, of R2; one in .which the substituent responsible
ment of bacterial infections due to gram-positive‘ organisms
for the asymmetry is located closer vto the nucleus than
but are generally ineffective against gram-negative or->
in. the corresponding isomer. Therefore, included within
ganisms, many of which are resistant to their action.
There has‘ now been discovered a series of novel and 35 the purview of this invention are the various stereoi‘someric
in fwhichithe acyl moiety is derived from acarboxylic
acid.
‘ modi?cations and mixtures thereof, of the‘compounds
valuable derivatives of. ,6-aminopenicillanic acid which
possess signi?cant. activity against gram-positive and gram
of Formula III above, all of which exhibit substantial‘ thera
negative organisms and which are,‘ therefore, of value in
the treatment of various bacterial ‘infections including
peutic
activity.
’
g
'
>
_
Also included in the present invention are the pharma
40
ceutically
acceptable salts of these novel ‘and valuable
several due to certain organisms resistant to the presently
TABLE L-ANTIBACTERIAL SPECTRA (-MCGJ
ML.) OF THE POTASSIUM SALTS ‘OF SEVERAL.
COMPOUNDS 0F Eon-Moran
Organism
1
-
2
“=3 ~
4
5
v8
a 0.39
100
100
100‘
100
_
100
100
100
100
100
100
100
> 100
100
100
"
100
100
100
» 100
100
Streptococcus faecalis-_
_ 1.56
12.5
’ 0. 78
12.5 _
1.
Erysipelothriz rhuisopathiac
____ __
Coryuebacterium diphtheriae.
Listeria monocytogencs._-_
Bacillus subtilis _______ -_
Streptococcus .agalactiae“
0. 78
~ 0. 78
0.
Diplococcus pueumom'ae
y
.0. 39
0. 78
6. 25
_ 3.12
0.39
. 6. 25
r 1-. 56
0. 78_
I
0. 09v
0.02
3.12
V
_
‘
0. 02
1.56.
3. 12
t
‘
0.02
V
0. 39
1.56
1. 56
0.39
0.78
6. 25
1. 56
6. 25
0.02
______ __
0. 39‘
0. 39.
0.19
3. 12
0.39
1. 56
0. 39.
3. 12
1. 56
0. 78 .
0. 78
1. 56v
1. 56
1.56
0. 78
50
3. 12
‘ 1.56
0. 19
12.5
3. 12
12. 5
1. 56
6. 25
1. 56
6. 25
1. 56
0.78
0. 09
.1. 56
6.25‘
0. 19
0.39
0. 78
. 6. 25
0.39
3. 12
25
6. 25
25
Bacterium ammouiaamesAerobactcr aerogeuem--.
Escherichta colt-"
. 0.19 ‘
0.39
0.39
6. 25 -
3.12
‘6. 25
0.19‘
‘ 1. 56v #0. 78
50
50
25
25
0. 78
‘
'
ertussts-
' shigellzzi 807L7I€i_____
Brucella brunchiseptt
Malleomyces mallet
Vibrio comma____
‘
0. 78
. 3.12
0. 78
0. 39
25
'
50
100‘
.. .
. 0.19
100‘
Mycobacterium beroliuense- _
100
Streptococcus pyogeues-Heru'm
, Staphylococcus aureus+se1um ____ __
25
'
“112.5
50
25
12. 5
.5
.
50
100
100
100
100
100
12.5
3. 12
_j
100
~
100
- 1.56
100
6. 25
0.09
100
12.5
50
. 50
100
100
100
100
100.
12. 5
100
0. 78
25
25
6.25
, 25
'
.
_100
' 00
,
12. 5
6. 25
0. 78
100
100'
100
‘100
1700
25
'
6. 25
100 ‘
I
1.56
50
25 ,'
12. 5
100
6. 25 y .312
25
25
6. 25
1%. 26
.,
.
