CA2073450A1 - Cycloalkyl-substituted glutaramide antihypertensive agents - Google Patents
Cycloalkyl-substituted glutaramide antihypertensive agentsInfo
- Publication number
- CA2073450A1 CA2073450A1 CA002073450A CA2073450A CA2073450A1 CA 2073450 A1 CA2073450 A1 CA 2073450A1 CA 002073450 A CA002073450 A CA 002073450A CA 2073450 A CA2073450 A CA 2073450A CA 2073450 A1 CA2073450 A1 CA 2073450A1
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
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- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07D211/40—Oxygen atoms
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- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract
Compounds of formula (I), wherein A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated; Y is an alkylene group of from 1 to 9 carbon atoms; R1 is H or (C1-C4)alkyl; R and R4 are H, (C1-C6)alkyl, (C3-C7)cycloalkyl, benzyl, or an alternative biolabile ester-forming group;
R2 is defined to include a range of substituent groups including (C1-C6)alkoxy, (C1-C4)alkoxy-(C1-C6)alkoxy and various substituted-alkyl, amino, substituted amino, aryl and heterocyclyl substituents linked directly or by O, S(O)n, NR6, CO or CONR6 wherein R6 is H, (C1-C4)alkyl or aryl(C1-C4)alkyl and n is 0, 1 or 2; R3 is a group of formula (II), wherein R13 is H, halo, 4-OH, 4-(C1-C6 alkoxy), 4-(C3-C7 cycloalkoxy), 4-(C2-C6 alkenyloxy), 4-[(C1-C6 alkoxy)carbonyloxy], 4-[(C3-C7 cycloalkyloxy)carbonyloxy], or 3-(C1-C4 alkyl)SO2NH-; and R14 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C6)alkanoyl or halo; or R3 is a group of formulae (III) or (IV), wherein said groups may optionally be substituted in the fused benzene ring by (C1-C4)alkyl, (C1-C4)alkoxy, OH, halo or CF3; or are atriopeptidase inhibitors or utility in the treatment of hypertension and heart failure.
R2 is defined to include a range of substituent groups including (C1-C6)alkoxy, (C1-C4)alkoxy-(C1-C6)alkoxy and various substituted-alkyl, amino, substituted amino, aryl and heterocyclyl substituents linked directly or by O, S(O)n, NR6, CO or CONR6 wherein R6 is H, (C1-C4)alkyl or aryl(C1-C4)alkyl and n is 0, 1 or 2; R3 is a group of formula (II), wherein R13 is H, halo, 4-OH, 4-(C1-C6 alkoxy), 4-(C3-C7 cycloalkoxy), 4-(C2-C6 alkenyloxy), 4-[(C1-C6 alkoxy)carbonyloxy], 4-[(C3-C7 cycloalkyloxy)carbonyloxy], or 3-(C1-C4 alkyl)SO2NH-; and R14 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C6)alkanoyl or halo; or R3 is a group of formulae (III) or (IV), wherein said groups may optionally be substituted in the fused benzene ring by (C1-C4)alkyl, (C1-C4)alkoxy, OH, halo or CF3; or are atriopeptidase inhibitors or utility in the treatment of hypertension and heart failure.
Description
: ~ :
W O 9t/13054 PCT/EP91/00296 7~5~) .
''Cycl~ y~ uted Glu~aramide Antihypertensive Agents"
This invention relates to a series of cycloalkyl-substituted glutaramide derivatives which are antihypertensive agents having utility in the treatment of various cardiovascular disorders, including hypertension and heart failure.
According to the specification of our European patent application 274234, we disclose certain cycloalkyl-substituted glutaramide derivatives which are inhibitors of the zinc dependent neutral endopeptidase E.C.3.4.24.11 (atriopeptidase) and which are thereby able to potentiate the biological effects of atrial natriuretic factor and in particular, are natriuretic, antihypertensive and diuretic agents of value in the treatment of various cardiovascular disorders. In our European patent application no. 89308740.3 we describe compounds which are inhibitors of the enzyme E.C.3.4.24.11 and, in addition, they are also able to inhibit angiotensin converting enzyme (ACE~, a ;~
further enzyme which is involved in the control of blood pressureO
The compounds thus have a dual pharmacological action through inhibiting two key enzymes involved in blood pressure control which makes them particularly useful in the treatment of various forms of hypertension and associated cardiovascular disorders, e.g. congestive heart failure and glaucoma.
According to the present inyention there are provided further related compounds having activity as atriopeptidase and ACE
inhibitors of the formula:
, , , 1 ", A Rl ~2 y ~ C ~ R3 / CHCH2 / \ CONH-CH
RO2C \ C02R ~;
(I) :
wherein:
A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated;
Y is an alkylene group of from 1 to 9 carbon atoms which may be straight or branched chain; ::
R is H or (Cl-C4)alkyl;
R and R are each independently H, (Cl-C6)alkyl, (C3-C7) cycloalkyl, benzyl, or an alternative biolabile ester-forming group;
R is hydroxy, (Cl-C6)alkoxy, hydroxy(C2-C6)alkoxy, (Cl-C6)alkyl-S(O)n-, (Cl-C4)alkoxy(Cl-C6)alkoxy, (Cl-C~)alkyl-S(O)n-(Cl-C6)-alkoxy, (Cl-C4)alkoxy(C2-C6)alkenyloxy, N3, (R )2N, (R )2N-(Cl-C6)alkoxy, (R )2N-(C2-C6)alkenyloxy, heterocyclyl-Z-, hetero-cyclyl(Cl-C4)alkyl-Z-, aryl-Z- or aryl(Cl-C4)alkyl-Z, wherein Z is ~ S()n or NR and R is H, (Cl-C4)alkyl or aryl(Cl-C4)alkyl;
or R is a group of the formula R7R CH- in which case Y may also :`
be a direct link and wherein R7 is (R5)2N(Cl-C4)alkyl, (Cl-C4)-alkoxy(C2-C4)alkylaminomethyl, heterocyclyl(Cl-C4)alkyl or aryl and R is (Cl-C6) alkoxy, (Cl-C4)alkoxy(C2-C6)alkoxy, ~ ..
hydroxy(C2-C6)alkoxy or hydroxy(C1-C6)alkyl; wherein aryl means phenyl or naphthyl which may optionally be substituted with, one or more OH, CN, CF3, (Cl-C4) alkyl, (C1-C4)alkoxy, halo, j ~:~
carbamoyl, aminosulphonyl, amino, mono or di(C1-C4 alkyl)amino, ~Cl-C4 alkanoyl)amino, amino(Cl-C4)alkyl, di(Cl-C4 alkyl)amino~
(Cl-C4)alkyl, or (Cl-C4) alkyl-S(O)n (Cl C4)alkyl groups a heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur containing heterocyclic group which may be saturated or unsaturated and which may optionally include a further oxygen or one to three nitrogen atoms in the ring and which may optionally be benzofused or substituted with one or more haloJ (Cl-C4)alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di-(Cl-C4 alkyl)amino or (Cl-C4 alkanoyl)amino groups; :~
or R is a group of the formula R9Co- wherein R9 is a l-piperidine or 1-piperazine group, either of which may optionally be .
substituted by OH, =O, (Cl-C4)alkyl or N(R5)2;
or R is a group of the formula R 0CONR6- wherein R6 is as previously defined, and R is (R )2N, (Cl-C4)alkoxy(C2-C4~alkyl~
Rl R CH-, or substituted phenyl wherein the substituent is (R )2N-(Cl-C4)alkyl, (Cl-C4)alkyl-S(0)n- or (Cl-C4)alkyl-S(O)n-(Cl-C4)alkyl;
with the proviso that R2 is not NH2 or CH3NH when Y is CH2;
R is a group of the formula:
- C~2 ~ ~ ~ R14 r-7 '~4, ' ~ , .: ; " , , , : :.: ,~
wherein Rl is H, halo, 4-OH, 4-(Cl-C6 alkoxy), 4-(C3-C7 cycloalkoxy) 4-(C2-C6 alkenyloxy), 4-[(Cl-C
alkoxy)carbonyloxyl, 4-[(C3-C7 cycloalkoxy)carbonyloxy], or 3-(Cl-C4 alkyl)SO2NH-; and R14 is H, (Cl-C4)alkyl, (Cl-C~)alkoxy, ' ~ -(C2-C6) alkanoyl or halo; or R is a group of the formula:
-CH2 `~
H
: -wherein said groups may optionally be substituted in the fused ~.
benzene ring by (Cl-C4)alkyl, (Cl-C4)alkoxy, OH, halo or CF3;
each R is H, (Cl-C6)alkyl, phenyl(Cl-C6)alkyl or the two gro~lps R are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(Cl-C4)alkyl-piperazinyl group;
R is (Cl-C4)alkyl-S(O) NH- or (Cl-C4)alkanoylamino and R is (Cl-C4)alkyl-S(0) (Cl-C4)alkyl or morpholinomethyl or R and R
are both morpholinomethyl or (Cl-C4)alkoxy(Cl-C4)alkoxy(Cl-C4)-alkyl;
n is 0, 1 or 2 and pharmaceutically acceptable salts thereof and bioprecursors therefor.
. . ' : . . ' ', ' . '' ' , : ' ' ' :;: ' , ', ' ,'', ' ' ';; ' ' ' ,''' . "" i;' , 1.:. . '' ' . .~ . ' PLC 534 ~ I
In the above definition~ unless otherwise indicated, alkyl groups having three or more carbon atoms may be straight or branched chain. The term halo means fluoro, chloro, bromo or iodo. When R includes a heterocyclic group, particular examples of heterocycles include pyridyl, pyrazinyl, pyrirnidinyl, pyridazinyl, pyrrolyl, piperidino, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, isoindolinyl, quinolyl, quinoxalinyl, ;
quinazolinyl and benzimidazolyl, each being optionally substituted as previously defined.
The compounds of formula (I) may contain several asymrnetric centres and thus they can exist as enantiomers and diastereomers.
The invention includes both the separated individual isomers as well as mixtures of isorners.
______ _ :
Wo gl/13054 2~7~5~ PCr/EP91/00 ~
The pharmaceutically acceptable salts of the compounds of formula (I) containing ~n acidic centre are those formed with bases which form non-toxic salts. Examples include the al~ali or alkaline earth metal salts such as the sodium, potassium or calcium salts or salts with amines such as diethy:Lamine.
Compounds having a basic centre can also form acid addition salts with pharmaceutically acceptable aclds. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate tosylate and lauryl sulphate salts.
The term bioprecursor in the above definition means a pharmaceutically acceptab]e biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a compound of the formula (I). Examples include biolabile ester derivatives and amide or amino acid derivatives of the compounds of formula I.
A preferred group of compounds of the formula (I) are those wherein A is (CH2)4 and Rl is H, i.e. compounds of the formula (II) wherein R, R , R and R are as previously defined for formula (I):
~ WO9~/13054 . . P~f~ 296 ~?-i?~ 3~S8 .
R2 y ~ / R3 CHCH CONH-CH
W O 9t/13054 PCT/EP91/00296 7~5~) .
''Cycl~ y~ uted Glu~aramide Antihypertensive Agents"
This invention relates to a series of cycloalkyl-substituted glutaramide derivatives which are antihypertensive agents having utility in the treatment of various cardiovascular disorders, including hypertension and heart failure.
According to the specification of our European patent application 274234, we disclose certain cycloalkyl-substituted glutaramide derivatives which are inhibitors of the zinc dependent neutral endopeptidase E.C.3.4.24.11 (atriopeptidase) and which are thereby able to potentiate the biological effects of atrial natriuretic factor and in particular, are natriuretic, antihypertensive and diuretic agents of value in the treatment of various cardiovascular disorders. In our European patent application no. 89308740.3 we describe compounds which are inhibitors of the enzyme E.C.3.4.24.11 and, in addition, they are also able to inhibit angiotensin converting enzyme (ACE~, a ;~
further enzyme which is involved in the control of blood pressureO
The compounds thus have a dual pharmacological action through inhibiting two key enzymes involved in blood pressure control which makes them particularly useful in the treatment of various forms of hypertension and associated cardiovascular disorders, e.g. congestive heart failure and glaucoma.
According to the present inyention there are provided further related compounds having activity as atriopeptidase and ACE
inhibitors of the formula:
, , , 1 ", A Rl ~2 y ~ C ~ R3 / CHCH2 / \ CONH-CH
RO2C \ C02R ~;
(I) :
wherein:
A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated;
Y is an alkylene group of from 1 to 9 carbon atoms which may be straight or branched chain; ::
R is H or (Cl-C4)alkyl;
R and R are each independently H, (Cl-C6)alkyl, (C3-C7) cycloalkyl, benzyl, or an alternative biolabile ester-forming group;
R is hydroxy, (Cl-C6)alkoxy, hydroxy(C2-C6)alkoxy, (Cl-C6)alkyl-S(O)n-, (Cl-C4)alkoxy(Cl-C6)alkoxy, (Cl-C~)alkyl-S(O)n-(Cl-C6)-alkoxy, (Cl-C4)alkoxy(C2-C6)alkenyloxy, N3, (R )2N, (R )2N-(Cl-C6)alkoxy, (R )2N-(C2-C6)alkenyloxy, heterocyclyl-Z-, hetero-cyclyl(Cl-C4)alkyl-Z-, aryl-Z- or aryl(Cl-C4)alkyl-Z, wherein Z is ~ S()n or NR and R is H, (Cl-C4)alkyl or aryl(Cl-C4)alkyl;
or R is a group of the formula R7R CH- in which case Y may also :`
be a direct link and wherein R7 is (R5)2N(Cl-C4)alkyl, (Cl-C4)-alkoxy(C2-C4)alkylaminomethyl, heterocyclyl(Cl-C4)alkyl or aryl and R is (Cl-C6) alkoxy, (Cl-C4)alkoxy(C2-C6)alkoxy, ~ ..
hydroxy(C2-C6)alkoxy or hydroxy(C1-C6)alkyl; wherein aryl means phenyl or naphthyl which may optionally be substituted with, one or more OH, CN, CF3, (Cl-C4) alkyl, (C1-C4)alkoxy, halo, j ~:~
carbamoyl, aminosulphonyl, amino, mono or di(C1-C4 alkyl)amino, ~Cl-C4 alkanoyl)amino, amino(Cl-C4)alkyl, di(Cl-C4 alkyl)amino~
(Cl-C4)alkyl, or (Cl-C4) alkyl-S(O)n (Cl C4)alkyl groups a heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur containing heterocyclic group which may be saturated or unsaturated and which may optionally include a further oxygen or one to three nitrogen atoms in the ring and which may optionally be benzofused or substituted with one or more haloJ (Cl-C4)alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di-(Cl-C4 alkyl)amino or (Cl-C4 alkanoyl)amino groups; :~
or R is a group of the formula R9Co- wherein R9 is a l-piperidine or 1-piperazine group, either of which may optionally be .
substituted by OH, =O, (Cl-C4)alkyl or N(R5)2;
or R is a group of the formula R 0CONR6- wherein R6 is as previously defined, and R is (R )2N, (Cl-C4)alkoxy(C2-C4~alkyl~
Rl R CH-, or substituted phenyl wherein the substituent is (R )2N-(Cl-C4)alkyl, (Cl-C4)alkyl-S(0)n- or (Cl-C4)alkyl-S(O)n-(Cl-C4)alkyl;
with the proviso that R2 is not NH2 or CH3NH when Y is CH2;
R is a group of the formula:
- C~2 ~ ~ ~ R14 r-7 '~4, ' ~ , .: ; " , , , : :.: ,~
wherein Rl is H, halo, 4-OH, 4-(Cl-C6 alkoxy), 4-(C3-C7 cycloalkoxy) 4-(C2-C6 alkenyloxy), 4-[(Cl-C
alkoxy)carbonyloxyl, 4-[(C3-C7 cycloalkoxy)carbonyloxy], or 3-(Cl-C4 alkyl)SO2NH-; and R14 is H, (Cl-C4)alkyl, (Cl-C~)alkoxy, ' ~ -(C2-C6) alkanoyl or halo; or R is a group of the formula:
-CH2 `~
H
: -wherein said groups may optionally be substituted in the fused ~.
benzene ring by (Cl-C4)alkyl, (Cl-C4)alkoxy, OH, halo or CF3;
each R is H, (Cl-C6)alkyl, phenyl(Cl-C6)alkyl or the two gro~lps R are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(Cl-C4)alkyl-piperazinyl group;
R is (Cl-C4)alkyl-S(O) NH- or (Cl-C4)alkanoylamino and R is (Cl-C4)alkyl-S(0) (Cl-C4)alkyl or morpholinomethyl or R and R
are both morpholinomethyl or (Cl-C4)alkoxy(Cl-C4)alkoxy(Cl-C4)-alkyl;
n is 0, 1 or 2 and pharmaceutically acceptable salts thereof and bioprecursors therefor.
. . ' : . . ' ', ' . '' ' , : ' ' ' :;: ' , ', ' ,'', ' ' ';; ' ' ' ,''' . "" i;' , 1.:. . '' ' . .~ . ' PLC 534 ~ I
In the above definition~ unless otherwise indicated, alkyl groups having three or more carbon atoms may be straight or branched chain. The term halo means fluoro, chloro, bromo or iodo. When R includes a heterocyclic group, particular examples of heterocycles include pyridyl, pyrazinyl, pyrirnidinyl, pyridazinyl, pyrrolyl, piperidino, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, isoindolinyl, quinolyl, quinoxalinyl, ;
quinazolinyl and benzimidazolyl, each being optionally substituted as previously defined.
The compounds of formula (I) may contain several asymrnetric centres and thus they can exist as enantiomers and diastereomers.
The invention includes both the separated individual isomers as well as mixtures of isorners.
______ _ :
Wo gl/13054 2~7~5~ PCr/EP91/00 ~
The pharmaceutically acceptable salts of the compounds of formula (I) containing ~n acidic centre are those formed with bases which form non-toxic salts. Examples include the al~ali or alkaline earth metal salts such as the sodium, potassium or calcium salts or salts with amines such as diethy:Lamine.
Compounds having a basic centre can also form acid addition salts with pharmaceutically acceptable aclds. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate tosylate and lauryl sulphate salts.
The term bioprecursor in the above definition means a pharmaceutically acceptab]e biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a compound of the formula (I). Examples include biolabile ester derivatives and amide or amino acid derivatives of the compounds of formula I.
A preferred group of compounds of the formula (I) are those wherein A is (CH2)4 and Rl is H, i.e. compounds of the formula (II) wherein R, R , R and R are as previously defined for formula (I):
~ WO9~/13054 . . P~f~ 296 ~?-i?~ 3~S8 .
R2 y ~ / R3 CHCH CONH-CH
2 2 \ C2R
(II
Also preferred are those compounds of formulae (I) and (TI) wherein R and R4 are both H (diacids) as well as biolabile mono and di-ester derivatives thereof wherein one or both of R and R4 is a biolabile ester-forming group.
The term biolabile ester-forming group is well understood in the art as meaning a group which provides an ester which can be readily cleaved in the body to liberate the corresponding diacid of formula (I) wherein R and R4 are both H. A number of such ester groups are well known, for example in the penicillin area or in the case of the ACE-inhibitor antihypertensive agents.
Ln the case of ehe compounds of for~ulae (I) and (II) such biolabile pro-drug esters are particularly advantag,eous in providing compounds of the formula (I) suitable for oral administration. The suitability of any particular e~ster-forming group can be assessed by conventional animal or in vitro enzyme hydrolysis studies. Thus, desirably for optimum effect, the ester should only be hydrolysed after abscrption. accordingly, the ester should be resistant S hydrolysis by digestive enzymes before . : , ~
,, ,. . . ... ... ~ .. . .... .
W O 9l/13054 PCT/~ D~
2~7~5~ ~ ~
absorption but should be readily hydrolyzed by, ror example, gut-wall, plasma or liver enzymes. In this wav the active di~cid is released into the bloodstream following oral absorption.
In addition to lower alkyl esters (particularly ethyl) and benzyl esters, alternative biolabile esters include alkanoyloxyalkyl esters, including alkyl, cycloalkyl and aryl substituted derivatives thereof, aroyloxyalkyl esters, arylesters 9 aralkylesters, halo~lkyl esters and hydroxyalkyl esters including ketal derivatives thereof, wherein said alkanoyl or alkyl groups have from 1 to 18 carbon atoms and are branched or straight chain and said aryl groups arè phenyl, naphthyl or indanyl optionally substituted with one or more (Cl-C14)alkyl, (Cl-C14)alkoxy or (C2-C14)alkoxycarbonyl groups or halo atoms.
Thus examples of R and R4 when they are biolabile ester groups include ethylj indanyl, isopropyl, n-butyl, sec-butyl9 t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl9 acetonyl~ -glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-2-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxyethyl, pentanoyloxyethyl, acetoxyethyl, acetoxyben~yl, pentanoyloxybenæyl, cyclohexyloxycarbonyloxyethyl, butyloxycarbonyloxyethyl, isobutyloxycarbonylethyl and ethoxycarbonyloxyethyl.
In one preferred aspect of the invention, the group R is 4-hvdroxybenzyl and the carbon atom to which it is attached is of (S) stereochemistry; the group N~lCH(R3)C02R being derived from L-~yrosine. Also preferred are compounds wherein R3 is 4-metnoxybenzyl.
