CA1266661A - Acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl l-prolines - Google Patents
Acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl l-prolinesInfo
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- CA1266661A CA1266661A CA000452213A CA452213A CA1266661A CA 1266661 A CA1266661 A CA 1266661A CA 000452213 A CA000452213 A CA 000452213A CA 452213 A CA452213 A CA 452213A CA 1266661 A CA1266661 A CA 1266661A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
ABSTRACT
ACYLMERCAPTOALKANOYL AND MERCAPTOALKANOYL
DERIVATIVES OF ARYL AND ARALKYL SULFINYL
OR SULFONYL L- PROLINES
This invention provides new acyl mercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl prolines of the formula
ACYLMERCAPTOALKANOYL AND MERCAPTOALKANOYL
DERIVATIVES OF ARYL AND ARALKYL SULFINYL
OR SULFONYL L- PROLINES
This invention provides new acyl mercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl prolines of the formula
Description
6~
~ A285 ACYLMERCAPTOALKANOYL AND MERCAPT~ALKANOYL
DERIVATIVES OF AR~L AMD ARALKYL SULFINYL
OR SULFONYL L-PROLINES
This invention relates to new acylmercaptoalkanoyl cm d mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl prolines of the formula (I) ()n S--(C~2)m-R
11 r R4-S-CH2-C~- C N _ - COOR
H
and pharmaceutically acceptable salts thereof.
R is hydrogen, lower alkyl, or a ;~ salt forming ion.
n is one or two.
m is zero or an integer from 1 to 4.
Rl is ~ , a 1- or 2~naphthyl Z0 of the formuIa ~ or biphenyl.
R2 is hydrogen, lower alkyI of 1 to 4 car~ons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl,~acetyloxy~ or ~ hydroxy. The hydroxy substituted compounds are ;~ obtained by hydrolysis of the corresponding acetyloxy compound as the last step in the synthetic procedure.
R3 is hydrogen, lower alkyl, or ; 30 ~ trifluoromethyl. ~
?
3 ~
:" ' :: ~ ''': : .. ` ;':: : :
6;66~
1~
R4 is hydrogen or R5-C- .
R5 is lower alkyl, -(CH2)p ~ , -(CH2) ~ CH2) ~ , or . .
- (CH2)~) ' p is zero or an integer from 1 to 4.
: 15 This invention in its broadest aspects :~ relates to the substituted proline compounds ~; of formula I above, to compositions containing :~ such compounds and to the method of using j such compounds as anti-hy~ertensive agents.
:The term lower alkyl represents straight or ~ branched chain hydrocarbon radicals having up to -~ ; ; : seven carbons, for exampie, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,;~hexyl, heptyl, etc. The preerred lower~
alkyl groups are up~to four carbons with methyl : and ethyl being most preferred. Similarly, the term lower alkoxy represents such lower alkyl groups bonded to an o~ygen. ~ ~ :
6~6~
~A285 The symbols -(CH~)p~ ~ , ( 2)Pt .
an~ -t~2)p ~ represent that the alkylene ~ridge is attached to an availahle car~on atom.
: ' Ondetti et al. in U.S. Patent 4,105,776 disclose that various acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of proline, hydroxy substituted proline, and alkyl substituted proline possess angiotensin converting enzyme inhibition activity and thus are useful as anti-hypertension agents.
Ondetti et al. in U.S. Patent 4,316,906 discloses that various acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of various ether and thioether 3- or 4-substituted prolines also possess angiotensin converting enzyme inhibition -~ activity. Among the compounds disclosed by Ondetti et al. are arylthio and aralkylthio 4-substituted prolines.
; : ~
: ~
.~ :
. . ' ' ~ ,., '' .' " ' ' , , ' '" ~ ~' '''' ' ' .
~`~' ' ' . ' ' ' ' ' '' " ' ~Z~i~66~
The compounds of formuIa I can be prepared as follows. The 4-substituted proline of the formula tII~ ~
.
~ ( 2)m Rl HN - - COOR
i (L) : H
: 15 is coupled with an acid or its chemical equivalent ; of the formuIa : O R
:~l 20 R5-C-CH2-CH-COOH
~.
to yield the compound o~ the formula :
~:~ 25 : : :
~:
:
, , -, :: . . . . .
- ~;
i66~
(IV) (C 2)m R
O R O ,~
Il l3 ll l l R5-C-CH2-CH - C - N t COOR
(L) H
This reaction can be performed in the presence of a coupling agent such as dicyclohexyl-carbodiimide or~the like, or by conversion o~ the acid of formula III to its mixed anhydride, symmetrical anhydride, acid halide, active ester lS or by use of Woodward reagent K, N-ethoxycarbonyl-
~ A285 ACYLMERCAPTOALKANOYL AND MERCAPT~ALKANOYL
DERIVATIVES OF AR~L AMD ARALKYL SULFINYL
OR SULFONYL L-PROLINES
This invention relates to new acylmercaptoalkanoyl cm d mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl prolines of the formula (I) ()n S--(C~2)m-R
11 r R4-S-CH2-C~- C N _ - COOR
H
and pharmaceutically acceptable salts thereof.
R is hydrogen, lower alkyl, or a ;~ salt forming ion.
n is one or two.
m is zero or an integer from 1 to 4.
Rl is ~ , a 1- or 2~naphthyl Z0 of the formuIa ~ or biphenyl.
R2 is hydrogen, lower alkyI of 1 to 4 car~ons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl,~acetyloxy~ or ~ hydroxy. The hydroxy substituted compounds are ;~ obtained by hydrolysis of the corresponding acetyloxy compound as the last step in the synthetic procedure.
R3 is hydrogen, lower alkyl, or ; 30 ~ trifluoromethyl. ~
?
3 ~
:" ' :: ~ ''': : .. ` ;':: : :
6;66~
1~
R4 is hydrogen or R5-C- .
R5 is lower alkyl, -(CH2)p ~ , -(CH2) ~ CH2) ~ , or . .
- (CH2)~) ' p is zero or an integer from 1 to 4.
: 15 This invention in its broadest aspects :~ relates to the substituted proline compounds ~; of formula I above, to compositions containing :~ such compounds and to the method of using j such compounds as anti-hy~ertensive agents.
:The term lower alkyl represents straight or ~ branched chain hydrocarbon radicals having up to -~ ; ; : seven carbons, for exampie, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,;~hexyl, heptyl, etc. The preerred lower~
alkyl groups are up~to four carbons with methyl : and ethyl being most preferred. Similarly, the term lower alkoxy represents such lower alkyl groups bonded to an o~ygen. ~ ~ :
6~6~
~A285 The symbols -(CH~)p~ ~ , ( 2)Pt .
an~ -t~2)p ~ represent that the alkylene ~ridge is attached to an availahle car~on atom.
: ' Ondetti et al. in U.S. Patent 4,105,776 disclose that various acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of proline, hydroxy substituted proline, and alkyl substituted proline possess angiotensin converting enzyme inhibition activity and thus are useful as anti-hypertension agents.
Ondetti et al. in U.S. Patent 4,316,906 discloses that various acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of various ether and thioether 3- or 4-substituted prolines also possess angiotensin converting enzyme inhibition -~ activity. Among the compounds disclosed by Ondetti et al. are arylthio and aralkylthio 4-substituted prolines.
; : ~
: ~
.~ :
. . ' ' ~ ,., '' .' " ' ' , , ' '" ~ ~' '''' ' ' .
~`~' ' ' . ' ' ' ' ' '' " ' ~Z~i~66~
The compounds of formuIa I can be prepared as follows. The 4-substituted proline of the formula tII~ ~
.
~ ( 2)m Rl HN - - COOR
i (L) : H
: 15 is coupled with an acid or its chemical equivalent ; of the formuIa : O R
:~l 20 R5-C-CH2-CH-COOH
~.
to yield the compound o~ the formula :
~:~ 25 : : :
~:
:
, , -, :: . . . . .