2g
:
25 '
100
100» _
100
100
100 ‘0. 39
50
-~0. 19
100
100
1 0.39 1045 119 108.09 103 19
‘
3.12
100
100
> 3.12
g
12. 5
6. 25
0.04
25 '
100
0. 78
100
100
,
a
'
0. 39
, 0.09‘
‘ 12. 5.
100 '
1g. 25
.56
v0. 78
0.39
100
, >100 ‘
, ‘12.5
100,
100
50
6. 25
0.19
6. 25
100
100
50
100
6.25
‘ 50
78
0. 39
12.5
12.5
‘25
50 25
0.09’ ' 0.39
Mycobactenum 60
‘100
3.12
1.56
100
12 5
100 -
0. 78
0. 39
0.09
0. 78
100
100 1
3.12
3.12
100
50
25
6. 25
1. 56‘
0.78
hilus
0. 09
0.78
.
~ 6. 25
0. 78
Lactobacillus casei _______ -_
Heme
‘
0. 39
1.56
11
100
0. 09
1.56
‘>10-
100
0. 78
0.39
9 ‘
100
0. 39
L56 '
7.
Staphylococcu3 aureus 4()()__
v 0. 39
a 1.56
i
staghglococcus aureus 376--
0.
. 3.12
-6
Sta h lococcus aureus ............ -- . 0-
Streptococcus pyogeues- .
(M78.-
_
.
‘
j
.
100
100
1100
100
100
100
0 78
00
_ -
V
.
100
100
100
25'
. 0. 78
25
0 39
100
00
045 104 1O(6.02
-
g 02
,1
50
100 ,
6. 25
3.12
0.19,
100
mg 78
.
______ __ 100
100
0.09 ‘
0. 78
0.09
0.78»
0. 78
0.39 i 25
12.5
100
100
100
100
I
100
100
100
0 045
0 78
0 19
0.39
0 04
0 04
0 78
0 78
1 56
1 56
3. 12
1 56
1 56
0 39
.
3,093,633
3
4
penicillins, that is, nonatoxic metal salts such as the so
dium, calcium and potassium salts, and non-toxic am
monium and substituted ammonium salts, for example,
salts of such non-toxic amines as procaine, dibenzylamine,
products are obtained by utilizing the appropriate form,
for example the d-, l- or dl-form, of the acid chloride as
reactant. The vdiastereoisomeric mixtures can, of course,
be resolved into the individual diastereoisomers by suitable
N,N’-bis(dehydroabietyl)ethylenediamine, N,N'-dibenzyl
means such as fractional crystallization, selective extrac
tion, or selective precipitation of an insoluble salt of one
ethylenediarnine, 1»ephenamine, N-benzyl-B-phenethyl
amine, l-methylpentylamine, 4,4'-dimethylbenzhydryl
diastereoisomer in the presence of the other.
It is preferred to utilize the reaction of 6-aminopenicil
salts with benzylpenicillin.
,
lanic with the appropriate acid chloride or bromide at pH
As mentioned above, the valuable and novel penicil 10 from about 3.0 to about 9.0 and at a temperature of from
lins of this invention demonstrate both gram-positive and
about 0° C. to about 50° C. A slight excess of the acid
amine and other amines which have been used to form
gram-negative antibacterial action.
The antibacterial spectra of several of the products of
halidetup to 10%) is generally used. After the reaction
is complete, generally 1 to 5 hours, the product is isolated
this invention are given in Table I. All compounds are
by conventional methods well known in the penicillin art.
used as their potassium salts.
The starting acids,
15
The particular compounds referred to are listed in
Table II.
are prepared by methods known in the art. One such
' procedure involves the condensation of the thio acid,
20 HOOC—-R1-—SH, such as thioglycolic acid, with the di
chloro or dibromo derivative of the R2 moiety, for exam
ple methylene bromide, in the presence of an alkalizing
agent, such as sodium hydroxide or potassium hydroxide.