.. . . . ... ..
W O 91/13054 ~ 5~ PCTiEPgl~00296 The substituent R Y is preferably (Cl-C6)alkoxy(Cl-C4~alkyl or (Cl-C4)alkoxy(Cl-C6)alkoxy(cl-C4~alkyl. Thus particular and preferred examples include ethoxvetkyl and 2-(methoxvethoxy)-propyl.
Also preferred are compounds where R Y is amino(C4-C9)alkyl.
A particular and preferred exa~ple of this type is 8-amino-octyl.
In a further group of preferred compounds Y is CU2 and R isof formula Rl CONR - wherein R is H. Particularly preferred are examples wherein RlO is substituted phenyl particularly when said substituent is H2NCH2-, (CH3)2NCH2- or CH3S(O?nCH2- (wherein n is O, 1 or 2).
Thus particular and preferred compounds of the invention include-: -N-[1-~2~S)-carboxy-4-(2-methoxyethoxy)pentylJ-l-cyclopentane-carbonyl]-(S)-tyrosine, N-~ 2(S)-carboxy-4-ethoxybutyl)-1-cyclopentanecarbonyl]-(S)- ~ ' tyrosine, N-[1-(2(R,S)-carboxy-10-aminodecyl)-1-cyclopentanecarbonyl]-(S)-tyrosine and N-~ 2(S)-carboxy-3-(4-aminomethylbenzamido)propyl~-l-cyclo-pentanecarbonyl]-(S)-tyrosine.
W O 91~13054 , P ~ /EPg1/00 ~
- 2~7~ ) :
' ~
The compounds of formula (L) are prepared by a number of I :
different processes:
a) One procedure involves the synthesis of a partially protected cycloalkyl-substituted glutaric acid derivative which is coupled to an amino acid ester derivative to give the desired glutaramide. Any reactive groups in R and R3 may require protection during the coupling step and such protecting groups are removed in the final stage of the process.
The synthetic route is illustrated in the following reaction scheme wherein A~ Y and R are as previously defined, R and R
are as defined for R and R with any reactive groups therein protected if necessary and Rl and R are as defined for R and R
excluding H, or they are conventional carboxylic acid protecting groups:
CHCU2 CO2~ + U2 \ 18 (III) I (IV) A Rl R2 _y ( C ~ R3' 2 \ CO2R 8 \~ , (l)'' ~, .. . ..
W O 91/130~4 ~ 5~ PCT/EP91~00296 11 t The reaction of the compounds of formula (TII) and (IV) is achieved using conventional amide coupling techniques. Thus in one process the reaction is achieved with the reactants dissolved in an organic sol~ent, e.g. dichloromethane, using a diimide condensing agont! for example l-ethyl-3-(dimethylaminopropyl)-carbodiimide, or N,~'-dicyclohexylcarbodiimide, advantageously in the presence of l-hydroxybenzotriazole and an organic base such as N-methylmorpholine. The reaction is generally complete after a period of from 12 to 24 hours at room temperature and the product is then isolated by conventional procedures, i.e. by washing with water or filtration to remove the urea biproduct and evaporation of the solvent. The product may be further purified by crystallisatlon or chromatography, if necessary.
The compounds of formula (V) include compounds of formula (I) wherein R and R are Cl-C6 alkyl or benzyl.
The diesters of formula (V) are subsequently reacted to give the monoester or diacid derivatives of formula (I) wherein one or both of R and R4 are H. The conditions used will depend on the precise nature of the groups R and R present in the compound of formula (V) and a number of variations are possible. Thus for example when both of Rl7 and Rl8 are benzyl, hydrogenation of the product will yield the diacid of formula (I) wherein R and R are both H. Alternatively if one of Rl7 and Rl8 is benzyl and the other is alkyl, hydrogenation will yield a ~onoester product.
This can then be hydrolysed, if desired, to again yield the diacic product. When Rl or Rl~ is t-butyl, treatment of the compound of formula (~r) with trifluoroacetic acid or hydrogen . . ; : .
WO 91/13054 ,j - ~ - P~/EY;~/0~5 2~?~7~5~ 12 chloride yields the corresponding acid. If some other carbo~ylic acid protecting group is used for ~ or R then clearly appropriate conditions for its removal must be e~ployed in the final step to give the ester or diacid product of formula (f).
For example when R or R is trimethylsilylethyl it may be removed by treatment with tetrabutylammonium fluoride. Any protecting groups present in R and R must also be removed and this may be performed concominantly with removal of protecting groups present in R17 and R18 or as a procedures appropriate to the particular protecting group employed. Thus, for example when R contains a substituted or protected amino group (for example a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino group) the compounds may be converted to the free amines by hydrogenation or hydrolysis as appropriate.
.
(b) In an alternative process, compounds of the formula (I) wherein R is R CONR - are prepared by a process which involves reacting an amine of the formula:
~ A ~ Rl R NH-~ ~ C J / R
CHCH CONH-CH
R170 C / 2 \ CO2R
(~Il) I
W O 91/~3054 ~73~L~ ` PCT/EP~1/00296 wherein A, Y, R , R , R , Rl and R are as previously defined;
with a carboxylic acid or acid chloride of the formulae:
':
:
Rl0co~H or Rlcocl ~ .
wherein R10 is as previously defined, and wherein any reactive groups therein are optionally protected, to yield for example a compound of the formula: .
:
R6 A~ Rl R C O N-Y \ C R3 R 02C ~ RO 2R
(VII) wherein Rl~ is as previously defined for R10 with any reactive group.s therein optionally protected; and subsequently removing any protecting groups, if present and hydrolysing the ester product to yield the compounds of formula (I) wherein R and R are H. ~:
:: .
.
: . , ~, W O 91/l3054 ' i PCT/EP91/O~?a.6 The reaction of the amine of formula (VI) and acid of formula R C02H is achieved using conventional amide coupling techniques a~ previously described. In the case where R1 is tR5)2N, the acid cllloride may be prepared by first reacting the amine with phosgene; subsequent reaction with the amine of formula (VI) yields the urea products. Subsequent removal of protecting groups is achieved using appropriate procedures as previously described.
The am1nes of formula (VI) are prepared following the same procedure outlined in process (a) above but using an acid of formula (III) wherein R? is a protected amine. Thus, in one ~ariant of this process, the coupling reaction with the amino acid derivative is achieved using a compound of formula (III) wherein R2 ls dibenzylamino or di(alpha-methylbenzyl)amino .
Hydrogenation of the coupled product of formula (V) gives the amine of for~ula (VI) wherein R is H.
c) Certain compounds of formula (I) are best prepared by routes which involve coupling a precursor stage to give a diester derivative of formula (V) type, which is then subjected to a chemical transformation reaction to give the particular R2 group desired.
Thus for example the coupling process may be performed using an acid of formula (III) wherein R is halo (e.g. bromo). This may then be reacted with an amine of formula (R )2NH to yield the compounds wherein R is (R )2N-, or with an azide to give compounds wherein R- is N3. Subsequent reduction of the azide group by catalytic hydrogenation, either on the protected prodvct or on the deprotected diacid, gives the corresponding amine o~
formula (I) wherein R is NH2.
j W O 91/130~4 ~ PCT/EP~/00296 -,~ s 15 In another variation, an acid of formula ~III) is used wherein R Y- is 2-propenyl. Reaction of the coupled product of formu]a (V~ with a (Cl-C6)alkanol or (Cl-C,)alkoxy(Cl-C6)alkanol in the presence of mercuric acetate and potassium iodide yields the 3-iodo-2-~(Cl-C6)alkoxy]- or 2-[(~l-c4~alkoxy(cl-c6)alk propyl derivative, subsequent reduction (e.g. with tributyltin hydride) yields the corresponding compound of formula (V) wherein Y is propyl and R is ~Cl-C6)alkoxy or (Cl-C4)alkoxy(Cl-C6)alkoxy attached at the 2-position. In a further variant of this process the iodo intermediate can be reacted with a heterocyclic compound (e.g. imidazole) to yield the compound of formula (V) wherein R
is of formula R R CH, R is heterocyclyl(Cl-C4)alkyl and R is t~l-C6)alkoxy.
Compounds of the formula (I) wherein Z is present and is S(O) or S(0)2 can naturally be prepared by oxidation of the corresponding thio derivatives where Z is S. The oxidation may be performed either on the protected diester formula (V) or on the deprotected diacid product. Appropriate reagents will be well known to those skilled in the art but, for example, metachloro-peroxybenzoic acid in excess can be used to give the corresponding sulphones (Z = SO2) or an equimolar amount of sodium metaperiodate to give the sulphoxides (Z = SO).
Appropriate reagents and conditions for all of the above transformations will be well known to those skilled in the art by reference to standard text books and to the examples provided hereafter. Other variations and possibilites for the convenient svnthesis of the range of R substituents will also be evident to those skilled in the art and the above are representacive of some of the variations which are possible.
:
, . , ;. . : ~.: , .
:, ' ' . ' ' ', ' ' ' ! ' , . . . : ' :
W O 91/13054 : PCT/EP91/00 ~
~7~
Compounds of che formula (I) wherein one or both of R and R
is a biolabile ester-forming group are prepared following similar procedures to those outlined above using the appropria~te ester group for R or R .
As well as removing any protecting group which may be present in R , a number of chemical transformation reactions are possible on the final mono-ester or diacid products as previously described. In each case the product ~ay be obtained as the free carboxylic acid or it may be neutralised with an appropriate base `
and isolated in salt form.
Appropriate coupling and protecting methods for all of the above steps and alternative variations and procedures will be ~ell known to those skilled in the art by reference to appropriate text books and to the examples provided hereafter.
The starting spiro-substituted glutaric acid ~ono esters of formula (III) may be prepared as described in our European patent application 274234. The amino acid esters of formula (IV) are generally known compounds which are either commercially available or they may be prepared by standard methods in accordance with literature precedents.
As previously mentioned, the compounds of the invention are potent inhibitors of the neutral endopeptidase (E.C.3.4.24.ll).
This enzyme is involved in the breakdown of a nu~ber of peptide hormones including 9 in particular the breakdown of atrial natriuretic factor (ANF?. Thus, the compounds of the invention, by preventing the degradation of ANF by endopeptidase ~.C.3.4.24. 11, can potentiate its biological effects and the compounds are thus diuretic, natriuretic and antihypertensive ~ 9l/l3054 17 ~7q~5~ PCT/EP9l/00~96 agents of utility in a number of disorders incl.uding hypertension, ;~
heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oedema, Menieres disease~ hyperaldosteroneism ~primary and secondary) and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), the modulation of gastric acid secretion and the treatment of hyperreninaemia.
Activity agalnst neutral endopeptidase E.C.3.4.24.11 is assessed using a procedure based on the assay described by J. T.
Gafford,.R. A. Skidgel, E. G. Erdos and L. B. Hersh, Biochemistry, 1983, 32, 3265-3271. The metbod involves determining the concentration of compound required to reduce by 50~ the rate of release of radiolabelled hippuric acid from hippuryl-L-phenylalanyl-L-arginine by a neutral endopeptidase preparation from rat kidney.
As previously mentioned, the compounds of the invention are also inhibitors of angiotensin converting enzyme. As such they are useful in tre~ting a further variety of conditions for which A~E inhibitors are known to be useful including limitation of ischaemic damage to the myocardium, protection of ~he kidney against hyperfiltration damage, prevention or reversal of left W O 91/13054 ~ PCr~EP~I/00 ventricular hypertrophy, memory enhancement, control of cognitive function, dementia, and preventing reocclusion following coronory angioplasty or coronory artery bypass surgery. Their activity against this enzyme is assessed using a modified procedure based on the assay described by Rohrbach, ~I.S., Anal. Biochem., 1978 84, 272. The metho~ involves determining the concentration af compound required to reduce by 50% the extent of release of radiolabelled hippuric acid from hi~puryl-L-histidyl-L-leucine by -~
angiotensin converting enzyme isolated from the rat kidney.
Inhibitory activity is also measured in vlvo following intravenous injection to anaesthetised rats using the methods described by I. L. Natoff et al, Journal of Pharmacological Methods, 1981, 5, 305 and by D. M. Gross et al, J. Pharmacol. Exp. ;
Ther., 1981, 216, 552. The dose of inhibitor required to reduce ; the pressor response produced by intravenous injection of angiotensin I (50 ng bolus) by 50% is determined.
The activity of the compounds as diuretic agents is determined by measuring their ability to increase urine output and sodium ion excretion in saline loaded conscious mice. In this test, male ~ice (Charles River CDl, 22-28 g) are acclimatised and `-starved overnight ln metabowls. The mice are dosed intravenously via the tail vein, with the test compound dissolvéd in a volume of saline solution equivalent to 2.5% of body weight. Urine samples are collected each hour for two hours in pre-weighed tubes and analysed for electrolyte concentration. Urine volume and sodium ion concentration from the test animals are compared to a contro~
group which rec~ived only saline.
The antihypertensive activity of the compounds is evaluated .. . . .
i : :
,C ~3~
0 91/13054 P ~ /EP91/a~296 19, ' ' - :"
by measuring the ~all in blood pressure following oral or intravenous administration to salt depleted, diuretic primed, spontaneously hypertensive rats, salt depleted renall~
hypertensi~re do~s, or DOCA/salt hypertensive rats.
For administration to man in the curative or prophylactic treatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the compounds will generally be in the range of from 3-lS00 mg daily for an average adult patient t70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier for administration singly, or i.n multiple doses, once or several times a day. Dosages for intravenous administration would typically be within the range 1 to 500 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The abo~e dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage "
ranges are merited, and such are within the scope of this invention.
For human use, the compounds of the formula (I) can be administered alone, but will generally be administered in ;~
admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical prac~ice. For example, they may be administered orally in ~he form of tablets containing such excipients as starch or lactose, - or in capsules or ovules either alone or in admixture with .. . .: , . . .. , . . , .. ... :
~; :
. .
e~cipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. The may be injected parenterally, for example, intravenously, intra-muscularly or subcutaneously. For parenteral administra-tion, they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
The compounds may be co-administered with other agents as may be beneficial for the control of blood pressure or the treatment of cardiac conditions or renal insufficiencyO
Thus for example they may be co-administered with digitalis or another cardiac-stimulant drug or with an alpha-blocker, beta~blocker, exogenous ANF or with a potassium channel activator or another diuretic agent as shall be determined by the physician as appropriate to the particular patient or disease state.
Thus in a further aspect the invention provides a pharmaceutical composition comprising a compound of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharma-ceutically acceptable diluent or carrier.
The invention also includes a compound of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for use in medicine, in particular in the treatment of hypertension, congestive heart failure or renal insufficiency in a human being.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use in medicine in particular for the treatment of hypertension, congestive heart failure or renal insufficiency in a human being.
The preparation of the compounds of the invention and of intermediates for use in their preparation is illustrated by the F~
~ ~ .
, .. ...
~ 91/13054 ; ~ ~ PC~/EP91/00296 ~1 ' following Examples. Thin layer chromatography was performed on silica plates using the following solvent systems: ethyl acetate, ¦
hexane, l:l(ss l); ethyl acetate, hexane, 1:3(ss-~); methyl :
isobutyl ketone, water, acetic acid, 2:1:1,(ss 3); diethyl ether, hexane, 3:7(ss 4); ethyl acetate(ss 5); diethyl ether(ss 6);
dichloromethane, methanol, acetic acid, 80:20:1(ss 7), diethyl :::
ether, hexane, l:l(ss 8), heXane, ethyl acetate, 4:1 (ss 9), or :~
n-butanol, acetic acid, water, 12:3:5 (ss 10) .
W O 91/130~4 PCT/EP9D~0~ ~
` 2~7~5~ t~
_ _ _ _ ~
1-(2-t-Butoxycarbonyl___ ethoxybutyl)cyclo~ntane carbox lic acid ____. __ Y
A solution of t-butyl 3-(1-carboxycyclopentyl~propanoate (300 g, 12.38 mmol) in dry tetrahydrofuran (10 ~1) was added to a stirred solution of lithium diisopropylamide (26 mmol) in a mixture of hexane (10.4 ml) and tetrahydrofuran (45 ml) at -70C
under nitrogen. After 1 hour a solution of 2-iodo-1-ethoxvethane (4.95 g, 24.8 m~ol) in dry tetrahydrofuran (10 ml) was added maintaining the temperature at -70C. After an hour at that temperature, the solution was allowed to warm up to room temperature overnight and left for a further two days. The mixture was then acidified to pEI 2 with 2N hydrochloric acid, and extracted with ether. The organic extract was washed with brine, dried (MgS04) and the solvent evaporated to give the crude acid which was chromatographed on silica. Elution with increasing proportions of ethyl acetate in hexane (1:4 to neat ethyl acetate) gave an oil (2.5 g, 55%). Rf 0.15 hexane, ethyl acetate, 401)o Found: C,65.10; H,9.36. C17H3005 requires C,64.94; H,9.62%.
EXAMP~ES 2-8 The following compounds were prepared by alkylating l-carboxy-cyclopentylpropanoic acid t-butyl ester using the appropriate bromo or iodocompound following the procedure of Example 1.
~Y r~ ~
Bu02C / \/ \ C()~i .; ~ . . ,, .......... .
. ~ ......... ~ .. .... . ; . .
W O 91/13054 PCT~EPgl/00~96 .
, ; :
Example R2~Y- For~ I Analysis ~
No isolated (Theoretical in brac~ets) T.L.C. C H N
. _ .
2 / oil 64.43 8.82 :~.
o ~ _OCH2-Rf 0.3 (64.02 9.05) /(ss 1), __ . __. . . I
(II
Also preferred are those compounds of formulae (I) and (TI) wherein R and R4 are both H (diacids) as well as biolabile mono and di-ester derivatives thereof wherein one or both of R and R4 is a biolabile ester-forming group.
The term biolabile ester-forming group is well understood in the art as meaning a group which provides an ester which can be readily cleaved in the body to liberate the corresponding diacid of formula (I) wherein R and R4 are both H. A number of such ester groups are well known, for example in the penicillin area or in the case of the ACE-inhibitor antihypertensive agents.
Ln the case of ehe compounds of for~ulae (I) and (II) such biolabile pro-drug esters are particularly advantag,eous in providing compounds of the formula (I) suitable for oral administration. The suitability of any particular e~ster-forming group can be assessed by conventional animal or in vitro enzyme hydrolysis studies. Thus, desirably for optimum effect, the ester should only be hydrolysed after abscrption. accordingly, the ester should be resistant S hydrolysis by digestive enzymes before . : , ~
,, ,. . . ... ... ~ .. . .... .
W O 9l/13054 PCT/~ D~
2~7~5~ ~ ~
absorption but should be readily hydrolyzed by, ror example, gut-wall, plasma or liver enzymes. In this wav the active di~cid is released into the bloodstream following oral absorption.
In addition to lower alkyl esters (particularly ethyl) and benzyl esters, alternative biolabile esters include alkanoyloxyalkyl esters, including alkyl, cycloalkyl and aryl substituted derivatives thereof, aroyloxyalkyl esters, arylesters 9 aralkylesters, halo~lkyl esters and hydroxyalkyl esters including ketal derivatives thereof, wherein said alkanoyl or alkyl groups have from 1 to 18 carbon atoms and are branched or straight chain and said aryl groups arè phenyl, naphthyl or indanyl optionally substituted with one or more (Cl-C14)alkyl, (Cl-C14)alkoxy or (C2-C14)alkoxycarbonyl groups or halo atoms.
Thus examples of R and R4 when they are biolabile ester groups include ethylj indanyl, isopropyl, n-butyl, sec-butyl9 t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl9 acetonyl~ -glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-2-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxyethyl, pentanoyloxyethyl, acetoxyethyl, acetoxyben~yl, pentanoyloxybenæyl, cyclohexyloxycarbonyloxyethyl, butyloxycarbonyloxyethyl, isobutyloxycarbonylethyl and ethoxycarbonyloxyethyl.
In one preferred aspect of the invention, the group R is 4-hvdroxybenzyl and the carbon atom to which it is attached is of (S) stereochemistry; the group N~lCH(R3)C02R being derived from L-~yrosine. Also preferred are compounds wherein R3 is 4-metnoxybenzyl.
.. . . . ... ..
W O 91/13054 ~ 5~ PCTiEPgl~00296 The substituent R Y is preferably (Cl-C6)alkoxy(Cl-C4~alkyl or (Cl-C4)alkoxy(Cl-C6)alkoxy(cl-C4~alkyl. Thus particular and preferred examples include ethoxvetkyl and 2-(methoxvethoxy)-propyl.
Also preferred are compounds where R Y is amino(C4-C9)alkyl.
A particular and preferred exa~ple of this type is 8-amino-octyl.
In a further group of preferred compounds Y is CU2 and R isof formula Rl CONR - wherein R is H. Particularly preferred are examples wherein RlO is substituted phenyl particularly when said substituent is H2NCH2-, (CH3)2NCH2- or CH3S(O?nCH2- (wherein n is O, 1 or 2).
