DERIVES D'AMINES ET D'ACIDES AMINES

DERIVATIVES OF AMINES AND AMINO ACIDS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
Novel compounds of the formula
<IMG>
wherein A is methylene, ethylene or ehtylidene; R1 is -C?CH
or -CH=CH2; R2 is hydrogen or COR wheretn R ts hydroxy, a
stralght or branched alkoxy group of from 1 to 8 carbon
atoms, -NR4R5 wherein each of R4 and R5 is hydrogen or a
straight or branched lower alkyl group of from 1 to 4
carbon atoms or <IMG> wherein R5 is hydrogen, a straight
or branched lower alkyl group of from 1 to 4 carbon atoms,
benzyl or p-hydroxybenzyl; Ra is hydrogen, <IMG> , alkyl-
carbonyl wherein the alkyl moiety has from 1 to 4 carbon
atoms and is straight or branched, alkoxycarbonyl wherein
the alkoxy motety has from 1 to 4 carbon atoms and is
straight or branched or <IMG> wherein R7 is selected
from hydrogen, a straight or branched lower alkyl group of
from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; and
Rb has the same meaning as defined for Ra except Rb is not
<IMG> , and Ra and Rb can be the same or different; with
the provisos that when R2 is hydrogen, R1 is -C?CH; when A
is ethylidene, R2 is hydrogen; and when Ra is <IMG> , A is

methylene; and pharmaceutically acceptable salts and
individual optical isomers thereof. The compounds are
irreversible enzyme inhibitors and are useful as anti-
infective agents, in the control of certain rapid growth
processes and in the inhibition of the immune response.
The compounds are also useful as intermediates in the
preparation of novel cephalosporin derivatives.

Revendications

M1-913 Ca.
CLAIMS
The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for preparing a compound of the Formula
<IMG>
wherein A is methylene, ethylene or ethylidene; R1 is
-CH=CH2 or -C?CH; R2 is hydrogen or COR wherein R is
hydroxy, a straight or branched alkoxy group of from 1 to
8 carbon atoms, -NR4R5 wherein each of R4 and R5 is
hydrogen or a straight or branched lower alkyl group of
from 1 to 4 carbon atoms, or <IMG> wherein R6 is
hydrogen, a straight or branched lower alkyl group of from
1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; Ra is
hydrogen, <IMG> alkylcarbonyl wherein the alkyl moiety
has from 1 to 4 carbon atoms and is straight or branched,
alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4
carbon atoms, and is straight or branched or <IMG>
wherein R7 is hydrogen, a straight or branched lower alkyl
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M1-913 Ca.
group of from 1 to 4 carbon atoms, benzyl or p-hydroxy-
benzyl; and Rb has the same meaning as defined for Ra
except Rb is not <IMG> and Ra and Rb can be the same or
different; with the provisos that when R2 is hydrogen, R1
is -C?CH; when A is ethylidene, R2 is hydrogen; and when
Ra is <IMG>, A is methylene; and pharmaceutically accept-
able salts thereof; which comprises
(a) when each of R2, Ra and Rb is hydrogen and
A is methylene or ethylidene treating one equivalent
of a suitably protected propargylamine derivative of
the formula (R8)3-Si-C?C-CH2-N=CHR9 wherein R8 is
C1-4,alkyl or triethylmethyl and R9 is phenyl,
(CH3)3C- or (CH3CH2)3C-, with a suitable strong
base, optionally in the presence of a divalent metal
cation, alkylating the thus formed protected pro-
pargylamine carbanion intermediate with 2-propenal or 2-
butenal, acylating the alkylated derivative with an appro-
priate acid halide, lower alkyl haloformate or tert-
butoxycarbonylazide followed by hydrolysis to give an amide
or carbamate which is treated with a suitable base to give
the carboxamide which is treated with trichloroacetonitrile
in a suitable solvent in the presence of a catalytic amount
of base at about -30° to 0°C for about 1/2 hour to 3 hours
to give the trichloromethylimidate ester which is heated
53

MI-913 Ca.
to about 110° to 140°C in a non-polar solvent for about 1
to 10 hours to give the trichloromethylacetamide which is
hydrolyzed using aqueous acid or base, said alkylating and
acylating reactions being carried out in an aprotic solvent
at about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when each of R2, Ra and Rb is hydrogen and A is
ethylene, treating 1-hydroxypent-2-enal with a metal acetyl-
ide of the formula HC?CM' wherein M' is sodium, lithium or
MgX' wherein X' is chlorine or bromine or with a complex of
lithium acetylide/ethylenediamine in a suitable solvent at
about -30° to 25°C for about 1 minute to 3 hours to give
hept-3-en-6-yne-1,5-diol which is treated with phthalimide,
triphenylphosphine and diethyl diazodicarboxylate in ether
solvents for about 1 to 12 hours at about 25° to 50°C to
give the diphthalimido derivative which is treated with
hydrazine hydrate in a lower alcohol solvent for about 1
to 6 hours at about 25° to 50°C followed by acid hydrolysis;
(c) when R2 is COR wherein R is hydroxy, R1 is -C?CH
and each of Ra and Rb is hydrogen, treating the correspond-
ing derivative wherein R2 is hydrogen and the amino and
acetylene groups are suitably protected as follows
<IMG>
wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or
triethylmethyl and n is 1 or 2, with a suitable
strong base and acylating the thus formed carbanion inter-
mediate with a suitable acylating reagent in an aprotic
solvent at about -120°C to about 25°C for about 1/2 hour
to 24 hours followed by acid or base hydrolysis;
54

M1-913 Ca.
(d) when R2 is COR wherein R is hydroxy, R1 is
-CH=CH2, and each of Ra and Rb is hydrogen, treating the
corresponding derivative wherein R1 is -C?CH with a suit-
able alkali metal in liquid ammonia and ammonium sulfate
at about -70° to 25°C until the blue color persists for
about 15 minutes or by reducing the corresponding deriva-
tive wherein R1 is -C?CH, each of Ra and Rb is alkylcarbon-
yl and R2 is COR wherein R is alkoxy by catalytic or
organic semi-hydrogenation;
(e) when Ra is <IMG>, R2 is hydrogen or COR wherein
R is hydroxy and Rb has the meaning defined in the
generic formula, treating a compound of the formula
<IMG>
wherein R1 and Rb have the meanings defined in the
generic formula and R3 is hydrogen or COOalkyl wherein
the alkyl moiety has from 1 to 8 carbon atoms and is
straight or branched wherein any free amino group is
suitably protected by a benzyloxycarbonyl group or by
reaction with an appropriate alkylisothiouronium salt,
in the presence of a base at a pH of about 10 and a
temperature of about 25°C for about 6 to 60 hours fol-
lowed by neutralization and acid hydrolysis when appro-
priate to remove any protecting group;

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(f) when Ra or Rb is alkylcarbonyl wherein the alkyl
moiety is straight or branched and has from 1 to 4 carbon
atoms and R2 is hydrogen or COR wherein R is hydroxy,
treating the corresponding derivative wherein Ra or Rb is
hydrogen or is suitably protected by a benzyloxycarbonyl
group or as an alkylisothiouronium salt or Rb is other
than hydrogen with an acid halide of the formula <IMG>
wherein halo is a halogen atom and R13 is a straight or
branched alkyl group of from 1 to 4 carbon atoms, or an
appropriate acid anhydride, in water in the presence of a
base at about 0° to 25°C for about 1/2 hour to 6 hours;
(g) when Ra or Rb is alkoxycarbonyl wherein the
alkoxy moiety is straight or branched and has from 1 to 4
carbon atoms, treating the corresponding derivative
wherein Ra or Rb is hydrogen or is suitably protected or
Rb is other than hydrogen with a halo alkylformate of the
formula <IMG> wherein halo is a halogen atom and R14
is a straight or branched alkyl group having from 1 to
carbon atoms in water in the presence of a base at about
0° to 25°C for 1/2 hour to 6 hours;
(h) when Ra or Rb is <IMG> wherein R7 has the
meaning defined in the generic formula, treating the cor-
responding derivative wherein Ra or Rb is hydrogen or is
suitably protected or Rb is other than hydrogen with an
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acid of the formula <IMG> or an anhydride thereof
wherein the amino group is suitably protected and R7 has
the meaning defined above in a suitable solvent and in
the presence of a dehydrating agent when the free acid is
employed at about 0° to 35°C for about 1 to 12 hours
followed by base hydrolysis;
(i) when R is a straight or branched alkoxy group of
from 1 to 8 carbon atoms, reacting an acid halide of the
corresponding derivative wherein R is hydroxy with an
alcohol of the formula R8-OH wherein R8 is a straight or
branched alkyl group having from 1 to 8 carbon atoms,
saturated with HCl gas at about 25°C for from 12 to 36
hours;
(j) when R is -NR4R5 treating an acid halide of the
corresponding derivative wherein R is hydroxy and Ra and Rb
have the meaning defined in the generic formula with the
proviso that any free amino group is suitably protected
with an excess of an amine of the formula HNR4R5 wherein
R4 and R5 have the meanings defined in the generic
formula or hexamethylenetetramine in a suitable solvent
at about 25°C for about 1 to 4 hours followed by acid
hydrolysis when appropriate to remove any protecting
group;
(k) when R is <IMG> wherein R6 has the meaning
defined in the generic formula, treating the corresponding
derivative wherein R is hydroxy or a functional derivative
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thereof and Ra and Rb have the meanings defined in
the generic formula with the proviso that any free
amino group is suitably protected with a compound of
the formula <IMG> , wherein R6 has the meaning
defined above and R12 is a lower alkyl group followed
by acid and base hydrolysis with the proviso that
when the free acid is employed the reaction is carried
out with a dehydrating agent; and
(1) when a pharmaceutically acceptable salt is
desired reacting the thus obtained compound with a
pharmaceutically acceptable acid base.
2. A compound of the formula
<IMG>
wherein Ra, Rb, A, R1 and R2 have the meanings defined
in claim 1 or a pharmaceutically acceptable salt thereof
when prepared by the process of claim 1.
3. The process of claim 1 wherein Ra and/or Rb is
hydrogen or alkylcarbonyl wherein the alkyl moiety has
from 1 to 4 carbon atoms and is straight or branched
which comprises
(a) when each of R2, Ra and Rb is hydrogen and A is
methylene or ethylidene treating one equivalent of a suit-
ably protected propargylamine derivative of the for-
mula (R8)3-SiC?C-CH2 N=CHR9 wherein R8 is C1-4 alkyl
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M1-913 Ca.
or triethylmethyl and R9 is phenyl, (CH3)3C- or
(CH3CH2)3C-, with a suitable strong base, optionally
in the presence of a divalent metal cation, alkylating
the thus formed protected propargylamine carbanion
intermediate with 2-propenal or 2-butenal, acylating
the alkylated derivative with an appropriate acid
halide, lower alkyl haloformate or tert-butoxycarbonylazide
followed by hydrolysis to give an amide or carbamate which
is treated with a suitable base to give the carboxamide
which is treated with trichloroacetonitrile in a suitable
solvent in the presence of a catalytic amount of base at
about -30° to 0°C for about 1/2 hour to 3 hours to give
the trichloromethylimidate ester which is heated to about
110° to 140°C in a non-polar solvent for about 1 to 10
hours to give the trichloromethylacetamide which is hydro-
lyzed using aqueous acid or base, said alkylating and acyla-
ting reactions being carried out in an aprotic solvent at
about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when each of R2, Ra and Rb is hydrogen and A is
ethylene, treating 1-hydroxypent-2-enal with a metal acetyl-
ide of the formula HC?CM' wherein M' is sodium, lithium or
MgX' wherein X' is chlorine or bromine or with a complex of
lithium acetylide/ethylenediamine in a suitable solvent at
about -70° to 25°C for about 1 minute to 3 hours to give
hept-7-en-6-yne-1,5-diol which is treated with phthalimide,
triphenylphosphine and diethyl diazodicarboxylate in ether
solvents for about 1 to 12 hours at about 25° to 50°C to
give the diphthalimido derivative which is treated with
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hydrazine hydrate in a lower alcohol solvent for about 1
to 6 hours at about 25° to 50°C followed by acid hydrolysis;
(c) when R2 is COR wherein R is hydroxy, R1 is -C?CH
and each of Ra and Rb is hydrogen, treating the correspond-
ing derivative wherein R2 is hydrogen and the amino and
acetylene groups are suitably protected as follows
<IMG>
wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl
or triethylmethyl and n is 1 or 2, with a suitable
strong base and acylating the thus formed carbanion inter-
mediate with a suitable acylating reagent in an aprotic
solvent at about -120°C to about 25°C for about 1/2 hour
to 24 hours followed by acid or base hydrolysis;
(d) when R2 is COR wherein R is hydroxy, R1 is
-CH=CH2, and each of Ra and Rb is hydrogen, treating the
corresponding derivative wherein R1 is -C?CH with a suit-
able alkali metal in liquid ammonia and ammonium sulfate
at about -70° to 25°C until the blue color persists for
about 15 minutes or by reducing the corresponding deriva-
tive wherein R1 is -C?CH, each of Ra and Rb is alkylcarbon-
yl and R2 is COR wherein R is alkoxy by catalytic or
organic semi-hydrogenation;
(e) when Ra or Rb is alkylcarbonyl wherein the alkyl
moiety is straight or branched and has from 1 to 4 carbon
atoms and R2 is hydrogen or COR wherein R is hydroxy,
treating the corresponding derivative wherein Ra or Rb is

