CA1101864A - Proline derivatives and related compounds - Google Patents
Proline derivatives and related compoundsInfo
- Publication number
- CA1101864A CA1101864A CA270,184A CA270184A CA1101864A CA 1101864 A CA1101864 A CA 1101864A CA 270184 A CA270184 A CA 270184A CA 1101864 A CA1101864 A CA 1101864A
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- Prior art keywords
- proline
- acid
- compound
- formula
- propanoyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Public Health (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
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Abstract
Abstract of the Disclosure New proline derivatives and related compounds which have the general formula are useful as angiotensin converting enzyme inhibitors.
Description
HA135b ,.. .
This invention relates to new pro~line derivatives and related compounds which have the general formula (I) R
R~ IRl ~ H2C - (C~l)m
This invention relates to new pro~line derivatives and related compounds which have the general formula (I) R
R~ IRl ~ H2C - (C~l)m
2 ~ )n ~H-~ CO - N - - ~H-COR
wherein R is hydroXy, NH2 or lower alkoxy;
: Rl and R4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;
R2 is hydrogen, lower alkyl, phenyI, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiome~hyl, phenyl-lower alkylthiomethyl, loMer alkano~l-amidomethyl, R5-C-, R5-~-C-,R5-NH-C-,R6~S- or R7;
; R3 ls hydrogen,hydroxy or lower alkyl;
R5 is lower alkyl, phenyl o~ phenyl-lower : ' - .
~ 4 ~IA135b alkyl;
R6 is lower alkyl, phenyl, substituted phenyl, (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino(carboxy)~
lower alkyl;
(HC) - CH2 IRl R4 R7 is R-OC-HC - N - CO - CH--(CH)- S(O) ;
M is 0 or S;
m is 1 to 3;
n and p each is 0 to 2, and to processes for maklng them.
The asterisks indicate asymmetric carbon atoms.
Each of the carbons bearing a substituent Rl, R3 and R~
is asymmetric when that suhstituent is~other than hydroyen.
~he invention in its broad aspects includes proline and related derivatives having formula I above. Within this broad group, because of their properties, certain subgroups -are preferred over ot~ers.
Broadly preferred are those compounds of formula I
wherein R is hydroxy or lower alkoxy; Rl is hydrogen or lower alkyl; R2 is hydrogen, R5-CO, R6-S-, or R7; R3;and R~ each is hydrogen; R5 is lower alkyl, especially methyl :: ~
or phenyl; X6 is lower alkyl, especially methyl or ethyl;
m is 2, n is 0, 1 or 2, especially 1; and R7 wherein R~ Rl, ,~:
R3, R~, m and n have the same preferences as above and p is 0.
Especially preferred are those compounds which have the formula (II) R2 S (CH2)n - CH - CO~ N ~ COR
* *
wherein R is hydroxy or lower alkoxy;
Rl is hydrogen or lower alkyl; -R2 is hydrogen, R5-CO-, R6-S- or R7;
R5 is lower alkyl or phenyl, especially the first;
R6 is lower alkyl; ~:
and n is 0, 1 or 2. ~.
Within the group of compounds represented by formula `~
II, the following are still more preferred subgroups in the order (a to r~ of increasing preference to the com-pounds which are especially preferred embodiments~
a) R is hydroxy b) n is 1 :~ 20 c) R2 is hydrogen or lower alkanoyl d) R2 is hydrogen e) R2 is acetyl f) Rl is hydrogen or lower alkyl .~
:'' g) Rl is hydrogen or methyl :
~ ~.
h) R is hydroxy, Rl is hydrogen or methyl i~ R is hydroxy, Rl is hydrogen or methyl, R2 is hydro~
gen or acetyl and n is 0, 1 or 2 ~;
j) R is hydroxy, Rl and R2 each lS hydrogen and n`is~Q ~ .
.
, ;,
wherein R is hydroXy, NH2 or lower alkoxy;
: Rl and R4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl;
R2 is hydrogen, lower alkyl, phenyI, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiome~hyl, phenyl-lower alkylthiomethyl, loMer alkano~l-amidomethyl, R5-C-, R5-~-C-,R5-NH-C-,R6~S- or R7;
; R3 ls hydrogen,hydroxy or lower alkyl;
R5 is lower alkyl, phenyl o~ phenyl-lower : ' - .
~ 4 ~IA135b alkyl;
R6 is lower alkyl, phenyl, substituted phenyl, (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino(carboxy)~
lower alkyl;
(HC) - CH2 IRl R4 R7 is R-OC-HC - N - CO - CH--(CH)- S(O) ;
M is 0 or S;
m is 1 to 3;
n and p each is 0 to 2, and to processes for maklng them.
The asterisks indicate asymmetric carbon atoms.
Each of the carbons bearing a substituent Rl, R3 and R~
is asymmetric when that suhstituent is~other than hydroyen.
~he invention in its broad aspects includes proline and related derivatives having formula I above. Within this broad group, because of their properties, certain subgroups -are preferred over ot~ers.
Broadly preferred are those compounds of formula I
wherein R is hydroxy or lower alkoxy; Rl is hydrogen or lower alkyl; R2 is hydrogen, R5-CO, R6-S-, or R7; R3;and R~ each is hydrogen; R5 is lower alkyl, especially methyl :: ~
or phenyl; X6 is lower alkyl, especially methyl or ethyl;
m is 2, n is 0, 1 or 2, especially 1; and R7 wherein R~ Rl, ,~:
R3, R~, m and n have the same preferences as above and p is 0.
Especially preferred are those compounds which have the formula (II) R2 S (CH2)n - CH - CO~ N ~ COR
* *
wherein R is hydroxy or lower alkoxy;
Rl is hydrogen or lower alkyl; -R2 is hydrogen, R5-CO-, R6-S- or R7;
R5 is lower alkyl or phenyl, especially the first;
R6 is lower alkyl; ~:
and n is 0, 1 or 2. ~.
Within the group of compounds represented by formula `~
II, the following are still more preferred subgroups in the order (a to r~ of increasing preference to the com-pounds which are especially preferred embodiments~
a) R is hydroxy b) n is 1 :~ 20 c) R2 is hydrogen or lower alkanoyl d) R2 is hydrogen e) R2 is acetyl f) Rl is hydrogen or lower alkyl .~
:'' g) Rl is hydrogen or methyl :
~ ~.
h) R is hydroxy, Rl is hydrogen or methyl i~ R is hydroxy, Rl is hydrogen or methyl, R2 is hydro~
gen or acetyl and n is 0, 1 or 2 ~;
j) R is hydroxy, Rl and R2 each lS hydrogen and n`is~Q ~ .
.
, ;,
- 3 - :
: ' ~ &9~ :
k) R is hydroxy, Rl is hydroyen, R2 is acetyl an~ n is 1~ R is hydroxy, Rl is methyl, R2 is acetyl and n is 1 m) R ls hydroxy, Rl and R2 each is hydrogen and n is 1 n) R is hydroxy, Rl is methyl, R2 is hydrogen and n is o) R is hydroxy, Rl is hydrogen, R2 is lower alkylthio and n is 1 p) R2 is lo ~ 71 R-OC N - OC~-CH - (CH2)n-S~;
each R is hydroxy; Rl is hydrogen or lower alkyl, es-pecially hydrogen or methyl; and n is 0 to 2, es-pecially 1 M
q) R2 is R5-M-C- wherein M is O or S
M
r) R2 is R5-NH-C- wherein M is O or S, preferably S.
It will be appreciated that combinations of the fore-going, where applicable, are amang the preferred groups. ;~
The stereoisomers in which the proline is in the L-form are especially preferred.
The lower alkyl groups represented by any of the vari-ables include straight and branched chain hydrocarbon radlcals ~rom methyl to heptyl, for example, methyl, ethyl, ~
propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, iso- ~;
pentyl and the like. The lower alkoxy groups are or the same kind having 1 to 7 carbons linked to oxygen, for ex-ample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, t-butoxy and the like. The Cl-C4 members, espe-cially Cl and C2 members, of both ~ - 4 -, ~186~ HA135b types are preferred. Phenylmethyl is the preferred phenyl-lower alkyl group.
The lower alkanoyl groups are those having the acyl radicals of ~he lower (C2-C7) fa-tty acids, Eor example, acetyl, propionyl, bu-tyryl, isobutyryl and the like. Similarly, those lower alkanoyl groups having up to four carbons, and especially acetyl, are preferred.
The four common halogens are included by the term '!halo" but chlorine and bromine are preferred. The substi-tuted phenyl groups preferably bear the substituent in the
: ' ~ &9~ :
k) R is hydroxy, Rl is hydroyen, R2 is acetyl an~ n is 1~ R is hydroxy, Rl is methyl, R2 is acetyl and n is 1 m) R ls hydroxy, Rl and R2 each is hydrogen and n is 1 n) R is hydroxy, Rl is methyl, R2 is hydrogen and n is o) R is hydroxy, Rl is hydrogen, R2 is lower alkylthio and n is 1 p) R2 is lo ~ 71 R-OC N - OC~-CH - (CH2)n-S~;
each R is hydroxy; Rl is hydrogen or lower alkyl, es-pecially hydrogen or methyl; and n is 0 to 2, es-pecially 1 M
q) R2 is R5-M-C- wherein M is O or S
M
r) R2 is R5-NH-C- wherein M is O or S, preferably S.
It will be appreciated that combinations of the fore-going, where applicable, are amang the preferred groups. ;~
The stereoisomers in which the proline is in the L-form are especially preferred.
The lower alkyl groups represented by any of the vari-ables include straight and branched chain hydrocarbon radlcals ~rom methyl to heptyl, for example, methyl, ethyl, ~
propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, iso- ~;
pentyl and the like. The lower alkoxy groups are or the same kind having 1 to 7 carbons linked to oxygen, for ex-ample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, t-butoxy and the like. The Cl-C4 members, espe-cially Cl and C2 members, of both ~ - 4 -, ~186~ HA135b types are preferred. Phenylmethyl is the preferred phenyl-lower alkyl group.
The lower alkanoyl groups are those having the acyl radicals of ~he lower (C2-C7) fa-tty acids, Eor example, acetyl, propionyl, bu-tyryl, isobutyryl and the like. Similarly, those lower alkanoyl groups having up to four carbons, and especially acetyl, are preferred.
The four common halogens are included by the term '!halo" but chlorine and bromine are preferred. The substi-tuted phenyl groups preferably bear the substituent in the
4-position of the ring. The hydroxy-lower alkyl groups have a hydroxy group on an alkyl chain like those described above, preferably on the terminal carbon, e.g., hydroxymethyl, 2-hydroxyethyl, etc. The amino(carboxy)lower alkyl groups have one amino and one carboxy on a lower alkyl group such as those described above, preferably both on one carbon, e.g., on the terminal carbon as in the preferred 2-amino-2- ~ ~ -carboxyethyl group.
The products of formula I and the preferred subgroups can be produced by various methods of synthesis.
In general, the products of this inven~ion are produced by acylating a compound of the formula (III) 3 I ' H2C ( ICH)m HN CH - COR
with an acid of the formula (IV) R~ 11 R2-- S - (CH) - CH - COOH
~ 4 HA135b or its chemical equivalent.
Thus, the inal product can be produced not only by direct acylation with an acid of formula IV but also by intermediates such as (a~ ~-haloalkanoic acids of the formula (V) X -(CH)n CH - COOH ~
wherein X is bromo, chloro or iodo, or (b~ a tosyloxyalkanoic acid, i.e., X ln formula V is -tosyloxy (CH3 ~ SO2Q-) (c) a substituted acrylic acid of the formula 14 1l (VI) CH C - COOH
The product of this acylation is then subjected to displacement or addition with the anion of a thiol or thioacid of the formula (VII) R2 - SH
Acylation can also be effected with a thiolactone of the formula (VIII) (CIH)n - CH
S =O
wherein n is 1 or 2, or a mercaptoalkanoic acid of the formula (IX) Y - S (CH)n - CH COR
:
~ 4 ~A~35b wherein Y is R2 or, in addition, if a product of formula I
wherein R2 is hydrogen is desired, then Y can also be a protecting group such as (a) CH3~ C112-, (b) ~ , (c) CH3CONHCH2, (d) R~O-C-CH-(CH) -S- or other sulfur protecting group. 'IDeprotection" can be effected by conventional means such as treatment with hot trifluoroacetic acid, cold trifluoromethanesulfonic acid, mercuric acetate, sodium in liquid ammonia, zinc and hydrochloric acid or the like~ For a review of these methods see Me-thoden der Organischen Chemie (Houben-Weyl), Vol. XV, part I, page 736 et seq. (1974).
When the acid of formula IV is used as the acylating agent, the acylation can be efected in the presence of a coupling agent like dicyclohexycarbodiimide or the like, or the acid can be activated by formation of its mixed anhydride, symmetrical anhydride, acid chloride, acid ester or use of Woodward reagen-t K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like. For a review of the methods for acylation, see Methoden der Organischen Chemie (Houben-Weyl), Vol. XV, part II, page 1 et seq. (1974).
Compounds of formula III lnclude, for example, proline, hydroxyproline, 4-methylproline, plpecolic acid,
The products of formula I and the preferred subgroups can be produced by various methods of synthesis.
In general, the products of this inven~ion are produced by acylating a compound of the formula (III) 3 I ' H2C ( ICH)m HN CH - COR
with an acid of the formula (IV) R~ 11 R2-- S - (CH) - CH - COOH
~ 4 HA135b or its chemical equivalent.
Thus, the inal product can be produced not only by direct acylation with an acid of formula IV but also by intermediates such as (a~ ~-haloalkanoic acids of the formula (V) X -(CH)n CH - COOH ~
wherein X is bromo, chloro or iodo, or (b~ a tosyloxyalkanoic acid, i.e., X ln formula V is -tosyloxy (CH3 ~ SO2Q-) (c) a substituted acrylic acid of the formula 14 1l (VI) CH C - COOH
The product of this acylation is then subjected to displacement or addition with the anion of a thiol or thioacid of the formula (VII) R2 - SH
Acylation can also be effected with a thiolactone of the formula (VIII) (CIH)n - CH
S =O
wherein n is 1 or 2, or a mercaptoalkanoic acid of the formula (IX) Y - S (CH)n - CH COR
:
~ 4 ~A~35b wherein Y is R2 or, in addition, if a product of formula I
wherein R2 is hydrogen is desired, then Y can also be a protecting group such as (a) CH3~ C112-, (b) ~ , (c) CH3CONHCH2, (d) R~O-C-CH-(CH) -S- or other sulfur protecting group. 'IDeprotection" can be effected by conventional means such as treatment with hot trifluoroacetic acid, cold trifluoromethanesulfonic acid, mercuric acetate, sodium in liquid ammonia, zinc and hydrochloric acid or the like~ For a review of these methods see Me-thoden der Organischen Chemie (Houben-Weyl), Vol. XV, part I, page 736 et seq. (1974).
When the acid of formula IV is used as the acylating agent, the acylation can be efected in the presence of a coupling agent like dicyclohexycarbodiimide or the like, or the acid can be activated by formation of its mixed anhydride, symmetrical anhydride, acid chloride, acid ester or use of Woodward reagen-t K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like. For a review of the methods for acylation, see Methoden der Organischen Chemie (Houben-Weyl), Vol. XV, part II, page 1 et seq. (1974).
Compounds of formula III lnclude, for example, proline, hydroxyproline, 4-methylproline, plpecolic acid,
5-hydroxypipecolic acid, azetidine-2-carboxylic acid, their lower alkyl esters and the like. The acylation of such compounds is described in greater detail below.
According to a preferred method for producing compounds ;~ of formula I, especially wherein R2 is R5-CO~, an acid or ester of formula III is coupled with a haloalkanoic acid of the formula HAl35b (V) R4 X-(CH) - CH- COOH
wherein X is a halogen, preferably chlorine or bromine. This can be effected by one of the known procedures in which the acid IV is activated, prior to reaction with the acid III, involving formation of a mixed anhydrlde, symmetrical anhydrlde, acid chloride, active ester, or use of Woodward reagent K, EEDQ
(N-ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline) or the like.
The product of this reaction is a compound of the formula (X) 13 4 1l H2C (CH)m : X - (CEI) - ca - co - N - CH-COR
The product o formula X is subjected to a displacement ~ :
reaction with the anion of a thioacid of the formula (VII) yielding a product of the formula (XI) R
~ R4 : Rl~ H2C1 (1 )m R2- S (CH) - CH - CO - N - CH-COR
When R2 is R5CO, this product can then be converted to the product . I - ::
(XII) R
4 1l 21 (1 )m HS - (CH)n- CEI - CO - N -CH-COR
HA135b ~ , by ammonolysis. When R2 is a protecting group, then -the compound of formula XII can be obtained by"deprotection"
as described above. When R is an ester group (i.e., R
is lower alkoxy), the ester group can be removed, e.g., when R is tert. butoxy or tert. amyloxy, by treatment of the ester of formula XI or XII with trifluoroacetic acid and anisole to give the corresponding free acid. When other alkoxy groups are present, alkaline hydrolysis will yield the corresponding acid.
A variation of this procedure involves the use of an acrylic acid of the formula (VI) 14 ~
CH=C-COOH
as starting material. This acrylic acid is first converted to the acid halide form then made to react with a compound of formula III to obtain a compound of the formula (XIII) R3 R~ Rl H2C (IC )m CH=C - CO- N - CH-COR
and this intermediate is subjected to the addition reaction with the thiol or thioacid VII as described above.
A tosyloxyalkanoic acid of the formula (XIV) R4 IRl CH3- ~ - 9O2O-(CH)n- CH- COOH
can also be used as the agent to acylate the acid of formula III, then the acylation product lS subjected to the displace-ment reaction, etc., as descrihed above.
The acrylic acid of formula VI can alternatively be first made to react with the thioacid of forrnula VII to IIA135b obtain a product of the formula (XV) R~ R
which is converted to its acid halide, e.g., with thionyl chloride, then coupled to the compound of formula III and the same sequence as above then followed.
The acid or ester of formula III can also be acylated with a "protected" form of a ~-mercaptoalkanoic acid of khe formula (~VI) 14 R~-S-(CH~ -CH-COOH
wherein R8 i5 the "protec-ting" group. Such "protecting" yroups can take the form described above.
Following the acylation, the produck can be "deprotected"
by one fo the known methods referred ko above.
SkiIl another acylating agent can take khe form of a thlolac-tone, e.g., ~-propiothiolactone, a-mekhyl-~-propiothio-lactone or khe like.
Additional dekails of preferred modes of producing compounds of this invention can be found in the followin~
and in khe specific examples.
According ko a particularly preferred modification, the acid or ester of formula III is acylated with a halo-alkanoyl halide of the formula (XVII) R~ Rl X-~CH)n- CH-COX
wherein each X is independenkly a halogen, preferably chlorine or hromine, Rl is hydrog~n, lower alkyl or phenyl-lower alkyl -~.n-HA135b and n is 0, 1 or 2. This reaction is effec-ted in an alXallne medium, e.g., dilute alkali metal hydroxide solu-tion, alkali metal bicarbona-te or alkall metal carbonate solution at a reduced temperature, e.g., about 0 to 153C. The reaction product is subjec-ted to displacement with the anion of the thiol or thio acid of the formula VII above, also in alkaline medium, preferably alkali metal carbonate solution, and then worked up in conventional manner. The product of this reaction, wherein R2 of formula I is R5-CO, is converted to the product wherein R2 is hydrogen by ammonolysis, e.g., alcoholic ammonia or concentrated ammonium hydroxide solution, or alkaline hydrolysis, e.g., with aqueous metal hydroxide.
When an acid of formula III is used as starting material, the final product obtained as the free carboxylic acid can then be :, converted to its ester, for example by esterification wlth a diazoalkane, like diazornethane, l-alkyl-3-p-tolyl-triazene, like l-n-butyl-3-p-tolyltriazene or the like. Treatment of an ester, preferably the methyl ester, with an alcoholic ammonia :
solution, converts the free acid to the amide, i.e., R is NH2.
According to another variation, an ester, preferably the t-butyl ester, of formula III, in an anhydrous medium such as dichloromethane, tetrahydrofuran, dioxane or the like, is treated with a thioalkanoic acid of the formula (XVIII) 2 2 n in the presence of dicyclohexylcarbodiimide, N,N'-ca~bonyl-bisimidazole, ethoxyacetylene, diphenylphosphoryl azide or similar coupling agents at a temperature in the range of about 0 to 10 C. The ester group (R) can then be removed, for HA135b example, by treatment with trifluoroacetic acid and anisole at about room temperature.
When an ester of formula III (e.g., R is lower alkoxy, especially~ t-butoxy) is acylated with a thiolactone, e.g., ~-propiothiolactone, ~-methyl-~-propiothiolactone or the like, khe reaction can be effected in an anhydrous solvent like tetrahydrofuran, dioxane, methylene ch:loride or the like at about 0 C. to about room tempera~ure. The ester group can be removed wit~ anisole and trifluoroacetic acid as described above. M
In similar manner, when R2 is R5-M-C-,-~products of formula I having this substituent are formed by reacting a compound of formula XII with the halogenated compound (XIX) M
or alternatively reacting a compound of formula X with an ~ ;
alkali metal salt or alkaline earth metal salt of the formula (XX) M
R5-M-C-S-Me wherein Me represents the alkali metal or alkaline earth metal.
M
When R2 is R5-NH-C-, products of formula I having this substituent are produced by reacting a compound of formula XII
with the appropriately substituted isocyanate or isothio-cyanate of the formula (XXI) R5-N=C=M - `
Alkernatively, the same products can be produced by coupling an acid of the formula 3~
- :
IIAl 3 5h ( XXII ) M R R
Il 14 11 R -NH- C S- (CH)-- CH-COOH
with an amino acid of formula III.
Compounds of formula I, wherein R2 :is lower alkyl, phenyl, substituted phenyl, phenyl-lower alkyl, tr:iphenyl-lower alkyl, lower alkylthiomethyl or phenyl-lower alkyLthiomethyl are produced by reacting a compound of formula XII with the corresponding halide R2X or by reacting a compound of formula X
with the corresponding thiol ~2SH in the same manner as described above.
When R is lower alkanoylamidomethyl, the product of formula I is produced by condensing a compound of formula XII
with the corresponding hydroxymethyl-lower alkanoylamide of th formula (XXIII) lower alkyl-CO-NHCH2OH
in thè presence of an acid catalyst like trifluoroaoetic acid.
Products of formula I wherein R2 is R6-5 can be prepared by any of the known methods for the synthesis of mixed disulfides, e.g., by the reaction of a compound of formula(XII)with a thiosulfinate(xxIv), thiosulfonate (XXV~, su]fenyl halide (XX~I), thiosulfate (XXVII) or sulfenyl thiocyanate (XXVIII) O
(XXIV) ~R6-S~S-R6 , (XXV) R6 11 5 R6 ' 6 (XXVII) R6-$-SO3H, (XXVIII) R6-S-SCN
In the particular case wherein R7 is R
l4 R~ CH2 - (lH)n -S(O) - (CH) -~ CH - CO - N ~ CH-COR, p n HA135b R, Rl, R3 and R~ are the same as -the corresponding subs-ti-tuents in formula I and p is O, the symmetrical disulfides can be obtained by direct oxidation of a compound of formula XII
with iodine. When p is 1 or 2, such products are obtained by the stepwise oxidation of the corresponding compound wherein p is O. Mixed disulfides are obtained by the modifiGation shown in the examples.
Products of formula I have one or more asymmetric carbons.
When Rl, R3 or R4 is other than hydrogen the carbon to which it is attached is asymmetric. These carbon atoms a~e indicated by an asterisk in formula I. The compounds accordingly exist in stereoisomeric forms or in racemic mixtures thereof. Al:L of these are within the scope of the invention. The above described synthesis can utilize the racemate or one of the enar2tiomers as starting material.
When the racemic starting material is used in the synthetic procedure~ the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. In general, the L-isomer wi~h respect to the carbon of the amino acid constitutes the preferred isomeric form. Also the D-isomer with respect to the a-carbon in the acyl side chain (i.e., the carbon bearing Rl) is preferred.
~ The compounds of this invention orm basic salts with various inorganic and organis bases which are also within the scope af the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which axe pre~erred~, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, HA135b hydrabamine salts, salts with amino acids like arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preerred, although other salts are also useful, e.g., in isolating or purifying the product, as illustrated in the examples in the case O,c the dicyclohexylamine salt.
The salts are ormed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen orm (e.g., polystyrene sulfonic acid resin like Dowex 50) or with an aqueous acid and extraction with~an organic solvent, e.g., ethyl acetate, dichloromethane or the like, the free acid form can be obtained, and, if desired, another salt formed.
, :
_ :
' .. , . .
HA135b Additional experimental details are Eound in the examples which are preferred embodiments ancl also serve as models for the preparation of other members oE the group.
The compounds of this invention inhi bit the conversion of the decapeptide angiotens in I to angiotensin II and therefore are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin Oll angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I.
Angiotensin I is converted by anyiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species , e . g ., rats and doys . The coM~ounds o~ t}lis invention intervene in the angiotensin (renin)-tanyiotensin I ~angiotensin II
se~uence by inhibiting anglotensin conver-ting enzyme and reducing or eliminating -the formation of the pressor substance angiotensin II . Thus by the adminis tration of a con~position contalning one or a cornbination o f compounds oE formula I
or physiologically acceptable salt thereof, angiotensin dependent hypertension in the species of marnmal suf feriny therefrom is alleviated. A slngle dose, or pre~erably two to four divided daily doses, provided on a basis of about 0. 1 to 100 mg. per kilogram per day, preferably about 1 to 50 mg. per kilogram per day is appropriate to reduce blood pressure as indicated in the animal model expeximents described by S.L~ Engel, T. R. Schaeffer, M.H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. 143 j 483 (1973) . The substance is preferably aclministered orally, but parenteral routes such as subcutaneous, intramuscular , intravenous or HA135b intraperitoneal can also be emyloyed.
Tiie compounds of this invention can be utilized to achieve the reduction o~ blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. ~bou-t 10 to 500 my. of a - compound or mixture of compounds oE formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, s~abilizer, flavor, etc., in a unit dosage foxm as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is sucl- tha~
a suitable dosaye in the range indi.cated is obtained.
Illustrative of the adjuvants which may be incorporated in t~blets, capsules and the like are the followin~: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegra~ing agent such as corn starch, potato starch, alginic acid and the like;
a lubricant such as magnesium stearate; a sweeteniny ayent such as sucrose, lactose or saccharin; a flavoriny agent such as peppermint, oil of wintergreen or cherry. When the dosaye unlt form is a capsule, it may contain in addition ~o Inaterials of the above type a liquid carrier such as a fa~ty oiI. Various other materials may be present as coatinys or to o-therwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, suyar or both. A syrup or elixir may contain the active compound, sucrose as a sweeteniny ayent, methyl and propyl parabens as preservatives, a dye and a flavoriny such as cherry or orange flavor.
Sterile coml~ositions ~or in~ectiol- can ~e ~ormula~ecl ~ 4 ~IAl35b accordiny to col-ventional pllarmclceutical practice by dissolving or suspending the active. substance in a vellicle such as water Eor injection, a naturally occurriny vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, an~ioxidants and tlle like can be incorporated as required. , The following e~amples are illustrative of the invention and constitute especially preferred embodiments. All tempera-tures are in degrees celsius.
8~
HA13$b E:xam~:l.e 1 .
1-(2-~3enzoyl~ ioacctyl)-L-Proline L-Proline (5.75 g.) is dissolved in N sodium hydroxide (50 ml.) and the solu-tion is chilled in an ice-water bath.
Sodium hydroxide 2N (26 ml.) and chloroacetyl chloride (5.65 g.) are added andthe mixture is s-tirred vigorously at room temperature for three hours. ~ suspension of thiobenzoic acid (7.5 g.) and potassium carbonate (4.8 g. ) in water (50 ml.
is added. After 18 hours stirring at room -temperature, the reaction mixture is acidified and extrac-ted with ethyl acetate.
The ethyl acetate layer is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo. ~he residue (14.6 g.) is dissolved in ethyl acetate (lS0 ml.) and dicyclohexylamine (lL ml.) is added. The crystals are filtered and recrystallized from ethyl acetate, yield 5.7 g. m.p.
151-152 . To convert tlle salt to the acid, the crystals are dissolved in a mixture of 5~ -aqueous potassium bisulfate (100 ml.) and ethyl acetate (300 mlr). The oryanic phase is ;~
washed once with water, dried over magnesiuln sulfate and concentrated to dryness in vacuo, yield 3.45 g.
Example 2 1-(2-Mercaptoacetyl)-L-Proline 1-(2~Benzoylthioacetyl)-L~proline (3.4 g.) is dissolved in a mixture of water (10.5 ml.) and concentrated al~nonia (6.4 ml.)~
After one hour, the reaction mixture is diluted with water and filtered. The filtrate is extracted witSI ethyl acetate and then acidi~ied with concentrated hydrochloric acid, saturated with sodium chloride and extracted twice with ethyl acetate. The ethyl acetate extracts are wasl~ed with saturated sodium chloride and concentrated to dryness, yield 1.5 c ~19-;4 The product, 1-(2-mercaptoacetyl)-L-prol:ine is crystallized from ethyl ace-tate (m.p. 133-13S).
Example 3 c ~ roline Methyl Ester ___ 1-(2-Benzoylthioacetyl)-L-proline obtained in Example 1, is dissolved in methanol and an ethereal solution of diazomethane is added until there is a persistent yellow color. After 15 minu-tes, a few drops of acetic acid are added and the solvent is removed in vacuo to obtain 1-(2-benzoylthioacetyl)-L-proline methyl ester.
Example 4 ~ -1-(2-~ercaptoacetyl)-L-Proline Amide The product of Example 3 is dissolved in 10% metha-nolic ammonia and the solution is s-tored at room tempera-ture in a pressure bottle. When thin layer chromatogra-phic analysis indicates that the two es-ter functions have been ammonolyzed, the reaction mixture is concentrated to dryness to obtain l-(2-mercaptoacetyl)-L-proline amide.
Example _ 1-(2-Benzoylthioacetyl)-L-Hydroxyproline By substituting L-hydroxyproline for the L-proline in the procedure of Example 1, 1-(2-benzoylthioacetyl)-L-hydroxyproline is obtained.
Example 6 1-(2-Mercaptoacetyl)~L-Hydroxyproline By treating the product of Example 5 with ammonia as in Example 2, 1-(2-mercaptoacetyl)-L-hydroxyproline is obtained.
Example 7 1-(2-Benzoylthioacetyl)-L-Azetidine-2-Carboxylic Acid By substituting L-aze-tidine-2-carboxylic acid for the ~' ~ A13S~
L-proline in the ~rocedure oE ~xam~le 1, 1-(2-benzoyl-thioacetyl)-L-azetidine-2-car~oxylic acid is obtained.
~ ~, 1-~2-Mercaptoacetyl)-L-~zetidine-2-Car~oxylic ~cid By treating the product of ~xample 7 with ammonia as in Example 2, 1-(2-mercaptoacetyl)-L-azetidine-2 carboxylic acid is obtained.
Example 9 1-(2-B _ oylthioacetyl)-L-pipecolic Acid By substitutinc~ L-pipecolic acid for the L-proline in the procedure of Example 1, 1-(2-benzoylthioacetyl)-L-pipecolic acid is obtained.
~xample 10 1 (2-Mercaptoacetyl)-L-Pipecolic Acid By treating the produc-t of Example 9 with ammonia as in Example 2, 1-(2-mercaptoacetyl)-L-pipecolic acicl is obtained.
xample 11 1-(2-~enzoyltlliopropanoylj-L-Proline L-Proline (5.75 g. ) is dissolved in aqueo~s N sodium hydroxide (50 ml.) and the solution is chilled in an ice bath with stirring. 2N sodium hydroxide (25 ml.) ancl 2-bromo-propionyl chloride (8~57 g.) are added in that order and the mixture is removed from the ice bath and stirred at room tempexature for one hour. A mixture of thiobenzoic acid (7.5 g.) and potassium carbonate (4.8 g.) in water (S0 ml.) is added and the mixture is stirred overnight at rQom temperature. ~fter acidification witll concen~trated hydro-chloric acid, the aqueous solution is extracted with e~hyl acetate and the organic phase is washed with water, dricd and - . ~ ~' . . , ' HA135b concentrated to dryness. The resiclue (14.7 ~.) is chromatographed on a column of 440 g. o silica gel witll a mlxture of benzene-acetic acid (7:1~. The ractions containinc3 the desired material are pooled, concentrated ~o dryness, and the residue is preci~itated -twice with ether-hexane and converted ~o a dicyclohexylamine salt in ether-hexane, yield 9.4 g.
m.P.l(142) 148-156.The dicyclohexylamine salt is converted back to the acid as in Example 1, yield 5.7 g xample 12 1-(2-Mercaptopropanoyl)-L-Proline 1-(2-~enzoylthiopropanoyl)-L-proline (5.7 g.) is dissolved in a mixture o water (12 ml.) and concentrated ammonium hydroxide (9 ml.) with stirring. ~ter one hour, the mixture is diluted with water (lQ ml.) and iltered.
The filtrate is extracted twice with ethyl acetate, concentrated to one-third of the original volume, acidi~ied with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried and concentrated to dryness in vacuo. The residue, 1-(2-mercaptopropanoyl)-L-proline, is crystallized from eth~l acetate-hexane, yield 3 g.,m.p. (105) 116-120 .