Thus particular and preferred compounds of the invention include-: -N-[1-~2~S)-carboxy-4-(2-methoxyethoxy)pentylJ-l-cyclopentane-carbonyl]-(S)-tyrosine, N-~ 2(S)-carboxy-4-ethoxybutyl)-1-cyclopentanecarbonyl]-(S)- ~ ' tyrosine, N-[1-(2(R,S)-carboxy-10-aminodecyl)-1-cyclopentanecarbonyl]-(S)-tyrosine and N-~ 2(S)-carboxy-3-(4-aminomethylbenzamido)propyl~-l-cyclo-pentanecarbonyl]-(S)-tyrosine.
W O 91~13054 , P ~ /EPg1/00 ~
- 2~7~ ) :
' ~
The compounds of formula (L) are prepared by a number of I :
different processes:
a) One procedure involves the synthesis of a partially protected cycloalkyl-substituted glutaric acid derivative which is coupled to an amino acid ester derivative to give the desired glutaramide. Any reactive groups in R and R3 may require protection during the coupling step and such protecting groups are removed in the final stage of the process.
The synthetic route is illustrated in the following reaction scheme wherein A~ Y and R are as previously defined, R and R
are as defined for R and R with any reactive groups therein protected if necessary and Rl and R are as defined for R and R
excluding H, or they are conventional carboxylic acid protecting groups:
CHCU2 CO2~ + U2 \ 18 (III) I (IV) A Rl R2 _y ( C ~ R3' 2 \ CO2R 8 \~ , (l)'' ~, .. . ..
W O 91/130~4 ~ 5~ PCT/EP91~00296 11 t The reaction of the compounds of formula (TII) and (IV) is achieved using conventional amide coupling techniques. Thus in one process the reaction is achieved with the reactants dissolved in an organic sol~ent, e.g. dichloromethane, using a diimide condensing agont! for example l-ethyl-3-(dimethylaminopropyl)-carbodiimide, or N,~'-dicyclohexylcarbodiimide, advantageously in the presence of l-hydroxybenzotriazole and an organic base such as N-methylmorpholine. The reaction is generally complete after a period of from 12 to 24 hours at room temperature and the product is then isolated by conventional procedures, i.e. by washing with water or filtration to remove the urea biproduct and evaporation of the solvent. The product may be further purified by crystallisatlon or chromatography, if necessary.
The compounds of formula (V) include compounds of formula (I) wherein R and R are Cl-C6 alkyl or benzyl.
The diesters of formula (V) are subsequently reacted to give the monoester or diacid derivatives of formula (I) wherein one or both of R and R4 are H. The conditions used will depend on the precise nature of the groups R and R present in the compound of formula (V) and a number of variations are possible. Thus for example when both of Rl7 and Rl8 are benzyl, hydrogenation of the product will yield the diacid of formula (I) wherein R and R are both H. Alternatively if one of Rl7 and Rl8 is benzyl and the other is alkyl, hydrogenation will yield a ~onoester product.
This can then be hydrolysed, if desired, to again yield the diacic product. When Rl or Rl~ is t-butyl, treatment of the compound of formula (~r) with trifluoroacetic acid or hydrogen . . ; : .
WO 91/13054 ,j - ~ - P~/EY;~/0~5 2~?~7~5~ 12 chloride yields the corresponding acid. If some other carbo~ylic acid protecting group is used for ~ or R then clearly appropriate conditions for its removal must be e~ployed in the final step to give the ester or diacid product of formula (f).
For example when R or R is trimethylsilylethyl it may be removed by treatment with tetrabutylammonium fluoride. Any protecting groups present in R and R must also be removed and this may be performed concominantly with removal of protecting groups present in R17 and R18 or as a procedures appropriate to the particular protecting group employed. Thus, for example when R contains a substituted or protected amino group (for example a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino group) the compounds may be converted to the free amines by hydrogenation or hydrolysis as appropriate.
.
(b) In an alternative process, compounds of the formula (I) wherein R is R CONR - are prepared by a process which involves reacting an amine of the formula:
~ A ~ Rl R NH-~ ~ C J / R
CHCH CONH-CH
R170 C / 2 \ CO2R
(~Il) I
W O 91/~3054 ~73~L~ ` PCT/EP~1/00296 wherein A, Y, R , R , R , Rl and R are as previously defined;
with a carboxylic acid or acid chloride of the formulae:
':
:
Rl0co~H or Rlcocl ~ .
wherein R10 is as previously defined, and wherein any reactive groups therein are optionally protected, to yield for example a compound of the formula: .
:
R6 A~ Rl R C O N-Y \ C R3 R 02C ~ RO 2R
(VII) wherein Rl~ is as previously defined for R10 with any reactive group.s therein optionally protected; and subsequently removing any protecting groups, if present and hydrolysing the ester product to yield the compounds of formula (I) wherein R and R are H. ~:
:: .
.
: . , ~, W O 91/l3054 ' i PCT/EP91/O~?a.6 The reaction of the amine of formula (VI) and acid of formula R C02H is achieved using conventional amide coupling techniques a~ previously described. In the case where R1 is tR5)2N, the acid cllloride may be prepared by first reacting the amine with phosgene; subsequent reaction with the amine of formula (VI) yields the urea products. Subsequent removal of protecting groups is achieved using appropriate procedures as previously described.
The am1nes of formula (VI) are prepared following the same procedure outlined in process (a) above but using an acid of formula (III) wherein R? is a protected amine. Thus, in one ~ariant of this process, the coupling reaction with the amino acid derivative is achieved using a compound of formula (III) wherein R2 ls dibenzylamino or di(alpha-methylbenzyl)amino .
Hydrogenation of the coupled product of formula (V) gives the amine of for~ula (VI) wherein R is H.
c) Certain compounds of formula (I) are best prepared by routes which involve coupling a precursor stage to give a diester derivative of formula (V) type, which is then subjected to a chemical transformation reaction to give the particular R2 group desired.
Thus for example the coupling process may be performed using an acid of formula (III) wherein R is halo (e.g. bromo). This may then be reacted with an amine of formula (R )2NH to yield the compounds wherein R is (R )2N-, or with an azide to give compounds wherein R- is N3. Subsequent reduction of the azide group by catalytic hydrogenation, either on the protected prodvct or on the deprotected diacid, gives the corresponding amine o~
formula (I) wherein R is NH2.
j W O 91/130~4 ~ PCT/EP~/00296 -,~ s 15 In another variation, an acid of formula ~III) is used wherein R Y- is 2-propenyl. Reaction of the coupled product of formu]a (V~ with a (Cl-C6)alkanol or (Cl-C,)alkoxy(Cl-C6)alkanol in the presence of mercuric acetate and potassium iodide yields the 3-iodo-2-~(Cl-C6)alkoxy]- or 2-[(~l-c4~alkoxy(cl-c6)alk propyl derivative, subsequent reduction (e.g. with tributyltin hydride) yields the corresponding compound of formula (V) wherein Y is propyl and R is ~Cl-C6)alkoxy or (Cl-C4)alkoxy(Cl-C6)alkoxy attached at the 2-position. In a further variant of this process the iodo intermediate can be reacted with a heterocyclic compound (e.g. imidazole) to yield the compound of formula (V) wherein R
is of formula R R CH, R is heterocyclyl(Cl-C4)alkyl and R is t~l-C6)alkoxy.
Compounds of the formula (I) wherein Z is present and is S(O) or S(0)2 can naturally be prepared by oxidation of the corresponding thio derivatives where Z is S. The oxidation may be performed either on the protected diester formula (V) or on the deprotected diacid product. Appropriate reagents will be well known to those skilled in the art but, for example, metachloro-peroxybenzoic acid in excess can be used to give the corresponding sulphones (Z = SO2) or an equimolar amount of sodium metaperiodate to give the sulphoxides (Z = SO).
Appropriate reagents and conditions for all of the above transformations will be well known to those skilled in the art by reference to standard text books and to the examples provided hereafter. Other variations and possibilites for the convenient svnthesis of the range of R substituents will also be evident to those skilled in the art and the above are representacive of some of the variations which are possible.
:
, . , ;. . : ~.: , .
:, ' ' . ' ' ', ' ' ' ! ' , . . . : ' :
W O 91/13054 : PCT/EP91/00 ~
~7~
Compounds of che formula (I) wherein one or both of R and R
is a biolabile ester-forming group are prepared following similar procedures to those outlined above using the appropria~te ester group for R or R .
As well as removing any protecting group which may be present in R , a number of chemical transformation reactions are possible on the final mono-ester or diacid products as previously described. In each case the product ~ay be obtained as the free carboxylic acid or it may be neutralised with an appropriate base `
and isolated in salt form.
Appropriate coupling and protecting methods for all of the above steps and alternative variations and procedures will be ~ell known to those skilled in the art by reference to appropriate text books and to the examples provided hereafter.
The starting spiro-substituted glutaric acid ~ono esters of formula (III) may be prepared as described in our European patent application 274234. The amino acid esters of formula (IV) are generally known compounds which are either commercially available or they may be prepared by standard methods in accordance with literature precedents.
As previously mentioned, the compounds of the invention are potent inhibitors of the neutral endopeptidase (E.C.3.4.24.ll).
This enzyme is involved in the breakdown of a nu~ber of peptide hormones including 9 in particular the breakdown of atrial natriuretic factor (ANF?. Thus, the compounds of the invention, by preventing the degradation of ANF by endopeptidase ~.C.3.4.24. 11, can potentiate its biological effects and the compounds are thus diuretic, natriuretic and antihypertensive ~ 9l/l3054 17 ~7q~5~ PCT/EP9l/00~96 agents of utility in a number of disorders incl.uding hypertension, ;~
heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oedema, Menieres disease~ hyperaldosteroneism ~primary and secondary) and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), the modulation of gastric acid secretion and the treatment of hyperreninaemia.
Activity agalnst neutral endopeptidase E.C.3.4.24.11 is assessed using a procedure based on the assay described by J. T.
Gafford,.R. A. Skidgel, E. G. Erdos and L. B. Hersh, Biochemistry, 1983, 32, 3265-3271. The metbod involves determining the concentration of compound required to reduce by 50~ the rate of release of radiolabelled hippuric acid from hippuryl-L-phenylalanyl-L-arginine by a neutral endopeptidase preparation from rat kidney.
As previously mentioned, the compounds of the invention are also inhibitors of angiotensin converting enzyme. As such they are useful in tre~ting a further variety of conditions for which A~E inhibitors are known to be useful including limitation of ischaemic damage to the myocardium, protection of ~he kidney against hyperfiltration damage, prevention or reversal of left W O 91/13054 ~ PCr~EP~I/00 ventricular hypertrophy, memory enhancement, control of cognitive function, dementia, and preventing reocclusion following coronory angioplasty or coronory artery bypass surgery. Their activity against this enzyme is assessed using a modified procedure based on the assay described by Rohrbach, ~I.S., Anal. Biochem., 1978 84, 272. The metho~ involves determining the concentration af compound required to reduce by 50% the extent of release of radiolabelled hippuric acid from hi~puryl-L-histidyl-L-leucine by -~
angiotensin converting enzyme isolated from the rat kidney.
Inhibitory activity is also measured in vlvo following intravenous injection to anaesthetised rats using the methods described by I. L. Natoff et al, Journal of Pharmacological Methods, 1981, 5, 305 and by D. M. Gross et al, J. Pharmacol. Exp. ;
Ther., 1981, 216, 552. The dose of inhibitor required to reduce ; the pressor response produced by intravenous injection of angiotensin I (50 ng bolus) by 50% is determined.
The activity of the compounds as diuretic agents is determined by measuring their ability to increase urine output and sodium ion excretion in saline loaded conscious mice. In this test, male ~ice (Charles River CDl, 22-28 g) are acclimatised and `-starved overnight ln metabowls. The mice are dosed intravenously via the tail vein, with the test compound dissolvéd in a volume of saline solution equivalent to 2.5% of body weight. Urine samples are collected each hour for two hours in pre-weighed tubes and analysed for electrolyte concentration. Urine volume and sodium ion concentration from the test animals are compared to a contro~
group which rec~ived only saline.
The antihypertensive activity of the compounds is evaluated .. . . .
i : :
,C ~3~
0 91/13054 P ~ /EP91/a~296 19, ' ' - :"
by measuring the ~all in blood pressure following oral or intravenous administration to salt depleted, diuretic primed, spontaneously hypertensive rats, salt depleted renall~
hypertensi~re do~s, or DOCA/salt hypertensive rats.
For administration to man in the curative or prophylactic treatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the compounds will generally be in the range of from 3-lS00 mg daily for an average adult patient t70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier for administration singly, or i.n multiple doses, once or several times a day. Dosages for intravenous administration would typically be within the range 1 to 500 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The abo~e dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage "
ranges are merited, and such are within the scope of this invention.
For human use, the compounds of the formula (I) can be administered alone, but will generally be administered in ;~
admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical prac~ice. For example, they may be administered orally in ~he form of tablets containing such excipients as starch or lactose, - or in capsules or ovules either alone or in admixture with .. . .: , . . .. , . . , .. ... :
~; :
. .
e~cipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. The may be injected parenterally, for example, intravenously, intra-muscularly or subcutaneously. For parenteral administra-tion, they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
The compounds may be co-administered with other agents as may be beneficial for the control of blood pressure or the treatment of cardiac conditions or renal insufficiencyO
Thus for example they may be co-administered with digitalis or another cardiac-stimulant drug or with an alpha-blocker, beta~blocker, exogenous ANF or with a potassium channel activator or another diuretic agent as shall be determined by the physician as appropriate to the particular patient or disease state.
Thus in a further aspect the invention provides a pharmaceutical composition comprising a compound of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharma-ceutically acceptable diluent or carrier.
The invention also includes a compound of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for use in medicine, in particular in the treatment of hypertension, congestive heart failure or renal insufficiency in a human being.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use in medicine in particular for the treatment of hypertension, congestive heart failure or renal insufficiency in a human being.
The preparation of the compounds of the invention and of intermediates for use in their preparation is illustrated by the F~
~ ~ .
, .. ...
~ 91/13054 ; ~ ~ PC~/EP91/00296 ~1 ' following Examples. Thin layer chromatography was performed on silica plates using the following solvent systems: ethyl acetate, ¦
hexane, l:l(ss l); ethyl acetate, hexane, 1:3(ss-~); methyl :
isobutyl ketone, water, acetic acid, 2:1:1,(ss 3); diethyl ether, hexane, 3:7(ss 4); ethyl acetate(ss 5); diethyl ether(ss 6);
dichloromethane, methanol, acetic acid, 80:20:1(ss 7), diethyl :::
ether, hexane, l:l(ss 8), heXane, ethyl acetate, 4:1 (ss 9), or :~
n-butanol, acetic acid, water, 12:3:5 (ss 10) .
W O 91/130~4 PCT/EP9D~0~ ~
` 2~7~5~ t~
_ _ _ _ ~
1-(2-t-Butoxycarbonyl___ ethoxybutyl)cyclo~ntane carbox lic acid ____. __ Y
A solution of t-butyl 3-(1-carboxycyclopentyl~propanoate (300 g, 12.38 mmol) in dry tetrahydrofuran (10 ~1) was added to a stirred solution of lithium diisopropylamide (26 mmol) in a mixture of hexane (10.4 ml) and tetrahydrofuran (45 ml) at -70C
under nitrogen. After 1 hour a solution of 2-iodo-1-ethoxvethane (4.95 g, 24.8 m~ol) in dry tetrahydrofuran (10 ml) was added maintaining the temperature at -70C. After an hour at that temperature, the solution was allowed to warm up to room temperature overnight and left for a further two days. The mixture was then acidified to pEI 2 with 2N hydrochloric acid, and extracted with ether. The organic extract was washed with brine, dried (MgS04) and the solvent evaporated to give the crude acid which was chromatographed on silica. Elution with increasing proportions of ethyl acetate in hexane (1:4 to neat ethyl acetate) gave an oil (2.5 g, 55%). Rf 0.15 hexane, ethyl acetate, 401)o Found: C,65.10; H,9.36. C17H3005 requires C,64.94; H,9.62%.
EXAMP~ES 2-8 The following compounds were prepared by alkylating l-carboxy-cyclopentylpropanoic acid t-butyl ester using the appropriate bromo or iodocompound following the procedure of Example 1.
~Y r~ ~
Bu02C / \/ \ C()~i .; ~ . . ,, .......... .
. ~ ......... ~ .. .... . ; . .
W O 91/13054 PCT~EPgl/00~96 .
, ; :
Example R2~Y- For~ I Analysis ~
No isolated (Theoretical in brac~ets) T.L.C. C H N
. _ .
2 / oil 64.43 8.82 :~.
o ~ _OCH2-Rf 0.3 (64.02 9.05) /(ss 1), __ . __. . . I
3 CH30(CH2)40(cH2)2 oil , 64.24 9.90 ?
Rf 0.45 ¦ (64.49 9.74) `~.
. (5sl) . .':
_ __ _ . ~ ' 4 CH30CH2CH=CHCH20(CH2)2 oil 62.36 8.83 Rf 0.45 (62.62 8.95) ¦ (S5 1) (O. 2 mole CH2C12) . ! !~ ~
Br(CH2)6- ¦ oil ~1 .
Rf 0.5 _ . I(ss 2) ; ' .
.
W O 9IJ130~4 PCr/EP9l/00 ~
~7~5~) ~
~4 6 ,, I oi~. 61.86 8.~q 3.36, , ~ ¦ Rf 0.4 (61.79 8.93 2.80)~ :
BOC-- N ~-~C~z~ j ~ (ss 1) (Q.25 mole ~H2Cl~
7 Br(CH2)8- oil 58.08 8.60 . . Rf 0.9 t58.15 8.60) . (ss 3) : 8R19OCH2 ~ -O(CH2)2 oil 65.36 8,97 . . Rf 0.9 (65.20 9.19) (ss 1) (0.5 mole H20) _ ... ~ . . _ _._ .
BOC = t-butoxycarbonyl R 9 = dimethyl-t-butylsilyl 1-[2(RS)-t-Butoxycarbonyl- _-azidodecyl~ cyclopentane carboxvlic acid Tetramethylguanidinium azide (0.7 g, 6 mmol) was added as a solution in chloroform (10 ml) to a solution of 1-[2(RS)-t-butoxycarbonyl-10-bromodecyl]-1-cyclopentane carboxylic acid (1.4 g, 3 mmol) in chloroform (10 ml). A few crystals of potassiu~
iodide were added and the resulting mixture was refluxed for 2 days. The cooled reactlon mixture was ehen diluted with :~
~ O 91~13054 2~3~ 5~ ~ PCT/EP9l/00296 chloroform (20 ml~ and washed with water (2 x 20 ml), dried (MgS04), filtered and evaporated. The residue was chromatographed on silica gel using a gradient of ethyl acetate and hexane to give the title compound as an oil (0.69 g, 54%). Found: C,63.84;
H,9.41; N,9.22. C2lH37N304 requires C,63.77; H,9.43; ~,10.62%o Rf 0.9 (ethyl acetate).
` ~ .
acid A mixture of 1-(2(R,S)-t-butoxycarbonyl-4-pentenyl)cyclo-pentane carboxylic acid (EP-A-0274234, Example 44) (28.24 g, 0.1 mmol) and (+)- pseudoephedrin were recrystallised three times from hexane to give a white crystaline solid (18.9 g, 42~3 m.p.
106.5-107.5C. 1~]DS+ 20.5 [~]26S + 70.7 (c = 1.07, methanol).
The above salt was dissolved in ether and washed with lN
hydrochloric aeid and saturated salt solution. Drying (MgS04) and evaporation gave the requlred R-acid as an oil (ll.9 g). Rf 0,7 ~;
(ethyl acetate, hexane, 1:1). [~i~D~- 11.8, [dl~655 _ 36.5 (c =
1.03, methanol).
,' XA~PLE ll 1-[2~ _)-t-Butoxycarbonyl-4-pentenyl]-1-cyclopentane carboxylic acid benzyl ester . . . _ _ . _ Anhydrous potassium carbonate (13.5 g, 98 mmol) was added in one portion to a stirred and ice-cooled solution of 1-[2(RS)-t butoxycarbonyl-4-pentenyl]-l-cyclopentane carhoxvlic acid (]0.95 g, 38 mmol~ and benzyl bromide (~.6 g, 38 mmol) in dry dimethyl-formamide (30 ~Il). After 3 hours the reaction mixture was diluted " :' , ' ' . ' : ' '~, : . ,' ' ' : : :, . ' :' : ' ' ' . :, . , : . ' . ' , ' ' : : ' : ' ' W O 91/13054 '. ; PCT/EP9~ ~
2~3~5~ `26 with ethyl ace~ate (100 ml) and water (100 mi). The or~anic phase was separated and washed with further por~ions of water (1 x 20 ml) lM hydrochloric acid (5 x 20 ml), brine (1 x 10 ml), dried (MgS04), and the solution filtered and evaporated to yield the -title compound as an oil (14.14 g, 98%). This oil was used without further purification. Rf 0.86 (ethylacetate, toluene~ ¦
1:4).