A modi?ed procedure which is also applicable involves
25 the condensation of the cuprous salt of the thio acid,
HOOC—'R1—-S—Cu, with the ldihalo substituted R2
moiety. This method is useful tor preparing those acids
wherein R2 is phenylene.
When the two sulfur atoms are bridged by a single
30
carbon atom, i.e., methylene, ethylidene, carboxymethyl
ene, the compounds can, in many cases, be prepared from
the corresponding formyl derivatives, such as formalde
hyde, acetaldehyde, glyoxylic acid, and the appropriate
mercaptan, for example, thioglycolic acid, according to
conventional procedures.
,
The valuable products of this invention are remarkably 35
The starting acids thus obtained are converted to the
effective in treating a number of gram-positive and grain
monofunctional derivatives
negative infections in animals including man. For this pur
pose, the pure materials or mixtures thereof with other an
tibiotics can ‘be employed.
They may be administered
alone or in combination with a pharmaceutical carrier se
lected on the basis pf the chosen route of administration
and standard pharmaceutical practice. For example, they
by conventional methods, such as by reaction of the re
spective anhydride, prepared by self-condensation of the
acid by 1,3-dicyclohexylcarbodiimide, with the appropri
ate M——H reactant; i.e., methanol, ammonia, glycine.
may \be administered orally in the form of tabletscontain
The acid anhydrides, chlorides and bromides are pre
ing such excipients as starch, milk sugar, certain types of
pared according to conventional methods.
clay, etc., or in capsules alone or in- admixture with the 45
The condensation of 6-aminopenicillanic acid with the
same or equivalent excipients. They may also be adminis
appropriate acid HOOC—R1-—S-—RZ—S—R1—COOH,
tercd orally in the form of elixirs or oral suspensions which
in the presence of a carbodiirnide, such as 1,3-dicyclohex
may contain ?avoring or coloring agents or be injected
ylcarbodiimide, can also be used to prepare the products
parenterally, that is, for example, intramuscularly or sub
of this invention in accordance with known procedures.
cutaneously. For parenteral administration they are best 50
Other substituted amides, that is, compounds wherein
used in the form of a sterile aqueous solution which may
one or both of the hydrogen atoms of the amido group,
contain other solutes, for example, enough saline or
represented by M inv Formula II, are replaced by alkyl or
glucose to make the solution isotonic.
hydroxyalkyl radicals containing up to 4 or more carbon
In addition to their activity against such organisms, the
atoms, phenyl, hydroxyphenyl, carboxyphenyl, tolyl and
compounds of this invention, carboxymethylmercap-to 55 benzyl, are also antagonistic toward a variety of microor
methylmercaptomethylpenicillin, for example, is orally
active in the treatment of Salmonella gallinarum infec
tions in chicks.
The new and valuable compounds of this invention are
ganisms and, hence, e?ective in treating many infections
in animals and man.
In addition to the compounds described herein, anal
ogous and isotelic compounds wherein oxygen replaces
prepared by the acylation of 6-aminopenicillanic acid with 60 sulfur, for example, carboxymethyloxymethyloxymethyl
penicillin, also possess similar activity.
to the desired side chain, for example, the monoacyl chlo
When prepared as described above the novel antibiotics
ride of methylene-bis-thioglycolic acid, in the presence of
are obtained as the sodium or potassium salts. They are
the acid anhydride, chloride or bromide corresponding
an acid acceptor.
readily converted to the acid form by neutralization with
They can also be prepared by the method of Sheehan 65 a mineral acid, such as sulfuric or hydrochloric acids,
et al., Journal of the American Chemical Society, 81, 3089
or a suitable ion exchange resin and are recovered by
(1959) which utilizes the reaction of D-penicillamine and
extraction of their aqueous solutions with a suitable Water
t-butylphthalimidomalonaldehydate as starting materials
immiscible organic solvent.