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hydrogen or is suitably protected by a benzyloxycarbonyl
group or as an alkylisothiouronium salt or Rb is other than
hydrogen with an acid halide of the formula <IMG>
wherein halo is a halogen atom and R13 is a straight or
branched alkyl group of from 1 to 4 carbon atoms, or an
appropriate acid anhydride, in water in the presence of a
base at about 0° to 25°C for about 1/2 hour to 6 hours;
(f) when R is a straight or branched alkoxy group of
from 1 to o carbon atoms, reacting an acid halide of the
corresponding derivative wherein R is hydroxy with an
alcohol of the formula R8-OH wherein R8 is a straight or
branched alkyl group having from 1 to 8 carbon atoms,
saturated with HCl gas at about 25°C for from 12 to 36 hours;
(g) when R is -NR4R5 treating an acid halide of the
corresponding derivative wherein R is hydroxy and Ra and Rb
have the meanings defined in claim 1 with the proviso that
any free amino group is suitably protected with an excess
of an amine of the formula HNR4R5 wherein R4 and R5 have
the meanings defined in claim 1 or hexamethylenetetramine
in a suitable solvent at about 25°C for about 1 to 4 hours
followed by acid hydrolysis when appropriate to remove any
protecting group;
(h) when R is <IMG> wherein R6 has the meaning
defined in claim 1, treating the corresponding derivative
wherein R is hydroxy or a functional derivative thereof
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and Ra and Rb have the meanings defined in claim 1
with the proviso that any free amino group is suitably
protected with a compound of the formula <IMG>
herein R8 has the meaning defined above and R12 is
a lower alkyl group followed by acid and base hydrolysis
with the proviso that when the free acid is employed
the reaction is carried out with a dehydrating agent;
and
(i) when a pharmaceutically acceptable salt is
desired reacting the thus obtained compound with a
pharmaceutically acceptable acid or base.
4. A compound of the formula
<IMG>
wherein Ra and/or Rb is hydrogen or alkylcarbonyl wherein
the alkyl moiety has from 1 to 4 carbon atoms and is
straight or branched and A, R1 and R2 have the meanings
defined in claim 3 or a pharmaceutically acceptable salt
thereof when prepared by the process of claim 3.
5. The process of claim 1 which comprises
(a) when each of R2, Ra and Rb is hydrogen and A is
methylene or ethylidene treating one equivalent of a suit-
ably protected propargylamine derivative of the formula
(R8)3-Si-C?C-CH2-N=CHR9 wherein R8 is C1-4 alkyl or tri-
ethylmethyl and R9 is phenyl, (CH3)3C- or (CH3CH2)3C-,
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with a suitable strong base, optionally in the presence of
a divalent metal cation, alkylating the thus formed protec-
ted propargylamine carbanion intermediate with 2-propenal
or 2-butenal, acylating the alkylated derivative with an appro-
priate acid halide, lower alkyl haloformate or tert-butoxycar-
bonylazide followed by hydrolysis to give an amide or carbamate
which is treated with a suitable base to give the carboxamide
which is treated with trichloroacetonitrile in a suitable
solvent in the presence of a catalytic amount of base at
about -30° to 0°C for about 1/2 hour to 3 hours to give
the trichloromethylimidate ester which is heated to about
110° to 140°C in a non-polar solvent for about 1 to 10
hours to give the trichloromethylacetamide which is hydro-
lyzed using aqueous acid or base, said alkylating and
acylating reactions being carried out in an aprotic solvent
at about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when each of R2, Ra and Rb is hydrogen and A is
ethylene, treating 1-hydroxypent-2-enal with a metal acetyl-
ide of the formula HC?CM' wherein M' is sodium, lithium or
MgX1 wherein X1 is chlorine or bromine or with a complex of
lithium acetylide/ethylenediamine in a suitable solvent at
about -30° to 25°C for about 1 minute to 3 hours to give
hept-3-en-6-yne-1,5-diol which is treated with phthalimide,
triphenylphosphine and diethyl diazodicarboxylate in ether
solvents for about 1 to 12 hours at about 25° to 50°C to
give the diphthalimido derivative which is treated with
hydrazine hydrate in a lower alcohol solvent for about 1
to 6 hours at about 25° to 50°C followed by acid hydrolysis;
63

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(c) when Ra is <IMG>, R2 is hydrogen and Rb has the
meaning defined in claim 1, treating a compound of the
formula
<IMG>
wherein R1 and Rb have the meanings defined in claim 1 and
R3 is hydrogen wherein any free amino group is suitably
protected by a benzyloxycarbonyl group or by reaction
with an appropriate alkylisothiouronium salt, in the
the presence of a base at a pH of about 10 and a temperature
of about 25°C for about 6 to 60 hours followed by neutraliza-
tion and acid hydrolysis when appropriate to remove any
protecting group;
(d) when Ra or Rb is alkylcarbonyl wherein the alkyl
moiety is straight or branched and has from 1 to 4 carbon
atoms and R2 is hydrogen or COR wherein R is hydroxy,
treating the corresponding derivative wherein Ra or Rb is
hydrogen or is suitably protected by a benzyloxycarbonyl
group or as an alkylisothiouroniumsalt or Rb is other than
hydrogen with an acid halide of the formula <IMG>
wherein halo is a halogen atom and R13 is a straight or
branched alkyl group of from 1 to 4 carbon atoms, or an
appropriate acid anhydride, in water in the presence of a
base at about 0° to 25°C for about 1/2 hour to 6 hours;
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(e) when Ra and Rb is alkoxycarbonyl wherein the
alkoxy moiety is straight or branched and has from 1 to 4
carbon atoms, treating the corresponding derivative
wherein Ra or Rb is hydrogen or is suitably protected or
Rb is other than hydrogen with a halo alkylformate of the
formula <IMG> 4 wherein halo is a halogen atom and R14
is a straight or branched alkyl group having from 1 to 4
carbon atoms in water in the presence of a base at about
0° to 25°C for 1/2 hour to 6 hours;
(f) when Ra or Rb is <IMG> wherein R7 has the
meaning defined in claim 1, treating the corresponding
derivative wherein Ra or Rb is a hydrogen or is suitably pro-
tected or Rb is other than hydrogen with an acid of the
formula <IMG> or an anhydride thereof wherein the
amino group is suitably protected and R7 has the meaning
defined above in a suitable solvent and in the presence
of a dehydrating agent when the free acid is employed at
about 0° to 35°C for about 1 to 12 hours followed by base
hydrolysis; and
(g) when a pharmaceutically acceptable salt is
desired reacting the thus obtained compound with a pharma-
ceutically acceptable acid or base.
6. A compound of the formula

MI-913 Ca.
<IMG>
wherein R2 is hydrogen, and Ra, Rb, R1 and A have the mean-
ings defined in claim 5 when prepared by the process of
claim 5.
7. The process of claim 1 which comprises
(a) when R2 is COR wherein R is hydroxy, R1 is
-C?CH and each of Ra and Rb is hydrogen, treating the
corresponding derivative wherein R2 is hydrogen and the
amino and acetylene groups are suitably protected as
follows
<IMG>
wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or tri-
ethylmethyl and n is 1 or 2, with a suitable strong base
and acylating the thus formed carbanion intermediate with a
suitable acylating reagent in an aprotic solvent at about
-120°C to about 25°C for about 1/2 hour to 24 hours followed
by acid or base hydrolysis;
(b) when R2 is COR wherein R is hydroxy R1 is
-CH=CH2, and each of Ra and Rb is hydrogen, treating the
corresponding derivative wherein R1 is -C?CH with a
suitable alkali metal in liquid ammonia and ammonium
sulfate at about -70° to 25°C until the blue color per-
sists for about 15 minutes or by reducing the corres-
ponding derivative wherein R1 is -C?CH, each of Ra and
Rb is alkylcarbonyl and R2 is COR wherein R is alkoxy
by catalytic or organic semi-hydrogenation;
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(c) when Ra is <IMG>, R2 is hydrogen or COR wherein
R is hydroxy and Rb has the meaning defined in claim 1
treating a compound of the formula
<IMG>
wherein R1 and Rb have the meanings defined in claim 1 and
R3 is hydrogen or COOalkyl wherein the alkyl moiety has
from 1 to 8 carbon atoms and is straight or branched
wherein any free amino group is suitably protected
by a benzyloxycarbonyl group or by reaction with
an appropriate alkylisothiouronium salt, in the presence of
a base at a pH of about 10 and a temperature of about 25°C
for about 6 to 60 hours followed by neutralization and
acid hydrolysis when appropriate to remove any protecting
group;
(d) when Ra or Rb is alkylcarbonyl wherein the alkyl
moiety is straight or branched and has from 1 to 4 carbon
atoms and R2 is hydrogen or COR wherein R is hydroxy,
treating the corresponding derivative wherein Ra or Rb is
hydrogen or is suitably protected by a benzyloxycarbonyl
group or as analkylisothiouronium salt or Rb is other than
<IMG>
hydrogen with an acid halide of the formula
wherein halo is a halogen atom and R13 is a straight or
branched alkyl group of from 1 to 4 carbon atoms, or an
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appropriate acid anhydride, in water in the presence of a
base at about 0° to 25°C for about 1/2 hour to 6 hours;
(e) when Ra or Rb is alkoxycarbonyl wherein the
alkoxy moiety is straight or branched and has from 1 to 4
carbon atoms, treating the corresponding derivative
wherein Ra or Rb is hydrogen or is suitably protected or
Rb is other than hydrogen with a halo alkylformate of the
<IMG>
formula wherein halo is a halogen atom and R14
is a straight or branched alkyl group having from 1 to 4
carbon atoms in water in the presence of a base at about
0° to 25°C for 1/2 hour to 6 hours;
(f) when Ra or Rb is <IMG> wherein R7 has the
meaning defined in claim 1, treating the corresponding
derivative wherein Ra or Rb is hydrogen or is suitably pro-
tected or Rb is other than hydrogen with an acid of the
formula or an anhydride thereof wherein the
<IMG>
amino group is suitably protected and R7 has the meaning
defined above in a suitable solvent and in the presence
of a dehydrating agent when the free acid is employed at
about 0° to 35°C for about 1 to 12 hours followed by base
hydrolysis;
(g) when R is a straight or branched alkoxy group of
from 1 to 8 carbon atoms, reacting an acid halide of the
corresponding derivative wherein R is hydroxy with an
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alcohol of the formula R8-OH wherein R8 is a straight or
branched alkyl group having from 1 to 8 carbon atoms,
saturated with HCl gas at about 25°C for from 12 to 36 hours;
(h) when R is -NR4R5 treating an acid halide of the
corresponding derivative wherein R is hydroxy and Ra and Rb
have the meanings defined in claim 1 with the proviso that
any free amino group is suitably protected with an excess
of an amine of the formula HNR4R5 wherein R4 and R5 have
the meanings defined in claim 1 or hexamethylenetetramine
in a suitable solvent at about 25°C for about 1 to 4 hours
followed by acid hydrolysis when appropriate to remove any
protecting group;
(i) when R is wherein R6 has the meaning
<IMG>
defined in claim 1, treating the corresponding derivative
wherein R is hydroxy or a functional derivative thereof
such as an acid anhydride and Ra and Rb have the meanings
defined in claim 1 with the proviso that any free amino
group is suitably protected with a compound of the formula
<IMG> wherein R6 has the meaning defined above
and R12 is a lower alkyl group followed by acid and base
hydrolysis with the proviso that when the free acid is
employed the reaction is carried out with a dehydrating
agent; and
(j) when a pharmaceutically acceptable salt is
desired reacting the thus obtained compound with a pharma-
ceutically acceptable acid or base.
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8. A compound of the formula
<IMG>
wherein R2 is COR and R, R1, Ra, Rb and A have the meanings
defined in claim 7 or a pharmaceutically acceptable salt
thereof when prepared by the process of claim 7.
9. The process of claim 1 wherein each of Ra and Rb
<IMG>
is hydrogen or Ra is , and R2 is hydrogen or COR
wherein R is hydroxy or a straight or branched alkoxy group
of from 1 to 8 carbon atoms which comprises
(a) when R2 is hydrogen and A is methylene or
ethylidene treating one equivalent of a suitably pro-
tected propargylamine derivative of the formula
(R8)3-Si-C?C-CH2-N=CHR9 wherein R8 is C1-4 alkyl or
triethylmethyl and R9 is phenyl, (CH3)3C- or
(CH3CH2)3C-, with a suitable strong base, optionally
in the presence of a divalent metal cation, alkylating
the thus formed protected propargylamine carbanion inter-
mediate with 2-propenal or 2-butenal, acylating the alkyl-
ated derivative with an appropriate acid halide, lower
alkyl haloformate or tert-butoxycarbonylazide followed by
hydrolysis to give an amide or carbamate which is treated
with a suitable base to give the carboxamide which is
treated with trichloroacetonitrile in a suitable solvent
in the presence of a catalytic amount of base at about

MI-913 Ca.
-30° to 0°C for about 1/2 hour to 3 hours to give the
trichloromethylimidate ester which is heated to about
110° to 140°C in a nonpolar solvent for about 1 to 10 hours
to give the trichloromethylacetamide which is hydrolyzed
using aqueous acid or base, said alkylating and acylating
reactions being carried out in an aprotic solvent at about
-125° to 25°C for about 1/2 hour to 24 hours;
(b) when R2 is hydrogen and A is ethylene, treating
1-hydroxypent-2-enal with a metal acetylide of the formula
HC?CM' wherein M' is sodium, lithium or MgX' therein X' is
chlorine or bromine or with a complex of lithium acetylide/
ethylenediamine in a suitable solvent at about -30° to 25°C
for about 1 minute to 3 hours to give hept-3-en-6-yne-1,5-
diol which is treated with phthalimide, triphenylphosphine
and diethyl diazodicarboxylate in ether solvents for about
1 to 12 hours at about 25° to 50°C to give the diphthalimido
derivative which is treated with hydrazine hydrate in a
lower alcohol solvent for about 1 to 6 hours at about 25°
to 50°C followed by acid hydrolysis;
(c) when R2 is COR, R1 is -C?CH and each of Ra and Rb
is hydrogen, treating the corresponding derivative wherein
R2 is hydrogen and the amino and acetylene groups are
suitably protected as follows
<IMG>
wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or tri-
ethylmethyl and n is 1 or 2, with a suitable strong base and
acylating the thus formed carbanion intermediate with a suit-
able acylating reagent in an aprotic solvent at about -120°C
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to about 25°C for about 1/2 hour to 24 hours followed
by acid or base hydrolysis;
(d) when R2 is COR R1 is -CH=CH2, and each of Ra
and Rb iS hydrogen, treating the corresponding derivative
wherein R1 is -C-CH with a suitable alkali metal in liquid
ammonia and ammonium sulfate at about -70° to 25°C
until the blue color persists for about 15 minutes or by
reducing the corresponding derivative wherein R1 is -C?CH,
each of Ra and Rb is alkylcarbonyl and R2 is COR wherein R
is alkoxy by catalytic or organic semi-hydrogenation;
<IMG>
(e) when Ra is treating a compound of the
formula
<IMG>
wherein R1 and Rb have the meanings defined in claim 1 and
R3 is hydrogen or COOalkyl wherein the alkyl moiety has
from 1 to 8 carbon atoms and is straight or branched
wherein any free amino group is suitably protected
by a benzyloxycarbonyl group or by reaction with an
an appropriate alkylisothiouronium salt, in the presence of
a base at a pH of about 10 and a temperature of about 25°C
for about 6 to 60 hours followed by neutralization and
acid hydrolysis when appropriate to remove any protecting
group;
(f) when R is a straight or branched alkoxy group of
from 1 to 8 carbon atoms, reacting an acid halide of the
72

MI-913 Ca.
corresponding derivative wherein R is hydroxy with an
alcohol of the formula R8-OH wherein R8 is a straight or
branched alkyl group having from 1 to 8 carbon atoms,
saturated with HCl gas at about 25°C for from 12 to 36 hours;
and
(g) when a pharmaceutically acceptable salt is
desired reacting the thus obtained compound with a pharma-
ceutically acceptable acid or base.
10. A compound of the formula
<IMG>
<IMG>
wherein each of Ra and Rb is hydrogen or Ra is R2
is hydrogen or COR wherein R is hydroxy or a straight or
branched alkoxy group of from 1 to 8 carbon atoms and A and
R1 have the meanings defined in claim 9 or a pharmaceutical1y
acceptable salt thereof when prepared by the process of
claim 9.
11. A process for preparing 1,4-hex-2-en-5-ynediamine
or a pharmaceutically acceptable salt thereof which comprises
treating one equivalent of a suitably protected propargyl-
amine derivative of the formula (CH3)3-Si-C?C-CH2-N=CHR9
wherein R9 is phenyl, (CH3)3C- or (CH3CH2)3C-, with
a suitable strong base, optionally in the presence
of a divalent metal cation, alkylating the thus
formed protected propargylamine carbanion intermediate
73