- ~;
i66~
(IV) (C 2)m R
O R O ,~
Il l3 ll l l R5-C-CH2-CH - C - N t COOR
(L) H
This reaction can be performed in the presence of a coupling agent such as dicyclohexyl-carbodiimide or~the like, or by conversion o~ the acid of formula III to its mixed anhydride, symmetrical anhydride, acid halide, active ester lS or by use of Woodward reagent K, N-ethoxycarbonyl-
2-ethoxy-1,2-dihydroquinoline or the like. For a review of the methods of acylation see Methoden der Organishchen Chemie (Houben-Weyl), Vol. XV, part II, page l et seq. (1974). Preferably, the acid halide, especially the acid chloride, of formuIa III is reacted with the acid of . formula II.
Oxidation of the compound of formula IV, for example, with.sodium metaperiodate yields the :; 25 ~ suIfinyl compound of the formula ~26~
(V) O
~ .
S--(CH2)m--R
: 5 f I 1~ f ~
R5-C-S-CH2-C~- C - N ¦(L) H
Similarly, oxidation of the compound of formula IV, for example, with two equivalents of hydrogen p roxide or metachloroperbenzoic acid yields the sulfonyl compound of the formula (VI) : 15 O o ' Z ~ R3 O ~
R5-C-S-CH2-CH - C - N ¦ ~COOR
(L) H
: Hydrolysis or ammonoIysis of the : :25 compounds of formuIa V or VI yields the corresponding sulfinyl or sulfonyl compounds wherein~R4 is hydrogen.
: Also, the sulfinyl and sulfonyl products : of~formula I wherein R4 is hydrogen can be ~
acylated with an acid halide, preferably acid :, ~: :
,:
: . ~
~z~
chloride, o~ the formuIa (VII) O
R5-C-Cl S O
I~
to yield products having other R5-C- groups.
The sulfonyl products of formuIa I can :. al~o be prepared as follows. An N-protected proline of the formula (VIII) : S-(C~ ) -R
2 m . 15 Prot-N - COOR
. (L) H
whesein Prot is a group such as benzyloxycarbonyl, is oxidized, for example, by treatment with hydrogen peroxide or metachloroperbenzoic acid to give the N-protected sulfonyl proline of the formula X) : o o ~ : 25 ~ ~ Q ~
S-(CH2)m-R~ : -Prot-~ ~ COOP
Removal of the N-protecting group by treatment with hydrogen bromide followed by coupling with the acid of formuIa III or its chemical equivalent yields the suIfonyl compound of formuIa VI.
The esters of formuIa I wherein R is lower alkyl can be obtained from the carboxylic acid compounds, i.e., wherein R is hydrogen, by conventional esterification procedure~, e. g., by esterification with a diazoalkane such as diazomethane, l-alkyl-3-p-tolyltriazine such as l-n-butyl-3-p-tolyltriazine, or the like. The esters can also be obtained by treating the acid with an alcohol of the formuIa R-OH in the presence of a Lewis acid such as suIfuric acid, boron trifluoride, etc., at room temperature.
`~ If the compounds of formula I are obtained in the ester form they can be converted to the carboxylic acid by conventional means. For example, if R is t-butyl treatment with trifluoro-acetic acid and anisole gives the carboxylic acid compound, i.e., R is hydrogen.
The compounds of formula I wherein R3 is other than hydrogen contain an asymmetric center.
These compounds ca~ accordingly exist in stereoisomeric forms or as racemic mixtures thereof. The synthesis~ described below can utilize the racemate or one of the enantiomers as starting materials.~ When the racemic starting material is used in the synthesis, the :
~2~
_g ;~ . stereoisomers obtained in the final product can be separated by conventional chromatographic or fractional crystallization procedures.
~: (0)~
S The -S-(CH2?m-Rl substituent on the L-proline ring also gives rise to isomers referred to as a- and ~-.
Preferably, if there is an asymmetric centex in the acylmercaptoalkanoyl or mercapto-alkanoyl sidechain it is in the D-con~iguration.
The compounds of this invention form basic salts with various inorganic and organic bases which are also within the scope of the invention.
Such salts include ammonium saits, alkali metal salts like lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, l-adamantanamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The ~ non-toxic, physiologicaIly acceptable salts are ;~ preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The salts are formed using conventional techniques.
25~ ~ ; Pre~erred compounds of this invention are those of formula I wherein:
R is~hydrogen or an alkali metal ion;
, ~;
~ Rl lS~ wherein R2~is hydrogen, ' , ~. ' '' ' ' .. `, ` ~", ' ' ~ ' ' ' ' " ' ~l2~i6~
. HA285 methyl, methoxy, chloro or fluoro, especially hydrogen;
m is zero, one or two, especially zero;
R3 is methyl; and R4 is hydrogen, 1l or O
"
The compounds of formula I, and the pharmaceutically and physiologically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angio-tensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensin, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the ~; causative~agent in several forms of hypertension ~-- 25 in various mammalian species, e.g., humans. The compounds of this invention intervene in the angiotensin -~ (renin) ~ angiotensin I ~
angiotensin II sequence~by inhibiting angiotensin ~ ~ converting enzyme and reducing or eliminating -t`:~ ~ 3~ the formation o~ the pressor sub~tance angiotensin ., ~ :
. ~
. ;~
~: : : :
~: :
. . ...... . .
, ~ ,: - .~:
.:
II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal (e~g., humans) S suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscuIar, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., pre~erably about 30 to 330 mg. of a com~ound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combi~ation with a compound of this invention are the thiazide diuretlcs, e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydro-flumethiazide, bendroflumethiazide, methyclothia-zide, trichlormethiazide, polythiazide or :
.
. ~ ~ . ~, .; ,:
~ : ~. : -.
: - I : ; :
- ~ :
..
, .
~6~
benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanidq, triamterene, amiloride and spironolactona and salts of such compounds.
The compounds of formula I can be formuIated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. o~ a compound of formuIa I is compounded with physiologicallylacceptable vehicle, carrier, excipient, binder, preservat ve, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention. Temperatures are given in degrees centigrade.
"' :
. , .
.
: :
,:
~:, ~2~6~
~.............. . ..
[1(S?~S];1-~]-~o~-~Lse a~c~5h~ o~Xopro~ 4~
tphenylsul~inyl)-L-pro~ine .
a) [l(S~,4S]-1-[3-(Acetylthio?-2-methyl-1-S oxopropyl]-4-(phe~yls~lfinyl)-L-proline A stirred cooled solution of [l(S),4S]-1-[3-~acetylthio)-2-methyl-1-oxopropyl]-4-(phenyl~hio)-L-proline (2.0 g., 5.4 mmole;
prepared as set forth in Example 58 (d) of U.S. Patent 4,316,90$) in 29 ml. of methanol is treated portionwise with sodium metaperiodate (1.4 g., 6.5 mm~le) dissolved in 12 ml. of water. The materials remain in solution. The cooling bath is removed and after a few minutes lS solid sodium iodate begins to separate. After stirring overnight at room temperature (mixture has darkened to a reddish-orange color), the solid is filtered off, washed with methanol, and the combined filtrates are concentrated on a ; 20 rotary evaporator to~remove the bulk of methanol.The residue is shaken with 80 ml. of ethyl acetate and 20 ml. of water, the layers are separated, and the organic phase is washed with water (2 x 20 ml.). A~ter back-extracting the combined aqueous layers with 20 ml. o~ ethyl acetate, the com~ined organic phases are dried~(MgSO4), flltered, and the solvent evaporated to give 1.~55 g. of a pale~ ye~low brittle foam.
- . ~
~, - , ,, : ;: .: , :, .
~ . :: : -This material is dissolved in 15 ml. of ethyl acetate and treated with 0.8 g. of dicyclo-hexylamine to give 2 ol g~ of colorless ~l(S),4S~-1-~3-(acetylthio)-2-methyl-1-oxopropyl]-4-~phenylsuIfinyl~-L-proline, dicycloh~xylamine salt; m.p. 192-194 (s. 189). [~]D = ~70 (c = 1.0, methanol). This salt is combined with 0.45 g. from a different experiment and crystallized from 25 ml. of boiling isopropanol to give 2.05 g. of dicyclohexylamine salt;
m.p. 198-200 (s. 194) [~]25 71 methanol). A sample recrystallized from ethanol melts at 198-200 (s, 194~.
S = -72 (c = 1.0, methanol).
