CA1291482C - Intermediates useful in the preparation of aminothiol substituted dipeptides - Google Patents
Intermediates useful in the preparation of aminothiol substituted dipeptidesInfo
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- CA1291482C CA1291482C CA000595459A CA595459A CA1291482C CA 1291482 C CA1291482 C CA 1291482C CA 000595459 A CA000595459 A CA 000595459A CA 595459 A CA595459 A CA 595459A CA 1291482 C CA1291482 C CA 1291482C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
ABSTRACT
A compound of the formula which is useful as an intermediate in the prepara-tion of aminothiol substituted dipeptides of the formula which are themselves useful as hypotensive agents due to their angiotensin converting enzyme inhibi-tion activity. The latter are also useful as anal-gesics due to enkephalinase inhibition activity when X is
A compound of the formula which is useful as an intermediate in the prepara-tion of aminothiol substituted dipeptides of the formula which are themselves useful as hypotensive agents due to their angiotensin converting enzyme inhibi-tion activity. The latter are also useful as anal-gesics due to enkephalinase inhibition activity when X is
Description
Intermediates Useful in the Preparation of Aminothiol Substituted Di~eptides _ _ .
This inven-tion is directed to the amino -thiol dipeptide compounds of formula I and salts thereof (I) 5~ R R1 0 * I I 1 11 3 , *R C~2 N (CL) C X
C=O
; ~2 X i~ an ami~o or imi~o acid o the formula R~
R
~C CH2 , 821 ~ ~ ' -N - C~XXR6 -N - C~XX~6 -N -- C~X~
I(L) I(L) 1~) H H H
4~Z E~315 H~IC ICH2 ~ R 11 ~R
-N C-COOR6 -N ~ C-COOR6 -N C_COC~
I (L) I (L) I (L~
H EI H
Q~OOR -N C-COOR6 ~) H (~) I (L) I ~L) ~ C-COOR6 H (L) 6 -N_C~-COOR6 ~j4 R4 R~; -N C-COOR6 ~(L) -N COOR6, -N---tCOOR6 ' H H EI
~ OCH3 -N~J -Nf~
( L ) COOR6 H H
O~N ~ N
-N~ COOR6 \~- COOR6 H EI
n is zero, one, or two.
R25 is lower alkyl of l to 4 carbons .
or - (CH~
- ~9~48~ HA315 R7 is hydrogen, lower alkyl, halogen, O ~Rl g hydroxy, -NH-C-lower alkyl, amino, R20 -NR-C-~C~2~m ~ ~ -(C3 ) ~ ( ~3)p -(CH2)m~3 , -(CH2)m~3, -(CH2) a 1- or 2-naphthyl of the ormula (CH2)~ ~ ~ , -(C~2)~ cycloalkyl, ~ ~14)p -O-C-N , -O-lower alkyl, -O-(CH2) a l- or 2-naphthyloxy of the formula -O-~C~2)m ~ , -S-lower alkyl, ~(R14)p -S-(CH2)~ ~ or a l- or 2-naphthylthio ( R13 ) p ~29~48~ HA315 of the formula R8 i5 halogen , -O-C-N
-O-(CH2)m ~ , -O-lower alkyl, a l- or ~R13)p
This inven-tion is directed to the amino -thiol dipeptide compounds of formula I and salts thereof (I) 5~ R R1 0 * I I 1 11 3 , *R C~2 N (CL) C X
C=O
; ~2 X i~ an ami~o or imi~o acid o the formula R~
R
~C CH2 , 821 ~ ~ ' -N - C~XXR6 -N - C~XX~6 -N -- C~X~
I(L) I(L) 1~) H H H
4~Z E~315 H~IC ICH2 ~ R 11 ~R
-N C-COOR6 -N ~ C-COOR6 -N C_COC~
I (L) I (L) I (L~
H EI H
Q~OOR -N C-COOR6 ~) H (~) I (L) I ~L) ~ C-COOR6 H (L) 6 -N_C~-COOR6 ~j4 R4 R~; -N C-COOR6 ~(L) -N COOR6, -N---tCOOR6 ' H H EI
~ OCH3 -N~J -Nf~
( L ) COOR6 H H
O~N ~ N
-N~ COOR6 \~- COOR6 H EI
n is zero, one, or two.
R25 is lower alkyl of l to 4 carbons .
or - (CH~
- ~9~48~ HA315 R7 is hydrogen, lower alkyl, halogen, O ~Rl g hydroxy, -NH-C-lower alkyl, amino, R20 -NR-C-~C~2~m ~ ~ -(C3 ) ~ ( ~3)p -(CH2)m~3 , -(CH2)m~3, -(CH2) a 1- or 2-naphthyl of the ormula (CH2)~ ~ ~ , -(C~2)~ cycloalkyl, ~ ~14)p -O-C-N , -O-lower alkyl, -O-(CH2) a l- or 2-naphthyloxy of the formula -O-~C~2)m ~ , -S-lower alkyl, ~(R14)p -S-(CH2)~ ~ or a l- or 2-naphthylthio ( R13 ) p ~29~48~ HA315 of the formula R8 i5 halogen , -O-C-N
-O-(CH2)m ~ , -O-lower alkyl, a l- or ~R13)p
2-naphthyloxy o~ the formula -O- (CH2)m~ (Rl4)p -S-lower alkyl, -S-(CH23m ~ (Rl3)p or a 1- or 2-naphthylthio of the formula -S-(CH2) ~ ~ 14)p R9 is keto or -(CH2)m ~ (Rl3)p Rlo is halogen or Y Rl6-R~ Rl2 and R'l2 are independently selected from hydrogen and lower alkyl or R'll, R12 and R'l2 are hydrogen and Rll is s ~ 14~p Rl3 is hydrogen, lower alkyl of l to 4 .carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyL.
R14 is hydrogen, lowsr alkyl of 1 to 4 carbons, lower alkoxy of l to 4 carbon~, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro~ tri1uoromethyl, or hydroxy.
m is zero, one~ tWQ, three, or four.
p is one, two or thr~e provided that p is more than one only if R13 or R14 is hydrogen, methyl, methoxy, chloro, or fluoro~
~15 is hydrogen or lower alkyl of 1 to 4 carbons.
Y i3 oxygen or sulfur.
Rl6 is lower alkyl of l to 4 carbons, -(CH~)m ~ , or the Rl6 groups join to l3 p complete an unsubstituted 5- or 6-membered ring /
_7_ HA315 or said ring in which one or more of the carbons has a lower alkyl of l to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.
R4 is hydrogen, lower alkyl, -(CH2)m-cycloalkyl, -(CH2)mt ~ J ( 2)m -(CH2)m ~ ~ I ~ , or ~
R5 is hydrogen, lower alkyl, -(CH2)r ~ , ( 2)r ~ - OH, -ICH2)r-oH~ (C~2)r ~ OH , OH
(CH2)r ~¦ ~ -(CH2)~N~ CH2)r NH2 H H
-(CH2~r-SH, -(CH2)r-S-lower alkyl, ~ NH ll - (CH2 ) r-NH-C ~ , or - (CH2 ) r-C-NH2 ?~H2 8~;3 E~A3 1 5 r is an integer from 1 to 4.
Rlg is lower alkyl, benzyl, or ~henethyl.
R20 is hydrogen, lower alkyl, benæyl or phenethyl.
R is hydrogen, lower alkyl, cycloalkyl t ( 2 m ~ , -(CH2)2-NH2~ -(CH2)3 NH2 ' ( 2)4 NH2' (CH2)2-OH, -(CH2)3--OH, ~CH ) -OH, -(CH2)2-SH, (CH2)3 -(CH2)4-SH.
Rl is hydrogen, lower alkyl, halo substituted lower alkyl, ~ -(CH2)~ ~ -OH
-(CH2)r ~ OH , -(CH2) OH H
tC 2)r ~ ~ I -(CH2)r-NH2~ ~(CH2)r~sH' N
H
-(CH2) -OH, -(CH2) -S-lowEr a~ ~ )2-S-(C~2)2-NHZ
NH N
2)r ~ , or -(CH2)r-C-NH2 , , _g_ R2 is ~(CH2)m~(R14)p ~ ~cH2)mt ~ (CH2)mt~3 ~ or (CH2)m~¦ .
R3 is hydrogen, lower alkyl, 2~m~ ~R14)p , -(CH~)m~
~ (CH2)m~3 , - (CH2)m~ , halo substituted lower alkyl, -(CH2)m-cycloalkyl, -(CH2)r~0H, 0~
- (CH2)~) - (CH2) r~OH (CH2) r~s H ~I
.
9L8~
( 2)r 2' (CH2)r-SR, -(CH2)r-S-lower alkyl, NH O
(CH2)r , or ~(CH2)r~C~NH2 NH
wherein m, R14, p and r are as defined above.
R6 is ~x~,lo~ ~ meth~x~x~yl,b~h~yl, O R O
Il l21 -CH-O-C-Rl8 , C - C-O-R , -CH-(CH2-OH)2, -CH2-CH-CH2 , -(CH2)2-NtC~3)2 ~r t 2 r t ) - OH O~
R17 is hydrogen, lower alkyl, cycloalkyl, or phenyl.
R18 is hydrogen, lower alkyl, lower aLko~y, or phenyl or R17 and R18 taken together are -(Cl~2)2-, -tCH2)3-, -CH=CH-, or ~ .
R21 and R22 are independently seleoted ~rom hydrogen and lower alkyl.
R23 i9 lower alkyl.
R24 is hydrogen, lower alkyl, ~ Rl4)p ~ , ~ ~ , or ~
This invention in its broadest aspects relates to the amino thiol dipeptide compounds of formula I above, intermediates useful in the preparation of such compounds, compositions containing such compounds and the method of using such compounds as pharmaceutical agents.
The term lower alkyl used in defining various SymbO19 refers ~o straight or branched chain radicals having up to seven carbons. The preferred lower alkyl groups are up to four carbons with methyl and ethyl most preferred Similarly the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to an oxygen or sulfur.
The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.
The term halogen refers to chloro, bromo and fluoro.
The term halo substi~uted lower alkyl refers to such lower alkyl groups described above in which one or more hydroge~s have been replaced by chloro, bromo or fluoro groups such as trifluoro-methyl, which is preferred, pentafluoroethyl,2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.
~2~
Th~ symbols ~C~m~ S ~ (cH2)m~! ' and (CH2)mt ~ represent that the alkylene bridge is attached to an available carbon atom.
Th~ compound~ of formula I ca~ be prepared according to the following procedure. An aldehyde of th~ ormula 15 (II) o R3-C~ - CH-CH
21E~ S
C=O C~2 oc~3 is reductively coupled with a dipeptide ester of the formula (III) R Rl o HN ~ C--X
: .
~2~ 2 ~ HA315 ~13-wherein R6 in the definition of X is an acid cleavable protecting group such as t-butyl, benzhydryl, or p-methoxybenzyl.
The resulting P-methoxybenzyl protected compound of the formula (IV) R Rl O
R3-CH - CH-CH2-N-C~- C X
NH S
C=O CH2 R2 [~
O~H3 is treated with trifluoroacetic acid and ani901e to remove ~le R6 ester group and mercuric trifluoroacetic acid to removQ the p-methoxybenzyl sulfur protecting group and give the amino ~hiol product of formula I.
The aldehyde intermedia~e of formula II can be prepare~ as follows. An N-protected carboxylic acid of the formula (V) O
R3-C~-C-OH
N~I
prot ~9~
whereln prot is a protecting group such as benzyl-oxycarbonyl is treated with diazomethane in the presence of N~methylmorpholine and isobutylchloro-formate to yield 5 (VI3 NH
prot The diazo compound of formula VI in methanol is treated with silver benzoate and triethylamine to yield the me~hyl estar of the formula (VII) o 1~
R3 CH C~2 C OC~3 N~
p~ot Removal of the N protecting group such as by hydrogenation followed by reaction with the acid chloride of the formula (VIII) R2-C-Cl . . .
~9~32 -15~
yields the methyl ester of the formula (IX)
R14 is hydrogen, lowsr alkyl of 1 to 4 carbons, lower alkoxy of l to 4 carbon~, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro~ tri1uoromethyl, or hydroxy.
m is zero, one~ tWQ, three, or four.
p is one, two or thr~e provided that p is more than one only if R13 or R14 is hydrogen, methyl, methoxy, chloro, or fluoro~
~15 is hydrogen or lower alkyl of 1 to 4 carbons.
Y i3 oxygen or sulfur.
Rl6 is lower alkyl of l to 4 carbons, -(CH~)m ~ , or the Rl6 groups join to l3 p complete an unsubstituted 5- or 6-membered ring /
_7_ HA315 or said ring in which one or more of the carbons has a lower alkyl of l to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent.
R4 is hydrogen, lower alkyl, -(CH2)m-cycloalkyl, -(CH2)mt ~ J ( 2)m -(CH2)m ~ ~ I ~ , or ~
R5 is hydrogen, lower alkyl, -(CH2)r ~ , ( 2)r ~ - OH, -ICH2)r-oH~ (C~2)r ~ OH , OH
(CH2)r ~¦ ~ -(CH2)~N~ CH2)r NH2 H H
-(CH2~r-SH, -(CH2)r-S-lower alkyl, ~ NH ll - (CH2 ) r-NH-C ~ , or - (CH2 ) r-C-NH2 ?~H2 8~;3 E~A3 1 5 r is an integer from 1 to 4.
Rlg is lower alkyl, benzyl, or ~henethyl.
R20 is hydrogen, lower alkyl, benæyl or phenethyl.
R is hydrogen, lower alkyl, cycloalkyl t ( 2 m ~ , -(CH2)2-NH2~ -(CH2)3 NH2 ' ( 2)4 NH2' (CH2)2-OH, -(CH2)3--OH, ~CH ) -OH, -(CH2)2-SH, (CH2)3 -(CH2)4-SH.