MI-913 Ca.
with 2-propenal acylating the alkylated derivative with an
appropriate acid halide, lower alkyl haloformate or tert-
butoxycarbonylazide followed by hydrolysis to give an amide
or carbamate of 1-amino-1-trimethylsilylacetylenebut-3-
en-2-ol which is treated with a suitable base to give the
carboxamide of 4-aminohex-1-en-5-yn-3-ol which is treated
with trichloroacetonitrile in a suitable solvent in the
presence of a catalytic amount of base at about -30° to 0°C
for about 1/2 hour to 3 hours to give the trichloromethyl-
imidate ester which is heated to about 110° to 140°C in a
nonpolar solvent for about 1 to 10 hours to give the tri-
chloromethylacetamide which is hydrolyzed using aqueous
acid or base, said alkylating and acylating reactions
being carried out in an aprotic solvent at about -125° to
25°C for about 1/2 hour to 24 hours; and when a pharma-
ceutically acceptable salt is desired reacting the thus
obtained compound with a pharmaceutically acceptable acid.
12. The compound 1,4-hex-2-en-5-ynediamine or a
pharmaceutically acceptable salt thereof when prepared by
the process of claim 11.
13. A process for preparing 2,5-hept-3-en-6-ynedi-
amine or a pharmaceutically acceptable salt thereof which
comprises treating 1-hydroxypent-2-enal with a metal
acetylide of the formula HC?CM' wherein M' is sodium,
lithium or MgX' wherein X' is chlorine or bromine or with
a complex of lithium acetylide/ethylenediamine in a suit-
74

MI-913 Ca.
able solvent at about -30° to 25°C for about 1 minute to 3
hours to give hept-3-en-6-yne-1,5-diol which is treated
with phthalimide, triphenylphosphine and diethyl diazo-
dicarboxy1ate in ether solvents for about 1 to 12 hours at
about 25° to 50°C to give the diphthalimido derivative
which is treated with hydrazine hydrate in a lower alcohol
solvent for about 1 to 6 hours at about 25° to 50°C followed
by acid hydrolysis; and when a pharmaceutically acceptable
salt is desired reacting the thus formed compound with a
pharmaceutically acceptable salt.
14. The compound 2,5-hept-3-en-6-ynediamine or a
pharmaceutically acceptable salt thereof when prepared by
the process of claim 13.
15. A process for preparing a compound of the formula
<IMG>
wherein A is methylene, R1 is -C?CH, R2 is COOH and each
of Ra and Rb is hydrogen which comprises treating 1 equiva-
lent of a carbamate of 1-amino-1-trimethylsilylacetylenebut-
3-en-2-ol with 1 equivalent of trichloroacetonitrile in a
suitable solvent in the presence of a catalytic amount
of base at about -30° to 0°C for about 1/2 hour to 3 hours
to give the trichloromethylimidate ether which is heated
to about 110° to 140°C in a non-polar solvent for about 1
to 10 hours to give the trichloromethylacetamide which is

MI-913 Ca.
treated with trifluoroacetic acid followed by treatment
with 1 equivalent of benzaldehyde to give N-(4-benzylimino-
4-trimethylsilylacetylenebut-2-enyl)trichloromethyl-
acetamide which is treated with 2 equivalents of a strong
base, acylated with a suitable acylating reagent and sub-
sequently hydrolyzed using aqueous acid.
16. The compound of the formula
<IMG>
wherein Ra, A, Rb, R1 and R2 have the meanings defined in
claim 15 or a pharmaceutically acceptable salt thereof
when prepared by the process of claim 15.
76

Description

~ ~ Z~ M~-91
FIELD OF INVENTION
This lnvention relates to novel pharmaceutically useful
acetylenic derivatives of amines and amino acids and novel
vtnyl derivatives of amino acids~
SUMMARY OF INVENTION
.
The compounds of the present invention are represented
by the following general Formula I
RaHN(A) C=f-C-R2 Formula I
H NHRb
wherein A is methylene, ethylene or ethylidene; R1 is -CeCH
or -CH=CH2; R2 is hydrogen or COR wherein R is hydroxy, a
straight or branched alkoxy group of from 1 to 8 carbon
atoms, -NR4R5 wherein each of R4 and Rs is hydrogen~ or a
straight or branched lower alkyl group of from 1 ~o 4 car-
bon atoms or -NH-CHCOOH wherein R~ is hydrogen, a straight
R~ -
5 or branched lower alkyl group of from 1 to 4 carbon a~oms3H~
benzyl or p-hydroxybenzyl 3 Ra iS hydrogen, H2N-C-~ alkyl-
carbonyl wherein the alkyl moiety has from 1 to 4 carbon
a~oms and is straight or branched,~alko~ycarbonyl wherein
the alkoxy moiety has from 1 to 4 carbon atoms and is
straight or branched or -~-CH-R7 wherein R7 is hydrogen, a
NHz
straight or branched lower alkyl group of from 1 to 4 carbon
atoms, benzyl or p-hydroxybenzyl; and Rb has the same mean-
HN
7ng defined for Ra except Rb iS no~ H2N-C-, and Ra and Rb

3~7~
MI-913
can be the same or different; with the provisos that when
R2 is hydrogen, R1 is -C-CH; when A is ethylidene, Rz is
HN
hydrogen; and when Ra iS HlN-C-~ A Ts methylene.
The pharmaceutically acceptable sal~s and individual
opttcal isomers of the compounds of general Formula I are
included within the scope of the present invention.
DETAILED DESCRIPTION OF INVENTION
In the above general Formula I methylene is taken to
mean -CH2-; ethylene is taken to mean -CH2CH2-; ~nd ethyli-
IH3
dene is taken to mean -CH-.
It is evident from the foregoing general Formula I that
. the compounds of the presen~ invention are acetylene deriva-
tives of amines and amino acids or are vinyl derivatives of
amino acids.
As set forth hereinabove Rb has the same meaning as Ra
H~
except Rb is not H2N-C-. That is, Rb is hydrogen, alkyl-
carbonyl wherein the alkyl moiety has from 1 to 4 carbon
atoms and is straight or branched, alkoxycarbonyl wherein
the alkoxy motety has from 1 to 4 carbon atoms and i5 straight
or branched or -~ CH-R7 wherein R7 is hydrogen, a straight
1H2
or branched lower alkyl group of from 1 to 4 carbon atoms,
benzyl or p~hydroxybenzyl.
As used in general Formula I the term alkylcarbonyl is
taken to mean the group -C~alkyl wherein the alkyl moie~y
-2-

~ 37 5 Ml-913
has from 1 to 4 carbon atoms and is straight or branched,
for example, methyl, ethyl, n-propyl, isopropyl, n^butyl,
isobutyl and tert-butyl.
As used in general Formula I the term alkoxycarbonyl
Ts taken to mean the group -C-O~alkyl wherein the alkoxy
moiety, that is, -0-alkyl, has from 1 to 4 carbon atoms and
is straight or branched, for example, methoxy, ethoxy, n-
propoxy, isopropoxy, n-butGxy, and tert-butoxy.
Illustrative examples of straigh~ or branched alkyl
groups having from 1 to 4 carbon atoms as used in general
Formula I are methyl, ethyl, n-propyl, n-butyl, isopropyl
and tert-butyl.
Illustrative example~ of alkoxy groups having from 1
to 8 carbon atoms as used in general Formula I are methoxy,
ethoxy, propoxy, butoxy, pentyloxy, and octyloxy.
Illustrative examples of pharmaceutically acceptable
salts of the compounds of this invention include non-toxic
acid addition salts formed with inorganie acids, such as3
hydrochloric, hydrobromic, sulfuric and phosphoric acid3
and organic acids, such as, methane sulfonic, salicylic,
maleic, malonic, tartaric, citric and ascorbic acids; and
non-toxic salts formed with inorganic or organic bases such
as those of alkali metals, for example, sodium, potassium
and lithium, alkaline earth metals, for example, calcium and
magnesium, light metals of Group lll A, for example, alumi-
num, organic amines, such as, primary, secondary or tert;ary
amines, for example, cyclohexylamine, ethylamine, pyridine~
me~hylamino ethanol, ethanolamine and piperazine. The salts
are prepared by conventional means.

- ~ ~2 ~ 37 5 Ml-913
Preferred compounds of this invention are those of
g~neral Formula I wherein R3 is hydrogen or alkylcarbonyl
wherein the alkyl moiety has from 1 to 4 carbon atoms and
is s~raTght or branched with compounds wherein R3 is hydro-
gen being more preferred. Compounds wherein A is methylene
or ethylidene are also preferred with compounds wherein A
is methylene being more preferred. Also compounds wherein
R2 is hydrogen or COR wherein R is hydroxy or a straight or
branched alkoxy group of from 1 to 8 carbon atoms represents
another preferred embodiment of this invention.
Illustrative examples of compounds of the present inven-
tion are the following:
1,4-hex-2 en-5-ynediamine,
1,5-hept-3-en-6-ynediamine,
2,5-hept-~-en-6-ynediamine,
2-acetylene-2,5-diaminopent-3-enoic acid~
2-acetylene-2,6 diaminohex-3-enoic acid,
2,6-diamino-2-vinylhex-3-énoic acid,
N-(1-acetylene-4-aminobut-2-enyl)~2-aminoace~amide,
N-(1-acetylene-4-aminobut~-enyl)acetamide,
N-(1-acetylene-5-aminopent-2-enyl)butyramide~
N-(1-acetylene-4-aminopent-2-enyl)acetamide,
methyl N-(1-acetylene-4-aminobut-2-enyl)carbamate,
methyl 2-acetylene-2,6-diaminohex-3-enoate,
tert-butyl 2l5-diamino-2-vinylpent-3-enoate3
n-hexyl 2,6-diamino-2-vinylhex 3-enoate,
ethyl 2-acetylene-5-amino-2-(1-oxoethylamino~pent-3-enoate,
n-butyl 5-amino~2-ethoxycarbonylamino-2-vinylhex-~-enoate,
2-acetylene-5-amino-2-(1-oxoethylamino)hex-~-enamide,
N-ethyl-2-acetylene-2,5 diaminopent-~-enamideg

~ 3~ 5 MI-913
N,N'-di-n-propyl-5-amino-2-mathoxycarbonylamino-2-vinylpent-
3-enamide,
2-acetylene-2,5-di-(1-oxopropylamino)pent-3-enoic acid,
isopropyl 2,5-di-(n-butoxycarbonylamino)-2-vinylhex-~
enoate,
2-[2-acetylene-2~5-diamino-1-oxopent-3-enylamino]acetic
acid, and
2~5-diamino-2-vinylpen~-~-enois acid.
The compounds of general Formula I are irreversible
inhibitors of decarboxylase enzymes which are involved in
polyamine formation rendering said compounds useful as
pharmacological agents. Polyamines, particularly putrescine,
spermidine and spermine are present in plant and animal
tissues and in some microorganisms. Al~hough the exact
physiological role of polyamines has not been clearly delin-
eated there is evidence to suggest that polyamines are
involved with cell division and growth. (H.G. Williams-
Ashman et al., The Italian J. Biochem~ 25, 5-32 (1976),
A. Raina and J. Janne, Med. BiolO 5~3 121-147 (1975) and
D~H. Russell, Life Sciences 13, 16~5-1647 (lg7~)). Poly-
amines are essential growth factors for or involved in the
growth processes of certain microorganisms, for example,
E. colT, Enterobacter, Klebsiella~ Staphylococcus aureus,
C. cadaveris~ Salmonella typhosa and Haemophilus parainflu-
?5 enza. Polyamines are associated with both normal and neo-
plastic rapid growth ~here being an increase in ~he synthe-
sis and accumulation of polyamines foilowing a stimulus
causing cellular proliferation. Also~ levels of polyamines
are known ~o be high in embryonic systems, leukemic cells
~0 and other rapidly growing tissues. !t is known that ~here
-5-

l~L23L3~5 M I - 91~
Is a correlation between the activity of the decarboxylase
enzymes of ornithine, S-adenosylmethionine, arginine and
lysine and polyamine formation.
The biosyntheses of putrescine, spermidine and spermine
are interrelated. Putrescine is the decarboxylation product
of ornithine, catalyzed by ornithine decarboxylase. Putres-
cine formation may also occur by decarboxylation of arginine
to form agmatine which is hydrolyzed to give pu~rescine and
urea. Arginine is also involved in ornithine formation by
action of the enzyme arginase. Activation of methionine by
S-adenosylmethionine synthetase forms S-adenosylmethionine
which is decarboxylated, after which the propylamine moiety
of activated methionine may be transferred to putrescine to
form spermidine and to spermidine to form spermine. Hence,
putrescine serves as a pr~cursor to spermidine and spermine
and additionally h~s been shown to have a marked regulatory
effect upon the polyamine biosynthetic pa~hway in that it
has been shown that increased synthesis of putrescine is
the first indicatîon that a tissue will undergo renewed
growth processes. Cadaverine which is the decarboxylation
product of lysine has been shown to stimulate the activity
of S-adenosyl methionine decarboxylase and is known to be
essential to growth processes of many microorganisms, for
example, H. paralnfluenza.
The compounds of general Formula I are irreversible
inhibitors of ornithine decarboxylase and lysine decarboxy-
lase rendering said compounds useful as an~iinfective agents
being effective in the control of microorganisms, for ex-
ample, bacteria, fungi and viruses which are dependent upon
~0 polyamines for growth~ for example, E co1i, Enterobacter,
-6-

3 MI-91~
~lebsiella, Staphylococcus aureus, C. cadaveris, viruses
such as~ H. parainfluenza~ picornaviruses, for example,
encephalomyocarditis, herpes simplex, poxviruses and arbo-
viruses, for example, Semliki forest. The compounds of
general Formula I wherein A is methylene or ethylidene are
also useful in the control of certain rapid growth processes.
For example, said compounds are useful in the inhibition of
spermatogenesis and embryogenesis and therefore the compounds
find use as male antifertility a~ents and abortifacients.
The compounds are also useful in the inhibition of the
immune response, thus the compounds are useful as immuno-
suppressants for the treatment, for example, of myasthenia
gravis, arthritis, multiple sclerosis and thè prevention of
tlssue or organ transplant rejection, and are useful in the
control of neoplastic growth, for example, solId tumors,
leukemias and lymphomas. The compounds are also useful as
inhibitors of prostatic ~hypertrophy, excessive scalp cell
srowth as found with the occurrence of dandruff and as in-
hibitors of abnormal cutaneous cell growth as found with a
psoriatic condition. In administering the compounds of
general Formula I wherein A is methylene or ethylene it may
be desirable to administer concurren~ly by known procedures
a monoamine oxidase inhibitor such as trans(~)-2-phenyl-
cycloproponamine or N-benzyl-N-methyl-2-propynylamine~ The
utility of compounds of general Formula I as irreversible
inhibitors of ornithine or S-adenosylmethionine d~carboxy-
lase enzymes may be measured as follows. An aqueous solu-
tTon of an appropriate compound is given orally or paren-
~erally to male rats or mice. From 1 to 48 hours after
administration of the compound the animals are sacrificed