Anal. calc'd. for C17H21N05S2 C12 23 C, 61.67; H, 7.85; N, 4.96; S, 11.35 Found: C, 61.34; H, 7.78; N, 4.97; S, 11.05.
This dicyclohexylamine salt (1.9 g.) is treated with 30 ml. of 10% potassium bisuIfate and extracted into ethyi acetate to give 1.3 g.
of [l(S),4S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline as a colorless amorphous solid. [~]D = -103 (c = 1.0, ethanol).
An:al. calc'd. for C17H21~O5 2 2 C, 52.02; H, 5.65; N, 3.57; S, 16.34 Found: C, 52.01; H, 5.58; N, 3.67; 5,; 16.07.
`: ^` , :
:~ , , .-. . ` . ,~
~5-b) 51(S),4S]-1-(3-Mercapto-2-me prop~ 4-(phenylsul~inyl)-L-proline The ll-ts),4S]~ 3-(acetylthio)-2-methyl-l-oxopropyl]-4-tphenylsuIfinyl)-L-proline from part (a) (1.3 g., 3.4 mmole) is hydrolyzed by treatment with 2.5 ml. of concentrated ammonia in 6 ml. of wa~er for one hour according to the procedure of Example 2 in U.S. Patent 4,316,906 to yield 1.05 g. of 11(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl)-L-proline as a colorless feathery solid (residue from ethyl acetate is rubbed under ether and evaporation repeated); m.p. 47-50 (s. approxi-mately 37)-[~]D = -67 ~c = 1.0, ethanol). Rf 0.37 (silica gel;dichloromethane/methanol/acetic acid;
90:5:5)-Anal- calc d- for C15H19N4S2 0~5 H2O
C, 51.40; H, 5.75; N, 4.00; S, 18.23 Found: C, 51.75; H, 5.72; N, 4.08; S, 17.89.
Treatment with l-adamantanamine in ethyl ac~tate yields [l(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsuIfinyl)-L-proline, 1-adamantanamine salt; m.p. 193-195 (dec.).
Anal. calc'd. for C15HlgNO4S2 . C10 17 2 C, 60.39; ~, 7.40; ~, 5.64; S, 12.90 Found:~ C, 60.37; H, 7.40; N, 5.67; S, 13.08.
.
, ~ :
::, "~
~;
~: . :
.~ :
, : . . . .
-:~:
.......
~L~ H~285 Examples 2 - 18 Following the procedure of Example 1 the acylmercaptoalkanoyl-4-(arylthio or aralkyl-thio) L-proline shown in Col. 1 is oxidized to the sulfinyl compound shown in Col. II.
Treatment with concentrated ammonia yields the mercaptoalkanoyl compound shown in Col. III.
; Col.
(C 2)m R
O R O
: 1~ 13 ll I
~ (L) : H
.
. . .
Col. II
~, O
, 11 S~(CH2)m~Rl:
l3 ~ h . R5-C-S-CH2-CH - C - N ~ COOH
~ , ~ : :
^ -, ~
, . , -:
- ...
:: : . ,,: . . :
Col. III
S- (,CH2 ) m-Rl 1 3 ~ ~
:..
.
~ ' ::-.; : :
:: :
~: :
j ~ . ~
:~
~2~666~
Ex. Rl m R3 R5 2 ~ zero -CH
Oxidation of the compound of formula IV, for example, with.sodium metaperiodate yields the :; 25 ~ suIfinyl compound of the formula ~26~
(V) O
~ .
S--(CH2)m--R
: 5 f I 1~ f ~
R5-C-S-CH2-C~- C - N ¦(L) H
Similarly, oxidation of the compound of formula IV, for example, with two equivalents of hydrogen p roxide or metachloroperbenzoic acid yields the sulfonyl compound of the formula (VI) : 15 O o ' Z ~ R3 O ~
R5-C-S-CH2-CH - C - N ¦ ~COOR
(L) H
: Hydrolysis or ammonoIysis of the : :25 compounds of formuIa V or VI yields the corresponding sulfinyl or sulfonyl compounds wherein~R4 is hydrogen.
: Also, the sulfinyl and sulfonyl products : of~formula I wherein R4 is hydrogen can be ~
acylated with an acid halide, preferably acid :, ~: :
,:
: . ~
~z~
chloride, o~ the formuIa (VII) O
R5-C-Cl S O
I~
to yield products having other R5-C- groups.
The sulfonyl products of formuIa I can :. al~o be prepared as follows. An N-protected proline of the formula (VIII) : S-(C~ ) -R
2 m . 15 Prot-N - COOR
. (L) H
whesein Prot is a group such as benzyloxycarbonyl, is oxidized, for example, by treatment with hydrogen peroxide or metachloroperbenzoic acid to give the N-protected sulfonyl proline of the formula X) : o o ~ : 25 ~ ~ Q ~
S-(CH2)m-R~ : -Prot-~ ~ COOP
Removal of the N-protecting group by treatment with hydrogen bromide followed by coupling with the acid of formuIa III or its chemical equivalent yields the suIfonyl compound of formuIa VI.
The esters of formuIa I wherein R is lower alkyl can be obtained from the carboxylic acid compounds, i.e., wherein R is hydrogen, by conventional esterification procedure~, e. g., by esterification with a diazoalkane such as diazomethane, l-alkyl-3-p-tolyltriazine such as l-n-butyl-3-p-tolyltriazine, or the like. The esters can also be obtained by treating the acid with an alcohol of the formuIa R-OH in the presence of a Lewis acid such as suIfuric acid, boron trifluoride, etc., at room temperature.
`~ If the compounds of formula I are obtained in the ester form they can be converted to the carboxylic acid by conventional means. For example, if R is t-butyl treatment with trifluoro-acetic acid and anisole gives the carboxylic acid compound, i.e., R is hydrogen.
The compounds of formula I wherein R3 is other than hydrogen contain an asymmetric center.
These compounds ca~ accordingly exist in stereoisomeric forms or as racemic mixtures thereof. The synthesis~ described below can utilize the racemate or one of the enantiomers as starting materials.~ When the racemic starting material is used in the synthesis, the :
~2~
_g ;~ . stereoisomers obtained in the final product can be separated by conventional chromatographic or fractional crystallization procedures.
~: (0)~
S The -S-(CH2?m-Rl substituent on the L-proline ring also gives rise to isomers referred to as a- and ~-.
Preferably, if there is an asymmetric centex in the acylmercaptoalkanoyl or mercapto-alkanoyl sidechain it is in the D-con~iguration.
The compounds of this invention form basic salts with various inorganic and organic bases which are also within the scope of the invention.
Such salts include ammonium saits, alkali metal salts like lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, l-adamantanamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The ~ non-toxic, physiologicaIly acceptable salts are ;~ preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The salts are formed using conventional techniques.
25~ ~ ; Pre~erred compounds of this invention are those of formula I wherein:
R is~hydrogen or an alkali metal ion;
, ~;
~ Rl lS~ wherein R2~is hydrogen, ' , ~. ' '' ' ' .. `, ` ~", ' ' ~ ' ' ' ' " ' ~l2~i6~
. HA285 methyl, methoxy, chloro or fluoro, especially hydrogen;
m is zero, one or two, especially zero;
R3 is methyl; and R4 is hydrogen, 1l or O
"
The compounds of formula I, and the pharmaceutically and physiologically acceptable salts thereof, are hypotensive agents. They inhibit the conversion of the decapeptide angio-tensin I to angiotensin II and, therefore, are useful in reducing or relieving angiotensin related hypertension. The action of the enzyme renin on angiotensin, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to angiotensin II. The latter is an active pressor substance which has been implicated as the ~; causative~agent in several forms of hypertension ~-- 25 in various mammalian species, e.g., humans. The compounds of this invention intervene in the angiotensin -~ (renin) ~ angiotensin I ~
angiotensin II sequence~by inhibiting angiotensin ~ ~ converting enzyme and reducing or eliminating -t`:~ ~ 3~ the formation o~ the pressor sub~tance angiotensin ., ~ :
. ~
. ;~
~: : : :
~: :
. . ...... . .