~xample 13 1-(3'-Benzoylt:hioproL~anoyl)-L-Proline L-Proline (5.75 g.) is dissolved in normal sodium hydroxide (50 ml.) and the solution is chilled in an ice bath.
3-Bromopropionyl chloride (8.5 g.) and 2N sodium hydroxide (27 M1.) are added and the mixture is s~irred for 1-0 m1nutes in the ice bath and three hours at room temperaturc. A
suspension of ~hioL~en~oic aci.d (7.5 q.) antl potassium carbonate (4.5 g.) in water ( 50 ml.) is added antl the mixture is stirred c 1864 ilA1~ 5b for 18 hours a~ room ~em~erature. Af~er acicliEication witl concentrated hydrochloric acid, the aqueous ~hase is extraete~ twice with etllyl acetate. The organic layers are driecl over magnesium sulfate and concentrated to dryness in vacuo -to obtain 1-(3-benzoyltlliopropanoyl)-L-proline, yield 7.1 g;, m.p. 101 102 ~etilyl acetate-hexane).
Example 1 L-Proline tert.-butyl ester , I.-Proline (230 g.) is dissolved in a mixture of wa-ter (1 1.) and 5 N sodium hydroxide (400 ml.). The solution is chilled in an ice bath, and under vigorous stirring, 5 N
sodium hydroxide (460 ml.) and benzyloxycarbonyl chloride (340 ml.) are added in five equal aliquo~s during a half hour period. ~fter one l~our stirring at room temperature, the mixture is extracted twice with ether and acidified with concentrated hydroc}lloric acid. The precipitate is ~iltered and dried. Yield 442 g. m.p. 78-80.
Tlle benzyloxycarbonyl-L-proline thus obtained (l~O g.) is dissolved in a mixture of dichlorometllane (300 ml.),liquid isobutylene (800 ml.) and concelltratecl sulfurie acid (7.2 ml.). The solution is shaken in a pressure bot-tle ~or 72 hours. The pressure is released, the isobutylene is allowed to evaporate and the solution is washed with 5% sodium carbonate, water, dried ovex mac3nesium sulfate and concentrated to dryness in vacuo,to obtain benzyloxy-carbonyl-L-proline tert.butyl ester, yield 205 g.
Benzyloxycarbonyl-L-proline tert.butyl este~ (205 g.) is dissolved in absoIute ethanol (1~2 1) and hydrogenatecl at normal pressuxe with 10% Pd on carbon (10 g.) until only a -trace of carbon dioxide is observed in the hydrogen exit cJas :
i5i6~
HA135b (24 hours). The catalyst is Eiltered off arld the fil~rate is concentrated ir. vacuo at 30 mm. ~IcJ. The residue is .
distilled in vacuo,,to obtain L-proline tert.butyl ester, b.p.lmm 50-51 Exampl~ 15 1-(3-Acetylthiopropanoyl)-L Proline tert-butyl Ester L-Proline tert-butyl ester (5.13 g.) is dissolved in dlchloromethane (40 ml.) and the solution is chilled in an ice-water bath. A solution of dicyclohexylcarbodiimide (6.18 g.) in dichloromethane (20 ml.) is added followed immediately by 3-acetylthiopropionic acid (4.45 g.). A~-ter 15 minutes stirring in the ice-water bath and 16 hours at room tempera-ture, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. l`he residue is , dissolved in ethyl acetate and washed neutral. Th~ orr3anic layer is dried over magnesium sulfate and concentrated to dryness in vacuo to obtain 9.8 cJ. of 1-(3-acetylthiopropanoyl)-L-proline tert-butyl ester~
Example lG
1-(3-Acetylthi~propanoyl~-L-Proline 1-(3-Acetylthiopropanoyl)-L-proline-t-buty1 ester (4~7 g.) is dissolved in a mixture o anisole (34 ml.) and trlfluoroacetic acid (68 ml.) and the mixture is kept at room temperature for one hour. rrhe solvents are removed in vacuo and the residue is precipitated from ether-hexane several times. The residue (3.5 g.) is dissolved in acetonitrile (25 mlO) and dicyclollexylamine (2.8 ml.) is added. The crystalline salt is filtered and recrystallized from isopropanol. Yield 3.8 y.. mOp~ 176-177 . 'l`he salt is reconverted -to 1-(3-acetylthiopropanoyl)-L-proline as in -~4 HA135b Example 1, yield 1.25 g., m.p. 89-90 ~ethyl acetate-hexane).
Examplc 17 1-(3-Mercaptopropalloyl)-L-proline ter~-bu~yl ~ster To a solution of L-proline -tert-butyl ester (`3.42 g ) in dry tetrahydrofuran (10 ml.) chilled in an ice bath, propiothiolactone (1.76 9.) is added. ~fter 5 mirlutes storage in - the ice bath and three hours at room temperature, the reaction mixture is diluted with ethyl acetate (200 ml.) and washed with 5~ potassium bisulfate, and water. The organlc layer is dried over magnesium sulfate and concentrated~to dryness in vacuo. The residue 1-(3-mercaptopropanoyl)-L-~proline tert-;, butyl ester is crystallized from ether-hexane, yield 3.7 g., m.p. 57 58.
' Example 18 1-(3-Mercaptopropanoyl)~-L-Proline Procedure ~
1-13-Benzoy~lthiopropanoyl)-L-proline (4.9 g.~ls dissolved in a mixture of water~(8 ml.) and concentrated ammonium hydroxide (5.6 ml.) and the solution is stored with stirring under argon for one hour~ The reaction mixture is diluted with water, filtered, and the filtrate is extracted with ethyl acetate~ The aqueous phase is acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The organic la~ers are washed with saturated sodium chloride, dried over magnesium sulfate, and ~concentrated to dryness in vacuo. The residue,l-~3-mercapto-propanoyl)-L-proline, is crystallized from ethyl acetate hexane, yield 2.5 y., m.p. 63-70 .
Procedure B
1-(3-~cetylthiopropanoyl)-L-proline (0.~ 9.) is dissolved , HA135b in 5.5 N methanolic ammollia (5 ml.) and the solu~ion ke~
under ar~on at roorn temperature. ~Eter 2 hours th~ solvent is removed in vacuo, the residue is dissolved in water and applied to an ion exchange column on the H cyclelDowex 50~Analytical grade)]and eluted with water. The fractiolls that ~ive thiol positive reaction are pooled and concentrated to dryness, yield 0.6 g. This product is crystallized from ethyl acetate-hexane as in Procedure A to obtain 1-(3-mercap-to~ropanoyl)-L-proline.
Procedure C
1-(3-Mercaptopropanoyl)-L-proline t-butyl ester (2.3 g.) is dissolved in a mixture of anisole (20 ml.) and triEluoro-acetic acid (45 ml.). After one hour storage at room temperature under aryon, the reaction mixture is concentrated to dryness in vacuo and the residue precipitated from ethyl acetate-hexane several times. The residue (1.9 cJ.) is dissolved in ethyl acetate (30 ml.) and dicyclohexylamine (1.85 ml.) lS
added. The crystalline salt is filtered and recrystallized from isopropanol, yield 2 g. m.p. 187-188.
The salt is converted to the acid as in Example 1, yield 1.3 g. The product is crystallized from etl-yl acetate hexane as in Procedure A.
Salts Sodium 1-(3-Mercaptopropanoyl)-L-proline (500 mg.) is dissolved in a mixture of water ~2~5 m~.) and N sodium hydroxidc (~.S ml.).
The solution is freeze dried to obtain the sodium s~lt.
Magnesium 1-(3-Mercaptopropanoyl)-L-proline (500 mg. ?, maynesium oxide (49~5 mg.), and water ~10 ml.) are stirred HA135b with slic3ht heating until complete solution is obtailled.
Tllen the solvent is rernoved by freeze dryin~J -to obtain the magnesium salt.
Calcium __ 1-(3~Mercaptopropanoyl~-2-proline t500 mg.) is dissolved in a mixture o~ calcium l~ydroxide (91 mg.) and water (10 ml.), and the solution is free~e dried to o~tain the calcium salt.
Potassium 1-(3-Mercaptopropanoyl)-L-proline(500 mg.) is dissolved in a mixture of potassium bicarbonate (246 mg.) and water (10 ml.) and freeze dried to obtain the potassium salt.
N-Methyl-D-Glucamine 1-(3-Mercaptopropanoyl)-L-proline (500 m~.) and N-rnethyl-D-glucamine (480 mg.) are dissolved in water (10 ml.) and freeze dricd to obtain the ~-methyl~D-glucamine salt.
~xample 19 1-(3-Mercaptopropanoyl)-L-IIydroxyproline By substitutiny L-hydroxyproline for the L-proline in the procedure of ~xarnple 11 and then -treating the product by Procedure A of Example 18, 1-(3-benzoylthiopropanoyl)-L-hydroxyproline and 1-(3-mercaptopropanoyl)-L-hydroxyproline, respectively, are obtained.
~xample 20 ,~
1-(3-Mercaptopropanoyl)-L-Aze-tidine-2-CarboxYlic ~cid By substituting L-azetidine-2-carboxylic acid tert-: .
butyl ester (prepared by substituting L-azetidine-2- ~ -carbox~lic acid for the proline in ~x~rnple 14) for ~lle L-proline tert-butyl ester in the procedur.c ~f ~xaml~le L5, . .
HA135b treating the product as in ~xample 16 and tlle 1-(3-acetyl-thiopropanoyl)-L-azetidine~2-carboxylic acid thus obtained by Procedure B of Example 18, 1-(3-acetylthiopropalloyl)-L-azetidine-2-carboxylic acid ter-t-butyl ester and 1-(3-mercapto-propanoyl)-L-azetidine-2-carboxylic acid, respectively, are obtained.
Example 21 1-(3-Mercaptopropanoyl~-L-Pipecolic ~cid By substituting L-pipecolic acid tert-butyl ester (prepared by substituting L-pipecolic acid ~or the L-proline in Example 14) for the L-proline -tert-butyl ester in the procedure of Example 15 and ~reatiny the product by Procedure C
of ~xample 18, 1-(3-mercaptopropanoyl)-L-pipecolic acid tert-butyl ester and 1-(3-mercaptopropanoyl)-L-pi~)ecolic acid, respectively, are obtained.
Example 22 1-(3-Mercaptopropanoyl)-~-Methyl-L-Proline By substituting 4-methyl-L-proline for L-proline in the procedure of Example :L3 and ~hen treating the product by Procedure A of Example 18, 1-(3-benzoylthiopropanoyl)-4-methyl-L-proline and 1-(3-mercaptopropanoyl)-4-metl~yl-L-proline, are obtained.
~ xarnple 23 1-(3-Mercaptopropanoyl)-5-llydroxy-L-Piuecolic Acid By substitutiny 5-hydroxy~ -pipecolic acid for L-proline in the procedure of ~xample 13 and then trea-ting the product by the Procedure A of Example 18, 1-(3-ben;zoyl-thiopropanoyl)-S-hydroxy-L-pipecolic, and 1-(3-mercapto-propanoyl)-5-hydroxy-L-pipecolic acid are ob~ained.
Example 2~
1-(3-Mercaptol~ropanoyl.)-D-Proline By substituting D-proline ~or L-pYoline in the proc~dure of Example 13 and then trea-ting the product by Procedure A of Example 18, 1-(3-benzoylthiopropanoyl)-D-proline and 1-(3-mercaptopropanoyl)-D-proline, m.p. 68-70 , are obtained.
- Example 25 3-Acetylthio-2-Methylpropanoic Acid ~ mixture of thloacetic acld~ ~50 y.) and metllacrylic acid (40.7 g.) is heated on the steam bath for one hour and ' '~
then stored a-t room temperature for 18 hours. After confirming by nmr spectroscopy that con~plete reaction of tlle metllacrylic acid has been,achieved, the reaction mi,xture is distilled in vacuo and the desired 3-acetylthio-2-methylpropanoic acid is separated in the fraction with bolling point 128.5 -131 ' (2.6 mmHc3.), yield 64 y. , Example 26 i~
3-Benzoylthio-2-Methylpropanoic Acid ~, By substituting thiobenzoic acid for the thioacetlc acid in the procedure of Example~2s, 3-benzoylthio-2-methylpropanoic acid is obtained.
Example 27 3-Phenylacetylthio-2-MethylproE~anoic ~cid By substituting thiophenylacetic acid for the thioacetic acld in the procedure of Example 25, 3-phenyl-acetyl thio-2-methylpropanoic acicd is obtained.
~.~ample 28 1-(3-~cetylthio-2-methylprc)E)anoyl)-L-Prolille tert-butyl Ester L-Proline tert-butyl ester (S.l g.) i~ dissolved in dichloro~ethalle (40 ml.) and the solution stirred and chilled .
-29- ~
~Q~
~ 135b in an ice bat}l. Dicyclohexylcarbodiilllide (G.2 cJ.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane ~5 ml.). After 15 minu~es s~irriny in the ice bath and 16 hours at room temperaturc, the precipitate is filtered of~ and the il-trate is concen~rated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column chroma-tography (silica gel-cllloroform), yield 7.9 g.
~xample 29 1 (3-~cet lth:o-2-me~h lpro ano l)-L-l'roline Y ~ Y ~ Y
Procedure ~
The 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester of ~xample 28 (7.8 y.) is dissolved ln a mixture of anisole (55 ml.) and trifluoroacetlc acld (110 ml.).
After one hour storage at room temperature the solvent is removed in vacuo and the residue is preci~itated several times from ether-hexane. The residue (6.8 g.) is dissolved in acetonitxile (40 ml.) and dicyclohexylamine (4.5 ml,) is added. The crystalline salt lS boiled Witil ~resh acetonitrile (100 ml~), chilled to room temperature and filtered, yield 3.8 g., m.p. (165) 187-188 . This material is recrystallized from isopropanol [a~D-67 (C 1.4, EtOH). The crystalline dicyclohexylamiDe salt is suspended in a mixture of 5% aqueous potassium bisul~ate and ethyl acetate. The or~anic l~hase ls washed with water and concentrated to dryncss. The residue is crystallized ~rom ethyl acetatc-hexane to yield the 1-(3-acetyl-
According to a preferred method for producing compounds ;~ of formula I, especially wherein R2 is R5-CO~, an acid or ester of formula III is coupled with a haloalkanoic acid of the formula HAl35b (V) R4 X-(CH) - CH- COOH
wherein X is a halogen, preferably chlorine or bromine. This can be effected by one of the known procedures in which the acid IV is activated, prior to reaction with the acid III, involving formation of a mixed anhydrlde, symmetrical anhydrlde, acid chloride, active ester, or use of Woodward reagent K, EEDQ
(N-ethoxycarbonyl-2-ethoxy-l,2-dihydroxyquinoline) or the like.
The product of this reaction is a compound of the formula (X) 13 4 1l H2C (CH)m : X - (CEI) - ca - co - N - CH-COR
The product o formula X is subjected to a displacement ~ :
reaction with the anion of a thioacid of the formula (VII) yielding a product of the formula (XI) R
~ R4 : Rl~ H2C1 (1 )m R2- S (CH) - CH - CO - N - CH-COR
When R2 is R5CO, this product can then be converted to the product . I - ::
(XII) R
4 1l 21 (1 )m HS - (CH)n- CEI - CO - N -CH-COR
HA135b ~ , by ammonolysis. When R2 is a protecting group, then -the compound of formula XII can be obtained by"deprotection"
as described above. When R is an ester group (i.e., R
is lower alkoxy), the ester group can be removed, e.g., when R is tert. butoxy or tert. amyloxy, by treatment of the ester of formula XI or XII with trifluoroacetic acid and anisole to give the corresponding free acid. When other alkoxy groups are present, alkaline hydrolysis will yield the corresponding acid.
A variation of this procedure involves the use of an acrylic acid of the formula (VI) 14 ~
CH=C-COOH
as starting material. This acrylic acid is first converted to the acid halide form then made to react with a compound of formula III to obtain a compound of the formula (XIII) R3 R~ Rl H2C (IC )m CH=C - CO- N - CH-COR
and this intermediate is subjected to the addition reaction with the thiol or thioacid VII as described above.
A tosyloxyalkanoic acid of the formula (XIV) R4 IRl CH3- ~ - 9O2O-(CH)n- CH- COOH
can also be used as the agent to acylate the acid of formula III, then the acylation product lS subjected to the displace-ment reaction, etc., as descrihed above.
The acrylic acid of formula VI can alternatively be first made to react with the thioacid of forrnula VII to IIA135b obtain a product of the formula (XV) R~ R
which is converted to its acid halide, e.g., with thionyl chloride, then coupled to the compound of formula III and the same sequence as above then followed.
The acid or ester of formula III can also be acylated with a "protected" form of a ~-mercaptoalkanoic acid of khe formula (~VI) 14 R~-S-(CH~ -CH-COOH
wherein R8 i5 the "protec-ting" group. Such "protecting" yroups can take the form described above.
Following the acylation, the produck can be "deprotected"
by one fo the known methods referred ko above.
SkiIl another acylating agent can take khe form of a thlolac-tone, e.g., ~-propiothiolactone, a-mekhyl-~-propiothio-lactone or khe like.
Additional dekails of preferred modes of producing compounds of this invention can be found in the followin~
and in khe specific examples.
According ko a particularly preferred modification, the acid or ester of formula III is acylated with a halo-alkanoyl halide of the formula (XVII) R~ Rl X-~CH)n- CH-COX
wherein each X is independenkly a halogen, preferably chlorine or hromine, Rl is hydrog~n, lower alkyl or phenyl-lower alkyl -~.n-HA135b and n is 0, 1 or 2. This reaction is effec-ted in an alXallne medium, e.g., dilute alkali metal hydroxide solu-tion, alkali metal bicarbona-te or alkall metal carbonate solution at a reduced temperature, e.g., about 0 to 153C. The reaction product is subjec-ted to displacement with the anion of the thiol or thio acid of the formula VII above, also in alkaline medium, preferably alkali metal carbonate solution, and then worked up in conventional manner. The product of this reaction, wherein R2 of formula I is R5-CO, is converted to the product wherein R2 is hydrogen by ammonolysis, e.g., alcoholic ammonia or concentrated ammonium hydroxide solution, or alkaline hydrolysis, e.g., with aqueous metal hydroxide.
When an acid of formula III is used as starting material, the final product obtained as the free carboxylic acid can then be :, converted to its ester, for example by esterification wlth a diazoalkane, like diazornethane, l-alkyl-3-p-tolyl-triazene, like l-n-butyl-3-p-tolyltriazene or the like. Treatment of an ester, preferably the methyl ester, with an alcoholic ammonia :
solution, converts the free acid to the amide, i.e., R is NH2.
According to another variation, an ester, preferably the t-butyl ester, of formula III, in an anhydrous medium such as dichloromethane, tetrahydrofuran, dioxane or the like, is treated with a thioalkanoic acid of the formula (XVIII) 2 2 n in the presence of dicyclohexylcarbodiimide, N,N'-ca~bonyl-bisimidazole, ethoxyacetylene, diphenylphosphoryl azide or similar coupling agents at a temperature in the range of about 0 to 10 C. The ester group (R) can then be removed, for HA135b example, by treatment with trifluoroacetic acid and anisole at about room temperature.
When an ester of formula III (e.g., R is lower alkoxy, especially~ t-butoxy) is acylated with a thiolactone, e.g., ~-propiothiolactone, ~-methyl-~-propiothiolactone or the like, khe reaction can be effected in an anhydrous solvent like tetrahydrofuran, dioxane, methylene ch:loride or the like at about 0 C. to about room tempera~ure. The ester group can be removed wit~ anisole and trifluoroacetic acid as described above. M
In similar manner, when R2 is R5-M-C-,-~products of formula I having this substituent are formed by reacting a compound of formula XII with the halogenated compound (XIX) M
or alternatively reacting a compound of formula X with an ~ ;
alkali metal salt or alkaline earth metal salt of the formula (XX) M
R5-M-C-S-Me wherein Me represents the alkali metal or alkaline earth metal.
M
When R2 is R5-NH-C-, products of formula I having this substituent are produced by reacting a compound of formula XII
with the appropriately substituted isocyanate or isothio-cyanate of the formula (XXI) R5-N=C=M - `
Alkernatively, the same products can be produced by coupling an acid of the formula 3~
- :
IIAl 3 5h ( XXII ) M R R
Il 14 11 R -NH- C S- (CH)-- CH-COOH
with an amino acid of formula III.
Compounds of formula I, wherein R2 :is lower alkyl, phenyl, substituted phenyl, phenyl-lower alkyl, tr:iphenyl-lower alkyl, lower alkylthiomethyl or phenyl-lower alkyLthiomethyl are produced by reacting a compound of formula XII with the corresponding halide R2X or by reacting a compound of formula X
with the corresponding thiol ~2SH in the same manner as described above.
When R is lower alkanoylamidomethyl, the product of formula I is produced by condensing a compound of formula XII
with the corresponding hydroxymethyl-lower alkanoylamide of th formula (XXIII) lower alkyl-CO-NHCH2OH
in thè presence of an acid catalyst like trifluoroaoetic acid.
Products of formula I wherein R2 is R6-5 can be prepared by any of the known methods for the synthesis of mixed disulfides, e.g., by the reaction of a compound of formula(XII)with a thiosulfinate(xxIv), thiosulfonate (XXV~, su]fenyl halide (XX~I), thiosulfate (XXVII) or sulfenyl thiocyanate (XXVIII) O
(XXIV) ~R6-S~S-R6 , (XXV) R6 11 5 R6 ' 6 (XXVII) R6-$-SO3H, (XXVIII) R6-S-SCN
In the particular case wherein R7 is R
l4 R~ CH2 - (lH)n -S(O) - (CH) -~ CH - CO - N ~ CH-COR, p n HA135b R, Rl, R3 and R~ are the same as -the corresponding subs-ti-tuents in formula I and p is O, the symmetrical disulfides can be obtained by direct oxidation of a compound of formula XII
with iodine. When p is 1 or 2, such products are obtained by the stepwise oxidation of the corresponding compound wherein p is O. Mixed disulfides are obtained by the modifiGation shown in the examples.
Products of formula I have one or more asymmetric carbons.
When Rl, R3 or R4 is other than hydrogen the carbon to which it is attached is asymmetric. These carbon atoms a~e indicated by an asterisk in formula I. The compounds accordingly exist in stereoisomeric forms or in racemic mixtures thereof. Al:L of these are within the scope of the invention. The above described synthesis can utilize the racemate or one of the enar2tiomers as starting material.
When the racemic starting material is used in the synthetic procedure~ the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. In general, the L-isomer wi~h respect to the carbon of the amino acid constitutes the preferred isomeric form. Also the D-isomer with respect to the a-carbon in the acyl side chain (i.e., the carbon bearing Rl) is preferred.
~ The compounds of this invention orm basic salts with various inorganic and organis bases which are also within the scope af the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which axe pre~erred~, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, HA135b hydrabamine salts, salts with amino acids like arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preerred, although other salts are also useful, e.g., in isolating or purifying the product, as illustrated in the examples in the case O,c the dicyclohexylamine salt.
The salts are ormed in conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble, or in water and removing the water by freeze drying. By neutralizing the salt with an insoluble acid like a cation exchange resin in the hydrogen orm (e.g., polystyrene sulfonic acid resin like Dowex 50) or with an aqueous acid and extraction with~an organic solvent, e.g., ethyl acetate, dichloromethane or the like, the free acid form can be obtained, and, if desired, another salt formed.
, :
_ :
' .. , . .
HA135b Additional experimental details are Eound in the examples which are preferred embodiments ancl also serve as models for the preparation of other members oE the group.
The compounds of this invention inhi bit the conversion of the decapeptide angiotens in I to angiotensin II and therefore are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin Oll angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I.
Angiotensin I is converted by anyiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species , e . g ., rats and doys . The coM~ounds o~ t}lis invention intervene in the angiotensin (renin)-tanyiotensin I ~angiotensin II
se~uence by inhibiting anglotensin conver-ting enzyme and reducing or eliminating -the formation of the pressor substance angiotensin II . Thus by the adminis tration of a con~position contalning one or a cornbination o f compounds oE formula I
or physiologically acceptable salt thereof, angiotensin dependent hypertension in the species of marnmal suf feriny therefrom is alleviated. A slngle dose, or pre~erably two to four divided daily doses, provided on a basis of about 0. 1 to 100 mg. per kilogram per day, preferably about 1 to 50 mg. per kilogram per day is appropriate to reduce blood pressure as indicated in the animal model expeximents described by S.L~ Engel, T. R. Schaeffer, M.H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. 143 j 483 (1973) . The substance is preferably aclministered orally, but parenteral routes such as subcutaneous, intramuscular , intravenous or HA135b intraperitoneal can also be emyloyed.
Tiie compounds of this invention can be utilized to achieve the reduction o~ blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. ~bou-t 10 to 500 my. of a - compound or mixture of compounds oE formula I or physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, s~abilizer, flavor, etc., in a unit dosage foxm as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is sucl- tha~
a suitable dosaye in the range indi.cated is obtained.
Illustrative of the adjuvants which may be incorporated in t~blets, capsules and the like are the followin~: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegra~ing agent such as corn starch, potato starch, alginic acid and the like;
a lubricant such as magnesium stearate; a sweeteniny ayent such as sucrose, lactose or saccharin; a flavoriny agent such as peppermint, oil of wintergreen or cherry. When the dosaye unlt form is a capsule, it may contain in addition ~o Inaterials of the above type a liquid carrier such as a fa~ty oiI. Various other materials may be present as coatinys or to o-therwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, suyar or both. A syrup or elixir may contain the active compound, sucrose as a sweeteniny ayent, methyl and propyl parabens as preservatives, a dye and a flavoriny such as cherry or orange flavor.
Sterile coml~ositions ~or in~ectiol- can ~e ~ormula~ecl ~ 4 ~IAl35b accordiny to col-ventional pllarmclceutical practice by dissolving or suspending the active. substance in a vellicle such as water Eor injection, a naturally occurriny vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, an~ioxidants and tlle like can be incorporated as required. , The following e~amples are illustrative of the invention and constitute especially preferred embodiments. All tempera-tures are in degrees celsius.
8~
HA13$b E:xam~:l.e 1 .
1-(2-~3enzoyl~ ioacctyl)-L-Proline L-Proline (5.75 g.) is dissolved in N sodium hydroxide (50 ml.) and the solu-tion is chilled in an ice-water bath.
Sodium hydroxide 2N (26 ml.) and chloroacetyl chloride (5.65 g.) are added andthe mixture is s-tirred vigorously at room temperature for three hours. ~ suspension of thiobenzoic acid (7.5 g.) and potassium carbonate (4.8 g. ) in water (50 ml.
is added. After 18 hours stirring at room -temperature, the reaction mixture is acidified and extrac-ted with ethyl acetate.
The ethyl acetate layer is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo. ~he residue (14.6 g.) is dissolved in ethyl acetate (lS0 ml.) and dicyclohexylamine (lL ml.) is added. The crystals are filtered and recrystallized from ethyl acetate, yield 5.7 g. m.p.
151-152 . To convert tlle salt to the acid, the crystals are dissolved in a mixture of 5~ -aqueous potassium bisulfate (100 ml.) and ethyl acetate (300 mlr). The oryanic phase is ;~
washed once with water, dried over magnesiuln sulfate and concentrated to dryness in vacuo, yield 3.45 g.
Example 2 1-(2-Mercaptoacetyl)-L-Proline 1-(2~Benzoylthioacetyl)-L~proline (3.4 g.) is dissolved in a mixture of water (10.5 ml.) and concentrated al~nonia (6.4 ml.)~
After one hour, the reaction mixture is diluted with water and filtered. The filtrate is extracted witSI ethyl acetate and then acidi~ied with concentrated hydrochloric acid, saturated with sodium chloride and extracted twice with ethyl acetate. The ethyl acetate extracts are wasl~ed with saturated sodium chloride and concentrated to dryness, yield 1.5 c ~19-;4 The product, 1-(2-mercaptoacetyl)-L-prol:ine is crystallized from ethyl ace-tate (m.p. 133-13S).
Example 3 c ~ roline Methyl Ester ___ 1-(2-Benzoylthioacetyl)-L-proline obtained in Example 1, is dissolved in methanol and an ethereal solution of diazomethane is added until there is a persistent yellow color. After 15 minu-tes, a few drops of acetic acid are added and the solvent is removed in vacuo to obtain 1-(2-benzoylthioacetyl)-L-proline methyl ester.
Example 4 ~ -1-(2-~ercaptoacetyl)-L-Proline Amide The product of Example 3 is dissolved in 10% metha-nolic ammonia and the solution is s-tored at room tempera-ture in a pressure bottle. When thin layer chromatogra-phic analysis indicates that the two es-ter functions have been ammonolyzed, the reaction mixture is concentrated to dryness to obtain l-(2-mercaptoacetyl)-L-proline amide.
Example _ 1-(2-Benzoylthioacetyl)-L-Hydroxyproline By substituting L-hydroxyproline for the L-proline in the procedure of Example 1, 1-(2-benzoylthioacetyl)-L-hydroxyproline is obtained.
Example 6 1-(2-Mercaptoacetyl)~L-Hydroxyproline By treating the product of Example 5 with ammonia as in Example 2, 1-(2-mercaptoacetyl)-L-hydroxyproline is obtained.
Example 7 1-(2-Benzoylthioacetyl)-L-Azetidine-2-Carboxylic Acid By substituting L-aze-tidine-2-carboxylic acid for the ~' ~ A13S~
L-proline in the ~rocedure oE ~xam~le 1, 1-(2-benzoyl-thioacetyl)-L-azetidine-2-car~oxylic acid is obtained.
~ ~, 1-~2-Mercaptoacetyl)-L-~zetidine-2-Car~oxylic ~cid By treating the product of ~xample 7 with ammonia as in Example 2, 1-(2-mercaptoacetyl)-L-azetidine-2 carboxylic acid is obtained.
Example 9 1-(2-B _ oylthioacetyl)-L-pipecolic Acid By substitutinc~ L-pipecolic acid for the L-proline in the procedure of Example 1, 1-(2-benzoylthioacetyl)-L-pipecolic acid is obtained.
~xample 10 1 (2-Mercaptoacetyl)-L-Pipecolic Acid By treating the produc-t of Example 9 with ammonia as in Example 2, 1-(2-mercaptoacetyl)-L-pipecolic acicl is obtained.
xample 11 1-(2-~enzoyltlliopropanoylj-L-Proline L-Proline (5.75 g. ) is dissolved in aqueo~s N sodium hydroxide (50 ml.) and the solution is chilled in an ice bath with stirring. 2N sodium hydroxide (25 ml.) ancl 2-bromo-propionyl chloride (8~57 g.) are added in that order and the mixture is removed from the ice bath and stirred at room tempexature for one hour. A mixture of thiobenzoic acid (7.5 g.) and potassium carbonate (4.8 g.) in water (S0 ml.) is added and the mixture is stirred overnight at rQom temperature. ~fter acidification witll concen~trated hydro-chloric acid, the aqueous solution is extracted with e~hyl acetate and the organic phase is washed with water, dricd and - . ~ ~' . . , ' HA135b concentrated to dryness. The resiclue (14.7 ~.) is chromatographed on a column of 440 g. o silica gel witll a mlxture of benzene-acetic acid (7:1~. The ractions containinc3 the desired material are pooled, concentrated ~o dryness, and the residue is preci~itated -twice with ether-hexane and converted ~o a dicyclohexylamine salt in ether-hexane, yield 9.4 g.
m.P.l(142) 148-156.The dicyclohexylamine salt is converted back to the acid as in Example 1, yield 5.7 g xample 12 1-(2-Mercaptopropanoyl)-L-Proline 1-(2-~enzoylthiopropanoyl)-L-proline (5.7 g.) is dissolved in a mixture o water (12 ml.) and concentrated ammonium hydroxide (9 ml.) with stirring. ~ter one hour, the mixture is diluted with water (lQ ml.) and iltered.
The filtrate is extracted twice with ethyl acetate, concentrated to one-third of the original volume, acidi~ied with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried and concentrated to dryness in vacuo. The residue, 1-(2-mercaptopropanoyl)-L-proline, is crystallized from eth~l acetate-hexane, yield 3 g.,m.p. (105) 116-120 .
~xample 13 1-(3'-Benzoylt:hioproL~anoyl)-L-Proline L-Proline (5.75 g.) is dissolved in normal sodium hydroxide (50 ml.) and the solution is chilled in an ice bath.
3-Bromopropionyl chloride (8.5 g.) and 2N sodium hydroxide (27 M1.) are added and the mixture is s~irred for 1-0 m1nutes in the ice bath and three hours at room temperaturc. A
suspension of ~hioL~en~oic aci.d (7.5 q.) antl potassium carbonate (4.5 g.) in water ( 50 ml.) is added antl the mixture is stirred c 1864 ilA1~ 5b for 18 hours a~ room ~em~erature. Af~er acicliEication witl concentrated hydrochloric acid, the aqueous ~hase is extraete~ twice with etllyl acetate. The organic layers are driecl over magnesium sulfate and concentrated to dryness in vacuo -to obtain 1-(3-benzoyltlliopropanoyl)-L-proline, yield 7.1 g;, m.p. 101 102 ~etilyl acetate-hexane).