~ ~ ~ Ml-913
and the ventral lobes of the prostate removed and homogen-
ized with the activity of ornithine and S-adenosylmethionine
decarboxylases being measured as generally described by
E.A. Pegg and H.G. Willaims-Ashman, Biochem. J. 108~ 573-
539 (1968) and J. Janne and H.G. Will;ams-Ashman, Biochem.
and Biophysr Res. Comm. 42, 222-228 (1971).
The compounds of general Formula I wherein A is methyl-
ene or ethylene are metabolic precursors of compounds having
the following structure
l-CH
Hooc(cH2)n- f H Formula ll
NH2
wherein n is 2 or 3 which are known to be irreversible
inhibitors of y-aminobutyric acid transaminase and upon
administration resul~s in higher brain levels of y-amin
butyric acid (GABA). As precursors of y-acetylenic-~-
aminobutyric acid the above-described compounds of Formula I
are useful in the treatment of disorders of the central
nervous system consisting o~ involuntary movement assoclated
with Huntington's chorea, Parkinsonism, extra-pyramidal
effects of drugs, for exampleJ neuroleptics, seizure dis-
orders associated with epilepsy, alcohol withdrawal, barbi-
turate withdrawal, psychoses associated with schizophreniaJ
depression, manic depression and hyperkinesis.
Several previous studies have shown that y-aminobutyric
acid is a major inhibitory transmltter of the central ner-
vous system as reportedJ for exampleg by Y. Godin et al.,
Journal Neurochemistry, 16, 869 (1969) and that disturbance
of the excitation and inhibition ;nterplay can lead to
diseased states such as Huntington's chorea (The Lancet,
-8-

~ 37 5 M~-91~
November 9, 1974g pp. 1122-112~) ~arkinsonism, schizophrenia,
epilepsy, depression, hyperkinesis and manic depression
dlsorders, Biochem. Pharmacol. 23, 2637-2649 (1g74).
That the compounds of general Formula I wherein A is
methylene or ethylene and R2 i5 hydrogen are converted
metabolically to the compounds of Formula ll may be demon-
strated by the protect;ve effect of the compounds on audio-
genic seizures in mice of the DBA strain measured by the
general method described by Simler et al.~ Biochem. Pharma-
co7. 22, 1701 (1g73) which is currently used to evidence
antiepîleptic activity.
The compounds of general Formula I wherein R2 i5 hydro-
gen are useful as chemical intermediates for the prepara~ion
of novel cephalosporin derivatives of the following general
Formula lll, and the compounds of general Formul~ I wherein
R2 is COR and R is hydroxy are useful as chemical inter-
mediates for the preparàtion of novel cephalosporin deriva-
tives of the following general Formula IV. The cephalosporin
compounds of Formulas lll and l~ are useful as antibioties.
C8CH O
H2N- (A) ~CH=CH-CH-NHCH2~CH2CNH~S
o , ~H2Y
COCM
Formula lll
Rl O
H2N (A)-CH-CH-C - C-NH~
NH2 0 ~ ~ CHzY
COOM
Formula IV

1 ~Z~ 37 ~ MI-913
In the above general Formulas III and IV A and R1 have the
meanlngs defined in general Formula I; M is hydrogen or a
negative charge; and Y is hydrogen or acetoxy.
The compounds of general Formulas III and IV and the
pharmaceutically acceptable salts and individual optical
Isomers thereof are novel compounds useful as antibiotics
and can be administered in a manner similar to that of many
well known cephalosporin derivatives, for example, cepha-
lexin, cephalothin, or cephaloglycine. The compounds of
general Formulas III and IV and pharmaceutically acceptable
salts and isomers thereof can be admînistered alone or in
the form of pharmaceutical preparations either orally or
parenterally and topically to warm blooded animals~ that is,
birds and mammals, for example, cats, dogs, bovine cows,
sheep, horses and humans. For oral administration the
compounds can be administered in the form of tablets,
capsules or pills or in the form of elixirs or suspensions.
For parenteral administration~ the compounds may best be
used in the form of a sterile aqueous solution which may
contain other solutes, for xample, enough saline or glucose
to make the solution isotonic. For topical administrat;on
the compounds of general Formulas III and IV, salts and
isomers thereof may be incorporated ;nto creams or ointments,
Illustrative examples of bacteria against which the
compounds of general Formulas III and IV and the pharmaceu-
t;cally acceptable salts and individual optical isomers
thereof are active are Staphylococcus aureus, Salmonella
schotmuehleri~ ~ , Diplococcus pneumoniae
and Streptococcus pyo~enes.
-10-

~ ~z ~ Ml-913
Illustrative pharmaceutically acceptable non-toxic
inorganic acid addition salts of the compounds of general
Formula lll are mineral acid addition salts, for example,
hydrogen chloride, hydrogen bromide, sulfates, sulfamates,
phosphate, and organic acid addition salts are, for example,
maleate, acetate~ citrate, oxalate, succinate, benzoate,
tartrate, fumarate, malate and ascorbate. The salts can be
formed by conventional means.
Illustrative examples of compounds of general Formulas
lll and IV are 7-[[2-[4~ acetylene-4-aminobut-2-enylamino~
methyl)phenyl]acetyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-
1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 7-[2-
aee~ylene-2,5-diamino-1-oxopent-3-enamino]-3-acetyloxy-
methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox-
ylic acid.
The preparation of the compounds of general Formulas
lll and IV is described`hereinbelow~
As pharmacolog;cally us~ful agents the compounds of
general Formula I can be administered in various manners to
the pa~ient being treated ~o ach;eve the desired effect.
The pharmacologically useful compounds of this invention can
be used alone or in combination with one another. Also,
the pharmacologically useful compounds of this invention
may be administered in the ~orm of a pharmaceutical prepa-
; 25 rat;on. The compounds may be admînistered orally, paren~-
erally, for example, intravenously, in~raperitoneally, or
; subcutaneously, or topically. The amount of compound
administered will vary over a wide range and can be any
effective amount. Depending on the patient to be treated,
the condftion being treated and the mode of administration,

~ ~ ~ ~ ~ ~ Ml-91~
the effective amount of compound administered will vary from
about 0,1 mg/kg to 500 mg/kg of body weight of the patient
per unit dose and preferably will be about 10 mg/kg to about
100 mg/kg of body weight of patient per unit dose. For
example, a typical unit dosage form may be a tablet con-
taining from 10 to ~00 mg of a compound of Formula I which
may be administered to the patient being treated 1 to 4
times daily to achieve the desired effect.
As used herein the term patient is taken to mean warm
blooded animals such as mammals, for example, cats, dogs,
rats, mice, guinea pigs, horses, bovine cows, sheep and
humans.
The solid unit dosage forms can be of the conventional
type. Thus, the solid form can be a capsule which can be of
the ordinary gelatin type containing a novel compound of
this invention and a carrier, for example, lubricant and
inert fillers such as lactose, sucrose and corn starch. In
another embodiment, the novel compounds are tableted with
conventional tablet bases such as lactose, sucrose or corn
starch in combination with binders such as acacia, corn
starch or gelatin, disintegrating agents such as orn starch,
potato -starch, or alginic acid and a lubricant such as
stearic acid, or magnesium stearateO
For parenteral administration the compounds may be
administered as injectable dosages of a solution or sus-
pension of the compound in a physiologically acceptable
diluent with a pharmaceutical carrier which can be a sterile
liquid such as water and oils with or without the addition
of a surfactan~ and other pharmaceutically acceptable
adjuvants. Illustrative of oils which can be employed in
~12-

~Z~37~ MI-913
these preparations are those cf petroleum, animal, vegetable
or synthetic origin, for example, peanut oil, soybean oil,
and mineral oil. In general, water, saline, aqueous dex-
trose, and related sugar solutions, ethanols and glycols
~uch as propylene glycol or polyethylene glycol are preferred
liquid carriersj particularly for injectable solutions.
The compounds can be administered in the form of a
depot injection or implant preparation which may be formu-
lated in such a manner 25 to permit a sustained release of
the active ingredient. The active ingredient can be com-
pressed into pellets or smal1 cylinders and implanted sub-
cutaneously or intramuscularly as depot injections or
implants. Implants may employ inert materials such as
biodegradable polymers or synthetic silicones, for example,
Sîlastic, silicone rubber manufactured by the Dow-Corning
Corporati~n.
The compounds of general Formula I wherein each of ~2,
Ra and Rb is hydrogen and A is methylene or ethylidene are
prepared by treating 1 equivalent of a suitably protected
propargylamine with a strong base, optionally in the pr~-
sence of a divalent metal cation, for example, zinc iodide
or magnesium bromide to ~orm a protected propargylamine
carbanion intermediate which is alkylated with 2-propenal
or butenal then acylated with an acid halide, such as,
~5 alkanoyl halides, for example, acetyl chloride or propionyl
chloride or aroyl halides, such as, benzoyl chloride or a
lower alkyl haloformate, or tert-butoxycarbonylazide and
subsequently hydrolyzed to an amide or carbamate of 1-amino-
1-trimethylsilylacetylenebut-~-en-2-ol which is treated with
a base, such as, sodium or potassium bicarbonate, sodium or
-13-

1~21375 Ml-9~3
potassium carbonate, sodium hydroxide or potassium hydroxide
to give the carboxamide of 4-aminohex-1-en-5-yn-~-ol which
is treated with trichloroacetonitrilP in a solvent, such as,
ethers, for example, diethyl etherJ tetrahydrofuran, diox-
ane, dimethoxyethaneJ hydrocarbons, such as, benzene or
toluene in the presence of a catalytic amount of a base
such as sodium hydride~ potassium tert-butoxide, lithium
alkylamides, for example, lithium diisopropylamide or alkyl
lithium at about -30C to 0C for about 1/2 hour to 3 hours
to give the trichloromethylimidate ester which is heated to
about 110 to 140C in a non-polar solvent, for example,
xylene, toluene, nitrobenzene or chlorobenzene for about
1 to 10 hours to give the trichloromethyl acetamide which
is hydrolyzed using aqueous acid, for example, hydrochloric
acid or aqueous base, for example, sodium or potassium
hydroxide.
The above described alkylation and acy1ation reaction
may be carried out in an aprotic solvent, for example,
benzene, toluene, e~hers, tetrahydrofuran, ~imethylsulfox-
ide or hexamethyl phosphortriamide. The react7On tempera-
tùre varies from about ~125 to 25C for about 1/2 hour to
24 hours.
Hydrolysis to give the amlde of 1-amino-1-trimethyl-
silylacetylenebut-3-en-2-ol is achieved by treatment with
hydrazine, phenylhydrazine or hydroxylamine or by treatment
with mineral acids, for example, hydrochloric acid followed
: by treatment with an organic base such as triethylamine or
pyridine in a lower alcoholic solvent, such as, methanol or
ethanol at about 80 to 110C for about 1/2 hour to 2 hours.
The suitably protected propargylamine employed in the

~ 2~L3~ ~ Ml-91~
above reaction may be represented by the following general
Formula V
(R8 )3 -5 i -C-C -IH2 Formula V
N=CHRg
wherein R8 is a straight or branched lower alkyl group hav-
ing from 1 to ~ carbon atoms3 such as, methyl, ethyl, n-
propyl and tert-butyl or triethylmethyl~ The compounds of
Formula V are prepared by the addition of protecting groups
on the acetylene function and the nitrogen function of pro-
pargylamine~ Protection of the nitrogen function of the
propargylamine is accomplished by forming in a known manner
a Schiff's base with a non-enolizable carbonyl bearing com-
pound selected from benzaldehyde, 2,2~dimethylpropanal and
- 2,2-diethylbutanal. Protection of the acetylenic function
is accomplished by reacting the above-described Schiff1s
base with a trialkylsilyl chloride wherein the alkyl moiety
has from 1 to 4 carbon atoms and is straight or branched,
f~r example, trimethylsilylchloride or ~riethylsilylchloride
forming in a known manner the corresponding trialkylsilyl
derivativeO
. Suitable strong bases which may be employed in the
above reaction to form the carbanion are those which will
abstract a proton from the carbon atom adjacent to the
acetylene moiety, such as~ alkyl li~hium, for example, butyl
lithium or phenyl lithium, lithlum di-alkylamide, for example,
lithium diisopropylamide, lith7um amide~ tertiary potassium
butylate or sodium amide.
: The compounds of general Formula I wherein each of R2,
Ra and Rb iS hydrogen and A is ethylene are prepared by
treating 1-hydroxypent-2-enal with a metal acetylide of the
-15-

MI-913
formula HC_CM' wherein M' is sodium, lithium or MgX' where-
in X' is chlorine or bromine or with a complex of lithium
acetylide/ethylenediamine in a solvent such as liquid
ammonia, dimethylsulfoxide, ethers, for example, tetra-
hydrofuran, dioxane, diethyl ether or dimethoxyethane atabout -~0 to 25C for about 1 minute to 3 hours to give
hept-3-en-5-yne-1,5-diol. When sodium or lithium acetylide
are employed liquid ammonia is the preferred solvent. When
lithium acetylide is employed ether solvents are also pre-
1~ ferred. Ether solvents are preferred when magnesium halideis employed with preferred reaction temperatures of about
0 to 25C. When the complex lithium acetylide-ethylene-
diamine is employed the preferred solvent is dimethylsulfox-
ide with a temperature of 25C and time of about 1 to 12
: 15 hoursO
The diol derivative ;s treated with phthalimide, tri-
phenylphosphine and diethyl diazodicarboxylate in ethers
such as tetrahydrofuranJ diethyl ether or dioxane for about
1 to 1 hours at about 25~ to 50C to a~ford the corres-
ponding diphthalimido derivative which is treated with
hydrazine hydrate in a lower alcohol solven~ such as
methanol or ethanol for about 1 to 6 hours at about 5
to 50C followed by treatment with acid, for ~xample,
6NHCl, for 1 to 10 hours at 100C,
The compounds of general Formula I wherein R, is
-C-CH, each of Ra and Rb is hydrogen, A is methylene or
ethylene, and R2 is COR wherein R is hydroxy are prepared
by treating the çorresponding derivative wherein R2 is
hydrogen and wherein the amino groups and the acetylene
~0 group are suitably protected~ having the structure
~16-

~z~375 Mj-91~
C--CSi(R10)3
RllHC=N-(CH2)n CH=CH-CH-N-CHR11 Formula VI
with a strong base and acylating the thus formed carbanion
intermed;ate followed by acid or base hydrolysis.
In the above general Formula VI R1o is a straight or
branched alkyl group having from 1 to 4 carbon atoms such
as methyl, ethyl, n-propyl3 isopropyl or n-butyl; R11 is
phenyl, tert-butyl or triethylmethyl; and n is the integer
1 or 2.
Suitable strong bases which may be employed in the
above reaction to form each carbanion are those which will
abstract a proton from the carbon atom adjacent to the
acetylene moiety, such asJ alkyl lithium, for example,
butyl lithium or phenyl lithium~ lithium di-alkylamide,
for example, lithium diisopropylamide, lithium amide~
tertiary potassium bu~ylate or sodium amide.
Suitable acylating agents which may be employed in the
above reaction are halo-formates, such as chloro methyl-
formate or chloro ethylformate, azido tert-butylformate,
~yanogen bromide, carbon dioxide, diethylcarbonate, phenyl-
isocyanate, triethoxymethylium tetrafluoroborate, N,N-
dimethylcarbamoyl chloride, 2-methylthio~1,3-dithiolinium
iodide, ethylene carbonate or ethylene trithiocarbonate.
When 2-methylth;o~ -dithiolinium iodide is employed the
additional step of alcoholysis with a lower alcohol, For
example, ethanol or lsopropyl alcohol is required prior to
deprotection by hydrolysisO
The acylating reaction may be carrled out in an aprotic
solvent, for example, benzene~ toluene, ethers, tetrahydro-
furan, dimethylsulFoxide, hexame~hyl phosphortriamide~ The
~17-