, ~ ,: - .~:
.:
II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a species of mammal (e~g., humans) S suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg. per kilogram of body weight per day is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscuIar, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of this invention and a diuretic can be administered in an effective amount which comprises a total daily dosage of about 30 to 600 mg., pre~erably about 30 to 330 mg. of a com~ound of this invention, and about 15 to 300 mg., preferably about 15 to 200 mg. of the diuretic, to a mammalian species in need thereof. Exemplary of the diuretics contemplated for use in combi~ation with a compound of this invention are the thiazide diuretlcs, e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydro-flumethiazide, bendroflumethiazide, methyclothia-zide, trichlormethiazide, polythiazide or :
.
. ~ ~ . ~, .; ,:
~ : ~. : -.
: - I : ; :
- ~ :
..
, .
~6~
benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanidq, triamterene, amiloride and spironolactona and salts of such compounds.
The compounds of formula I can be formuIated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg. o~ a compound of formuIa I is compounded with physiologicallylacceptable vehicle, carrier, excipient, binder, preservat ve, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The following examples are illustrative of the invention. Temperatures are given in degrees centigrade.
"' :
. , .
.
: :
,:
~:, ~2~6~
~.............. . ..
[1(S?~S];1-~]-~o~-~Lse a~c~5h~ o~Xopro~ 4~
tphenylsul~inyl)-L-pro~ine .
a) [l(S~,4S]-1-[3-(Acetylthio?-2-methyl-1-S oxopropyl]-4-(phe~yls~lfinyl)-L-proline A stirred cooled solution of [l(S),4S]-1-[3-~acetylthio)-2-methyl-1-oxopropyl]-4-(phenyl~hio)-L-proline (2.0 g., 5.4 mmole;
prepared as set forth in Example 58 (d) of U.S. Patent 4,316,90$) in 29 ml. of methanol is treated portionwise with sodium metaperiodate (1.4 g., 6.5 mm~le) dissolved in 12 ml. of water. The materials remain in solution. The cooling bath is removed and after a few minutes lS solid sodium iodate begins to separate. After stirring overnight at room temperature (mixture has darkened to a reddish-orange color), the solid is filtered off, washed with methanol, and the combined filtrates are concentrated on a ; 20 rotary evaporator to~remove the bulk of methanol.The residue is shaken with 80 ml. of ethyl acetate and 20 ml. of water, the layers are separated, and the organic phase is washed with water (2 x 20 ml.). A~ter back-extracting the combined aqueous layers with 20 ml. o~ ethyl acetate, the com~ined organic phases are dried~(MgSO4), flltered, and the solvent evaporated to give 1.~55 g. of a pale~ ye~low brittle foam.
- . ~
~, - , ,, : ;: .: , :, .
~ . :: : -This material is dissolved in 15 ml. of ethyl acetate and treated with 0.8 g. of dicyclo-hexylamine to give 2 ol g~ of colorless ~l(S),4S~-1-~3-(acetylthio)-2-methyl-1-oxopropyl]-4-~phenylsuIfinyl~-L-proline, dicycloh~xylamine salt; m.p. 192-194 (s. 189). [~]D = ~70 (c = 1.0, methanol). This salt is combined with 0.45 g. from a different experiment and crystallized from 25 ml. of boiling isopropanol to give 2.05 g. of dicyclohexylamine salt;
m.p. 198-200 (s. 194) [~]25 71 methanol). A sample recrystallized from ethanol melts at 198-200 (s, 194~.
S = -72 (c = 1.0, methanol).
Anal. calc'd. for C17H21N05S2 C12 23 C, 61.67; H, 7.85; N, 4.96; S, 11.35 Found: C, 61.34; H, 7.78; N, 4.97; S, 11.05.
This dicyclohexylamine salt (1.9 g.) is treated with 30 ml. of 10% potassium bisuIfate and extracted into ethyi acetate to give 1.3 g.
of [l(S),4S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline as a colorless amorphous solid. [~]D = -103 (c = 1.0, ethanol).
An:al. calc'd. for C17H21~O5 2 2 C, 52.02; H, 5.65; N, 3.57; S, 16.34 Found: C, 52.01; H, 5.58; N, 3.67; 5,; 16.07.
`: ^` , :
:~ , , .-. . ` . ,~
~5-b) 51(S),4S]-1-(3-Mercapto-2-me prop~ 4-(phenylsul~inyl)-L-proline The ll-ts),4S]~ 3-(acetylthio)-2-methyl-l-oxopropyl]-4-tphenylsuIfinyl)-L-proline from part (a) (1.3 g., 3.4 mmole) is hydrolyzed by treatment with 2.5 ml. of concentrated ammonia in 6 ml. of wa~er for one hour according to the procedure of Example 2 in U.S. Patent 4,316,906 to yield 1.05 g. of 11(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl)-L-proline as a colorless feathery solid (residue from ethyl acetate is rubbed under ether and evaporation repeated); m.p. 47-50 (s. approxi-mately 37)-[~]D = -67 ~c = 1.0, ethanol). Rf 0.37 (silica gel;dichloromethane/methanol/acetic acid;
90:5:5)-Anal- calc d- for C15H19N4S2 0~5 H2O
C, 51.40; H, 5.75; N, 4.00; S, 18.23 Found: C, 51.75; H, 5.72; N, 4.08; S, 17.89.
Treatment with l-adamantanamine in ethyl ac~tate yields [l(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsuIfinyl)-L-proline, 1-adamantanamine salt; m.p. 193-195 (dec.).
Anal. calc'd. for C15HlgNO4S2 . C10 17 2 C, 60.39; ~, 7.40; ~, 5.64; S, 12.90 Found:~ C, 60.37; H, 7.40; N, 5.67; S, 13.08.
.
, ~ :
::, "~
~;
~: . :
.~ :
, : . . . .
-:~:
.......
~L~ H~285 Examples 2 - 18 Following the procedure of Example 1 the acylmercaptoalkanoyl-4-(arylthio or aralkyl-thio) L-proline shown in Col. 1 is oxidized to the sulfinyl compound shown in Col. II.
Treatment with concentrated ammonia yields the mercaptoalkanoyl compound shown in Col. III.
; Col.
(C 2)m R
O R O
: 1~ 13 ll I
~ (L) : H
.
. . .
Col. II
~, O
, 11 S~(CH2)m~Rl:
l3 ~ h . R5-C-S-CH2-CH - C - N ~ COOH
~ , ~ : :
^ -, ~
, . , -:
- ...
:: : . ,,: . . :
Col. III
S- (,CH2 ) m-Rl 1 3 ~ ~
:..
.
~ ' ::-.; : :
:: :
~: :
j ~ . ~
:~
~2~666~
Ex. Rl m R3 R5 2 ~ zero -CH
3 ~ Cl zero -C~3 -CH3
4 ~ F zero -CH -C H
~ CH zero 3 3 6 ~ OCH3 zero -CH3 -C~3 ,7 ~ one 33 8 ~ F two -H -CH3 CH3 three -CH3 -CH3 ~ four -CH -CH
1 ~ CF3 zero 3 3 12 ~ o-3-CH3 ero -CH3 -C~3 13 ~ F one -CH3 14 ~ ~ two -CH3(CH
6~
H~285 Ex. Rl m R3 R5 zero -CH3 ~ (CN2) 16 ~ zero -CH3 -C~3 0 17 ~ one -CX
18_~ ~ three -CH3 C~2 ~' Similarly, by employing two equivalents of hydxogen peroxide in place of the sodium metaperiodate in the procedure of Examples 1 to : 18, the corresponding sulfonyl compounds would : : be ohtained.
Example 19 ~' .
[l(S),4S]~ (3-Mercapto-2-methyl-1-oxopropyl)-4-~phenylsu~fonyl)-L-proline .
; a) :N-Carbobenzy~oxy-cis-4-tphenylsul~onyl)-L-proline :~
: 25 :: ~ A:s irred solution of N-car~obenzyloxy-cis-4~(phenylthio)-L-proline (8.2 g., 23;mmole;
: ; prepared as set forth in Example 58 (b)~ of : : : U.S. Patent 4,316,906) in 95 ml. of acetic acid:i~s treated portionwlse with 30~hydrogen :30 ~ peroxide (IS.6 g., 140 mmole). The temperature . HA285 ~0-drops from 26 to 24 then gradually rises to 30. After standing overnight at room temperatuxe, the solution is concentrated to approximately 5~% of its volume on a rotary -~ S evaporator at 0.2 mm. (water bath temperature less than 30). The residue is diluted with 300 ml. of dichloromethane, washed with water (3 x 100 ml.), and after back-extracting the combined washes with 100 ml. of ichloro-10 methane, the combined organic layers are dried (MgSO4) and evaporated, finally at 0.2 mm., to gi~e 8.0 g. of ~-carbobenzyloxy-cis-4-~phenyl-sulfonyl)-L-proline as a colorless brittle foam.