1-[2(RS)-t-Butoxycarbo y -4-oxobutyl~ yclopentane _arboxylic a _d benzyl ester Osmium tetroxide (56 mg, 0.2 mmol) was added as a 2.5% w/v solution in t-butanol (2.25 ml) to a stirred solution of 1-[2(RS)-t-bu~oxycarbonyl-4-pentenyl]l-cyclopentane carboxylic acid benzyl ester (8.25 g, 22 mmol) in acetonitrile (60 ml) and water (10 ml) at room te~perature. After 30 minutes, the black-brown solution was treated with sodium metaperiodate (10 g, 47 mm:l) in one portion. Stirring was continued for 18 hours and then the suspended solid was filtered and washed with a small portion of acetonitrile. The filtrate was evaporated and the dark residue was chromatographed on silica gel eluting with a gradient of ethyl acetate and hexane to yield the title compound as an oil (3.77 g, 45%). Rf 0.58 (diethyl ether, petrol, 1:1).
,, : ~. , ,~. :. . - ,. . . , : . ::
I;
0 91/13054 ~ PCT/E ~1/002g6 _-[2(~S)-t-Butoxycarbo_v1-3-carboxy~ opyll~l-cyclopentane carboxylic acid benzyl ester _ ..
Potassium permanganate (7.6 g, 48 mmol) as a solution in water (48 ml) was added slowly to a stirred solution of l-[2(RS)-t-butoxycarbonyl-4-oxobutyl]-1-cyclopentane carboxylic acid benzyl ~
ester (51 g, 12 mmol) in t-butanol (70 ml) and lM sodium ~;
dihydrogen phosphate buffer solution (20 ml). The resulting mixture was stirred vigorously for 30 minutes. Excess oxidant was destroyed by the addition of solid sodium metabisulphate t8 g).
The brown suspension was filtered, the filter pad being washed with ethyl acetate (50 ml). The filtrate was separated into two phases and the aqueous phase was extracted with ethylacetate (30 ml). The combined organic solutions were dried (MgS04), filtered and evaporated to give the title compound as aD oil t4.52 g, 96%).
Rf 0.7 (ss 5j.
' ' N-~ 3-[4-(t-Butoxycarbonylaminomethyl)b~nzoylamino]-2(S)-t-butoxycarbonylpropyl~-l-cyclopentanecarbonyl~-O~t-butyl-(S)-osine-t-butyl ester To an ice-cold solution of 4--t-butoxycarbonylaminomethyl-benzoic acid (0.689 g, 2.74 mmol) in dry dichloromethane (30 ml) was added l-hydroxybenztriazole (0.409 g, 3.02 mmol), l-ethyl-3-(dimethylaminopropyl)-carbodiimide (0.684 g, 3.57 mmol~ and N-methylmorpholine (0.360 g, 3.57 mmol) and the resulting solution stirred at 0C for 30 minutes. N-[1-(3-Aminopropyl-2(S)-t-butoxycarbonyl)-l-cyclopeneanecarbonyll-0-t-butyl-(S)-tyrosine : ' ' . ',, . : .', . ' . ' . : ': ' ' ' ': ., ': . ' : `,; , ;.,: ': .: .,. ' ' :: :,' : ' : . :; ' : :. : ' ' ~ . ' , . ':: ' ' ' ' : : : : ' '- ' ; . : ' ' ' : : : : : . .: . . : , " : : ,. .; ,:,' ' ', , .:,: ' . ,. , :
W O 91/13054 ~` i PCT/EP91/00 ~
2@7~5~ 28 t-butyl ester was ad~ed to this solution and stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the resultant oil dissolved in ethyl acetate (~0 ml) and washed with 2M hydrochloric acid (50 ml), saturated aqueous sodiu~ bicarbonate (2 ~ 5~ ~1) and saturated brine (50 ~1), dried (MgS04) and the solu~ion fi].tered and evaporated to yield the crude product as an oil. Chromatography on silica gel using dichloromethaneldieehyl ether as eluent gave the title compound (1.695 g, 79%) as a white foam. Rf 0.52 (dichloromethane, diethyl ether, 1:1). Found: C,67.52; H,8.47;
N,5.26. C44H65N309 requires C,67.75; H,8.40; N,5.39%
EXAMPI,ES 15-18 The following compounds were prepared following the procedure of Example 14, using the appropriate carboxylic acid derivative of formula R C02H.
~ ( 3)3 ..
R CONH ~ ~
(CH3)3CO,~C CO~H C02C(Cl'.3)3 W O 91/13054 2 ~ PCT/EP91/00296 29 ~
. _ Example¦ RlO¦ Form Analysis %
No isolated (Theoretical in brackets) T.L.C. C H N
. _ '~ `
foam 69.21 8.70 5.65 (CH3)2NCH2- ~Rf 0.38(69.55 8.68 5.93) ~ ~;
~ (ss 3) `
16 foam 67.57 8.22 3.94 CH3SCH2- ~ (f505)5(67.25 8.08 4.02) 17 CH3S02NH foam 58.52 8.00 5.39 (S~CH-Rf 0.83(58.78 8.13 5.56) CH3SCH2CH2(ss 5) _ _ _ 18 CH30CH2CH20C\H2 foam 64.70 8.89 3.69 CH-0.29 (64.37 8.96 3.66) _ CH30CH2CHOCH2 _ . ~ :
, .
W O 91/13054 ` ` PCr~EP9~0 EXAMP_E 19 N~ ~ thoxy-2-(t-butoxYcarbonyl)butyl~-cyc'opentarlecarbonyl]--0-methyl-(S)-t~rosine t-butvl ester l-Ethyl-3-(3-dimethylaminopropyl)carbodiimi~e hydrochloride (762 mg~ 3.98 mmol) was added to an ice cold stirred mixture of 1-(2-t-butoxycarbonyl-4-ethoxybutyl)cyclopentane carboxylic acid from Example 1 (626 mg, 1.99 mmol), 0-methyl-(S)-tyrosine t-butyl ester (500 mg, 1.99 mmol), l-hydroxybenzotriazole (269 mg, 1.99 mmol) and N-methylmorpholine (0.44 ml, 3.98 mmol) in dry methylenechloride (10 ml). After standing at room temperature for 16 hours the mixture was diluted with methylene chloride, washed with water, dried (MgS04) and evaporated under reduced pressure to give an oil. Chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (4:1) gave the pure diester (975 mg;
89%) as an oil. Found: C,67.54; H,8.74; N,2.13. C31H49N07. 0025 H20 requires C,67.42; H,9.03; N,2.53%.
.... . . ., :
The following compounds were prepared as described above using the appropriate cyclopentane carboxylic acid of Examples 1-6 and 8-10 in the coupling step together with the appropriate amine of formula (IV).
~ ~lo (C~3)3co~c ~ ~ ~ C0~ ~ C0~?~
Examples 25 and 26 are the 2(R) isomers, Example 28 is the 2(~) isomer.
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91J13054 '~? ~ PCT/EPg~/0~29 N-[1-~2(S)-t-Butoxvcarbonyl)-5-iodo-4-(2-methoxyethoxypentvl~-]-cyclopentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester Mercuric acetate (662 mg, 2.08 mmol) was added to a stirred solution of the diester from Example 26 (892 mg, 1.6 mmol) in ~-methoxyethanol (4 ml). After 20 hours at room tempera~ure, 2N
sodium hydroxide (3.6 ml) was added followed by potassium iodide (2.9 g, 17.5 mmol) dissolve~ in water (3 ml~. The mixture was diluted with water, extracted with diethyl ether and the extract washed with water. Drying over MgS04 and evaporation gave an oil which was dissolved in carbon tetrachloride. Iodine (406 mg, 1.6 mmol) was àdded and the solution stirred for six hours. The mixture was then filtered, evaporated under reduced pressure and the residue chroma~ographed on silica. Elut.ion with a mixture of diethyl ether and hexane (4:6) gave the title product as an oil (620 mg, 51%). Rf 0.35 (diethyl ether, hexane, 1:1).
N~ 2(S)-t-Butoxycarbony )=5-iodo-4-(2-methoxyethoxypen -l-cyclopetanecarbonyl]-0-methyl-(S)-tyrosine _-but~ ester The title compound was prepared from Example 25 using the procedure of Example 30 above. The product was obtained as an oil ~;
(57% yield). Rf 0.28, (diethyl ether, hexane, 1:1). Found:
C,55.60; H,6.99; N,1.92. C33H52IN08 requires C,55.23; H,7.30;
N,1.95%.
W O 91/13054 ,~ ~ P ~ /EP9l/00 .~ 34 F,XAMP~E 32 N~ 2(S)-(t-~utoxYcarbonyl)-4-(2-methoxyethoxy)~entyl~-1-cyclo-. _ _ . _ . . . .. . . ~ ~ _ . ... _ _ ., . .. . _ _ . _ . _ _ . _ .
~ent neca bonyl_-0-t-butyl-(S)-tyrosine t-butyl_ester Tributyltin ~Iydride (0.5 ml, 1.86 mmol) was added to a solution of the iodo compound from Example 30 (590 mg, 0.78 mmol) in dry tetrahydrofuran (ln ml). After heating at 55C for 16 hours, the solution was diluted with diethyl ether, washed with dilute potassium fluoride solution (x4) and then with saturated salt solution. Drying (MgS04) and evaporation under reduced pressure gave an oil which was chromatographed on silica. Elution with a mixture of diethyl ether and hexane (1:1) gave the required product as an oil (410 mg, 83%). Rf 0.32 (ether/he~ane 1:1).
Found: C,68.00; H,9.25; N,2.25. C36H~gN0~ requires C,68.21;
H,9.38; N,2.21%.
N-_l-~?(S)-(tert-Butoxycarbonyl)-4(2-methox ethoxy)pentyl~-l-cyclo entanecarbonyl]-0-methyl-(S)-tyrosine tert-butyl ester A solution of the iodo compound from Example 31, (430 mg, 0.6 mmol) in ethyl acetate (30 ml) containing triethylamine (67 mg, 0.66 mmol) was hydrogenated over 10~ palladium on charcoal at room temperature at 50 p.s.i. (3.45 bar! pressure. The mi~ture was filtered, the solvent evaporated and the residue chromatographed on silica to give the title compound as an oil (300 mg, 85~) Rf 0.2 (diethyl ether, hexane, 1:1).
:- , :. ... . : . ..
~ W O 9l/13054 ~g~ PC~/EP~1/00296 ................................................. ~
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__ .
N~ (S)-(t-Butoxycarbonyl)-5-(1-imidazolyl)-4-metho~ypentyl}-1-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester a) Mercuric acetate (797 mg, 2.5 mmol) was added to a solution of the diester of Example 25 (1.14 g, 2.21 mmol) in dry methanol (5 ml). After stirring for an hour at room temperature, 2N sodium hydroxide (5.5 ml) was added followed by potassium iodide (1.83 g, 11.05 mmol) dissolved in water ~2.5 ml). Water was added and the mixture extracted with ether. The organic extract was washed with water, dried (MgS04) and evaporated to give an oil, which was dissolved in carbon tetrachloride. Iodine (558 mg, 2.2 mmol) was added and after stirring at 0C under nitrogen for 1.5 hours, the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a mixture of diethyl ether and hexane (4:6) to give N~[1-~2(S~-(t~butoxycarbonyl)-5-iodo-4-methoxypentyl~-l-cyclopentanecarbonyl~-(S)-0-methyl-tyrosine t~butyl ester as an unstable oil (1.27 g, 85%). Rf 0.37 (diethyl ether, hexane, 1:1) which was used directly for the next step.
b) A solution of the above iodide (620 mg, 0.92 mmol) and imidazole (627 mg, 9.2 mmol) in acetonitrile (12 ml) was refluxed for 24 hours. Evaporation of the solvent under reduced pressure gave a gum ~hich was chromatographed on silica. Elution with a mixture of ethanol and ethyl acetate (l:l9) gave the title product as a gum. Rf 0.4 (ethanol, ethyl acetate, 1:9). Found: C,66.05;
H,8.22; N,6.80. C34H5lN307 r q W O 91/13054 ` : PCTIEP91/00 ~
2~?73f~ 36 N-Fl-~8-Morpholino-2-(t-butoxycarbonyl~oct ~ -1 cyclopentane , ,, ,. ., ... .. ~ . i carboxy]-(S)-0-methv]tvrosine t-butyl eseer . _ . _ _... ~ .. .,.. ... .... _ _ _ . _ _ _ I
The bromo compound from Example 23 (1.2 g, 1.88 mmol) and morpholine (650 mg, 7.5 mmol) were heated at 50C in dimethyl-formamide (lS ml) containing potassium iodide (120 mg). After 20 hours, water was added and the mixture extracted with ethyl acetate. Washing with water, drying (MgS04) and evaporation gave an oil (1.2 g) which was chromatographed on silica. Gradient elution starting with hexane, ethyl acetate (7:3) progressing to neat ethyl acetate and finally with ethyl acetate, ethanol, (95:5) gave the required compound as a gum (1.0 g). Rf 0.3 (hexane, diethyl ether, 1:1). Found: C,68.10; H,9.50; N,4.14. C37H60N207.
0.5 CH3C02C2H5 requires C,68.09; H,9.37; N,4.30~.
N-[1-2(S?- - utoxycarbonyl-3-(diethylaminocarbonylamino)propyl-l-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester . _ Phosgene (72 mg, 0.7 mmol) as a 12.5% w/v solution in toluene (0.6 ml) was added in one portion to a stirred and cooled solution of diethylamine (85 mg, 0.65 mmol) and N-methyl morpholine (73 mg, 0.7 mmol) in methylene chloride (10 ml). After stirring at 0C
for 2 hours, nitrogen was bubbled gently through the solution to remove excess phosgene. To this solution at room temperature was added more N-methylmorpholine (73 mg, 0.7 mmol) and ~-~1-(3-aminopropyl-2(S)-c-butoxycarbonyl)-l-cyclopenrane-carbonyl]-0-e-butyl-(S)-tyrosine t-butyl ester (360 mg, 0.65 mmo]) ~VO 91/l30 Y 2072~50 rcr/~ "~" ll - 37 '~
as a solution in methylene chloride (3 ml). After stirring at room temperature overnight, the solvent was evaporated and the , ~
residue was dissolved in ethyl acetate (15 ~1). This solution was ~ ;
washed with water (2 x 5 ml), lM hydrochloric acid (2 x 5 ml)~
saturated sodium bicarbonate solution (1 x 5 ml), brine (l x 5 ml), dried (MgS0.), filtered and evaporated. The residual oil was chromatographed on silica gel using a gradient of methylene chloride and methanol saturated with aqueous a~monia to give the title compound as an oil (332 ~g, 82~). Rf 0.67 (ethyl acetate).
N-[1-(2(RS)-c-Butoxycarbonyl-3-~4-keto-1-piperidylcarbony~
propyl)-l-cyclopentanecarbonyl]-0 methyl-(S)-tyrosine t-butyl ester a) 4-Piperidone was coupled to 1-~2(RS)-t-butoxycarbonyl-3-carboxypropyl]-l-cyclopentanecarboxylic acid benzyl ester (Example ~;
13) using the procedure of Example 14 to give 1-[2(RS)-t-butoxy-carbonyl-3-(4-keto-1-piperidylcarbonyl~propyl]l-cyclopentane carboxylic acid benzyl ester.
b) The above product was dissolved in an ethanol, water mixture (9:1) and hydrogenated at room temperature under an atmosphere of hydrogen (60 p.s.i., 4.1 bar) over 10~ palladium on carbon for 3 hours. The reaction mixture was filtered, and the filtrate evaporated to dryness. The residue was azeotroped with dichloromethane to yield 1-(2tRS)-t-butoxycarbonyl-3-(4-ke~o-l-piperidylcarbonvl~propyl)-l-cyclopentane-carboxvlic acid as a foam. Rf 0.21 (ethyl acetate). Found: C,62.42; H,8.02; N,3.67.
C34H50N208 requires C,62.97; H,8.19; N,3.67~.
; . . : : :. ,:. ::, - . , . ,. . ' W O 91/13054 : PCr/EP91/OD
~ 38 c) The above acid was coupled to 0-methyl-(S)tyrosine-t-butyl ester following the procedure of Example 19 to yield the title product as a foam, Rf 0.71 (echyl acetate). I
.. ... _ I
N~ (2(RS)-t-Butoxycarbony1-3-(4-hydroxy-1-piperi_inylcarbonyl) propyl)-l-cyclopentanecarbo~]-0-methyl-(S)t~rosine t-bu yl ster t lM Hydrochloric acid was added to a stirred ice~cooled solution of N-[1-(2(RS)-t-butoxycarbonyl-3-(4-keto-1-piperidyl-carbonyl)propyl)-l-cyclopentanecarbonyl] 0-methyl-(S)-tyrosine t-butyl ester (400 mg, 0.6 mmol) in ethanol (3 ml~ and water (2 ~1) -to adjust the pH of the solution to between 4 and 6. More ethanol was added as necessary to maintain a homogeneous solution. To the above solution was added sodium cyanoborohydride (45 mg, 0.7 m~ol) in one portion. The resulting mixture was allowed to warm to room temperature overnight. The ethanol was evaporated and the aqueous residue was partitioned between ethyl acetate (20 ml) and water 20 (ml). The organic phase was separated and washed with water (1 x lG ml), lM hydrochloric acid (2 x 10 ml), saturated sodium bicarbonate solution (1 x 10 ml), brine (1 x 10 ml), dried (MgS04) , and filtered. The filtrate was e~aporated and the residue was chromatographed on silica gel eluting with a gradient of ethyl acetate and hexane to yield the title compound as a gum (160 mg, 38%). Rf 0.29 (ethyl acetate).
.. : ,, ,., ,, . ; ~ ~ . , : ::: :, ~ :: : .: . .
W O ~1/13054 PCTiEP91/00296 ~i~73~50 - ~
_AMP~E 39 N-~1-(2(RS?-t-Butoxycarbonyl-3-(4-di~ethylamino-1-piperidyl-carbonyl)propyl)-l-cyclopentanecarbonyl]-0-methyl-(S)tyrosine t-:
butyl ester Sodium cyanoborohydride (60 mg, 0.9 m~ol) was added in one portion to a stirred and ice-cooled mixture of N-[1-(2(RS)-t-butoxycarbonyl-3-(4-keto-1-piperidylcarbonyl)propyl)~l-cyclo- z pentanecarbonyl]-0-methyl-(S)tyrosine t-butyl ester (550 mg, 0.9 mmol) from Example 37), anhydrous sodium acetate (730 mg, 9 mmol, and dimethylamine hydrochloride (360 mg, 4.5 mmol) in dry methanol (15 ml). The mixture was allowed to warm to room temperature.
After 24 hours, the solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated and washed with water (1 x 10 ml), saturated sodium bicarbonate solution (2 x 15 ml), brine (1 x 10 ml), dried (MgS04) and filtered. The filtrate was evaporated and the crude residue was chromatographed on silica gel to yield the title product as a gum (313 mg, 54%). Rf 0.32 (SS 3).
N-[1-~2(S)-t-Butoxycarbonyl-3-(4-methanesulphonylmethylbenzoyl-amino)propyl ~ -c t-butyl ester 90% ~letachloroperoxybenzoic acid (0.29 g, 1.5 mmol) was added i:
in one portion to a stirred and ice-cooled solution of N-[l-2(S)-t-butoxycarbonyl-3-(4-methylthiomethvlbenzoylamino)propyl -l-cyclopentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester.
(Example 1~, 0.38 g, 0.5 mmol~ in methylene chloride (10 ml). The solution was allowed to warm to room temperature overnight. The W O 9l/130S4 PC~tEP91/Ofl ~
;~7:~S~ 40 solvent was evaporated and the residue was dissolved in ethyl acetate (20 ml). This solution was washed with saturated sodium bicarbonate solution (2 x 10 ml), 10% aqueous sodium carbonate solution (1 x 10 ml), brine (1 x 10 ml), dried (MgS04), filtered and evaporated to give the title compound as a white foam (0.39 g, 100~). Found: C,63.21; H,7.46; N,3.58. C40H58N209S. H20 requires C,63.13; H,7.94; N,3.68%. Rf 0.66 (ethyl acetate).
EXAMP~E 41 N~ (2(S)-t-ButoxYcarbonyl-3-(2(S)-methanesul~honamido-4~methane-sulphonylbutyrylamino?eropyl)-l-cyclopentanecarbonyl]-O-t-bu_yl-(S)-tyroslne t-butyl ester The title compound was prepared from Example 17 by oxidation with metachloroperoxybenzoic acid following the procedure of Example 40 and was obtained as a foam. Rf 0.63 (ethyl acetate).
Found: C,56.09; H,7.47; N,5.58. C H N S requires C,56.39; H,7~80;
N,5.33%.
N-~ 2-(t-Buto_ycarbonyl)-4-(4-hydroxymethylphenoxy)buty cYclopentanecarbonylJ-O-methyl-(S)-tyrosine t-butyl ester lM Tetrabutylammonium fluoride (2.16 ml) was added at 10C
under nitrogen to a stirred solution of the product of Example 29 (800 mg, 1.08 mmol) in tetrahydrofuran (10 ml). ~fter standing at room temperature for 2~ days, the mixture was diluted with ethyl acetate, washed with 0.5N hydrochloric acid followed by water, dried (MgS04) and the solvent evaporated under reduced pressure.
The residue was chromatographed on silica, eluting with increasing W O 91~3~S4 ~3~ PCr/EP91/O~g6 ~ `. ` .
4 ~
proportions of ethyl ace~ate in hexane (from 3:7 to l:l) to gi~e a clear oil (610 mg, 90%). Rf 0.4 (hexane, ethyl acetate, l:l).