for a series of reactions. Substitution of the phenoxy
The acid forms of the novel antibiotics of the present
acetyl chloride utilized by Sheehan et al., by, for example,
invention are, in turn, easily converted to salts by reac
the monoacid chloride of methylene-bis—thioglycolic acid
tion with a suitable base. Thus, treatment of the desired
in the reaction sequence produces carboxytnethylmercap
antibiotic in aqueous solution with ammoniinn hydroxide
tomethylmercaptomethylpenicillin potassium salt. The
produces the ammonium salt. In like manner other
diasteroisomers, or mixtures thereof, of these valuable 75 salts such as the calcium, magnesium, barium, potassium
3,093,632.‘
residue taken up in acetone‘ and then evaporated to dry
and sodium, are formed. In'addition, amine salts,,such
as the procaine, dibenzylamine, N,N’-di'benzylethylenedi- ,
amine, l-ephenamine and, N-benzyl-B-phenethylamine
ness to complete removal of the excess thionyl chloride.
salts, are prepared by: reacting a solution of the desired
antibiotic in an aqueous or non-aqueous solvent with the
desired amine. Alternatively, the amine salts are pre
The acid anhydrides are obtained by reacting the ap
propriate acid with one equivalent of 1,3-dicyclohexyl
pared in aqueous solution by?reacting a metal salt of the
desired antibiotic, erg.‘ the sodliurn- salt, Withthe desired‘
amine salt, tor example, ‘the amine hydrochloride salt.
hours at room temperature, the reaction mixture is ?ltered
to remove the dicyclohexylurea, the ?ltrate. concentrated
C. Preparation 0]‘ the Acid Anhydrides
carbodiimide in tetrahydrofuran ‘solution. Afterff'o‘u'r
and the product allowed to crystallize.
1017
The presence of the one or more carboxyl groups in
the side chain, of course, [gives rise to the formation of a
, variety of salts depending upon’ the number of carboxyl
D. Preparation of the Monofmictio?al Derivatives '
(Esters, amides and carboxymethyl substituted amides
groups present and the equivalents of base employedjin
salt formation. For example, when R, is a?rdicarboxy
ethyl, —CH(COOH)-~CH(COOH)-—, any or all of the
4 carboxy groups in the penicillin molecule‘ can be in-v
volved in salt formation.
7
- i
it
of the starting acids). The nionofunctionaljderivatives
listed above are prepared from the-appropriate .anhydride‘
‘by reaction ‘with one equivalent of the'proper alcohol,"
amino acid (glycine; a- and p-alanine) or ammonia ac
-
cording to standard procedures.
E. The monofunctional derivatives prepared in D
This invention is further illustrated by the following
exam'ple‘s,~whic‘h are'not'to'be construed as imposing any
above are converted to their monoaci-d chlorides accord-i
a ing
to procedure B.
limitationslon the scope thereon? On the contrary, it is to‘
be‘ clearly understood that resort may be had to various
F. The starting acids bearing an hydroxyl group in the
other embodiments, modi?cations and equivalents thereof
which‘ readily suggest themselves. to those skilled in the
R2 moiety are converted to their acyl derivatives by re
” action with the appropriate acyla-ting agent, anhydride
art without departing from the spirit of the present inven
tion and/ or the scope of theappended claims.
or acid chloride, according to conventional procedures. 7
. 1
For the purpose of convenience, general procedures for
the preparations of the novel reactants usefulin‘carrying
outthis invention are given below;
_
l
i
,
-
a <
EXAMPLE I
Fifty millimoles of the acyl chloride of methylene-bis
thioaglycolic acid in 100 ml. acetone is added 'dropwise to
i
'
a solution of 50 millimoles of 6-aminopenicillanic acidin
a. Mercaptoace'tic acid or, ‘when R1 is ethylidene,‘a
mercaptopropionic \acid, ‘are reacted with the ‘appropriate
250 ml. of 3% sodium bicarbonate and.1(_)0 m1.‘ of‘ace-.