The above N-carbo~enzyloxy-cis-4-(phenyl-15 sulfon~l)-L-proline is dissolved in 60 ml. of ethyl acetate and treated with 3.1 g. of l-adamantanamine to precipitate, after cooling overnight, 10.2 g. of N-carboben2yloxy-cis-4-(phenylsulfonyl)-L-proline, l-adamantanamine salt;
20 m.p. 225-227 (dec.j. ~a]D5 = ~ 31 (c = 1.0, methanol). A sample stirred with boiling ethanol ~; and cooled shows no change in m.p. or ~a]D .
Anal calc'd for C N NO S C H N:
C, 64.42; H, 6.71; N, 5.18; S, 5.98 ~ Found: C, 64.57; H, 6.96; N, 5.18; S, 5.68.
: , . ~ :
-.: : , ~ : , :
126~66~L
This l-adamantanamine salt (3.0 g.) is suspended in 15 ml. of ethyl acetate, stirred, and treated with 8 ml. of N hydrochloric acid.
When two clear layers are obtained, thay ar~
separated and the aqueous phase is extracted with additional ethyl acetate (3 x 15 ml.).
The combined organic layers are dried (MgS04) and the solvent evaporated to give 2.3 g. of N-carbobenzyloxy-cis-4-(phenylsulfonyl)-L-proline as a colorless sticky foam.
b) cis-4-(PhenylsuIfonyl~-L-proline, hydrobromide The above N-carbobenzyloxy-cis-4-(phenylsuIfonyl)-L-proline (2.0 g., 5 mmole) is treated with 10 ml. of hydrogen bromide in acetic acid (30-32~), stoppered loosely, and swirled to obtain a yellow-orange solution.
After 30 minutes, the solution is diluted with several ~olumes of ether to precipitate an oil which crystallizes on rubbing. Following cooling for one hour, the colorless solid is filtered under nitrogen, washed with ether, and dried ln vacuo to give 1.6 g. of cis-4-(phenylsulfonyl)-L-prol ne, hydrobromide m.p.
200-202 (s 195~). la]D = +7 (c = 1.0, methanol).
Anal. calc'd. for CllH13NO4S . HBr C, 39.29; H, 4.20; N, 4.17; S, 9.54;
Br, 23.77 Found: C, 39.12; H, 4.18; N, 4.13; S, 9.51;
~r, 23~69.
"
~!
', ~
, ~ ' ' : _ ;' 1, :
~ . . .
', :
:., ~266G Ei~
~A285 ~22-':
c) [l(S),4S]-1-[3-(Acetylthio)-2-methyl~l-- oxopr_pyl]-4-(phenylsulfonYl)-L-proline Interaction of cis-4-(phenylsulfonyl)-L-proline, hydrobromide (3.1 g., 9.2 mmole) S and D-3-acetylthio-2-methylpropionyl chloride (2.0 g., 11 mmole) in 40 ml. of water in the presence of sodium carbonate according to the procedure of Example l(d) of U.S. Patent 4,316,906 (using approximately 13 ml. of 20%
sodium carbonate solution to maintain the pH
at 8.0 to 8.4) yields 3.7 g. of a colorless sticky product.' The dicyclohexylamine salt (prepared in 30 ml. of ethyl acetate employing 1.7 g. of dicyclohexylamine) weighs 4.3 g.;
m.p. 235-237 (dec.) (s. 225). [~]D = -71 (c = 1.0, methanol). Following trituration with 20 ml. of acetonitrile one obtains 4.0 g.
of colorless solid dicyclohexyl mine salt;
m.p. 236-238 (dec.? (s. 228). []25 = -71 (c = 1.0, methanol).
Anal. calc'd. for C17H21N06S2 12 23 C, 59.97; H, 7.64, N, 4~82; S, 11.04 ~; Found: C, 59.87; H, 7.71; N, 4.71; S, 10.87.
,; .
This dicyclohexylamine salt is treated with 50 ml. of 10% potassium bisulfate and : ~
extracted into ethyl acetate to yield 2.8 g.
of [l(S)~4S]~ 3-(acetylthio~-2-methyl-l-oxopropyl]-4-(phenylsuIfonyl)-L-proline as a colorless amorphous solid; m.p. 55-58.
.
:
~: . ... . .
- .
.
Rf 0.03 (silica gel;toluene/acetic acid; 85 15);
R~ 0.30 (silica gel; dichloromethane/
methanol/acetic acid; 90 5 5?
d) ~l(S),4S]-1-(3-Merca~to-2-methyl-1-oxopropyl)-4-(phenylsulfonxl)-L-~roline The above ~liS),4S]~ 3-(acetylthio)-2-methyl-l-oxopropyl]-4-(phenylsulfonyl)-L-proline (2.8 g., 7.0 mmole~ is hydrolyzed with
~ CH zero 3 3 6 ~ OCH3 zero -CH3 -C~3 ,7 ~ one 33 8 ~ F two -H -CH3 CH3 three -CH3 -CH3 ~ four -CH -CH
1 ~ CF3 zero 3 3 12 ~ o-3-CH3 ero -CH3 -C~3 13 ~ F one -CH3 14 ~ ~ two -CH3(CH
6~
H~285 Ex. Rl m R3 R5 zero -CH3 ~ (CN2) 16 ~ zero -CH3 -C~3 0 17 ~ one -CX
18_~ ~ three -CH3 C~2 ~' Similarly, by employing two equivalents of hydxogen peroxide in place of the sodium metaperiodate in the procedure of Examples 1 to : 18, the corresponding sulfonyl compounds would : : be ohtained.
Example 19 ~' .
[l(S),4S]~ (3-Mercapto-2-methyl-1-oxopropyl)-4-~phenylsu~fonyl)-L-proline .
; a) :N-Carbobenzy~oxy-cis-4-tphenylsul~onyl)-L-proline :~
: 25 :: ~ A:s irred solution of N-car~obenzyloxy-cis-4~(phenylthio)-L-proline (8.2 g., 23;mmole;
: ; prepared as set forth in Example 58 (b)~ of : : : U.S. Patent 4,316,906) in 95 ml. of acetic acid:i~s treated portionwlse with 30~hydrogen :30 ~ peroxide (IS.6 g., 140 mmole). The temperature . HA285 ~0-drops from 26 to 24 then gradually rises to 30. After standing overnight at room temperatuxe, the solution is concentrated to approximately 5~% of its volume on a rotary -~ S evaporator at 0.2 mm. (water bath temperature less than 30). The residue is diluted with 300 ml. of dichloromethane, washed with water (3 x 100 ml.), and after back-extracting the combined washes with 100 ml. of ichloro-10 methane, the combined organic layers are dried (MgSO4) and evaporated, finally at 0.2 mm., to gi~e 8.0 g. of ~-carbobenzyloxy-cis-4-~phenyl-sulfonyl)-L-proline as a colorless brittle foam.
The above N-carbo~enzyloxy-cis-4-(phenyl-15 sulfon~l)-L-proline is dissolved in 60 ml. of ethyl acetate and treated with 3.1 g. of l-adamantanamine to precipitate, after cooling overnight, 10.2 g. of N-carboben2yloxy-cis-4-(phenylsulfonyl)-L-proline, l-adamantanamine salt;
20 m.p. 225-227 (dec.j. ~a]D5 = ~ 31 (c = 1.0, methanol). A sample stirred with boiling ethanol ~; and cooled shows no change in m.p. or ~a]D .
Anal calc'd for C N NO S C H N:
C, 64.42; H, 6.71; N, 5.18; S, 5.98 ~ Found: C, 64.57; H, 6.96; N, 5.18; S, 5.68.