Found: C,69.47; H,8.01; ~92.31. C36H5~N03 requires C,69 09;
H,8.21; N,2.24%.
N-[1-~2-(t-Butoxycarbony_)-4-(4-~bis-t-b_toxycarbonylaminome~hvl~-phenoxy_butyl~-l-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester Di-t-butyliminodicarboxylate (333 mg, 1.53 mmol) and triphenylphosphine (402 mg, 1.53 mmol) were added at 10C under nitrogen to a stirred solution of the product of Example 42 (640 mg, 1.023 mmol) in tetrahydrofuran ~6 ml). Diethyldiazodi-carboxylate (0.24 ml, 1.53 mmol) in tetrahydrofuran (2 ml~ was slowly added dropwise and the mixture stirred for 20 hours at room temperature. The mixture was then evaporated to dryoess, the residue preabsorbed on silica and chromatographed. Elution with increasing proportions of ethyl acetate in hexane (from 5:95 to 1:4~ gave the required product as a clear gum (166 mg, 20%) Rf 0.55. (hexane, ethyl acetate, 1:1). .
. ' I~ :: ; ' . . . . I ' . . ' " .' . ' . ' ' ' ' W O 91/13054 - PC~EP9~0 ~
2~ 5~ 42 N=E1-~2(S)-Carboxy-4-(2-methoxyethoxy)pentyl~-1-cyclopentane-carbonyl]-(S)-tyrosine Trifluoroacetic acid (5 ml) was added to an ice cold solution of N-[1-~2(S)-t-buto~ycarbonyl)-4-(2-methoxyetho~y)pentyl~-cyclo~
pentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester (from Example 32, 390 mg, 0.62 mmol~ and anisole (998 mg, 9.2 mmol) in dry methylenechloride (5 ml). After standing at 0C overnight the solution was evaporated to dryness under reduced pressure and dried azeotropically with toluene. The residual gum was dissolved in ether and the product was extracted with lN sodium hydroxide (10 ml). The basic extract was then acidified with concentrated hydrochloric acid, saturated with salt and extracted with ethyl acetate. Washing with brine, drying (MgS04) and evaporation gave 2 glass which was crushed to a white powder t275 mg). Rf 0.52 (ss 7). Found: C,61.22; H,7.52; N,2.99. C24H35N08, 0.1 CH3C02C2H5, 0.25 H20 requires Cj61.20; H,7.64; N,2.92%.
The following compounds were prepared from the corresponding 0-methyl or 0-t-butyl tyrosine t-butyl ester, derivative as 2~?~5~
W O 91/~3054 ~CT/~P91/00296 appropriate by treat~ent with trifluoroacetic acid following the procedure of Examp].e 44. Examples 49, 50, 52 and 53 were purified by ion-exchange chromatography using Dowex AG 50W - X8 resin 2nd eluting with 5% aqueous pyridine. Examples 51 and 52 are the 2S
isomers.
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i513 46 N~[1-(2(S)-_ r oxy-3-~ (S)-methanesulphonamido-4-methane-sulphonyl-butyrylamino7propyl)-1-cyclopentanecarbonyl]-(S)-tyrosine .... ..
Hydror,en chloride gas was passed gent.Ly through a stirred and ice-cooled solution of N-[1-(2(S)-t-butoxycarbonyl-3-i2(S)-methanesulphonamido-4-methanesulphonylbutyrylamin~ propyl)-1-cyclopentane-carbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester (227 mg, 0.29 mmol) and anisole (470 mg, 4.3 mmol) in dry dichloromethane (5 ml) until saturation was achieved. The resulting solution was allowed to stand overnight at 0C. The solvent and excess hydrogen chloride were evaporated under reduced pressure and the residue was partitioned between ethyl acetate (19 ml) and saturated sodium bicarbonate solution (5 ml~. The organlc phase was separated and extracted with more saturated sodium r bicarbonate solution (2 x 5 ml). The combined aqueous extract~
were washed with ether (2 x 5 ml) and acidified to pH 3 with concentrated hydrochloric aci.d in the presence of ethyl acetate (15 ml). The acidic layer was separated and extracted with ethyl acetate (5 ml). The combined organic solutions were dried (MgS04), filtered and evaporated to give the title co~pound as a white solid (140 mg, 78~). Found: C,47.32; H,5.86; N,6.39.
C25H37N3011S2. 0.75 H20 requires C,47.71; H,6.17; N,6.68X.
~3~S~) 91tl3054 : PCT/EP91/002g6 47 ,.
1'he following Examples were prepared from the corresponding t-butyl protected compounds by treat~ent wi~h hydrogen chloride following the procedure gi~ren in Example 54.
p~ 6 r~
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_ . _ _ _ , N~ (2(S)-Carboxy-3-methoxvethoxypropyl)-1-cYclopentanecarbonyl1-O-methyl-S)-tyrosine An ice-cold solution of the diester from Example 28 (1.4 g) and anisol (3.0g) in dry methylene chloride (20 ml) was saturated with hydrogen chloride gas. After 30 minutes the mixture was allowed to attain room temperature and after a further 30 minutes the solvent was evaporated. The residue was chromatographed using , silica gel and eluting with dichloromethane, methanol, acetic acid (95:5:0.5) to give the ethyl ester as an oil. This product was dissolved in ethanol (2 ml) and dioxane (2 ml) and hydrolysed with lN sodium hydroxide (6 ml). After standing at room temperature for 2 hours ~ost of the solvent was evaporated under reduced pressure, water was added, the mixture acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Washing with water, drying (MgS04) and evaporation gave the title product as an oil. Rf 0.18 (ss 7). Found: C,60.45; H,7.43; N,3.36. C23H33~08o `
0.25 H20 requires C,60.58; H,7.40; N,3.07%.
N~ (2(R,S)-Carboxyl-10-azidodecyl)-1-cyclopentanecarbonyl]-(S)-tyrosine The title compound was prepared from Example 27 by treatment with hydrogen chloride followed by alkaline hydrolysis following th2 procedure of Exar;ple 64 above; the product was obtained as a gu~.
Rf 0.79, (ss 3).
~ 0 9~/130~4 2~73~ PC~/EP91/002~6 _AMPLE 66 N~ 2(R,S)-Carboxyl-10-aminodecyl)-1-cyclopentanecarbonyl~-(S)-tyrosine _ _ .
The title co~pound was prepared from the azido derivative of Example 65 above by hydrogenation, following the procedure given in Example 37 (part b). The product was obtained as a foam Rf 0.59, (ss 3). Found: C,64.10; H,8.49; N,4.73. C26FI40N2O6. 0.5 H20 requires C964.30; H,8.51; N,5.76%.
,;' N-[1-~2(S)-Carboxy-3-(4-methanesulphinylmethylben~oylamino)-propyl~l-cyclopentanecarbonyl]-(S)tyrosine To a cooled solution of sodium metaperiodate (39.5~mg, 0.18 mmol) in water (2 ml) was added N-[1-~2(S)-carboxy-3-(4-methyl-thiomethylbenzoylamino)propyl~-l-cyclopentanecarboxy]-(S)-tyrosine from Example 56, (87 mg, 0.16 mmol) as a solution in methanol (9 ml). Methanol was added as needed to achieve a homogeneous solution. The reaction mixture was allowed to stir at 0C
overnight. The methanol was evaporated and ~the aqueous residue ~ -was diluted with water (5 ml) saturated with solid sodium chloride and extracted with ethyl acetate (6 x 5 ml). The combined organic extracts were dried ~MgS04), filtered and evaporated to give the title compound as a white solid (71 mg, oOZ). Found: C,57.07;
C28H34N28S~ 0-25 CH2C12' H20 requires C,56.75;
H,6.15; N,4.69%. Rf 0~48 (ss 3).
' `: ' . .
, ' ' :, : ', ' ' . :' ", ;~' , ' ;,.,' ,'.' .' ' " . i `., ' :' '., ' '.' W 0 91/l3054 . PCT/EP9l/0 ~?~ 52 N-Ll-~2(S)-Carbo~y-5-~1-(4-methylpiperazinyl~-4-methoxypentvl~
cyclopentanecarbonyl]-0-methyl-tS)tyrosine a) The procedure of Exa~ple 34 was followed but using N-methyl-piperazine in step (b~ to give N~ 2(S)-tt-butoxycarbonyl)-5-~(4-methylpiperazinyl)~-4-methoxypentyl~-1-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester as a gum. Rf 0.19 (methanol~
dichloromethane, acetic acid, 10:90:1). Found: C,67.01; H,9.12;
N,6-42- C36H59N307 requires C,66.95; H~9.21; N~6.51%.
b) ~eprotection of the above diester with trifluoroacetic acid following the procedure of Exa~ple 44, followed by ion-exchange -chromatography gave the title diacid as a white powder. Rf O.lS
(ss-3). Found: C,62.68; H,8.37; N,7.76. C28H43N307 requires C,63.02; H,8.12; N,7.87%.
~ ~ .
91~130S4 ~73~L~ PC~/E~9~ 6 53 ;~
PR~PARATION I
3~Methoxvethoxy-2-methoxyethoxymethyl ~roprionic acid ~, a) To a solution of t-butyl 2-(bromethyl)acrylate (2.0 g, 9.00 mmol) in 2-methoxyethanol (30 ml) at room temperature was added, in one portion, potassium carbonate (2.5 g, 18 mmol) and the mixture stirred at room temperature for 72 hours. The reaction was diluted wi;h distilled water (100 ml) and extracted with dichloromethane (100 ml). The layers were separated and the aqueous layer further extracted with dichloromethane (2 x 50 ml)~
The combined organic extracts were dried over magnesium sulphate~
filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with ethylacetate/ -hexane to give t-butyl-3-methoxyethoxy-2-methoxyethoxymethyl-propionate as a yellow oil (1.947 g, 74%), Rf 0.33 (ethyl acetate/
hexane 1:1). Found: C,57.67; H,9.85. C14H2806 requires C,57051;
H,9.65%
.
b) t-Butyl-3-methoxyethoxy-2-methoxyethoxymethylproprionate (1.60 g, 5.47 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0C. The solution was saturated with hydrogen chloride and stirred for 3 hours at 0C. ~vaporation of the solvent under reduced pressure gàve the title compound as an oil (1.292 8, v l00%) Found: C 49.90; H,8.41. C]oH2006. 0.07 CH2C 2 q C,49.93; H,8.38/o.
.,. .. . ,.- . , . - ~ - :
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~73~$~ 54 _(2-Iodoethoxy?-methoxybutane a) A solution of 4-methoxybutanol (3.64 g, 34.9 mmol) in dry tetrahydrofuran (20 ml) was added dropwise under nitrogen to a stirred suspension of sodium hydride (1.05 g, 34.9 mmol, 80%
dispersion in oil) in dry tetrahydrofuran (55 ml) keeping the temperature at 10C. The resulting mixture was stirred at room te~perature for 11~ hours, cooled to 10C and 1,3,2-dioxathiolane-2,2-dioxide (4.77 g, 38.4 mmol) in dry tetrahydrofuran (30 ml) was added dropwise. After a further two hours at room temperature9 water (0.63 ml, 34.9 mmol) was added followed carefully, with cooling, by concentrated sulphuric acid. After a final 1 hour stirring, solid sodium bicarbonate (7 g) was added with water (10 ml). The mixture was filtered, evaporated to a small volume without heat at reduced pressure and the residue partitioned between ethyl acetate and saturated salt solution. The organic extract on washing with brine9 drying (MgS04) and evaporation ga~e 2-(4-methoxybutoxy)ethanol (4.54 g, 88%). Rf 0.25 (hexane, ethylacetate, 1:1). Found: C,54.98; H,10.65. C7R1603. 0.25 H20 requires C,55.06; H,10.89%.
b) 4-Methylbenzenesulphonyl chloride (17.52 g, 91.90 mmol) was added to an ice cooled stirred solution of the alcohol from part a) (4.54 g, 30.63 mmol) and ~-methylmorpholine (10.44 ml, 94.96 mmoi) in dry meth~lene chloride ~100 ml). After standing at O~C for 20 hours, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica eluting with increasing proportions of ethyl acetate in hexane to give the 4-methylbenzenesulphonate as an oil (6.58 g, 71%).
c) Sodium iodide (7.25 g, 48~35 mmol) was added to a stirred !
2~73~5q) 91/13054 PCT/EP9l~90296 ~
solution of the above product (7.31 g, 24.17 mmol) in dimethyl-acetamide (30 ml), and the mixture was maintained at 60-65~ for for 20 hours. On cooling, water was added and the product extracted with ether. The organic extract was washed succesivel~
with water, dilute sodium thiosulphate solution and water, dried (~gS04) and evaporated to give the product as an oil (5.85 g, 94%). Rf 0.45 (hexane, ethyl acetate, 1:1). Found: C,32.23;
H,5.51. C7H15I02 requires C,32.56; ~1~5-86~-' 4-~2-Iodoethoxy)piperidine-l-carboxylic acid t-butyl ester The title compound was prepared fro~ 4-hydroxypyridine-1-carboxylic acid t-butyl ester following the procedure of Preparation 2 and was obtained as a clear oil. Rf 0.4 (hexane, ethyl acetate, 4:1). Found: C,40.94; H,6.20; N,3.93. Cl2H22IN0 requires: C,40.58; H,6.24; N,3.94%.
.: . - - :
PREPARATIO~ 4 1-(2-Iodoethoxy)-4-methoxy-but-2-ene __. _ _ a) Dimethyl-t-butylsilyloxyethanol (5.29 g, 30 mmol) in tetrahydrofuran (20 ml) was added dropwise under nitrogen at 10-15~C to a stirred suspension of sodium hydride (900 mg, 30 mmol, 80% dispersion in oil) in tetrahydrofuran (80 ml). On stirring at room temperature for an hour l-bromo-4-methoxy-2-butene (5.0 g, 30 mmol) in tetrahydrofuran (20 ml) was added dropwise with ice cooling. The mixture was then stirred at room te~perature overnight, cooled in ice and ether (100 ml) adde~, followed carefully by water (100 ml). The organic phase was ~`~" ~
~ .~
W O 9~/13054 PC~tEP91/00 ~ ~ ~ ? ~ 5 ~ 56 washed with water, dried (MgSO4) and evaporation gave the crude product which was chronlacographed on silica. Elution with a mixture of hexane and e.hyl acetate (9:1) gave a pale yellow volatile oil (4.6 g, 59%).
lM Tetrabutylammonium fluoride in tetrahydrofuran (33.7 m~ol~
was added to a stirred ice cooled solution of the above product (4.38 g, 16.83 mmol) in tetrahydrofuran (25 ml~. On stirring at room temperature overnight, ether was added and the mixture was washed with 0.SN hydrochloric acid and water. The aqueous washings were saturated with salt and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated salt solution, dried (MgS04) and evaporation gave a yellow oil (10.8 g). Chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (1:1~ gave 2-(4-methoxy-2-butenoxy)ethanol as an oil (1.59 g, 65%). Rf 0.14 (hexane, ethyl acetate, 1~
b3 The above product was reacted with 4-methylbenzenesulphonyl chloride followed by sodium iodide following the procedure of Preparation l(b) to give the title compound as a pale yellow oil.
Rf 0.34 thexane, ethyl acetate, 1:1). Found: C,32.47; H,5.04.
C7H13O2f requires C,32.83; H,5.12%.
_-C~!loromethoxytetra_ydropyran 4-Hydroxytetrahydropyran (8.0 g, 70.33 ~mol) was saturated with hydrogen chloride gas at 0C, S-trioxane (3.24 g, 35.3 mmol) was added with stirring and hydrogen chloride introduced for a further 4 hours. The resulting solution was then diluted with a O 91/130~4 ~3~5~ PCT/EP91/00296 1:1 mixture of ethet and hexane (150 ~1), dried over MgS04 and the solvent evaporated under reduced pressure. Distillation gave a clear oil, b.p. 100-110C/10 torr (13.3 pa) which was used directly.
1-(2-Iodoethoxy)-4-(dimethyl-t-butylsilyloxymethyl)benzene a) Alpha,4-bis(Dimethyl-t-butylsilyloxy)toluene Imidazole (49!34 g, 0.724 mmol) and dimethyl-t-butylsilyl chloride (54.62 g, 0.362 mmol) were added successively under nitrogen at 15C to a stirred solution of 4-hydroxymethylphenol (15 g, 0.121 mmol) in dry di~ethylformamide (55 ml). On stirring at roo~
temperature for 24 hours, water was added and the mixture extracted with ether. The extract was washed with water, dried ~MgS04) and evaporation gave an oil which was chromatographed on silica gel. Elution with hexane and then a mixture of ether in hexane (5:953 gave a clear oil. ~36.35 g, 85%).
b) 4-(Di~ethyl-t-butylsilyloxymethyl)phenol lM Tetrabutylammoniu~ fluoride in tetrahydrofuran (76.85 ml) was added dropwise at 0C to a stirred solution of the product from part (a) (27.1 g, 76.8 mmol) in dry tetrahydrofuran (100 ml).
Af~er a further 30 minutes, ammonium chloride solution was added and the mixture extracted with ether. The extract was washed with water, dried (MgS04) and evaporated under reduced pressure.
Chromatography on silica gel eluting with increasing proportions of ethyl acetate in hexane gave the required product as a clear oil (4.15 g, 23~). Rf 0.4 (hexane, ethvl acetate, 4:1). Found:
C,64.26; H,9.57. C13H2202Si, 0-25 H20 requires C,64.2~; H,9-34%.
. ~
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W O 91/13054 ~ : PCr/EP9~OQ ~ ~
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c) 1-(2-Chloroethoxy)-4-~d methyl-t-butylsilyloxy-methyl)benzene Sodium hydride (515 ~g, 17.6 ~mol, 80% dispersion in oil) was added under nitrogan at room temperature to a stirred solution of the phenol from part (b) (4.09 g, 17.16 mmol) in dry dimethylformamide (30 ml). The mixture was heated at 60C for 30 minutes, cooled and 2-(4-methyl-ben~enesulphonyloxy)-1-chloro-ethane (3.11 ml, 17.16 mmol) added in one portion. The mix~ure was then reheated to 60C for 3 hours~ cooled, diluted with water and extracted with ether. The organic extract was washed with water, dried (MgS04) and solvent evaporated under reduced pressure. Chromatography on silica gel, eluting with a mixture of ethylacetate and hexane (1:9) gave the required compound as a waxy ~`
solid (2.48 g, 47~). Found: C,59.64; H,8.19. C15H25C102S
requires C,59.87; H, 8.37%.
d) 1-(2-Iodoethoxy)-4-(dimethyl-t-butylsilyloxymethyl)beni~ene A mixture of sodium iodide (2.44 g, 16.28 mmol) and chlorocompound from part (c) (2.45 g, 8.14 mmol) were refluxed in acetone for 3O5 1 days. The solvent was evaporated off and the residue partitioned between ether and water, dried (MgS04) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of ether and hexane (1:4) to give a clear oil (2.71 g, 85%). Rf 0.8 (ethylacetate, hexane 1:4).
. ~ .
w~ 91/13054 z~73~ p~T/~ 29~ 1 I .
N~ (3-Ami opropyl-2(S)-t-buto_ycarbonyl)-l=cyclopentane-carbonyl]-O-t-butyl-(S)-tyrosine-t-butyl ester a) To an ice cold solution of l-t2-t-butyloxycarbonyl-3-dibenzylaminopropyl)-l-cyc10pentane carboxylic acid (12.7 g9 27 mmole) in dry dichloromethane (1~0 ml) was added l-hydroxy-benztriazole (4.2 g, 31 mmole), and 1-ethyl-3-(dimethylamino-propyl)-carbodiimide (7 g, 36 mmole) and the resulting solution stirred at 0C for 30 minutes. To this solution was added O-t-butyltyrosine t-butyl ester (8.4 g~ 28.6 mmole) and N-methylmorpholine (5.25 g~ 52 mmole) and the solution allow~d to stand overnight at room temperature. The solvent was evaporated under reduced pressure and the ~esultant mobile oil was dissolved in methylene chloride and washed with water (2 x ), 2M
hydrochloric acid and saturated aqueous sodium bicarbonate (1 x) dried (MgSO4), and the solution filtered and evaporated to yield the crude product as a gum. Recrystallisation from n-hexane gave N-[1-(2-t-butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentane-carbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester as a solid (13 g, 69%), m.p. 82-87C. A further batch of material was obtained by evaporation of the supernatant liquors and further recrystallisation. Found: C,74.12; H,8.69; N,3~87. C45H62N206 requires C,74.34; H,8.59; N,3.85%.
.
:. : ~: ,. . :; :: :. .: .~ : : . : :: :
W O 91~13054 PC~/EP91/00 2~ i5~ ~, .
b) ~-[1-(2-t-~utyloxycarbonyl-3-dibenzylaminopropyl)-1- ~ .
cyclopentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butYl ester (~rom . .
part a), 19 g) was dissolved in an ethanol:water mixture ~8:1~ 300 r.~l) and hydrogenated under an at~osphere of hydrogen (60 p.s.i~
4.1 bar) at room te~perature, over 20% paIladiu~ hydroxide on carbon (2 g). After 24 hours, the solution was filtered through a solkafloc pad, and the filtrate evaporated to yield an oil which crystallised. This was triturated with hexane, chilled and filtered to yield the pure enantiomer title co~pound as a solid (6 g, 42%) m.p. 122-127C. Found: C,67.90: H,9.33; ~,5.08.