Example 1 L-Proline tert.-butyl ester , I.-Proline (230 g.) is dissolved in a mixture of wa-ter (1 1.) and 5 N sodium hydroxide (400 ml.). The solution is chilled in an ice bath, and under vigorous stirring, 5 N
sodium hydroxide (460 ml.) and benzyloxycarbonyl chloride (340 ml.) are added in five equal aliquo~s during a half hour period. ~fter one l~our stirring at room temperature, the mixture is extracted twice with ether and acidified with concentrated hydroc}lloric acid. The precipitate is ~iltered and dried. Yield 442 g. m.p. 78-80.
Tlle benzyloxycarbonyl-L-proline thus obtained (l~O g.) is dissolved in a mixture of dichlorometllane (300 ml.),liquid isobutylene (800 ml.) and concelltratecl sulfurie acid (7.2 ml.). The solution is shaken in a pressure bot-tle ~or 72 hours. The pressure is released, the isobutylene is allowed to evaporate and the solution is washed with 5% sodium carbonate, water, dried ovex mac3nesium sulfate and concentrated to dryness in vacuo,to obtain benzyloxy-carbonyl-L-proline tert.butyl ester, yield 205 g.
Benzyloxycarbonyl-L-proline tert.butyl este~ (205 g.) is dissolved in absoIute ethanol (1~2 1) and hydrogenatecl at normal pressuxe with 10% Pd on carbon (10 g.) until only a -trace of carbon dioxide is observed in the hydrogen exit cJas :
i5i6~
HA135b (24 hours). The catalyst is Eiltered off arld the fil~rate is concentrated ir. vacuo at 30 mm. ~IcJ. The residue is .
distilled in vacuo,,to obtain L-proline tert.butyl ester, b.p.lmm 50-51 Exampl~ 15 1-(3-Acetylthiopropanoyl)-L Proline tert-butyl Ester L-Proline tert-butyl ester (5.13 g.) is dissolved in dlchloromethane (40 ml.) and the solution is chilled in an ice-water bath. A solution of dicyclohexylcarbodiimide (6.18 g.) in dichloromethane (20 ml.) is added followed immediately by 3-acetylthiopropionic acid (4.45 g.). A~-ter 15 minutes stirring in the ice-water bath and 16 hours at room tempera-ture, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. l`he residue is , dissolved in ethyl acetate and washed neutral. Th~ orr3anic layer is dried over magnesium sulfate and concentrated to dryness in vacuo to obtain 9.8 cJ. of 1-(3-acetylthiopropanoyl)-L-proline tert-butyl ester~
Example lG
1-(3-Acetylthi~propanoyl~-L-Proline 1-(3-Acetylthiopropanoyl)-L-proline-t-buty1 ester (4~7 g.) is dissolved in a mixture o anisole (34 ml.) and trlfluoroacetic acid (68 ml.) and the mixture is kept at room temperature for one hour. rrhe solvents are removed in vacuo and the residue is precipitated from ether-hexane several times. The residue (3.5 g.) is dissolved in acetonitrile (25 mlO) and dicyclollexylamine (2.8 ml.) is added. The crystalline salt is filtered and recrystallized from isopropanol. Yield 3.8 y.. mOp~ 176-177 . 'l`he salt is reconverted -to 1-(3-acetylthiopropanoyl)-L-proline as in -~4 HA135b Example 1, yield 1.25 g., m.p. 89-90 ~ethyl acetate-hexane).
Examplc 17 1-(3-Mercaptopropalloyl)-L-proline ter~-bu~yl ~ster To a solution of L-proline -tert-butyl ester (`3.42 g ) in dry tetrahydrofuran (10 ml.) chilled in an ice bath, propiothiolactone (1.76 9.) is added. ~fter 5 mirlutes storage in - the ice bath and three hours at room temperature, the reaction mixture is diluted with ethyl acetate (200 ml.) and washed with 5~ potassium bisulfate, and water. The organlc layer is dried over magnesium sulfate and concentrated~to dryness in vacuo. The residue 1-(3-mercaptopropanoyl)-L-~proline tert-;, butyl ester is crystallized from ether-hexane, yield 3.7 g., m.p. 57 58.
' Example 18 1-(3-Mercaptopropanoyl)~-L-Proline Procedure ~
1-13-Benzoy~lthiopropanoyl)-L-proline (4.9 g.~ls dissolved in a mixture of water~(8 ml.) and concentrated ammonium hydroxide (5.6 ml.) and the solution is stored with stirring under argon for one hour~ The reaction mixture is diluted with water, filtered, and the filtrate is extracted with ethyl acetate~ The aqueous phase is acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The organic la~ers are washed with saturated sodium chloride, dried over magnesium sulfate, and ~concentrated to dryness in vacuo. The residue,l-~3-mercapto-propanoyl)-L-proline, is crystallized from ethyl acetate hexane, yield 2.5 y., m.p. 63-70 .
Procedure B
1-(3-~cetylthiopropanoyl)-L-proline (0.~ 9.) is dissolved , HA135b in 5.5 N methanolic ammollia (5 ml.) and the solu~ion ke~
under ar~on at roorn temperature. ~Eter 2 hours th~ solvent is removed in vacuo, the residue is dissolved in water and applied to an ion exchange column on the H cyclelDowex 50~Analytical grade)]and eluted with water. The fractiolls that ~ive thiol positive reaction are pooled and concentrated to dryness, yield 0.6 g. This product is crystallized from ethyl acetate-hexane as in Procedure A to obtain 1-(3-mercap-to~ropanoyl)-L-proline.
Procedure C
1-(3-Mercaptopropanoyl)-L-proline t-butyl ester (2.3 g.) is dissolved in a mixture of anisole (20 ml.) and triEluoro-acetic acid (45 ml.). After one hour storage at room temperature under aryon, the reaction mixture is concentrated to dryness in vacuo and the residue precipitated from ethyl acetate-hexane several times. The residue (1.9 cJ.) is dissolved in ethyl acetate (30 ml.) and dicyclohexylamine (1.85 ml.) lS
added. The crystalline salt is filtered and recrystallized from isopropanol, yield 2 g. m.p. 187-188.
The salt is converted to the acid as in Example 1, yield 1.3 g. The product is crystallized from etl-yl acetate hexane as in Procedure A.
Salts Sodium 1-(3-Mercaptopropanoyl)-L-proline (500 mg.) is dissolved in a mixture of water ~2~5 m~.) and N sodium hydroxidc (~.S ml.).
The solution is freeze dried to obtain the sodium s~lt.
Magnesium 1-(3-Mercaptopropanoyl)-L-proline (500 mg. ?, maynesium oxide (49~5 mg.), and water ~10 ml.) are stirred HA135b with slic3ht heating until complete solution is obtailled.
Tllen the solvent is rernoved by freeze dryin~J -to obtain the magnesium salt.
Calcium __ 1-(3~Mercaptopropanoyl~-2-proline t500 mg.) is dissolved in a mixture o~ calcium l~ydroxide (91 mg.) and water (10 ml.), and the solution is free~e dried to o~tain the calcium salt.
Potassium 1-(3-Mercaptopropanoyl)-L-proline(500 mg.) is dissolved in a mixture of potassium bicarbonate (246 mg.) and water (10 ml.) and freeze dried to obtain the potassium salt.
N-Methyl-D-Glucamine 1-(3-Mercaptopropanoyl)-L-proline (500 m~.) and N-rnethyl-D-glucamine (480 mg.) are dissolved in water (10 ml.) and freeze dricd to obtain the ~-methyl~D-glucamine salt.
~xample 19 1-(3-Mercaptopropanoyl)-L-IIydroxyproline By substitutiny L-hydroxyproline for the L-proline in the procedure of ~xarnple 11 and then -treating the product by Procedure A of Example 18, 1-(3-benzoylthiopropanoyl)-L-hydroxyproline and 1-(3-mercaptopropanoyl)-L-hydroxyproline, respectively, are obtained.
~xample 20 ,~
1-(3-Mercaptopropanoyl)-L-Aze-tidine-2-CarboxYlic ~cid By substituting L-azetidine-2-carboxylic acid tert-: .
butyl ester (prepared by substituting L-azetidine-2- ~ -carbox~lic acid for the proline in ~x~rnple 14) for ~lle L-proline tert-butyl ester in the procedur.c ~f ~xaml~le L5, . .
HA135b treating the product as in ~xample 16 and tlle 1-(3-acetyl-thiopropanoyl)-L-azetidine~2-carboxylic acid thus obtained by Procedure B of Example 18, 1-(3-acetylthiopropalloyl)-L-azetidine-2-carboxylic acid ter-t-butyl ester and 1-(3-mercapto-propanoyl)-L-azetidine-2-carboxylic acid, respectively, are obtained.
Example 21 1-(3-Mercaptopropanoyl~-L-Pipecolic ~cid By substituting L-pipecolic acid tert-butyl ester (prepared by substituting L-pipecolic acid ~or the L-proline in Example 14) for the L-proline -tert-butyl ester in the procedure of Example 15 and ~reatiny the product by Procedure C
of ~xample 18, 1-(3-mercaptopropanoyl)-L-pipecolic acid tert-butyl ester and 1-(3-mercaptopropanoyl)-L-pi~)ecolic acid, respectively, are obtained.
Example 22 1-(3-Mercaptopropanoyl)-~-Methyl-L-Proline By substituting 4-methyl-L-proline for L-proline in the procedure of Example :L3 and ~hen treating the product by Procedure A of Example 18, 1-(3-benzoylthiopropanoyl)-4-methyl-L-proline and 1-(3-mercaptopropanoyl)-4-metl~yl-L-proline, are obtained.
~ xarnple 23 1-(3-Mercaptopropanoyl)-5-llydroxy-L-Piuecolic Acid By substitutiny 5-hydroxy~ -pipecolic acid for L-proline in the procedure of ~xample 13 and then trea-ting the product by the Procedure A of Example 18, 1-(3-ben;zoyl-thiopropanoyl)-S-hydroxy-L-pipecolic, and 1-(3-mercapto-propanoyl)-5-hydroxy-L-pipecolic acid are ob~ained.
Example 2~
1-(3-Mercaptol~ropanoyl.)-D-Proline By substituting D-proline ~or L-pYoline in the proc~dure of Example 13 and then trea-ting the product by Procedure A of Example 18, 1-(3-benzoylthiopropanoyl)-D-proline and 1-(3-mercaptopropanoyl)-D-proline, m.p. 68-70 , are obtained.
- Example 25 3-Acetylthio-2-Methylpropanoic Acid ~ mixture of thloacetic acld~ ~50 y.) and metllacrylic acid (40.7 g.) is heated on the steam bath for one hour and ' '~
then stored a-t room temperature for 18 hours. After confirming by nmr spectroscopy that con~plete reaction of tlle metllacrylic acid has been,achieved, the reaction mi,xture is distilled in vacuo and the desired 3-acetylthio-2-methylpropanoic acid is separated in the fraction with bolling point 128.5 -131 ' (2.6 mmHc3.), yield 64 y. , Example 26 i~
3-Benzoylthio-2-Methylpropanoic Acid ~, By substituting thiobenzoic acid for the thioacetlc acid in the procedure of Example~2s, 3-benzoylthio-2-methylpropanoic acid is obtained.
Example 27 3-Phenylacetylthio-2-MethylproE~anoic ~cid By substituting thiophenylacetic acid for the thioacetic acld in the procedure of Example 25, 3-phenyl-acetyl thio-2-methylpropanoic acicd is obtained.
~.~ample 28 1-(3-~cetylthio-2-methylprc)E)anoyl)-L-Prolille tert-butyl Ester L-Proline tert-butyl ester (S.l g.) i~ dissolved in dichloro~ethalle (40 ml.) and the solution stirred and chilled .
-29- ~
~Q~
~ 135b in an ice bat}l. Dicyclohexylcarbodiilllide (G.2 cJ.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane ~5 ml.). After 15 minu~es s~irriny in the ice bath and 16 hours at room temperaturc, the precipitate is filtered of~ and the il-trate is concen~rated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column chroma-tography (silica gel-cllloroform), yield 7.9 g.
~xample 29 1 (3-~cet lth:o-2-me~h lpro ano l)-L-l'roline Y ~ Y ~ Y
Procedure ~
The 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester of ~xample 28 (7.8 y.) is dissolved ln a mixture of anisole (55 ml.) and trifluoroacetlc acld (110 ml.).
After one hour storage at room temperature the solvent is removed in vacuo and the residue is preci~itated several times from ether-hexane. The residue (6.8 g.) is dissolved in acetonitxile (40 ml.) and dicyclohexylamine (4.5 ml,) is added. The crystalline salt lS boiled Witil ~resh acetonitrile (100 ml~), chilled to room temperature and filtered, yield 3.8 g., m.p. (165) 187-188 . This material is recrystallized from isopropanol [a~D-67 (C 1.4, EtOH). The crystalline dicyclohexylamiDe salt is suspended in a mixture of 5% aqueous potassium bisul~ate and ethyl acetate. The or~anic l~hase ls washed with water and concentrated to dryncss. The residue is crystallized ~rom ethyl acetatc-hexane to yield the 1-(3-acetyl-
6~
HA135b thlo-2-D-metllylpropanoyl-L-proline,m.p.~3-85~ 162~c,1.7,~tOII).
Procedure B
_ 3-Acetylthio-2-methylpropanoic acid (8.1 y~) and thionyl chloride (7 g.) are Mixed and the sus~ensioll is stirred for 16 hours at room temperature. The reaction mixture is concentrated to dryness and distilled in v~cuo (b.p 80 ).
This 3-acetylthio-2-methylpropanoic acid chlorlde (5.4 g.) and 2N sodium hydroxide (15 ml.) are added to a solution of L-proline (3.45 g.) in normal sodium hydroxide (30 ml.) chilled in an ice water bath. ~fter 3 hours s'~irring a~
room temperature, the mixture is extra~ted with e~her, the aqueous phase is acidified and extracted with e-thyl ace~ate.
Tlle or~anic phase is dried over magnesium sulfate ~nd concentrated to dryness to obtain 1-(3-acetyl-thio-2-DL-metllyl~ropanoyl-L
proline. ~ ~
Procedure C ;
- Methacryloyl chloride (4.16 g.) is added to a solution o L-proline (3.45 g.) in a mixture of water (100 ml ) and sodium blcarbonate (12 g.) chilled in an ice water bath, with vigorous stirring. When the addition is compLeted, the mixture ; ;
is stirred at room temperature for two hours, and then extracted ~ ~
with ether. The aqueous phase is acidified with N hydrochloric ~ -acid and extracted with ethyl acetate. The organic phase is concentrated to dryness in vacuo, the residue is mixed with thiolacetic acid (3.5 g.~, a few crystals of azobisisobuty-ronitrile are added a~d the mixture is heated on the steam bath for two hours. The reaction mix-ture is dissolved in~benzene-acetic acid ~75:25), and applied to a column of silica gel.
Elution witll the same solverl~ mixturc yields thc 1-~3-acetylthio-2-DL-methylpropanoyl)-L-urolinc~.
HA13Sb ample 30 1-(3-Benzoyl~hio-2-metllylpropanoyl)-L-prolille tert-butyl Ester By substituting 3-benzoylthio~2-methylpropanoic acid for the 3-acetylthio-2-methylpropanoic acid in t:lle proced~rc of Example 23, 1-(3~benzoylthio-2-methylpro~anoyl)-L-proline tert.butyl ester is obtained.
~xample 31 1-(3-Phenylacetylthio-2-met_ylpropanoyl)-L-ProIine ter~-butyI Ester By substituting 3-phenylacetylthio-2-methylpropanoic 10 acid for the 3-acetylthio-2-methylpropanoic acid in the procedure of Example 28, 1-(3-phenylacetylthio-2-methylprouanoyl)-L-proline tert butyl ester is obtained.
xamplc 32 1-(3-Benzoylt;hio-2-methylpropanoyl)-L-proline By substituting 1-(3-benzoylthio-2-methylpropanoyl)-L-proline tert-butyl ester for the 1-(3-acetyltllio)-2- ;~
methylpropanoyl)-l-proline tert-butyl ester in Procedure of Example 29, 1-(3-benzoylthio-2-metllylpropanoyl)-L-prollne is obtained.
E~ample 33 (3-phenylacetyltllio-~ e~Vl~5lC~ L 1~ L ~
~y substitutin~ 3-phenylacetylthio-2-metllylpropanoyl)-L-proline tert-butyl ester for 1-(3-acetylthio-2-me~hylpro~anoyl)-; L-proline tert-butyl ester ln Procedure A of ~xample 2~, 3-phenylacetylthio-2-methylpropanoyl)-L-proline is obtained.
Example 34 1-(3-MercaPto-2-D-metl~ ~ropanoyl)-L-proline . . . :
1-(3-Mercapto-2-methylpropanoyl)-L~proline is obtained by treating the product o~ each o~ Examyles 29, 32 and 30 33 as follows:
, HA135b The thioester (0.85 c~.) is dissolved in 5.5 N
methanolic ammonia and the solution is kept at room temperature for 2 hours. The solvent is removed ln vacuo and the residue is dissolved in water, applied to a ion e~chanye column on the H cycle (Dowex 50, analytical grade) and elu~ed witll water. ~he ~ractions that yive positlve thiol rea~tion are pooled and freeze dried. The residue is crystalli~ed from ethyl acetate-hexane, yield 0.3 g. The 1-(3-mercapto 2~-methylpropanoyl-L-proline has m.p. 103-104 , [~] 131 (C,2,~tOH).
Example 35 1-(3-~cetyltllio 2--methylpropanoyl)-L-Proline Met}lyl ~s~cr ~,~
1-(3-Acetylthio-2-methylpropanoyl) L-proline is reacted with an ethereal solution o~ diazome-thane accordinc;
to the procedure described in ~xample 3 to obtain 1-(3-acetyl~-thio-2-methylpropanoyl)-L-proline methyl ester.
Example 36 ~ ' 1-(3-Merca~to-2-methYlpropanoyl) L Proline amide ;~
By substituting 1-(3-acetylthio-2-metllylpropalloyl)-L-proline methyl ester in the procedure of ~xample 4, 1-(3 mercap-to-2-methylpro~anoyl)-L proline amide is obtaincd.
Example 37 3=Acetylthio-2-Benzylpropanoic ~cid By substituting 2-benzylacrylic acid for the methacrylic acid in the procedure of Example 2S, 3 acetyl-thio-2-benzylpropanoic acid is obtained.
3 Acetyltl?io-2 benzylpropanoyl) L-Prolille tcr~-buty:L E:s~er By substituting 3 acetyl~hio-2-ben~ylpropalloic acid for the 3-acetylthio-2 methylpropanoic acid in tl~e procedure of ~ 6~ HA135b Example 22, 1-(3-acetylthio-2-benzylpropanoyl)-L-proline tert-butyl ester is obtained.
Example 39 1-(3~Acet~lthio-2-benzylpropanoyl)-L-Proline The product of Example 38 is substituted for the 1-(3-acetylthio-2-methylpropanoyl-L-proline terl-butyl ester in the Procedure A of Example 29 to obtain 1-(3-acetylthio-2-benzylpropanoyl)-L-proline.
Example 40 1-(3-Mercapto-2-benzylpropanoyl) L-Proline 1-(3-Acetylthio-2 benzylpropanoyl)-L-proline is treated with methanolic ammonia according to the procedure of Example :~
34 to obtain 1-(3-mercapto-2-benzylpropanoyl)-L-proline as an oil, Rf = 0.47 (silica gel, benzene-acetic acid (75:25).
Example 41 1-(3-Mercapto~2-methylpropanoyl)-L-Hydroxy Proline By substituting L-hydroxy proline tert-butyl ester in the procedure of Example 28, treating the product according to Procedure A of Example 29 and then continuing as in Example 34, 1-~3-acetylthio-2-methylpropanoyl)-L-hydroxyproline tert-butyl ester, l-(3-acetylthio-2-methylpropanoyl)-L-hydroxyproline and 1-(3-mercapto-2-methylpropanoyl)-L-hydroxyproline, respecti~ely, are obtained.
Example 42 1-(3-Mercapto-2-methylpropanoyl)-L-Azetidine-2-Carboxylic Acid By substituting L-azetidine-2-carboxylic acid tert- ~
butyl ester in the procedure of Example 2~, treating the product ~.
according to the Procedure A of Example 29 and thén continuing as .
-3~- .
` ~'1 in Example 34, 1-(3-acetylthio-2-methylpropanoyl)-L-azetidine-2-carboxylic acid tert-butyl ester, 1,3-acetylthio-2-methyl-propanoyl)-L-azetidine-2-carboxylic acid and 1-(3-mercapto-2-methylpropanoyl-L-azetidine-2-carboxylic acid are obtained.
Example 43 1-(3-Mercapto~2-methylpropdnoly)-L~Pipecolic Acid By substituting L--pipecolic acid in the procedure of Example 28, treating the product according to Procedure A of Example 29 and then continuing as in ~xample 34, 1-(3-acetyl~
thio~2~methylpropanoyl)~L~pipecolic acid tert-butyl ester, 1-(3-acetylthio-2-methylpropanoyl)-L-pipecolic acid and 1-(3-mercapto~2~methylpropanoyl)-L~pipecolic acid, respectively, are obtained. -~
Example 44 1-(4-Benzoylthiobutanoyl)-L-Proline To a solution of L-proline (2.88 g.) in normal sodium hydroxide (25 ml.) chilled in an ice bath, 2N sodium hydroxide (12.5 ml.) and 4-chlorobutyryl chloride (3.5 g.) are added.
. ~ ~
The reac-tion mixture is stirred at room temperature for 3.5 ~ ~;
hours and a suspension of thiobenzoic acid (3.75 g.) and ~ ;~
potassium carbonate (2.A g.) in water (25 ml.) is added. After overnight stirring at room temperature, the reaction mixture is acidified with concentrated hydrochloric acid and extracted with ~
ethyl acetate. The organic layer is dried over magnesium sul- ~ ;
fate and concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with benzene-acetic acid (7 1). The fractions containing the desired material are pooled and concentra-ted to dryness, yield 1.35 g. A small aliquot of this material is dissolved in ethyl acetate and dicyclohexylamine is added until pH 8-10 (on a wet pH paper).
': ~
~35- ~-The dicyclohexylamine salt crystallizes out, immediately, m.p.
159-161.
Example ~5 1-(4-Mercaptobutanoyl)-L-Proline 1-(4-Benzylthiobutanoyl)-L-proline (1 03 g.) is dissolved in a mixture o water (4 ml.) and concentrated ammonia (2.7 ml.). A~ter one hour stirring at room tempera-ture, the mixture is diluted with water, filtered, extracted with ethyl acetate, and the aqueous phase was concentrated in vacuo.
This ammonium sal-t of 1-(4-mercaptobutanoyl)-L--proline is purified by ion e~change chromatography on a column of diethyl-aminoethyl-Sephadex (cross lin~ed dextran) with a gradient of ammonium bicarbonate, yield 0.7 ~. The ammonium salt is dissolved in water (2 ml.) and applied to a column of Dowex 50 sulfonic acid resin analytical grade in the hydrogen form, and the free acid is eluted with water. The fractions containing the desired material (sulfhydryl reagent and carboxyl reagent positive) are pooled and freeze dried to obtain l-(4-mercaptobutanoyl)-L-proline. The dicyclohexyl ammonium salt is produced by the procedure of Example 44, m.p. 157-158.
Example 46 - ~ :
4-Bromo-2-Methyl~utanoic Acid Ethyl-4-bromo-2-methylbutanoate [G. Jones and J. Wood, Tetrahedron, 21, 2961 (1965)] (1.04 g.) is dissolved in dichloromethane (50 ml.) and cooled to -10. A 1 M solution or boron tribromide in dichloromethane (50 ml.) is added dropwise with stirring and the stirring is continued for 1 hour at -10 and 2 hours at 25. The reaction is terminated - l~O~B64 by the careful addition of water. The layers are separated and the organic phase is washed with water, dried and concen-trated to dryness to obtain 4-bromo-2-methylbutanoic acid.
Example 47 1-(4-Benzoylthio-2-methy~lbutanoyl)-L-Proline a) 4-Bromo-2-methylbutanoic acid (8 g.) and thionyl chloride (7 g.) are mixed and the mixture is stirred Eor 16 hours at room temperature. The reaction mixture is concentrated to dryness and distilled in vacuo.
.
b) To a solution of L-proline (2.88 g.) in normal sodium hydroxide (25 ml.) chilled in an ice bath, 2N sodium hydroxide (12.5 ml.) and the 4-bromo-2-methylbutanoic acid chloride obtained in part (a) (3.9 g.) are added. The reaction - -mixture is stirred at room temperature for 3.5 hours and a suspension of thiobenzoic acid (3.75 g.) and potassium carbonate (2.4 g.) in water (25 ml.) is added. After overnight stirring at room temperature, the reaction mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with benzene-acetic acid (7:13. The fractions containing the desired product, l-(4-benzoylthio-2-methylbutanoyl)-L-proline are pooled and concentrated to dryness in vacuo.
Example 48 1-(4-Mercapto-2-methylbutanoyl)-L-Proline ~-By substituting 1-(4-benzoylthio-2-methylbutanoyl)-L-proline for the 1-(4-benzoylthiobutanoyl)-L-proline-in the procedure of Example 45, l-(mercapto-2-methylbutanoyl)-L-proline in obtained.
~J ~
'`
ExampLe 49 4-Bromo 2-benzylbutanoic acid By substituting ethyl-4-bromo-2-benzylbutanoate ~prepared by thc procedure of G. Jones and J. Wood [Tetrahedron, 21, 2961 (1965) starting with diethylbenzylmalonate]] for the ethyl-4-bromo-2-methylbutanoate in the procedure of Example 46, 4-bromo-2-benzylbutanoic acid is obtained.
Example 50 l-(4-Benzoylthio-2-benzylbu-tanoyl) L-Proline By substituting 4-bromo-2-benzylbutanoic acid for the 4-bromo-2-methylbutanoic acid in the procedure of Example 47, 1-(4-benzoylthio-2-benzylbutanoyl)-L-proline is obtained.
Examp~e 51 1-(4-Mercapto-2-benzylbutanoyl)--L-Proline By substituting 1-(4-benzoylthio-2-benzylbutanoyl)-L-proline for the l-(4-benzoylthiobutanoyl)-L-proline in the procedure of Example 45, 1-(mercapto-2-benzylbutanoyl)- -L-proline is obtained.
Example 52 1-(4-Mercaptobutanoyl)-L-Hydroxyproline By substituting L-hydroxyproline for -the L-proline in the procedure of Example 44 and subjecting the product to ammonolysis as in Example 45, l-(4-benzoylthiobutanoyl)-L-hydroxy-proline and l-(4-mercaptobutanoyl~-L-hydroxyproline, respectively, are obtained.
_ample 53 l-(4-Mercaptobutanoyl)-L-Azetidine-2-Carboxylic Acid --By substituting L-azetidine-2-carboxylic acid for the L-proline in the procedure of Example 44 and subjecting the l~ `
, 364 ~ ~
product to ammonolysis as in Example 45, l-(4-benzoylthio-butanoyl)-L-azetidine-2-carboxylic acid and l-(~-mercapto-butanoyl)-L-azetidine-2-carboxylic acid, respectively, are obtained~
E~
1=(4-Mercaptobutanoyl)-L-Pipecolic Acid By substituting L-pipecolic acid for the L-proline in the procedure of Example 44 and subjecting the product to ammonolysis as in Example 45, 1-(4-benzoylthiobutanoyl)-L-pipecolic acid and 1-(4-mercaptobutanoyl)-L-pipecolic acid, :
respectively, are obtained.
~., . ~ .
Example 55 ~;
1-(3-Acetylthiobutanoyl)-L-Proline tert-butyl Ester Dicyclohexylcarbodiimide (6.2 g.) and 3-acetylthio-butyric acid (4.86 g.) are added to a solution of L-proline tert-butyl ester (5.1 ~.) in dichloromethane (60 ml.) stirred in an ice bath. After 15 minutes the ice bath is removed , , and the mixture is stlrred at room temperature for 16 hours. ~;
The precipitate is filtered, the filtrate is concentrated to dryness and the residue is chromatographed on a column of `~
silica gel with chloroform to obtain l-(3~acetylthiobutanoyl)-L-proline tert-butyl ester, yield 5.2 g. ~;
Example 56 ;
1-(3-Acetylthiobutanoyl)-L-Proline The l-(3-acetylthiobutanoyl)-L-proline tert-butyl ester ~
of Example 55 (5.2 g.) is dissolved in a mixture of trifluoro- ~.
acetic acid (60 ml.) and anisolé (30 ml.) and the solution is kept at room temperature for one hour. The solvents are removed in vacuo and the residual l-(3-acetylthiobutanoyl)-L-prollne is reprecipitated from ether-hexane several times, yield - -~
~`
4 g.. The dicyclohexylamine salt is made by the procedure of Example 44, m.p. 175-17~.
Example 57 1-(3-Merc ptobutanoyl)-L-Proline The 1-(3-acetylthiobutanoyl)-L-proline of Example 56 (0.86 g.) is dissolved in 5~5 N. methanolic ammonia (20 ml.) and the reaction mixture is stored at room temperature for 2 hours. The solvent is removed in vacuo and the residue chromatographed on an ion exchange column (Dowex 50) with water. The fractions containing the desired 1-(3-mercaptobutanoyl)-L-proline are pooled and lyophilized, yield 0.6 g. The dicyclohexylamine salt is produced by the procedure of Example 44, m.p. 183-184.
Example 58 1-[3-[[(Ethoxy)carbonyl]thio]propanoyl]-L-proline Ethyl chloroformate ~1.2 g.) is added to a solution of 3~mercaptopropanoyl-L-proline (2.03 g.) in normal sodium bicar-bonate (30 ml.) and the mixture is stirred vigorously at 5 for one hour, and for two hours at room temperature. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and concentra-ted to dryness to yield 1-[3-[[(ethoxy)carbonyl~thio]propanoyl]-L-proline.
' ~' ~ :
Example 59 1-[3-[[(E-thoxy)thiocarbonyl]-thio]propanoyl]-L-proline Aqueous 2N sodium hydroxide (25 ml) and 3-hromopropionyl chloride (8.5 g) are added to a solution of L-proline (5.75 g) in N sodium hydroxide (50 ml) chilled and s-tlrred in an ice bath. After five minutes -the ice bath i5 removed and the stirring is continued at room temperature. After three hours ethyl xantogenic acid potassium salt ~9.6 g) is added and the mixture is stirred overnigh-t at room temperature. The solution ~ ~ -is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated to dry-ness and the residue is chromatographed on a column o~ silica gel with a mixture of benzene-acetic acid (7:1) as solven-t, to ~;
yield 1-[3-[[(ethoxy)thiocarbonyl]thio]propanoyl]-L-proline, p. 94_95o.
Example 6~
1-[3-[[(Benzylthio)carbonyl]thio]propanoyl]-L-proline A solution o~ benzylthiocarbonyl chloride (11 ml) in dioxane (20 ml) is added in five portions to a solution of 1-(3-mercaptopropanoyl)-~-proline (1.6 g) in normal sodium bicarbonate (24 ml) chilled in an ice bath, over a period of 30 minutes. The ice bath is removed and the stirring is continued for 2.5 hours at room temperature. After acid-ification with concentrated hydrochloric acid, the aqueous phase is extrac~ed with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness to yield 1-[3- E [ (benzylthio)carbonyl]thio]propanoyl]-~-proline.
.
.~ . .
_ample 61 1-[3-[[(Ethylthio)thiocarbonyl]thio]propanoyl~-.
Aqueous 2N sodium hydroxide (25 ml) and 3-bromopropionyl chloride (8.5 g) are added to a solution of L-proline (5.75 g) in N sodium hydroxide (50 ml~ chilled and stirred in an ice bath. After five minutes, the ice bath is removed and the stirring is continued at room temperature. After three hours, ethyl trithiocarbonate potassium salt (10.5 g~ is added and the mixture is stirred at room temperature overnight. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness to yield 1-[3-[[(ethylthio]t~iccarbonyl]thio]propanoyl]-L-proline.
Example 62 ;
3~[[(Methylamino)thiocarbonyl]thio]propionic acid ~ ethylisothiocyanate (4 g) is added to a solution of 3-mercaptopropionic acid (5.3 g) in a mixture of pyridine (250 ml) and 0.5 N sodium hydroxide (100 ml). The solution is kept at 40 for two hours and concentrated to dryness in vacuo. The residue is dissolved in water (100 ml.), _ acidi-fied with concentrated hydrochloric acid and extracted with ether. The organic phase is concentrated to dryness to yield 3-[[(methylamino)thiocarbonyl]thio]propionic acid, m.p. 86-87.
Example_ 3 1~[3-[[(Methylamino)thiocarbonyl]thio~propanoyl]-L-prollne tert-butyl ester To a solution of L-proline tert-butyl ester ~1.71 g) and hydroxybenzotriazole (1.35 g) in dichloromethane (lO m]) chilled and stirred in an ice bath, dicyclohexylcarbodiimide (2.06 gl and 3-methylaminothiocarbonylthiopropionic acid (1.79 g) are added. A~ter 15 minutes, the bath is removed and the stirring -is continued overnight. The precipitate is filtered off and the filtrate is diluted with ethyl acetate and washed neutral.
The organic phase is concentrated to dryness to yield l-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline tert-butyl ester, m.p. 129-130.