: , . ~ :
-.: : , ~ : , :
126~66~L
This l-adamantanamine salt (3.0 g.) is suspended in 15 ml. of ethyl acetate, stirred, and treated with 8 ml. of N hydrochloric acid.
When two clear layers are obtained, thay ar~
separated and the aqueous phase is extracted with additional ethyl acetate (3 x 15 ml.).
The combined organic layers are dried (MgS04) and the solvent evaporated to give 2.3 g. of N-carbobenzyloxy-cis-4-(phenylsulfonyl)-L-proline as a colorless sticky foam.
b) cis-4-(PhenylsuIfonyl~-L-proline, hydrobromide The above N-carbobenzyloxy-cis-4-(phenylsuIfonyl)-L-proline (2.0 g., 5 mmole) is treated with 10 ml. of hydrogen bromide in acetic acid (30-32~), stoppered loosely, and swirled to obtain a yellow-orange solution.
After 30 minutes, the solution is diluted with several ~olumes of ether to precipitate an oil which crystallizes on rubbing. Following cooling for one hour, the colorless solid is filtered under nitrogen, washed with ether, and dried ln vacuo to give 1.6 g. of cis-4-(phenylsulfonyl)-L-prol ne, hydrobromide m.p.
200-202 (s 195~). la]D = +7 (c = 1.0, methanol).
Anal. calc'd. for CllH13NO4S . HBr C, 39.29; H, 4.20; N, 4.17; S, 9.54;
Br, 23.77 Found: C, 39.12; H, 4.18; N, 4.13; S, 9.51;
~r, 23~69.
"
~!
', ~
, ~ ' ' : _ ;' 1, :
~ . . .
', :
:., ~266G Ei~
~A285 ~22-':
c) [l(S),4S]-1-[3-(Acetylthio)-2-methyl~l-- oxopr_pyl]-4-(phenylsulfonYl)-L-proline Interaction of cis-4-(phenylsulfonyl)-L-proline, hydrobromide (3.1 g., 9.2 mmole) S and D-3-acetylthio-2-methylpropionyl chloride (2.0 g., 11 mmole) in 40 ml. of water in the presence of sodium carbonate according to the procedure of Example l(d) of U.S. Patent 4,316,906 (using approximately 13 ml. of 20%
sodium carbonate solution to maintain the pH
at 8.0 to 8.4) yields 3.7 g. of a colorless sticky product.' The dicyclohexylamine salt (prepared in 30 ml. of ethyl acetate employing 1.7 g. of dicyclohexylamine) weighs 4.3 g.;
m.p. 235-237 (dec.) (s. 225). [~]D = -71 (c = 1.0, methanol). Following trituration with 20 ml. of acetonitrile one obtains 4.0 g.
of colorless solid dicyclohexyl mine salt;
m.p. 236-238 (dec.? (s. 228). []25 = -71 (c = 1.0, methanol).
Anal. calc'd. for C17H21N06S2 12 23 C, 59.97; H, 7.64, N, 4~82; S, 11.04 ~; Found: C, 59.87; H, 7.71; N, 4.71; S, 10.87.
,; .
This dicyclohexylamine salt is treated with 50 ml. of 10% potassium bisulfate and : ~
extracted into ethyl acetate to yield 2.8 g.
of [l(S)~4S]~ 3-(acetylthio~-2-methyl-l-oxopropyl]-4-(phenylsuIfonyl)-L-proline as a colorless amorphous solid; m.p. 55-58.
.
:
~: . ... . .
- .
.
Rf 0.03 (silica gel;toluene/acetic acid; 85 15);
R~ 0.30 (silica gel; dichloromethane/
methanol/acetic acid; 90 5 5?
d) ~l(S),4S]-1-(3-Merca~to-2-methyl-1-oxopropyl)-4-(phenylsulfonxl)-L-~roline The above ~liS),4S]~ 3-(acetylthio)-2-methyl-l-oxopropyl]-4-(phenylsulfonyl)-L-proline (2.8 g., 7.0 mmole~ is hydrolyzed with
5 ml. of concentrated ammonia in 12 ml. of water over a period of one hour according to the procedure of Example 2 in U.S. Patent 4,316,906 to yield 2.5 g. of ~l(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl3-4-(phenylsulfonyl)-L-proline as a color-lees feathery amorphous solid; m.p. 59-62 (s. 50)-~]D = -64 (c = l.Ot ethanol). Rf 0.24 ~` (silica gel; dichloromethane/methanol/acetic acid;
90:5:5).
Anal. calc'd. for Cl5Hl9No5s2 0-25H2O--~ C, 49.77; H, 5.43, N, 3.87; S, 17.72 Found: C, 49.62; H, 5.58; N, 3.92; S, 17.40.
: ~ : .. .. .. .
Examples 20 - 30 ollowing the procedure of Examp1e 19 but employing the N-protected proline show in Col. I~one obtains, after oxidation with 25 ~ 2 equivalen~s of hydrogen peroxide and~removal of;the~protecting group, the sulfonyl substituted proline;shown in Col.~ II. Coupling with the acid chloride (or other acid ac~iva~ed~form) of Col.~III yields the ac~lmercaptoalkanoyl ;30~ product of Col. IV. Hydrolysis with conce~trated ~` , . . ' ' : - ' :~6~
ammonia gives the mercaptoalkanoyl product of Col. V.
Col. I
( 2)m Il r CH2-O-C - N ~ COOH
Col. II
,:
Q O
(CH2)m-R
. . .
XN ~ - COOH
(L) ~: H
'~:
Co~.~III
o R O
; R5-C-S-CH2-CH -C - Cl 1 ~ ~ : , :
, ::~ ~ :
. ~
'' ; ' . ' . '~ 4 :~26i6g~6~
Col. IV
O O
: ( 2)m R
O R O ~
R5-c-s-cH2~cH - C N - - COOH
H
Col. V
.
~" O O
S - (CH ) -R
~ , 2 m : : 13 2 CN C - N t COOH
H
'~"~
~: - . - . . :, : , .
666:~
Ex. Rl m R3 R5 20 . ~ zero -CH
21 _ ~ Cl one -CH -CH
22 ~ F two -CH
23 ~ - CH3 zero -CH
24 ~ OCH3 one -CH -CH
: ~ .
~ four -CH -C`
~ 26 ~ three -CH3 -CH3 :~, O
~ 27 ~ 0-C-CH3 zero -H 3 ,;
,' ~ :
~ 28 ~ one CF3 -CN3 . ~-~ ~ :
:, ::: : : :: - ., ,~
66~L
HA2 8 5 ..
Ex. Rl m R35 ~ two -C2~5 N
~--Cl zero -CH3 ~3 :~ ~ -C'~2 :
.
~' .
, :
i ::
: ~ :
~:, ~ : : , -~6~;~6:!L
, 28-:.
Example 31 ~l(S),4S~ 3-Mercapto-2-meth~l-1-oxopro~yl)-4-~henylsulfinyl)-L-proline, sodium salt An aqueous solution of the product from : 5 Example 1 is treated with sodium bicarbonate and lyophili~ed to give [ltS),4SI-1-(3-mercapto-2-methyl-l-oxopropyl) 4-(phenylsulfinyl)-L-proline, sodium salt.
Similarly, by employing potassium bicarbonate in the above procedure, one obtains the corresponding potassium salt.
In an an~logous manner, sodium or potassium salts of the products of Examples 2 to 30 can be prepared-Example 32 1000 tablets each containing lO0 mg.
. of [l(S),4S]-l-(3-mercapto-2-methyl-l-oxo~ropyl)-`i' 4-(phenylsulfinyl)-L-proline, sodium salt are ~ prepared con~aining the ~ollowing ingredients:
.~ : 20 ~l(S),4S~-1-(3-Mercapto-2-methyl-l-oxopropyl)-4-(phenylsul~inyl)-~-proline, : sodium salt 100 mg.
.':: ~orn tarch 50 mg.
Gelatin 7.5 mg.
~ ~ Avicel (microcrystalline cellulose~ 25 mg.
Magnesium stear~te :2.5 mg.
185 mg.
3~ ~
.:~:: : :
* Trade Mark ,: :
90:5:5).