C31H50N206 requires C,68.09; H,g.22; N~5-12%-.
.
,
Rf 0.45 ¦ (64.49 9.74) `~.
. (5sl) . .':
_ __ _ . ~ ' 4 CH30CH2CH=CHCH20(CH2)2 oil 62.36 8.83 Rf 0.45 (62.62 8.95) ¦ (S5 1) (O. 2 mole CH2C12) . ! !~ ~
Br(CH2)6- ¦ oil ~1 .
Rf 0.5 _ . I(ss 2) ; ' .
.
W O 9IJ130~4 PCr/EP9l/00 ~
~7~5~) ~
~4 6 ,, I oi~. 61.86 8.~q 3.36, , ~ ¦ Rf 0.4 (61.79 8.93 2.80)~ :
BOC-- N ~-~C~z~ j ~ (ss 1) (Q.25 mole ~H2Cl~
7 Br(CH2)8- oil 58.08 8.60 . . Rf 0.9 t58.15 8.60) . (ss 3) : 8R19OCH2 ~ -O(CH2)2 oil 65.36 8,97 . . Rf 0.9 (65.20 9.19) (ss 1) (0.5 mole H20) _ ... ~ . . _ _._ .
BOC = t-butoxycarbonyl R 9 = dimethyl-t-butylsilyl 1-[2(RS)-t-Butoxycarbonyl- _-azidodecyl~ cyclopentane carboxvlic acid Tetramethylguanidinium azide (0.7 g, 6 mmol) was added as a solution in chloroform (10 ml) to a solution of 1-[2(RS)-t-butoxycarbonyl-10-bromodecyl]-1-cyclopentane carboxylic acid (1.4 g, 3 mmol) in chloroform (10 ml). A few crystals of potassiu~
iodide were added and the resulting mixture was refluxed for 2 days. The cooled reactlon mixture was ehen diluted with :~
~ O 91~13054 2~3~ 5~ ~ PCT/EP9l/00296 chloroform (20 ml~ and washed with water (2 x 20 ml), dried (MgS04), filtered and evaporated. The residue was chromatographed on silica gel using a gradient of ethyl acetate and hexane to give the title compound as an oil (0.69 g, 54%). Found: C,63.84;
H,9.41; N,9.22. C2lH37N304 requires C,63.77; H,9.43; ~,10.62%o Rf 0.9 (ethyl acetate).
` ~ .
acid A mixture of 1-(2(R,S)-t-butoxycarbonyl-4-pentenyl)cyclo-pentane carboxylic acid (EP-A-0274234, Example 44) (28.24 g, 0.1 mmol) and (+)- pseudoephedrin were recrystallised three times from hexane to give a white crystaline solid (18.9 g, 42~3 m.p.
106.5-107.5C. 1~]DS+ 20.5 [~]26S + 70.7 (c = 1.07, methanol).
The above salt was dissolved in ether and washed with lN
hydrochloric aeid and saturated salt solution. Drying (MgS04) and evaporation gave the requlred R-acid as an oil (ll.9 g). Rf 0,7 ~;
(ethyl acetate, hexane, 1:1). [~i~D~- 11.8, [dl~655 _ 36.5 (c =
1.03, methanol).
,' XA~PLE ll 1-[2~ _)-t-Butoxycarbonyl-4-pentenyl]-1-cyclopentane carboxylic acid benzyl ester . . . _ _ . _ Anhydrous potassium carbonate (13.5 g, 98 mmol) was added in one portion to a stirred and ice-cooled solution of 1-[2(RS)-t butoxycarbonyl-4-pentenyl]-l-cyclopentane carhoxvlic acid (]0.95 g, 38 mmol~ and benzyl bromide (~.6 g, 38 mmol) in dry dimethyl-formamide (30 ~Il). After 3 hours the reaction mixture was diluted " :' , ' ' . ' : ' '~, : . ,' ' ' : : :, . ' :' : ' ' ' . :, . , : . ' . ' , ' ' : : ' : ' ' W O 91/13054 '. ; PCT/EP9~ ~
2~3~5~ `26 with ethyl ace~ate (100 ml) and water (100 mi). The or~anic phase was separated and washed with further por~ions of water (1 x 20 ml) lM hydrochloric acid (5 x 20 ml), brine (1 x 10 ml), dried (MgS04), and the solution filtered and evaporated to yield the -title compound as an oil (14.14 g, 98%). This oil was used without further purification. Rf 0.86 (ethylacetate, toluene~ ¦
1:4).
1-[2(RS)-t-Butoxycarbo y -4-oxobutyl~ yclopentane _arboxylic a _d benzyl ester Osmium tetroxide (56 mg, 0.2 mmol) was added as a 2.5% w/v solution in t-butanol (2.25 ml) to a stirred solution of 1-[2(RS)-t-bu~oxycarbonyl-4-pentenyl]l-cyclopentane carboxylic acid benzyl ester (8.25 g, 22 mmol) in acetonitrile (60 ml) and water (10 ml) at room te~perature. After 30 minutes, the black-brown solution was treated with sodium metaperiodate (10 g, 47 mm:l) in one portion. Stirring was continued for 18 hours and then the suspended solid was filtered and washed with a small portion of acetonitrile. The filtrate was evaporated and the dark residue was chromatographed on silica gel eluting with a gradient of ethyl acetate and hexane to yield the title compound as an oil (3.77 g, 45%). Rf 0.58 (diethyl ether, petrol, 1:1).
,, : ~. , ,~. :. . - ,. . . , : . ::
I;
0 91/13054 ~ PCT/E ~1/002g6 _-[2(~S)-t-Butoxycarbo_v1-3-carboxy~ opyll~l-cyclopentane carboxylic acid benzyl ester _ ..
Potassium permanganate (7.6 g, 48 mmol) as a solution in water (48 ml) was added slowly to a stirred solution of l-[2(RS)-t-butoxycarbonyl-4-oxobutyl]-1-cyclopentane carboxylic acid benzyl ~
ester (51 g, 12 mmol) in t-butanol (70 ml) and lM sodium ~;
dihydrogen phosphate buffer solution (20 ml). The resulting mixture was stirred vigorously for 30 minutes. Excess oxidant was destroyed by the addition of solid sodium metabisulphate t8 g).
The brown suspension was filtered, the filter pad being washed with ethyl acetate (50 ml). The filtrate was separated into two phases and the aqueous phase was extracted with ethylacetate (30 ml). The combined organic solutions were dried (MgS04), filtered and evaporated to give the title compound as aD oil t4.52 g, 96%).
Rf 0.7 (ss 5j.
' ' N-~ 3-[4-(t-Butoxycarbonylaminomethyl)b~nzoylamino]-2(S)-t-butoxycarbonylpropyl~-l-cyclopentanecarbonyl~-O~t-butyl-(S)-osine-t-butyl ester To an ice-cold solution of 4--t-butoxycarbonylaminomethyl-benzoic acid (0.689 g, 2.74 mmol) in dry dichloromethane (30 ml) was added l-hydroxybenztriazole (0.409 g, 3.02 mmol), l-ethyl-3-(dimethylaminopropyl)-carbodiimide (0.684 g, 3.57 mmol~ and N-methylmorpholine (0.360 g, 3.57 mmol) and the resulting solution stirred at 0C for 30 minutes. N-[1-(3-Aminopropyl-2(S)-t-butoxycarbonyl)-l-cyclopeneanecarbonyll-0-t-butyl-(S)-tyrosine : ' ' . ',, . : .', . ' . ' . : ': ' ' ' ': ., ': . ' : `,; , ;.,: ': .: .,. ' ' :: :,' : ' : . :; ' : :. : ' ' ~ . ' , . ':: ' ' ' ' : : : : ' '- ' ; . : ' ' ' : : : : : . .: . . : , " : : ,. .; ,:,' ' ', , .:,: ' . ,. , :
W O 91/13054 ~` i PCT/EP91/00 ~
2@7~5~ 28 t-butyl ester was ad~ed to this solution and stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the resultant oil dissolved in ethyl acetate (~0 ml) and washed with 2M hydrochloric acid (50 ml), saturated aqueous sodiu~ bicarbonate (2 ~ 5~ ~1) and saturated brine (50 ~1), dried (MgS04) and the solu~ion fi].tered and evaporated to yield the crude product as an oil. Chromatography on silica gel using dichloromethaneldieehyl ether as eluent gave the title compound (1.695 g, 79%) as a white foam. Rf 0.52 (dichloromethane, diethyl ether, 1:1). Found: C,67.52; H,8.47;
N,5.26. C44H65N309 requires C,67.75; H,8.40; N,5.39%
EXAMPI,ES 15-18 The following compounds were prepared following the procedure of Example 14, using the appropriate carboxylic acid derivative of formula R C02H.
~ ( 3)3 ..
R CONH ~ ~
(CH3)3CO,~C CO~H C02C(Cl'.3)3 W O 91/13054 2 ~ PCT/EP91/00296 29 ~
. _ Example¦ RlO¦ Form Analysis %
No isolated (Theoretical in brackets) T.L.C. C H N
. _ '~ `
foam 69.21 8.70 5.65 (CH3)2NCH2- ~Rf 0.38(69.55 8.68 5.93) ~ ~;
~ (ss 3) `
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, .
W O 91/13054 ` ` PCr~EP9~0 EXAMP_E 19 N~ ~ thoxy-2-(t-butoxYcarbonyl)butyl~-cyc'opentarlecarbonyl]--0-methyl-(S)-t~rosine t-butvl ester l-Ethyl-3-(3-dimethylaminopropyl)carbodiimi~e hydrochloride (762 mg~ 3.98 mmol) was added to an ice cold stirred mixture of 1-(2-t-butoxycarbonyl-4-ethoxybutyl)cyclopentane carboxylic acid from Example 1 (626 mg, 1.99 mmol), 0-methyl-(S)-tyrosine t-butyl ester (500 mg, 1.99 mmol), l-hydroxybenzotriazole (269 mg, 1.99 mmol) and N-methylmorpholine (0.44 ml, 3.98 mmol) in dry methylenechloride (10 ml). After standing at room temperature for 16 hours the mixture was diluted with methylene chloride, washed with water, dried (MgS04) and evaporated under reduced pressure to give an oil. Chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (4:1) gave the pure diester (975 mg;
89%) as an oil. Found: C,67.54; H,8.74; N,2.13. C31H49N07. 0025 H20 requires C,67.42; H,9.03; N,2.53%.
.... . . ., :
The following compounds were prepared as described above using the appropriate cyclopentane carboxylic acid of Examples 1-6 and 8-10 in the coupling step together with the appropriate amine of formula (IV).
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91J13054 '~? ~ PCT/EPg~/0~29 N-[1-~2(S)-t-Butoxvcarbonyl)-5-iodo-4-(2-methoxyethoxypentvl~-]-cyclopentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester Mercuric acetate (662 mg, 2.08 mmol) was added to a stirred solution of the diester from Example 26 (892 mg, 1.6 mmol) in ~-methoxyethanol (4 ml). After 20 hours at room tempera~ure, 2N
sodium hydroxide (3.6 ml) was added followed by potassium iodide (2.9 g, 17.5 mmol) dissolve~ in water (3 ml~. The mixture was diluted with water, extracted with diethyl ether and the extract washed with water. Drying over MgS04 and evaporation gave an oil which was dissolved in carbon tetrachloride. Iodine (406 mg, 1.6 mmol) was àdded and the solution stirred for six hours. The mixture was then filtered, evaporated under reduced pressure and the residue chroma~ographed on silica. Elut.ion with a mixture of diethyl ether and hexane (4:6) gave the title product as an oil (620 mg, 51%). Rf 0.35 (diethyl ether, hexane, 1:1).
N~ 2(S)-t-Butoxycarbony )=5-iodo-4-(2-methoxyethoxypen -l-cyclopetanecarbonyl]-0-methyl-(S)-tyrosine _-but~ ester The title compound was prepared from Example 25 using the procedure of Example 30 above. The product was obtained as an oil ~;
(57% yield). Rf 0.28, (diethyl ether, hexane, 1:1). Found:
C,55.60; H,6.99; N,1.92. C33H52IN08 requires C,55.23; H,7.30;
N,1.95%.
W O 91/13054 ,~ ~ P ~ /EP9l/00 .~ 34 F,XAMP~E 32 N~ 2(S)-(t-~utoxYcarbonyl)-4-(2-methoxyethoxy)~entyl~-1-cyclo-. _ _ . _ . . . .. . . ~ ~ _ . ... _ _ ., . .. . _ _ . _ . _ _ . _ .
~ent neca bonyl_-0-t-butyl-(S)-tyrosine t-butyl_ester Tributyltin ~Iydride (0.5 ml, 1.86 mmol) was added to a solution of the iodo compound from Example 30 (590 mg, 0.78 mmol) in dry tetrahydrofuran (ln ml). After heating at 55C for 16 hours, the solution was diluted with diethyl ether, washed with dilute potassium fluoride solution (x4) and then with saturated salt solution. Drying (MgS04) and evaporation under reduced pressure gave an oil which was chromatographed on silica. Elution with a mixture of diethyl ether and hexane (1:1) gave the required product as an oil (410 mg, 83%). Rf 0.32 (ether/he~ane 1:1).
Found: C,68.00; H,9.25; N,2.25. C36H~gN0~ requires C,68.21;
H,9.38; N,2.21%.
N-_l-~?(S)-(tert-Butoxycarbonyl)-4(2-methox ethoxy)pentyl~-l-cyclo entanecarbonyl]-0-methyl-(S)-tyrosine tert-butyl ester A solution of the iodo compound from Example 31, (430 mg, 0.6 mmol) in ethyl acetate (30 ml) containing triethylamine (67 mg, 0.66 mmol) was hydrogenated over 10~ palladium on charcoal at room temperature at 50 p.s.i. (3.45 bar! pressure. The mi~ture was filtered, the solvent evaporated and the residue chromatographed on silica to give the title compound as an oil (300 mg, 85~) Rf 0.2 (diethyl ether, hexane, 1:1).
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N~ (S)-(t-Butoxycarbonyl)-5-(1-imidazolyl)-4-metho~ypentyl}-1-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester a) Mercuric acetate (797 mg, 2.5 mmol) was added to a solution of the diester of Example 25 (1.14 g, 2.21 mmol) in dry methanol (5 ml). After stirring for an hour at room temperature, 2N sodium hydroxide (5.5 ml) was added followed by potassium iodide (1.83 g, 11.05 mmol) dissolved in water ~2.5 ml). Water was added and the mixture extracted with ether. The organic extract was washed with water, dried (MgS04) and evaporated to give an oil, which was dissolved in carbon tetrachloride. Iodine (558 mg, 2.2 mmol) was added and after stirring at 0C under nitrogen for 1.5 hours, the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a mixture of diethyl ether and hexane (4:6) to give N~[1-~2(S~-(t~butoxycarbonyl)-5-iodo-4-methoxypentyl~-l-cyclopentanecarbonyl~-(S)-0-methyl-tyrosine t~butyl ester as an unstable oil (1.27 g, 85%). Rf 0.37 (diethyl ether, hexane, 1:1) which was used directly for the next step.
b) A solution of the above iodide (620 mg, 0.92 mmol) and imidazole (627 mg, 9.2 mmol) in acetonitrile (12 ml) was refluxed for 24 hours. Evaporation of the solvent under reduced pressure gave a gum ~hich was chromatographed on silica. Elution with a mixture of ethanol and ethyl acetate (l:l9) gave the title product as a gum. Rf 0.4 (ethanol, ethyl acetate, 1:9). Found: C,66.05;
H,8.22; N,6.80. C34H5lN307 r q W O 91/13054 ` : PCTIEP91/00 ~
2~?73f~ 36 N-Fl-~8-Morpholino-2-(t-butoxycarbonyl~oct ~ -1 cyclopentane , ,, ,. ., ... .. ~ . i carboxy]-(S)-0-methv]tvrosine t-butyl eseer . _ . _ _... ~ .. .,.. ... .... _ _ _ . _ _ _ I
The bromo compound from Example 23 (1.2 g, 1.88 mmol) and morpholine (650 mg, 7.5 mmol) were heated at 50C in dimethyl-formamide (lS ml) containing potassium iodide (120 mg). After 20 hours, water was added and the mixture extracted with ethyl acetate. Washing with water, drying (MgS04) and evaporation gave an oil (1.2 g) which was chromatographed on silica. Gradient elution starting with hexane, ethyl acetate (7:3) progressing to neat ethyl acetate and finally with ethyl acetate, ethanol, (95:5) gave the required compound as a gum (1.0 g). Rf 0.3 (hexane, diethyl ether, 1:1). Found: C,68.10; H,9.50; N,4.14. C37H60N207.
0.5 CH3C02C2H5 requires C,68.09; H,9.37; N,4.30~.
N-[1-2(S?- - utoxycarbonyl-3-(diethylaminocarbonylamino)propyl-l-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester . _ Phosgene (72 mg, 0.7 mmol) as a 12.5% w/v solution in toluene (0.6 ml) was added in one portion to a stirred and cooled solution of diethylamine (85 mg, 0.65 mmol) and N-methyl morpholine (73 mg, 0.7 mmol) in methylene chloride (10 ml). After stirring at 0C
for 2 hours, nitrogen was bubbled gently through the solution to remove excess phosgene. To this solution at room temperature was added more N-methylmorpholine (73 mg, 0.7 mmol) and ~-~1-(3-aminopropyl-2(S)-c-butoxycarbonyl)-l-cyclopenrane-carbonyl]-0-e-butyl-(S)-tyrosine t-butyl ester (360 mg, 0.65 mmo]) ~VO 91/l30 Y 2072~50 rcr/~ "~" ll - 37 '~
as a solution in methylene chloride (3 ml). After stirring at room temperature overnight, the solvent was evaporated and the , ~
residue was dissolved in ethyl acetate (15 ~1). This solution was ~ ;
washed with water (2 x 5 ml), lM hydrochloric acid (2 x 5 ml)~
saturated sodium bicarbonate solution (1 x 5 ml), brine (l x 5 ml), dried (MgS0.), filtered and evaporated. The residual oil was chromatographed on silica gel using a gradient of methylene chloride and methanol saturated with aqueous a~monia to give the title compound as an oil (332 ~g, 82~). Rf 0.67 (ethyl acetate).
N-[1-(2(RS)-c-Butoxycarbonyl-3-~4-keto-1-piperidylcarbony~
propyl)-l-cyclopentanecarbonyl]-0 methyl-(S)-tyrosine t-butyl ester a) 4-Piperidone was coupled to 1-~2(RS)-t-butoxycarbonyl-3-carboxypropyl]-l-cyclopentanecarboxylic acid benzyl ester (Example ~;
13) using the procedure of Example 14 to give 1-[2(RS)-t-butoxy-carbonyl-3-(4-keto-1-piperidylcarbonyl~propyl]l-cyclopentane carboxylic acid benzyl ester.
b) The above product was dissolved in an ethanol, water mixture (9:1) and hydrogenated at room temperature under an atmosphere of hydrogen (60 p.s.i., 4.1 bar) over 10~ palladium on carbon for 3 hours. The reaction mixture was filtered, and the filtrate evaporated to dryness. The residue was azeotroped with dichloromethane to yield 1-(2tRS)-t-butoxycarbonyl-3-(4-ke~o-l-piperidylcarbonvl~propyl)-l-cyclopentane-carboxvlic acid as a foam. Rf 0.21 (ethyl acetate). Found: C,62.42; H,8.02; N,3.67.
C34H50N208 requires C,62.97; H,8.19; N,3.67~.
; . . : : :. ,:. ::, - . , . ,. . ' W O 91/13054 : PCr/EP91/OD
~ 38 c) The above acid was coupled to 0-methyl-(S)tyrosine-t-butyl ester following the procedure of Example 19 to yield the title product as a foam, Rf 0.71 (echyl acetate). I
.. ... _ I
N~ (2(RS)-t-Butoxycarbony1-3-(4-hydroxy-1-piperi_inylcarbonyl) propyl)-l-cyclopentanecarbo~]-0-methyl-(S)t~rosine t-bu yl ster t lM Hydrochloric acid was added to a stirred ice~cooled solution of N-[1-(2(RS)-t-butoxycarbonyl-3-(4-keto-1-piperidyl-carbonyl)propyl)-l-cyclopentanecarbonyl] 0-methyl-(S)-tyrosine t-butyl ester (400 mg, 0.6 mmol) in ethanol (3 ml~ and water (2 ~1) -to adjust the pH of the solution to between 4 and 6. More ethanol was added as necessary to maintain a homogeneous solution. To the above solution was added sodium cyanoborohydride (45 mg, 0.7 m~ol) in one portion. The resulting mixture was allowed to warm to room temperature overnight. The ethanol was evaporated and the aqueous residue was partitioned between ethyl acetate (20 ml) and water 20 (ml). The organic phase was separated and washed with water (1 x lG ml), lM hydrochloric acid (2 x 10 ml), saturated sodium bicarbonate solution (1 x 10 ml), brine (1 x 10 ml), dried (MgS04) , and filtered. The filtrate was e~aporated and the residue was chromatographed on silica gel eluting with a gradient of ethyl acetate and hexane to yield the title compound as a gum (160 mg, 38%). Rf 0.29 (ethyl acetate).