Example 64 l-[3-[[(Methylamino)thiocarbonyl]thio]propanoyl]-L-proline A) l-(MethylaminothiocarbonylthiopropanoyI)-L-proline tert- `
butyl ester (0.98 g) is dissolved in a mixture of anisole (3.6 ~ ;
ml) and trifluoroacetic acid (7.5 ml). After one hour at room temperature the mixture is concentrated to dryness in vacuo and the residue precipitated from ether-hexane three times. This material is chromatographed on a column of silica gel with a solvent mixture of benzene~acetic acid (75:25) to yield 1~[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline, ;
Rf = 0.4 [silica gel-benzene:acetic acid (75:25)]. The dicyclohexylammonium salt has m.p. 127-129.
~ .
;~
.: .
Gg~
~) Methylisothiocyanate (4 g) ls added to a solution of 3-mercaptopropanoyl-L-proline (10.1 CJ) in a mixture of pyridine (250 ml) and 0.5 ~ sodium hydroxide (lO0 ml). The solution is kept at 40 for two hours and concentrated to dryness ln vacuo.
The residue is dissolved in wa-ter (100 ml), acidified with con-centrated hydrochloric acid and extra~ted with ethyl acetate.
The organic phase is concentrated to dryness to yield l-~3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline.
Example 65 l-_[3-[[(Ethylamino)carbonyl]thio]propanoyl]-L-proline Ethylisocyanate (0.45 ml) is added to a solution of l-~3-mercaptopropanoyl)-L-proline (1 g) in a mixture of N
sodium hydroxide t5 ml) and pyridine (5 ml). The solution is heated at 40 for four hours and concentrated ln vacuo.
The residue is distributed between 0.1 N hydrochloric acid and ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated to dryness to yield 1-[3-[[(ethylamino)carbonyl]thio]propanoyl]-L-proline.
The dicyclohexylammonium salt is prepared by adding dicyclo-hexylamine to a solution of the free acid in ethyl acetate, ~;~
m.p. 150-152.
Examp_e_66 ' 1_[3-[[(Ethoxy?carbonyl]thio]-2-methylpropanoyl]-L-proline ~ `
By substituting 1-(3-mercapto-2-methylpropanoyl]-L-proline for the 3-mercaptopropanoyI-L-proline in the procedure of Example 58, l-[3-[~(ethoxy)carbonyl]thio]-2-methylpropanoyl]-L-proline is obtained~
~, ~
flA135b arnpl.e 67 1-[3-[[~thoxy)carborlyl]thio]butanoyl]-1.-proline By substituting 1-[3-mercaptobutanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of ~,cample 58, 1-3-[[(ethoxy)carbonyl]-thlo~butanoyl]-L-proline is obtained.
Examplc 68 1-[3-[[(Ethoxy)thiocarbonyl]thioJpropanoyl]-L-azetidine-2-carboxylic acld By substituting L-azetidine-2-carboxylic acid for L-proline in the procedure o~ Example 59, 1-[3-[[(ethoxy)-thiocarbonyl]thioJpropanoyl]-L-azetidine-2-carboxylic acid is obtained.
E'x rnple 69 1-[3-[[(~thoxy)thiocarbonyl]thio]propanoyl]-L-pipecolic acid ~ -By substituting L-pipecolic acid for L-proline in the procedure of Example 59, 1-[3-[[(ethoxy~thiocarbonyl]thio]pro-panoyl]-L-pipecolic acid i5 obtained.
Example 70 1-[4-[~(Benzyltllio)carbonyl]tllio]butalloy1J-I,-pLo]illc . .
, By substitutin~ 4-mercaptobutanoyl-L-proline ~or the 3-mercaptopropalloyl-L-proline in the proc-edure of ~xaml)lc 60, I-[4-[[(benzylthio]carbonyl]thio]bu~anoyl]-L-proline is obtained.
~xample 71 1-[2-[[(~enzylthio)carbonyl]thlo]propanoyl]-L-!jroline By substitutin~ 2-mercaptopropanoyl-L-prolirle for the 3-mercaptopropanoyl-L-proline in the procedurc of ~xa~ple 60, 1-[2~[[(benzyltllio)carbonyl~thio]propanoyl]-L-prolille is ob~ained.
Examp_e 72 1-[3-[[(E-thylthio)thiocarbonyl]thio]propanoyl]-L-proline methyl ester A solution of 1-[3-[[(ethyl-thio)thiocarbonyl]thio~-propanoyl]-L-proline in ethyl acetate i5 treated with an ethereal solution of diazomethane until persistent yellow color. After discharginy the yellow color with a few drops of acetic acid, ;
the solvents are removed in vacuo to yield l--[3-[[(ethylthio)-thiocarbonyllthio]propanoyl]-L-proline methyl ester.
Example 73 1-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-5-hydroxy-L-pipecolic acid By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the Procedure B of Example 64, 1- E 3-[[(methylamino)thiocarbonyl]thio]-propanoyl]-5-hydroxy-L-pipecolic acid is obtained.
Example 74 1-[3-[ E (Methylamiho)thiocarbonyl]thio]-2-methylpropanoyl]-L-proline amide By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline amide for the 3-mercaptopropanoyl-L-proline in the Procedure B of Example 64, 1-[3-[[(methylamino)thiocarbonyl]thio]-2-methyl-propanoyl]-L-proline amide is obtained.
Example 75 1-[3-[[(Phenoxy)carbonyl]thio]propanoyl]-L-proline By substituting phenylchloroformate for ethyl chloroformate in the procedure of ~xample 5~, 1-[3-[[(phenoxy)carbonyl]thio]-propanoyl]-I.-proline is obtained. -Example 76 1-[3 [~(Phenoxy)carbonyl}thio]butanoyl]-L-proline By substituting phenylchloroformate for the ethyl chloroformate and 4-mercaptobutanoyl-L-prolirle for the 3-mercaptopropanoyl-L-proline in the procedure of Example 58, 1-[3-[[(phenoxy)carbonyl]thio]butanoyl]-~-proline is obtained.
Example 77 1=[3-[[(Phenylamino)carbonyl]thio]propanoyl]-L-proline By substituting phenylisocyanate for the ethylisocyanate in the procedure of Example 65, 1-[3-[~(phenylamino)carbonyl]-thio]propanoyl] L-proline is obtained.
Example 78 1-[3-[[(Phenethylamino)carbonyl]thio]propanoyl]-L-proline :
By substituting phenethylisocyanate for the ethylisocyana-te in the procedure of Example 65, 1-[3-[[(phenethylamino)carbonyl]-thio]propanoyl]-L-proline is obtained. -~
Example 79 .
1 [3-[[(Ethylamino)carbonyl]thio]-2-benzylpropanoyl]-L-proline By substituting 1-(3-mercapto-2-benzylpropanoyl)-L-proline for the l-(3-mercaptopropanoyl)-L-proline in the procedure of Example 65, 1-[3-[[(ethylamino)carbonyl]thio]-2-benzylpropanoyl~-L-proline is ohtained.
., ~
Example 80 l-(3-Methyl-thiopropanoyl)-L-proline A) Methyl 3-methyl-thiopropionate (51 g) is saponiEied with a 10% sodium hydroxide solution (150 ml, 30 minutes at 100).
The cooled solu-tion is extracted with ether and then acidified.
The crude acid thus obtained is distilled and converted to the acid chloride with thionyl chloride.
A solution of L-proline (11.5 g) in N sodium hydroxide ~100 cc) is chilled in an ice bath and the 3-methylthiopropanoic acid chloride (6.9 g) is added dropwise with viyorous stirring over a ten minutes period. ~fter five hours the reaction mixture is acidified and extracted with ethyl ether to yield l-(3-me-thylthiopropanoyl)-L-proline. The dicyclohexylammonium salt is prepared by adding dicyclohexylamine to a solution o~ the free acid in e-thyl acetate, m.p. 169-171.
B) Methyl iodide (71 g) is added to a solution of 1-~3-mercaptopropanoyl)-L-proline ethyl ester (115 ~) and sodium (11.5 g) in ethanol (400 ml). The reaction is allowed to proceed overnight, the ethanol is removed in vacuo and the residue is dissolved in a mixture of ethyl acetate and water.
The organic layer is dried and concentrated to dryness ln vacuo.
The resulting 1-~3-methylthiopropanoyl)-L-proline ethyl ester (98 g) is suspended in a mixture o~ methanol (200 ml) and 5 N
sodium hydroxide (200 ml) and stirred at room temperature for five hours. The methanol is removed ln vacuo, and the aqueous phase is extracted with ethyl acetate, acidified and ~eextracted with ethyl acetate. This last organic phase is washed with water, dried and concentrated to dryness to yield l-(3-methylthio-propanoyl)-L-proline.
.
.
Example 81 ~=~ :
Aqueous 2 N sodium hydroxide (25 ml) and 3-bromopropionyl chloride (8.5 g) are added to a solution of l-proline (5.75 g) in N-sodium hydroxide (50 ml) chilled and stirred in an ice bath. After five minutes~ the ice bath is removed and the stirring is continued for three hours at room temperature. The reaction mixture is acidified with concentrated hydrochloric acid ~extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness ln vacuo. The residue is dissolved in a mixture of 4-chlorobenzenethiol (8 g), sodium hydroxide (4.2 g) and ethanol (300 ml). The solution is refluxed for 6 hours. The solvent is removed ln vacuo and the residue is dissolved in water, acidified with concentrated hydro-chloric acid and extracted with ethyl acetate. The or~anic layer is washed with water, dried, and concentrated to dryness ln vacuo to yield 1-[3-~4-chlorophenylthio)propanoyl]-L-proline.
Example 82 1,[[(3-Benzylthiomethyl)thio~propanoyl]-L-proline 1-(3-Mercaptopropanoyl)-L-proline (8.1 g) is dissolved in boiling liquid ammonia (100 ml) and small pieces of sodium are added until permanent blue color is obtained which is then discharged with a small piece of ammonium chloride. Benzyl-thiomethyl chloride (6.9 g) is added and the ammonia is allowed to evaporate. The final traces of ammonia are removed ln vacuo, the residue is dissolved in water and extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness ~ .
~ .
to yield l-[[(3-benzylthiomethyl)thio]pxopanoyl]-L-proline.
Example 83 1-[[(3-Acetamidomethyl)thio]propanoyl]-L-proline 1-(3-Mercaptopropanoyl)-L-proline (2 gl and N-hydroxy-methylacetamide (0.89 g) are dissolved in trifluoroacetic acid (10 ml) and the solution is stored at room temperature for one hour. The excess tirfluoroacetic acid is removed ln vacuo and the residue is precipitated several times from ether-hexane.
Finally, the residue is distributed between dilute hydrochloric acid and ethyl aceta-te~ The organic layer is washed with water, dried and concentrated to dryness to yield l-[[3-acetamido-methyl)thio]propanoyl]-L-proline.
Example 84 .
l-(Methylthioacetyl)-L-proline S
By substituting methyl mè~thylthioacetate for the methyl 3-methylthiopropionate in the Procedure A of Example 80, 1-(methyIthioacetyl)~L-proline, m.p. 123-124, is obtained.
~xample 85 l-(Benzylthioacetyl)-L-proline By substituting benzylthioacetyl chloride for the 3-methylthiopropanoyl chloride in the Procedure A of Example 80, l-(benzylthioacetyl)-L-proline, m.p. 86-88, is obtainea.
3L~ 4 HA135b E~ample 86 -1-~3-[(2-~henylc~hyl)t}lio]~ropanoyl]-rl-pro~ e _ By substitutincJ phenethylbromide for thc metllyl iodidc in the Procedure B of Example 80, 1-[3-~(2-pllellyletllyl)~hio)proparloyl]-L-proline is obtained.
.
~xample 87 1-[3-[(Triphenylmcth l)~hio~pro~anoyl]-L-prolinc By substituting triphenylmethyl chloride ~or thc metllyl iodide in the Procedure B of Example 80, 1-[3-[(tri~henylmethyl)-thio]propanoyll-L-proline is obtained.
Example 88 ___ 1-(3-~lethylthio-2-lnetllylpropanoyl)-L,-prolirle amiclc By substitutiny 1-(3-mercapto-2-methylpropanoyl)-L-proline amide for the 1-(3-mercaptopropanoyIj-L-proline ethyl estcr in the Procedure B o~ Example 80 and eliminatillc~ the saponification step, I-(3-methylthio-2-methylpropanoyl)-L-r?roline amide is obtained.
~xample 89 1- (3-~;ethylthiol?ropalloyl)-I,-aze~:icl~ e-2-carboxy:Lic ac,icl :
By substi-tuting L-azetidine-2-carboxylic acid for the L-proline in the Procedure A of Example 80,1-(3-rr,ethylthioproPanoyl)-L-azetidine-2-carboxylic acid is obtained. ~, .
'.
... . : .
', :
i4 Example 90 1-[3-(4-Methoxyphenylthio)propanoyl~-L-proline By substituting 4-methoxybenzenethiol for the 4-chloro-benzenethiol in the procedure of E~ample 81, 1~[3-(4-methoxy-phenylthio)propanoyl] L-proline is obtained.
Example 91 l-(3-Methylthiopropanoyl)-L-pipecolic acid ~
,, By substituting L-pipecolic acid for the I.-proline in the Procedure A of Example 80, 1-(3-methylthiopropanoyl)-L- ~;
pipecolic acid is obtained.
Example 92 1-[2-(4-Chlorophenylthio propanoyl]-L-proline .
By substituting 2-bromopropionyl chloride for the 3-bromopropionyl chloride in the procedure of Example 81, 1-[2-(4-chlorophenylthio-propanoyl~-L-proline is obtained.
Example 93 1-[3-[(Diphenylmethyl)thio]-2-benzylpropanoyl)]-L-proline Diphenylmethanol (0.92 g) and 1-(3-mercapto-2~benzyl-propanoyl)-L-proline (1.5 g) are dissolved in trifluoroacetic acid (10 ml) and the solution is kept at room temperature for 30 minutes. The excess trifluoroacetic acid is removed ln vacuo to yield l-[3-[(diphenylmethyl)thio]-2-benzylpropanoyl]-L-proline.
. .
~ ~ .
. ,, , ;, ~
~1.9.'f~ 364 Example 94 1-~4-(4-Chlorophenylthio)butanoyl]-L-proline .
By substitutlng 4-bromopropionyl chloride for the 3-bromopropionyl chloride in -the procedure of Example 81, 1-[4-(4-chlorophenyl-thio)butanoyl]-L-proline is ob-tained.
Example 95 1-[3-[(Benzylthiomethyl)thio]butanoyl]-L-proline By substituting 3-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 82, 1-[3-[(benzyl-thiomethyl)thio]butanoyl]-L-proline is obtained.
Example 96 1-[[4-[(Acetamidome hyl)thio]-2-methylbutanoyl~-L-proline By substituti.ng 1-(4-mercapto-2-methylbutanoyl)- :~
L-proline for the 1-(3-mercaptopropanoyl)-L-proline in the procedure of Example 83, 1-[[4-(acetamidomethyl)thio]-2-methylbutanoyl]-L-proline is obtained.
Example 97 1-[3-(Ethyldithio)propanoyl]-L-proline :
A) 3~Mercaptopropanoyl-L-proline (10 g) is added to a solution of ethylthiosulfinate (8.4 g) in methanol (100 ml) and the reaction mixture is stirred vigorously at room ..
temperature for four hours. The methanol is re.moved in vacuo to yield l-(3-ethyldithiopropanoyl)-L-proline.
'~
B) A solution of ethylthiosulfinate (8.4 g) in : .
ethanol (50 ml) is added to an aqueous solution of 3-mercapto-propanoyl-L-proline (10 g) maintained at pH 6-7 by careful : .
addition of sodium hydroxide. The mixture is stirred vigorously ~:
.
- ' : .' :
at room temperature until negative thiol reaction. The mix-ture is diluted with water, adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase i5 acidified to pH 3 and extracted again with ethyl acetate. This lattex extract is washed with water, dried and concentrated to dryness -to yield 1-~3-(ethyldithio)propanoyl]-L-proline., Example 98 1-[3-[(4-Methylphenyl)dithio]propanoyl]-L-pro'llne A solution of 4-methylphenylsulfenyl chloride (1.76 g.) ~'~
in ether (20 ml) is added to a solution of 3-mercaptopropanoyl-I.-proline (2 g) in 0.5 N sodium hydroxide (20 ml) chilled in an ice bath. The mixture is stirred vigorously for one hour, and the aqueous phase is separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness to yield 1-[[3-(4-methylphenyl)dithio]propanoyl]-L-Proline.
Example 99 1-[3-~Phenyldithi'o-propanoyl}-L-proline By substituting phenylthiosulfinate [prepared from phenyl-disulfide according to U. Weber and P. Eartter, Z. Physiol. Chem.,351, 1384 (1970)] for the ethylthiosulfinate in the procedure of Example 97, 1-[3-(phenyldithio-propanoyl]-L-proline is obtained.
Example 100 ~ ' 1-~3-[(2-Phenylethyl~dithio]propanoyl]-L-proIine By substituting 2-phenylethylthiosulfinate (prepared from phenethyldisulfide) for the ethylthiosuflinate in the procedure ~, of Example g7, 1-[3-[(2-phenylethyl)dithio]propanoyl]-L-proline is obtained.
~ . . .
.
6~
Example 101 .
l-[3-[(2-Hydroxye-thyl)dlthio]propanoyl]-L-proline To a solution of 1,1'-[(sulfinylthio)-bis-(3-propanoyl)]-bis-L-proline (21 g) in methanol (100 ml), mercap-toethanol(4.2 g) is added and the reaction mixture is stirred vigorously at room temperature for four hours. The me-thanol is removed in vacuo and -the residue is pruified by chromatography on a silica gel column to yield 1-[3-[(2-hydroxyethyl)dithio]propanoyl]-L-proline.
Example 102 1-[2-(Ethyldithio)propanoyl]-L-proline ` ~ :
By substituting 2-mercaptopropanoyl-L-proline for 3-mercaptopropanoyl-L-proline in the procedure oE Example 97, 1-[2-(ethyldithio)propanoyl]-L-proline is obtained.
Example 103 1-[3-[(~-Methylphenyl)dithio~utanoyl]-I-proline `~
By substituting 3-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-~-proline in the procedure of Example 98, ~ ~
l-[3-(4-methylphenyl)dithio]butanoyl]-L proline is obtained. -Exampl`e 104 l-[3-(Ethyldithio)-2-methylpropanoyl]-I,-proline methyl ester .
By substituting l-(3-mercapto-2-methylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97 and then treating the product with ethereal diazomethane as in the procedure of Example 72, 1-[3-(ethyldithio)-2-~ethylpro-panoyl]-L-proline methyl ester is obtained.
~ ':
.
Example 105 l-[3-(Ethyldithio)propanoyl]-L-azetidine-2-carboxylic acid By suhstituting 3-mercaptopropanoyl-L-azetidine-2-carboxylic acid Eor the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, 1~[3-(ethyldithio)propanoyl]-L-aze-tidine-2-carboxylic acid is obtained.
Example 106 1-[3-[(4-Methylphenyl)dithio]-2-methylpropanoyl]-L-hydroxyproline :
By substituting 1-(3-!mercapto-2-methylpropanoyl)-L-hydroxy proline for the 3-mercaptop~opanoyl-L-proline in the procedure of Example 98, 1-~(3-[4-methylphenyl)dithio]-2-methylpropanoyl]-L-hydroxyproline is obtained.
Example 107 l-~4-~Ethyldithio)butanoyl]-L-pipecolic acid By substituting 4-mercaptobutanoyl-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, l-~4-(ethyldithio-butanoyl]-L-pipecolic acid is o~tained.
Example 108 1-[3-(Ethyldithio)propanoyl]-5-hydroxy-L-pipecolic acid By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, 1-[3-(ethyldithio)propanoyl]-5-hydroxy-L-pipecolic acid is obtained.
, ~,.-~ .
Example 109 1-[3-[(2-Amino-2-carboxyethyl)di hio]propanoyl]-L-proline A 0.5 M solution of thiocyanogen in glacial acetic acid is prepared by shaking for ten minutes in a sealed flask 600 mg of dry lead thiocyanate with a solution o 75 ~1 of bromine in 3 ml of acetic acid. After removal of lead bromide and excess lead thiocyanate by centrifugation, 2.5 ml of this solution is mixed with 2.5 ml of a 0.41 M solution of cysteine hydrochloride ~i previously neutralized with dilute sodium hydroxide. This mixture is immediately added to 0.75 ml of a 1.9 M solution of 3-mercaptopropanoyl L-proline previously neutralized with dilute i sodium hydroxide. After twenty minutes the mixture is titrated to incipient brown color with alcoholic iodine, and adjusted to pH 3. The precipitate is removed by fiItration and the filtrate is applied to a column of cation exchange resin (Dowex 50~. The column is washed with water until no more acidic material is ~;~
removed and then eluted with pyridine-acetate buffer pH 6Ø ~ ' The fractions containing the disulfide of cysteine and 3-mercaptopropanoyl-L-proline are pooled and concentrated to dryness.
Example 110 1,1'-~Dithiobis)4~propanoyl)]-bis-L-proline 3-Mercaptopropanoyl L-proline (0.95 g) is dissolved in water (20 ml) and the pH is adjusted to 6.5 with N-sodium hydroxide. An ethanolic solution of iodine is added drop- ~;
wise while maintaining the pH at 6.5 with careful addition of N sodium hydroxide. When a permanent yellow color_is obtained the addition of iodine is stopped and the color , .
is discharged with a small amount of sodium thiosulfate.
The reaction mixture is acidified with concentrated h~dro-chloric acid and extracted with ethyl aceta-te. ~he organic phase is washed with water, dried and concentra-ted to dryness to yield l,l'-[dithiobis(3-propanoyl)]-bis-L--proline. The di-cyclohexylammonium salt is prepared by additlon o~ dicyclo-hexylamine to a solution of the free acid in acetonitrlle, m.p. 179-180.
Example 111 1,1'-[Dithiobis(2-D-methyl-3-propanoyl)]-bis-L-proline By substituting 3-mercapto-2-D-methylpropanoyl-L-proline for the 3-mercaptopropanoyl~L-proline in the procedure of Example llO~ 1,1'-[dithiobis~2-D-methyl-3-propanoyl)]-bis-L-proline is obtained, m.p. 236-237.
Examp~l'e 112 'l,l'-[Dithiobis(2-propanoyl)-bis-L-proline By substituting 2-mercaptopropanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, 1,1'-[dithiobis)2Npropanoyl)]-bis-L-proline is obtained.
Example 113 l,l'-(Dithiobisacetyl)-bis-L-hydroxy proline By substituting 1-(2-mercaptoacetyl)-L-hydroxyproline for the 3-mercaptopropionyl-L-proline in the procedure of ~ -Example llO, l,l'-(dithiobisacetyl)-bis-L-hydroxyproline is ' obtained.
Example 114 ,~
1,1'-(Dithiobisacetyl)-bis-L-azetidine-2-carboxylic ac~id B~ substituting 1-(2-mercaptoacetyl)-L-azetidine-2- -carboxylic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, l,ll-(dithiobisacetyl)-bis-L- , azetidine-2~carboxylic acid is obtained.
Example 115 ..
1,1'-[Di-thiobis(3-propanoyl)]-bis-L-pipecolic acid By substituting 3-mercaptopropanoyl-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, 1,1'-[dithiobis(3-propanoyl)]-bis-L-pipecolic acid is obtained. ' E~ample 116 1,1'-[Dithiobis(3-propanoyl)]-bis-4-methyl-L-prolihe ;
By substituting 1-(3-mercaptopropanoyl)-4-methyl-I,-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110~ 1,1'-[dithiobis(3-propanoyl)]-bis-4-methyl-L-proline is obtained.
Example 117 1,1'-~Dithiobis(3-propanoyl)]-bis-5-hydroxy-L-pipecolic acid ~
" .~ .
By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L~
pipecolic acid for the 3-mercaptopropanoyl-L-proline in the pro~ ~ ~, cedure of Example 110, 1,1'-[dithiobis(3-propanoyl)]-bis-5-hydroxy ' ,;
L-pipecolic acid is obtained. ~ , Example 118 ,~
1,1'-~Dithiobis(2-benzyl-3-propanoyl)]-bis-L-proline By substituting 1-(3-mercapto 2-benzylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of ,Example ', 110l l,l'-[dithiobis(2-benzyl-3-propanoyl)]-bis-L-proline is ;' obtained. ' ~', ' EY~ample 119 1,1'-~Dithiobis)2-methyl-3-propanoyl)]-bis-I,-pipecolic acid By substituting 1-(3-mercapto-2-methylpropanoyl)-I,-pipecolic acid for the 3-mercaptopropanoyl-L--proline in the procedure of Example 110, 1,1'-[dithiobis(2-methyl 2-propanoyl)}-bis-L-pipecolic acid is obtained. ;
Example 120 1,1'-~Dithiobis)4-butanoyl)~-bis-L-proline By substituting 4-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, 1,1'-~dithiobis(4-butanoyl)]-bis-L-proline is obtained.
Example 121 1,1'-[Dithiobis(2-benzyl-4-butanoyl)}-bis-L-proline By substituting 1-(4-mereapto-2-benzylbutanoyl)-L-proline for the 3-mereaptopropanoyl-L-proline in the procedure o~
Example 110, 1,1'-[dithiobis(2-benzyl-4-butanoyl)]-bis-L-proline is obtained.
Example 122 1,1l-[Dithiobis(3-butanoyl)]-bis-L-proline ~' .
By substituting 3-mercaptobutanoyl-L-proline for the ~ ;' 3-mereaptopropanoyl-L-proline in the proeedure of Example 110, 1,l'~[dithiobis(3-butanoyl)]-bis-L-proline is obtained. ~-6~ :
Example 123 1,1'-[Dithiobis(3-propanoyl)]-bis-L-proline methyl ester A solution of l,l'-[dithiobis(3-propanoyl)l-bis-L-proline in methanol is treated with ethereal diazomethane ;
until persistent yellow color~ After fifteen minutes a few drops of acetic acid are added and the solvents are .
removed in vacuo to yield, l,l'-[dithiobis(3 propanoyl)l--bis-L-proline methyl ester.
Example 124 l,l'-[Dithiobis(3-propanovl)]-bis-L-proline amide A solution of 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline methyl ester in methanol is saturated with am- . :
monia while cooling in an ice-water bath. The reaction ~:
mixture is stored for 16 hours at room temperature in a pressure bottle, and then the solvents are removed ln . ~ .
vacuo to yield l,l'-[dithiobis(3-propanoyl)]-bis-L-proline amide. ~ ~.
3~
1,1'-[Dlthiobis(2-phenyl-3-propanoyl)]-bis-L-proline :::
By substituting 1-(3-mercapto-2-phenylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example llO, l,l'-[dithiobis(2-phenyl-3-pro-panoyl)]-bis-L-proline is obtained.
.. . ', ;,.
P3~4~
Example 126 1,1'-[(Sulfinylthio)-bis-(3-propanoyl)]-bis--L-proline .
While cooling in an ice bath 0.12 mo:Le of peracetic acid is added to a stirred solution o~ l,l'--[dithiobis(3-propanoyl)]-bis-L-proline (40 g) in glacial acetic acid (500 ml). The reaction mixture is allowed to stand over-night at room temperature and the solvent is then removed ln vacuo to ~ield l,l'-[(sulfinylthio)-bis-(3-propanoyl)]-bis-L-proline.
Example 127 1,1'-[(Sulfon~lthio)-bis-(3-propanoyl)]-bis-L-prollne A 30% solution of hydrogen peroxide (2.0 ml) is added to a solution of l,l'-Edithiobis(3-propanoyl)]-bis-L-proline (4 g) in glacial acetlc acid (80 ml) and the solution is stored for thirty hours at room temperature.
The solvent is removed ln vacuo to yield l,l'-[(sulfonyl-thio)-bis-(3-propanoyl)]-bis-L-proline.
Example 128 -.
1,1'-[(Sulfinylthio)-bis-(2-propanoyl)]-bis~L-proline --By substituting 1,1'-[dithiobis(2-propanoyl)]-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-(2-propanoyl)]-bis-L-proline is obtained.
6~
Example 129 1,1'-[(Sul~inylthlo)-bis-acetyl]-bis-L-azetidine-2-carbox -Y .
lic acid By substitut.ing l,l'-(dithiobisacetyl)-bis-L-azeti-dine ca.rboxylic acid for the l,l'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-acetyl]-bis-L-azetidine-2-carboxylic acid is obtained.
Example 130 ~:
l,l'-[(Sul~inylthio) bis-(3-propanoyl)]-bis-4-methyl-L-proline -.
.
By substituting 1,1'-[dithiobis(3-propanoyl)]-bis- ~; :
4-methyl-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[~sul-finylthio)-bis-(3-propanoyl)]-bis-4-methyl-L-proline is . :-obtained.
Example 131 ::~
1,1'-[(Sulfinylthio)-bis-(2-benzyl-3-pro_ noyl)]-bis-L-proline By substituting 1,1'-[dithiobis(2-benzyl-3~propa-noyl)]-bis-L-proline for the 1,1'-~dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-t2-benzyl-3-propanoyl)]-bis-L-proline is obtained.
Example 132 1,1'-~(Sulfinylthio)-bls-(4-butanoyl)~-bis-I.-proline By substitu-ting 1,1'-[dithiobis(4-butanoyl)]-bis-L-proline for the 1,1'-[dithiobis(3--propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-~(sulfinyl--thio)-bis-(4-butanoyl)]~bis-L-proline is obtained.
;9L
Example 133 1 l'-[(Sulfin l-thio)-bis-(3-butano l)]-bis-L-proline ,, Y Y
By subs-tituting 1,1'-[dithiobis(3-bu-tanoyl)]-bis-L-prol.ine for the l,l'-[dithiobis(3-propanoyl)~-bis-L-proline in the procedure of Example 126, l,l'-[(sulfinyl-thio~-bis-(3-butanoyl)]-bis-L-proline is obtained.
Example 134 1,1'-[(Sulfinyl-thio)-bis-~2-methyl-3-propanoyl)-bis-L-pro-line By substituting 1,1'-[dithiobis(2-methyl-3-propan~
oyl)]-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, 1ll'-[(sul-finylthio)-bis-(2-methyl-3-propanoyl)~-bis-h-proline is obtained.
, Example 135 :
1,1'-~(Sulfinylthio)-bis-(2-phenyl-3-propanoyl)]-bis-L-proline By substituting 1,1'-[dithiobis(2-phenyl-3-propa-noyl)l-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]- .
bis-L~proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-(2-phenyl-3-propanoyl)]-bis-L-proline is ~ :
obtained. :`
Example 136 1-[3-1[3-(2-Carboxy-l-pyrrolidinyl)-3-oxopropyl]-dithio]-2-methylpropanoyl]-L-proline By substituting 1,1'-1~sulfinylthio)-bis-(2-methyl-3-propanoyl)]-bis-L proline for the ethylthiosulfinate in the procedure of Example 97, 1-[3-[13-(2-carboxy-1-pyrro-lidinyl)-3-oxopropyl]dithio]-2-methylpropanoyl]-L-proline is obtained.
~ /~
36~L
Example 137 l,l'-[(Sulfonyl-thio)-bis-acetyl)-bis-L-hydroxyproline sy substituting l,l'-(dithiobisacety:L)-bis-L-hy-droxy proline ~or the l,l'-[dithiobis(3-propanoyl)-bis-L-proline in -the procedure of Example 127, l,l'-[(sulfonyl-thio)-bis-acetyl)-bis-L-hydroxyproline is obtained~
Example 138 ~ ;
1,1'-[(Sulfonylthio)~bis~(3-propanoyl)]-bis-L-pipecolic acid By substituting 1,1'-[dithiobis(3-propanoyl)]-bis-L-pipecolic acid for the 1,1'-[dithiobis(3-propanoyl~]-bis-L-proline in the procedure of Example 127, l,l'-[~sul-fonylthio)-bis-(3-propanoyl)]-bis-L-pipecolic acid is ob-tained.
Example 139 1,1'-[(Sulfonylthio)-b_s-(3-propanoyl)]-bis-5-hydroxy-L-pipecolic acid ~ ~
: ' , By substituting 1,1'-[dithiobis(3-propanoyl)]-bis- ;
5-hydroxy-L-pipecolic acid for the 1,1'-[dithiobis-(3- ;
propanoyl)]-bis-L-proline in the procedure of Example 127, 1,1'-[(sulfonylthio)-bis-(3-propanoyl)]-bis-5-hydroxy-L-pipecolic acid is obtained.
Example 140 1,1'-[(Sulfonylthio)-bls-(2-methyl-3-propanoyl)]-bis-L-pipecolic acid :
By substituting 1,1'-[dithiobis(2-methyl-3-propa-noyl)]-bis-L-pipecolic acid for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 127, 1,1'-[(sulfonylthio)-bis-(2-methyl-3-propanoyl)]-bis-L-pipecolic acid is obtained.
': :
E_ mple 141 l,l'-[(Sulfonylthio)-bls-(2-ben2yl-4-butanoyl)]-bis-L~
proline By subs-titu-ting 1,1'-[di-thiobis(2-benzyl-4-bu-tan-onyl)]-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 127, l,l'-l(sul-fonylthio)-bis-(2-benzyl-4-butanoyl)]-bis-L-proline is ob-tained.
Example 142 3-Acetylthio-2-phenylpropanoic acid By substi-tuting 2-phenylacrylic acid for the meth-acrylic acid in -the procedure of Example 25, 3-acetylthio-2-phenylpropanoic acid is obtained.