Anal. calc'd. for Cl5Hl9No5s2 0-25H2O--~ C, 49.77; H, 5.43, N, 3.87; S, 17.72 Found: C, 49.62; H, 5.58; N, 3.92; S, 17.40.
: ~ : .. .. .. .
Examples 20 - 30 ollowing the procedure of Examp1e 19 but employing the N-protected proline show in Col. I~one obtains, after oxidation with 25 ~ 2 equivalen~s of hydrogen peroxide and~removal of;the~protecting group, the sulfonyl substituted proline;shown in Col.~ II. Coupling with the acid chloride (or other acid ac~iva~ed~form) of Col.~III yields the ac~lmercaptoalkanoyl ;30~ product of Col. IV. Hydrolysis with conce~trated ~` , . . ' ' : - ' :~6~
ammonia gives the mercaptoalkanoyl product of Col. V.
Col. I
( 2)m Il r CH2-O-C - N ~ COOH
Col. II
,:
Q O
(CH2)m-R
. . .
XN ~ - COOH
(L) ~: H
'~:
Co~.~III
o R O
; R5-C-S-CH2-CH -C - Cl 1 ~ ~ : , :
, ::~ ~ :
. ~
'' ; ' . ' . '~ 4 :~26i6g~6~
Col. IV
O O
: ( 2)m R
O R O ~
R5-c-s-cH2~cH - C N - - COOH
H
Col. V
.
~" O O
S - (CH ) -R
~ , 2 m : : 13 2 CN C - N t COOH
H
'~"~
~: - . - . . :, : , .
666:~
Ex. Rl m R3 R5 20 . ~ zero -CH
21 _ ~ Cl one -CH -CH
22 ~ F two -CH
23 ~ - CH3 zero -CH
24 ~ OCH3 one -CH -CH
: ~ .
~ four -CH -C`
~ 26 ~ three -CH3 -CH3 :~, O
~ 27 ~ 0-C-CH3 zero -H 3 ,;
,' ~ :
~ 28 ~ one CF3 -CN3 . ~-~ ~ :
:, ::: : : :: - ., ,~
66~L
HA2 8 5 ..
Ex. Rl m R35 ~ two -C2~5 N
~--Cl zero -CH3 ~3 :~ ~ -C'~2 :
.
~' .
, :
i ::
: ~ :
~:, ~ : : , -~6~;~6:!L
, 28-:.
Example 31 ~l(S),4S~ 3-Mercapto-2-meth~l-1-oxopro~yl)-4-~henylsulfinyl)-L-proline, sodium salt An aqueous solution of the product from : 5 Example 1 is treated with sodium bicarbonate and lyophili~ed to give [ltS),4SI-1-(3-mercapto-2-methyl-l-oxopropyl) 4-(phenylsulfinyl)-L-proline, sodium salt.
Similarly, by employing potassium bicarbonate in the above procedure, one obtains the corresponding potassium salt.
In an an~logous manner, sodium or potassium salts of the products of Examples 2 to 30 can be prepared-Example 32 1000 tablets each containing lO0 mg.
. of [l(S),4S]-l-(3-mercapto-2-methyl-l-oxo~ropyl)-`i' 4-(phenylsulfinyl)-L-proline, sodium salt are ~ prepared con~aining the ~ollowing ingredients:
.~ : 20 ~l(S),4S~-1-(3-Mercapto-2-methyl-l-oxopropyl)-4-(phenylsul~inyl)-~-proline, : sodium salt 100 mg.
.':: ~orn tarch 50 mg.
Gelatin 7.5 mg.
~ ~ Avicel (microcrystalline cellulose~ 25 mg.
Magnesium stear~te :2.5 mg.
185 mg.
3~ ~
.:~:: : :
* Trade Mark ,: :
6~6~i~
suf~icient bulk quantities of the [l~S),4S~
(3-mercapto-2-methyl l-oxopropyl) 4-(phenylsulfinyl)-L-proline, sodium salt and corn starch are admixed with an aqueous solution of the gelatin. The rnixture is dried and ground to a fine powdex. The Avicel and then the magnesium steara~e are admixed with the granulation.
This mixture isl then compressed in a tablet press to form 1000 tablets each containing 100 mg.
of acti~e ingredient.
In a similar manner, tablets can ~e prepared containing 50 mg. o~ active ingredient.
The products of Examples 2 to 30 can be formuIated according to this procedure.
Example 33 Two piece #l gelatin capqules each containing 100 mg. of [l(S),4S]-1-(3-mercapto-~; 2-methyl-1-oxopropyl)-4-~phenylsulfonyl)-L-proline, sodium salt are filled with a mixture of the following ingredient :
[l~S),4S]-1-(3-mercapto-2-` methyl-l-oxopropyl)-4-(phenyl-; sulfonyl)-L-proline, sodium salt 100 mg.
Magne~ium~stearate 7 mg.
Lactose 193 m~
300 mg.
In a qimilar manner, capsules can be prepared con~aining the products of any of Exampleq 1 to 18 and;~20 to 30.
,:
:"
" ~
* Trade Mark .. ,~-:: : :
~ ~ , ~6~
Example 34 lOOO tablets each containing the following ingredients:
~l(S),4S]-1-(3-Mercapto-2-methyl-l-oxopropyl)-4-(phenyl-sulfinyl)-L-proline, sodium salt 100 mg.
Avicel 100 mg.
Hydrochlorothiazide 12.5 mg.
Lactose 113 mg.
Corn starch 17.5 mg.
Stearic acid ~ 7 _ mg.
- 350 mg.
are produced from sufficient bulk quantities by 15slugging the [l(S),4S]-1-(3 mercapto-2-methyl-l-oxopropyl)-4-(phenylsuIfinyl)-L-proline, sodium salt, Avicel, and a portion of the stearic ~; acid. The slugs are ground and passed through ;` a #2 screen, then mixed with the hydrochloro-~ 2Qthiazide, lactose, corn starch, and remainder - of the stearic acid. The mixture is com~ressed into 350 mg. capsule shaped tablets in a tablPt press. The tablets are scored for dividing in half.
Similarly, the products of Examples 2 to 30 can be ormulated according to this procedure.
:
, :
* Trade Mark ~2666~;~
.
Example 35 An injectable solution is prepared as follows:
[l(S),4S]-1-(3-mercapto-2-S methyl-l-oxopropyl~-4-(phenyl-sulfonyl)-L-proline, sodium salt 500 g.
Methyl paraben 5 g.
Propyl paraben 1 g.
Sodium chloride 25 g.
Water for injection 5 1.
The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injestion and then the volume is brought up to 5 liters. The solution is filtered throuyh a sterile filter and asceptically filled into presterilized vials which are then closed with presterilized rubber closures.
Each vial contains 5 ml. of solution in a concentration of 100 mg. of active ingredient per ml. of solution for injection.
In a similar manner, the products of Examples 1 to 18 and 20 to 30 can be formulated as described above.
-~ ; 25 , -,: : :
.
::-. . : .
. .. . .. .
suf~icient bulk quantities of the [l~S),4S~
(3-mercapto-2-methyl l-oxopropyl) 4-(phenylsulfinyl)-L-proline, sodium salt and corn starch are admixed with an aqueous solution of the gelatin. The rnixture is dried and ground to a fine powdex. The Avicel and then the magnesium steara~e are admixed with the granulation.
This mixture isl then compressed in a tablet press to form 1000 tablets each containing 100 mg.
of acti~e ingredient.
In a similar manner, tablets can ~e prepared containing 50 mg. o~ active ingredient.
The products of Examples 2 to 30 can be formuIated according to this procedure.
Example 33 Two piece #l gelatin capqules each containing 100 mg. of [l(S),4S]-1-(3-mercapto-~; 2-methyl-1-oxopropyl)-4-~phenylsulfonyl)-L-proline, sodium salt are filled with a mixture of the following ingredient :
[l~S),4S]-1-(3-mercapto-2-` methyl-l-oxopropyl)-4-(phenyl-; sulfonyl)-L-proline, sodium salt 100 mg.
Magne~ium~stearate 7 mg.
Lactose 193 m~
300 mg.
In a qimilar manner, capsules can be prepared con~aining the products of any of Exampleq 1 to 18 and;~20 to 30.