31~2137~
Ml-91~
reaction temperature varles from -120C to about 25C, a
preferred temperature being about -70C, and the reaction
time vartes from about 1/2 hour to 24 hours.
Hydrolysis is achieved by treatment with aqueous acid,
for example, hydrochloric acid, or aqueous base, for ex-
ample, sodium hydroxide or potassium hydroxide.
The compounds of Formula Vl are prepared by the addi-
tion of protecting groups on the acetylene function and the
amino groups of a compound of the formula:
C_CH
H2NCH2(CH2) ~ CH~CH-CH Formula Vll
o~ ~
NH2
Pro~ection of the amino groups is accomplished ~y forming
in a known manner a Schiff's base with a nonwenolizable
carbonyl bearing compound selected from benzaldehyde, 2~2-
d;methylpropanal and 2,2-diethylbutanal. Protection of
the acetylenic function is accomplished by reacting the
above-described Schiff's base with a trialkylsilyl chlor-
ide wherein the alkyl moiety has from 1 to 4 oarbon atoms
and is straight or branched, for exampleJ trimethylsilyl-
chloride or triethylsilylchloride forming in a known
manner the corresponding trialkylsilyl derivative,
The compounds of general Formula I wherein R1 is
-CH=CH2, R2 is COR wherein R is hydroxy and each Qf Ra and
Rb iS hydrogen are prepared by trcating the corresponding
derivative wherein R1 is -C-CH with sodium~ potassium or
lithium in liquid ammonia and ammonium sulfate at about
-70 to 25~C until the blue color persists for about 15
minutes. These compounds may also be prepared by cata-
lytic or organic semi-hydrogenation of the corresponding

~ ~ 2 ~ 37 5 Ml-913
derivative wherein R1 is -C--CH/ Rz is COR and R is alkoxy
and each of Ra and Rb iS alkylcarbonyl. After reduction
the protecting groups are rernoved by acid or base hydroly-
sis~ Catalytic hydrogenation may be carried out in the
presence of a base, for example, pyridine or triethylamine
using inorganic catalysts as described by E.N. Marvell and
1. Li3 Synthesis, No. 8, August, 1973, pp. 457-468, for
example, palladium-on-barium sulfate or the Lindlar cata-
lyst, that is, lead-poisoned palladium-on-calcium carbo-
nate. The hydrogenation process is continued until thereis a reduction in the uptake of hydrogen.
The organic semi-hydrogenation is achieved by reacting
equimolar amounts of the appropriate acetylene derivative
and catecholborane under a nitrogen atmosphere at abou~
70C for about 2 hours by the general procedures described
by H.C. Brown and S.K. Gupta~ J. Am. Chem. Soc. 94
4~70-4~71 (1972) and H.C. Brownl et al., J. Am. Chem. Soc.
95, 5786-5788 and 6456-6457 (1973).
The compounds of general Formula I wherein Ra iS
H~
H2N-C-, R2 is hydrogen or COR wherein R is hydroxy and Rb
has the meaning deflned in general Formula I are prepared
by treating a compound of the formula
~1
H2NCH2c =f -C-R3 Formula Vlll
H NHRb
wherein R1 and Rb have the meanings defined in Formula I
and R3 is hydrogen or COOalkyl wherein the alkyl group has
from 1 to 8 carbon atoms and is s~raight or branchedl for
example, methylJ ethyl) isopropyl or n-butyl, with the
-19

~ 3~ ~ M1-913
proviso that any free amino group is suitably protected
with, for example, benzyloxycarbonyl,with an alkylisothio-
uronium salt, for example, ethylisothiouronium hydroaro-
mide, by procedures generally known in the art; for example,
Organic Synthesis, Ill, p. 440 (1955). The reaction is
carried out in the presence of a base, such as, aqueous
sodium hydroxide or potassium hydroxide at a pH of about
10 at a temperature of about 25C for about 6 to 60 hours
after which the reaction mixture is neutralized with con-
centrated hydrochloric acid and the product isolated. When
appropriate, protecting groups are removed by acid hydroly-
sis, for example, treatment with HBr in dioxane. The
preparation of compounds of Formula Vlll is described
hereinbelow.
Following is d~scribed the preparation of compounds
of general Formula I wherein Ra and/or Rb are other than
HN
hydrogen and Ra is other than H2N-~- including compounds of
general Formula Vlll. The following description is appli-
çable to all the above said compounds, however, it is
necessary to protect one or the other of the amino groups
prior to ~reatment with the appropriate reactant, that is,
acid halide or anhydride, alkyl haloformate or acid of the
formula HOOCCH-Rz or anhydride thereof as described below
H2
to give compounds wherein either or bo~h of Ra and Rb iS
other than hydrogen as follows: When Ra is hydrogen and
Rb is other than hydrogen, the amino group to which Ra iS
attached is protected as a phthalimido derivative by
treating the correspond;ng derivative wherein R~ is hydro-
-20-

~Z~3~i
MI-91~
gen and R2 is hydrogen or COR wherein R ;s a straight or
branched alkoxy group having from 1 to 8 carbon atoms, with
a carbalkoxyphthalimide wherein the alkoxy moiety has from
1 to 4 carbon atoms, for example, carbethoxyphthalimide in
a solvent such as an ether or a lower alcohol, such as,
methanol, for 1/2 to 3 hours at about O to 50C followed
by extraction with acid, for example, hydrochloric acid
prior to treatment with the appropriate reactant described
below to give compounds wherein Rb is other than hydrogen.
The phthalimide group is subsequently removed by treatment
with hydrazine in a lower alcohol solvent, such as, metha-
nol at about 50 to 100C for about 1 to 4 hours. The
~ thus obtained compounds, that is, compounds wherein Ra is
`~ hydrogen and Rb iS other than hydrogen may be treated with
the appropriate reactants described below to glve compounds .
wherein Ra and Rb are both other than hydrogen and Ra is
H~
no~ HzN-C- and may be the same or different. In preparing
compounds wherein R~ is other than hydrogen and Rb iS
hydrogen the amino group to which Rb iS attached is pro-
tected with, for example, a benzyloxycarbonyl group bytreatment of the corresponding derivative wherein Rb is
hydrogen and R2 is hydrogen or COR wherein R is a straight
or branched alkoxy group having from 1 to 8 carbon atoms
with a benzyl haloformate, such as, benzyl chloroformate
prior ~o treatmen~ with the appropriate reactant described
below to g;ve compounds wherein Ra 75 other than hydrogen
HN
or HzN-C-. The benzyloxy group is subsequently removed by
aeid hydrolysis, for example, by treatment with HBr in
.
- 21 -

1 ~ Z ~ ~75 Ml-91~
dioxane. When desired, the compounds thus obtained wherein
R2 is COR and R is a straight or branched alkoxy group hav-
ing from 1 to 8 carbon atoms are hydrolyzed with base using
for example, sodium hydroxide or sodium borate in an aqueous
lower alcohol, for example, m~thanol, solvent for 2 to 4
hours at about 25C to give the corresponding acidsJ that
is, compounds wherein R is hydroxyO
The compounds of general Formulas I and Ylll wherein
Ra or Rb iS alkylcarbonyl wherein the alkyl moiety is
straight or branched and has from 1 ~o 4 carbon atoms and
Rz is hydrogen or COR wherein R is hydroxy or a straight or
branched alkoxy group having from 1 to 8 carbon atoms are
pr~pared by treating the corresponding derivatives wherein
Ra or Rb iS hydrogen or is suitably protected or as to
compounds of Formula 1, Rb iS other than hydrogen as de-
scribed above with an acid halide of the formula R13C-halo
wherein halo is a halogen a~om, for exampleg chlorine or
bromine and R~3 is a straight or branched alkyl group having
from 1 to 4 carbon atoms or an appropriate acid anhydride,
in water in the presence of a base such as sodium hydroxide
or sodium borate at a temperature of about 0 to 25C for
about 1/2 hour to 6 hours. When appropriate, protecting
groups are removed as described hereinabove by treatment
with hydrazine or acid.
The compounds of general Formulas I and Vlll wherein
Ra or Rb iS alkoxycarbonyl wherein the alkoxy mo;ety is
straight or bran~hed and has from 1 to 4 carbon atoms and
R2 IS hydrogen or COR wherein R is hydroxy or a straight or
branched alkoxy group having from 1 to 8 carbon atoms are
-~2-

~Z~ 3~7~ Ml-91~
prepared by treating the corresponding derivative wherein
Ra or Rb i5 hydrogen or is suitably protected or as to com-
pounds of Formula 1, Rb iS other than hydrogen as described
hereinabove with an alkyl haloformate of the formula
R
halo-C-QR14 wherein halo is a halogen atom such as chlorine
or bromine and Rl~ is a straight or branched alkyl group
having from 1 to ~ carbon atoms in water in the presenc~ of
a base such as sodium hydroxide or sodium borate at a
temperature of about 0 to 25C for about 1/2 hour to 6
hours. When appropriat~ protecting groups are removed as
described hereinabove by treatment with hydrazine or acid.
The compounds of general Formulas I and Vl l l wherein
Ra or Rb is -~-CH-R7 wherein R7 is hydrogen, a straight or
NH2
branched lower alkyl group of from 1 to 4 carbon a~oms~
15 benzyl or p-hydroxybenzyl and R2 is hydrogen or COR wherein
R is hydroxy or a straight or branched alkoxy group having
from 1 to 8 carbon a~oms are prepared by ~reating the
correspond ing derivative wherein Ra or Rb iS hydrogen or is
suitably protected or as to compounds of.Formula 1, Rb is
other than hydrogen as described hereinabove with an acid
of the formula HOOC-IH-R7, or an anhydride thereof, wherein
NH2
the amino group is pro~ectP.d wi~h a suitable blocking group
such as benzyloxycarbonyl or tert-butoxycarbonyl and R7 has
the meaning de~ined hereinabove in an ether, such as, tetra-
hydrofuran or dioxane, methylenP chloride or chloroform and
-2~-

1~2~37~i
Ml-91~
in the presence of a dehydrating agent, such as, dicyclo-
hexylcarbodiimide when the free acid is employed, at a temp-
erature o~ about 0 to 35C for about 1 to 12 hours followed
by acid and base hydrolysis and when appropriate, treatment
with hydrazine to remove the protecting groups.
The compounds of the general Formula I wherein R is a
straight or branched alkoxy group of from 1 to 8 carbon
~toms may also be prepared by conver~ing the correspondin~
compound wherein Rl is hydroxy to the acid halide by, for
example, treatment with thionyl chloride, followed by
alcoholysis with an alcohol of the formula R80H as defined
above by procedures generally known in the art.
The compounds of this invention wherein R is -NR4R5
wherein each of R4 and Rs is hydrogen or a lower alkyl group
of from 1 to 4 carbon atoms are prepared by an acylation
reaction of an acid halide, for example, an acid chloride,
of the corresponding compound wherein R is hydroxy and Ra
and Rb nave the meanings defined in general Formula I with
the proviso that any free amino group is suitably protected
with groups, such as~ carboben~yloxy or tert-butoxycarbonyl
with an excess of an appropriate amine which may be repre-
sented as HNR4R5. The reaction is carried out in methylene
chloride, chloroform, dimethyl formamide, or ethers such as
tetrahydrofuran and dioxane, or benzene at about 25C for
about 1 to 4 hours. Suitable amines are ammonia, or a
compound which is a poten~ial source of ammonTa, for
example, hexamethylenetetramine; primary amines, for
example, methylamine, ethylamine or n-propylamine; and
secondary amlnes, for examplel dimethylamine, diethyl-
~0 amine, or di-n-butylamine. Following ~he acylation
-2~-

~Z~37~
Ml-91~
reaction the protecting groups are removed by treatment
with acid, for example, trifluoroacetic acid or hydrogen
bromlde in dioxane~
The compounds of general Formula I wherein R is
-NH-CH-COOH are prepared by reacting the corresponding
derivative wherein R is hydroxy or a ~unctional derlvative
thereof, such as, an acid anhydride and Ra and Rb have the
meanings defined in Formula I ~ith the proviso that any
~ree amino group is protected with a suitable blocking
group, such as, benzyloxycarbonylj tert-butoxycarbonyl by
reacting the amine protected free acid with a compound of
the structure NH2-fH-COOR12 wherein R~ has the meaning
R~ .
deflned in general Formula I and R12 is a lower alkyl group,
for example, methyl or ethyl in an ether solution9 such as,
tetrahydrofuran or dioxane at about 0O to 35C for about
1 to 20 hours followed by acid then base hydrolysis5 for
example, with 2 N aqueous NH3 at about 0 to 50C for
about 1 to 20 hours, to remove the protecting group(s),
- with the proviso that when the amine protected free acid
is employed the reaction is carri~d out using a dehydrating
agent such as dicyclohexylcarbodiimide.
The individual optical isomers of the compounds of
general Formula I wherein Ra and Rb are hydrogen and R2
is hydrogen or COR wherein R is hydroxy may be sep~rated
by protecting the amino group distal to the acetylene
functio~ using carboethoxyphthalimide in a solvent such
as tetrahydrofuran, diethyl ether or lower alcohols such
as methanol or ethanol. When R2 is COR and R is hydroxy
-25-

llZ137S Ml-913
the compound is first converted to the lower alkyl ester,
for example, the methyl ester. The protected amine deriva-
tive is then resolved using either a (+) or (-) binaphthyl-
phosphoric acid salt by the method described by R. Viterbo
et al., in Tetrahedron Letters 48, 4617-4620 (lg71) and in
U.S. patent 3,848,o~o or by using (~) camphor-10-sulfonic
acid. The resolved phthalimido compound is then depro-
tected using hydrazine to remove the phthalimide group
followed by acid or base hydrolysis to cleave the ester
when R2 is COR and R is hydroxy. The thus resolved acids
and amines may be employed to prepare the individual iso-
mers of compounds of the invention wherein Ra or Rb iS
other than hydrogen and R~ is COR and R is other than
hydroxy in the same manner as described hereinabove for
the racemic mixtures of compounds wherein Ra or Rb is
hydrogen and R2 is hydrogen or COR wherein R is hydroxy.
The compounds of general Formula I wherein A is
methylene, R1 is -C--CH, R2 is COR wherein R is hydroxy and
each of Ra and Rb iS hydrogen, that is, 2-ace~ylene-2,5-
diam;nopent-~-enoic acld may also be prepared by treating
a suitably protected propargylam;ne of Formula V with a
strong base, alkylating the thus formed carbanion inter-
mediate with alkylbromide, treating the alkylated inter-
; mediate with a strong base and acylating the thus formed
second carbanion intermediate with a suitable acylating
reagen~ and subsequently remov;ng the protecting groups
by treatment with phenylhydrazine or hydra~ine and a base
such as potassium or sodium hydroxide to give 2-acetylene-
2-aminopent-4-enoic acid. The acid is converted to the
ester using methanol/HCl then treated with an acid halide
~26~