1-(3-Acetylthio-2-phenylpropanoyl)-L-proline tert-butyl ester By substituting 3-acetylthio-2-phenylpropanoic acid for the 3-acetylthio-2-methylpropanoic acid in the proce-dure of ExampIe 28, 1-(3-acetylthio-2-phenylpropanoyl3-L-proline tert-butyl ester is obtained.
Example 143 1-(3-Mercapto-2-phenylpropanoyl)-L-proline By substituting 1-(3-acetylthio-2 phenylpropanoyl)-L-proline tert-butyl ester for the 1-(3-acetylthio-2-me-thyl-propanoyl-L-proline tert-butyl ester in the pro-cedure of Example 29, and subjecting the product to am-monolysis as in Example 34, 1-(3-acetylthio-2-phenylpro-panoyl)-L-proline and 1-(3-mercapto-2-phenylpropanoyl)-L-proline are obtained.
.:
36~
HA135b Example 144 1-[3-(Acetylthio)-DL-propanoyl]pipecolic acid Pipecolic acid (6.5 g.) is suspended in 200 ml.
of dimethylacetamide. 3-acetylthiopropanoyl chlorlde (8.3 g.) is added dropwise at 23 to the suspension. A
clear solution forms and the temperature rises to 28 .
To this clear solution is added N-methylmorpholine (1~.1 g.).
An immediate precipitate forms and the temperature rises to 34 . The mixture is heated on a steam bath for 1 hour when a clear solution forms. Qn cooling, the precipitated solid is filtered to yield 5.1 g. of 1-[3-(ace-tylthio)-DL-propanoyl]pipecolic acid, m.p. 190-200. The solvent is removed and the viscous residue is triturated with isopropyl ether to yield 7.8 y. of product, m.p. 98-101 . Recrystalliza- ;~
tion from acetone-hexane yields d constant melting solid, m.p. 102-104 ; Rf 0.72 [silica gel, benzene, acetic acid~(7~:2)].
Example 145 DL-1-(3-Mercaptopropanoyl)pipecolic acid 12 ml. of concentrated ammonium hydroxide is stirred under nitrogen at 10 for about l5 minutes, then solid 1-[3-tacetylthio)-DL-propanoyl]-pipecolic acid (6.6 g.) is added at 5 to 10 . A clear solution forms after 2-3 minutes. The ice bath is removed and the solution lS stirred at room temperature under nltrogen for 45 minutes. The solution ls made strongly acid with 20~ HCl ~cooling) and the precipitated oil is extracted with 3 x 150 ml. of ethyl acetate. The ethyl acetate extracts are dried over magnesium sulfate and the solvent is removed to yield 6.0 g. of DL-1-(3-mercaptopropanoyl)pipccolic acid, Rf 0.77 [sllica gel, 3d benzene,acctic acid (7:1)].
-~,7-HA135b Example 146 1-(3-Mercaptopropanoyl)-L-pipecolic acid By substituting L-pipecolic acid Eor the DL-pipecolic acid in the procedure of Example 144 and then submitting the product to the procedure of Example 145, 1-[3-(acetylthio)propanoyl]-L-pipecolic acid and 1-(3-mercaptopropanoyl)-L-pipecolic acid Rf 0.80 [silica gel, benzene, acetic acid (7:1)], [a] -51.5 (c, 1.0 abs.
ethanol), are obtained.
Example 147 1~[3-(Acetylthio)-2-methylpropanoyl-DL-pipecollc acid 6.5 g. (0.05 m.) of pipecolic acid are suspended in dimethylacetamide (200 mg.), 9.0 g. (0.05 m.) of 3-acetylthio-2-methylpropanoyl chloride is added dropwise.
The temperature rises to 29 and a clear solution forms Then 10.1 g. of N-methylmorpholine is added a]l at once and the temperature rises to 34~. The mixture is heated on a steam bath for 1 hour when a clear solution forms.
This is allowed tP stand at room temperature overnight and the solid which precipitates is filtered to yield 6.1 g.j m.p~ 203-204 . The solvent is removed and the viscous residue is triturated with water and 20% HCl. The yellow oil is extracted with 3 x 150 ml. of ethyl acetate.
~he ethyl acetate extracts are dried over magnesium sulfate and removed to yield 14 g. of 1-[3-(acetylthio)-2-methyl-propanoyl-DL-pipecolic acid as a viscous oil.
Example 148 1-(3-Merca~to-2-methylpro~anoyl)-DL~pipecolic acid ~ .
Aqueous NH4011 (30 ml. water and 20 ml. conc. NH40H) is stirred under nitro~en a~ 10 for 15 minutes. This i9 -6~-~ ~.
~ .
HA135b added to 13.0 g. (0.05 m) of 1-[3-(acetylthio)-2-methylpropanoyl]-DL-pipecolic acid and -the resulting solution is stirred for 10 minutes under nitroyen; then at room temperature for 50 minutes. It is then treated with water ~;
and 20~ HCl and the yellow oil extracted with 3 x 150 ml.
of ethyl acetate. The ethyl acetate extract is dried over - -magnesium sulfate and removed to yield 11.1 g. 1-(3-mercapto-2-methylpropanoyl)-DL-pipecolic acid as a viscous oil. R~ 0.62 [silica gel, benzene, acetic acid (7:2)].
Example 149 3-[(4-Methoxyphenyl)methylthio]--2-methylpropanoic acid p-Methoxy-~-toluene thiol (15.4 g., 0.1 mol.) is added to a solution of methacrylic acid (8.6 g., 0.1 mol.) in 50 ml. 2~ sodium hydroxide. The mixture is heated on the steam bath ~or three hours, then refluxed for two :
hours and cooled. The mixture is~extracted with ether, then the aqueous layer is acidifled with concentrated HCl and extracted with dichloromethane. The acidic extracts are washed wlth brine, dried (MgSO4) and evaporated in~vacuo.
2n The resulting semi-solid is taken up in 50 ml. of dlchloro-methane, diluted with 50 ml. hexane, and chilled. 3-[(4 methoxyphenyl)methylthio]-2-methylpropanoic acid is collected as a white crystalline solid, m.p. 74-82 ~5.5 g.).
Example 150 1-[3-(4-Methoxyphenyl?methylthio~-2-met proline tert-butyl ester ~
3-~(4-methoxyphenyl)methylthio]-2-methylpropanoic acid (3.6 g., 0.015 mol.~, L-proline tert-butyl ester (2.6 g., 0.015 mol.), and dicyclohexylcarbodiimide (3.1 g., .
i~l864 HA135b 0.015 mol.~ are dissolved in 50 m:L. oE dichloromethane and stirred thirty minu-tes at 0 . The cooling bath is removed and the mixture stirred overnight (sixteen hours).
The resulting suspension is filtered and the filtrate washed with 5~ potassium bisulfate, salurated sodium bicarbonate and brine, then dried (MgSO4~ ancl evaporated in vacuo.
The resulting clear oil is applied to a 250 ml. silica gel column and chromatographed using 20% ethyl acetate/
hexane as eluant. The main fraction (Rf = 0.70, silica gel, ethyl acetate) is evaporated to 5.5 g. (g3~) of 1-[3-(4-methoxyphenyl)methyl-thio3-2-methylpropanoyl-L-proline tert-butyl ester as a clear oil. Rf = 0.70 (silica gel, ethyl acetate); Rf = 0.60 (silica gel, ether).
Exam~le 151 1- ~ 2-methylpropanoyl)-L-proline The ester from Example 150 (1.2 g., 0.003 mol.), anisole (5 ml.) and trifluoromethanesulfonic acid (0.5~ml.) are dissolved in 20 ml. of -trifluoroacetic acid under nitrogen, and the resultinq red solution let stand one hour at room temperature. The solution is evaporated in vacuo to a red residue which is taken up in ethyl acetate and washed with water! brine, then dried (MgSO4) and evaporated.
The residue is repeatedly triturated with hexane and the residual hexane evaporated; the oil residue amounts to 0.4 g~ A portion (180 mg.) of this material ig subjected to preparative thin-layer chromatography on 2 mm silica gel plates using benzenejacetic acid 75:25 as eluant. The main nitroprusside-positive band (Rf = 0.40) is recovered, affording 135 mg. of 1-(3-mercapto-2-méthylpropanoyl)-L-proline as an oil. TLC using ben~ene/ace-tic acid 75:25 :
HA135b (R = 0 40) and chloroform/methanol/acetic acid 50:40:10 (Rf = 0.62).
Example 152 1-(3-Mercapto-2-D-methylpropanoyl)-L-proline IJnder a blanket of argon 1-[3-(acetylthio)-2-~methylpropanoyl]-L-proline (10.0 g.) is slurried in water (150 ml.) at 10 . To this mixture is added 5N
sodium hydroxide and the pH of the solution maintained at 13 for 1.5 hours. After this time, when the uptake of sodium hydroxide had ceased, the solution is acidified to a pH = 2.0 with concentrated sulEuric acid.
The aqueous solution is then extracted three times with methylene chloride ~3 x 150 ml.) and the combined methylene chloride fractions concentrated to an oil. The concentrate is taken up in ethyl acetate, filtered and the filtrate diluted with hexane (30 ml.).
: -An additional amount Oe hexane is added after 1/2 hour and then the mixture cooled to 10 for 1 hour.
The crystals are filtered and washed with hexane (2 x 25 ml.) and dried to constant weight to give 1-(3-mercapto-2-D methylpropanoyl)-L-proline as white crystals, 6.26 g., m.p. 100-102.
Example 153 .. . ~ ~ :
1-~3-Tosyloxy-2-methylpropanoyl]-L-proline By substituting 3-tosyloxy-2-methylpropanoic acid chloride for the 3-acetylthio-2-methylpropanoic acid chloride in the procedure of Example 29b 1-[3-tos~loxy-2-methylpropanoyl]~L-proliAe is obtained.
., .
-~71-- ' .
. . ' . ~ : . ~' ,'' ~1~1864 i~A135b Example 154 1-L~ Y_thio-2-methylpropanoyl]-L-proline 1-[3-Tosyloxy-2-methylpropanoyl~-L-proline (3.5 g.) is added to a solution of thiolacetlc acid ~1.14 g.), and triethylamine (3.5 ml.) in ethyl acetate (20 ml.). The solution is maintained at 50 for three hours, cooled, diluted with ethyl acetate (100 ml.), and washed with dilute hydrochloric acid. ~he organic layer is dried and concentrated to dryness in vacuo. The residue is dissolved in acetonitrile and dicyclohexylamine is added. The crystalline precipitate is recrystallized -~
from isopropanol to yield l-[3-acetylthio-2-D-methyl-propanoyl)-L-proline, dicyclohexylamine salt, m.p.
187-188 , Ea]D -67 (c 1,4, EtOH). This salt is converted to the free acidj m.p. 83-85 (an isomorphic form of m.p. 104-105 is obtained if the crystallizing solution is seeded wi-th high melting material).
Example 155 1-~3-Mercaptopropanoyl)-L-proline, t-butyl ester To a stirred solution of 1.71 g. (10 mmoles) of proline t-butyl ester and 1.35 g. (l0 mmoles) of 1-hydroxybenzotriazole hydrate in 20 ml. of N,N-dimethyl-formamide at 0-5 are added 2.06 g. (10 mmole) of N,N'-dicyclohexylcarbodiimide. The mixture is stirred for 10 minutes, followed by the addition of 1.06 g. (10 mmole) of 3~mercaptopropanoic acid in 2 ml. of N,N-dimethyl-formamide- The mixture is then stirred at 0-5 for 1 hour, and at room -temperature overnlght. ~
The precipitated N,N'-dicyclohexylurea is filtered off, and the filtrate concentrated in vacuo. ~--72~
~ .
4 HA135b The residue is taken up in ethyl ace-ta-te, washed thoroughly with saturated aqueous sodi~lm bicarbona-te, dried, and concen-trated in vacuo to 2.5 g. of oil.
The oil is taken up in 1:1 ethyl acetate-hexane and applied to a silica gel column (100 g.). Elution with 1:1 ethyl acetate-hexane aEfords 1.40 g. (54~) of 1~(3-mercaptopropanoyl)-L-proline/ t-butyl ester as an oil, which crystallizes on standing. Recrystallization from ether-hexane yields 0.9 g. of colorless crystalline solid, m.p. 55-60, identical to the compound of Example 17.
Example 156 1-(3-Mercaptop _panoyl)-L-proline A solution of 75 mg. (0.27 mmole) of 1-[3-[[(ethyl-amino)earbonyl]thio]propanoyl]-L-proline in 1 ml. eaeh of coneentrated ammonium hydroxide anù water is allowed to stand at room temperature for 18 hours under argon~ The~
`solution is diluted with a small amount of water~and extraeted with ether. The aqueous layer is acidified with eold coneentrated hydrochloric acid and extraeted with ethyl acetate. The combined extracts are dried and eoncentrated in vacuo to give a eompound identical with the product of Example 18. TLC (silica gel; benzene:acetic acld 7:3) Rf 0.~.
Example 157 Methaeryloyl-L-Proline L-preline (23.0 g., 0.2 mol.) is dissolved in 100 ml. water and stirred in an iee bath. ~ethacryloyl .
- ehloride (19.6 ml., 0.2 mol.~ in 25 ml. of methyl isobutyl ketone is added dropwise over three hours. Sedium hydroxlde '~
HA135b solution (2N) is added simultaneously, maintaining the pH of ~he reaction mixture at 7Ø Addition of base is continued for four hours after addition of acid chloride has been completed. The reaction mixture is adjusted to pH 5 with concentrated HCl and extracted with ethyl acetate. The aqueous layer is then acidified to pH 2.5 and extracted thorouyhly with ethyl acetate. The acidic extracts are washed with brine and drled (MgSO4). The ethyl acetate solution is trea-ted with dicyclohexylamine (40 ml.) and chilled overnight. The resulting white pre-cipitate is filtered and dried, yielding 29 g. (39~) of `~
white solid, m.p. 202-210 . The solid is crystallized from 1.5 liters 3:1 acetonitrile/isopropanol to yield 19.7 g.
of methacryloyl-L-proline, dicyclohexylamine salt as fine white needles, m.p. 202-210 .
The salt is dissolved in water/ethyl acetate and the mixture acidified with concnetrated HCl. The resulting suspension is filtered to remove a fine white precipitate which is washed well with ethyl acatate. The filtrate is saturated with sodium chloride and extracted thoroughly with ethyl acetate. The extracts are washed with brine, dried (MgSO4) and evaporated to a clear oil which solidifies. Crystallization Erom ethyl acetate/hexane yields 7.5 g. (83%) of methacryloyl-L-proline as a white crystalline solidr m.p. 89-93 . An analytical sample is obtained by recrystallization, m.p. 95-98.
Example 158 ~.
1-(3-Acetylthio-2-D-methylpropanoyl)-L-proline Methacyloyl-L-proline (183 mg., 0.001 mol.) is dissol~ed in thiolace~ic aci(l (0.5 ml.) an~ allowe~l
HA135b thlo-2-D-metllylpropanoyl-L-proline,m.p.~3-85~ 162~c,1.7,~tOII).
Procedure B
_ 3-Acetylthio-2-methylpropanoic acid (8.1 y~) and thionyl chloride (7 g.) are Mixed and the sus~ensioll is stirred for 16 hours at room temperature. The reaction mixture is concentrated to dryness and distilled in v~cuo (b.p 80 ).
This 3-acetylthio-2-methylpropanoic acid chlorlde (5.4 g.) and 2N sodium hydroxide (15 ml.) are added to a solution of L-proline (3.45 g.) in normal sodium hydroxide (30 ml.) chilled in an ice water bath. ~fter 3 hours s'~irring a~
room temperature, the mixture is extra~ted with e~her, the aqueous phase is acidified and extracted with e-thyl ace~ate.
Tlle or~anic phase is dried over magnesium sulfate ~nd concentrated to dryness to obtain 1-(3-acetyl-thio-2-DL-metllyl~ropanoyl-L
proline. ~ ~
Procedure C ;
- Methacryloyl chloride (4.16 g.) is added to a solution o L-proline (3.45 g.) in a mixture of water (100 ml ) and sodium blcarbonate (12 g.) chilled in an ice water bath, with vigorous stirring. When the addition is compLeted, the mixture ; ;
is stirred at room temperature for two hours, and then extracted ~ ~
with ether. The aqueous phase is acidified with N hydrochloric ~ -acid and extracted with ethyl acetate. The organic phase is concentrated to dryness in vacuo, the residue is mixed with thiolacetic acid (3.5 g.~, a few crystals of azobisisobuty-ronitrile are added a~d the mixture is heated on the steam bath for two hours. The reaction mix-ture is dissolved in~benzene-acetic acid ~75:25), and applied to a column of silica gel.
Elution witll the same solverl~ mixturc yields thc 1-~3-acetylthio-2-DL-methylpropanoyl)-L-urolinc~.
HA13Sb ample 30 1-(3-Benzoyl~hio-2-metllylpropanoyl)-L-prolille tert-butyl Ester By substituting 3-benzoylthio~2-methylpropanoic acid for the 3-acetylthio-2-methylpropanoic acid in t:lle proced~rc of Example 23, 1-(3~benzoylthio-2-methylpro~anoyl)-L-proline tert.butyl ester is obtained.
~xample 31 1-(3-Phenylacetylthio-2-met_ylpropanoyl)-L-ProIine ter~-butyI Ester By substituting 3-phenylacetylthio-2-methylpropanoic 10 acid for the 3-acetylthio-2-methylpropanoic acid in the procedure of Example 28, 1-(3-phenylacetylthio-2-methylprouanoyl)-L-proline tert butyl ester is obtained.
xamplc 32 1-(3-Benzoylt;hio-2-methylpropanoyl)-L-proline By substituting 1-(3-benzoylthio-2-methylpropanoyl)-L-proline tert-butyl ester for the 1-(3-acetyltllio)-2- ;~
methylpropanoyl)-l-proline tert-butyl ester in Procedure of Example 29, 1-(3-benzoylthio-2-metllylpropanoyl)-L-prollne is obtained.
E~ample 33 (3-phenylacetyltllio-~ e~Vl~5lC~ L 1~ L ~
~y substitutin~ 3-phenylacetylthio-2-metllylpropanoyl)-L-proline tert-butyl ester for 1-(3-acetylthio-2-me~hylpro~anoyl)-; L-proline tert-butyl ester ln Procedure A of ~xample 2~, 3-phenylacetylthio-2-methylpropanoyl)-L-proline is obtained.
Example 34 1-(3-MercaPto-2-D-metl~ ~ropanoyl)-L-proline . . . :
1-(3-Mercapto-2-methylpropanoyl)-L~proline is obtained by treating the product o~ each o~ Examyles 29, 32 and 30 33 as follows:
, HA135b The thioester (0.85 c~.) is dissolved in 5.5 N
methanolic ammonia and the solution is kept at room temperature for 2 hours. The solvent is removed ln vacuo and the residue is dissolved in water, applied to a ion e~chanye column on the H cycle (Dowex 50, analytical grade) and elu~ed witll water. ~he ~ractions that yive positlve thiol rea~tion are pooled and freeze dried. The residue is crystalli~ed from ethyl acetate-hexane, yield 0.3 g. The 1-(3-mercapto 2~-methylpropanoyl-L-proline has m.p. 103-104 , [~] 131 (C,2,~tOH).
Example 35 1-(3-~cetyltllio 2--methylpropanoyl)-L-Proline Met}lyl ~s~cr ~,~
1-(3-Acetylthio-2-methylpropanoyl) L-proline is reacted with an ethereal solution o~ diazome-thane accordinc;
to the procedure described in ~xample 3 to obtain 1-(3-acetyl~-thio-2-methylpropanoyl)-L-proline methyl ester.
Example 36 ~ ' 1-(3-Merca~to-2-methYlpropanoyl) L Proline amide ;~
By substituting 1-(3-acetylthio-2-metllylpropalloyl)-L-proline methyl ester in the procedure of ~xample 4, 1-(3 mercap-to-2-methylpro~anoyl)-L proline amide is obtaincd.
Example 37 3=Acetylthio-2-Benzylpropanoic ~cid By substituting 2-benzylacrylic acid for the methacrylic acid in the procedure of Example 2S, 3 acetyl-thio-2-benzylpropanoic acid is obtained.
3 Acetyltl?io-2 benzylpropanoyl) L-Prolille tcr~-buty:L E:s~er By substituting 3 acetyl~hio-2-ben~ylpropalloic acid for the 3-acetylthio-2 methylpropanoic acid in tl~e procedure of ~ 6~ HA135b Example 22, 1-(3-acetylthio-2-benzylpropanoyl)-L-proline tert-butyl ester is obtained.
Example 39 1-(3~Acet~lthio-2-benzylpropanoyl)-L-Proline The product of Example 38 is substituted for the 1-(3-acetylthio-2-methylpropanoyl-L-proline terl-butyl ester in the Procedure A of Example 29 to obtain 1-(3-acetylthio-2-benzylpropanoyl)-L-proline.
Example 40 1-(3-Mercapto-2-benzylpropanoyl) L-Proline 1-(3-Acetylthio-2 benzylpropanoyl)-L-proline is treated with methanolic ammonia according to the procedure of Example :~
34 to obtain 1-(3-mercapto-2-benzylpropanoyl)-L-proline as an oil, Rf = 0.47 (silica gel, benzene-acetic acid (75:25).
Example 41 1-(3-Mercapto~2-methylpropanoyl)-L-Hydroxy Proline By substituting L-hydroxy proline tert-butyl ester in the procedure of Example 28, treating the product according to Procedure A of Example 29 and then continuing as in Example 34, 1-~3-acetylthio-2-methylpropanoyl)-L-hydroxyproline tert-butyl ester, l-(3-acetylthio-2-methylpropanoyl)-L-hydroxyproline and 1-(3-mercapto-2-methylpropanoyl)-L-hydroxyproline, respecti~ely, are obtained.
Example 42 1-(3-Mercapto-2-methylpropanoyl)-L-Azetidine-2-Carboxylic Acid By substituting L-azetidine-2-carboxylic acid tert- ~
butyl ester in the procedure of Example 2~, treating the product ~.
according to the Procedure A of Example 29 and thén continuing as .
-3~- .
` ~'1 in Example 34, 1-(3-acetylthio-2-methylpropanoyl)-L-azetidine-2-carboxylic acid tert-butyl ester, 1,3-acetylthio-2-methyl-propanoyl)-L-azetidine-2-carboxylic acid and 1-(3-mercapto-2-methylpropanoyl-L-azetidine-2-carboxylic acid are obtained.
Example 43 1-(3-Mercapto~2-methylpropdnoly)-L~Pipecolic Acid By substituting L--pipecolic acid in the procedure of Example 28, treating the product according to Procedure A of Example 29 and then continuing as in ~xample 34, 1-(3-acetyl~
thio~2~methylpropanoyl)~L~pipecolic acid tert-butyl ester, 1-(3-acetylthio-2-methylpropanoyl)-L-pipecolic acid and 1-(3-mercapto~2~methylpropanoyl)-L~pipecolic acid, respectively, are obtained. -~
Example 44 1-(4-Benzoylthiobutanoyl)-L-Proline To a solution of L-proline (2.88 g.) in normal sodium hydroxide (25 ml.) chilled in an ice bath, 2N sodium hydroxide (12.5 ml.) and 4-chlorobutyryl chloride (3.5 g.) are added.
. ~ ~
The reac-tion mixture is stirred at room temperature for 3.5 ~ ~;
hours and a suspension of thiobenzoic acid (3.75 g.) and ~ ;~
potassium carbonate (2.A g.) in water (25 ml.) is added. After overnight stirring at room temperature, the reaction mixture is acidified with concentrated hydrochloric acid and extracted with ~
ethyl acetate. The organic layer is dried over magnesium sul- ~ ;
fate and concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with benzene-acetic acid (7 1). The fractions containing the desired material are pooled and concentra-ted to dryness, yield 1.35 g. A small aliquot of this material is dissolved in ethyl acetate and dicyclohexylamine is added until pH 8-10 (on a wet pH paper).
': ~
~35- ~-The dicyclohexylamine salt crystallizes out, immediately, m.p.
159-161.
Example ~5 1-(4-Mercaptobutanoyl)-L-Proline 1-(4-Benzylthiobutanoyl)-L-proline (1 03 g.) is dissolved in a mixture o water (4 ml.) and concentrated ammonia (2.7 ml.). A~ter one hour stirring at room tempera-ture, the mixture is diluted with water, filtered, extracted with ethyl acetate, and the aqueous phase was concentrated in vacuo.
This ammonium sal-t of 1-(4-mercaptobutanoyl)-L--proline is purified by ion e~change chromatography on a column of diethyl-aminoethyl-Sephadex (cross lin~ed dextran) with a gradient of ammonium bicarbonate, yield 0.7 ~. The ammonium salt is dissolved in water (2 ml.) and applied to a column of Dowex 50 sulfonic acid resin analytical grade in the hydrogen form, and the free acid is eluted with water. The fractions containing the desired material (sulfhydryl reagent and carboxyl reagent positive) are pooled and freeze dried to obtain l-(4-mercaptobutanoyl)-L-proline. The dicyclohexyl ammonium salt is produced by the procedure of Example 44, m.p. 157-158.
Example 46 - ~ :
4-Bromo-2-Methyl~utanoic Acid Ethyl-4-bromo-2-methylbutanoate [G. Jones and J. Wood, Tetrahedron, 21, 2961 (1965)] (1.04 g.) is dissolved in dichloromethane (50 ml.) and cooled to -10. A 1 M solution or boron tribromide in dichloromethane (50 ml.) is added dropwise with stirring and the stirring is continued for 1 hour at -10 and 2 hours at 25. The reaction is terminated - l~O~B64 by the careful addition of water. The layers are separated and the organic phase is washed with water, dried and concen-trated to dryness to obtain 4-bromo-2-methylbutanoic acid.
Example 47 1-(4-Benzoylthio-2-methy~lbutanoyl)-L-Proline a) 4-Bromo-2-methylbutanoic acid (8 g.) and thionyl chloride (7 g.) are mixed and the mixture is stirred Eor 16 hours at room temperature. The reaction mixture is concentrated to dryness and distilled in vacuo.
.
b) To a solution of L-proline (2.88 g.) in normal sodium hydroxide (25 ml.) chilled in an ice bath, 2N sodium hydroxide (12.5 ml.) and the 4-bromo-2-methylbutanoic acid chloride obtained in part (a) (3.9 g.) are added. The reaction - -mixture is stirred at room temperature for 3.5 hours and a suspension of thiobenzoic acid (3.75 g.) and potassium carbonate (2.4 g.) in water (25 ml.) is added. After overnight stirring at room temperature, the reaction mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with benzene-acetic acid (7:13. The fractions containing the desired product, l-(4-benzoylthio-2-methylbutanoyl)-L-proline are pooled and concentrated to dryness in vacuo.
Example 48 1-(4-Mercapto-2-methylbutanoyl)-L-Proline ~-By substituting 1-(4-benzoylthio-2-methylbutanoyl)-L-proline for the 1-(4-benzoylthiobutanoyl)-L-proline-in the procedure of Example 45, l-(mercapto-2-methylbutanoyl)-L-proline in obtained.
~J ~
'`
ExampLe 49 4-Bromo 2-benzylbutanoic acid By substituting ethyl-4-bromo-2-benzylbutanoate ~prepared by thc procedure of G. Jones and J. Wood [Tetrahedron, 21, 2961 (1965) starting with diethylbenzylmalonate]] for the ethyl-4-bromo-2-methylbutanoate in the procedure of Example 46, 4-bromo-2-benzylbutanoic acid is obtained.
Example 50 l-(4-Benzoylthio-2-benzylbu-tanoyl) L-Proline By substituting 4-bromo-2-benzylbutanoic acid for the 4-bromo-2-methylbutanoic acid in the procedure of Example 47, 1-(4-benzoylthio-2-benzylbutanoyl)-L-proline is obtained.
Examp~e 51 1-(4-Mercapto-2-benzylbutanoyl)--L-Proline By substituting 1-(4-benzoylthio-2-benzylbutanoyl)-L-proline for the l-(4-benzoylthiobutanoyl)-L-proline in the procedure of Example 45, 1-(mercapto-2-benzylbutanoyl)- -L-proline is obtained.
Example 52 1-(4-Mercaptobutanoyl)-L-Hydroxyproline By substituting L-hydroxyproline for -the L-proline in the procedure of Example 44 and subjecting the product to ammonolysis as in Example 45, l-(4-benzoylthiobutanoyl)-L-hydroxy-proline and l-(4-mercaptobutanoyl~-L-hydroxyproline, respectively, are obtained.
_ample 53 l-(4-Mercaptobutanoyl)-L-Azetidine-2-Carboxylic Acid --By substituting L-azetidine-2-carboxylic acid for the L-proline in the procedure of Example 44 and subjecting the l~ `
, 364 ~ ~
product to ammonolysis as in Example 45, l-(4-benzoylthio-butanoyl)-L-azetidine-2-carboxylic acid and l-(~-mercapto-butanoyl)-L-azetidine-2-carboxylic acid, respectively, are obtained~
E~
1=(4-Mercaptobutanoyl)-L-Pipecolic Acid By substituting L-pipecolic acid for the L-proline in the procedure of Example 44 and subjecting the product to ammonolysis as in Example 45, 1-(4-benzoylthiobutanoyl)-L-pipecolic acid and 1-(4-mercaptobutanoyl)-L-pipecolic acid, :
respectively, are obtained.
~., . ~ .
Example 55 ~;
1-(3-Acetylthiobutanoyl)-L-Proline tert-butyl Ester Dicyclohexylcarbodiimide (6.2 g.) and 3-acetylthio-butyric acid (4.86 g.) are added to a solution of L-proline tert-butyl ester (5.1 ~.) in dichloromethane (60 ml.) stirred in an ice bath. After 15 minutes the ice bath is removed , , and the mixture is stlrred at room temperature for 16 hours. ~;
The precipitate is filtered, the filtrate is concentrated to dryness and the residue is chromatographed on a column of `~
silica gel with chloroform to obtain l-(3~acetylthiobutanoyl)-L-proline tert-butyl ester, yield 5.2 g. ~;
Example 56 ;
1-(3-Acetylthiobutanoyl)-L-Proline The l-(3-acetylthiobutanoyl)-L-proline tert-butyl ester ~
of Example 55 (5.2 g.) is dissolved in a mixture of trifluoro- ~.
acetic acid (60 ml.) and anisolé (30 ml.) and the solution is kept at room temperature for one hour. The solvents are removed in vacuo and the residual l-(3-acetylthiobutanoyl)-L-prollne is reprecipitated from ether-hexane several times, yield - -~
~`
4 g.. The dicyclohexylamine salt is made by the procedure of Example 44, m.p. 175-17~.
Example 57 1-(3-Merc ptobutanoyl)-L-Proline The 1-(3-acetylthiobutanoyl)-L-proline of Example 56 (0.86 g.) is dissolved in 5~5 N. methanolic ammonia (20 ml.) and the reaction mixture is stored at room temperature for 2 hours. The solvent is removed in vacuo and the residue chromatographed on an ion exchange column (Dowex 50) with water. The fractions containing the desired 1-(3-mercaptobutanoyl)-L-proline are pooled and lyophilized, yield 0.6 g. The dicyclohexylamine salt is produced by the procedure of Example 44, m.p. 183-184.
Example 58 1-[3-[[(Ethoxy)carbonyl]thio]propanoyl]-L-proline Ethyl chloroformate ~1.2 g.) is added to a solution of 3~mercaptopropanoyl-L-proline (2.03 g.) in normal sodium bicar-bonate (30 ml.) and the mixture is stirred vigorously at 5 for one hour, and for two hours at room temperature. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and concentra-ted to dryness to yield 1-[3-[[(ethoxy)carbonyl~thio]propanoyl]-L-proline.
' ~' ~ :
Example 59 1-[3-[[(E-thoxy)thiocarbonyl]-thio]propanoyl]-L-proline Aqueous 2N sodium hydroxide (25 ml) and 3-hromopropionyl chloride (8.5 g) are added to a solution of L-proline (5.75 g) in N sodium hydroxide (50 ml) chilled and s-tlrred in an ice bath. After five minutes -the ice bath i5 removed and the stirring is continued at room temperature. After three hours ethyl xantogenic acid potassium salt ~9.6 g) is added and the mixture is stirred overnigh-t at room temperature. The solution ~ ~ -is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated to dry-ness and the residue is chromatographed on a column o~ silica gel with a mixture of benzene-acetic acid (7:1) as solven-t, to ~;
yield 1-[3-[[(ethoxy)thiocarbonyl]thio]propanoyl]-L-proline, p. 94_95o.
Example 6~
1-[3-[[(Benzylthio)carbonyl]thio]propanoyl]-L-proline A solution o~ benzylthiocarbonyl chloride (11 ml) in dioxane (20 ml) is added in five portions to a solution of 1-(3-mercaptopropanoyl)-~-proline (1.6 g) in normal sodium bicarbonate (24 ml) chilled in an ice bath, over a period of 30 minutes. The ice bath is removed and the stirring is continued for 2.5 hours at room temperature. After acid-ification with concentrated hydrochloric acid, the aqueous phase is extrac~ed with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness to yield 1-[3- E [ (benzylthio)carbonyl]thio]propanoyl]-~-proline.
.
.~ . .
_ample 61 1-[3-[[(Ethylthio)thiocarbonyl]thio]propanoyl~-.