Rl is hydrogen, lower alkyl, halo substituted lower alkyl, ~ -(CH2)~ ~ -OH
-(CH2)r ~ OH , -(CH2) OH H
tC 2)r ~ ~ I -(CH2)r-NH2~ ~(CH2)r~sH' N
H
-(CH2) -OH, -(CH2) -S-lowEr a~ ~ )2-S-(C~2)2-NHZ
NH N
2)r ~ , or -(CH2)r-C-NH2 , , _g_ R2 is ~(CH2)m~(R14)p ~ ~cH2)mt ~ (CH2)mt~3 ~ or (CH2)m~¦ .
R3 is hydrogen, lower alkyl, 2~m~ ~R14)p , -(CH~)m~
~ (CH2)m~3 , - (CH2)m~ , halo substituted lower alkyl, -(CH2)m-cycloalkyl, -(CH2)r~0H, 0~
- (CH2)~) - (CH2) r~OH (CH2) r~s H ~I
.
9L8~
( 2)r 2' (CH2)r-SR, -(CH2)r-S-lower alkyl, NH O
(CH2)r , or ~(CH2)r~C~NH2 NH
wherein m, R14, p and r are as defined above.
R6 is ~x~,lo~ ~ meth~x~x~yl,b~h~yl, O R O
Il l21 -CH-O-C-Rl8 , C - C-O-R , -CH-(CH2-OH)2, -CH2-CH-CH2 , -(CH2)2-NtC~3)2 ~r t 2 r t ) - OH O~
R17 is hydrogen, lower alkyl, cycloalkyl, or phenyl.
R18 is hydrogen, lower alkyl, lower aLko~y, or phenyl or R17 and R18 taken together are -(Cl~2)2-, -tCH2)3-, -CH=CH-, or ~ .
R21 and R22 are independently seleoted ~rom hydrogen and lower alkyl.
R23 i9 lower alkyl.
R24 is hydrogen, lower alkyl, ~ Rl4)p ~ , ~ ~ , or ~
This invention in its broadest aspects relates to the amino thiol dipeptide compounds of formula I above, intermediates useful in the preparation of such compounds, compositions containing such compounds and the method of using such compounds as pharmaceutical agents.
The term lower alkyl used in defining various SymbO19 refers ~o straight or branched chain radicals having up to seven carbons. The preferred lower alkyl groups are up to four carbons with methyl and ethyl most preferred Similarly the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to an oxygen or sulfur.
The term cycloalkyl refers to saturated rings of 3 to 7 carbon atoms with cyclopentyl and cyclohexyl being most preferred.
The term halogen refers to chloro, bromo and fluoro.
The term halo substi~uted lower alkyl refers to such lower alkyl groups described above in which one or more hydroge~s have been replaced by chloro, bromo or fluoro groups such as trifluoro-methyl, which is preferred, pentafluoroethyl,2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.
~2~
Th~ symbols ~C~m~ S ~ (cH2)m~! ' and (CH2)mt ~ represent that the alkylene bridge is attached to an available carbon atom.
Th~ compound~ of formula I ca~ be prepared according to the following procedure. An aldehyde of th~ ormula 15 (II) o R3-C~ - CH-CH
21E~ S
C=O C~2 oc~3 is reductively coupled with a dipeptide ester of the formula (III) R Rl o HN ~ C--X
: .
~2~ 2 ~ HA315 ~13-wherein R6 in the definition of X is an acid cleavable protecting group such as t-butyl, benzhydryl, or p-methoxybenzyl.
The resulting P-methoxybenzyl protected compound of the formula (IV) R Rl O
R3-CH - CH-CH2-N-C~- C X
NH S
C=O CH2 R2 [~
O~H3 is treated with trifluoroacetic acid and ani901e to remove ~le R6 ester group and mercuric trifluoroacetic acid to removQ the p-methoxybenzyl sulfur protecting group and give the amino ~hiol product of formula I.
The aldehyde intermedia~e of formula II can be prepare~ as follows. An N-protected carboxylic acid of the formula (V) O
R3-C~-C-OH
N~I
prot ~9~
whereln prot is a protecting group such as benzyl-oxycarbonyl is treated with diazomethane in the presence of N~methylmorpholine and isobutylchloro-formate to yield 5 (VI3 NH
prot The diazo compound of formula VI in methanol is treated with silver benzoate and triethylamine to yield the me~hyl estar of the formula (VII) o 1~
R3 CH C~2 C OC~3 N~
p~ot Removal of the N protecting group such as by hydrogenation followed by reaction with the acid chloride of the formula (VIII) R2-C-Cl . . .
~9~32 -15~
yields the methyl ester of the formula (IX)
3 1 2 C oC 3 N}l C=O
The methyl ester of formula IX is treated with lithium diisopropyl~mine and the disulfide of the formula (X~
(H3CO ~ CH -S) at low temper2ture to yield the protected sulfide of the formula (XI) o R3 C~ - C~ - C- OC~3 N~ S
,, I ;0 ~ H2 OC~3 ~ HA315 The methyl ester of formula XI is treated with lithium chloride and sodium borohydride to yield the alcohol of the formula (XII) R3- CH ~ ---- CH - CH - O~
NH - S
C-O C~2 The alcohol of formula XII is treated with pyridin-ium-l-sulfonate and dimethylsulfoxide in the presence of diisopropylethylamine to yield the aldehyde of formula II.
The dipeptides of formula III are described in the literature. They can be obtained by reacting the N-pro~ected amino acid o~ the formula (XIII) Prot-N- C~ - C-O~
wherein the N-protecting group is benzyloxy-carbonyl, t-butoxycarbonyl, or ~-methoxybenzyl-oxycarbonyl with the imino or amino acid ester of the formula (XIV~
H-X
Removal of the N-protecting group yields the intermediate of formula III. When the imino or amino acid of formula XIV is known in the acid form it can be readily convert~d to the ester by conventional means. For example, the esters where R6 is t-butyl can be obtained by treating the corresponding N-carbobenzyloxy imino or amino acid with isobutylene under acidic conditions and then removing the N-carbobenzyloxy protecting group by catalytic hydrogenation.
In the above reactions if any or all of R, R1, R3 and R5 are 15 (CH2)r ~ OH , -~CH2)r ~ OH
OH
~(CH23r~NH2 ~ ~C~2)r~N~N ~ -(CH2)r-SH
H
-(CH~)r-OH , or ~NH
(C~2)r C~
then the hydroxyl, amino, imidazolyl, mercaptan or guanidinyl function should be protected during the reactlon. Sultabla protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benz-hydryl, trityl, etc., and nitro in the case of guanidinyl. The protectlng group is removed by hydrogenation, treatment with acid, or other known methods following completion of the .reaction.
The ester products of formula I whereln R6 is -$H-O-C-R18 may be obtained by employing the dipeptide of formula III in the above reactions with such es~er group already in place. Such ester reactants can be prepared by trea~ing the dipeptide of formula III wherein R6 is hydrogen with an acid - chloride such as O o Il 11 ~ C~2-0-C-Cl or (H3C)3-C-o-C-C
so as to protect the N-atom. The protected compound is then reacted in the presence of a base with a compound of formula (~V) , - HA315 wherein L is a leaving group such as chlorin~, bromine, tolylsulfonyl, etc., followed by removal of the N-protecting group such as by treatment with acid or hydrogenation.
The ester products of formula I wherein R6 is o -CH-O-C-R18 can also be obtained by treating the product of formula I wherein R6 is hydrogen with a molar excess of the compound of ormula XV.
The ester products of formula I wherein R6 i -C - C-C-R23 can be prepared by treating R2~
~he product of formula I wherein ~6 is hydrogen wi~h a molar excess of the co~pound of the formula (XVI) I- C - ~- O -R23 The ester products of formula I wherein R6 i H (CH2 OH)2 or C~2 IC~ IC~2 can OH O~
be prepared by coupling the product of ormula I
~A315 wherein R6 is hydrogen with a molar exce~ of the compound of the fonmula (xvII) c~-(cE2-oprot)2 OH
or the formula (XVIII) OH Prot OProt in the presence of a coupling agent such as dicyclohexylcarbodiimide followed by removal of ~he hydroxyl protecting groups.
Similarly, the ester products of formula I
wherein R6 is -(CH2)2 N(C~3)2 -CH2 ~ can be prepared by coupling the product of formula I wherein R6 is hydrogen with a molar exce~s of the compound of the formula (XIX) ~O-C~2-C~2-N-(CH3)2 or the formula (~X) Ho-(CH2)r ~ ) in the presence of a coupling agent such as dicyclohexylcarbodiimide.
The products o formula I wherein R7 is amino may be obtained by reducing the correspond ing products of formula I wherein R7 is azido.
Preferred compounds o~ this invention wi~h respect to the peptide part of the structure of formula I are those wherein:
R is hydrogen or straight or branched chain lower alkyl of 1 to 4 carbons.
~ 1 is hydrogen, s~raight or branched chain lower alkyl or 1 to 4 carbons,-CF3, -(C~2)r~N~2 wherein r is an integer from 1 to 4, ~22--CH2 ~ , -CH2 ~ OH , -CH2 ~ ~ OH
OH
-CH2 ~ , -CH2 ~ N , -CH2-SHr -(C~)2 S ~H2)2 2 H H
~NH
-(CH2~2-s-cH ~ -(CH2)3NHC , -CH2-OH, O O
li 11 -CH2-C-NH2, or -(CH ) -C-NH
R4 is hydroge~, cyclohexyl or phenyl.
R5 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, -CH20H, -CH2 ~ , -CH2 ~ OH , -CH2 ~ OH
OH
-C~2 ~ ~ -CH2 ~ ~ ' -(CH2)4 NH2 H H
NH
CH -SH, -(CH2)2-S-CH3, (CH2)3 NH~
O o -C~2-C-NH ( 2)2 R6 is hydrogen, straight or branched chain 5 lower alkyl of 1 to 4 carbons, alkali metal salt, O
-~H_(CH2-OH)2 ,-CH2-1H~IH~ 2)2 N(C 3 2 OH OH
or -(CH2~r ~
r is an integer from 1 to 4.
R23 is straight or branched chain lower alkyl of 1 to 4 carbons, especiallv -C(C~3)3 .
R17 is hydrogen t straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl.
R18 is straight or branched chain lower alkyl of 1 to 4 carbons or phenyl.
R7 is hydrogen.
R7 is hydroxy.
R7 is straight or branched chain lower alkyl of 1 to 4 carbons or cyclohexyl.
~.~9~4~
. - HA315 R7 is amino.
R7 is -O lower alkyl wherein lower alkyl is straight or branched chain of l to 4 carbons.
R7 is S - (CH2)m~
wherein m is zero, one or two ancl Rl3 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R7 is _O~ (CH2) l-naphthyloxy or 2-naphthyloxy wherein m is zero, lS one, or two and R13 is hydrogen, methyl, me~hoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R7 is -S-lower alkyl wherein lower alkyl is straight or branched chain of l to 4 carbons.
R7 is ~S~ ~CH2)m~
~13 l-naphthylthio, or 2-naphthylthio wherein m is zero, one, or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R~ is -O-lower alkyl wherein lower alkyl is straight or branched chain of l to 4 carbons.
R8 is -O-(CH2) ~ R
wherein m i~ zero, one, or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bxomo, fluoro, or hydroxy.
~8 is -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons.
R8 is -S- (CH2)m~
, R13 wherein m is zero, one or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxyO
Rg is phenyl, 2-hydroxyphenyl, or 4-hydroxy-phenyl.
Rlo are both fluoro or chloro.
Rlo are both -Y~R16 wherein Y is O or S, R16 is straight or branched chain lower alkyl of 1 to 4 carbons or the R16 groups join to complete an unsub~tituted 5- or 6-membered ring or said ring in which one or more o~ the available carbons has a methyl or dimethyl substituent.
Rll, Rll, R12 and R12 are all hydrogen, or Rll is phenyl, 2-hydroxyphenyl, or 4-hydroxy-phenyl and ~ R12 and Ri2 are hydrogen.
R24 is phenyl- .
Most preferred compounds of this invention with respect to the peptide part of the structure o~ formula I are those wherein:
~ 4~ - HA315 X is -N - CH-COOR6 , l7
The methyl ester of formula IX is treated with lithium diisopropyl~mine and the disulfide of the formula (X~
(H3CO ~ CH -S) at low temper2ture to yield the protected sulfide of the formula (XI) o R3 C~ - C~ - C- OC~3 N~ S
,, I ;0 ~ H2 OC~3 ~ HA315 The methyl ester of formula XI is treated with lithium chloride and sodium borohydride to yield the alcohol of the formula (XII) R3- CH ~ ---- CH - CH - O~
NH - S
C-O C~2 The alcohol of formula XII is treated with pyridin-ium-l-sulfonate and dimethylsulfoxide in the presence of diisopropylethylamine to yield the aldehyde of formula II.
The dipeptides of formula III are described in the literature. They can be obtained by reacting the N-pro~ected amino acid o~ the formula (XIII) Prot-N- C~ - C-O~
wherein the N-protecting group is benzyloxy-carbonyl, t-butoxycarbonyl, or ~-methoxybenzyl-oxycarbonyl with the imino or amino acid ester of the formula (XIV~
H-X
Removal of the N-protecting group yields the intermediate of formula III. When the imino or amino acid of formula XIV is known in the acid form it can be readily convert~d to the ester by conventional means. For example, the esters where R6 is t-butyl can be obtained by treating the corresponding N-carbobenzyloxy imino or amino acid with isobutylene under acidic conditions and then removing the N-carbobenzyloxy protecting group by catalytic hydrogenation.