,:
:"
" ~
* Trade Mark .. ,~-:: : :
~ ~ , ~6~
Example 34 lOOO tablets each containing the following ingredients:
~l(S),4S]-1-(3-Mercapto-2-methyl-l-oxopropyl)-4-(phenyl-sulfinyl)-L-proline, sodium salt 100 mg.
Avicel 100 mg.
Hydrochlorothiazide 12.5 mg.
Lactose 113 mg.
Corn starch 17.5 mg.
Stearic acid ~ 7 _ mg.
- 350 mg.
are produced from sufficient bulk quantities by 15slugging the [l(S),4S]-1-(3 mercapto-2-methyl-l-oxopropyl)-4-(phenylsuIfinyl)-L-proline, sodium salt, Avicel, and a portion of the stearic ~; acid. The slugs are ground and passed through ;` a #2 screen, then mixed with the hydrochloro-~ 2Qthiazide, lactose, corn starch, and remainder - of the stearic acid. The mixture is com~ressed into 350 mg. capsule shaped tablets in a tablPt press. The tablets are scored for dividing in half.
Similarly, the products of Examples 2 to 30 can be ormulated according to this procedure.
:
, :
* Trade Mark ~2666~;~
.
Example 35 An injectable solution is prepared as follows:
[l(S),4S]-1-(3-mercapto-2-S methyl-l-oxopropyl~-4-(phenyl-sulfonyl)-L-proline, sodium salt 500 g.
Methyl paraben 5 g.
Propyl paraben 1 g.
Sodium chloride 25 g.
Water for injection 5 1.
The active substance, preservatives, and sodium chloride are dissolved in 3 liters of water for injestion and then the volume is brought up to 5 liters. The solution is filtered throuyh a sterile filter and asceptically filled into presterilized vials which are then closed with presterilized rubber closures.
Each vial contains 5 ml. of solution in a concentration of 100 mg. of active ingredient per ml. of solution for injection.
In a similar manner, the products of Examples 1 to 18 and 20 to 30 can be formulated as described above.
-~ ; 25 , -,: : :
.
::-. . : .
. .. . .. .
Claims (22)
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof wherein:
R is hydrogen, lower alkyl, or a salt forming ion;
n is one or two;
m is zero or an integer from 1 to 4;
R1 is , a 1- or 2-naphthyl of the formula ;
R2 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, acetyloxy, or hydroxy;
R3 is hydrogen lower alkyl, or trifluoromethyl;
R4 is hydrogen or ;
R5 is lower alkyl, , ; and p is zero or an integer from 1 to 4.
or a pharmaceutically acceptable salt thereof wherein:
R is hydrogen, lower alkyl, or a salt forming ion;
n is one or two;
m is zero or an integer from 1 to 4;
R1 is , a 1- or 2-naphthyl of the formula ;
R2 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, acetyloxy, or hydroxy;
R3 is hydrogen lower alkyl, or trifluoromethyl;
R4 is hydrogen or ;
R5 is lower alkyl, , ; and p is zero or an integer from 1 to 4.
2 . A compound of claim 1 wherein:
R is hydrogen or an alkali metal salt ion;
R1 is ;
R2 is hydrogen, methyl, methoxy, chloro, or fluoro;
m is zero, one or two;
R3 is methyl; and R4 is hydrogen, .
R is hydrogen or an alkali metal salt ion;
R1 is ;
R2 is hydrogen, methyl, methoxy, chloro, or fluoro;
m is zero, one or two;
R3 is methyl; and R4 is hydrogen, .
3. A compound of claim 1 or 2 wherein n is one.
4. A compound of claim 1 or 2 wherein n is two.
5. A compound of claim 1 or 2 wherein R1 is phenyl.
6. The compound of claim 1 having the name [1(S),4S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline, or a salt thereof.
7. The compound of claim 1 having the name [1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline, or a salt thereof.
8. The compound of claim 1 having the name [l(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl)-L-proline, or a salt thereof.
9. The compound of claim 1 having the name [1(S),4S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfonyl)-L-proline, or a salt thereof.
10. The compound of claim 1 having the name [1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfonyl)-L-proline, or a salt thereof.
11. The compound of claim 1 having the name [1(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfonyl)-L-proline, or a salt thereof.
12. A pharmaceutical composition useful in the treatment of hypertension in mammals comprising an effective amount of a compound of the formula:
or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor, wherein:
R is hydrogen, lower alkyl, or a salt forming ion, n is one or two;
m is zero or an integer from 1 to 4;
R1 is , a 1- or 2-naphthyl of the formula ;
R2 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, acetyloxy, or hydroxy;
R3 is hydrogen, lower alkyl, or trifluoromethyl, R4 is hydrogen or ;
R5 is lower alkyl, , ; and p is zero or an integer from 1 to 4.
or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor, wherein:
R is hydrogen, lower alkyl, or a salt forming ion, n is one or two;
m is zero or an integer from 1 to 4;
R1 is , a 1- or 2-naphthyl of the formula ;
R2 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, acetyloxy, or hydroxy;
R3 is hydrogen, lower alkyl, or trifluoromethyl, R4 is hydrogen or ;
R5 is lower alkyl, , ; and p is zero or an integer from 1 to 4.
13. A composition of claim 12 wherein:
R is hydrogen or an alkali metal salt ion;
R1 is ;
R2 is hydrogen, methyl, methoxy, chloro, or fluoro;
m is zero, one or two;
R3 is methyl; and R4 is hydrogen, .
R is hydrogen or an alkali metal salt ion;
R1 is ;
R2 is hydrogen, methyl, methoxy, chloro, or fluoro;
m is zero, one or two;
R3 is methyl; and R4 is hydrogen, .
14. A composition of claim 12 or 13 wherein n is one.
15. A composition of claim 12 or 13 wherein n is two.
16. A composition of claim 12 or 13 wherein R1 is phenyl.
17. A composition of claim 12 wherein the compound is [1(S),4S3-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline, or a salt thereof.
18. A composition of claim 12 wherein the compound is [1(5),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfinyl)-L-proline, or a salt thereof.
19. A composition of claim 12 wherein the compound is [1(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfinyl)-L-proline, or a salt thereof.
20. A composition of claim 12 wherein the compound is [1(S),4S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfonyl)-L-proline, or a salt thereof.
21. A composition of claim 12 wherein the compound is [1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylsulfonyl)-L-proline, or a salt thereof.
22. A composition of claim 12 wherein the compound is [1(S),4S]-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(phenylsulfonyl)-L-proline, or a salt thereof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000615516A CA1271966A (en) | 1983-04-25 | 1984-04-17 | Aryl and aralkyl sulfonyl l-prolines |
| CA452213A CA1266661C (en) | 1983-04-25 | 1984-04-17 | Acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl l-prolines |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48847783A | 1983-04-25 | 1983-04-25 | |
| CA452213A CA1266661C (en) | 1983-04-25 | 1984-04-17 | Acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl l-prolines |
| US488,477 | 1995-06-08 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615516A Division CA1271966A (en) | 1983-04-25 | 1984-04-17 | Aryl and aralkyl sulfonyl l-prolines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA1266661A true CA1266661A (en) | 1990-03-13 |
| CA1266661C CA1266661C (en) | 1990-03-13 |
Family
ID=34117156
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615516A Expired - Lifetime CA1271966A (en) | 1983-04-25 | 1984-04-17 | Aryl and aralkyl sulfonyl l-prolines |
| CA452213A Expired CA1266661C (en) | 1983-04-25 | 1984-04-17 | Acylmercaptoalkanoyl and mercaptoalkanoyl derivatives of aryl and aralkyl sulfinyl or sulfonyl l-prolines |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615516A Expired - Lifetime CA1271966A (en) | 1983-04-25 | 1984-04-17 | Aryl and aralkyl sulfonyl l-prolines |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1271966A (en) |
-
1984
- 1984-04-17 CA CA000615516A patent/CA1271966A/en not_active Expired - Lifetime
- 1984-04-17 CA CA452213A patent/CA1266661C/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1271966C (en) | 1990-07-24 |
| CA1266661C (en) | 1990-03-13 |
| CA1271966A (en) | 1990-07-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 19980313 |