Aqueous 2N sodium hydroxide (25 ml) and 3-bromopropionyl chloride (8.5 g) are added to a solution of L-proline (5.75 g) in N sodium hydroxide (50 ml~ chilled and stirred in an ice bath. After five minutes, the ice bath is removed and the stirring is continued at room temperature. After three hours, ethyl trithiocarbonate potassium salt (10.5 g~ is added and the mixture is stirred at room temperature overnight. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness to yield 1-[3-[[(ethylthio]t~iccarbonyl]thio]propanoyl]-L-proline.
Example 62 ;
3~[[(Methylamino)thiocarbonyl]thio]propionic acid ~ ethylisothiocyanate (4 g) is added to a solution of 3-mercaptopropionic acid (5.3 g) in a mixture of pyridine (250 ml) and 0.5 N sodium hydroxide (100 ml). The solution is kept at 40 for two hours and concentrated to dryness in vacuo. The residue is dissolved in water (100 ml.), _ acidi-fied with concentrated hydrochloric acid and extracted with ether. The organic phase is concentrated to dryness to yield 3-[[(methylamino)thiocarbonyl]thio]propionic acid, m.p. 86-87.
Example_ 3 1~[3-[[(Methylamino)thiocarbonyl]thio~propanoyl]-L-prollne tert-butyl ester To a solution of L-proline tert-butyl ester ~1.71 g) and hydroxybenzotriazole (1.35 g) in dichloromethane (lO m]) chilled and stirred in an ice bath, dicyclohexylcarbodiimide (2.06 gl and 3-methylaminothiocarbonylthiopropionic acid (1.79 g) are added. A~ter 15 minutes, the bath is removed and the stirring -is continued overnight. The precipitate is filtered off and the filtrate is diluted with ethyl acetate and washed neutral.
The organic phase is concentrated to dryness to yield l-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline tert-butyl ester, m.p. 129-130.
Example 64 l-[3-[[(Methylamino)thiocarbonyl]thio]propanoyl]-L-proline A) l-(MethylaminothiocarbonylthiopropanoyI)-L-proline tert- `
butyl ester (0.98 g) is dissolved in a mixture of anisole (3.6 ~ ;
ml) and trifluoroacetic acid (7.5 ml). After one hour at room temperature the mixture is concentrated to dryness in vacuo and the residue precipitated from ether-hexane three times. This material is chromatographed on a column of silica gel with a solvent mixture of benzene~acetic acid (75:25) to yield 1~[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline, ;
Rf = 0.4 [silica gel-benzene:acetic acid (75:25)]. The dicyclohexylammonium salt has m.p. 127-129.
~ .
;~
.: .
Gg~
~) Methylisothiocyanate (4 g) ls added to a solution of 3-mercaptopropanoyl-L-proline (10.1 CJ) in a mixture of pyridine (250 ml) and 0.5 ~ sodium hydroxide (lO0 ml). The solution is kept at 40 for two hours and concentrated to dryness ln vacuo.
The residue is dissolved in wa-ter (100 ml), acidified with con-centrated hydrochloric acid and extra~ted with ethyl acetate.
The organic phase is concentrated to dryness to yield l-~3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline.
Example 65 l-_[3-[[(Ethylamino)carbonyl]thio]propanoyl]-L-proline Ethylisocyanate (0.45 ml) is added to a solution of l-~3-mercaptopropanoyl)-L-proline (1 g) in a mixture of N
sodium hydroxide t5 ml) and pyridine (5 ml). The solution is heated at 40 for four hours and concentrated ln vacuo.
The residue is distributed between 0.1 N hydrochloric acid and ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated to dryness to yield 1-[3-[[(ethylamino)carbonyl]thio]propanoyl]-L-proline.
The dicyclohexylammonium salt is prepared by adding dicyclo-hexylamine to a solution of the free acid in ethyl acetate, ~;~
m.p. 150-152.
Examp_e_66 ' 1_[3-[[(Ethoxy?carbonyl]thio]-2-methylpropanoyl]-L-proline ~ `
By substituting 1-(3-mercapto-2-methylpropanoyl]-L-proline for the 3-mercaptopropanoyI-L-proline in the procedure of Example 58, l-[3-[~(ethoxy)carbonyl]thio]-2-methylpropanoyl]-L-proline is obtained~
~, ~
flA135b arnpl.e 67 1-[3-[[~thoxy)carborlyl]thio]butanoyl]-1.-proline By substituting 1-[3-mercaptobutanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of ~,cample 58, 1-3-[[(ethoxy)carbonyl]-thlo~butanoyl]-L-proline is obtained.
Examplc 68 1-[3-[[(Ethoxy)thiocarbonyl]thioJpropanoyl]-L-azetidine-2-carboxylic acld By substituting L-azetidine-2-carboxylic acid for L-proline in the procedure o~ Example 59, 1-[3-[[(ethoxy)-thiocarbonyl]thioJpropanoyl]-L-azetidine-2-carboxylic acid is obtained.
E'x rnple 69 1-[3-[[(~thoxy)thiocarbonyl]thio]propanoyl]-L-pipecolic acid ~ -By substituting L-pipecolic acid for L-proline in the procedure of Example 59, 1-[3-[[(ethoxy~thiocarbonyl]thio]pro-panoyl]-L-pipecolic acid i5 obtained.
Example 70 1-[4-[~(Benzyltllio)carbonyl]tllio]butalloy1J-I,-pLo]illc . .
, By substitutin~ 4-mercaptobutanoyl-L-proline ~or the 3-mercaptopropalloyl-L-proline in the proc-edure of ~xaml)lc 60, I-[4-[[(benzylthio]carbonyl]thio]bu~anoyl]-L-proline is obtained.
~xample 71 1-[2-[[(~enzylthio)carbonyl]thlo]propanoyl]-L-!jroline By substitutin~ 2-mercaptopropanoyl-L-prolirle for the 3-mercaptopropanoyl-L-proline in the procedurc of ~xa~ple 60, 1-[2~[[(benzyltllio)carbonyl~thio]propanoyl]-L-prolille is ob~ained.
Examp_e 72 1-[3-[[(E-thylthio)thiocarbonyl]thio]propanoyl]-L-proline methyl ester A solution of 1-[3-[[(ethyl-thio)thiocarbonyl]thio~-propanoyl]-L-proline in ethyl acetate i5 treated with an ethereal solution of diazomethane until persistent yellow color. After discharginy the yellow color with a few drops of acetic acid, ;
the solvents are removed in vacuo to yield l--[3-[[(ethylthio)-thiocarbonyllthio]propanoyl]-L-proline methyl ester.
Example 73 1-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-5-hydroxy-L-pipecolic acid By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the Procedure B of Example 64, 1- E 3-[[(methylamino)thiocarbonyl]thio]-propanoyl]-5-hydroxy-L-pipecolic acid is obtained.
Example 74 1-[3-[ E (Methylamiho)thiocarbonyl]thio]-2-methylpropanoyl]-L-proline amide By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline amide for the 3-mercaptopropanoyl-L-proline in the Procedure B of Example 64, 1-[3-[[(methylamino)thiocarbonyl]thio]-2-methyl-propanoyl]-L-proline amide is obtained.
Example 75 1-[3-[[(Phenoxy)carbonyl]thio]propanoyl]-L-proline By substituting phenylchloroformate for ethyl chloroformate in the procedure of ~xample 5~, 1-[3-[[(phenoxy)carbonyl]thio]-propanoyl]-I.-proline is obtained. -Example 76 1-[3 [~(Phenoxy)carbonyl}thio]butanoyl]-L-proline By substituting phenylchloroformate for the ethyl chloroformate and 4-mercaptobutanoyl-L-prolirle for the 3-mercaptopropanoyl-L-proline in the procedure of Example 58, 1-[3-[[(phenoxy)carbonyl]thio]butanoyl]-~-proline is obtained.
Example 77 1=[3-[[(Phenylamino)carbonyl]thio]propanoyl]-L-proline By substituting phenylisocyanate for the ethylisocyanate in the procedure of Example 65, 1-[3-[~(phenylamino)carbonyl]-thio]propanoyl] L-proline is obtained.
Example 78 1-[3-[[(Phenethylamino)carbonyl]thio]propanoyl]-L-proline :
By substituting phenethylisocyanate for the ethylisocyana-te in the procedure of Example 65, 1-[3-[[(phenethylamino)carbonyl]-thio]propanoyl]-L-proline is obtained. -~
Example 79 .
1 [3-[[(Ethylamino)carbonyl]thio]-2-benzylpropanoyl]-L-proline By substituting 1-(3-mercapto-2-benzylpropanoyl)-L-proline for the l-(3-mercaptopropanoyl)-L-proline in the procedure of Example 65, 1-[3-[[(ethylamino)carbonyl]thio]-2-benzylpropanoyl~-L-proline is ohtained.
., ~
Example 80 l-(3-Methyl-thiopropanoyl)-L-proline A) Methyl 3-methyl-thiopropionate (51 g) is saponiEied with a 10% sodium hydroxide solution (150 ml, 30 minutes at 100).
The cooled solu-tion is extracted with ether and then acidified.
The crude acid thus obtained is distilled and converted to the acid chloride with thionyl chloride.
A solution of L-proline (11.5 g) in N sodium hydroxide ~100 cc) is chilled in an ice bath and the 3-methylthiopropanoic acid chloride (6.9 g) is added dropwise with viyorous stirring over a ten minutes period. ~fter five hours the reaction mixture is acidified and extracted with ethyl ether to yield l-(3-me-thylthiopropanoyl)-L-proline. The dicyclohexylammonium salt is prepared by adding dicyclohexylamine to a solution o~ the free acid in e-thyl acetate, m.p. 169-171.
B) Methyl iodide (71 g) is added to a solution of 1-~3-mercaptopropanoyl)-L-proline ethyl ester (115 ~) and sodium (11.5 g) in ethanol (400 ml). The reaction is allowed to proceed overnight, the ethanol is removed in vacuo and the residue is dissolved in a mixture of ethyl acetate and water.
The organic layer is dried and concentrated to dryness ln vacuo.
The resulting 1-~3-methylthiopropanoyl)-L-proline ethyl ester (98 g) is suspended in a mixture o~ methanol (200 ml) and 5 N
sodium hydroxide (200 ml) and stirred at room temperature for five hours. The methanol is removed ln vacuo, and the aqueous phase is extracted with ethyl acetate, acidified and ~eextracted with ethyl acetate. This last organic phase is washed with water, dried and concentrated to dryness to yield l-(3-methylthio-propanoyl)-L-proline.
.
.
Example 81 ~=~ :
Aqueous 2 N sodium hydroxide (25 ml) and 3-bromopropionyl chloride (8.5 g) are added to a solution of l-proline (5.75 g) in N-sodium hydroxide (50 ml) chilled and stirred in an ice bath. After five minutes~ the ice bath is removed and the stirring is continued for three hours at room temperature. The reaction mixture is acidified with concentrated hydrochloric acid ~extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness ln vacuo. The residue is dissolved in a mixture of 4-chlorobenzenethiol (8 g), sodium hydroxide (4.2 g) and ethanol (300 ml). The solution is refluxed for 6 hours. The solvent is removed ln vacuo and the residue is dissolved in water, acidified with concentrated hydro-chloric acid and extracted with ethyl acetate. The or~anic layer is washed with water, dried, and concentrated to dryness ln vacuo to yield 1-[3-~4-chlorophenylthio)propanoyl]-L-proline.
Example 82 1,[[(3-Benzylthiomethyl)thio~propanoyl]-L-proline 1-(3-Mercaptopropanoyl)-L-proline (8.1 g) is dissolved in boiling liquid ammonia (100 ml) and small pieces of sodium are added until permanent blue color is obtained which is then discharged with a small piece of ammonium chloride. Benzyl-thiomethyl chloride (6.9 g) is added and the ammonia is allowed to evaporate. The final traces of ammonia are removed ln vacuo, the residue is dissolved in water and extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated to dryness ~ .
~ .
to yield l-[[(3-benzylthiomethyl)thio]pxopanoyl]-L-proline.
Example 83 1-[[(3-Acetamidomethyl)thio]propanoyl]-L-proline 1-(3-Mercaptopropanoyl)-L-proline (2 gl and N-hydroxy-methylacetamide (0.89 g) are dissolved in trifluoroacetic acid (10 ml) and the solution is stored at room temperature for one hour. The excess tirfluoroacetic acid is removed ln vacuo and the residue is precipitated several times from ether-hexane.
Finally, the residue is distributed between dilute hydrochloric acid and ethyl aceta-te~ The organic layer is washed with water, dried and concentrated to dryness to yield l-[[3-acetamido-methyl)thio]propanoyl]-L-proline.
Example 84 .
l-(Methylthioacetyl)-L-proline S
By substituting methyl mè~thylthioacetate for the methyl 3-methylthiopropionate in the Procedure A of Example 80, 1-(methyIthioacetyl)~L-proline, m.p. 123-124, is obtained.
~xample 85 l-(Benzylthioacetyl)-L-proline By substituting benzylthioacetyl chloride for the 3-methylthiopropanoyl chloride in the Procedure A of Example 80, l-(benzylthioacetyl)-L-proline, m.p. 86-88, is obtainea.
3L~ 4 HA135b E~ample 86 -1-~3-[(2-~henylc~hyl)t}lio]~ropanoyl]-rl-pro~ e _ By substitutincJ phenethylbromide for thc metllyl iodidc in the Procedure B of Example 80, 1-[3-~(2-pllellyletllyl)~hio)proparloyl]-L-proline is obtained.
.
~xample 87 1-[3-[(Triphenylmcth l)~hio~pro~anoyl]-L-prolinc By substituting triphenylmethyl chloride ~or thc metllyl iodide in the Procedure B of Example 80, 1-[3-[(tri~henylmethyl)-thio]propanoyll-L-proline is obtained.
Example 88 ___ 1-(3-~lethylthio-2-lnetllylpropanoyl)-L,-prolirle amiclc By substitutiny 1-(3-mercapto-2-methylpropanoyl)-L-proline amide for the 1-(3-mercaptopropanoyIj-L-proline ethyl estcr in the Procedure B o~ Example 80 and eliminatillc~ the saponification step, I-(3-methylthio-2-methylpropanoyl)-L-r?roline amide is obtained.
~xample 89 1- (3-~;ethylthiol?ropalloyl)-I,-aze~:icl~ e-2-carboxy:Lic ac,icl :
By substi-tuting L-azetidine-2-carboxylic acid for the L-proline in the Procedure A of Example 80,1-(3-rr,ethylthioproPanoyl)-L-azetidine-2-carboxylic acid is obtained. ~, .
'.
... . : .
', :
i4 Example 90 1-[3-(4-Methoxyphenylthio)propanoyl~-L-proline By substituting 4-methoxybenzenethiol for the 4-chloro-benzenethiol in the procedure of E~ample 81, 1~[3-(4-methoxy-phenylthio)propanoyl] L-proline is obtained.
Example 91 l-(3-Methylthiopropanoyl)-L-pipecolic acid ~
,, By substituting L-pipecolic acid for the I.-proline in the Procedure A of Example 80, 1-(3-methylthiopropanoyl)-L- ~;
pipecolic acid is obtained.
Example 92 1-[2-(4-Chlorophenylthio propanoyl]-L-proline .
By substituting 2-bromopropionyl chloride for the 3-bromopropionyl chloride in the procedure of Example 81, 1-[2-(4-chlorophenylthio-propanoyl~-L-proline is obtained.
Example 93 1-[3-[(Diphenylmethyl)thio]-2-benzylpropanoyl)]-L-proline Diphenylmethanol (0.92 g) and 1-(3-mercapto-2~benzyl-propanoyl)-L-proline (1.5 g) are dissolved in trifluoroacetic acid (10 ml) and the solution is kept at room temperature for 30 minutes. The excess trifluoroacetic acid is removed ln vacuo to yield l-[3-[(diphenylmethyl)thio]-2-benzylpropanoyl]-L-proline.
. .
~ ~ .
. ,, , ;, ~
~1.9.'f~ 364 Example 94 1-~4-(4-Chlorophenylthio)butanoyl]-L-proline .
By substitutlng 4-bromopropionyl chloride for the 3-bromopropionyl chloride in -the procedure of Example 81, 1-[4-(4-chlorophenyl-thio)butanoyl]-L-proline is ob-tained.
Example 95 1-[3-[(Benzylthiomethyl)thio]butanoyl]-L-proline By substituting 3-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 82, 1-[3-[(benzyl-thiomethyl)thio]butanoyl]-L-proline is obtained.
Example 96 1-[[4-[(Acetamidome hyl)thio]-2-methylbutanoyl~-L-proline By substituti.ng 1-(4-mercapto-2-methylbutanoyl)- :~
L-proline for the 1-(3-mercaptopropanoyl)-L-proline in the procedure of Example 83, 1-[[4-(acetamidomethyl)thio]-2-methylbutanoyl]-L-proline is obtained.
Example 97 1-[3-(Ethyldithio)propanoyl]-L-proline :
A) 3~Mercaptopropanoyl-L-proline (10 g) is added to a solution of ethylthiosulfinate (8.4 g) in methanol (100 ml) and the reaction mixture is stirred vigorously at room ..
temperature for four hours. The methanol is re.moved in vacuo to yield l-(3-ethyldithiopropanoyl)-L-proline.
'~
B) A solution of ethylthiosulfinate (8.4 g) in : .
ethanol (50 ml) is added to an aqueous solution of 3-mercapto-propanoyl-L-proline (10 g) maintained at pH 6-7 by careful : .
addition of sodium hydroxide. The mixture is stirred vigorously ~:
.
- ' : .' :
at room temperature until negative thiol reaction. The mix-ture is diluted with water, adjusted to pH 8 and extracted with ethyl acetate, the aqueous phase i5 acidified to pH 3 and extracted again with ethyl acetate. This lattex extract is washed with water, dried and concentrated to dryness -to yield 1-~3-(ethyldithio)propanoyl]-L-proline., Example 98 1-[3-[(4-Methylphenyl)dithio]propanoyl]-L-pro'llne A solution of 4-methylphenylsulfenyl chloride (1.76 g.) ~'~
in ether (20 ml) is added to a solution of 3-mercaptopropanoyl-I.-proline (2 g) in 0.5 N sodium hydroxide (20 ml) chilled in an ice bath. The mixture is stirred vigorously for one hour, and the aqueous phase is separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated to dryness to yield 1-[[3-(4-methylphenyl)dithio]propanoyl]-L-Proline.
Example 99 1-[3-~Phenyldithi'o-propanoyl}-L-proline By substituting phenylthiosulfinate [prepared from phenyl-disulfide according to U. Weber and P. Eartter, Z. Physiol. Chem.,351, 1384 (1970)] for the ethylthiosulfinate in the procedure of Example 97, 1-[3-(phenyldithio-propanoyl]-L-proline is obtained.
Example 100 ~ ' 1-~3-[(2-Phenylethyl~dithio]propanoyl]-L-proIine By substituting 2-phenylethylthiosulfinate (prepared from phenethyldisulfide) for the ethylthiosuflinate in the procedure ~, of Example g7, 1-[3-[(2-phenylethyl)dithio]propanoyl]-L-proline is obtained.
~ . . .
.
6~
Example 101 .
l-[3-[(2-Hydroxye-thyl)dlthio]propanoyl]-L-proline To a solution of 1,1'-[(sulfinylthio)-bis-(3-propanoyl)]-bis-L-proline (21 g) in methanol (100 ml), mercap-toethanol(4.2 g) is added and the reaction mixture is stirred vigorously at room temperature for four hours. The me-thanol is removed in vacuo and -the residue is pruified by chromatography on a silica gel column to yield 1-[3-[(2-hydroxyethyl)dithio]propanoyl]-L-proline.
Example 102 1-[2-(Ethyldithio)propanoyl]-L-proline ` ~ :
By substituting 2-mercaptopropanoyl-L-proline for 3-mercaptopropanoyl-L-proline in the procedure oE Example 97, 1-[2-(ethyldithio)propanoyl]-L-proline is obtained.
Example 103 1-[3-[(~-Methylphenyl)dithio~utanoyl]-I-proline `~
By substituting 3-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-~-proline in the procedure of Example 98, ~ ~
l-[3-(4-methylphenyl)dithio]butanoyl]-L proline is obtained. -Exampl`e 104 l-[3-(Ethyldithio)-2-methylpropanoyl]-I,-proline methyl ester .
By substituting l-(3-mercapto-2-methylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97 and then treating the product with ethereal diazomethane as in the procedure of Example 72, 1-[3-(ethyldithio)-2-~ethylpro-panoyl]-L-proline methyl ester is obtained.
~ ':
.
Example 105 l-[3-(Ethyldithio)propanoyl]-L-azetidine-2-carboxylic acid By suhstituting 3-mercaptopropanoyl-L-azetidine-2-carboxylic acid Eor the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, 1~[3-(ethyldithio)propanoyl]-L-aze-tidine-2-carboxylic acid is obtained.
Example 106 1-[3-[(4-Methylphenyl)dithio]-2-methylpropanoyl]-L-hydroxyproline :
By substituting 1-(3-!mercapto-2-methylpropanoyl)-L-hydroxy proline for the 3-mercaptop~opanoyl-L-proline in the procedure of Example 98, 1-~(3-[4-methylphenyl)dithio]-2-methylpropanoyl]-L-hydroxyproline is obtained.
Example 107 l-~4-~Ethyldithio)butanoyl]-L-pipecolic acid By substituting 4-mercaptobutanoyl-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, l-~4-(ethyldithio-butanoyl]-L-pipecolic acid is o~tained.
Example 108 1-[3-(Ethyldithio)propanoyl]-5-hydroxy-L-pipecolic acid By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, 1-[3-(ethyldithio)propanoyl]-5-hydroxy-L-pipecolic acid is obtained.
, ~,.-~ .
Example 109 1-[3-[(2-Amino-2-carboxyethyl)di hio]propanoyl]-L-proline A 0.5 M solution of thiocyanogen in glacial acetic acid is prepared by shaking for ten minutes in a sealed flask 600 mg of dry lead thiocyanate with a solution o 75 ~1 of bromine in 3 ml of acetic acid. After removal of lead bromide and excess lead thiocyanate by centrifugation, 2.5 ml of this solution is mixed with 2.5 ml of a 0.41 M solution of cysteine hydrochloride ~i previously neutralized with dilute sodium hydroxide. This mixture is immediately added to 0.75 ml of a 1.9 M solution of 3-mercaptopropanoyl L-proline previously neutralized with dilute i sodium hydroxide. After twenty minutes the mixture is titrated to incipient brown color with alcoholic iodine, and adjusted to pH 3. The precipitate is removed by fiItration and the filtrate is applied to a column of cation exchange resin (Dowex 50~. The column is washed with water until no more acidic material is ~;~
removed and then eluted with pyridine-acetate buffer pH 6Ø ~ ' The fractions containing the disulfide of cysteine and 3-mercaptopropanoyl-L-proline are pooled and concentrated to dryness.
Example 110 1,1'-~Dithiobis)4~propanoyl)]-bis-L-proline 3-Mercaptopropanoyl L-proline (0.95 g) is dissolved in water (20 ml) and the pH is adjusted to 6.5 with N-sodium hydroxide. An ethanolic solution of iodine is added drop- ~;
wise while maintaining the pH at 6.5 with careful addition of N sodium hydroxide. When a permanent yellow color_is obtained the addition of iodine is stopped and the color , .
is discharged with a small amount of sodium thiosulfate.
The reaction mixture is acidified with concentrated h~dro-chloric acid and extracted with ethyl aceta-te. ~he organic phase is washed with water, dried and concentra-ted to dryness to yield l,l'-[dithiobis(3-propanoyl)]-bis-L--proline. The di-cyclohexylammonium salt is prepared by additlon o~ dicyclo-hexylamine to a solution of the free acid in acetonitrlle, m.p. 179-180.
Example 111 1,1'-[Dithiobis(2-D-methyl-3-propanoyl)]-bis-L-proline By substituting 3-mercapto-2-D-methylpropanoyl-L-proline for the 3-mercaptopropanoyl~L-proline in the procedure of Example llO~ 1,1'-[dithiobis~2-D-methyl-3-propanoyl)]-bis-L-proline is obtained, m.p. 236-237.
Examp~l'e 112 'l,l'-[Dithiobis(2-propanoyl)-bis-L-proline By substituting 2-mercaptopropanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, 1,1'-[dithiobis)2Npropanoyl)]-bis-L-proline is obtained.
Example 113 l,l'-(Dithiobisacetyl)-bis-L-hydroxy proline By substituting 1-(2-mercaptoacetyl)-L-hydroxyproline for the 3-mercaptopropionyl-L-proline in the procedure of ~ -Example llO, l,l'-(dithiobisacetyl)-bis-L-hydroxyproline is ' obtained.
Example 114 ,~
1,1'-(Dithiobisacetyl)-bis-L-azetidine-2-carboxylic ac~id B~ substituting 1-(2-mercaptoacetyl)-L-azetidine-2- -carboxylic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, l,ll-(dithiobisacetyl)-bis-L- , azetidine-2~carboxylic acid is obtained.
Example 115 ..
1,1'-[Di-thiobis(3-propanoyl)]-bis-L-pipecolic acid By substituting 3-mercaptopropanoyl-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, 1,1'-[dithiobis(3-propanoyl)]-bis-L-pipecolic acid is obtained. ' E~ample 116 1,1'-[Dithiobis(3-propanoyl)]-bis-4-methyl-L-prolihe ;
By substituting 1-(3-mercaptopropanoyl)-4-methyl-I,-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110~ 1,1'-[dithiobis(3-propanoyl)]-bis-4-methyl-L-proline is obtained.
Example 117 1,1'-~Dithiobis(3-propanoyl)]-bis-5-hydroxy-L-pipecolic acid ~
" .~ .
By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L~
pipecolic acid for the 3-mercaptopropanoyl-L-proline in the pro~ ~ ~, cedure of Example 110, 1,1'-[dithiobis(3-propanoyl)]-bis-5-hydroxy ' ,;
L-pipecolic acid is obtained. ~ , Example 118 ,~
1,1'-~Dithiobis(2-benzyl-3-propanoyl)]-bis-L-proline By substituting 1-(3-mercapto 2-benzylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of ,Example ', 110l l,l'-[dithiobis(2-benzyl-3-propanoyl)]-bis-L-proline is ;' obtained. ' ~', ' EY~ample 119 1,1'-~Dithiobis)2-methyl-3-propanoyl)]-bis-I,-pipecolic acid By substituting 1-(3-mercapto-2-methylpropanoyl)-I,-pipecolic acid for the 3-mercaptopropanoyl-L--proline in the procedure of Example 110, 1,1'-[dithiobis(2-methyl 2-propanoyl)}-bis-L-pipecolic acid is obtained. ;
Example 120 1,1'-~Dithiobis)4-butanoyl)~-bis-L-proline By substituting 4-mercaptobutanoyl-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example 110, 1,1'-~dithiobis(4-butanoyl)]-bis-L-proline is obtained.
Example 121 1,1'-[Dithiobis(2-benzyl-4-butanoyl)}-bis-L-proline By substituting 1-(4-mereapto-2-benzylbutanoyl)-L-proline for the 3-mereaptopropanoyl-L-proline in the procedure o~
Example 110, 1,1'-[dithiobis(2-benzyl-4-butanoyl)]-bis-L-proline is obtained.
Example 122 1,1l-[Dithiobis(3-butanoyl)]-bis-L-proline ~' .
By substituting 3-mercaptobutanoyl-L-proline for the ~ ;' 3-mereaptopropanoyl-L-proline in the proeedure of Example 110, 1,l'~[dithiobis(3-butanoyl)]-bis-L-proline is obtained. ~-6~ :
Example 123 1,1'-[Dithiobis(3-propanoyl)]-bis-L-proline methyl ester A solution of l,l'-[dithiobis(3-propanoyl)l-bis-L-proline in methanol is treated with ethereal diazomethane ;
until persistent yellow color~ After fifteen minutes a few drops of acetic acid are added and the solvents are .
removed in vacuo to yield, l,l'-[dithiobis(3 propanoyl)l--bis-L-proline methyl ester.
Example 124 l,l'-[Dithiobis(3-propanovl)]-bis-L-proline amide A solution of 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline methyl ester in methanol is saturated with am- . :
monia while cooling in an ice-water bath. The reaction ~:
mixture is stored for 16 hours at room temperature in a pressure bottle, and then the solvents are removed ln . ~ .
vacuo to yield l,l'-[dithiobis(3-propanoyl)]-bis-L-proline amide. ~ ~.
3~
1,1'-[Dlthiobis(2-phenyl-3-propanoyl)]-bis-L-proline :::
By substituting 1-(3-mercapto-2-phenylpropanoyl)-L-proline for the 3-mercaptopropanoyl-L-proline in the procedure of Example llO, l,l'-[dithiobis(2-phenyl-3-pro-panoyl)]-bis-L-proline is obtained.
.. . ', ;,.
P3~4~
Example 126 1,1'-[(Sulfinylthio)-bis-(3-propanoyl)]-bis--L-proline .
While cooling in an ice bath 0.12 mo:Le of peracetic acid is added to a stirred solution o~ l,l'--[dithiobis(3-propanoyl)]-bis-L-proline (40 g) in glacial acetic acid (500 ml). The reaction mixture is allowed to stand over-night at room temperature and the solvent is then removed ln vacuo to ~ield l,l'-[(sulfinylthio)-bis-(3-propanoyl)]-bis-L-proline.
Example 127 1,1'-[(Sulfon~lthio)-bis-(3-propanoyl)]-bis-L-prollne A 30% solution of hydrogen peroxide (2.0 ml) is added to a solution of l,l'-Edithiobis(3-propanoyl)]-bis-L-proline (4 g) in glacial acetlc acid (80 ml) and the solution is stored for thirty hours at room temperature.
The solvent is removed ln vacuo to yield l,l'-[(sulfonyl-thio)-bis-(3-propanoyl)]-bis-L-proline.
Example 128 -.
1,1'-[(Sulfinylthio)-bis-(2-propanoyl)]-bis~L-proline --By substituting 1,1'-[dithiobis(2-propanoyl)]-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-(2-propanoyl)]-bis-L-proline is obtained.
6~
Example 129 1,1'-[(Sul~inylthlo)-bis-acetyl]-bis-L-azetidine-2-carbox -Y .
lic acid By substitut.ing l,l'-(dithiobisacetyl)-bis-L-azeti-dine ca.rboxylic acid for the l,l'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-acetyl]-bis-L-azetidine-2-carboxylic acid is obtained.
Example 130 ~:
l,l'-[(Sul~inylthio) bis-(3-propanoyl)]-bis-4-methyl-L-proline -.
.
By substituting 1,1'-[dithiobis(3-propanoyl)]-bis- ~; :
4-methyl-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[~sul-finylthio)-bis-(3-propanoyl)]-bis-4-methyl-L-proline is . :-obtained.
Example 131 ::~
1,1'-[(Sulfinylthio)-bis-(2-benzyl-3-pro_ noyl)]-bis-L-proline By substituting 1,1'-[dithiobis(2-benzyl-3~propa-noyl)]-bis-L-proline for the 1,1'-~dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-t2-benzyl-3-propanoyl)]-bis-L-proline is obtained.
Example 132 1,1'-~(Sulfinylthio)-bls-(4-butanoyl)~-bis-I.-proline By substitu-ting 1,1'-[dithiobis(4-butanoyl)]-bis-L-proline for the 1,1'-[dithiobis(3--propanoyl)]-bis-L-proline in the procedure of Example 126, l,l'-~(sulfinyl--thio)-bis-(4-butanoyl)]~bis-L-proline is obtained.
;9L
Example 133 1 l'-[(Sulfin l-thio)-bis-(3-butano l)]-bis-L-proline ,, Y Y
By subs-tituting 1,1'-[dithiobis(3-bu-tanoyl)]-bis-L-prol.ine for the l,l'-[dithiobis(3-propanoyl)~-bis-L-proline in the procedure of Example 126, l,l'-[(sulfinyl-thio~-bis-(3-butanoyl)]-bis-L-proline is obtained.
Example 134 1,1'-[(Sulfinyl-thio)-bis-~2-methyl-3-propanoyl)-bis-L-pro-line By substituting 1,1'-[dithiobis(2-methyl-3-propan~
oyl)]-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 126, 1ll'-[(sul-finylthio)-bis-(2-methyl-3-propanoyl)~-bis-h-proline is obtained.
, Example 135 :
1,1'-~(Sulfinylthio)-bis-(2-phenyl-3-propanoyl)]-bis-L-proline By substituting 1,1'-[dithiobis(2-phenyl-3-propa-noyl)l-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]- .
bis-L~proline in the procedure of Example 126, l,l'-[(sul-finylthio)-bis-(2-phenyl-3-propanoyl)]-bis-L-proline is ~ :
obtained. :`
Example 136 1-[3-1[3-(2-Carboxy-l-pyrrolidinyl)-3-oxopropyl]-dithio]-2-methylpropanoyl]-L-proline By substituting 1,1'-1~sulfinylthio)-bis-(2-methyl-3-propanoyl)]-bis-L proline for the ethylthiosulfinate in the procedure of Example 97, 1-[3-[13-(2-carboxy-1-pyrro-lidinyl)-3-oxopropyl]dithio]-2-methylpropanoyl]-L-proline is obtained.