In the above reactions if any or all of R, R1, R3 and R5 are 15 (CH2)r ~ OH , -~CH2)r ~ OH
OH
~(CH23r~NH2 ~ ~C~2)r~N~N ~ -(CH2)r-SH
H
-(CH~)r-OH , or ~NH
(C~2)r C~
then the hydroxyl, amino, imidazolyl, mercaptan or guanidinyl function should be protected during the reactlon. Sultabla protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benz-hydryl, trityl, etc., and nitro in the case of guanidinyl. The protectlng group is removed by hydrogenation, treatment with acid, or other known methods following completion of the .reaction.
The ester products of formula I whereln R6 is -$H-O-C-R18 may be obtained by employing the dipeptide of formula III in the above reactions with such es~er group already in place. Such ester reactants can be prepared by trea~ing the dipeptide of formula III wherein R6 is hydrogen with an acid - chloride such as O o Il 11 ~ C~2-0-C-Cl or (H3C)3-C-o-C-C
so as to protect the N-atom. The protected compound is then reacted in the presence of a base with a compound of formula (~V) , - HA315 wherein L is a leaving group such as chlorin~, bromine, tolylsulfonyl, etc., followed by removal of the N-protecting group such as by treatment with acid or hydrogenation.
The ester products of formula I wherein R6 is o -CH-O-C-R18 can also be obtained by treating the product of formula I wherein R6 is hydrogen with a molar excess of the compound of ormula XV.
The ester products of formula I wherein R6 i -C - C-C-R23 can be prepared by treating R2~
~he product of formula I wherein ~6 is hydrogen wi~h a molar excess of the co~pound of the formula (XVI) I- C - ~- O -R23 The ester products of formula I wherein R6 i H (CH2 OH)2 or C~2 IC~ IC~2 can OH O~
be prepared by coupling the product of ormula I
~A315 wherein R6 is hydrogen with a molar exce~ of the compound of the fonmula (xvII) c~-(cE2-oprot)2 OH
or the formula (XVIII) OH Prot OProt in the presence of a coupling agent such as dicyclohexylcarbodiimide followed by removal of ~he hydroxyl protecting groups.
Similarly, the ester products of formula I
wherein R6 is -(CH2)2 N(C~3)2 -CH2 ~ can be prepared by coupling the product of formula I wherein R6 is hydrogen with a molar exce~s of the compound of the formula (XIX) ~O-C~2-C~2-N-(CH3)2 or the formula (~X) Ho-(CH2)r ~ ) in the presence of a coupling agent such as dicyclohexylcarbodiimide.
The products o formula I wherein R7 is amino may be obtained by reducing the correspond ing products of formula I wherein R7 is azido.
Preferred compounds o~ this invention wi~h respect to the peptide part of the structure of formula I are those wherein:
R is hydrogen or straight or branched chain lower alkyl of 1 to 4 carbons.
~ 1 is hydrogen, s~raight or branched chain lower alkyl or 1 to 4 carbons,-CF3, -(C~2)r~N~2 wherein r is an integer from 1 to 4, ~22--CH2 ~ , -CH2 ~ OH , -CH2 ~ ~ OH
OH
-CH2 ~ , -CH2 ~ N , -CH2-SHr -(C~)2 S ~H2)2 2 H H
~NH
-(CH2~2-s-cH ~ -(CH2)3NHC , -CH2-OH, O O
li 11 -CH2-C-NH2, or -(CH ) -C-NH
R4 is hydroge~, cyclohexyl or phenyl.
R5 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbons, -CH20H, -CH2 ~ , -CH2 ~ OH , -CH2 ~ OH
OH
-C~2 ~ ~ -CH2 ~ ~ ' -(CH2)4 NH2 H H
NH
CH -SH, -(CH2)2-S-CH3, (CH2)3 NH~
O o -C~2-C-NH ( 2)2 R6 is hydrogen, straight or branched chain 5 lower alkyl of 1 to 4 carbons, alkali metal salt, O
-~H_(CH2-OH)2 ,-CH2-1H~IH~ 2)2 N(C 3 2 OH OH
or -(CH2~r ~
r is an integer from 1 to 4.
R23 is straight or branched chain lower alkyl of 1 to 4 carbons, especiallv -C(C~3)3 .
R17 is hydrogen t straight or branched chain lower alkyl of 1 to 4 carbons, or cyclohexyl.
R18 is straight or branched chain lower alkyl of 1 to 4 carbons or phenyl.
R7 is hydrogen.
R7 is hydroxy.
R7 is straight or branched chain lower alkyl of 1 to 4 carbons or cyclohexyl.
~.~9~4~
. - HA315 R7 is amino.
R7 is -O lower alkyl wherein lower alkyl is straight or branched chain of l to 4 carbons.
R7 is S - (CH2)m~
wherein m is zero, one or two ancl Rl3 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R7 is _O~ (CH2) l-naphthyloxy or 2-naphthyloxy wherein m is zero, lS one, or two and R13 is hydrogen, methyl, me~hoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R7 is -S-lower alkyl wherein lower alkyl is straight or branched chain of l to 4 carbons.
R7 is ~S~ ~CH2)m~
~13 l-naphthylthio, or 2-naphthylthio wherein m is zero, one, or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro, or hydroxy.
R~ is -O-lower alkyl wherein lower alkyl is straight or branched chain of l to 4 carbons.
R8 is -O-(CH2) ~ R
wherein m i~ zero, one, or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bxomo, fluoro, or hydroxy.
~8 is -S-lower alkyl wherein lower alkyl is straight or branched chain of 1 to 4 carbons.
R8 is -S- (CH2)m~
, R13 wherein m is zero, one or two and R13 is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxyO
Rg is phenyl, 2-hydroxyphenyl, or 4-hydroxy-phenyl.
Rlo are both fluoro or chloro.
Rlo are both -Y~R16 wherein Y is O or S, R16 is straight or branched chain lower alkyl of 1 to 4 carbons or the R16 groups join to complete an unsub~tituted 5- or 6-membered ring or said ring in which one or more o~ the available carbons has a methyl or dimethyl substituent.
Rll, Rll, R12 and R12 are all hydrogen, or Rll is phenyl, 2-hydroxyphenyl, or 4-hydroxy-phenyl and ~ R12 and Ri2 are hydrogen.
R24 is phenyl- .
Most preferred compounds of this invention with respect to the peptide part of the structure o~ formula I are those wherein:
~ 4~ - HA315 X is -N - CH-COOR6 , l7
4 R5 H2C CH2 I~L) 6 f 2)t~ H
S S
H21C I H2 ~Y
-N C-COOR6 , or -N J
t (L) Y ~) R is hydroge~ or methyl.
Rl is hydrogen, methyl, or ~(CH2)4NH2 R6 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbon~, or an alkali me ~ ~t.
R4 is cy~lohexyl or phenyl and R5 is hydrogen.
R4 is hydrogen and R5 is methyl, -CH2-CH(CH3)2, C 2 ~ , -CH2 ~ OH , : 25 -CH2 ~ O~ , -CH2 ~ ~ , or -CH
H H
~9~4~3~
R7 is hydrogen, cyclohexyl, lower alkoxy of 1 to 4 carbons, -(CH2) -O-(CH2) ~ , or -S-~CH2)m ~ R
wherein m is zero, one, or two and R13 is hydrogen, methyl, methoxy, methylthio, Cl, Br ~, or hydroxy, especially preferred wherein R7 is hydrogen.
t is two or three, especially where t is two.
Preferred compounds of this invention with respect to the thiol substituted portion of the structure of formula I are ~hose wherein:
R2 iS
- -(CH2) ~ R14 wherein m is zero, one, or two and R14 is hydrogenp methyl, methoxy, methylthio, Cl, Br, F, or hydroxy, especially phenyl.
R3 is straight or branched chain lower alkyl of 1 to 4 carbons, -(CH2)r-NH2, -(CH2)m ~ , or -(CH2)m ~
wherein m is zero, one, or two, Rl4 is hydrogen,methyl, methoxy, methylthio, Cl, Br, F, or hydroxy, and r is an integer from l to 4, especially benzyl.
~29~32 ~ HA315 The compounds of formula I whereinR6 is hydrogen form salts with a variety of inorganic or organic bases. The nontoxic, pharmaceutically acceptable salts are preferred, although other sal~s are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as calcium or magnesium, and salts deri~ed from amino acids such as arginine, lysine, etc.
The salt~ are obtained by reacting the acid form of the compound with an equivalent of the base supplying the desired ion in a medium in which the ~alt precipitates or in aqueous medium and ~hen lyophilizing.
Similarly, the compounds of formula I
form sal~s with a ~ariety of inorganlc ~nd organic acid3. Again, the non-toxic pharmaceutically acceptable sait are preferred, although other salts are also useful in isolating or puriying the product.
Such pharmaceutically acceptable salts include those formed with hydrochloric acid, 4E~
. methanesulfonic acid, sulfuric acid, maleic acid, etc. The salts are obtained by reactmg the product with an equivalent amount of the acid in a medi~m in which the S salt precipitates.
As shown above, the peptide portion of the molecule of the products of formula I
represented by R R O
-N - C~ - C-X
(L) is ln the L-configuration (R1 is other than hydrogen). One or two asymmetric centers are also present in the t~iol substituted portion of the molecule as represented by the * in formula I.
lS Of course, if R3 is hydrogen, then only one center i5 present. Thus, the compounds of formula I
can exist in diastereoisometric forms~or in mixtures ~hereof. The above described processes ca~ utilize racemate enantiomer~ or diastereomers as starting materials. When diastereomeric productR are pxepared, they can be separated by conventional chromatographic or fxactional crystallization methods.
~:9~4~
~ HA315 The products of formula I wherein the imino acid ring is monosubstituted give rise to cis-trans isomerism. The configuration of the final product will depend upon the configuration S of the R7, R8 and Rg substituent in the starting material of formula XIV.
The comDounds of ~ormula I, and the pharma-ceutically acceptable salts thereof, are hypotensive agents. They inhibit the oonversion of the decapeptide angiotensin X to angiotensi~ II
and, therefore, are useful in reducing or relieving angiotensin related hypertension.
The action o the enzyme renin on angiotensinogen, a pseudoglubulin in blood plasma, produces angio~ensin I. Angiotensin I is converted by angiotensin converting enz~me (ACEI to angiotensin II. The latter is an active pressor substance which has been Lmplicated as the causa-tive agent in several forms of hypertension in various mammalian species, e.g., humans.
The compounds of this invention intervene in the angiotensin~gen ~ (renin) ~ anqiotensin I ~
angiotensin II sequence by inhi~iting angiotensin converting enzyme and reducing or elLminating the formation of ~he pressor ~ubstance angio-tensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a specie~ of mammal (e.g., humans) suffering therefrom is alleviated.
~;~9~L~82 A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg., preferably about 1 to 50 mg., per kg. of body weight per day is appropriate to reduce blood pressure.
The substance i5 preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, 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 aaily dosage of about 30 to 600 mg., preferably about 30 to 330 mg. of a compound of this invention, and about lS 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 co~bination wi~h a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochlorothiazide, flumethia-zide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichloromethiazide, poly-thiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spiro-nolactone and salts of such compounds.
The compounds of formula ~ can be fonmulated for use in the reduction of blood ~9~Z
_32_ 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.
of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage fo~m 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 compounds of formula I wherein X is -NH-CH-COOR6 also possess enkephalinase R
inhibition activity and are useful as analgesic agents. Thus, by the administra~ion of a composition containing one or a combination of such compounds of formula I or a pharmaceutically acceptable salt thereof, pain is alleviated in the mammalia~ host. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to about 100 mg. per kilogram of body weight per day, preferably about 1 to about 50 mg. per kilogram per day, produces the desired analgesic activity.
The composition is preferably administered orally but parenteral routes such as ~ubcutaneous can also be employed.
91 ~2 H~315 The followins e~amples are i'l!s_ratl~e of the invention. Temperatures are given in deqrees centigrada. LH~20 re~ers to a Se~ha~ex chroma~ography ~el commercially availsble from Phar~acia Fine CAemicals.
* Trade Mark ~2~8~
HA~15 Ex~mple 1 ~_~
butyll-L-alanYll-L-~rollne (isomer A) a) (4-Methoxvphenyl)methyl disulfide A benzene solution of iodine is added to a stirred mixture of 4-methoxybenzenemethanethiol (25 g., 0.162 mole) in benzene (300 ml.) and water - (300 ml.) containing sodium bicarbonate (29.4 g., 0.35 mole) until the color of iodine persis~s.
After stirring for 15 minutes, the excess iodine is quenched with sodium thiosulfate. The benzene fraction is washed with water, aqueous sodium thiosulfate, lN sodium bicarbonate, and brine.
After drying over anhydrous MgS04, the solvent is removed at reduced pressure to give a brown solid that is washed with ether to give a light tan solid. This material is dissolved in hot ethyl acetate for recrystallization and while cooling the colorless solution turns dark brown which is indicative of iodine. The resulting solution is cooled in an ice bath and the resulting solid is collected by filtration. This solid is then recrystallized from e~hyl acetate and washed with ether to give 15.1 g. of (4-methoxyphenyl)methyl disulfide as a colorless solid; m.p. 98 - 100.
Anal. calc'd. for C16~l802S2:
C, 62.71; H, 5.92; S, 20.92 Found: C, 62.60; H, 5.97; S, 20.86.
~.~91~8~ - HA315 b~ (S)-3 [~Benzyloxycarbonyl~aminoL l-diazo-4-phenyl-2-butanone Isobutyl chloroformate (23.4 ml., 180 mmole) is added to a solution of N-~e~zyloxycarbonyl-L-phenyl~lanine (53.9 g., 1~4 mmole) and N-methyl-morpholine (19.8 ml., 180 mmole~ in dry tetrahydrofuran (250 ml.) at -20 under argon.