tone at 4° C. The pH is maintained ‘at 7.5-8.0 by the
‘
A.‘ Preparation of the Add Reactants‘
addition “of aqueous sodium hydroxide. Aiter one hour,
dibromo icompound having the tormula§ Br—‘-R2‘—'-Br, in
100 m1. of water is added, the pH adjusted to 7.0 with
A aqueous phosphoric acid ‘and the mixture extractedwith
an equal volume of ether. The aqueous layer is retained,
a Zqto 1 molar’ratio with 4 moles of sodium‘hydroxide
present lasl N sodium hydroxide; The mixture is stirred
overnightat room temperature, ‘then washed ‘with "ether,
adjusted to pH 2.5 with’ :aqueous phosphoric acid and
acidi?ed and the acid solution extractedwith ether.‘ The‘
ethereal solution is dried over'anhydrous sodium suiphate,
concentrated under, reduced pressure :and theviscous resi
extracted twice with one volume of n-butanol. The com-,
bined n-butanol extracts are washed twice with ‘.1/ l0'fvol
‘‘ ume of, water and then extracted with one-half'volume
due ‘allowed to stand until crystallization occurs. -
40
b. Two moles of mercaptoacetic acid, or u-mercapto
propionic acid, one mole of the dibromo compound,
B-r—-R§—Br,‘and 4 moles of sodium hydroxide are re
acted altogether. infmethanol solution. The mixture=is re
of water, sufficient 5 N KOH being added ‘to bring the
pH to 6.5. The aqueous layer is ‘freeze-dried to give
the potassium salt of car-boxymethylmercaptomethylmen‘
captomethylpenicillin.
“
iiuxed for_5 hours after which it is concentrated and an 45
_
nxAMPLn I_I
N.
equal volume of water, added. The solution is washed
A solution of l‘ millimole of methylene-bis-thioglycolic
with ether and then extracted with ether at pH 2. The
acid in 10 ml. of tetrahydrofuran and a. solution of 1
ethereal solution is dried'over sodium sulfate, evaporated
and the. oily residue allowedtolcrystallize. ‘
‘_ p
c. .Two moles of‘ ethylmercaptoacetate, or of ‘ethyl-0L1
mercaptopropionate, one mole ‘of. ethyldibromo acetate,
millimole of 1,3-dicyclohexylcarbodiimide in' 5’ ml; of
. tetrahydrofuranare added- simultaneously ‘to a solution
of 1 millimole of 6-aminopenicillanic acid in'20 ml. of
and two moles of metallic: sodium are re?uxed in benzene
for 5 hours. The solution isthen cooled,lwashed, with
water and the benzene removed. by distillation. 'Ilhe resi
due is saponi?ed with sodium hydroxide solution until 55
watentetrahydrofuran (1:|1) containing su?icient sodium
bicarbonate toygive a clear solution. The mixture is
stirred at room temperature for 3 hours, then diluted
with water, ?ltered to remove 1,3-dicyclohexylurea and
‘anhydrous sodium sulfate then concentrated. The viscous
unreacted 1,3-dicyclohexylcarbodiimide. 'I‘he ?ltrate is
extracted with 20 ml. of ether, only the aqueous phase
‘being maintained. The aqueous phase is then extracted
with 3X50
volumes of n-butanol at pH 2.0 and the
‘residue crystallizes upon ‘standing.
.combined n-butanol ‘fractions washed once with water.
the reaction. is one phase. It is then acidi?ed and ex
tracted with nabutanol. The butanol extract is dried with .
,
I
d. The procedure of b is followed but the oily product 60 The n-butanol phase is then extracted with 2X50 ml.