~ /~
36~L
Example 137 l,l'-[(Sulfonyl-thio)-bis-acetyl)-bis-L-hydroxyproline sy substituting l,l'-(dithiobisacety:L)-bis-L-hy-droxy proline ~or the l,l'-[dithiobis(3-propanoyl)-bis-L-proline in -the procedure of Example 127, l,l'-[(sulfonyl-thio)-bis-acetyl)-bis-L-hydroxyproline is obtained~
Example 138 ~ ;
1,1'-[(Sulfonylthio)~bis~(3-propanoyl)]-bis-L-pipecolic acid By substituting 1,1'-[dithiobis(3-propanoyl)]-bis-L-pipecolic acid for the 1,1'-[dithiobis(3-propanoyl~]-bis-L-proline in the procedure of Example 127, l,l'-[~sul-fonylthio)-bis-(3-propanoyl)]-bis-L-pipecolic acid is ob-tained.
Example 139 1,1'-[(Sulfonylthio)-b_s-(3-propanoyl)]-bis-5-hydroxy-L-pipecolic acid ~ ~
: ' , By substituting 1,1'-[dithiobis(3-propanoyl)]-bis- ;
5-hydroxy-L-pipecolic acid for the 1,1'-[dithiobis-(3- ;
propanoyl)]-bis-L-proline in the procedure of Example 127, 1,1'-[(sulfonylthio)-bis-(3-propanoyl)]-bis-5-hydroxy-L-pipecolic acid is obtained.
Example 140 1,1'-[(Sulfonylthio)-bls-(2-methyl-3-propanoyl)]-bis-L-pipecolic acid :
By substituting 1,1'-[dithiobis(2-methyl-3-propa-noyl)]-bis-L-pipecolic acid for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 127, 1,1'-[(sulfonylthio)-bis-(2-methyl-3-propanoyl)]-bis-L-pipecolic acid is obtained.
': :
E_ mple 141 l,l'-[(Sulfonylthio)-bls-(2-ben2yl-4-butanoyl)]-bis-L~
proline By subs-titu-ting 1,1'-[di-thiobis(2-benzyl-4-bu-tan-onyl)]-bis-L-proline for the 1,1'-[dithiobis(3-propanoyl)]-bis-L-proline in the procedure of Example 127, l,l'-l(sul-fonylthio)-bis-(2-benzyl-4-butanoyl)]-bis-L-proline is ob-tained.
Example 142 3-Acetylthio-2-phenylpropanoic acid By substi-tuting 2-phenylacrylic acid for the meth-acrylic acid in -the procedure of Example 25, 3-acetylthio-2-phenylpropanoic acid is obtained.
1-(3-Acetylthio-2-phenylpropanoyl)-L-proline tert-butyl ester By substituting 3-acetylthio-2-phenylpropanoic acid for the 3-acetylthio-2-methylpropanoic acid in the proce-dure of ExampIe 28, 1-(3-acetylthio-2-phenylpropanoyl3-L-proline tert-butyl ester is obtained.
Example 143 1-(3-Mercapto-2-phenylpropanoyl)-L-proline By substituting 1-(3-acetylthio-2 phenylpropanoyl)-L-proline tert-butyl ester for the 1-(3-acetylthio-2-me-thyl-propanoyl-L-proline tert-butyl ester in the pro-cedure of Example 29, and subjecting the product to am-monolysis as in Example 34, 1-(3-acetylthio-2-phenylpro-panoyl)-L-proline and 1-(3-mercapto-2-phenylpropanoyl)-L-proline are obtained.
.:
36~
HA135b Example 144 1-[3-(Acetylthio)-DL-propanoyl]pipecolic acid Pipecolic acid (6.5 g.) is suspended in 200 ml.
of dimethylacetamide. 3-acetylthiopropanoyl chlorlde (8.3 g.) is added dropwise at 23 to the suspension. A
clear solution forms and the temperature rises to 28 .
To this clear solution is added N-methylmorpholine (1~.1 g.).
An immediate precipitate forms and the temperature rises to 34 . The mixture is heated on a steam bath for 1 hour when a clear solution forms. Qn cooling, the precipitated solid is filtered to yield 5.1 g. of 1-[3-(ace-tylthio)-DL-propanoyl]pipecolic acid, m.p. 190-200. The solvent is removed and the viscous residue is triturated with isopropyl ether to yield 7.8 y. of product, m.p. 98-101 . Recrystalliza- ;~
tion from acetone-hexane yields d constant melting solid, m.p. 102-104 ; Rf 0.72 [silica gel, benzene, acetic acid~(7~:2)].
Example 145 DL-1-(3-Mercaptopropanoyl)pipecolic acid 12 ml. of concentrated ammonium hydroxide is stirred under nitrogen at 10 for about l5 minutes, then solid 1-[3-tacetylthio)-DL-propanoyl]-pipecolic acid (6.6 g.) is added at 5 to 10 . A clear solution forms after 2-3 minutes. The ice bath is removed and the solution lS stirred at room temperature under nltrogen for 45 minutes. The solution ls made strongly acid with 20~ HCl ~cooling) and the precipitated oil is extracted with 3 x 150 ml. of ethyl acetate. The ethyl acetate extracts are dried over magnesium sulfate and the solvent is removed to yield 6.0 g. of DL-1-(3-mercaptopropanoyl)pipccolic acid, Rf 0.77 [sllica gel, 3d benzene,acctic acid (7:1)].
-~,7-HA135b Example 146 1-(3-Mercaptopropanoyl)-L-pipecolic acid By substituting L-pipecolic acid Eor the DL-pipecolic acid in the procedure of Example 144 and then submitting the product to the procedure of Example 145, 1-[3-(acetylthio)propanoyl]-L-pipecolic acid and 1-(3-mercaptopropanoyl)-L-pipecolic acid Rf 0.80 [silica gel, benzene, acetic acid (7:1)], [a] -51.5 (c, 1.0 abs.
ethanol), are obtained.
Example 147 1~[3-(Acetylthio)-2-methylpropanoyl-DL-pipecollc acid 6.5 g. (0.05 m.) of pipecolic acid are suspended in dimethylacetamide (200 mg.), 9.0 g. (0.05 m.) of 3-acetylthio-2-methylpropanoyl chloride is added dropwise.
The temperature rises to 29 and a clear solution forms Then 10.1 g. of N-methylmorpholine is added a]l at once and the temperature rises to 34~. The mixture is heated on a steam bath for 1 hour when a clear solution forms.
This is allowed tP stand at room temperature overnight and the solid which precipitates is filtered to yield 6.1 g.j m.p~ 203-204 . The solvent is removed and the viscous residue is triturated with water and 20% HCl. The yellow oil is extracted with 3 x 150 ml. of ethyl acetate.
~he ethyl acetate extracts are dried over magnesium sulfate and removed to yield 14 g. of 1-[3-(acetylthio)-2-methyl-propanoyl-DL-pipecolic acid as a viscous oil.
Example 148 1-(3-Merca~to-2-methylpro~anoyl)-DL~pipecolic acid ~ .
Aqueous NH4011 (30 ml. water and 20 ml. conc. NH40H) is stirred under nitro~en a~ 10 for 15 minutes. This i9 -6~-~ ~.
~ .
HA135b added to 13.0 g. (0.05 m) of 1-[3-(acetylthio)-2-methylpropanoyl]-DL-pipecolic acid and -the resulting solution is stirred for 10 minutes under nitroyen; then at room temperature for 50 minutes. It is then treated with water ~;
and 20~ HCl and the yellow oil extracted with 3 x 150 ml.
of ethyl acetate. The ethyl acetate extract is dried over - -magnesium sulfate and removed to yield 11.1 g. 1-(3-mercapto-2-methylpropanoyl)-DL-pipecolic acid as a viscous oil. R~ 0.62 [silica gel, benzene, acetic acid (7:2)].
Example 149 3-[(4-Methoxyphenyl)methylthio]--2-methylpropanoic acid p-Methoxy-~-toluene thiol (15.4 g., 0.1 mol.) is added to a solution of methacrylic acid (8.6 g., 0.1 mol.) in 50 ml. 2~ sodium hydroxide. The mixture is heated on the steam bath ~or three hours, then refluxed for two :
hours and cooled. The mixture is~extracted with ether, then the aqueous layer is acidifled with concentrated HCl and extracted with dichloromethane. The acidic extracts are washed wlth brine, dried (MgSO4) and evaporated in~vacuo.
2n The resulting semi-solid is taken up in 50 ml. of dlchloro-methane, diluted with 50 ml. hexane, and chilled. 3-[(4 methoxyphenyl)methylthio]-2-methylpropanoic acid is collected as a white crystalline solid, m.p. 74-82 ~5.5 g.).
Example 150 1-[3-(4-Methoxyphenyl?methylthio~-2-met proline tert-butyl ester ~
3-~(4-methoxyphenyl)methylthio]-2-methylpropanoic acid (3.6 g., 0.015 mol.~, L-proline tert-butyl ester (2.6 g., 0.015 mol.), and dicyclohexylcarbodiimide (3.1 g., .
i~l864 HA135b 0.015 mol.~ are dissolved in 50 m:L. oE dichloromethane and stirred thirty minu-tes at 0 . The cooling bath is removed and the mixture stirred overnight (sixteen hours).
The resulting suspension is filtered and the filtrate washed with 5~ potassium bisulfate, salurated sodium bicarbonate and brine, then dried (MgSO4~ ancl evaporated in vacuo.
The resulting clear oil is applied to a 250 ml. silica gel column and chromatographed using 20% ethyl acetate/
hexane as eluant. The main fraction (Rf = 0.70, silica gel, ethyl acetate) is evaporated to 5.5 g. (g3~) of 1-[3-(4-methoxyphenyl)methyl-thio3-2-methylpropanoyl-L-proline tert-butyl ester as a clear oil. Rf = 0.70 (silica gel, ethyl acetate); Rf = 0.60 (silica gel, ether).
Exam~le 151 1- ~ 2-methylpropanoyl)-L-proline The ester from Example 150 (1.2 g., 0.003 mol.), anisole (5 ml.) and trifluoromethanesulfonic acid (0.5~ml.) are dissolved in 20 ml. of -trifluoroacetic acid under nitrogen, and the resultinq red solution let stand one hour at room temperature. The solution is evaporated in vacuo to a red residue which is taken up in ethyl acetate and washed with water! brine, then dried (MgSO4) and evaporated.
The residue is repeatedly triturated with hexane and the residual hexane evaporated; the oil residue amounts to 0.4 g~ A portion (180 mg.) of this material ig subjected to preparative thin-layer chromatography on 2 mm silica gel plates using benzenejacetic acid 75:25 as eluant. The main nitroprusside-positive band (Rf = 0.40) is recovered, affording 135 mg. of 1-(3-mercapto-2-méthylpropanoyl)-L-proline as an oil. TLC using ben~ene/ace-tic acid 75:25 :
HA135b (R = 0 40) and chloroform/methanol/acetic acid 50:40:10 (Rf = 0.62).
Example 152 1-(3-Mercapto-2-D-methylpropanoyl)-L-proline IJnder a blanket of argon 1-[3-(acetylthio)-2-~methylpropanoyl]-L-proline (10.0 g.) is slurried in water (150 ml.) at 10 . To this mixture is added 5N
sodium hydroxide and the pH of the solution maintained at 13 for 1.5 hours. After this time, when the uptake of sodium hydroxide had ceased, the solution is acidified to a pH = 2.0 with concentrated sulEuric acid.
The aqueous solution is then extracted three times with methylene chloride ~3 x 150 ml.) and the combined methylene chloride fractions concentrated to an oil. The concentrate is taken up in ethyl acetate, filtered and the filtrate diluted with hexane (30 ml.).
: -An additional amount Oe hexane is added after 1/2 hour and then the mixture cooled to 10 for 1 hour.
The crystals are filtered and washed with hexane (2 x 25 ml.) and dried to constant weight to give 1-(3-mercapto-2-D methylpropanoyl)-L-proline as white crystals, 6.26 g., m.p. 100-102.
Example 153 .. . ~ ~ :
1-~3-Tosyloxy-2-methylpropanoyl]-L-proline By substituting 3-tosyloxy-2-methylpropanoic acid chloride for the 3-acetylthio-2-methylpropanoic acid chloride in the procedure of Example 29b 1-[3-tos~loxy-2-methylpropanoyl]~L-proliAe is obtained.
., .
-~71-- ' .
. . ' . ~ : . ~' ,'' ~1~1864 i~A135b Example 154 1-L~ Y_thio-2-methylpropanoyl]-L-proline 1-[3-Tosyloxy-2-methylpropanoyl~-L-proline (3.5 g.) is added to a solution of thiolacetlc acid ~1.14 g.), and triethylamine (3.5 ml.) in ethyl acetate (20 ml.). The solution is maintained at 50 for three hours, cooled, diluted with ethyl acetate (100 ml.), and washed with dilute hydrochloric acid. ~he organic layer is dried and concentrated to dryness in vacuo. The residue is dissolved in acetonitrile and dicyclohexylamine is added. The crystalline precipitate is recrystallized -~
from isopropanol to yield l-[3-acetylthio-2-D-methyl-propanoyl)-L-proline, dicyclohexylamine salt, m.p.
187-188 , Ea]D -67 (c 1,4, EtOH). This salt is converted to the free acidj m.p. 83-85 (an isomorphic form of m.p. 104-105 is obtained if the crystallizing solution is seeded wi-th high melting material).
Example 155 1-~3-Mercaptopropanoyl)-L-proline, t-butyl ester To a stirred solution of 1.71 g. (10 mmoles) of proline t-butyl ester and 1.35 g. (l0 mmoles) of 1-hydroxybenzotriazole hydrate in 20 ml. of N,N-dimethyl-formamide at 0-5 are added 2.06 g. (10 mmole) of N,N'-dicyclohexylcarbodiimide. The mixture is stirred for 10 minutes, followed by the addition of 1.06 g. (10 mmole) of 3~mercaptopropanoic acid in 2 ml. of N,N-dimethyl-formamide- The mixture is then stirred at 0-5 for 1 hour, and at room -temperature overnlght. ~
The precipitated N,N'-dicyclohexylurea is filtered off, and the filtrate concentrated in vacuo. ~--72~
~ .
4 HA135b The residue is taken up in ethyl ace-ta-te, washed thoroughly with saturated aqueous sodi~lm bicarbona-te, dried, and concen-trated in vacuo to 2.5 g. of oil.
The oil is taken up in 1:1 ethyl acetate-hexane and applied to a silica gel column (100 g.). Elution with 1:1 ethyl acetate-hexane aEfords 1.40 g. (54~) of 1~(3-mercaptopropanoyl)-L-proline/ t-butyl ester as an oil, which crystallizes on standing. Recrystallization from ether-hexane yields 0.9 g. of colorless crystalline solid, m.p. 55-60, identical to the compound of Example 17.
Example 156 1-(3-Mercaptop _panoyl)-L-proline A solution of 75 mg. (0.27 mmole) of 1-[3-[[(ethyl-amino)earbonyl]thio]propanoyl]-L-proline in 1 ml. eaeh of coneentrated ammonium hydroxide anù water is allowed to stand at room temperature for 18 hours under argon~ The~
`solution is diluted with a small amount of water~and extraeted with ether. The aqueous layer is acidified with eold coneentrated hydrochloric acid and extraeted with ethyl acetate. The combined extracts are dried and eoncentrated in vacuo to give a eompound identical with the product of Example 18. TLC (silica gel; benzene:acetic acld 7:3) Rf 0.~.
Example 157 Methaeryloyl-L-Proline L-preline (23.0 g., 0.2 mol.) is dissolved in 100 ml. water and stirred in an iee bath. ~ethacryloyl .
- ehloride (19.6 ml., 0.2 mol.~ in 25 ml. of methyl isobutyl ketone is added dropwise over three hours. Sedium hydroxlde '~
HA135b solution (2N) is added simultaneously, maintaining the pH of ~he reaction mixture at 7Ø Addition of base is continued for four hours after addition of acid chloride has been completed. The reaction mixture is adjusted to pH 5 with concentrated HCl and extracted with ethyl acetate. The aqueous layer is then acidified to pH 2.5 and extracted thorouyhly with ethyl acetate. The acidic extracts are washed with brine and drled (MgSO4). The ethyl acetate solution is trea-ted with dicyclohexylamine (40 ml.) and chilled overnight. The resulting white pre-cipitate is filtered and dried, yielding 29 g. (39~) of `~
white solid, m.p. 202-210 . The solid is crystallized from 1.5 liters 3:1 acetonitrile/isopropanol to yield 19.7 g.
of methacryloyl-L-proline, dicyclohexylamine salt as fine white needles, m.p. 202-210 .
The salt is dissolved in water/ethyl acetate and the mixture acidified with concnetrated HCl. The resulting suspension is filtered to remove a fine white precipitate which is washed well with ethyl acatate. The filtrate is saturated with sodium chloride and extracted thoroughly with ethyl acetate. The extracts are washed with brine, dried (MgSO4) and evaporated to a clear oil which solidifies. Crystallization Erom ethyl acetate/hexane yields 7.5 g. (83%) of methacryloyl-L-proline as a white crystalline solidr m.p. 89-93 . An analytical sample is obtained by recrystallization, m.p. 95-98.
Example 158 ~.
1-(3-Acetylthio-2-D-methylpropanoyl)-L-proline Methacyloyl-L-proline (183 mg., 0.001 mol.) is dissol~ed in thiolace~ic aci(l (0.5 ml.) an~ allowe~l
-7~-HA135b to stand at room temperature for sixteen hours. The solution is evaporated ln vacuo to a yellow residue.
Preparative thin layer chromatography (silica gel, di-chloromethane/methanol/acetic acid 90:5:5) allows isolation of a clear oil (240 mg.) as -the main fraction. TLC (dichloro-methane/methanol/acetic acid 90:5:5) shows ~his material to be l-(3-acetyl-thio-2-DL-methylpropanoyl)-L-proline corresponding to the product of Example 29B. Rf = 0.35;
(benzene/acetic acid 75:25) Rf = 0.38.
The oil is dissolved in 3 ml. acetonitrile, treated wi-th dicyclohexylamine until the solution is basic, and chilled. A white crystalline solid (106 mg.) m.p. 175-181 , is collected. Crystallization from isopropanol gives l-(3-acetylthio-2-D-methylpropanoyl)-L-proline, dicyclohexylamine salt/ rn.p. 187-188 , identical with this product in Example 29A.
Example 159 l-[Dithiobis-(2-methyl-3~propanoyl)]-bis-L-proline By substituting 3,3'-dithiobis-2-methylpropanoic acid for the 3-ace~tylthio-2-methylpropanoic acid ln the pîO- :
cedure of Example 29B, l-[dithiobis-t2-methyl-3-propanoyl)]-bls-L-proline is obtained.
Exam~le 160 1-(3-Mercapto-2 - methylpropanoyl)-L-proline Zinc dust (10.0 g.) is added to a slurxy of the product of Example 159 (5~0 g.) in 100 ml. of 1 O N
sulf~uric acid and the mixture is stirred at 18 for four hours under a blanket of nitrogen. ~he solution is then filtered, the Zinc washed with wat~r (20 ml.) and the combined filtrates are ~tracted with methylene chloride -75~
HA135b (3 x 75 ml~). The methylene chloride washes are back extracted with water (25 ml.) and then the organic solution concentrated to an oil. This oil is taken up in ethyl acetate (20 ml.) and filtered. Hexane ~15 ml.) is added to the filtrate and the mixture is stirred for 15 minutes. After this time, an additional volume of hexane (30 ml.) is added and the solution cooled to 5 for 1 hour. The mixture is then fil~ered, and the product is washed with hexane (2 x 10 ml.) and dried to give 4.17 g.
of white crystals o~ the product, 1-(3-mercapto-2-methylpropanoyl~-L-proline. TLC, Rf = 0.60 ~Solvent system: benzene/acetic acid 75:25).
Example 161 3-Benzylthio-2-methylpropanoic acid By substituting a-toluenethiol for p-methoxy a-toluenethiol in the procedure of Example 149, 3~benzylthio-2-methylpropanoiC acid is obtained.
Example 162 1-[3-(Benz~lthio)-2-methylpropanoyl]-L-proline tert.
bu-tyl ester By sub~ti-tuting 3-benzylthio-2-methylpropanoic ~`
acid for the 3-[(4-methoxyphenyl)methylthio]-2-methyl-propanoic acid in the procedure of Example 150, 1-[3-:
~benzylthio)-2-methylpropanoyl]-L-proline tert. butyl ester is obtained.
Example 163 1=[3-(Benzylthio)-2-methylpropanoylJ-~-proline 1-[3-(benzylthio)i-2-methylpropanoyl]-~-proline tert. butyl ester (7.8 g.) is dissolved in a mixture of anisole (55 ml.) and trif:luoroacetic acid (110 ml.~. Afier HA135b one hour storage at room temperature, the solvent is removed in vacuo and the residue is dissolved in ether, washed several times with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness in vacuo to yield 1-~3-(benzylthio)-2-methylpropanoyl}-L-proline.
Rf 0.5 (Silica gel~ Benzene/acetic acid 3:1) Rf 0.5.
(Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Example 164 1-(3-Mercapto-2-methylpropanoyl)-L-proline 1-[3-(benzylthio)-2-methylpropanoyl]-L-proline (0.1 g.) is suspended in boiling liquid ammonia (10 ml.) and small pieces of sodium are added with stirring until persistent blue color. The color is discharged with a few crystals of ammonium sulfate and the ammonia is~allowed to evaporate under a current of nitrogen. The residue is dissolved in a mixture of dilute hydrochloric acid and ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to yield l-(3-mercapto-2-methylpropanoyl)-L-proline. R~: 0.35 (Silica gel; Benzene/acetic acid 3!1), Rf 0.5 (Sillca gel; Methyl-ethylketone/acetic acld~ -pyridine/water ~ 2:1? identical to the compound of Example 34.
Example 165 3-Triphenylmethylthio-2-methylpropanoic acid A solution of 3-mercapto-2-methylpropanoic acld (1.2 g.)~and tritylchloride (2.9 g.) in me~hylene chloride (50 ml.) is kept at room temperature for 2 hours.
~The mixture is warmed in a steam bath for 20 minutes and then evaporated to dryness in vacuo and -he residue is d1ssolved HA135b in saturated aqueous sodium bicarbonate and the solution is washed with ethyl acetate. The aqueous phase is acidified to pH 3 and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to give 3-triphenylmethylthio-2-methylpropanoic acid. ~f 0.8 (Silica gel, BenzeneJace-tic acid 3:1).
Example 166 1-[3-(Triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester By substituting 3-triphenylmethylthio-2-methyl-propanoic acid ~or the 3-[(4-methoxyphenyl)methylthio]-2-methylpropanoic acid in the procedure of Example 150, 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester is obtained.
Example 167 1-[3-(Triphenylmethylthio)-2-methylpropanoyl]-L-proline 3-Triphenylmethylthlo-2-methylpropanoic acid (1.8 g.) and N,N'-carbonyldiimidazole t0.8 g.) are~
dissolved in tetrahydrofuran (10 ml.) with stirring at ~ ~-room temperature. After twenty minutes, the solution is added to a mixture of L-proline (0.6 g.) and N-methyl-morpholine (I g~) in dimethylacetamide (20 ml.) The resulting mixture is stirred overnight at room temperature, çoncentrated ta dryness and the residue dissolved in a mixture of ethyl acetate and lQ% aqueous potassium bisulfate.
The orga~ic layer is separated and dried and concentrated t~ dryness in vac:uo to obtain 1-[3-(triphenylmethylthio)-2-methylpropanoyl~-L-proline Rf: = 0.4 (~ilica gel, Benzene/acetic acid 3:1), Rf 1~0 (Silica gel, Methyl-ethyl-ketone/acetic acid/pyridine/water 14:1:2 ~ HA135b Exarnple 168 1-[3-Mercapto-2-methylpropanoyl)-L-proline 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester ~5 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.).
A~ter one hour storaye at room temperature, the solvents are removed in vacuo and the residue i5 applied to a column of silica gel equilibrated with benzene:acetic acid (75:25) and eluted with the same solvent. The fractions corresponding to the component with Rf 0.40 (TLC silica gel with same system) are pooled and concentrated to dryness to yield l-[3-mercapto-2-methylpropanoyl)-L-proline. Rf 0.62 (silica gel, chloroform/methanol:
acetic acid:water 50:40:10), identical to the compound of Example 34.
Example 169 3-(Tetrahydropyran-2-ylthio)-2-methylpropanoic acid To a solution of 3-mercapto-2-methylprop noi~c acid (2.4 g.) and freshly distillled 2,3-dihydro-4EI-pyrane (1.9 g.) in benzene (60 ml.), boron trifluoride etherate (2.8 g.) is added. After two hours, potassium carbonate (4 g.) is added, the mixture is stirred and filtered. The iltrate is concentrated to dryness to~
yield 3-(tetrahydropyran-2-ylthio)-2-methylpropanoic acid.
Example _ 0 1-~3-(Tetrahydropyran-2-ylthio)-2-methylpropanoyl]-L-proline By substituting 3 (tetrahydropyran-2-ylthio)-2-methylpropanolc acid for the 3-triphenylmethylthio-2-methylpropanoic acid in the procedure of ~xample 167, 1-[3-(tetrahydropyran-2-ylthio)-2-methylpropanoyl]-L-proline HA135b `
is obtained. Rf: 0.$ (Silica gel, Benzene/acetic acid 3:1; Rf: 0.75 (Silica gel, Methyl-ethylketone/Acetic acid/
pyridine/water; 14:1:2:1).
Example 171 1-(3-Mercapto-2-methylpropanoyl~-L-proline A solution of 1-~3-(tetrahydroPyran-2-ylthio)~2-methylpropanoyl)-L-proline (1 g.) in a mixture of methanol (25 ml.) and concentrated hydrochloric acid (25 ml.) is stored at room temperature for 30 minutes. The solvents are removed in vacuo to yield 1-(3-mercapto-2-methyl-propanoyl~-L-proline. ~: 0.35 (silica gel, Benzene/
acetic acid, 3:1), Rf 0.5 (silica gel, Methyl-ethylketone/
acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Example 172 3-Acetamidomethylthio-2-methylp~opanoic acid 3-Mercapto-2-methylpropanoic acid (2.4 g~) and N-hydroxymethylasetamide (1.3 g.) are dissolved in tri~luoroacetic acid and the solution is stored at room temperature for one hour. The trifluoroacetic acid is removed in vacuo and the residue is dried in vacuo over potassium hydroxide to yield 3~acetamidomethylthio-2-methylpropanoic acid.
Example 173 1-[3-(Acetamidomethylthio)-2-methylpxopanoyl]-L-proline By substituting 3~acetamidomethylthio-2-methyl-propanoic acid for the 3-(tetrahydropyran-2-yl hio)-2-methylpropanoic acid in the procedure of Example 170 1-[3-(ace~amido~ethylthio~2---~0--.:
10 ~ 4 HA13Sb methylpropanoyl]-L-proline is obtained. Rf 0.2 (Sllica gel, Benzene/acetic acid 3:1) R 0 3 tSilica gelr Methyl-ethylketon~/acetic acid/pyridine/water 14:1:2 Example 174 1-(3-Mercapto-2-methylpropanoyl ? -L-proline 1-[3-(acetamidomethylthio)-2-methylpropanoyl~-L-proline (1.4 g.) and mercuric acetate (1.93 g.) are dissolved in a mixture of acetic acid (25 ml.) and water (25 ml.).
After one hour stirring on the steam bath, hydrogen sulfide is bubbled through until no more precipitation of~mercuric ~ -sulfide i5 observed. The mixture is filterd, the precipitate is washed with ethanol, and the filtrate is concentrated to dryness in vacuo to ~ield l-(3-mercapto-2-rnethylpropanoyl)-L-proline. Rf: 0.35 ~Silica gel, Benzene/Acetic acid 3:1);
Rf : 0.5 ~Silica gel, Methyl-ethylketone~Acetic acid/
pyridine/water 14:1:2:1) identical to the compound of ~ ~`
Example 34.
Example 175 1-(3-Mercapto-2-methylpropanoyl)-L-proline tert butyl ester To the cold (5 ) solution of 1.2 g. (lO m~ol.) of 3 mercapto-2-methylpropanoic acid and 1.7 g. ~lO mMol.) of L-proline tert. butyl ester in 25 ml. dichloromethane 2.26 g. of dicyclohexylcarbodiimide in 5 ml. dlchloromethane iS added in portions. After 2 hours at room temperature, 5 drops of acetic acid are added, the mixture is filtered and the filtrate èvaporated to an oily residue. This residue is take~ up in 20 ml. of petroleum ether-ethyl acetate (3:1) and applied to a 150 ml. silica gel column prepared in petroleum ether. The fraction eluted with 3~ petroleum ether-ethyl acetate (1:1) contains the product, .
11~18~4 HA135b 1-(3-mercapto-2-methylpropanoyl)-L-proline tert.butyl ester.
This raction (0.6 g.) is dried over P205 in vacuo or 12 hours. Rf 0.6 (Silica gel, Benzene/Acetic acid 3:1), Rf 0.8 (Silica gel, Methyl-ethylketone/acetic acid/pyridine/
water 14:1:2:1).
Example 176 1-(3-Mercapto-2-methylpropanoyl)-L-proline By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline tert. butyl ester for the l-(3-mercaptopropanoyl-L-proline tert.butyl ester in the procedure of Example 18C, 1-(3-mercapto-2 methylpropanoyl)-L-proline is obtained.
R~ 0.35 ~Silica gel, Benzene/acetic acid 3:1), Rf 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/Pyridine/Water 14:1:2:1), identical ~o t~ compo~lod of Ex~rplo 34 :
36~
HA135b The racemic form of ~he linal product in any of the foregoing examples is produced by utilizing the ~L-form of the starting amino acid instead of the L-~orm.
~ imilarly, the D-form of the final products in any of the foregoing examples is produced ~y utiliziny the D-form of the starting amino acid instead of the L-form.
Example 177 .
lO00 ta~lets each containing lO0 mg. bf l-(2-mercaptopropanoyl)-L~proline are produced from the following lO ingredients:
l-(2-Mercaptopropanoyl)-L-prolinelO0 ~.
Corn starch 50 g.
Gela-tin 7-5 g-Avicel (microcrystalline ccllulose) 25~ g-Magnesium stearate ~ 2.5 y.
The l-(2-mercaptopropanoyl)-L-proline and corn starch are admixed with an aqueous solutlon of the gelatin.
The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to ~orm lO00 tablets each containing lO0 mg. of active ingredient.
xampIe 178 By substituting lO0 y. o~ l-(3-mercapto-2-D-methylpropanoyl)-L-proline for the l-(2-mercaptopropanoyl)-L proline in Example 177, 1000 tablets each containing lO0 mg.
of the l-(3-mercapto-2-D-methylpropanoyl-L-proline are produced.
, :; :: : : .
- : . . ...
HA135b Example_ 179 1000 tablets each co~taining 200 mg. of 1-(2-mercaptoacetyl)-L-proline are produced from the following ingredients:
1-(2-Mercaptoacetyl)-L-proline200 g.
Lactose 100 g.
Avicel 150 g.
Corn starch 50 y.
Magnesium stearate 5 g.
The 1-(2-mercaptoacetyl)-~-proline, lac~ose and Avicel are admixed, then blended with the corn starch.
Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 505 mg. tablets each containing 200 mg. of active ingredient. The tablets are coated ~ith a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6.
Example I80 ~ ~
Two piece #1 gelatin capsules each containing 2~0 mg.
of 1-(2-mercaptopropanoyl)-L-proline are filled wlth a mixture of the following ingredients:
1-(2-Mercaptopropanoyl~-L-proline 250 mg.
Magnesium stearate 7~ mg.
USP lactose 193 mg.
Example 181 An injectable solution is produced as follows:
1-(2-Mercaptopropanoyl)-L-prollne500 mg.
Methyl paraben 5 g.
Propyl paraben -L g~
Sodium chloride 25 g.
Wa-Lcr for injec~io~ 5 1.
6~
HAl35b he active substance, preservatives and sodium chloride are dissolved in 3 li~ers of water for injcction and then the volume is hrought up to 5 liters. The solution is filtered through a sterile Eilter and aseptically filled into presterilized vials which are then closed with pre-sterilized rubber closures. Each vial contains 5 ml. of solu~ion in a concentration of lO0 my. of active ingredient per ml. o solution for injection.
Example 182 By substituting lO0 g. oE l,l'-[dithiobis(2-D-methy~l-3-propanoyl)~-bis-L-proline or the l-(2-mercaptopropanoyl)-L-proline in Example 177, lO00 tablets each containing lO0 mg.
of the l,l'-[dithiobisl2-D-methyl-3-propanoyl)]-bis-L
proline are produced.
Each oE the products o~ the examples can be similarly formulated by substi-tuting it for ~he active _ngredlent in ~xamples 177, 179, 180 or 181 :
', ;.~'' . ' , --as-., ~
Preparative thin layer chromatography (silica gel, di-chloromethane/methanol/acetic acid 90:5:5) allows isolation of a clear oil (240 mg.) as -the main fraction. TLC (dichloro-methane/methanol/acetic acid 90:5:5) shows ~his material to be l-(3-acetyl-thio-2-DL-methylpropanoyl)-L-proline corresponding to the product of Example 29B. Rf = 0.35;
(benzene/acetic acid 75:25) Rf = 0.38.