After stirring fox 15 minutes, the N-methyl-morpholine hydrochloride is removed by filtration and the filtrate is treated with a cold (O), etheral solution of diazomethane. The resulting mixture is allowed to warm to room temperature and stirred for 2 hours. The excess diazomethane is remsved by bubbling a stream of nitroge~ ~hrough the reaction mixture for 30 minutes. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. The resulting solution is washed with water (t~icej, lN sodium bicarbonate (twice), 0.25 M citric acid ~twice), and brine. After drying over anhydxous MyS04, the solvent is removed at reduced pressure and the residue is dissolved in isopropyl ether. The resulting precipitate is collected by filtration to gi~e 41.07 g. of (S)-3-[(benzyloxycarbonyl)-ami~o]-1-diazo-4-phenyl-2-butanone as a light yellow solid. TLC(silica gel, hexane:ethyl acetate; (3:1) Rf = 0.12.
~ 82 HA315 c) (s)-~ -[(Benzy ~x ~ r ~ amin~l-benzenebutanolc acld, methYl ester To a solution of (S)-3 [(benzyloxycarbonyl)-amino]-1-diazo-4-phenyl-2-butanone (10 g., 30.8 mmole) ~n methanol (100 ml.~ is added 0.5 ml.
of a solution of silv~r benzoate (1.0 g.) in tri-ethylamine (12.5 ml.). After nitrogen evolution ceases, an additiona1 0.5 ml. of the silver benzoate/triethyla~ine solution is added and stirring continued for an additional 15 minutes.
The reaction mixture is trcatcd with activated charcoal and filtered ~hrough C~lite. The filtrate i~ concontrated at reduced pressure and th~ residue i3 di~olved in othyl ace~ate. This solution i~ wa~hod wi~h water, lN hydrochloric acid, lN ~odi~m bicArbonate ~twice), and brine.
~fter d~yi~g ov~r anhydrou9 MgS04, ~he solY@nt is removed at reduced p~e~sure and th~ residue is chxomatoqraphed (Flori~il, ether) ~o give 9.43 g. of (S)~ (ben2yloxycarbonyl)a~ino]~benzenebutanoic acid, me~hyl o~tex a~ a waxy yellow ~olid.
T~C (silicæ g~l; h~ane:e~hyl ace~at~; 4:1) R ~ 0.25 d) ~
A ~i~tu~ of (S)-3 -[(b~nzylo~ycarbonyl)-amino]-benz~nebut~oic acid, ~ethyl ~qte~
(10.O g., 30.5 mmol~), p-tolue~3ul0nic acid monohydrat~ (5.8 g., 30 . 5 ~mole ), and pal1adium hydroxide carbon cataly~t (1.0 g.) in 95% ethanol * Trade Mark ~ HA315 (170 ml.) is stirred under a hydrogen atmosphere (balloon). The sys~em is evacuated and refilled with fresh hydrogen every 20 minutes. After 1.5 hours, the catalyst is removed by filtration and the filtrate is concentrated at reduced pressure to give a colorless solid.
To a solution of the above colorless solid and diisopropylethylamine (8.23 ml., 47.2 mmole) in anhydrous tetrahydrofuran (150 ml.) at 0 is added benzoyl chloride (6.27 ml., 54 mmole). After stirring for 30 minutes, the mixture is warmed to room temperature and stirring continued for 45 minutes. The reaction mixture is then treated with lN sodium bicar~onate (150 ml.). After stirring for 30 minutes, ~he bulk of the tetrahydrofuran is removed at reduced pressure and the residue is extracted with ethyl acetate. The ethyl acetate fraction is wash~d with water (twice), lN hydrochloric acid (twice3, lN sodium bicarbonate (twice~, and brine. After drying over anhydrous MgS04, ~he solvent is removed at reduced pressure ~nd the residue is washed with hexane to give 8.1S g. of (S)- ~ -(benzoylamino)-benzene-butanoic acid, methyl ester as a colorless solid.
TLC ~silica gel; hexane:ethyl acetate, 1:1) Rf = 0.38.
e 3 ( s ) - ~ ~ ( Benzoylamino ) - ~ - L [ ( 4-methoxYphenyl)-methyllthiol-benzenebutanoic acid, methyl ester To a solution of freshly distilled diiso-propylamine (2.07 ml., 14.8 mmole) in dry tetra-hydrofuran (20 ml.) at 0 under argon is added a hexane ~olution of n-butyl lithium (6.02 ml. of a 2.4 M solution, 14.5 mmole). After stirring at 0 for 30 minutes, the resulting solution of lithium diisopropylamide is cooled to -78 and a solution of (S)-3 -(benzoylamino)-benzenebutanoic acid, methyl ~ster (2.0 g., 6.72 mmole) in tetrahydrofuran (20 ml.) is added dropwise over a period of 5 minutes. After stirring at -78 for 15 minutes, a solutio~ of (4-methoxyphenyl)methyl disulfide (2.5 g., 8.07 mmole) in tetrahydrofuran (9 ml.) is added. After 5 minutes at -7~, the mixture is warmed to 0~ and stirring continued for 45 minutes. The reaction is guenched with lN
hydrochloric acid and diluted wi~h ethyl acetate.
The resulting solution is washed with water, lN
hydrochloric acid, lN sodium bicarbonate, and brine. Af~er drying over anhydrous MgS04, the solvent is removed at reduced pressure and the residue is flash chromatographed ~silica gel LPS-l;
benzene:ethyl acetate, 93:7) to give 1.85 g. of pale yellow solid (S)- ~ -(benzoylamino)- a -[t(4-methoxyphenyl)methyl~thio]-benzenebutanoic acid, methyl ester as a mixture of diastereomers.
~LC (silica gel; ben2ene:ethyl acetate, 9:1) Rf = 0.29 and 0.26.
f) (S)- 3 -(Benzoylamino)- - L [ ( 4-methoxyphenvl)-methyl~thiol-benzenebutanol ~isomer A~
Lithium chloride (0.7 g., 4 eg.) and sodium borohydride (0.62 g., 4 eg.) are added to a solution of (S~-g -(benzoylamino)- ~[[(4-methoxyphenyl)methyl]thio]-benzenebutanoic acid, methyl ester (1.8S g., 4.11 mmole) in tetra-hydrofuran ~25 ml.) and absolute ethanol (25 ml.). After stirring at room ~emperature for 21 hours, the mixture is quenched with lN hydro-chloric acid and diluted with ethyl acetate. The resulting solution is washed with water, lN hydro-chloric acid, lN sodium bicarbonate, and brine.
After drying over anhydrous MgS04, ~he solvent is removed at reduced pressure and the residue flash chromatographed (silica gel r.ps-l; be~zene:acetone, 91:9) ~o give the separated diastereomers of (S) B -(benzoylamino)- a -tt(4-methoxyphenyl)-methyl]thio]-ben~enebutanol as colorless solids.
I~omer A; 0.48 g.; TLC (silica gel; benzene:
acetone, 9:1) Rf - 0.27; and isomer B; 0.52 g.;
TLC (silica gel; henzene:acetone, 9:1) Rf = 0.16.
g) (S)-3 -(Benzoylamino)-~ -[~L4-methox~-he~vl?methvl]thio]-benzenebutanal (isomer A) A mixture of anhydrous dimethylsulfoxide (5 ml.) and pyridinium-l-sulfonate (0.91 g.,
S S
H21C I H2 ~Y
-N C-COOR6 , or -N J
t (L) Y ~) R is hydroge~ or methyl.
Rl is hydrogen, methyl, or ~(CH2)4NH2 R6 is hydrogen, straight or branched chain lower alkyl of 1 to 4 carbon~, or an alkali me ~ ~t.
R4 is cy~lohexyl or phenyl and R5 is hydrogen.
R4 is hydrogen and R5 is methyl, -CH2-CH(CH3)2, C 2 ~ , -CH2 ~ OH , : 25 -CH2 ~ O~ , -CH2 ~ ~ , or -CH
H H
~9~4~3~
R7 is hydrogen, cyclohexyl, lower alkoxy of 1 to 4 carbons, -(CH2) -O-(CH2) ~ , or -S-~CH2)m ~ R
wherein m is zero, one, or two and R13 is hydrogen, methyl, methoxy, methylthio, Cl, Br ~, or hydroxy, especially preferred wherein R7 is hydrogen.
t is two or three, especially where t is two.
Preferred compounds of this invention with respect to the thiol substituted portion of the structure of formula I are ~hose wherein:
R2 iS
- -(CH2) ~ R14 wherein m is zero, one, or two and R14 is hydrogenp methyl, methoxy, methylthio, Cl, Br, F, or hydroxy, especially phenyl.
R3 is straight or branched chain lower alkyl of 1 to 4 carbons, -(CH2)r-NH2, -(CH2)m ~ , or -(CH2)m ~
wherein m is zero, one, or two, Rl4 is hydrogen,methyl, methoxy, methylthio, Cl, Br, F, or hydroxy, and r is an integer from l to 4, especially benzyl.
~29~32 ~ HA315 The compounds of formula I whereinR6 is hydrogen form salts with a variety of inorganic or organic bases. The nontoxic, pharmaceutically acceptable salts are preferred, although other sal~s are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include metal salts such as sodium, potassium or lithium, alkaline earth metal salts such as calcium or magnesium, and salts deri~ed from amino acids such as arginine, lysine, etc.
The salt~ are obtained by reacting the acid form of the compound with an equivalent of the base supplying the desired ion in a medium in which the ~alt precipitates or in aqueous medium and ~hen lyophilizing.
Similarly, the compounds of formula I
form sal~s with a ~ariety of inorganlc ~nd organic acid3. Again, the non-toxic pharmaceutically acceptable sait are preferred, although other salts are also useful in isolating or puriying the product.
Such pharmaceutically acceptable salts include those formed with hydrochloric acid, 4E~
. methanesulfonic acid, sulfuric acid, maleic acid, etc. The salts are obtained by reactmg the product with an equivalent amount of the acid in a medi~m in which the S salt precipitates.
As shown above, the peptide portion of the molecule of the products of formula I
represented by R R O
-N - C~ - C-X
(L) is ln the L-configuration (R1 is other than hydrogen). One or two asymmetric centers are also present in the t~iol substituted portion of the molecule as represented by the * in formula I.
lS Of course, if R3 is hydrogen, then only one center i5 present. Thus, the compounds of formula I
can exist in diastereoisometric forms~or in mixtures ~hereof. The above described processes ca~ utilize racemate enantiomer~ or diastereomers as starting materials. When diastereomeric productR are pxepared, they can be separated by conventional chromatographic or fxactional crystallization methods.
~:9~4~
~ HA315 The products of formula I wherein the imino acid ring is monosubstituted give rise to cis-trans isomerism. The configuration of the final product will depend upon the configuration S of the R7, R8 and Rg substituent in the starting material of formula XIV.
The comDounds of ~ormula I, and the pharma-ceutically acceptable salts thereof, are hypotensive agents. They inhibit the oonversion of the decapeptide angiotensin X to angiotensi~ II
and, therefore, are useful in reducing or relieving angiotensin related hypertension.
The action o the enzyme renin on angiotensinogen, a pseudoglubulin in blood plasma, produces angio~ensin I. Angiotensin I is converted by angiotensin converting enz~me (ACEI to angiotensin II. The latter is an active pressor substance which has been Lmplicated as the causa-tive agent in several forms of hypertension in various mammalian species, e.g., humans.
The compounds of this invention intervene in the angiotensin~gen ~ (renin) ~ anqiotensin I ~
angiotensin II sequence by inhi~iting angiotensin converting enzyme and reducing or elLminating the formation of ~he pressor ~ubstance angio-tensin II. Thus by the administration of a composition containing one (or a combination) of the compounds of this invention, angiotensin dependent hypertension in a specie~ of mammal (e.g., humans) suffering therefrom is alleviated.
~;~9~L~82 A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg., preferably about 1 to 50 mg., per kg. of body weight per day is appropriate to reduce blood pressure.
The substance i5 preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, 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 aaily dosage of about 30 to 600 mg., preferably about 30 to 330 mg. of a compound of this invention, and about lS 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 co~bination wi~h a compound of this invention are the thiazide diuretics, e.g., chlorothiazide, hydrochlorothiazide, flumethia-zide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichloromethiazide, poly-thiazide or benzthiazide as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spiro-nolactone and salts of such compounds.
The compounds of formula ~ can be fonmulated for use in the reduction of blood ~9~Z
_32_ 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.
of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage fo~m 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 compounds of formula I wherein X is -NH-CH-COOR6 also possess enkephalinase R
inhibition activity and are useful as analgesic agents. Thus, by the administra~ion of a composition containing one or a combination of such compounds of formula I or a pharmaceutically acceptable salt thereof, pain is alleviated in the mammalia~ host. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to about 100 mg. per kilogram of body weight per day, preferably about 1 to about 50 mg. per kilogram per day, produces the desired analgesic activity.
The composition is preferably administered orally but parenteral routes such as ~ubcutaneous can also be employed.
91 ~2 H~315 The followins e~amples are i'l!s_ratl~e of the invention. Temperatures are given in deqrees centigrada. LH~20 re~ers to a Se~ha~ex chroma~ography ~el commercially availsble from Phar~acia Fine CAemicals.
* Trade Mark ~2~8~
HA~15 Ex~mple 1 ~_~
butyll-L-alanYll-L-~rollne (isomer A) a) (4-Methoxvphenyl)methyl disulfide A benzene solution of iodine is added to a stirred mixture of 4-methoxybenzenemethanethiol (25 g., 0.162 mole) in benzene (300 ml.) and water - (300 ml.) containing sodium bicarbonate (29.4 g., 0.35 mole) until the color of iodine persis~s.
After stirring for 15 minutes, the excess iodine is quenched with sodium thiosulfate. The benzene fraction is washed with water, aqueous sodium thiosulfate, lN sodium bicarbonate, and brine.