‘is chromatographed on‘ silica gel using chloroform as
portions of water, su?icient potassium hydroxide (6 N)
3eluent. .The appropriate fraction is‘ crystallized. _
‘
'
' solution being added to each portion during extraction‘ to
Procedure 0 is useful in preparing those reactant acids
produce an aqueous extract of pH 7.0. The combined
“aqueous extracts are washed with 20 ml. of ether then
wherein R2 contains a carboxy group.
.
Procedure a is
‘used to prepare-those starting acids wherein R2‘ is an un 65 freeze dried to give the dipotassium salt of carboxy
substituted alkylene radical. Procedure b is used in
instances wherein di?iculty is encountered in obtaining
a pure product by procedure a. Procedure d is employed
‘for those compounds which fail to give crystalline prod
ucts when prepared according to procedure. b.
‘
B. Acid Chlorides
The acid chlorides are prepared by re?uxing the app
methyl-mercaptomethylmercaptomethylpenicillin identical
‘a to the product of Example I.
EXAMPLE III
The procedure of Example I is repeated but using the
appropriate acid chloride in place of the acid chloride of
_pmethylene~bis-thioglycolic acid.
The compounds thus
prepared-are listed in Table I. In each instance, the po
propriate acid with an excess of thionyl chloride until
tassium salt is obtained and M of Formula I represents
evolution of hydrogen chloride and sulfur dioxide ceases.
75
The excess thionyl chloride is removed by distillation, the
3,093,633
7
TABLE III
Method1
B _______________ _.
R1
R:
—CHr-—
—
w
Method 1
B ............... _. -om-
——G
[El
10
CHa-CH: _®
trans
GHQ-‘CH:
-—CH:—
—CH;—
-—C C12
-—CH C1—CH C1
-—CH Bl‘mCHz-2
1 The method column refers to the procedure used to prepare the
starting acid.
U
I The isomeric compound is also obtained;
EXAMPLE IV
The :anhydride of methylene-bis-th'ioglycolic acid is re
20
acted with 6-aminopenicillanic acid according to the pro
cedure of Example I. The product thus obtained is iden
tical to the product obtained in Example I.
In like manner the potassium salt of carboxyethylidene
25
mercaptomethylmercaptoethylidenepenicillin is obtained
from its respective anhydride.
EXAMPLE V
The monoacid chloride of the monomethyl ester of
methylene-bis-thioglycolic :acid is reacted with 6-amino
30
penicillanic acid according to vthe procedure of Example I.
The product obtained is the potassium salt of carbometh
oxymethylmercaptomethylmercaptomethylpenicillin.
CH;
In like manner, the monoesters of the products of Ex
ample III are produced from their appropriate monoacid
35 chlorides, prepared according to the procedure of D
above. The monomethyl, monoethyl, monopropyl, mono
isopropyl, mono-n-butyl and the mono-isobutyl esters are
40
thus prepared.
EXAMPLE v1
- Substitution of the monoamides in place of the mono
esters in Example V, produces the monoamide derivatives
of the products of Example HI.
EXAMPLE VII
CHa-CH=
Following the procedure of Example VI, but using the
@
45
N-oarboxymethyl and the N-a and B-carboxyethyl sub
stituted amides, the corresponding carboxymethylimido,
carboxyethylimido and carboxyethylideneimido deriva
tives of the products of Example III are produced.
EXAMPLE VIII
50
Following the procedure of Example I but using Z-ace
’ toxy - 1,3 - propylene - bis - thioglycolic acid as acylating
agent, carboxymethylmercapto - (2 - acetoxy)propylmer
Q
captomethylpenicillin potassium salt is prepared.
In like manner, the following compounds are prepared:
3,093,633
9
10
EXAMPLE IX
rated and substituted derivatives thereof wherein the sub~
The products of the preceding examples are converted
stituent is selected from the group consisting of hydroxy,
cal-boxy, halogen and alkanoyloxy radical of a hydrocar
to their free acid forms by neutralization of the aqueous
solutions of their potassium salts with 6 N hydrochloric
acid to pH 2.2. The acids are recovered by extraction
bon camboxylic acid containing 1 to 4 carbon atoms.
into methylisobutylketone followed by evaporation of the
2. The compound represented by the formula of claim
1 wherein R1 is methylene, R2 is alkylene containing up to
solvent.
four carbon atoms and M is hydroxyl.