.. : ,, ,., ,, . ; ~ ~ . , : ::: :, ~ :: : .: . .
W O ~1/13054 PCTiEP91/00296 ~i~73~50 - ~
_AMP~E 39 N-~1-(2(RS?-t-Butoxycarbonyl-3-(4-di~ethylamino-1-piperidyl-carbonyl)propyl)-l-cyclopentanecarbonyl]-0-methyl-(S)tyrosine t-:
butyl ester Sodium cyanoborohydride (60 mg, 0.9 m~ol) was added in one portion to a stirred and ice-cooled mixture of N-[1-(2(RS)-t-butoxycarbonyl-3-(4-keto-1-piperidylcarbonyl)propyl)~l-cyclo- z pentanecarbonyl]-0-methyl-(S)tyrosine t-butyl ester (550 mg, 0.9 mmol) from Example 37), anhydrous sodium acetate (730 mg, 9 mmol, and dimethylamine hydrochloride (360 mg, 4.5 mmol) in dry methanol (15 ml). The mixture was allowed to warm to room temperature.
After 24 hours, the solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated and washed with water (1 x 10 ml), saturated sodium bicarbonate solution (2 x 15 ml), brine (1 x 10 ml), dried (MgS04) and filtered. The filtrate was evaporated and the crude residue was chromatographed on silica gel to yield the title product as a gum (313 mg, 54%). Rf 0.32 (SS 3).
N-[1-~2(S)-t-Butoxycarbonyl-3-(4-methanesulphonylmethylbenzoyl-amino)propyl ~ -c t-butyl ester 90% ~letachloroperoxybenzoic acid (0.29 g, 1.5 mmol) was added i:
in one portion to a stirred and ice-cooled solution of N-[l-2(S)-t-butoxycarbonyl-3-(4-methylthiomethvlbenzoylamino)propyl -l-cyclopentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester.
(Example 1~, 0.38 g, 0.5 mmol~ in methylene chloride (10 ml). The solution was allowed to warm to room temperature overnight. The W O 9l/130S4 PC~tEP91/Ofl ~
;~7:~S~ 40 solvent was evaporated and the residue was dissolved in ethyl acetate (20 ml). This solution was washed with saturated sodium bicarbonate solution (2 x 10 ml), 10% aqueous sodium carbonate solution (1 x 10 ml), brine (1 x 10 ml), dried (MgS04), filtered and evaporated to give the title compound as a white foam (0.39 g, 100~). Found: C,63.21; H,7.46; N,3.58. C40H58N209S. H20 requires C,63.13; H,7.94; N,3.68%. Rf 0.66 (ethyl acetate).
EXAMP~E 41 N~ (2(S)-t-ButoxYcarbonyl-3-(2(S)-methanesul~honamido-4~methane-sulphonylbutyrylamino?eropyl)-l-cyclopentanecarbonyl]-O-t-bu_yl-(S)-tyroslne t-butyl ester The title compound was prepared from Example 17 by oxidation with metachloroperoxybenzoic acid following the procedure of Example 40 and was obtained as a foam. Rf 0.63 (ethyl acetate).
Found: C,56.09; H,7.47; N,5.58. C H N S requires C,56.39; H,7~80;
N,5.33%.
N-~ 2-(t-Buto_ycarbonyl)-4-(4-hydroxymethylphenoxy)buty cYclopentanecarbonylJ-O-methyl-(S)-tyrosine t-butyl ester lM Tetrabutylammonium fluoride (2.16 ml) was added at 10C
under nitrogen to a stirred solution of the product of Example 29 (800 mg, 1.08 mmol) in tetrahydrofuran (10 ml). ~fter standing at room temperature for 2~ days, the mixture was diluted with ethyl acetate, washed with 0.5N hydrochloric acid followed by water, dried (MgS04) and the solvent evaporated under reduced pressure.
The residue was chromatographed on silica, eluting with increasing W O 91~3~S4 ~3~ PCr/EP91/O~g6 ~ `. ` .
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proportions of ethyl ace~ate in hexane (from 3:7 to l:l) to gi~e a clear oil (610 mg, 90%). Rf 0.4 (hexane, ethyl acetate, l:l).
Found: C,69.47; H,8.01; ~92.31. C36H5~N03 requires C,69 09;
H,8.21; N,2.24%.
N-[1-~2-(t-Butoxycarbony_)-4-(4-~bis-t-b_toxycarbonylaminome~hvl~-phenoxy_butyl~-l-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester Di-t-butyliminodicarboxylate (333 mg, 1.53 mmol) and triphenylphosphine (402 mg, 1.53 mmol) were added at 10C under nitrogen to a stirred solution of the product of Example 42 (640 mg, 1.023 mmol) in tetrahydrofuran ~6 ml). Diethyldiazodi-carboxylate (0.24 ml, 1.53 mmol) in tetrahydrofuran (2 ml~ was slowly added dropwise and the mixture stirred for 20 hours at room temperature. The mixture was then evaporated to dryoess, the residue preabsorbed on silica and chromatographed. Elution with increasing proportions of ethyl acetate in hexane (from 5:95 to 1:4~ gave the required product as a clear gum (166 mg, 20%) Rf 0.55. (hexane, ethyl acetate, 1:1). .
. ' I~ :: ; ' . . . . I ' . . ' " .' . ' . ' ' ' ' W O 91/13054 - PC~EP9~0 ~
2~ 5~ 42 N=E1-~2(S)-Carboxy-4-(2-methoxyethoxy)pentyl~-1-cyclopentane-carbonyl]-(S)-tyrosine Trifluoroacetic acid (5 ml) was added to an ice cold solution of N-[1-~2(S)-t-buto~ycarbonyl)-4-(2-methoxyetho~y)pentyl~-cyclo~
pentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester (from Example 32, 390 mg, 0.62 mmol~ and anisole (998 mg, 9.2 mmol) in dry methylenechloride (5 ml). After standing at 0C overnight the solution was evaporated to dryness under reduced pressure and dried azeotropically with toluene. The residual gum was dissolved in ether and the product was extracted with lN sodium hydroxide (10 ml). The basic extract was then acidified with concentrated hydrochloric acid, saturated with salt and extracted with ethyl acetate. Washing with brine, drying (MgS04) and evaporation gave 2 glass which was crushed to a white powder t275 mg). Rf 0.52 (ss 7). Found: C,61.22; H,7.52; N,2.99. C24H35N08, 0.1 CH3C02C2H5, 0.25 H20 requires Cj61.20; H,7.64; N,2.92%.
The following compounds were prepared from the corresponding 0-methyl or 0-t-butyl tyrosine t-butyl ester, derivative as 2~?~5~
W O 91/~3054 ~CT/~P91/00296 appropriate by treat~ent with trifluoroacetic acid following the procedure of Examp].e 44. Examples 49, 50, 52 and 53 were purified by ion-exchange chromatography using Dowex AG 50W - X8 resin 2nd eluting with 5% aqueous pyridine. Examples 51 and 52 are the 2S
isomers.
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i513 46 N~[1-(2(S)-_ r oxy-3-~ (S)-methanesulphonamido-4-methane-sulphonyl-butyrylamino7propyl)-1-cyclopentanecarbonyl]-(S)-tyrosine .... ..
Hydror,en chloride gas was passed gent.Ly through a stirred and ice-cooled solution of N-[1-(2(S)-t-butoxycarbonyl-3-i2(S)-methanesulphonamido-4-methanesulphonylbutyrylamin~ propyl)-1-cyclopentane-carbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester (227 mg, 0.29 mmol) and anisole (470 mg, 4.3 mmol) in dry dichloromethane (5 ml) until saturation was achieved. The resulting solution was allowed to stand overnight at 0C. The solvent and excess hydrogen chloride were evaporated under reduced pressure and the residue was partitioned between ethyl acetate (19 ml) and saturated sodium bicarbonate solution (5 ml~. The organlc phase was separated and extracted with more saturated sodium r bicarbonate solution (2 x 5 ml). The combined aqueous extract~
were washed with ether (2 x 5 ml) and acidified to pH 3 with concentrated hydrochloric aci.d in the presence of ethyl acetate (15 ml). The acidic layer was separated and extracted with ethyl acetate (5 ml). The combined organic solutions were dried (MgS04), filtered and evaporated to give the title co~pound as a white solid (140 mg, 78~). Found: C,47.32; H,5.86; N,6.39.
C25H37N3011S2. 0.75 H20 requires C,47.71; H,6.17; N,6.68X.
~3~S~) 91tl3054 : PCT/EP91/002g6 47 ,.
1'he following Examples were prepared from the corresponding t-butyl protected compounds by treat~ent wi~h hydrogen chloride following the procedure gi~ren in Example 54.
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_ . _ _ _ , N~ (2(S)-Carboxy-3-methoxvethoxypropyl)-1-cYclopentanecarbonyl1-O-methyl-S)-tyrosine An ice-cold solution of the diester from Example 28 (1.4 g) and anisol (3.0g) in dry methylene chloride (20 ml) was saturated with hydrogen chloride gas. After 30 minutes the mixture was allowed to attain room temperature and after a further 30 minutes the solvent was evaporated. The residue was chromatographed using , silica gel and eluting with dichloromethane, methanol, acetic acid (95:5:0.5) to give the ethyl ester as an oil. This product was dissolved in ethanol (2 ml) and dioxane (2 ml) and hydrolysed with lN sodium hydroxide (6 ml). After standing at room temperature for 2 hours ~ost of the solvent was evaporated under reduced pressure, water was added, the mixture acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Washing with water, drying (MgS04) and evaporation gave the title product as an oil. Rf 0.18 (ss 7). Found: C,60.45; H,7.43; N,3.36. C23H33~08o `
0.25 H20 requires C,60.58; H,7.40; N,3.07%.
N~ (2(R,S)-Carboxyl-10-azidodecyl)-1-cyclopentanecarbonyl]-(S)-tyrosine The title compound was prepared from Example 27 by treatment with hydrogen chloride followed by alkaline hydrolysis following th2 procedure of Exar;ple 64 above; the product was obtained as a gu~.
Rf 0.79, (ss 3).
~ 0 9~/130~4 2~73~ PC~/EP91/002~6 _AMPLE 66 N~ 2(R,S)-Carboxyl-10-aminodecyl)-1-cyclopentanecarbonyl~-(S)-tyrosine _ _ .
The title co~pound was prepared from the azido derivative of Example 65 above by hydrogenation, following the procedure given in Example 37 (part b). The product was obtained as a foam Rf 0.59, (ss 3). Found: C,64.10; H,8.49; N,4.73. C26FI40N2O6. 0.5 H20 requires C964.30; H,8.51; N,5.76%.
,;' N-[1-~2(S)-Carboxy-3-(4-methanesulphinylmethylben~oylamino)-propyl~l-cyclopentanecarbonyl]-(S)tyrosine To a cooled solution of sodium metaperiodate (39.5~mg, 0.18 mmol) in water (2 ml) was added N-[1-~2(S)-carboxy-3-(4-methyl-thiomethylbenzoylamino)propyl~-l-cyclopentanecarboxy]-(S)-tyrosine from Example 56, (87 mg, 0.16 mmol) as a solution in methanol (9 ml). Methanol was added as needed to achieve a homogeneous solution. The reaction mixture was allowed to stir at 0C
overnight. The methanol was evaporated and ~the aqueous residue ~ -was diluted with water (5 ml) saturated with solid sodium chloride and extracted with ethyl acetate (6 x 5 ml). The combined organic extracts were dried ~MgS04), filtered and evaporated to give the title compound as a white solid (71 mg, oOZ). Found: C,57.07;
C28H34N28S~ 0-25 CH2C12' H20 requires C,56.75;
H,6.15; N,4.69%. Rf 0~48 (ss 3).
' `: ' . .
, ' ' :, : ', ' ' . :' ", ;~' , ' ;,.,' ,'.' .' ' " . i `., ' :' '., ' '.' W 0 91/l3054 . PCT/EP9l/0 ~?~ 52 N-Ll-~2(S)-Carbo~y-5-~1-(4-methylpiperazinyl~-4-methoxypentvl~
cyclopentanecarbonyl]-0-methyl-tS)tyrosine a) The procedure of Exa~ple 34 was followed but using N-methyl-piperazine in step (b~ to give N~ 2(S)-tt-butoxycarbonyl)-5-~(4-methylpiperazinyl)~-4-methoxypentyl~-1-cyclopentanecarbonyl]-0-methyl-(S)-tyrosine t-butyl ester as a gum. Rf 0.19 (methanol~
dichloromethane, acetic acid, 10:90:1). Found: C,67.01; H,9.12;
N,6-42- C36H59N307 requires C,66.95; H~9.21; N~6.51%.
b) ~eprotection of the above diester with trifluoroacetic acid following the procedure of Exa~ple 44, followed by ion-exchange -chromatography gave the title diacid as a white powder. Rf O.lS
(ss-3). Found: C,62.68; H,8.37; N,7.76. C28H43N307 requires C,63.02; H,8.12; N,7.87%.
~ ~ .
91~130S4 ~73~L~ PC~/E~9~ 6 53 ;~
PR~PARATION I
3~Methoxvethoxy-2-methoxyethoxymethyl ~roprionic acid ~, a) To a solution of t-butyl 2-(bromethyl)acrylate (2.0 g, 9.00 mmol) in 2-methoxyethanol (30 ml) at room temperature was added, in one portion, potassium carbonate (2.5 g, 18 mmol) and the mixture stirred at room temperature for 72 hours. The reaction was diluted wi;h distilled water (100 ml) and extracted with dichloromethane (100 ml). The layers were separated and the aqueous layer further extracted with dichloromethane (2 x 50 ml)~
The combined organic extracts were dried over magnesium sulphate~
filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with ethylacetate/ -hexane to give t-butyl-3-methoxyethoxy-2-methoxyethoxymethyl-propionate as a yellow oil (1.947 g, 74%), Rf 0.33 (ethyl acetate/
hexane 1:1). Found: C,57.67; H,9.85. C14H2806 requires C,57051;
H,9.65%
.
b) t-Butyl-3-methoxyethoxy-2-methoxyethoxymethylproprionate (1.60 g, 5.47 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0C. The solution was saturated with hydrogen chloride and stirred for 3 hours at 0C. ~vaporation of the solvent under reduced pressure gàve the title compound as an oil (1.292 8, v l00%) Found: C 49.90; H,8.41. C]oH2006. 0.07 CH2C 2 q C,49.93; H,8.38/o.
.,. .. . ,.- . , . - ~ - :
... : . .... .. ~, ...... : .. ... ... . .
W O 9It~3054 : P ~/~P~
~73~$~ 54 _(2-Iodoethoxy?-methoxybutane a) A solution of 4-methoxybutanol (3.64 g, 34.9 mmol) in dry tetrahydrofuran (20 ml) was added dropwise under nitrogen to a stirred suspension of sodium hydride (1.05 g, 34.9 mmol, 80%
dispersion in oil) in dry tetrahydrofuran (55 ml) keeping the temperature at 10C. The resulting mixture was stirred at room te~perature for 11~ hours, cooled to 10C and 1,3,2-dioxathiolane-2,2-dioxide (4.77 g, 38.4 mmol) in dry tetrahydrofuran (30 ml) was added dropwise. After a further two hours at room temperature9 water (0.63 ml, 34.9 mmol) was added followed carefully, with cooling, by concentrated sulphuric acid. After a final 1 hour stirring, solid sodium bicarbonate (7 g) was added with water (10 ml). The mixture was filtered, evaporated to a small volume without heat at reduced pressure and the residue partitioned between ethyl acetate and saturated salt solution. The organic extract on washing with brine9 drying (MgS04) and evaporation ga~e 2-(4-methoxybutoxy)ethanol (4.54 g, 88%). Rf 0.25 (hexane, ethylacetate, 1:1). Found: C,54.98; H,10.65. C7R1603. 0.25 H20 requires C,55.06; H,10.89%.
b) 4-Methylbenzenesulphonyl chloride (17.52 g, 91.90 mmol) was added to an ice cooled stirred solution of the alcohol from part a) (4.54 g, 30.63 mmol) and ~-methylmorpholine (10.44 ml, 94.96 mmoi) in dry meth~lene chloride ~100 ml). After standing at O~C for 20 hours, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica eluting with increasing proportions of ethyl acetate in hexane to give the 4-methylbenzenesulphonate as an oil (6.58 g, 71%).
c) Sodium iodide (7.25 g, 48~35 mmol) was added to a stirred !
2~73~5q) 91/13054 PCT/EP9l~90296 ~
solution of the above product (7.31 g, 24.17 mmol) in dimethyl-acetamide (30 ml), and the mixture was maintained at 60-65~ for for 20 hours. On cooling, water was added and the product extracted with ether. The organic extract was washed succesivel~
with water, dilute sodium thiosulphate solution and water, dried (~gS04) and evaporated to give the product as an oil (5.85 g, 94%). Rf 0.45 (hexane, ethyl acetate, 1:1). Found: C,32.23;
H,5.51. C7H15I02 requires C,32.56; ~1~5-86~-' 4-~2-Iodoethoxy)piperidine-l-carboxylic acid t-butyl ester The title compound was prepared fro~ 4-hydroxypyridine-1-carboxylic acid t-butyl ester following the procedure of Preparation 2 and was obtained as a clear oil. Rf 0.4 (hexane, ethyl acetate, 4:1). Found: C,40.94; H,6.20; N,3.93. Cl2H22IN0 requires: C,40.58; H,6.24; N,3.94%.
.: . - - :
PREPARATIO~ 4 1-(2-Iodoethoxy)-4-methoxy-but-2-ene __. _ _ a) Dimethyl-t-butylsilyloxyethanol (5.29 g, 30 mmol) in tetrahydrofuran (20 ml) was added dropwise under nitrogen at 10-15~C to a stirred suspension of sodium hydride (900 mg, 30 mmol, 80% dispersion in oil) in tetrahydrofuran (80 ml). On stirring at room temperature for an hour l-bromo-4-methoxy-2-butene (5.0 g, 30 mmol) in tetrahydrofuran (20 ml) was added dropwise with ice cooling. The mixture was then stirred at room te~perature overnight, cooled in ice and ether (100 ml) adde~, followed carefully by water (100 ml). The organic phase was ~`~" ~
~ .~
W O 9~/13054 PC~tEP91/00 ~ ~ ~ ? ~ 5 ~ 56 washed with water, dried (MgSO4) and evaporation gave the crude product which was chronlacographed on silica. Elution with a mixture of hexane and e.hyl acetate (9:1) gave a pale yellow volatile oil (4.6 g, 59%).
lM Tetrabutylammonium fluoride in tetrahydrofuran (33.7 m~ol~
was added to a stirred ice cooled solution of the above product (4.38 g, 16.83 mmol) in tetrahydrofuran (25 ml~. On stirring at room temperature overnight, ether was added and the mixture was washed with 0.SN hydrochloric acid and water. The aqueous washings were saturated with salt and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated salt solution, dried (MgS04) and evaporation gave a yellow oil (10.8 g). Chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (1:1~ gave 2-(4-methoxy-2-butenoxy)ethanol as an oil (1.59 g, 65%). Rf 0.14 (hexane, ethyl acetate, 1~
b3 The above product was reacted with 4-methylbenzenesulphonyl chloride followed by sodium iodide following the procedure of Preparation l(b) to give the title compound as a pale yellow oil.
Rf 0.34 thexane, ethyl acetate, 1:1). Found: C,32.47; H,5.04.
C7H13O2f requires C,32.83; H,5.12%.
_-C~!loromethoxytetra_ydropyran 4-Hydroxytetrahydropyran (8.0 g, 70.33 ~mol) was saturated with hydrogen chloride gas at 0C, S-trioxane (3.24 g, 35.3 mmol) was added with stirring and hydrogen chloride introduced for a further 4 hours. The resulting solution was then diluted with a O 91/130~4 ~3~5~ PCT/EP91/00296 1:1 mixture of ethet and hexane (150 ~1), dried over MgS04 and the solvent evaporated under reduced pressure. Distillation gave a clear oil, b.p. 100-110C/10 torr (13.3 pa) which was used directly.
1-(2-Iodoethoxy)-4-(dimethyl-t-butylsilyloxymethyl)benzene a) Alpha,4-bis(Dimethyl-t-butylsilyloxy)toluene Imidazole (49!34 g, 0.724 mmol) and dimethyl-t-butylsilyl chloride (54.62 g, 0.362 mmol) were added successively under nitrogen at 15C to a stirred solution of 4-hydroxymethylphenol (15 g, 0.121 mmol) in dry di~ethylformamide (55 ml). On stirring at roo~
temperature for 24 hours, water was added and the mixture extracted with ether. The extract was washed with water, dried ~MgS04) and evaporation gave an oil which was chromatographed on silica gel. Elution with hexane and then a mixture of ether in hexane (5:953 gave a clear oil. ~36.35 g, 85%).
b) 4-(Di~ethyl-t-butylsilyloxymethyl)phenol lM Tetrabutylammoniu~ fluoride in tetrahydrofuran (76.85 ml) was added dropwise at 0C to a stirred solution of the product from part (a) (27.1 g, 76.8 mmol) in dry tetrahydrofuran (100 ml).