The oil is dissolved in 3 ml. acetonitrile, treated wi-th dicyclohexylamine until the solution is basic, and chilled. A white crystalline solid (106 mg.) m.p. 175-181 , is collected. Crystallization from isopropanol gives l-(3-acetylthio-2-D-methylpropanoyl)-L-proline, dicyclohexylamine salt/ rn.p. 187-188 , identical with this product in Example 29A.
Example 159 l-[Dithiobis-(2-methyl-3~propanoyl)]-bis-L-proline By substituting 3,3'-dithiobis-2-methylpropanoic acid for the 3-ace~tylthio-2-methylpropanoic acid ln the pîO- :
cedure of Example 29B, l-[dithiobis-t2-methyl-3-propanoyl)]-bls-L-proline is obtained.
Exam~le 160 1-(3-Mercapto-2 - methylpropanoyl)-L-proline Zinc dust (10.0 g.) is added to a slurxy of the product of Example 159 (5~0 g.) in 100 ml. of 1 O N
sulf~uric acid and the mixture is stirred at 18 for four hours under a blanket of nitrogen. ~he solution is then filtered, the Zinc washed with wat~r (20 ml.) and the combined filtrates are ~tracted with methylene chloride -75~
HA135b (3 x 75 ml~). The methylene chloride washes are back extracted with water (25 ml.) and then the organic solution concentrated to an oil. This oil is taken up in ethyl acetate (20 ml.) and filtered. Hexane ~15 ml.) is added to the filtrate and the mixture is stirred for 15 minutes. After this time, an additional volume of hexane (30 ml.) is added and the solution cooled to 5 for 1 hour. The mixture is then fil~ered, and the product is washed with hexane (2 x 10 ml.) and dried to give 4.17 g.
of white crystals o~ the product, 1-(3-mercapto-2-methylpropanoyl~-L-proline. TLC, Rf = 0.60 ~Solvent system: benzene/acetic acid 75:25).
Example 161 3-Benzylthio-2-methylpropanoic acid By substituting a-toluenethiol for p-methoxy a-toluenethiol in the procedure of Example 149, 3~benzylthio-2-methylpropanoiC acid is obtained.
Example 162 1-[3-(Benz~lthio)-2-methylpropanoyl]-L-proline tert.
bu-tyl ester By sub~ti-tuting 3-benzylthio-2-methylpropanoic ~`
acid for the 3-[(4-methoxyphenyl)methylthio]-2-methyl-propanoic acid in the procedure of Example 150, 1-[3-:
~benzylthio)-2-methylpropanoyl]-L-proline tert. butyl ester is obtained.
Example 163 1=[3-(Benzylthio)-2-methylpropanoylJ-~-proline 1-[3-(benzylthio)i-2-methylpropanoyl]-~-proline tert. butyl ester (7.8 g.) is dissolved in a mixture of anisole (55 ml.) and trif:luoroacetic acid (110 ml.~. Afier HA135b one hour storage at room temperature, the solvent is removed in vacuo and the residue is dissolved in ether, washed several times with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness in vacuo to yield 1-~3-(benzylthio)-2-methylpropanoyl}-L-proline.
Rf 0.5 (Silica gel~ Benzene/acetic acid 3:1) Rf 0.5.
(Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Example 164 1-(3-Mercapto-2-methylpropanoyl)-L-proline 1-[3-(benzylthio)-2-methylpropanoyl]-L-proline (0.1 g.) is suspended in boiling liquid ammonia (10 ml.) and small pieces of sodium are added with stirring until persistent blue color. The color is discharged with a few crystals of ammonium sulfate and the ammonia is~allowed to evaporate under a current of nitrogen. The residue is dissolved in a mixture of dilute hydrochloric acid and ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to yield l-(3-mercapto-2-methylpropanoyl)-L-proline. R~: 0.35 (Silica gel; Benzene/acetic acid 3!1), Rf 0.5 (Sillca gel; Methyl-ethylketone/acetic acld~ -pyridine/water ~ 2:1? identical to the compound of Example 34.
Example 165 3-Triphenylmethylthio-2-methylpropanoic acid A solution of 3-mercapto-2-methylpropanoic acld (1.2 g.)~and tritylchloride (2.9 g.) in me~hylene chloride (50 ml.) is kept at room temperature for 2 hours.
~The mixture is warmed in a steam bath for 20 minutes and then evaporated to dryness in vacuo and -he residue is d1ssolved HA135b in saturated aqueous sodium bicarbonate and the solution is washed with ethyl acetate. The aqueous phase is acidified to pH 3 and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to give 3-triphenylmethylthio-2-methylpropanoic acid. ~f 0.8 (Silica gel, BenzeneJace-tic acid 3:1).
Example 166 1-[3-(Triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester By substituting 3-triphenylmethylthio-2-methyl-propanoic acid ~or the 3-[(4-methoxyphenyl)methylthio]-2-methylpropanoic acid in the procedure of Example 150, 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester is obtained.
Example 167 1-[3-(Triphenylmethylthio)-2-methylpropanoyl]-L-proline 3-Triphenylmethylthlo-2-methylpropanoic acid (1.8 g.) and N,N'-carbonyldiimidazole t0.8 g.) are~
dissolved in tetrahydrofuran (10 ml.) with stirring at ~ ~-room temperature. After twenty minutes, the solution is added to a mixture of L-proline (0.6 g.) and N-methyl-morpholine (I g~) in dimethylacetamide (20 ml.) The resulting mixture is stirred overnight at room temperature, çoncentrated ta dryness and the residue dissolved in a mixture of ethyl acetate and lQ% aqueous potassium bisulfate.
The orga~ic layer is separated and dried and concentrated t~ dryness in vac:uo to obtain 1-[3-(triphenylmethylthio)-2-methylpropanoyl~-L-proline Rf: = 0.4 (~ilica gel, Benzene/acetic acid 3:1), Rf 1~0 (Silica gel, Methyl-ethyl-ketone/acetic acid/pyridine/water 14:1:2 ~ HA135b Exarnple 168 1-[3-Mercapto-2-methylpropanoyl)-L-proline 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester ~5 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.).
A~ter one hour storaye at room temperature, the solvents are removed in vacuo and the residue i5 applied to a column of silica gel equilibrated with benzene:acetic acid (75:25) and eluted with the same solvent. The fractions corresponding to the component with Rf 0.40 (TLC silica gel with same system) are pooled and concentrated to dryness to yield l-[3-mercapto-2-methylpropanoyl)-L-proline. Rf 0.62 (silica gel, chloroform/methanol:
acetic acid:water 50:40:10), identical to the compound of Example 34.
Example 169 3-(Tetrahydropyran-2-ylthio)-2-methylpropanoic acid To a solution of 3-mercapto-2-methylprop noi~c acid (2.4 g.) and freshly distillled 2,3-dihydro-4EI-pyrane (1.9 g.) in benzene (60 ml.), boron trifluoride etherate (2.8 g.) is added. After two hours, potassium carbonate (4 g.) is added, the mixture is stirred and filtered. The iltrate is concentrated to dryness to~
yield 3-(tetrahydropyran-2-ylthio)-2-methylpropanoic acid.
Example _ 0 1-~3-(Tetrahydropyran-2-ylthio)-2-methylpropanoyl]-L-proline By substituting 3 (tetrahydropyran-2-ylthio)-2-methylpropanolc acid for the 3-triphenylmethylthio-2-methylpropanoic acid in the procedure of ~xample 167, 1-[3-(tetrahydropyran-2-ylthio)-2-methylpropanoyl]-L-proline HA135b `
is obtained. Rf: 0.$ (Silica gel, Benzene/acetic acid 3:1; Rf: 0.75 (Silica gel, Methyl-ethylketone/Acetic acid/
pyridine/water; 14:1:2:1).
Example 171 1-(3-Mercapto-2-methylpropanoyl~-L-proline A solution of 1-~3-(tetrahydroPyran-2-ylthio)~2-methylpropanoyl)-L-proline (1 g.) in a mixture of methanol (25 ml.) and concentrated hydrochloric acid (25 ml.) is stored at room temperature for 30 minutes. The solvents are removed in vacuo to yield 1-(3-mercapto-2-methyl-propanoyl~-L-proline. ~: 0.35 (silica gel, Benzene/
acetic acid, 3:1), Rf 0.5 (silica gel, Methyl-ethylketone/
acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Example 172 3-Acetamidomethylthio-2-methylp~opanoic acid 3-Mercapto-2-methylpropanoic acid (2.4 g~) and N-hydroxymethylasetamide (1.3 g.) are dissolved in tri~luoroacetic acid and the solution is stored at room temperature for one hour. The trifluoroacetic acid is removed in vacuo and the residue is dried in vacuo over potassium hydroxide to yield 3~acetamidomethylthio-2-methylpropanoic acid.
Example 173 1-[3-(Acetamidomethylthio)-2-methylpxopanoyl]-L-proline By substituting 3~acetamidomethylthio-2-methyl-propanoic acid for the 3-(tetrahydropyran-2-yl hio)-2-methylpropanoic acid in the procedure of Example 170 1-[3-(ace~amido~ethylthio~2---~0--.:
10 ~ 4 HA13Sb methylpropanoyl]-L-proline is obtained. Rf 0.2 (Sllica gel, Benzene/acetic acid 3:1) R 0 3 tSilica gelr Methyl-ethylketon~/acetic acid/pyridine/water 14:1:2 Example 174 1-(3-Mercapto-2-methylpropanoyl ? -L-proline 1-[3-(acetamidomethylthio)-2-methylpropanoyl~-L-proline (1.4 g.) and mercuric acetate (1.93 g.) are dissolved in a mixture of acetic acid (25 ml.) and water (25 ml.).
After one hour stirring on the steam bath, hydrogen sulfide is bubbled through until no more precipitation of~mercuric ~ -sulfide i5 observed. The mixture is filterd, the precipitate is washed with ethanol, and the filtrate is concentrated to dryness in vacuo to ~ield l-(3-mercapto-2-rnethylpropanoyl)-L-proline. Rf: 0.35 ~Silica gel, Benzene/Acetic acid 3:1);
Rf : 0.5 ~Silica gel, Methyl-ethylketone~Acetic acid/
pyridine/water 14:1:2:1) identical to the compound of ~ ~`
Example 34.
Example 175 1-(3-Mercapto-2-methylpropanoyl)-L-proline tert butyl ester To the cold (5 ) solution of 1.2 g. (lO m~ol.) of 3 mercapto-2-methylpropanoic acid and 1.7 g. ~lO mMol.) of L-proline tert. butyl ester in 25 ml. dichloromethane 2.26 g. of dicyclohexylcarbodiimide in 5 ml. dlchloromethane iS added in portions. After 2 hours at room temperature, 5 drops of acetic acid are added, the mixture is filtered and the filtrate èvaporated to an oily residue. This residue is take~ up in 20 ml. of petroleum ether-ethyl acetate (3:1) and applied to a 150 ml. silica gel column prepared in petroleum ether. The fraction eluted with 3~ petroleum ether-ethyl acetate (1:1) contains the product, .
11~18~4 HA135b 1-(3-mercapto-2-methylpropanoyl)-L-proline tert.butyl ester.
This raction (0.6 g.) is dried over P205 in vacuo or 12 hours. Rf 0.6 (Silica gel, Benzene/Acetic acid 3:1), Rf 0.8 (Silica gel, Methyl-ethylketone/acetic acid/pyridine/
water 14:1:2:1).
Example 176 1-(3-Mercapto-2-methylpropanoyl)-L-proline By substituting 1-(3-mercapto-2-methylpropanoyl)-L-proline tert. butyl ester for the l-(3-mercaptopropanoyl-L-proline tert.butyl ester in the procedure of Example 18C, 1-(3-mercapto-2 methylpropanoyl)-L-proline is obtained.
R~ 0.35 ~Silica gel, Benzene/acetic acid 3:1), Rf 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/Pyridine/Water 14:1:2:1), identical ~o t~ compo~lod of Ex~rplo 34 :
36~
HA135b The racemic form of ~he linal product in any of the foregoing examples is produced by utilizing the ~L-form of the starting amino acid instead of the L-~orm.
~ imilarly, the D-form of the final products in any of the foregoing examples is produced ~y utiliziny the D-form of the starting amino acid instead of the L-form.
Example 177 .
lO00 ta~lets each containing lO0 mg. bf l-(2-mercaptopropanoyl)-L~proline are produced from the following lO ingredients:
l-(2-Mercaptopropanoyl)-L-prolinelO0 ~.
Corn starch 50 g.
Gela-tin 7-5 g-Avicel (microcrystalline ccllulose) 25~ g-Magnesium stearate ~ 2.5 y.
The l-(2-mercaptopropanoyl)-L-proline and corn starch are admixed with an aqueous solutlon of the gelatin.
The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with the granulation. This is then compressed in a tablet to ~orm lO00 tablets each containing lO0 mg. of active ingredient.
xampIe 178 By substituting lO0 y. o~ l-(3-mercapto-2-D-methylpropanoyl)-L-proline for the l-(2-mercaptopropanoyl)-L proline in Example 177, 1000 tablets each containing lO0 mg.
of the l-(3-mercapto-2-D-methylpropanoyl-L-proline are produced.
, :; :: : : .
- : . . ...
HA135b Example_ 179 1000 tablets each co~taining 200 mg. of 1-(2-mercaptoacetyl)-L-proline are produced from the following ingredients:
1-(2-Mercaptoacetyl)-L-proline200 g.
Lactose 100 g.
Avicel 150 g.
Corn starch 50 y.
Magnesium stearate 5 g.
The 1-(2-mercaptoacetyl)-~-proline, lac~ose and Avicel are admixed, then blended with the corn starch.
Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 505 mg. tablets each containing 200 mg. of active ingredient. The tablets are coated ~ith a solution of Methocel E 15 (methyl cellulose) including as a color a lake containing yellow #6.
Example I80 ~ ~
Two piece #1 gelatin capsules each containing 2~0 mg.
of 1-(2-mercaptopropanoyl)-L-proline are filled wlth a mixture of the following ingredients:
1-(2-Mercaptopropanoyl~-L-proline 250 mg.
Magnesium stearate 7~ mg.
USP lactose 193 mg.
Example 181 An injectable solution is produced as follows:
1-(2-Mercaptopropanoyl)-L-prollne500 mg.
Methyl paraben 5 g.
Propyl paraben -L g~
Sodium chloride 25 g.
Wa-Lcr for injec~io~ 5 1.
6~
HAl35b he active substance, preservatives and sodium chloride are dissolved in 3 li~ers of water for injcction and then the volume is hrought up to 5 liters. The solution is filtered through a sterile Eilter and aseptically filled into presterilized vials which are then closed with pre-sterilized rubber closures. Each vial contains 5 ml. of solu~ion in a concentration of lO0 my. of active ingredient per ml. o solution for injection.
Example 182 By substituting lO0 g. oE l,l'-[dithiobis(2-D-methy~l-3-propanoyl)~-bis-L-proline or the l-(2-mercaptopropanoyl)-L-proline in Example 177, lO00 tablets each containing lO0 mg.
of the l,l'-[dithiobisl2-D-methyl-3-propanoyl)]-bis-L
proline are produced.
Each oE the products o~ the examples can be similarly formulated by substi-tuting it for ~he active _ngredlent in ~xamples 177, 179, 180 or 181 :
', ;.~'' . ' , --as-., ~
Claims (54)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the formula wherein R is hydroxy, NH2 or lower alkoxy; R1 and R4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; R2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoylamidomethyl, R5-?-, R5-M-?-, R5-NH-?- or R6-S-; R3 is hydrogen, hydroxy or lower alkyl; R5 is lower alkyl, phenyl or phenyl-lower alkyl; R6 is lower alkyl, phenyl, substituted phenyl, wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, hydroxy-lower alkyl or amino(carboxy)lower alkyl; M is O or S; m is 1, 2 or 3;
n and p each is 0, 1 or 2; and basic salts thereof, characterized by acylating a compound of the formula with an acid of the formula or its chemical equivalent.
n and p each is 0, 1 or 2; and basic salts thereof, characterized by acylating a compound of the formula with an acid of the formula or its chemical equivalent.
2. A process according to claim 1 wherein a compound of the formula is acylated with a mercaptoalkanoic acid of the formula to form a product of the formula
3. A process according to claim 1 wherein a proline compound of the formula is acylated with an acid of the formula to form a product of the formula
4. A process according to claim 1 wherein a proline compound of the formula in the L-form is acylated with an acid of the formula to form a product of the formula wherein the proline moiety is in the L-form.
5. A process according to claim 1 wherein a proline compound of the formula in the L-form is acylated with an acid of the formula or its chemical equivalent to form a product of the formula wherein the proline moiety is in the L-form.
6. A process according to claim 1 wherein a proline compound of the formula in the L-form is acylated with an acid of the formula wherein R1 is C1-C4 alkyl to form a product of the formula wherein R1 is C1-C4 alkyl and the proline moiety is in the L-form.
7. A process according to claim 1 wherein a proline compound of the formula in the L-form is acylated with a mercaptoalkanoic acid of the formula to form a product wherein the proline moiety is in the L-form.
8. A process according to claim 1 wherein L-proline-t-butyl ester is reacted with 3-acetylthiopropionic acid to form 1-(3-acetylthiopropanoyl)-L-proline-t-butyl ester.
9. A process according to claim 1 wherein L-proline-t-butyl ester is reacted with 3-acetylthio-2-methylpropanoic acid to form 1-(3-acetylthio-2-methyl-propanoyl)-L-proline-t-butyl ester.
10. A process according to claim 1 wherein L-proline is reacted with 3-acetylthio-2-D-methyl-propanoic acid to form 1-(3-acetylthio-2-D-methyl-propanoyl)-L-proline.
11. A process according to claim 1 wherein L-proline-t-butyl ester is reacted with 3-methylaminocarbonylthio-propionic acid to form 1-[3-[[(methylamino)thiocarbonyl]-thio]propanoyl]-L-proline-t-butyl ester.
12. A process according to claim 1 wherein L-proline is reacted with 3-methylthiopropanoic acid chloride to form 1-(3-methylthiopropanoyl) L-proline.
13. A process according to claim 1 wherein L-proline is reacted with methylthioacetic acid chloride to form 1-(methylthioacetyl)-L-proline.
14. A process according to claim 1 wherein L-proline is reacted with benzylthioacetyl chloride to form 1-(benzylthioacetyl)-L-proline.
15. A process according to claim 1 wherein pipecolic acid is reacted with 3-acetylthiopropanoyl chloride to form 1-[3-(acetylthio)propanoyl]pipecolic acid.
16. A process according to claim 1 wherein pipecolic acid is reacted with 3-acetylthio-2-methyl-propanoyl chloride to form 1-[3-(acetylthio)-2-methylpropanoyl)-pipecolic acid.
17. A process according to claim 1 wherein L-proline-t-butyl ester is reacted with 3-[(4-methoxyphenyl)methylthio-2-methylpropanoic acid to form 1-[3-(4-methoxyphenyl)-methylthio]-2-methylpropanoyl-L-prollne-t-butyl ester.
18. A process according to claim 1 wherein L-proline-t-butyl ester is reacted with 3-mercaptopropanoic acid to form 1-(3-mercaptopropanoyl)-L-proline-t-butyl ester.
19. A process according to claim 1 wherein L-proline-t-butyl ester is reacted with 3-triphenylmethylthio-2-methyl-propanoic acid to form 1-[3-(triphenylmethylthio)-2-methyl-propanoyl]-L-proline-t-butyl ester.
20. A process according to claim 1 wherein L-proline is reacted with 3-acetamidomethylthio-2-methylpropanoic acid to form 1-[3-(acetamidomethylthio)-2-methylpropanoyl]-L-proline.
21. A process according to claim 1 wherein L-proline is acylated with 3-acetylthio-2-methyl-propanoic acid or its chemical equivalent to form 1-(3-acetylthio-2-methyl-propanoyl)-L-proline.
22. A process according to claim 1 wherein L-proline is acylated with 4-benzoylthiobutanoic acid or its chemical equivalent to form 1-(4-benzoylthiobutanoyl)-L-proline.
23. A process according to claim 1 wherein pipecolic acid is reacted with 3-acetylthiopropionic acid or its chemical equivalent to form 1-[3-(acetylthio)propanoyl]-pipecolic.
24. A process according to claim 1 wherein pipecolic acid is reacted with 3-acetylthio-2-methylpropionic acid or its chemical equivalent to form 1-(3-acetylthio-2 methylpropanoyl)pipecolic acid.
25. A process according to claim 1 wherein L-proline is reacted with 3-[(4-methoxyphenyl)methylthio]-2-methyl-propanoic acid or its chemical equivalent to form 1-[3-(4-methoxyphenyl)methylthio]-2-methylpropanoyl-L-proline.
26. A process according to claim 1 wherein L-proline is acylated with 3-benzylthio-2-methylpropanoic acid or its chemical equivalent to form 1-[3-(benzylthio)-2-methylpropanoyl]-L-proline.
27. A process according to claim 1 wherein L-proline is acylated with 3-triphenylmethylthio-2-methylpropanoic acid or its chemical equivalent to form 1-[3-(triphenyl-methylthio)-2-methylpropanoyl]-L-proline.
28. A compound of the formula wherein R is hydroxy, NH2 or lower alkoxy; R1 and R4 each is hydrogen, lower alkyl, phenyl or phenyl-lower alkyl; R2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoylamidomethyl, R5-?-, R5-M-?-, R5-NH-?- or R6-S-; R3 is hydrogen, hydroxy or lower alkyl; R5 is lower alkyl, phenyl or phenyl-lower alkyl; R6 is lower alkyl, phenyl, substituted phenyl, wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, hydroxy-lower alkyl or amino(carboxy)lower alkyl; M is O or S; m is 1, 2 or 3;
n and p each is 0, 1 or 2; and basic salts thereof, whenever prepared by the process of claim 1.
n and p each is 0, 1 or 2; and basic salts thereof, whenever prepared by the process of claim 1.
29. A compound as in claim 28 having the formula whenever prepared by the process of claim 2.
30. A compound as in claim 28 having the formula whenever prepared by the process of claim 3.
31. A compound as in claim 28 having the formula wherein the proline moiety is in the L-form, whenever prepared by the process of claim 4.
32. A compound as in claim 28 having the formula wherein the proline moiety is in the L-form, whenever prepared by the process of claim 5.
33. A compound as in claim 28 having the formula wherein R1 is C1-C4 alkyl and the proline moiety is in the L-form, whenever prepared by the process of claim 6.
34. A compound as in claim 28 having the formula wherein the proline moiety is in the L-form, whenever prepared by the process of claim 7.
35. A compound as in claim 28 having the name 1-(3-acetylthiopropanoyl)-L-proline-t-butyl ester, whenever prepared by the process of claim 8.
36. A compound as in claim 28 having the name 1-(3-acetylthio-2-methyl-propanoyl-L-proline-t-butyl ester, whenever prepared by the process of claim 9.
37. A compound as in claim 28 having the name 1-(3-acetylthio-2-D-methyl-propanoyl)-L-proline, whenever prepared by the process of claim 10.
38. A compound as in claim 28 having the name 1-(3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline-t-butyl ester, whenever prepared by the process of claim 11.
39. A compound as in claim 28 having the name 1-(3-methylthiopropanoyl)-L-proline, whenever prepared by the process of claim 12.
40. A compound as in claim 28 having the name 1-(methylthioacetyl)-L-proline, whenever prepared by the process of claim 13.
41. A compound as in claim 28 having the name 1-(benzylthioacetyl)-L-proline, whenever prepared by the process of claim 14.
42. A compound as in claim 28 having the name 1-[3-(acetylthio)propanoyl]pipecolic acid, whenever prepared by the process of claim 15.
43. A compound as in claim 28 having the name 1-[3-(acetylthio)-2-methylpropanoyl)pipecolic acid, whenever prepared by the process of claim 16.
44. A compound as in claim 28 having the name 1-[3 (4-methoxyphenyl)methylthio]-2-methylpropanoyl-L-pproline-t-butyl ester, whenever prepared by the process of claim 17.
45. A compound as in claim 28 having the name 1-(3-mercaptopropanoyl)-L-proline-t-butyl ester, whenever prepared by the process of claim 18.
46. A compound as in claim 28 having the name 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline-t-butyl ester, whenever prepared by the process of claim 19.
47. A compound as in claim 28 having the name 1-[3-(acetamidomethylthio)-2-methylpropanoyl]-L-proline, whenever prepared by the process of claim 20.
48. A compound as in claim 28 having the name 1-(3-acetylthio-2-methylpropanoyl)-L-proline, whenever prepared by the process of claim 21.
49. A compound as in claim 28 having the name 1-(4-benzoylthiobutanoyl)-L-proline, whenever prepared by the process of claim 22.
50. A compound as in claim 28 having the name 1-(3-acetylthiopropanoyl)pipecolic acid, whenever prepared by the process of claim 23.
51. A compound as in claim 28 having the name 1-(3-acetylthio-2-methylpropanoyl)pipecolic acid, whenever prepared by the process of claim 24.
52. A compound as in claim 28 having the name 1-[3-(4-methoxyphenyl)methylthio]-2-methylpropanoyl]-L-proline, whenever prepared by the process of claim 25.
53. A compound as in claim 23 having the name 1-(3-benzylthio-2-methylpropanoyl)-L-proline, whenever prepared by the process of claim 53.
54. A compound as in claim 28 having the name 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline, whenever prepared by the process of claim 54.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA334,755A CA1102337A (en) | 1976-02-13 | 1979-08-30 | Proline derivatives and related compounds |
| CA349,474A CA1103255A (en) | 1976-02-13 | 1980-04-09 | Proline derivatives and related compounds |
| CA349,475A CA1103256A (en) | 1976-02-13 | 1980-04-09 | Proline derivatives and related compounds |
| CA349,476A CA1103257A (en) | 1976-02-13 | 1980-04-09 | Proline derivatives and related compounds |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/657,792 US4046889A (en) | 1976-02-13 | 1976-02-13 | Azetidine-2-carboxylic acid derivatives |
| US657,792 | 1976-02-13 | ||
| US69843276A | 1976-06-21 | 1976-06-21 | |
| US698,432 | 1976-06-21 | ||
| US751,851 | 1976-12-22 | ||
| US05/751,851 US4105776A (en) | 1976-06-21 | 1976-12-22 | Proline derivatives and related compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1101864A true CA1101864A (en) | 1981-05-26 |
Family
ID=27417986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA270,184A Expired CA1101864A (en) | 1976-02-13 | 1977-01-21 | Proline derivatives and related compounds |
Country Status (31)
| Country | Link |
|---|---|
| JP (1) | JPS604815B2 (en) |
| AR (4) | AR222445A1 (en) |
| AT (1) | AT365569B (en) |
| AU (1) | AU509899B2 (en) |
| BG (3) | BG37075A3 (en) |
| CA (1) | CA1101864A (en) |
| CH (3) | CH622503A5 (en) |
| DD (1) | DD129442B3 (en) |
| DE (2) | DE2703828C2 (en) |
| DK (1) | DK157487C (en) |
| ES (5) | ES455803A1 (en) |
| FI (1) | FI66596C (en) |
| FR (1) | FR2340932A1 (en) |
| GB (1) | GB1576161A (en) |
| GR (1) | GR69811B (en) |
| HK (1) | HK20281A (en) |
| HU (1) | HU181965B (en) |
| IE (1) | IE44707B1 (en) |
| IL (1) | IL51297A (en) |
| IT (1) | IT1062293B (en) |
| KE (1) | KE3136A (en) |
| MY (2) | MY8200075A (en) |
| NL (1) | NL168509C (en) |
| NO (1) | NO146985C (en) |
| NZ (1) | NZ183130A (en) |
| PH (1) | PH12970A (en) |
| PL (1) | PL118161B1 (en) |
| RO (1) | RO69941A (en) |
| SE (2) | SE423812B (en) |
| SU (1) | SU747422A3 (en) |
| YU (1) | YU40664B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100361971C (en) * | 2005-09-19 | 2008-01-16 | 华中师范大学 | Double functional group L-proline derivative with adjustable catalytic activity and its prepn |
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| US4206122A (en) * | 1978-04-14 | 1980-06-03 | E. R. Squibb & Sons, Inc. | Derivatives of pyrrolidinecarboxaldehyde and piperidinecarboxaldehyde and intermediates therefor |
| US4053651A (en) | 1976-05-10 | 1977-10-11 | E. R. Squibb & Sons, Inc. | Compounds and method for alleviating angiotensin related hypertension |
| AU518147B2 (en) * | 1976-12-03 | 1981-09-17 | E.R. Squibb & Sons, Inc. | Derivatives of thiazolidine, thiazine and morpholine carboxylic acids |
| US4129566A (en) * | 1978-02-15 | 1978-12-12 | E. R. Squibb & Sons, Inc. | Derivatives of dehydrocyclicimino acids |
| US4113715A (en) * | 1977-01-17 | 1978-09-12 | E. R. Squibb & Sons, Inc. | Amino acid derivatives |
| FR2412537A1 (en) * | 1977-12-22 | 1979-07-20 | Science Union & Cie | NEW SUBSTITUTE THIOBUTYRAMIDES, THEIR METHODS OF OBTAINING AND THEIR PHARMACEUTICAL APPLICATION |
| CA1120400A (en) * | 1977-12-27 | 1982-03-23 | Zola P. Horovitz | Method of treating hypertension and medicaments therefor |
| PH15381A (en) * | 1978-02-21 | 1982-12-17 | Squibb & Sons Inc | Halogen substituted mercaptoacylamino acids |
| JPS559058A (en) * | 1978-07-06 | 1980-01-22 | Dainippon Pharmaceut Co Ltd | 1-(3-mercapto-2-methylpropanoyl)prolyl amino acid derivative |
| CA1109475A (en) * | 1978-07-27 | 1981-09-22 | Miguel A. Ondetti | Thiopropanoylamino acid derivatives |
| CA1144930A (en) * | 1978-08-11 | 1983-04-19 | Miguel A. Ondetti | Mercaptoacyl derivatives of substituted prolines |
| NZ190995A (en) * | 1978-09-05 | 1982-03-09 | American Cyanamid Co | Substituted omega propionyl or butyryl l-prolines and pharmaceutical compositions |
| NL7809120A (en) * | 1978-09-07 | 1980-03-11 | Oce Andeno B V Grubbenvorsterw | PROCESS FOR THE PREPARATION OF PROLINE DERIVATIVES. |
| NL7809121A (en) * | 1978-09-07 | 1980-03-11 | Oce Andeno B V Grubbenvorsterw | OPTICALLY ACTIVE DERIVATIVES OF MERCAPTO-ISO BUTIC ACID. |
| GR73585B (en) * | 1978-09-11 | 1984-03-26 | Univ Miami | |
| US4690937A (en) * | 1979-08-14 | 1987-09-01 | University Of Miami | Anti-hypertensive agents |
| ZA794723B (en) * | 1978-09-11 | 1980-08-27 | Univ Miami | Anti-hypertensive agents |
| JPS5540622A (en) * | 1978-09-14 | 1980-03-22 | Santen Pharmaceut Co Ltd | Hypotensive agent |
| US4483861A (en) * | 1978-10-31 | 1984-11-20 | Santen Pharmaceutical Co., Ltd. | Antihypertensive sulfur-containing compounds |
| US4198515A (en) * | 1978-12-08 | 1980-04-15 | E. R. Squibb & Sons, Inc. | Mercaptoacyl derivatives of 4,5-dihydro-1H-pyrrole-2-carboxylic acids and 1,4,5,6-tetrahydropyridine-2-carboxylic acids |
| US4347371A (en) * | 1978-12-30 | 1982-08-31 | Santen Pharmaceutical Co., Ltd. | Disulfide compounds |
| US4410542A (en) | 1978-12-30 | 1983-10-18 | Santen Pharmaceutical Co., Ltd. | Disulfide compounds |
| CA1138452A (en) * | 1979-01-15 | 1982-12-28 | John Krapcho | Carbamate derivatives of mercaptoacyl hydroxy prolines |
| US4461896A (en) * | 1979-02-07 | 1984-07-24 | Norwich Eaton Pharmaceuticals, Inc. | 1-[Acylthio) and (mercapto)-1-oxoalkyl]-1,2,3,4-tetrahydroquinoline-2-carboxylic acids |
| US4220791A (en) * | 1979-03-08 | 1980-09-02 | E. R. Squibb & Sons, Inc. | Mercaptoacylpyrazolidinone carboxylic acid derivatives |
| ZA802420B (en) * | 1979-05-18 | 1981-04-29 | Squibb & Sons Inc | Aminoacyl derivatives of mercaptoacyl amino acids |
| US4234489A (en) * | 1979-06-25 | 1980-11-18 | E. R. Squibb & Sons, Inc. | Pyroglutamic acid derivatives and analogs |
| JPS5629403U (en) * | 1979-08-13 | 1981-03-20 | ||
| DE2937779A1 (en) * | 1979-09-19 | 1981-04-09 | Hoechst Ag, 6000 Frankfurt | AMINO ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| GB2066240A (en) * | 1979-12-10 | 1981-07-08 | Squibb & Sons Inc | Derivatives of mercaptoacyl amino acids |
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| CA946836A (en) * | 1970-03-18 | 1974-05-07 | Miguel A. Ondetti | Enzyme inhibitor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100361971C (en) * | 2005-09-19 | 2008-01-16 | 华中师范大学 | Double functional group L-proline derivative with adjustable catalytic activity and its prepn |
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