After drying over anhydrous MgS04, the solvent is removed at reduced pressure to give a brown solid that is washed with ether to give a light tan solid. This material is dissolved in hot ethyl acetate for recrystallization and while cooling the colorless solution turns dark brown which is indicative of iodine. The resulting solution is cooled in an ice bath and the resulting solid is collected by filtration. This solid is then recrystallized from e~hyl acetate and washed with ether to give 15.1 g. of (4-methoxyphenyl)methyl disulfide as a colorless solid; m.p. 98 - 100.
Anal. calc'd. for C16~l802S2:
C, 62.71; H, 5.92; S, 20.92 Found: C, 62.60; H, 5.97; S, 20.86.
~.~91~8~ - HA315 b~ (S)-3 [~Benzyloxycarbonyl~aminoL l-diazo-4-phenyl-2-butanone Isobutyl chloroformate (23.4 ml., 180 mmole) is added to a solution of N-~e~zyloxycarbonyl-L-phenyl~lanine (53.9 g., 1~4 mmole) and N-methyl-morpholine (19.8 ml., 180 mmole~ in dry tetrahydrofuran (250 ml.) at -20 under argon.
After stirring fox 15 minutes, the N-methyl-morpholine hydrochloride is removed by filtration and the filtrate is treated with a cold (O), etheral solution of diazomethane. The resulting mixture is allowed to warm to room temperature and stirred for 2 hours. The excess diazomethane is remsved by bubbling a stream of nitroge~ ~hrough the reaction mixture for 30 minutes. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. The resulting solution is washed with water (t~icej, lN sodium bicarbonate (twice), 0.25 M citric acid ~twice), and brine. After drying over anhydxous MyS04, the solvent is removed at reduced pressure and the residue is dissolved in isopropyl ether. The resulting precipitate is collected by filtration to gi~e 41.07 g. of (S)-3-[(benzyloxycarbonyl)-ami~o]-1-diazo-4-phenyl-2-butanone as a light yellow solid. TLC(silica gel, hexane:ethyl acetate; (3:1) Rf = 0.12.
~ 82 HA315 c) (s)-~ -[(Benzy ~x ~ r ~ amin~l-benzenebutanolc acld, methYl ester To a solution of (S)-3 [(benzyloxycarbonyl)-amino]-1-diazo-4-phenyl-2-butanone (10 g., 30.8 mmole) ~n methanol (100 ml.~ is added 0.5 ml.
of a solution of silv~r benzoate (1.0 g.) in tri-ethylamine (12.5 ml.). After nitrogen evolution ceases, an additiona1 0.5 ml. of the silver benzoate/triethyla~ine solution is added and stirring continued for an additional 15 minutes.
The reaction mixture is trcatcd with activated charcoal and filtered ~hrough C~lite. The filtrate i~ concontrated at reduced pressure and th~ residue i3 di~olved in othyl ace~ate. This solution i~ wa~hod wi~h water, lN hydrochloric acid, lN ~odi~m bicArbonate ~twice), and brine.
~fter d~yi~g ov~r anhydrou9 MgS04, ~he solY@nt is removed at reduced p~e~sure and th~ residue is chxomatoqraphed (Flori~il, ether) ~o give 9.43 g. of (S)~ (ben2yloxycarbonyl)a~ino]~benzenebutanoic acid, me~hyl o~tex a~ a waxy yellow ~olid.
T~C (silicæ g~l; h~ane:e~hyl ace~at~; 4:1) R ~ 0.25 d) ~
A ~i~tu~ of (S)-3 -[(b~nzylo~ycarbonyl)-amino]-benz~nebut~oic acid, ~ethyl ~qte~
(10.O g., 30.5 mmol~), p-tolue~3ul0nic acid monohydrat~ (5.8 g., 30 . 5 ~mole ), and pal1adium hydroxide carbon cataly~t (1.0 g.) in 95% ethanol * Trade Mark ~ HA315 (170 ml.) is stirred under a hydrogen atmosphere (balloon). The sys~em is evacuated and refilled with fresh hydrogen every 20 minutes. After 1.5 hours, the catalyst is removed by filtration and the filtrate is concentrated at reduced pressure to give a colorless solid.
To a solution of the above colorless solid and diisopropylethylamine (8.23 ml., 47.2 mmole) in anhydrous tetrahydrofuran (150 ml.) at 0 is added benzoyl chloride (6.27 ml., 54 mmole). After stirring for 30 minutes, the mixture is warmed to room temperature and stirring continued for 45 minutes. The reaction mixture is then treated with lN sodium bicar~onate (150 ml.). After stirring for 30 minutes, ~he bulk of the tetrahydrofuran is removed at reduced pressure and the residue is extracted with ethyl acetate. The ethyl acetate fraction is wash~d with water (twice), lN hydrochloric acid (twice3, lN sodium bicarbonate (twice~, and brine. After drying over anhydrous MgS04, ~he solvent is removed at reduced pressure ~nd the residue is washed with hexane to give 8.1S g. of (S)- ~ -(benzoylamino)-benzene-butanoic acid, methyl ester as a colorless solid.
TLC ~silica gel; hexane:ethyl acetate, 1:1) Rf = 0.38.
e 3 ( s ) - ~ ~ ( Benzoylamino ) - ~ - L [ ( 4-methoxYphenyl)-methyllthiol-benzenebutanoic acid, methyl ester To a solution of freshly distilled diiso-propylamine (2.07 ml., 14.8 mmole) in dry tetra-hydrofuran (20 ml.) at 0 under argon is added a hexane ~olution of n-butyl lithium (6.02 ml. of a 2.4 M solution, 14.5 mmole). After stirring at 0 for 30 minutes, the resulting solution of lithium diisopropylamide is cooled to -78 and a solution of (S)-3 -(benzoylamino)-benzenebutanoic acid, methyl ~ster (2.0 g., 6.72 mmole) in tetrahydrofuran (20 ml.) is added dropwise over a period of 5 minutes. After stirring at -78 for 15 minutes, a solutio~ of (4-methoxyphenyl)methyl disulfide (2.5 g., 8.07 mmole) in tetrahydrofuran (9 ml.) is added. After 5 minutes at -7~, the mixture is warmed to 0~ and stirring continued for 45 minutes. The reaction is guenched with lN
hydrochloric acid and diluted wi~h ethyl acetate.
The resulting solution is washed with water, lN
hydrochloric acid, lN sodium bicarbonate, and brine. Af~er drying over anhydrous MgS04, the solvent is removed at reduced pressure and the residue is flash chromatographed ~silica gel LPS-l;
benzene:ethyl acetate, 93:7) to give 1.85 g. of pale yellow solid (S)- ~ -(benzoylamino)- a -[t(4-methoxyphenyl)methyl~thio]-benzenebutanoic acid, methyl ester as a mixture of diastereomers.
~LC (silica gel; ben2ene:ethyl acetate, 9:1) Rf = 0.29 and 0.26.
f) (S)- 3 -(Benzoylamino)- - L [ ( 4-methoxyphenvl)-methyl~thiol-benzenebutanol ~isomer A~
Lithium chloride (0.7 g., 4 eg.) and sodium borohydride (0.62 g., 4 eg.) are added to a solution of (S~-g -(benzoylamino)- ~[[(4-methoxyphenyl)methyl]thio]-benzenebutanoic acid, methyl ester (1.8S g., 4.11 mmole) in tetra-hydrofuran ~25 ml.) and absolute ethanol (25 ml.). After stirring at room ~emperature for 21 hours, the mixture is quenched with lN hydro-chloric acid and diluted with ethyl acetate. The resulting solution is washed with water, lN hydro-chloric acid, lN sodium bicarbonate, and brine.
After drying over anhydrous MgS04, ~he solvent is removed at reduced pressure and the residue flash chromatographed (silica gel r.ps-l; be~zene:acetone, 91:9) ~o give the separated diastereomers of (S) B -(benzoylamino)- a -tt(4-methoxyphenyl)-methyl]thio]-ben~enebutanol as colorless solids.
I~omer A; 0.48 g.; TLC (silica gel; benzene:
acetone, 9:1) Rf - 0.27; and isomer B; 0.52 g.;
TLC (silica gel; henzene:acetone, 9:1) Rf = 0.16.
g) (S)-3 -(Benzoylamino)-~ -[~L4-methox~-he~vl?methvl]thio]-benzenebutanal (isomer A) A mixture of anhydrous dimethylsulfoxide (5 ml.) and pyridinium-l-sulfonate (0.91 g.,
5.65 ml.) at room temperature under argon is stirred for 15 minutes and then diluted with dry methylene chloride (5 ml.). To the resulting solution is added a solu~ion of ~S)-~ -(benzoyl-~9~
~ HA315 amino)~ [(4-methoxyphenyl)methyl]thio] benzene-butanol (isomer A) (O.48 g., 1.13 mmole) and diisopropylethylamine (1.98 ml., 11.3 mmole) in methylene chloride (7 ml.). After stirring for 15 S minu~es, the ~ixture ls diluted with ethyl acetate and washed with water (twice), lN sodium bicar-bonate (twice), and brine. After drying over anhydrous MgS04, the solvent is removed at reduced pressure to give 0.45 g. of (S)- ~-(benzoylamino)-10 a - [ [ ( 4-methoxyphenyl]methyl]thio]-benzenebutanal (isomer A) as a pale yellow solid. TLC (silica gel; benzene:acetone, 9:1) Rf = 0.44.
h) 1-~N-t(3S)-3-(Benzoylamlno)-2-tt(4-methoxy-phenyl)methyl]thio~ henylbutyl]-L-alanYll-L
p~roline~ dimethYlethyl ester (isomer A) A mi~ture of (S)- ~ -~benzoylamino) a -[[(4 methoxyphenyl)methyl]thio]-ben2enebutanal (isomer A) (0.45 g., 1.07 mmole~, L-alanyl-L-proline, l,l-dimethylethyl ester (O.78 g., 3.21 mmole), and crushed 3A molecular sieves (2 g.~ in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After 2.5 hours, sodium cyano-borohydride ~0.20 g., 3 eq.) i added and stirring `
continued for 15 hours. The reaction mixture isfiltered to remove the sieves and the filtrate is diluted with ethyl acetate and washed with water, lN hydrochloric acid (twice), lN sodium bicarbonate, and brine. Af~er drying over anhydrous MgS04, the solvent is remoYed to give ~ ~ HA315 the desired product, as a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone, 4:1) isomer A at Rf = 0.30 and isomer B at Rf = 0.13. Flash chromatography (silica gel LPS~l; benzene:acetone, 7:3) affords impure product ~isomer A). Repeated flash chroma-tography (silica gel LPS-l; ethyl ac:etate:benzene,
~ HA315 amino)~ [(4-methoxyphenyl)methyl]thio] benzene-butanol (isomer A) (O.48 g., 1.13 mmole) and diisopropylethylamine (1.98 ml., 11.3 mmole) in methylene chloride (7 ml.). After stirring for 15 S minu~es, the ~ixture ls diluted with ethyl acetate and washed with water (twice), lN sodium bicar-bonate (twice), and brine. After drying over anhydrous MgS04, the solvent is removed at reduced pressure to give 0.45 g. of (S)- ~-(benzoylamino)-10 a - [ [ ( 4-methoxyphenyl]methyl]thio]-benzenebutanal (isomer A) as a pale yellow solid. TLC (silica gel; benzene:acetone, 9:1) Rf = 0.44.
h) 1-~N-t(3S)-3-(Benzoylamlno)-2-tt(4-methoxy-phenyl)methyl]thio~ henylbutyl]-L-alanYll-L
p~roline~ dimethYlethyl ester (isomer A) A mi~ture of (S)- ~ -~benzoylamino) a -[[(4 methoxyphenyl)methyl]thio]-ben2enebutanal (isomer A) (0.45 g., 1.07 mmole~, L-alanyl-L-proline, l,l-dimethylethyl ester (O.78 g., 3.21 mmole), and crushed 3A molecular sieves (2 g.~ in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After 2.5 hours, sodium cyano-borohydride ~0.20 g., 3 eq.) i added and stirring `
continued for 15 hours. The reaction mixture isfiltered to remove the sieves and the filtrate is diluted with ethyl acetate and washed with water, lN hydrochloric acid (twice), lN sodium bicarbonate, and brine. Af~er drying over anhydrous MgS04, the solvent is remoYed to give ~ ~ HA315 the desired product, as a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone, 4:1) isomer A at Rf = 0.30 and isomer B at Rf = 0.13. Flash chromatography (silica gel LPS~l; benzene:acetone, 7:3) affords impure product ~isomer A). Repeated flash chroma-tography (silica gel LPS-l; ethyl ac:etate:benzene,
6:4) yives 0.20 g. of 1-[N-[(3S)-3-(benzoyla~ino)-2-[[(4-methoxyphenyl)me~hyl]thio]-4--phenylbutyl]-L-alanyl]-L-proline, 1,1-dimethyle~lyl ester ~ omer A) as a nearly colorless oil.
i) l~rN-~(3S)-3-(BenzoYlamino)-2-mercaPto-4-~henYl-butYll-L-alanYl]-L-~roline (isomer A~
A solution of the l,1-dimethyle~hyl ester product from part (h) (0.57 g., 0.88 Mmole) and anisole (1.0 ml.~ rifluoroacetic acid (l9 ml.) is stirred at room temperature for 1 hour. After cooling to 0, mercuric trifluoro-acetate (376 mg., 0.88 mmole~ is added. After stirring for 1 hour, the bulk of the tri~luoroacetic acid is removed at reduced pressure. The residue is treated with ether to afford a colorless solid which is collected by filtration (535 ~g.).