- l~Z137$ Ml-913
such as a lower alkanoyl halide, for example, acetyl
chloride or an aroyl halide, such as, benzoyl chloride or
with a lower alkyl haloformate such as methyl chloroformate
followed by treatment with an organic base such as pyridine
or triethylamine and treating the thus formed ester amide
in aqueous lower alcohols, such as, methanol or ethanol
with selenium dioxide For 1 to 6 hours at about 80 to 110C
to give the es~er amide of 2~acetylene-2-amino-3-hydroxy-
pent-4-enoic acid which is treated with trichloroacetroni-
trile in a solvent, such as, ethers, for example, diethylether, tetrahydrofuran, dioxane, dimethoxyethane, hydro-
carbons, such as, benzene or toluene in the presence of a
catalytic amount of a base such as sodium hydride, potassium
tert-butoxide, lithium alkylamides, for example, lithium
diisopropylamide or alkyl lithium at about -30 to 0C for
; about 1/2 hour to 3 hours followed by heating to about
110 to 140C in a non-polar solvent, for example, xylene,
toluene, nitrobenzene, or chlorobenzene for about 1 to 10
hours and subsequently hydrolyzing with aqueous acid, for
-20 example, hydrochloric acid or aqueous base, for example,
sodium hydroxide.
Suftable strong bases which may be employed in the
- above reaction to form each carbanion are those which will
abstract a proton from the carbon atom adjacent to the
acetylene moiety, such as, alkyl lithium, for example,
butyl lithium or phenyl lithium, lithium di-alkylamide, for
example, lithium diisopropylamide, lithium amide, tertiary
po~assium butylate or sodium amide.
Suitable acylating reagents which may be employed in
the above reaction are halo-formates, such as chloro methyl-
-27

llZl 37 ~ Ml-913
formate or chloro ethylformate, azido tert-butylformate,
cyanogen bromide, carbon dioxide, diethylcarbonate, phenyl-
isocyanate, triethoxymethylium tetrafluoroborate, N,N-
dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium
iodide, ethylene carbonate or ethylene trithiocarbonate.
When 2-methylt~io~ dithiolinium iodide is employed the
additional step of alcoholysis with a lower alcohol, for
example ethanol or isopropyl alcohol is required prior to
deprotection by hydrolysisO
The acylating reaction may be carried out in an aprotic
solvent, for example, benzene, toluene, ethers, tetrahydro-
furan, dimethylsulfoxide, hexamethyl phosphortriamide. The
reaction temperature varies from -120C to about 25C, a
preferred temperature being about -70C, and the reaction
time varies from about 1/2 hour to 24 hours.
EXAMPLE 1
7-~2-~4-(l-Acetylene-5-aminopent-2-enylaminomethyl)phen
acetyl~amino~-3-acetyloxymethyl-~-oxo-5-thio-1-az_bicyclo-
l4.2.0~oct-2-ene-2-carboxy iC acid
.
- A mixture of 1 9 of 3 acetyloxymethyl-7-[[2-[4-chloro-
methyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.03-
oct-2-ene-2-carboxylic acid and 1 g of 1,5-hept-3-en-6-ynedi-
amine whereln the amino group distal to the acetylene func-
- tion is protected as phthalimido in 50 ml of ethanol was
stirred at 25C for 24 hours after which the solvent is
removed leaving a residue which is treated with hydrazine
and chromatographed on 5 i lica gel using benzPne-acetone as
the eluant to give 7-[[2-[4-1-acetylene-5-aminopent-2-enyl-
acetyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo-
(4.200]oc~-2-ene-2-carboxylic acidO
28-

3~ ~
Ml-913
EXAMPLE 2
7-r2-Acetylene-2,5-diamino-1-oxopent-3-enamino]-~-acetyloxy-
methyl-~-oxo-5-thio-1-azabicycloL4.2.0~oct-2-ene-2-carboxylic
aci
A mixture of 1 9 of 3-acetyloxymethyl-7-amino-8-oxo-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and
1 9 of 2-acetylene-2,5-diaminopent-3-enoic acid chloride
wherein the free amino groups are protected with tert-butoxy-
carbonyl in 50 ml of ethyl acetate is refiuxed for 2 hours
after which the solvent is r~moved leaving a residue which
is chromatographed on silica gèl using benzene-acetone as
the eluant to give 7-[[2-acetylene-2,5-diamino-1-oxopent-
3-enamino]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-
oct-2-ene-2-carboxylic acid wherein the amino groups are
protected with tert-butoxycarbonyl. The protected cephalo-
sporin compound is treated with trifluoroacetic acid for
1/2 hour at 25C under nitrogen atmosphere then diluted
with ether until precipitation stops and filtered to give
the di-trifluoroacetic salt of the title cephalosporin
which can be converted to the free base by use of ion
cxchange resin.
The following examples are illustrative of pharmaceuti-
cal preparations of compounds of general Formula 1.
F XAMPLE ~
An illustrative compositTon for hard gelatin capsules
is as follows:
(a) 1,4-hex-2-en-5-ynediamine 20 mg
(b) talc 5 mg
(c) lactose 90 mg
The formulation is prepared by passing the dry powders
of (a) and (b~ through a fine mesh screen and mixing them
~9~

1 ~%~5 Ml 91~
well. The powder is then filled into hard gelatin capsules
at a net fill of 115 mg per capsule.
EXAMPLE 3A
An illustrative composition for tablets is as follows:
(a) 2-acetylene-2,5-diaminopent- 20 mg
~-enoic acid
(b) starch 4~ mg
(c) lac~ose 45 mg
(d) magnesium s~earate 2 mg
The granulation obtained upon mixing the lactose with
the compound (a) and part of the starch and granulated with
starch paste is dried, screened, and mixed with the magne-
sium stearate3 The mixture is compressed into tablets
weighing 110 ~9 each.
EXAMPLE 4
An illustrative ~omposition for an injectable suspen-
sion is the following 1 ml ampul for an intramuscular in-
jection.
Wei~ht per cent
(a) 2,5-hept-~-en-6-ynediamine loO
(b) polyvinylpyrroiidone 0.5
(c) lecithin 0.25
(d~ water for injectton to make 100.0
The materials (a)~(d) are mixed, homogenized and filled
into 1 ml ampuls which are sealed and autoclaved 20 minutes
at 121C. Each ampul contains 10 mg per ml of novel com-
pound (a)~
The following examples further illustrate the compounds
of the invention.
-~0-

~ 375 Ml-913
EXAMPLE 5
1,4 Hex 2-en 5 ynediamine dihydrochloride
A solution of 21.5 g (0.1 M) of ~-trimethylsilylprop-2-
ynyl-1-iminobenzyl in 500 ml of tetrahydrofuran at -70C
is treated with 66.5 ml of a 1.5 M solution of n-butyl-
lithium. After 5 minutes at -70C a solution of zinc
iodide, prepared from 8.o 9 of ~inc and 25.4 9 of iodine
in 100 ml of tetrahydrofuran, is added. The resulting
solution is stirred at -70C for 20 minutes ~fter which
5.6 g (0.1 M, 6.65 ml) of 2-propenal is added dropwise at
~70C. The solution is maintained at -70C for 30 minutes
then 7.8 9 (0.1 M, 7.0 ml) of acetyl chloride is added.
The solution is allowed to warm to room temperatyre and
diluted with ether, washed well with aqueous sodium bi-
- carbonate followed by aqueous sodium chloride then dried
over magnesium su1fate and evaporated leaving an oil which
is taken up in 200 ml of isopropyl alcohol and treated
with 10 9 (0.0~3 M) of phenylhydrazine. The mixture is
heated at reflux for 20 minutes then the solvent evapora~ed.
The residue is dissolved in chloroform and applied to a
column of silicon dioxide packed with chloroform. Elution
with chloroform followed by 5~0 methanol/chloroform gives
~he acetamide of 1-trimethylsilylacetylene-1-aminobut-3-
en-2-ol which is dissolved in 30 ml of methanol and trea~ed
with 2.5 9 of potassium hydroxide in 30 ml of water at
room temperature after which the methanol is filtered off.
The aqueous residue is saturated with sodium chloride and
extracted well with methylene chloride. The organic phase
Ts dried over magnesium sulfate and concentra~ed leaving
~0 a residue which is recrystallized from chloro~orm/petroleum
-31-

llZ1375 Ml-91~
.
ether to give the acetamide of 4-aminohex-1-en-5-yn-3-ol
(M.P. 94C) of which 994 mg (6.5 mM) is taken up in 15 ml
of tetrahydrofuran and added to 24 mg of a 50~ dispension
(0.5 mM) of sodium hydride. After 5 minutes at about 25C
the solution is added dropwise via syringe to a solution
nf 9~5 mg (6.5 mM) of trichloroacetonitrile in 30 ml of
te~rahydrofuran precooled to -23C ~dry ice/carbon tetra-
chloride). The resulting solution is stirred for 1-1/2
hours at -23~C then evaporated at about 25C leaving an
oil whieh is dissolved in 30 ml of xylene and heated at
reflux for ~ hours then allowed to stand overnight at about
25C. The resulting precipitate is collected, recrystal~
li~ed from chloroform and combined with 40 ml of 6 N HCl
and 100 ml of methanol. The solution is heated at reflux
for 12 hours ~hen concentrated. The resulting residue
is washed well with chloroform, treated with charcoal,
filtered and evaporated leaving a residue which is recrys-
tallized from ethanol to give 1,4-hex-2-en-5-ynediamine
dihydrochloride, M.P. 175C (dec.).
EXAMPLE 6
1,5-He~t-3-en-6-ynediam7ne
To a solution of sodium acetylide, prepared from 2.3 9
(0.1 M) of sodium in 500 ml of ammonla, is added 35 9
(35 mM) of 5-hydroxypent-2-enal. One hour later ammonium
chloride is added and the ammonia allowed to evaporate.
The residue is taken up in ether, filtered and concentrated
leaving a residue which is taken up in 200 ml of tetra-
hydrofuran and stirred for 48 hours at 25~ with 18.~ 9
(70 mM) o~ triphenylphosphine, 12.1 9 (70 mM) of diethyl
~0 azodicarboxylate and 10.2 (70 mM) of phthalimide. Th~
-32-

~Z~3~S Ml-91~
precipitate which forms is filtered of~, recrystallized
from methanol then dissolved in 30 ml of ethanol. The
ethanol solution is treated with hydrazine hydrate (1.74 9)
at reflux overnight after which the solvent is evaporated
and the residue treated with 5~ aqueous potassium hydroxide
until basic, eXtracted with dichlorome~hane~ evaporated
and distilled to give 1.5-hept-~ en-6-ynediam;ne.
EXAMPLE 7
2-Acetylene-2,5-diaminopent-3-enoic acid hydrochloride
A solution of 2 9 (18 mM) of 1,4-hex-2-en-5-ynediamine
tn ~0 ml of benzene is treated with ~.8 9 (~6 mM) of ben~al-
dehyde at 25C in the presence of magnesium sulfate. After
1 hour the solution is filtered and the benzene distilled
off using a Dean-Stark apparatus leaving a residue which
iS distilled (Kugelrohr, 160C, 0.1 mM) to glve an oil
which is taken up in 100 ml of tetrahydrofuran and trea~ed
with 14 ml of a 1.0 M solution (14 mM) of ethyl magnesium
bromide at 0C. After 30 minutes 1.5 9 (14 mM) of chloro-
trimethylsilane in 15 ml of tetrahydrofuran is added. The
solution îs stirred for 1 hour at 0C then brine is added
and the mixture extracted with ether~ The organic layer is
washed wel! with brine, then dried and concentrated. The
res;due is dis~illed (Kugelrohr, 175C, 0.1 mm) to afford
an oil which is taken up in 10 ml of tetrahydrofuran and
treated with lithium diisopropylamide, prepared from 8.4 mM
of diisopropylamide and 4.2 ml of a 2 M solution of n-butyl-
lithium, at -78C~ After 5 minutes o.8 9 (8.4 mM) of methyl
chloroformate in 5 ml of tetrahydrofuran is added and the
solution is immediately quenched wi~h brille and extracted
with ether. The ether extract is dried and evaporated
-~3-

~ ~ ~ ~ ~ ~ ~ Ml~
leav;ng a residue which is refluxed in 50 ml of 6 N hydro-
chloric acid for three hours. On cooling the solution is
extracted with methylenechloride. The aqueous solution is
evaporated to dryness and the resulting residue triturated
with ethanol. The insoluble salts are filtered off and the
ethanol solution is treated with 800 ,~9 (8.4 mM) of tri-
ethylamine. The resulting precipitate is filtered off and
recrystallized from ethanol/water (9:1) to give 2-acetylene-
2,5-diaminopent-3-enoic acid hydrochloride.
EXAMPLE 8
2,5-Diamino-2-vinylpent-3-enoic ac;d
To a suspension of 1.54 9 (10 mM) of 2-acetylene-2~5-
diaminopent-~-enoic acid and 2 9 (1.4 mM) of ammonium sul-
fate in 100 ml of ammonia is added lithium at reflux until
the blue color persists for 15 minutes after which ammonium '
chloride is added and the ammonia allowed to evaporate.
The residue is dissolved in water and applied to a column
of Amberlite 120 H+. The product is eluted with 2 M ammon-
ium hydroxide and recrystall-ized from water/ethanol to give
295-diamino-2-vinylpent-3-enoic acid.
EXAMPLE 9
2-Acetylene-2,5-diaminoQent-3-eno~c acid
A solution of 2105 9 (0.1 M) of 3-trimethylsilylprop-
~-ynyl-1-iminobenzyl in 600 ml of tetrahydrofuran at -78C
iS treated with 50 ml of a 2.0 M solution of n-butyllîthium
followed by the addition of 12.1 g (0.1 M) of allyl bromide
After 3 hours at ~78~C 50 ml of a 2,0 ~ solution of n-butyl-
lithtum is added followed by the addition of 9.4 9 (0.1 M)
of methyl chloroformate~ After 30 min~tes at -78~C the
~0 r action mixture is treated with brine then extracted wi~h
-~4-

~ Z ~ 37 5 Ml-91~
ether. The ether solution is dried over magnesium sulfate
and evaporated to afford an oil which is dissolved in 100 ml
of pentane and treated with 10.8 9 (0~1 M) of phenylhydra-
zine. After 1 hour at 25C the precipitate is filtered off
and the filtrate evaporated and treated with 12 9 (0.7 M)
of potassium hydroxide in 40 ml of methanol and 40 ml of
water overnight at 25C. The methanol is evaporated off
and the aqueous solution washed with dich!oromethane, acidi-
fied using 6 N hydrochloric acid, rewashed with dichloro-
methane and evapora~ed to dryness. The residue is triturated
with ethanol, filtered and the filtrate evaporated leaving
a residue which is dissolved in water. The pH of the water
solution is adjusted to 6 and applied to an Amberlite resin.
Elution with 1 M ammonium hydroxide affords 2-acetylene-2-
aminopent-4-envic acid which is treated overnight at 25C
with methanol saturated with dry HCl after which the solvent
is evaporated to give the methyl ester hydrochloride. The
methyl ester hydrochloride (10 g, 0905 M) is suspended in
20 ml of dichloromethane and treated with 10 9 (0.1 M) of
triethylamine and 3.9 g (0.05 M) of acetyl chloride over-
night at ~5C. The solut;on is then washed with water,
dried and evaporated leaving a residue which is recrystal-
li~ed from ethylacetate ~o give methyl ~-acetylene~
oxoethylamino)pen~-4-enoate (10 mM) which is taken up in
20 ml of ethanol and 5 ml of water and treated with 1.11 g
(10 mM) of selenium dioxide. The mixture is heated to re-
flux for 4 hours after which the solvent is evaporated9
.
The resulting residue is taken up in ~ther and washed with
sodlum bioarbonate solution. The ether solution is dried~
-~5-