EXAMPLE x
The free acids of Example VIII are transformed to their
sodium, calcium, ammonium, procaine, N,N’-dibenzyl
ethylenediamine, dibenzylamine, 1~ephenamine, N-benzyl
?-phenethylamine, benzim‘idazole, 2,5-diphenylpiperazine
3. The compound represented by the formula of claim
1 wherein R 1 is methylene, R2 is unsaturated alkylene con
10 taining two to four carbon atoms and M is hydroxy.
4. The compound represented by the formula of claim
1 wherein R1 is ethylidene, R2 is alkylene containing up to
four carbon atoms and M is hydroxy.
and benzhydrylamine salts by reaction of aqueous solu
5. The compound represented by the formula of claim
tions thereof with one equivalent of the appropriate base.
15 1 wherein R1 is methylene, R2 is substituted alkylene con
The
are recovered by freeze drying.
taining up to 4 carbon atoms wherein the substituent is
EXAMPLE XI
halogen and M is hydroxy.
The procedure of Example IX is repeated using two
6. The compound represented by the ‘formula of claim
equivalents of the above listed bases per equivalent of
1_ wherein R1 is methylene, R; is substituted alkylene con
the penicillin compounds.
20 taining up to 4 carbon atoms wherein the substituent is
carboxy and M is hydroxy.
EXAMPLE XII
7. The compound represented by the formula of claim
The penicillin's of the preceding examples which con
1 wherein R1 is methylene, R2 is alkylene containing up
tain one or more carboxy groups in the R2 moiety are
treated with one equivalent of each of the bases of Exam
to four carbon atoms and M is vamido.
ple X per carboxy group present in the molecule. The 25 8. Canboxymethylmercaptomethylmercaptomethylpeni
cillin potassium salt.
products are isolated according to the procedure of Ex
9. Carboxymethylmercaptoethylmercaptomethylpcnicil
ample X.
What is claimed is:
1. A compound selected ‘from the group consisting of
compoundsvrepresented by the formula:
lin potassium salt.
10. Carboxymethylmercapto ~ (a,l3-dimethyl)ethy1mer
30
captomethylpenicillin potassium salt.
11. Carboxymethylmercapto - trans - 1,2 - cyclohexyl
mercaptomethylpenicillin potassium salt.
12. Carboxymethylmercaptoethylidenemercaptomethyl
penicillin potassium salt.
35
and the pharmaceutically acceptable salts thereof wherein
‘M is selected from the ‘group consisting of hydroxy, alkoxy
containing 1 to 4 carbon atoms, amido, car-boxymethyl
imido, carboxyethylimido and carboxyethylideneimido; R1
13. Carboxymethylmercapto - (B - hydroxy)propy1mer
captomethylpenicillin sodium salt.
References Cited in the ?le of this patent
UNITED STATES PATENTS
is selected from the group consisting of methylene and 40 2,479,295
ethyiidene; R2 is selected —from the group consisting of
2,479,296
cycloalkylene containing 4 to 6 carbon atoms, phenylene,
2,479,297
2,5-thienylene, 2-carboxy-3,4-thienylene, methylene and
substituted methylene wherein the substituent is selected
2,941,995
16,
16,
16,
21,
1949
1949
1949
1960
FOREIGN PATENTS
from the group consisting of carboxy, and halogen; alkyl- 45
ene containing 2 to 4 carbon atoms which may be unsatu
Behrens et al __________ __ Aug.
Behrens et a1 __________ __ Aug.
Behrens et al __________ .. Aug.
Doyle et al ____________ __ June
569,728
Belgium _____________ __ Nov. 15, 1958
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