The above solid ~53$ mg.) is dissolved in 80% acetic acid (20 ml.) and hydrogen sulfide is bubbled through the solutio~ or 30 minutes. The re~ulting black mercuric sulfide is removed by filtration through Ce}ite. The filtrate is ~L~9~
~ HA315 refiltered through a Teflon millipore filter and concentrated at reduced pressure. The re6idue is chased twice with absolute ethanol, dissolved in water (8 ml.), treated with lN hydrochloric acid (0.5 ml.), and lyophilized to give 0.33 g. of 1-[N-[(3S) 3-(benzoylamino)-2-mercapto-4-phenyl-butyl]~L-alanyl]-L-proline (isomer A) as a colorless solid; m.p. 142-176 (dec.); [~]20 = -89.6 (c = 1.07, methanol). TLC (silica gel, n-butanol:
acetic acid:water, 4:1:1) Rf = 0.50.
Anal. calc d- for 25~31 3 4 2 C, 58.54; H, 6.44; N, 8.19; Cl, 6~91;
S, 6.25; S~, 6.45.
Found: C, 58.54; ~, 6.44; N, 8.15; Cl, 6.91;
S, 6.15; S~, 6.2S.
EXamD1e 2 1-[N-~(3S) 3 (BenzoYlamino) 2-merca~t -4-phenyl-butyll-~-alanyll-L-proline, ~onohydrochloride ~omer Bl a) 1- ~
~r~xy~eAyl )methYl 1 thio 1-4-~henylbutyll-L-alanyll-L-prolin_, 1,l-dimethYleth~l ester (isomer B) The parti~lly purified mixture of diastereo-mer~ from Example l(h), in which isomer B i5 the major component, is rechromatoyraphed (flash, silica gel LPS-l; chloroform:metha~ol, 99:1) to give 0.26 g. o~ 1-tM-t(3S)-3-(benzoylamino)-2-~ 2 HA315 _43 [[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-L-alanyl]-L~prollne, 1,l-dimethylethyl ester (isomer a ) as a colorless oll. TLC (silica gel;
chloroform:methanol, 96:4) Rf = 0.28.
b) 1-[N-[(3S~-3-(BenzoYlamino)-2-mercapto-4-phenylbutyll-L-alanYll-L ~roline, monohydro-chloride (isomer_B) ~ solution of the l,l-dime~hylethyl ester product from part (a~ (0.26 g., 0.40 mmole) and 10 anisole (0.5 ml. ) in trifluoroacetic acid (9.5 ml. ) is stirred at room t~peratur~ for one hour.
After cooling to 0, m~rcuric tri1uoroacetate (171 mg.,l eq.) i-q added. Aftor stirring for 45 minutes, th~ bulk of tha trifluoroac~tic acid is removed at r~duc~d pre sure. The re~idue is treated with ethe~ to give a colo~le~s product which is collected by filtration (260 mg.~.
Th~ abov~ colorle~s solid (260 mg.~ is dissol~ed in 80% ac~tic acid (lO ml.) and hydrogen sulfid~ is bubbled throuqh this ~olutio~ for 30 minutes. The resulting ~lack mercuric sulfide i5 re~oved by iltra~ion through Calite. The product i~ refiltered (Te~lon millipore) and the iltrate is concentrated at reduce~ pro sur~. Th~ re~idue is cha3ed onc~ with ab~olute eth~nol, dissolved in wa~er (10 ml.), and then treated wi~h lN hydro-chloric acid. Th~ resulting solution i5 lyophi-lized to give a white flufy solid (150 mg.).
Thi~ mat~rial i~ di5solved in wat~r (9 ml.), filtered (T~10n millipore), and relyophili2ed * Trade Mark 9:~L4~
~ ~ HA315 .
to a white fluffy solid which is then dried under vacuum over phosphorus pentoxide to give 136 mg.
of l-[N-[(3S)-3-(benzoyl~mino)-2-mercapto-4-phenylbutyl]-L-alanyl]-L-proline,`monohydro~
chloride (isomer B); m.p. 147-162; [~ ]D
= -64.5 (c = 1.06, me~hanol~. TLC (silica gel;
n-butanol:acetic acid:water, 4:1:1) Rf = 0.47.
Anal- calc d- for C25H31N34S HCl 0 3 2 C, 58.5~; H, 6.44; N, 8.20; S, 6.25;
Cl, 6.92; S~, 6.45 Found: C, 58.58; ~, 6.50; N, 8.14; S, 6.15;
C1, 6.71; SH, 6.10.
ExamPle 3 1-[N-r(3S)-3-(Benzoylamlno)-2-mercapto-4-phenyl-butyll-L-lysY11-~-proline, monohydrochloride ~isomer Al a) 1-[~ -[(Benzylox~carbonYll-N6-[(1,1-dimethyl-ethy~_~ster ,~ .
A suspension of Nf- L (benzyloxy)carbonyl]-N6~[(1,l-dimethylethoxy)carbonyl]-L-lysine, dicyclohexylamine sal~ (10.0 g., 17.8 mmole) in ethyl acetate (300 ml.) is extracted with lN
hydrochloric acid (three times). The organic phase is then washed with water and brine. After drying ovex anhydrous MgS04, the solvent is removed to give 5.81 g. of N2-[(benzyloxy)-carbonyl~-N6-~(1,1-dimethylethoxy)carbonyl]-L-lysine as a pale yellow oil.
To a solution of N2-[(benzyloxy)carbonyl]-N6-[(l,1-dimethylethoxy)carbonyl]-L-lysine (S.81 g., 15.3 mmole) and L-proline, 1,l-dimethylethyl ester (2.80 g., 16~4 mmole) in dry methylene chloride (70 ml.) is added l-hydroxybenzotriazole (2.02 g., 14.95 mmole) and dicyclohexylcarbodiimide (3.09g., 14.98 mmole). After stirring at room temperature for 15 hours, the mixture is filtered to remove the dicyclohexylurea. The filtra~e is concentrated at reduced pressure and the residue is dissolved in ether and refiltered. The filtrate is washed with water (twice), lN hydro-chloric acid (twice), lN sodium bicarbonate, and brine. After drying over anhydrous MgS04, the solvent is removed at reduced pressure and the residue is flash chromatographed ~silica gel LPS-l; hexane:ethyl acetate, 1:1) to give 8.13 g. of 1-[N2-[(bénzyloxy)carbonyl]-N6 [(1,1-dimethyle~hoxy)carbonyl]-L-lysyl]-L-proline, l,l-dimethylethyl ester as a colorless oil.
TLC (silica gel; hexane:ethyl acetate, 1:1) R = 0.21.
b) l-~N6 L( ~ Di-ethy~Q~E3~ nY~ y~yl]_ L-Prol~r~ _ethyle~yl ester A mixture of the l,1-dime~hylethyl ester product from part ~a) (4.13 q., 7.73 mmole) and palladium hydro~ide/carbon catalyst (400 mg.) in ethyl acetate (90 ml.) a~d ethanol (10 ml.) is stirred under a hydrogen atmosphere (balloon).
The system is evacuated and refilled with fresh hydrogen every 30 minutes. Ater stirring for 3 hours, the catalyst is removed by filtration (Teflon millipore) and the filtrate is concen trated at reduced pressure to give 3.15 g. of 5 l-[N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester as a colorless solid.
c) l-L~-t(3s)-3-(Benzo~lamlno)-2-Lt PhenYl~ thyl]thiol-4-phenYlbutyl]-N6 [(1,1-lQ dimethYlethoxv~carbonyll-L-lYsYll-L-Proline~
dime~hylethYl ester (isomer A~
A mixture of (Sj-~ -(benzoylamino)-~ -[[(4-methoxyphenyl~methyl]thio]-benzene-butanal (isomer A) (O.S9 g. 1.40 mmole), 1-[N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, l,l-dimethylethyl ester (1.55 g., 3.88 mmole~, and crushed 3~ molecular sieves (2.0 g.) in tetrahydrofuran ~5 ml.) and absolute ethanol (S ml.) is stirred at room temperature under argon. ~fter stirring for 2 hours, sodium ~yanoborohydride (0.27 g., 3 eg.) is added and stirring conti~ued for 18 hours. The reaction mixture is filtered through Celite to remova the sieves. The filtrate is then diluted with ~thyl acetate and washed with water, lN hydrochloric acid ~twice), lN sodium bicarbona~e, and brine.
~fter drying over an~ydrous MgS04, the solvent is removed at reduced pressure to give the desired product, a mixture of diastereomers, as a pale yellow oil. TLC (silica gel,benzene:acetone 4~3~
4:1) isomer A at Rf = 0.31, and isomer B at Rf =
0.15. Repeated chromatography (flash, silica gel LPS-1; chloroform:methanol, 98:2; hexane:acetone, 65:35; benzene:acetone, 4:1; ethyl acetate:hexane, 6:4; ethyl acetate:hexane, 6:4) gives 0.41 g. of 1-~N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl~
methyl]thiol-4-phenylbutyl]-N6-[(1,l-dime~hyl-ethoxy~carbonyl]-L-lysyl]-L-proline,1,1-dimethyl-ethyl ester (isomer A) as a colorless oil.
d) l-[N~[(3s)-3-(Be~g~y~yLL=~ o~sA:~
ph2nylbutyl]-L~lysyll~L-~ro~ æ~=ol9 chloride ~isomer A) A solutio~ of the l,l-dimethylethyl ester product from part (c) (0.41 g., 0.51 mmole) and anisole (O.6 ml.) in trifluoroacetic acid ~12 ml.
is stirred at room temperature for one hour.
After cooli~g to 0, mercuric trifluoroacetate (217 mg., 1.0 eg.) is added. After stirring for one hour at 0, the bulk of the trifluoroacetic acid i reMoved at reduced pressure. The residue i9 treated with ether to give a colorless solid which is collected by fil~ration (0.49 g.).
This solid (0.49 g.) i~ dissolved in 80%
acetic acid (17 ml.) and hydrogen sulfide is bubbled ~hrough the solution ~or 30 minutes. The resulting black mercuxic sulide is removed by filtration through Celite. The filtrate is refiltered (Teflon millipore) and then concentrated at reduced pressure. The residue is dissolved in water (10 ml.) and treated with lN
hydrochloric acid (l.S ml.) and then lyophilized.
The material is redissolved in water containing a small amount of hydrochloric acid and relyophilized. The material is finally lyophilized from water to give 290 mg. of l-[N-~(3S)-3-(benzoylami~o)-2-mercapto-4-phenyl-butyl]-L-lysyl]-L-proline, monohydrochloride ~isomer A); m.p. 157 - laoo; [ a ]20 = -60.0 (c = 1.15, methanol). TLC (silica gel; n-butanol:
acetic acid:water, 4:1:1) Rf = 0.16.
Anal.calc d- for C2a~38N4~S 2~ 2 C, 54.45; ~, 6.85; N, 9.07; S, 5.19;
Cl, 11.48; SH, 5.35 Found: C, 54.35; ~, 6.~7; N, 8.97; S, 5.20 Cl, 11.36; SH, 5.23.
Examples 4 - 42 Following the procedure of Examples 1 to 3 the c~rboxylic acid methyl ester shown in Col. I
is reacted with (~-~ethoxyphenyl)methyl disulfide to yield the carboxylic acid methyl e~ter shown in Col. r I. This is ~hen converted to the corresponding alcohol and then the aldehyde show~
in Col. III. The aldehyde is then reacted with ~he peptldyl ester shown i~ Col. IV to yield the protected sulfide product shown in Col. V.
Removal of the S-protecting group a~d the carboxylic acid ester group yield~ the final product shown in Col. VI.
il2 HA315 Col. I
R3 -CR-CH2 -COC}I3 NH
C-O
Col . I I
3 ~ CH-- COCH3 oc~3 Col. III
R -CH CH --CH
3, NH S
C=O CH2 Col. IV
R Rl O
HN--CH--C~X
(L) Col. V
R Rl O
R3 C~ CH--CE[2 N- CH--C ~X
NH S ( ) C=O C~
N~2 y oc~3 ol. VI
R3~ CH--CEI2-- N--CH-- C--X
NH SEI ~ L ) C-O
N}~2 ' ,.
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~9~32 _65-The R1 protecting groups in Examples 20 to 26, the R3 protecting group in Example 29, and R5 protecting group in Example 35 are removed as the last step in the synthesis. The 4-azidoproline of S Example 30 when treated with the reducing agent will yield a 4-aminoproline product. The R6 est~r yroups shown in Examples 37 to 42 are not removed.
Exam~les 43 _SS
1-[N-E(3S)-3-(Benzoylamino)-2-[[(~-methoxy-phenyl)methyl]thio]-4-phenylbutyl]-L-alanyl]-L-proline ~isomer A) is treated with the reagent listed below in Col. I to give the product shown in Col. II.
Col II
S-CH2 ~ OCH3 11 ~
~ C- NH- C~ -CH -C~ - N~- C~ - C - N ~ COOR6 Deprotection by kreatlment with mercuric trifluoro acetate yields the de~ired final product.