~12~375 Ml-91~
evaporated and the mixture of diastereomeric alcohols puri-
fied by chromatography on Florisil. The alcohol is dis-
so1ved in 15 ml of tetrahydroFuran and added to 24 mg of
a 50~ dispension (0.5 mM) of sodium hydride. After 5 min-
utes at about 25C the solution is added dropwise viasyringe to a solution of 9~5 mg (6~5 mM) of trichloro-
methylacetonitrile in 15 ml of tetrahydrofuran precoo!ed
to -23C. The resulting solution is stirred for 1-1/2
hours at -2~C then evaporated at about 25C leaving an
~0 oil which is dissolved in 30 ml of xylene and heated to
reflux for 3 hours then allowed to stand overnight at
about 25Co The precipitate is collected, recrystallized
from chloroform and combined with 40 ml of meth~nol and
40 ml of 6 N HCl and heated at reflux for 12 hours then
concentrated. The resulting residue is washed well with
chloroform, treated with charcoal, filtered and evaporated
leaving a residue which is recrystal1ized from ethanol to
give 2-acetylene-2,5~diaminopent-~-enoic acidO
When tn the procedure of Example 5 an appropriate
amount of 2-butenal is substituted for 2-propenal, 2,5
hept-~-en-6-ynediamine dihydrochloride Is obtained.
When in the procedure of Example 7 an appropriate
amount of 1J5-hept-~-en-6-ynediamine is substituted for
1,4-hex-2-en-5-ynediamine, 2-acetylene-2,6-diaminohex-3-
enoic acld is obtained.
EXAMPLE 10
N-(1-Acetylene-4-aminobut-2-enyl)acetamide
A solution of 242 mg (1 mM) of N-(4-acetylene-4-amino~
but-2-enyl)phthalimide în 10 ml of chloroform is treated
~0 with 1 ml of triethylamine followed by 78 mg (1 mM~ of
36-

1~21375 Ml-91~
acetyl chloride in 5 ml oF chloroform. After 1 hour at
25C the solution is washed with water~ dried and concen-
trated. The resulting residue is dissolved in 10 ml of
ethanol and treated with 60 mg (1~1 mM) of hydrazine hy-
drate at reflux for 2 hours after which the solvent isevaporated. The residue is treated with 1 N sodium hydrox-
ide solution until the solid dissolves then is extracted
with dichloromethane. The organic phase is dried and con-
centrated to give N-(1-acetylene-4-amino-but-2-enyl)acet-
amide.
N-(4-Acetylene-4-aminobut-2-enyl)phthalimide us~d in
the above procedure is prepared as follows A solution of
1~.5 9 (6106 mM) of carbethoxyphthalimide in 70.ml of
tetrahydrofuran is added dropwise to a solution of 6.91 g
(61.6 mM) of 1-acetylene-1l4-but-2 endiamine in 30 ml of
tetrahydrofuran in an ice-bath. After completion of the
addition the mixture is stirred for 2 hours at 25C then
diluted with ether, and the solution is extracted with
1 N hydrochloric acid (3 x 100 ml). The aqueous phase is
washed several times with ether then concentrated to dry-
ness leOving a residue which is recrystalli~ed from etha-
nol to give N-(4-acetylene-4-aminobut-2-enyl)phthamlimide
HCl which is converted to the free baseO
When în the procedure of Example 10 an appropriate
25 amount of ethyl chloroformate is used in place of acetyl
chlorid N-(1-ace~ylene-4-aminQbut-2-enyl)ethyl carbamate
is obtained~
When in the procedure of Example lU an appropriate
amoun~ of benzyl chloroformate is subs~itu~ed for acetyl
chloride, N-(1-acetylene-4-aminobut-2-enyl)ben~yl.car-
-37~

~ 37 ~ Ml-913
bama$e is obtained.
EXAMPLE 11
N~ Acetylene-4-aminobut-2-enYl)-2-aminopropionamide
A solution of 492 mg (2 mM) oF N~ acetylene-4-amino-
but-2-enyl)benzyl carbamate in 4 ml o$ dichloromethane is
treated with 446 mg (2 mM) of N-carbobenzoxyalanine and
412 mg (2 mM) of N,N' dicyclohexylcarbodiimide for about
15 hours at 25C af~er which the solution is cooled to
0C and the precipitated dicyclohexylurea filtered off.
The filtrate is diluted with 20 ml of dichloromethane and
washed with 1 N hydrochloric acid, water and aqueous
sodium bicarbonate, then dried and concentrated. The
resulting residue is treated with 6 ml of a 40~ (w/w)
solution of hydrogen bromide in dioxane at 25C for 30
minutes then diluted with ether and the precipitated N-
(4~acetylene-4-aminobut-2-enyl)-2-aminopropionamide di-
hydrobromide collectedO
EXAMPLE 12
N-(4-Acetylene-4-am~nobut-2-enyl)acetamide
A solution of 492 mg (2 mM) of N-(1-acetylene-4-
aminobut-2-enyl)benzyl carbamate in 10 ml of chloroform is
treated with 202 mg (2 mM) of triethylamine followed by
160 mg (~.1 mM) o~ acetyl chloride. After 1 hour at 25C
the solution is washed with water, dilute hydrochloric
2$ acid, and aqueous sodlum carbonate, then dried and con-
centratedO The resulting residue is treated with 6 ml
of a 40~ (w/w) solution of hydrogen bromide in dioxane
for ~0 minutes at 25CJ then e~her is added on the preci-
pitated N-(4-ace~ylene-4-aminobut-2-enyl)acetamide hydro-
~0 bromide is collected.
-38-

~ 12 ~ 37 5 Ml-91~
When in the above procedure an appropriate amount of
ethyl chloroformate is substituted For acetyl chloride,
N-(l~-acetylene-4-aminobut-2-enyl)ethyl carbamate is
obtained.
EXAMPLE 13
N~ Acetylene-4-aminobut-2-enyl)-2-aminopropionamide
i HBr
A solution of 450 mg (2 mM) of N-carbobenzoxyalanine
in 10 ml of dichloromethane is treated with 202 mg (2 mM)
of triethylamine followed by 218 mg (2 mM) of ethyl chloro-
forma~e. After 1 hour at 25C the solution is treatedwith 484 mg (2 mM) of N-(4-acetylene-4-aminobut-2-enyl)-
phthalimide in 10 ml of chloroform and maintained at 5C
for one hour after which the solution is washed with 1 N
hydrochloric acid, water and aqueous sodium carbonate then
dried and concentrated. The residue is dissolved in 15 ml
of ethanol and treated with 110 mg (2 mM) of hydrazine
hydrate at reflux for 2 hours after which the solvent is
evaporatedO The residue is trea~ed with 5~ aqueous sodium
hydroxide and extracted with dichloromethane. The organic
phase is dried and concentrated and the resulting residue
is treated with 5 ml o~ a 40% (w/w) solution of hydrogen
bromide in dioxane. After ~0 minutes at 25C the mixture
is treated with ether and the precipitated N~ acetylene-
4-aminobut-2-enyl)-2-aminopropionamide dihydrobromide
~5 collected.
EXAMPLE 14
1 Acetylen2~1,4 but 2 en~1ene-bls 2 amino~ro~ionamlde
HBr
A solution of 900 mg (4 mM) of N-carbobenzoxyalanine
in 10 ml of dichloromethane is treated with 405 mg (4 mM)
~39~

~lZ~375
of triethylamine followed by ~35 mg (4 mM) of e~hyl chloro-
formate. After 1 hour at 25C the solution is treated with
224 mg (? mM) of l-acetylene-lJ4-but-2-enediamine in 5 ml
of dichloromethane. The solution is maintained a~ 25C
for 1 hour then is washed with water, dried and concentrated.
The resulting residue is trea~ed with 6 ml of a ~0% (w/w)
solution of hydrogen bromide in dioxane for 30 minutes at
25~C then diluted with ether. The precipitate is collected
~o afford 1-acetylene-1,4-but-2-enylene-bis-2-aminopropion-
~0 amide dihydrobromide.
EXAMPLE 15
1 Acetylene-1,4 but 2 enylene bis-acetamlde
A solution of 0.5 g (4.5 mM) of 1-acetylenç-1,4-but-2-
endiamine in 50 ml of ether containing 0.91 g (9.0 mM) of
triethylamine is treated with 0.7 g (9.0 mM) of ace~yl
chloride. After 1 hour the ether solution is washed with
brine~ dried and evapor`ated to afford 1-acetylene-t,4-bu~-
2-enylene-bis-acetamide.
EXAMPLE 16
_
Methyl 2-acetylene-2,5-d _minopent-3-enoate di HCl
2-Acetylene-2,5-dlaminopPn-t-~-enoic acid ~500 mg,
.2 mM) is added to 40 ml of methanol which had been sat-
urated with dry hydrogen chloride~ The solu~ion is hea~ed
at reflux for 12 hours, then the solvent is evaporated to
afford methyl 2-acetylene-2J5-diaminopent-~-enoate di-
hydrochloride.
EXAMPLE_l~
2-Acetylene-2,5-di-(1-oxoethylamino)pent-~-enoic acid
To a solution of ~12 mg ~2.~ mM) of 2-acetylene-2,5-
~0 diaminop~nt-3-enoic acid in 2~5 ml of 1 N sodium hydroxide
- ~0-

~l~ ~ ~ Ml-91~
at 0C are added simultaneously from two syringes 312 mg
(4 mM) of acetyl chloride diluted in 1 ml of THF and 4 ml
of 1 N sodium hydroxideO After ~0 minutes at 0C the solu-
tion is acidified by the addition of 6 N hydrochloric acid,
then extracted well with dichloromethaneO The organic
phase is dried and concentrated to afford 2-acetylene-2~5-
di-(1-oxoethylamino)pent-3-enoic ac;d.
In a similar manner only substituting an appropriate
amount of ethyl chloroformate ~or acetyl chloride~ 2-acetyl-
ene-2,5-di-(1-ethoxycarbonylamino)pent-~-enoic acid ;s
obtaîned.
EXAMPLE 18
2-Acetylene-2~5-di-N-(2-aminopropylcarbonylamino)pent-
~enoic aci
A solution of 240 mg (1 mM) of methyl 2-acetylene-2,5-
diam;nopent-~-enoate dihydrochlor;de in 4 ml of me~hylene
chloride containing 200~mg of triethylamine iS treated
with 440 mg (2 mM) of N-carbobenzoxy alanine and 412 mg
(2 mM~ of N~N'-dicyclohexylcarbodiimide overnight at 25C~
The mixture is then cooled to 0C and the precipitated di-
cyclohexyl urea filtered offO The flltrate is diluted withmethylene fhloride) washed with wat r, bicarbonate~ dilute
hydroehlorîc acid, then dried and concentrated. The resi-
due ;s treated with 10 ml of ethanol and 10 ml of a 40~
(w/w) solutton of hydrogen bromide in dioxane for 30 min-
~tes at 25C after which 50 ml of ether is added and theresulting precipi~atP collPcted. The precipitate is
treated with 15 ml of 1 N aqueous sodium hydroxide over-
nlght at 25C. The p~ of the solution is adjusted to
neutral and the product isolated from an*Amberlite 120 H~
* Trade Mark
-i -41-

375 ~1-gl~
resin by elution with 2 M ammonium hydroxlde to give 2-
acetylene-2,5-di-N-(2-aminopropylcarbonylamino)pent-~-
enoic acid.
N-Propyl-2-acetylene-2~5-dtaminopent-~-enamide dihydro-
romi e
To a solution of 312 mg (2 mM) of 2-acetylene-2,5-
diaminopent-3-enoic acid di HBr acid in 2.5 ml of 1 N
aqueous sodium hydroxide at 0C are added simultaneously
from two syringes 680 mg (4 mM) of benzyl chloroformate in
dioxane (2 ml) and 4 ml of 1 N sodium hydroxlde. After 30
minutes at 0C the solution is acidified by the addition
of 6 N hydrochloric acid, then extracted well with di-
chloromethane. The organic phase is dried and concentrated
to afford 2-acetylene-~,5-di-(benzyloxycarbonylamino)pent-
3-enoic acid which is dissolved in 15 ml of dichloromethane
and treated with 220 mg of thionyl chloride at 25C for
one hour. Propylamine (250 mg) is then added and the solu-
tion stirred at 25C for one hour, then washed with water,
dried and concentrated~ The residue is treated with 12 ml
of a solution of dioxane containing hydrogen bromide (~0
w/w) and allowed to stand for 30 minutes at 25C. Ether
(50 ml) is then added and the resulting precipitate col-
lected to afford N-propyl-2-acetylene-2,5-diaminopent-~-
enamide dihydrobromide.
EXAMPLE 20
2-~2-Acetylene-2~5-diamlno-1-oxopent-3-en~lamino)propionic
acl
To ~ mg (1 mM) of 2-acetylene-2/5-di-(benzyloxy-
carbonylamino)pent-~-enoic acid in 15 ml or methyl~ne
chloride is added 205 mg (2 mM) of triethyTamine followed
-42-

1 1Z ~ 37 5 Ml-913
109 mg (1 mM) of ethyl chloroformate. The solution is
stirred for one hour at 25C, then 103 mg (1 mM) of alanine
mPthyl ester tn 5 ml of methylene chloride is added. This
solution is kept overnight at 25C, washed with water, dried
and evaporated to dryness. The residue iS treated with
10 ml of a 40~ (w/w) solution of hydrogen bromide in dioxane
at 25C for 30 minutes. Ether (50 ml) is then added and
the precipitate collected. The precipitate is treated with
~0 ml of a 1 N sodium hydroxide solution overnight at 25C,
the pH adjusted to 6.5~ and applied to an Amberlite 120 H~
resin. Elution with 2 N ammonium hydroxide affords 2-(2-
acetylene-2,5-diamino-1-oxopent-3-enylamino)propionic acidO
EXAMPLE 21
,
M th l 2-acet lene-2 5-di-(1-oxoeth lamino) ent-3-enoate
e y _ Y l ~ ~ P_ _
A solution of 170 mg (1 mM) of 2-acetylene-2,5-di-
(1-oxoethylamino)pent-3-enoic acid in 10 ml of chloroform
is cooled to -5C and 78 mg of thionyl chloride in chloro-
form ls addedO After ~0 minutes 1 ml of methanol is addedO
Evaporation of the solvent y~telds methyl 2-acetylene-2,5-
di-(1-oxoethylamino)pent-3-enoate.
Alternatively the compounds of general Formula I
wherein A is methylene, R1 is -C-CH, R2 is COOH and R3 is
hydrogen may also be prepared by treatlng 1 equivalent of a
tert-butyl carbamate of 1-amino-1-trimethylsilylacetylene-
but 3-en-2-ol with 1 equivalent of trichloroacetonitrile
in a solvent, such as) ethers, for example/ die~hyl e~her,
- - tetrahydrofuran, dioxane, dimethoxyethane, hydrocarbons,
such as, benzene or toluene in the presence of a catalytic
amount of a base such as sodium hydr7de~ potassium ter~-
butoxide~ lithium alkylamides3 for examplej lithium diiso-
~43~

~lZ1375 Ml-91~
propylamide or alkyl lithium at 110 to 140C in a non-
polar solvent, for example, xylene, toluene, nitrobenzene
or chlorobenzene for about 1 to 10 hours to give the tri-
chloromethyl.acetamide which is treated with trifluoro-
acetic acid at about 0 to 25C for about 1/2 hour to ~hours followed by treatment with 1 equivalent o~ benzalde-
hyde a~ about 0 to 25C for about 1 to ~ hours to give
N-(4-benzylimino-4-trimethylsilylacetylenebut-2-enyl)tri-
chloromethylacetamide which is treated with 2 equivalents
of a strong base, such as, an alkyl lithium, for example,
butyl lithium or phenyl lithium, lithium dialkylamide,
such as, lithium diisopropylamide, lithium amide, tertiary
potassium butylate or sodium amide followed by acylation
with a suitable acylating reagent and subsequent hydrolysis
using aqueous acid~ for example, hydrochloric or toluene
sulfonic acidc
Suitable acyla-ting reagents for use in the above
reaction are for example, halo-formates, such as, methyl
chloroformate, azido tert-butylformate, cyanogen bromtde,
carbon dioxide, diethylcarbonate, phenylisocyanate, tri
ethoxymethylium tetrafluoroborateJ N,N-dimethylcarbamoyl
chloride, 2-methylthio-1,3-dithiolinium iodide, eth~lene
carbonate or ethylene trithiocarbonateO When 2-methylthio-
~ dithiolinium iodide is employed the additional step of
a1coholysis with a lower alcohol, for example, ethanol or
Isopro?yl alcohol is required prior to deprotection by
hydrolysis. The acylating reaction is generally carried
out at abou~ -120~ to 25C, preferably -70C and for
about 1/2 hour ~o 24 hours in an aprot;c soivent, for
~0 example, benzene, toluene, e~hers, such as, tetrahydro-

~ 3~ ~ Mi-91~
furan, dimethylsulfoxide, or hexamethylphosphortriamide.
The following specific ~xample furthPr illustrates the
processO
E MPLE 22
2-Acetylene-2,5-diaminopent-3-enoic acid
A solution of 21.5 9 (0.1 M) of ~-trTmethylsilylprop-
2-ynyl-1-iminoben~yl in 500 ml of tetrahydrofuran at -70C
is treated with n-butyllithium (66.7 ml of a 1.5 M solu-
tion) and five minutes later a solution of zînc iodide,
prepared from 8.0 9 of zinc an`d 25.4 g (0.1 M) of iodide
in 100 ml of tetrahydrofuran, is added. The resulting
solution is stirred at -70C for 20 minutcs after whieh
506 g (0.1 M, 6.65 ml) of 2-propenal is added dropwise at
-70C. The solution is maintained at -70C for 30 minutes
then 14.7 g (0.1 M) of tert-butoxycarbonyl a~ide is added.
The solution is allowed to warm to room temperature, di-
luted with ether, washe~d well with aqueous sodium bicar-
bonate, followed by aqueous sodium chloride, dried over
rnagnesium sulfate and evaporated to afford an oil which
; 20 is taken up in 200 ml of isopropyl alcohol, treated with
10 9 (0.093 M) of phenylhydrazine, heated to reflux for
20 minutes then evaporated~ The resulting residue is
dissolved in chloroform and applied to a column of silicon
dioxide (300 9) packed with chloroform. Elution with
chloroform followed by 5% methanol/chloroform gives the
carbama~e of 1-amino-1-trimethylsilylacetylenebut-3 en-
2-ol, 1.94 9 (605 mM) of which is dissolved in 15 ml of
tetrahydrofuran and added to sodium hydride (24 mg of a
50% dispension, 0O5 mM). After 5 minu~es a~ room tempera~
~0 ture this solution i5 added dropwise via syringe to a
_1~5_

~12~375 Ml~913
solution of 935 mg (6.5 mM) of trichloroacetonitrile in
30 ml of tetrahydrofuran precooled to -23C. The resulting
solution ts stirred for 1-1/2 hours at -~C then evaporated
at room temperature leaving an oil which is dissolved in
xylene and heated to reflux for ~ hours then allowed to
stand overnight at room temperature. The resulting precipi-
tate is collected and recrystallized from chloroform to give
a white solid 4.0 9 (10 mM) of which is added to 4 ml of
trifuloroacetic acid at 0C. Thirty minutes later the
0 solvent is evaporated leaving a residue which is suspended
in 20 ml of dichloromethane and loO 9 (10 mM) of benzalde-
hyde and 2 9 of triethylamine are added. The mixture is
st7rred for 4 hours at 25C then washed well with water~
dried and evaporated. The resulting residue is recrystal-
lized from ethyl acetate, and 4.1 9 (10 mM) of the solid
Tn 10 ml of tetrahydrofuran is added to lithium diisopropyl-
amTde, prepared from 2.02 g (20 mM) of d;isopropylamine and
10 ml of a 2 M solution (20 mM) of n-butyllithium, contain-
ing 10 ml of hexamethylphosphortriamide at ~78Co After
20 minutes at -78C, 940 mg (10 mM) of methyl chloroformate
;n 5 ml of tetrahydrofuran ls added and after 30 minutes at
-78C 600 mg of acetic acid is added followed by waterO
The mixture is extracted with ether, the ether solution
wash d with brine, dried and concentrated. The resulting
residue is treated with ~0 ml-of 6 N HCl and ~0 ml of
ethanol for 24 hours at reflux. ~n cooling the solution
is washed with dich10romethane then concentrated to dryness
leaving a residue which is taken up in the minimum quantity
oF water. The pH of the aqueous solution is adjusted to 6
and applied to an Amberlite resin 120 H~ Elution with
-46

~2~37~ gl~
1 M ammonium hydroxide affords 2-acetylene-2~5-diaminopent-
~-enoic acid which is recrystallized from wat~r/ethanol.
EXAMPLE 23
2-Acetylene-2-amino-5-guanidinopent-3-enoic acid
To a solution of 1.9 9 (10 mM) of 2-acetylene-2,5-
diaminopent-3-enoic acid monohydrochloride in 10 ml of 2 M
sodium hydroxide solution is added ~.7 9 (20 mM) of ethyl-
thiouronium hydrobromide. The pH of the solution is main-
tained at 10 by the addition of 2 ~ sodium hydroxide dur-
ing 48 hours at 28C after which the pH is adjusted to 6,
and the solution applied to an Amberlite resin 120 H~.
The product is eluted with 2 M ammonium hydroxide solu~ion
and recrystallized from methanol-water to give 2-acetylene-
2-amino-5-guanidinopent-3-enoic acid.
EX~MPLE 24-
~-Acetylene-2-acetamido-5-aminopent-~-enoic acid
(A) A solution of~1.68 9 ~10 mM) of methyl 2-acetyl-
ene-2,5-diaminopent-~-enoate in 15 ml of tetrahydrofuran
is added to 2.2 g (10 mM) of N-carboethoxyphthalimide in
~0 30 ml of tetrahydrofuran at 0C. After ~ hours at 25C
the solution is diluted with ether then extracted wlth 1 N
HCl. The aqueous phase ts washed with e~her than concen-
trated to dryness leaving a residue which is recrystal-
li2ed from ethanol to give methyl 2-acetylene-2-amino 5;
phthalimidopent-~-enoate hydrochloride.
(e) A solution of ~O0 9 (10 mM) of methyl 2-aeetylene-
2-amino-5-phthalimidopent-3-enoate, prepared from the hydro-
chloride obtained above, in 50 ml of chloroform is trea~ed
with 2.0 9 (20 mM~ of ~r ieth`jlam,nQ followed by trea~ment
with 780 mg (10 mM) of acetyl chloride~ After 1 hour at
-47-

~ 37S Ml-913
25C the solution is washed with 1 N HCl, dried and concen-
trated to give methyl 2-acetylene-2-acetamido-5-phthal-
imidopent-3-enoate which is dissolved in 100 ml of ethanol.
The ethanol solution is treated with 600 mg (10 mM) of
hydra ine hydrate at reflux for 2 hours then the solvent
is evaporated~ The remaining residue is treated with 1 N
sodium hydroxide until the solid dissolves then extracted
with dichloromethane. The organic phase is dried and
concentrated to give methyl 2-acetylene-2-acetamido~5-
aminopent-3-enoate which is trèated with 40 ml of 2 N
sodium hydroxide at 25C for 4 hours after which the pH
is adjusted to 6~ and the solution is applied to an
Amberlit~ 120 H~ resin. Elution with 2 M sodium hydroxide
gives 2-acety1ene-2-acetamido-5-amînopent-~-enoic acid.
When in procedure (B) above an appropriate amount of
benzyl chloroformate or ethyl chloroformate is substituted
for acetyl chloride, 2-acetylene-2-benzyloxycarbonyl-
amino-5-aminopent-3-enoic acid and 2-acetylene-2-ethoxy-
carbonylamino-5-aminopent-~-enoic acid are obtained
` 20 respectively.
EXAMPLE 25
2-Acetylene-2-amino-5-acetamidopent-3-enoic acid
A solution of 2.8 g (10 mM) of methyl 2-acetylene-2-
benzyloxycarbonylamino-5-aminopent-~-enoate prepared by
treating 2-acetylene-2-benzyloxycarbonylamino-5-aminopent-
~-enoic acid with methanol saturated with HCl, in 20 ml of
chloroform is treated with 1 g (10 mM) of triethylamine
followed by treatment with 780 mg (10 mM) of acetyl chlor-
Ide. After 1 hour at 25C the 531u~60~ is w3shed with 1 N
HCl, dried and evaporated. The resulting residue is
-~8-

l~Z1375 M1~913
$reated with ~0 ml of a 40% (w/w) solution of hydrogen bro-
mide in dioxane for ~0 minutes at 25C then ether is added
and the precipitated 2-acetylene-2-amino-5-acetamidopent-
3-enoic acid hydrobromide collected.
EXAMPLE 26
N-Propyl 2-acetylene-2-acetamido-5-aminopent-3-enamide
Methyl 2-acetylene-2-acetamido-5-phthalimidopent-3-
enoate (~O4 9, 10 mM) is treated with 40 ml of 2 N sodium
hydroxide at 25C for ~ hours after which the solution is
acidified and extracted well with dichloromethane. The
organic phase is dried and concentrated to afford 2-acetyl-
ene-2-acetamido-5-phthalimidopent-3-enoic acid. The acid
is dissolved in 40 ml of chloroform and treated with 1.2 9
(10 mM) of thionyl chloride at 25C for 4 hours after which
1.2 g (20 mM) of propylamine is addedO The solution is
stirred at 25C for 2 hours then washed with 1 N HCl,
dried and concentrated to afford N-propyl-2-acetylene-2-
acetamido-5-phthalimidopent-3-enamide~ The amide is
dissolved in 40 ml of ethanol and treated with 600 mg
(10 mM) of hydrazine hydrate at reflux for 2 hours. The
solution is then concentrated, and the residue treated
with 1 N sodium hydroxide until the solid dissolves then
extracted well with dichloromethane. The organic phase is
dried and concentrated to afford N-propyl-2-acetylene-2-
acetamido-5-aminopent-~-enamide.
EXAMPLE 27
2-Acetylene-2-(2-aminopr~plonamido~-5-amlnopent-~-enoic
aci
A solu~ion of 2.1 g (10 mM) of N-carbobenzoxyalanine
in 50 ml of dichloromethane is treated with 1.0 9 (10 mM)
.
~9

1~2~375 . Ml-913
of triethylamine followed by 1.1 9 (10 mM) of ethyl chloro-
formateO After 1 hour at 25C the solution is treated with
3.0 g (10 mM) of methyl 2-acetylene-2-amino-5-phthalimido-
pent-3-enoate in 40 ml of chloroform and maintained at
25C for 1 hour after which the solution is washed with 1 N
HCl, water and aqueous sodium carbonate then dried and con-
centrated. The residue is dissolved in 60 ml of ethanol
and treated with 550 mg (10 mM) of hydrazine hydrate at
reflux for 2 hours, after which the solvent is evaporated.
The residue is treated with 5~ aqueous sodium hydroxide
; and extracted with dichloromethane. The organic phase is
dried and concentrated, and the resulting residue is
treated with 5 ml of a 40~ (w/w) solutlon of hydrogen
bromide in dioxane. After 30 minutes at 25C the mixture
~5 is treated with ether and the precipitated methyl 2-acetyl-
ene-~-(2-aminopropionamido)-5-aminopent-~-enoate dihydro-
bromide collected. The ester dihydrobromide salt is
treated with 40 ml of 2 N sodium hydroxide for 4 hours a~
25C, the pH is adjusted to 6 and ~he solution is applied
to an Amberlite 120 H resin. Elution with 2 M ammonium
hydroxide affords 2-acetylene-2-(2-amtnopropionamtdo)-5-
aminopent-3-enoic acido
EXAMPLE_28
Methyl~ t~ ene-2-amino-5-(2-aminopropionamido)pent-2-
noate I y ro romi e an 2-acety ene-2-amlno-5-~2~amino-
oroDionam laol ~ent-2-eno ic ac l
A solution of 2.9 9 (10 mM) of mPthyl-2-acetylene-2-
benzyloxycarbonylamino-5-aminopent-3-enoate in 40 ml of
dichloromethane is treated with 2020 mg (10 mM) of N-car-
bobenzoxyalanine and 2.1 9 ~10 m~) of N,N'-uioyclohexyl
carbodiimide for about 15 hours at 25C after which the
5 0 r

~ lZl 37 5 Ml-913
solutlon is cooled to 0C and the precipitated dicyclo^
hexylurea fil~ered off. The filtrate is diluted with 20 ml
of dichloromethane and washed with 1 N hydrochlorîc acidJ
wat~r and aqueous sodium bicarbonate~ then dried and con-
centrated. The resulting residue is treated with 40 ml
of a 40% (w/w) solutTon of hydrogen bromide in dioxane at
25C for 30 minutes then diluted with ether. The precipi-
tate is collected to afford methyl 2-ace~ylene-2-amino-5-
(2-aminopropionamido)pent-2-enoate dihydrobromide. The
methyl ester dihydrobromide is treated with 40 ml of 2 N
sodium hydroxtde for 4 hours at 25C. The pH of the solu-
tion is adjusted to 6 and applied to an Amberlite resin
120 H~. Elution with 2 M ammonium hydroxide affords 2-
acetylene-2-amino-5~(2-aminopropionamido)pent-2~enolc acid.
When R is a straigh~ or branched alkoxy group of from
1 to 8 carbon atoms, reacting an acid halide of the corres-
ponding derivative wherein R is hydroxy with an~alcohol of
the formula R8-OH wherein R8 is a straight or branched
alkyl group having from 1 to 8 carbon atoms, saturated~wlth
HCl gas at about 25'C for from 12 to ~6 hours~
.
~51~