. ~291~2 ~ 315 -66~
Exa~ple Col. I R6 43 Cl-CH-O-C-C H -CH-O-C-C H
bo ~Jo 44 Cl-CH-O-C-C ~5 -CH-O-C-C H
CH(CH3)2 CHtCH3)2 O O
Il 11 Cl CH2-0-C-C(C83)3 -CH2-0-C-C~C~3)3 O O
46 Br-CH -O-C-CH -CH2-0-C-CH3 O O
47 Cl-C~2-o~ C~ -O-C
O O
48 I-C~2-!C-O-CtCH3)3 -CH2-C-O-CtCH3)3 ~ 3 tl 49 I-C . C-O-CH3 -C - C-O-CH3 c~3 CH3 Example Col. I R
CH~ ¦ CH2 O-CH ~)~ 1 -C% ~CH2-OH) 2 51 CH--CK ~ CH2 ~ t OH O o OH OH
HC~)2 ~)) 2 52HO-CEI2~I2 N ~CH3) 2-CH2-CH2 N ~CK3) 2 53HO- ~CH2) 2~~ 'CH2) 2~) 54~O~ 2) 3~~ (C~2) 3~
55HO- (CH2) 2~~CH2 2~) In the case of Examples 50 to 55, the reaction with the reagerlt lis~ed in Col. I is performed in ~he presence of a coupling agent such as dicyclohexylcarbodiimide.
xample 56 butyl]-L-a~ y~ e~ollne, sodium salt (isomer A1 l-[N-[(3S)-3-(Ben20y}a~ino)-2~mercapto-4-S phenylbutyl]-~-alanyl~-L-prolin~ (isomer A) (1 mmole) is dissolved in water (50 ml.). Aqueous sodium bicarbonat~ (0.1 N, 20 ml.) is added and the aqueou~ solution is lyophilized. It is then dissolved in water (10 ml.) and applied o~ a column (5 am. x 60 cm.) of Sephadex chromatography gel G-10 and eluted with wa~r. Fractions containing th~ desired product are p~oled and lyophilized to giv~ 1-tN-t(35)-3-~benzoylamino)-2-~er~apto-4-phenylb--tyl]-L-ala~yl]~-proline, sodiu~ ~alt (isomer A).
E~am~le 57 1000 tablet~ each containing th~ following ingredi~nt~
1-EN-~(35)-3-~B~nzoyl~mi~o)-20 2-mo~capto-4 phenyLbutyl~-L-alanyl~ prolino, sodiu~ ~alt ~i~o~or A3 100 m~.
Corn ~tarc:h 50 mg.
Gel atir~ 7 . 5 mg .
25 Avicel(~i~rocry~talline cellulo$e)25 mg.
Magnesiu~ stearate 2.5 m~.
185 mg.
are prepar~d ~rom su~ici~nt bulk guantitie~ by mixing th~ 1 ~N-~(35)-3-tben20yla~ino)-2-mercapto~
4-phonylbutyl]-L-alanyl}-~-prolin~, sotium salt * Trade Mark ~ 9~48~ .
~isomer A) and corn starch with an agueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with granulation.
This mixture is then compres~ed in a tablet press to form 1000 tablets each containing lOQ mg. of active ingredient.
In a similar manner, t~blets containing 100 mg. of the product o~ any of Examples 1 to 55 can be prepared~
A similar procedure can be employed to fonm tablets contai~i~g 50 mg. of active ingredient.
Example 58 Two piece #1 gelatin capsules each containing 50 mg. of 1-tN-[(3S)-3-(benzoylamino)-2-mercapto-4-phenylbutyl]-L~lysyl~-L-proline, monohydrochloride (isomer A) are filled with a mixtur~ of the following.ingredients:
1-tN-~(35)-3~(benzoylamino)-20 2-marcapto-4-phenylbutyl]-L-lysyl]-L-proline, monohydro-chloride (isomer A) 50 mg.
Magnesium stearat~ 7 mg.
Lactose 193 ~
250 mg.
In a similar ~anner cap~ule~ containing 50 mg. of ~he product of any of Examples 1,2 and 4 to 56 can be prepared.
L8;~ -Example 59 An injectable solution is prepared as follows:
l-[N-[(3S)-3-(Benzoylamino)-2-5 mercapto-4-phenylbutylJ-L-alanyl]-L-proline, sodium salt (isomer A) sao g .
Methyl paraben 5 g.
Propyl paraben l g.
10 Sodium chloride 25 g.
Water or injection 5 The active substance, preservatives, and sodium chloride are diss~lved in 3 liters of water - for injection and ~hen the volume is brought up to 5 liters. T~e solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are closes with presterilized rubber clo~uxes. ~ach vial contains 5 ~1~ of solution in a co~centration of 100 mg. of active ingredient per ml. of solution for injection.
In a similar manner, an injectable solution containing 100 mg. o~ active ingredient per ml. of solution can be prepared for the product of any of Examples l to 56.
9~ 3Z
Example 60 1000 tablets each containing the following ingredients:
1-[N-[(3S)-3-(Benzoylamino)-5 2 mercapto-4-phenylbutyl]-L-alanyl]-L-proline, sodium salt (isomer A) 100 mg.
Avicel 100 mg.
~ydrochlorothiazide 12.5 mg.
10 Lactose 113 mg.
Cornstarch 17.5 mg.
Stearic Acid 7 mg.
350 mg.
are prepared from sufficient bulk quantitites by slugging the 1-tN-[(3S)-3-lbenzoylamino)-2-mercapto-4-phenylbutyl]-L-alanyl]-L-proline, sodium salt (isomer A), Avicel, and a portion of the stearic acid. The slugs are ground and passed through a ~2 scree~, then mixed with the hydro-chlorothiazide, lactose, cornstarch, and remainder of the stearic acid. The ~ixture is compressed - into 350 mg. capsule shaped tablets in a tablet press. The tablets are scored for dividing in . half.
In a similar manner, tablets can be prepared containing 100 mg. of the product of any of Examplas 1 to 55.
.,
i) l~rN-~(3S)-3-(BenzoYlamino)-2-mercaPto-4-~henYl-butYll-L-alanYl]-L-~roline (isomer A~
A solution of the l,1-dimethyle~hyl ester product from part (h) (0.57 g., 0.88 Mmole) and anisole (1.0 ml.~ rifluoroacetic acid (l9 ml.) is stirred at room temperature for 1 hour. After cooling to 0, mercuric trifluoro-acetate (376 mg., 0.88 mmole~ is added. After stirring for 1 hour, the bulk of the tri~luoroacetic acid is removed at reduced pressure. The residue is treated with ether to afford a colorless solid which is collected by filtration (535 ~g.).
The above solid ~53$ mg.) is dissolved in 80% acetic acid (20 ml.) and hydrogen sulfide is bubbled through the solutio~ or 30 minutes. The re~ulting black mercuric sulfide is removed by filtration through Ce}ite. The filtrate is ~L~9~
~ HA315 refiltered through a Teflon millipore filter and concentrated at reduced pressure. The re6idue is chased twice with absolute ethanol, dissolved in water (8 ml.), treated with lN hydrochloric acid (0.5 ml.), and lyophilized to give 0.33 g. of 1-[N-[(3S) 3-(benzoylamino)-2-mercapto-4-phenyl-butyl]~L-alanyl]-L-proline (isomer A) as a colorless solid; m.p. 142-176 (dec.); [~]20 = -89.6 (c = 1.07, methanol). TLC (silica gel, n-butanol:
acetic acid:water, 4:1:1) Rf = 0.50.
Anal. calc d- for 25~31 3 4 2 C, 58.54; H, 6.44; N, 8.19; Cl, 6~91;
S, 6.25; S~, 6.45.
Found: C, 58.54; ~, 6.44; N, 8.15; Cl, 6.91;
S, 6.15; S~, 6.2S.
EXamD1e 2 1-[N-~(3S) 3 (BenzoYlamino) 2-merca~t -4-phenyl-butyll-~-alanyll-L-proline, ~onohydrochloride ~omer Bl a) 1- ~
~r~xy~eAyl )methYl 1 thio 1-4-~henylbutyll-L-alanyll-L-prolin_, 1,l-dimethYleth~l ester (isomer B) The parti~lly purified mixture of diastereo-mer~ from Example l(h), in which isomer B i5 the major component, is rechromatoyraphed (flash, silica gel LPS-l; chloroform:metha~ol, 99:1) to give 0.26 g. o~ 1-tM-t(3S)-3-(benzoylamino)-2-~ 2 HA315 _43 [[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-L-alanyl]-L~prollne, 1,l-dimethylethyl ester (isomer a ) as a colorless oll. TLC (silica gel;
chloroform:methanol, 96:4) Rf = 0.28.
b) 1-[N-[(3S~-3-(BenzoYlamino)-2-mercapto-4-phenylbutyll-L-alanYll-L ~roline, monohydro-chloride (isomer_B) ~ solution of the l,l-dime~hylethyl ester product from part (a~ (0.26 g., 0.40 mmole) and 10 anisole (0.5 ml. ) in trifluoroacetic acid (9.5 ml. ) is stirred at room t~peratur~ for one hour.
After cooling to 0, m~rcuric tri1uoroacetate (171 mg.,l eq.) i-q added. Aftor stirring for 45 minutes, th~ bulk of tha trifluoroac~tic acid is removed at r~duc~d pre sure. The re~idue is treated with ethe~ to give a colo~le~s product which is collected by filtration (260 mg.~.
Th~ abov~ colorle~s solid (260 mg.~ is dissol~ed in 80% ac~tic acid (lO ml.) and hydrogen sulfid~ is bubbled throuqh this ~olutio~ for 30 minutes. The resulting ~lack mercuric sulfide i5 re~oved by iltra~ion through Calite. The product i~ refiltered (Te~lon millipore) and the iltrate is concentrated at reduce~ pro sur~. Th~ re~idue is cha3ed onc~ with ab~olute eth~nol, dissolved in wa~er (10 ml.), and then treated wi~h lN hydro-chloric acid. Th~ resulting solution i5 lyophi-lized to give a white flufy solid (150 mg.).
Thi~ mat~rial i~ di5solved in wat~r (9 ml.), filtered (T~10n millipore), and relyophili2ed * Trade Mark 9:~L4~
~ ~ HA315 .
to a white fluffy solid which is then dried under vacuum over phosphorus pentoxide to give 136 mg.
of l-[N-[(3S)-3-(benzoyl~mino)-2-mercapto-4-phenylbutyl]-L-alanyl]-L-proline,`monohydro~
chloride (isomer B); m.p. 147-162; [~ ]D
= -64.5 (c = 1.06, me~hanol~. TLC (silica gel;
n-butanol:acetic acid:water, 4:1:1) Rf = 0.47.
Anal- calc d- for C25H31N34S HCl 0 3 2 C, 58.5~; H, 6.44; N, 8.20; S, 6.25;
Cl, 6.92; S~, 6.45 Found: C, 58.58; ~, 6.50; N, 8.14; S, 6.15;
C1, 6.71; SH, 6.10.
ExamPle 3 1-[N-r(3S)-3-(Benzoylamlno)-2-mercapto-4-phenyl-butyll-L-lysY11-~-proline, monohydrochloride ~isomer Al a) 1-[~ -[(Benzylox~carbonYll-N6-[(1,1-dimethyl-ethy~_~ster ,~ .
A suspension of Nf- L (benzyloxy)carbonyl]-N6~[(1,l-dimethylethoxy)carbonyl]-L-lysine, dicyclohexylamine sal~ (10.0 g., 17.8 mmole) in ethyl acetate (300 ml.) is extracted with lN
hydrochloric acid (three times). The organic phase is then washed with water and brine. After drying ovex anhydrous MgS04, the solvent is removed to give 5.81 g. of N2-[(benzyloxy)-carbonyl~-N6-~(1,1-dimethylethoxy)carbonyl]-L-lysine as a pale yellow oil.
To a solution of N2-[(benzyloxy)carbonyl]-N6-[(l,1-dimethylethoxy)carbonyl]-L-lysine (S.81 g., 15.3 mmole) and L-proline, 1,l-dimethylethyl ester (2.80 g., 16~4 mmole) in dry methylene chloride (70 ml.) is added l-hydroxybenzotriazole (2.02 g., 14.95 mmole) and dicyclohexylcarbodiimide (3.09g., 14.98 mmole). After stirring at room temperature for 15 hours, the mixture is filtered to remove the dicyclohexylurea. The filtra~e is concentrated at reduced pressure and the residue is dissolved in ether and refiltered. The filtrate is washed with water (twice), lN hydro-chloric acid (twice), lN sodium bicarbonate, and brine. After drying over anhydrous MgS04, the solvent is removed at reduced pressure and the residue is flash chromatographed ~silica gel LPS-l; hexane:ethyl acetate, 1:1) to give 8.13 g. of 1-[N2-[(bénzyloxy)carbonyl]-N6 [(1,1-dimethyle~hoxy)carbonyl]-L-lysyl]-L-proline, l,l-dimethylethyl ester as a colorless oil.
TLC (silica gel; hexane:ethyl acetate, 1:1) R = 0.21.
b) l-~N6 L( ~ Di-ethy~Q~E3~ nY~ y~yl]_ L-Prol~r~ _ethyle~yl ester A mixture of the l,1-dime~hylethyl ester product from part ~a) (4.13 q., 7.73 mmole) and palladium hydro~ide/carbon catalyst (400 mg.) in ethyl acetate (90 ml.) a~d ethanol (10 ml.) is stirred under a hydrogen atmosphere (balloon).
The system is evacuated and refilled with fresh hydrogen every 30 minutes. Ater stirring for 3 hours, the catalyst is removed by filtration (Teflon millipore) and the filtrate is concen trated at reduced pressure to give 3.15 g. of 5 l-[N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester as a colorless solid.
c) l-L~-t(3s)-3-(Benzo~lamlno)-2-Lt PhenYl~ thyl]thiol-4-phenYlbutyl]-N6 [(1,1-lQ dimethYlethoxv~carbonyll-L-lYsYll-L-Proline~
dime~hylethYl ester (isomer A~
A mixture of (Sj-~ -(benzoylamino)-~ -[[(4-methoxyphenyl~methyl]thio]-benzene-butanal (isomer A) (O.S9 g. 1.40 mmole), 1-[N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, l,l-dimethylethyl ester (1.55 g., 3.88 mmole~, and crushed 3~ molecular sieves (2.0 g.) in tetrahydrofuran ~5 ml.) and absolute ethanol (S ml.) is stirred at room temperature under argon. ~fter stirring for 2 hours, sodium ~yanoborohydride (0.27 g., 3 eg.) is added and stirring conti~ued for 18 hours. The reaction mixture is filtered through Celite to remova the sieves. The filtrate is then diluted with ~thyl acetate and washed with water, lN hydrochloric acid ~twice), lN sodium bicarbona~e, and brine.
~fter drying over an~ydrous MgS04, the solvent is removed at reduced pressure to give the desired product, a mixture of diastereomers, as a pale yellow oil. TLC (silica gel,benzene:acetone 4~3~
4:1) isomer A at Rf = 0.31, and isomer B at Rf =
0.15. Repeated chromatography (flash, silica gel LPS-1; chloroform:methanol, 98:2; hexane:acetone, 65:35; benzene:acetone, 4:1; ethyl acetate:hexane, 6:4; ethyl acetate:hexane, 6:4) gives 0.41 g. of 1-~N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl~
methyl]thiol-4-phenylbutyl]-N6-[(1,l-dime~hyl-ethoxy~carbonyl]-L-lysyl]-L-proline,1,1-dimethyl-ethyl ester (isomer A) as a colorless oil.
d) l-[N~[(3s)-3-(Be~g~y~yLL=~ o~sA:~
ph2nylbutyl]-L~lysyll~L-~ro~ æ~=ol9 chloride ~isomer A) A solutio~ of the l,l-dimethylethyl ester product from part (c) (0.41 g., 0.51 mmole) and anisole (O.6 ml.) in trifluoroacetic acid ~12 ml.
is stirred at room temperature for one hour.
After cooli~g to 0, mercuric trifluoroacetate (217 mg., 1.0 eg.) is added. After stirring for one hour at 0, the bulk of the trifluoroacetic acid i reMoved at reduced pressure. The residue i9 treated with ether to give a colorless solid which is collected by fil~ration (0.49 g.).
This solid (0.49 g.) i~ dissolved in 80%
acetic acid (17 ml.) and hydrogen sulfide is bubbled ~hrough the solution ~or 30 minutes. The resulting black mercuxic sulide is removed by filtration through Celite. The filtrate is refiltered (Teflon millipore) and then concentrated at reduced pressure. The residue is dissolved in water (10 ml.) and treated with lN
hydrochloric acid (l.S ml.) and then lyophilized.
The material is redissolved in water containing a small amount of hydrochloric acid and relyophilized. The material is finally lyophilized from water to give 290 mg. of l-[N-~(3S)-3-(benzoylami~o)-2-mercapto-4-phenyl-butyl]-L-lysyl]-L-proline, monohydrochloride ~isomer A); m.p. 157 - laoo; [ a ]20 = -60.0 (c = 1.15, methanol). TLC (silica gel; n-butanol:
acetic acid:water, 4:1:1) Rf = 0.16.
Anal.calc d- for C2a~38N4~S 2~ 2 C, 54.45; ~, 6.85; N, 9.07; S, 5.19;
Cl, 11.48; SH, 5.35 Found: C, 54.35; ~, 6.~7; N, 8.97; S, 5.20 Cl, 11.36; SH, 5.23.
Examples 4 - 42 Following the procedure of Examples 1 to 3 the c~rboxylic acid methyl ester shown in Col. I
is reacted with (~-~ethoxyphenyl)methyl disulfide to yield the carboxylic acid methyl e~ter shown in Col. r I. This is ~hen converted to the corresponding alcohol and then the aldehyde show~
in Col. III. The aldehyde is then reacted with ~he peptldyl ester shown i~ Col. IV to yield the protected sulfide product shown in Col. V.
Removal of the S-protecting group a~d the carboxylic acid ester group yield~ the final product shown in Col. VI.
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R3 -CR-CH2 -COC}I3 NH
C-O
Col . I I
3 ~ CH-- COCH3 oc~3 Col. III
R -CH CH --CH
3, NH S
C=O CH2 Col. IV
R Rl O
HN--CH--C~X
(L) Col. V
R Rl O
R3 C~ CH--CE[2 N- CH--C ~X
NH S ( ) C=O C~
N~2 y oc~3 ol. VI
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~1 ~
: ' :
~9~32 _65-The R1 protecting groups in Examples 20 to 26, the R3 protecting group in Example 29, and R5 protecting group in Example 35 are removed as the last step in the synthesis. The 4-azidoproline of S Example 30 when treated with the reducing agent will yield a 4-aminoproline product. The R6 est~r yroups shown in Examples 37 to 42 are not removed.
Exam~les 43 _SS
1-[N-E(3S)-3-(Benzoylamino)-2-[[(~-methoxy-phenyl)methyl]thio]-4-phenylbutyl]-L-alanyl]-L-proline ~isomer A) is treated with the reagent listed below in Col. I to give the product shown in Col. II.
Col II
S-CH2 ~ OCH3 11 ~
~ C- NH- C~ -CH -C~ - N~- C~ - C - N ~ COOR6 Deprotection by kreatlment with mercuric trifluoro acetate yields the de~ired final product.
. ~291~2 ~ 315 -66~
Exa~ple Col. I R6 43 Cl-CH-O-C-C H -CH-O-C-C H
bo ~Jo 44 Cl-CH-O-C-C ~5 -CH-O-C-C H
CH(CH3)2 CHtCH3)2 O O
Il 11 Cl CH2-0-C-C(C83)3 -CH2-0-C-C~C~3)3 O O
46 Br-CH -O-C-CH -CH2-0-C-CH3 O O
47 Cl-C~2-o~ C~ -O-C
O O
48 I-C~2-!C-O-CtCH3)3 -CH2-C-O-CtCH3)3 ~ 3 tl 49 I-C . C-O-CH3 -C - C-O-CH3 c~3 CH3 Example Col. I R
CH~ ¦ CH2 O-CH ~)~ 1 -C% ~CH2-OH) 2 51 CH--CK ~ CH2 ~ t OH O o OH OH
HC~)2 ~)) 2 52HO-CEI2~I2 N ~CH3) 2-CH2-CH2 N ~CK3) 2 53HO- ~CH2) 2~~ 'CH2) 2~) 54~O~ 2) 3~~ (C~2) 3~
55HO- (CH2) 2~~CH2 2~) In the case of Examples 50 to 55, the reaction with the reagerlt lis~ed in Col. I is performed in ~he presence of a coupling agent such as dicyclohexylcarbodiimide.
xample 56 butyl]-L-a~ y~ e~ollne, sodium salt (isomer A1 l-[N-[(3S)-3-(Ben20y}a~ino)-2~mercapto-4-S phenylbutyl]-~-alanyl~-L-prolin~ (isomer A) (1 mmole) is dissolved in water (50 ml.). Aqueous sodium bicarbonat~ (0.1 N, 20 ml.) is added and the aqueou~ solution is lyophilized. It is then dissolved in water (10 ml.) and applied o~ a column (5 am. x 60 cm.) of Sephadex chromatography gel G-10 and eluted with wa~r. Fractions containing th~ desired product are p~oled and lyophilized to giv~ 1-tN-t(35)-3-~benzoylamino)-2-~er~apto-4-phenylb--tyl]-L-ala~yl]~-proline, sodiu~ ~alt (isomer A).
E~am~le 57 1000 tablet~ each containing th~ following ingredi~nt~
1-EN-~(35)-3-~B~nzoyl~mi~o)-20 2-mo~capto-4 phenyLbutyl~-L-alanyl~ prolino, sodiu~ ~alt ~i~o~or A3 100 m~.
Corn ~tarc:h 50 mg.
Gel atir~ 7 . 5 mg .
25 Avicel(~i~rocry~talline cellulo$e)25 mg.
Magnesiu~ stearate 2.5 m~.
185 mg.
are prepar~d ~rom su~ici~nt bulk guantitie~ by mixing th~ 1 ~N-~(35)-3-tben20yla~ino)-2-mercapto~
4-phonylbutyl]-L-alanyl}-~-prolin~, sotium salt * Trade Mark ~ 9~48~ .
~isomer A) and corn starch with an agueous solution of the gelatin. The mixture is dried and ground to a fine powder. The Avicel and then the magnesium stearate are admixed with granulation.
This mixture is then compres~ed in a tablet press to form 1000 tablets each containing lOQ mg. of active ingredient.
In a similar manner, t~blets containing 100 mg. of the product o~ any of Examples 1 to 55 can be prepared~
A similar procedure can be employed to fonm tablets contai~i~g 50 mg. of active ingredient.
Example 58 Two piece #1 gelatin capsules each containing 50 mg. of 1-tN-[(3S)-3-(benzoylamino)-2-mercapto-4-phenylbutyl]-L~lysyl~-L-proline, monohydrochloride (isomer A) are filled with a mixtur~ of the following.ingredients:
1-tN-~(35)-3~(benzoylamino)-20 2-marcapto-4-phenylbutyl]-L-lysyl]-L-proline, monohydro-chloride (isomer A) 50 mg.
Magnesium stearat~ 7 mg.
Lactose 193 ~
250 mg.
In a similar ~anner cap~ule~ containing 50 mg. of ~he product of any of Examples 1,2 and 4 to 56 can be prepared.
L8;~ -Example 59 An injectable solution is prepared as follows:
l-[N-[(3S)-3-(Benzoylamino)-2-5 mercapto-4-phenylbutylJ-L-alanyl]-L-proline, sodium salt (isomer A) sao g .
Methyl paraben 5 g.
Propyl paraben l g.
10 Sodium chloride 25 g.
Water or injection 5 The active substance, preservatives, and sodium chloride are diss~lved in 3 liters of water - for injection and ~hen the volume is brought up to 5 liters. T~e solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials which are closes with presterilized rubber clo~uxes. ~ach vial contains 5 ~1~ of solution in a co~centration of 100 mg. of active ingredient per ml. of solution for injection.
In a similar manner, an injectable solution containing 100 mg. o~ active ingredient per ml. of solution can be prepared for the product of any of Examples l to 56.
9~ 3Z
Example 60 1000 tablets each containing the following ingredients:
1-[N-[(3S)-3-(Benzoylamino)-5 2 mercapto-4-phenylbutyl]-L-alanyl]-L-proline, sodium salt (isomer A) 100 mg.
Avicel 100 mg.
~ydrochlorothiazide 12.5 mg.
10 Lactose 113 mg.
Cornstarch 17.5 mg.
Stearic Acid 7 mg.
350 mg.
are prepared from sufficient bulk quantitites by slugging the 1-tN-[(3S)-3-lbenzoylamino)-2-mercapto-4-phenylbutyl]-L-alanyl]-L-proline, sodium salt (isomer A), Avicel, and a portion of the stearic acid. The slugs are ground and passed through a ~2 scree~, then mixed with the hydro-chlorothiazide, lactose, cornstarch, and remainder of the stearic acid. The ~ixture is compressed - into 350 mg. capsule shaped tablets in a tablet press. The tablets are scored for dividing in . half.
In a similar manner, tablets can be prepared containing 100 mg. of the product of any of Examplas 1 to 55.
.,
Claims
1. A compound of the formula wherein R2 is , or ;
and R3 is hydrogen, lower alkyl, , halo substituted lower alkyl, -(CH2)m-cycloalkyl, wherein cycloalkyl means a saturated ring of 3 to 7 carbon atoms, , -(CH2)r-OH, , -(CH2)r-NH2, -(CH2)r-SH, -(CH2)r-S-lower alkyl, or -(CH2)r-?-NH2;
and wherein R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, tri-fluoromethyl or hydroxy;
m is zero, one, two, three or four;
p is one, two or three provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro or fluoro; and r is an integer from 1 to 4.
and R3 is hydrogen, lower alkyl, , halo substituted lower alkyl, -(CH2)m-cycloalkyl, wherein cycloalkyl means a saturated ring of 3 to 7 carbon atoms, , -(CH2)r-OH, , -(CH2)r-NH2, -(CH2)r-SH, -(CH2)r-S-lower alkyl, or -(CH2)r-?-NH2;
and wherein R14 is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, tri-fluoromethyl or hydroxy;
m is zero, one, two, three or four;
p is one, two or three provided that p is more than one only if R14 is hydrogen, methyl, methoxy, chloro or fluoro; and r is an integer from 1 to 4.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US602,030 | 1984-04-19 | ||
| US06/602,030 US4500518A (en) | 1984-04-19 | 1984-04-19 | Amino thiol dipeptides |
| CA477942A CA1270350C (en) | 1984-04-19 | 1985-03-29 | Amino thio dipeptides |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA477942A Division CA1270350C (en) | 1984-04-19 | 1985-03-29 | Amino thio dipeptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1291482C true CA1291482C (en) | 1991-10-29 |
Family
ID=25670630
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA477942A Expired CA1270350C (en) | 1984-04-19 | 1985-03-29 | Amino thio dipeptides |
| CA000595458A Expired - Fee Related CA1291481C (en) | 1984-04-19 | 1989-03-31 | Intermediates useful in the preparation of aminothiol substituted dipeptides |
| CA000595459A Expired - Lifetime CA1291482C (en) | 1984-04-19 | 1989-03-31 | Intermediates useful in the preparation of aminothiol substituted dipeptides |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA477942A Expired CA1270350C (en) | 1984-04-19 | 1985-03-29 | Amino thio dipeptides |
| CA000595458A Expired - Fee Related CA1291481C (en) | 1984-04-19 | 1989-03-31 | Intermediates useful in the preparation of aminothiol substituted dipeptides |
Country Status (1)
| Country | Link |
|---|---|
| CA (3) | CA1270350C (en) |
-
1985
- 1985-03-29 CA CA477942A patent/CA1270350C/en not_active Expired
-
1989
- 1989-03-31 CA CA000595458A patent/CA1291481C/en not_active Expired - Fee Related
- 1989-03-31 CA CA000595459A patent/CA1291482C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA1270350A (en) | 1990-06-12 |
| CA1291481C (en) | 1991-10-29 |
| CA1270350C (en) | 1990-06-12 |
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| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 19971029 |