Af~er a further 30 minutes, ammonium chloride solution was added and the mixture extracted with ether. The extract was washed with water, dried (MgS04) and evaporated under reduced pressure.
Chromatography on silica gel eluting with increasing proportions of ethyl acetate in hexane gave the required product as a clear oil (4.15 g, 23~). Rf 0.4 (hexane, ethvl acetate, 4:1). Found:
C,64.26; H,9.57. C13H2202Si, 0-25 H20 requires C,64.2~; H,9-34%.
. ~
., . ~, .: .. . .: : `: ~
W O 91/13054 ~ : PCr/EP9~OQ ~ ~
~ ~, 2~?7~
c) 1-(2-Chloroethoxy)-4-~d methyl-t-butylsilyloxy-methyl)benzene Sodium hydride (515 ~g, 17.6 ~mol, 80% dispersion in oil) was added under nitrogan at room temperature to a stirred solution of the phenol from part (b) (4.09 g, 17.16 mmol) in dry dimethylformamide (30 ml). The mixture was heated at 60C for 30 minutes, cooled and 2-(4-methyl-ben~enesulphonyloxy)-1-chloro-ethane (3.11 ml, 17.16 mmol) added in one portion. The mix~ure was then reheated to 60C for 3 hours~ cooled, diluted with water and extracted with ether. The organic extract was washed with water, dried (MgS04) and solvent evaporated under reduced pressure. Chromatography on silica gel, eluting with a mixture of ethylacetate and hexane (1:9) gave the required compound as a waxy ~`
solid (2.48 g, 47~). Found: C,59.64; H,8.19. C15H25C102S
requires C,59.87; H, 8.37%.
d) 1-(2-Iodoethoxy)-4-(dimethyl-t-butylsilyloxymethyl)beni~ene A mixture of sodium iodide (2.44 g, 16.28 mmol) and chlorocompound from part (c) (2.45 g, 8.14 mmol) were refluxed in acetone for 3O5 1 days. The solvent was evaporated off and the residue partitioned between ether and water, dried (MgS04) and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of ether and hexane (1:4) to give a clear oil (2.71 g, 85%). Rf 0.8 (ethylacetate, hexane 1:4).
. ~ .
w~ 91/13054 z~73~ p~T/~ 29~ 1 I .
N~ (3-Ami opropyl-2(S)-t-buto_ycarbonyl)-l=cyclopentane-carbonyl]-O-t-butyl-(S)-tyrosine-t-butyl ester a) To an ice cold solution of l-t2-t-butyloxycarbonyl-3-dibenzylaminopropyl)-l-cyc10pentane carboxylic acid (12.7 g9 27 mmole) in dry dichloromethane (1~0 ml) was added l-hydroxy-benztriazole (4.2 g, 31 mmole), and 1-ethyl-3-(dimethylamino-propyl)-carbodiimide (7 g, 36 mmole) and the resulting solution stirred at 0C for 30 minutes. To this solution was added O-t-butyltyrosine t-butyl ester (8.4 g~ 28.6 mmole) and N-methylmorpholine (5.25 g~ 52 mmole) and the solution allow~d to stand overnight at room temperature. The solvent was evaporated under reduced pressure and the ~esultant mobile oil was dissolved in methylene chloride and washed with water (2 x ), 2M
hydrochloric acid and saturated aqueous sodium bicarbonate (1 x) dried (MgSO4), and the solution filtered and evaporated to yield the crude product as a gum. Recrystallisation from n-hexane gave N-[1-(2-t-butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentane-carbonyl]-0-t-butyl-(S)-tyrosine t-butyl ester as a solid (13 g, 69%), m.p. 82-87C. A further batch of material was obtained by evaporation of the supernatant liquors and further recrystallisation. Found: C,74.12; H,8.69; N,3~87. C45H62N206 requires C,74.34; H,8.59; N,3.85%.
.
:. : ~: ,. . :; :: :. .: .~ : : . : :: :
W O 91~13054 PC~/EP91/00 2~ i5~ ~, .
b) ~-[1-(2-t-~utyloxycarbonyl-3-dibenzylaminopropyl)-1- ~ .
cyclopentanecarbonyl]-0-t-butyl-(S)-tyrosine t-butYl ester (~rom . .
part a), 19 g) was dissolved in an ethanol:water mixture ~8:1~ 300 r.~l) and hydrogenated under an at~osphere of hydrogen (60 p.s.i~
4.1 bar) at room te~perature, over 20% paIladiu~ hydroxide on carbon (2 g). After 24 hours, the solution was filtered through a solkafloc pad, and the filtrate evaporated to yield an oil which crystallised. This was triturated with hexane, chilled and filtered to yield the pure enantiomer title co~pound as a solid (6 g, 42%) m.p. 122-127C. Found: C,67.90: H,9.33; ~,5.08.
C31H50N206 requires C,68.09; H,g.22; N~5-12%-.
.
,
Claims (23)
1. A compound having the formula-:
(I) wherein:
A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated;
Y is an alkylene group of from 1 to 9 carbon atoms which may be straight or branched chain;
R1 is H or (C1-C4)alkyl;
R and R4 are each independently H, (C1-C6)alkyl, (C3-C7) cycloalkyl, benzyl, or an alternative biolabile ester-forming group;
R2 is hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, (C1-C6)alkyl-S(O)n-, (C1-C4)alkoxy(C1-C6)alkoxy, (C1-C4)alkyl-S(O)n-(C1-C6)-alkoxy, (C1-C4)alkoxy(C2-C6)alkenyloxy, N3, (R5)2N, (R5)2N-(C1-C6)alkoxy, (R5)2N-(C2-C6)alkenyloxy, heterocyclyl-Z-, hetero-cyclyl(C1-C4)alkyl-Z-, aryl-Z- or aryl(C1-C4)alkyl-Z, wherein Z is O, S(O) or NR6 and R6 is H, (C1-C4)alkyl or aryl(C1-C4)alkyl;
or R2 is a group of the formula R7R8CH- in which case Y may also be a direct link and wherein R7 is (R5)2N(C1-C4)alkyl, (C1-C4)-alkoxy(C2-C4)alkylaminomethyl, heterocyclyl(C1-C4)alkyl or aryl and R8 is (C1-C6) alkoxy, (C1-C4)alkoxy(C2-C6)alkoxy, hydroxy(C2-C6)alkoxy or hydroxy(C1-C6)alkyl; wherein aryl means phenyl or naphthyl which may optionally be substituted with, one or more OH, CN, CF3, (C1-C4) alkyl, (C1-C4)alkoxy, halo, carbamoyl, aminosulphonyl, amino, mono or di(C1-C4 alkyl)amino, (C1-C4 alkanoyl)amino, amino(C1-C4)alkyl, di(C1-C4 alkyl)amino-(C1-C4)alkyl, or (C1-C4) alkyl-S(O)n-(C1-C4)alkyl groups and heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur containing heterocyclic group which may be saturated or unsaturated and which may optionally include a further oxygen or one to three nitrogen atoms in the ring and which may optionally be benzofused or substituted with one or more halo, (C1-C4)alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di-(C1-C4 alkyl)amino or (C1-C4 alkanoyl)amino groups;
or R2 is a group of the formula R9CO- wherein R9 is a 1-piperidine or 1-piperazine group, either of which may optionally be substituted by OH, =0, (C1-C4)alkyl or N(R5)2;
or R is a group of the formula R10CONR6- wherein R6 is as previously defined, and R10 is (R6)2N, (C1-C4)alkoxy(C2-C4)alkyl, R11R12CH-, or substituted phenyl wherein the substituent is (R5)2N-(C1-C4)alkyl, (C1-C4)alkyl-S(O)n- or (C1-C4)alkyl-S(O)n-(C1-C4)alkyl;
with the proviso that R2 is not NH2 or CH3NH when Y is CH2;
R3 is a group of the formula:
wherein R13 is H, halo, 4-OH, 4-(C1-C6 alkoxy), 4-(C3-C7 cycloalkoxy) 4-(C2-C6 alkenyloxy), 4-[(C1-C6 alkoxy)carbonyloxy], 4-[(C3-C7 cycloalkoxy)carbonyloxy], or 3-(C1-C4 alkyl)SO2NH-; and R14 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C6) alkanoyl or halo; or R3 is a group of the formula:
or wherein said groups may optionally be substituted in the fused benzene ring by (C1-C4)alkyl, (C1-C4)alkoxy, OH, halo or CF3;
each R5 is H, (C1-C6)alkyl, phenyl(C1-C6)alkyl or the two groups R5 are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1-C4)alkyl-piperazinyl group;
R11 is (C1-C4)alkyl-S(O)nNH- or (C1-C4)alkanoylamino and R12 is (C1-C4)alkyl-S(O)n(C1-C4)alkyl or morpholinomethyl or R11 and R12 are both morpholinomethyl or (C1-C4)alkoxy(C1-C4)alkoxy(C1-C4)-alkyl;
n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof or bioprecursor therefor.
(I) wherein:
A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated;
Y is an alkylene group of from 1 to 9 carbon atoms which may be straight or branched chain;
R1 is H or (C1-C4)alkyl;
R and R4 are each independently H, (C1-C6)alkyl, (C3-C7) cycloalkyl, benzyl, or an alternative biolabile ester-forming group;
R2 is hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, (C1-C6)alkyl-S(O)n-, (C1-C4)alkoxy(C1-C6)alkoxy, (C1-C4)alkyl-S(O)n-(C1-C6)-alkoxy, (C1-C4)alkoxy(C2-C6)alkenyloxy, N3, (R5)2N, (R5)2N-(C1-C6)alkoxy, (R5)2N-(C2-C6)alkenyloxy, heterocyclyl-Z-, hetero-cyclyl(C1-C4)alkyl-Z-, aryl-Z- or aryl(C1-C4)alkyl-Z, wherein Z is O, S(O) or NR6 and R6 is H, (C1-C4)alkyl or aryl(C1-C4)alkyl;
or R2 is a group of the formula R7R8CH- in which case Y may also be a direct link and wherein R7 is (R5)2N(C1-C4)alkyl, (C1-C4)-alkoxy(C2-C4)alkylaminomethyl, heterocyclyl(C1-C4)alkyl or aryl and R8 is (C1-C6) alkoxy, (C1-C4)alkoxy(C2-C6)alkoxy, hydroxy(C2-C6)alkoxy or hydroxy(C1-C6)alkyl; wherein aryl means phenyl or naphthyl which may optionally be substituted with, one or more OH, CN, CF3, (C1-C4) alkyl, (C1-C4)alkoxy, halo, carbamoyl, aminosulphonyl, amino, mono or di(C1-C4 alkyl)amino, (C1-C4 alkanoyl)amino, amino(C1-C4)alkyl, di(C1-C4 alkyl)amino-(C1-C4)alkyl, or (C1-C4) alkyl-S(O)n-(C1-C4)alkyl groups and heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur containing heterocyclic group which may be saturated or unsaturated and which may optionally include a further oxygen or one to three nitrogen atoms in the ring and which may optionally be benzofused or substituted with one or more halo, (C1-C4)alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di-(C1-C4 alkyl)amino or (C1-C4 alkanoyl)amino groups;
or R2 is a group of the formula R9CO- wherein R9 is a 1-piperidine or 1-piperazine group, either of which may optionally be substituted by OH, =0, (C1-C4)alkyl or N(R5)2;
or R is a group of the formula R10CONR6- wherein R6 is as previously defined, and R10 is (R6)2N, (C1-C4)alkoxy(C2-C4)alkyl, R11R12CH-, or substituted phenyl wherein the substituent is (R5)2N-(C1-C4)alkyl, (C1-C4)alkyl-S(O)n- or (C1-C4)alkyl-S(O)n-(C1-C4)alkyl;
with the proviso that R2 is not NH2 or CH3NH when Y is CH2;
R3 is a group of the formula:
wherein R13 is H, halo, 4-OH, 4-(C1-C6 alkoxy), 4-(C3-C7 cycloalkoxy) 4-(C2-C6 alkenyloxy), 4-[(C1-C6 alkoxy)carbonyloxy], 4-[(C3-C7 cycloalkoxy)carbonyloxy], or 3-(C1-C4 alkyl)SO2NH-; and R14 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C2-C6) alkanoyl or halo; or R3 is a group of the formula:
or wherein said groups may optionally be substituted in the fused benzene ring by (C1-C4)alkyl, (C1-C4)alkoxy, OH, halo or CF3;
each R5 is H, (C1-C6)alkyl, phenyl(C1-C6)alkyl or the two groups R5 are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1-C4)alkyl-piperazinyl group;
R11 is (C1-C4)alkyl-S(O)nNH- or (C1-C4)alkanoylamino and R12 is (C1-C4)alkyl-S(O)n(C1-C4)alkyl or morpholinomethyl or R11 and R12 are both morpholinomethyl or (C1-C4)alkoxy(C1-C4)alkoxy(C1-C4)-alkyl;
n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof or bioprecursor therefor.
2. A compound according to claim 1 wherein A is (CH2)4 and R1 is H having the formula:
(II) wherein R, R2, R3 and R4 are as previously defined for formula (I).
(II) wherein R, R2, R3 and R4 are as previously defined for formula (I).
3. A compound as claimed in claim 1 wherein R and R4 are both H.
4. A compound as claimed in claim 2 wherein R and R4 are both H.
5. A compound as claimed in claim 1 wherein one or both of R and R4 is a biolabile ester-forming group and said group is ethyl, indanyl, isopropyl, n-butyl, sec-butyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-2-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxy-ethyl, pentanoyloxyethyl, acetoxyethyl, acetoxybenzyl, pentanoyloxybenzyl, cyclohexyloxycarbonyloxyethyl, butyl-oxycarbonyloxyethyl, isobutyloxycarbonylethyl or ethoxy-carbonyloxyethyl.
6. A compound as claimed in claim 2 wherein one or both of R and R4 is a biolabile ester-forming group and said group is ethyl, indanyl, isopropyl, n-butyl, sec-butyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-2-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxy-ethyl, pentanoyloxyethyl, acetoxyethyl, acetoxybenzyl, pentanoyloxybenzyl, cyclohexyloxycarbonyloxyethyl, butyl-oxycarbonyloxyethyl, isobutyloxycarbonylethyl or ethoxy-carbonyloxyethyl.
7. A compound as claimed in any one of claims 1 to 6 wherein R3 is 4-hydroxybenzyl and the carbon atom to which it is attached is of (S) sterochemistry, or R3 is 4-methoxybenzyl.
8. A compound as claimed in any one of claims 1 to 6 wherein the substituent R2Y is (C1-C6)alkoxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkoxy(C1-C6)alkyl, H2N(C4-C9)alkyl, or R10CONHCH2- wherein R10 is substituted phenyl and said substituents are as previously defined in claim 1.
9. A compound as claimed in claim 7 wherein the substituent R2Y is (C1-C6) alkoxy(C1-C4) alkyl, (C1-C4)alkoxy-(C1-C4)alkoxy(C1-C6)alkyl, H2N(C4-C9)alkyl, or R10CONHCH2-wherein R10 is substituted phenyl and said substituents are as previously defined in claim 1.
10. The compound N-[1-{2(S)-carboxy-4-(2-methoxyethoxy)-pentyl}-1-cyclopentanecarbonyl]-(S)-tyrosine,
11. The compound N-[1-(2(S)-carboxy-4-ethoxy-butyl)-1-cyclopentanecarbonyl]-(S)-tyrosine.
12. The compound N-[1-(2(R,S)-carboxy-10-aminodecyl)-1-cyclopentanecarbonyl]-(S)-tyrosine.
13. The compound N-[1-{2(S)-carboxy-3-(4-aminomethyl-benzamido)propyl}-1-cyclopentanecarbonyl]-(S)-tyrosine.
14. A process for preparing a compound of the formula (I) as defined in claim 1 which comprises subjecting a compound of the formula:
(V) wherein A, Y and R1 are as previously defined, R2' and R3' are as defined for R2 and R3 with any reactive groups therein protected if necessary and R17 and R18 are as defined for R and R4 excluding H, or they are conventional carboxylic acid protecting groups; to a hydrolysis or hydrogenation or other deprotection reaction to remove any protecting group present in R2' or R3', and either to remove both of R17 and R18 to yield the corresponding dicarboxylic acid wherein R and R4 are both H or to remove one of R17 and R18 to yield the corresponding mono-ester product wherein one of R and R4 is H and the other is a biolabile ester-forming group; and optionally forming a pharma-ceutically acceptable salt of the product.
(V) wherein A, Y and R1 are as previously defined, R2' and R3' are as defined for R2 and R3 with any reactive groups therein protected if necessary and R17 and R18 are as defined for R and R4 excluding H, or they are conventional carboxylic acid protecting groups; to a hydrolysis or hydrogenation or other deprotection reaction to remove any protecting group present in R2' or R3', and either to remove both of R17 and R18 to yield the corresponding dicarboxylic acid wherein R and R4 are both H or to remove one of R17 and R18 to yield the corresponding mono-ester product wherein one of R and R4 is H and the other is a biolabile ester-forming group; and optionally forming a pharma-ceutically acceptable salt of the product.
15. A process according to claim 14 wherein R17 is t-butyl and R18 is t-butyl and said groups are removed by treatment with anhydrous trifluoroacetic acid or hydrogen chloride to yield the corresponding dicarboxylic acid of formula (I) wherein R and R4 are both H.
16. A process according to claim 14 wherein R17 is t-butyl and R13 is (C1-C6)alkyl and said groups are removed by treatment with anhydrous trifluoroacetic acid or hydrogen chloride followed by hydrolysis with aqueous alkali to yield the corresponding dicarboxylic acid of formula (I) when R
and R4 are both H.
and R4 are both H.
17. A process according to claim 14 wherein R3 is 4-hydroxybenzyl and the carbon atom to which it is attached is of (S) stereochemistry, or R3 is 4-methoxybenzyl.
18. A process according to claim 14 wherein the substituent R2Y is (C1-C6)alkoxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C6)alkoxy-(C1-C4)alkyl, H2N(C4-C9)alkyl or R10CONHCH2- wherein R10 is substituted phenyl and said substituents are as previously defined in claim 1.
19. A pharmaceutical composition comprising a compound of the formula (I) or (II) as claimed in any one of claims 1 to 6 and 9 to 13 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier.
20. A compound of the formula (I) or (II) as claimed in any one of claims 1 to 6 and 9 to 13 or a pharmaceutically i acceptable salt thereof or bioprecursor therefor, for use in medicine.
21. A compound of the formula (I) or (II) as claimed in any one of claims l to 6 and 9 to 13 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for the treatment of hypertension, heart failure, renal insufficiency, angina, premenstrual syndrome, cyclical oedema, Menieres disease, hyperaldosteronism (primary and secondary) hypercalciuria, glaucoma, asthma, inflamma-tion, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), the modulation of gastric acid secretion or the treatment of hyperreninaemia.
22. A process for preparing a pharmaceutical composition which comprises admixing a compound of the formula (I) or (II) as claimed in any one of claims 1 to 6 and 9 to 13, or a pharmaceutically acceptable salt thereof or bioprecursor therefor, with a pharmaceutically acceptable diluent or carrier.
23. A commercial package containing, as active pharma-ceutical ingredient, a compound of the formula (I) or (II) as claimed in any one of claims 1 to 6 and 9 to 13, or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with instructions for its use for the treatment of hypertension, heart failure, renal insufficiency, angina, premenstrual syndrome, cyclical oedema, Menieres disease, hyperaldosteronism (primary and secondary) hypercalciuria, glaucoma, asthma, inflamma-tion, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), the modulation of gastric acid secretion or the treatment of hyperreninaemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909004260A GB9004260D0 (en) | 1990-02-26 | 1990-02-26 | Therapeutic agents |
| GB9004260.7 | 1990-02-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2073450A1 true CA2073450A1 (en) | 1991-08-27 |
Family
ID=10671620
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002073450A Abandoned CA2073450A1 (en) | 1990-02-26 | 1991-02-14 | Cycloalkyl-substituted glutaramide antihypertensive agents |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0594588A1 (en) |
| JP (1) | JPH05504146A (en) |
| CA (1) | CA2073450A1 (en) |
| FI (1) | FI923780A (en) |
| GB (1) | GB9004260D0 (en) |
| IE (1) | IE910615A1 (en) |
| PT (1) | PT96863A (en) |
| WO (1) | WO1991013054A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5298492A (en) * | 1992-08-04 | 1994-03-29 | Schering Corporation | Diamino acid derivatives as antihypertensives |
| US5208236A (en) * | 1992-09-23 | 1993-05-04 | Schering Corporation | N-(acylaminomethyl)glutaryl amino acids and use |
| PT655461E (en) * | 1993-11-16 | 2000-11-30 | Novartis Ag | CYCLE DERIVATIVES OF AMINO ACIDS |
| US5432186A (en) * | 1993-11-16 | 1995-07-11 | Ciba-Geigy Corporation | Cyclic amino acid derivatives |
| AU1416501A (en) * | 1999-11-18 | 2001-05-30 | Ajinomoto Co., Inc. | Novel phenylalanine derivatives |
| US6660756B2 (en) | 2001-03-28 | 2003-12-09 | Pfizer Inc. | N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase |
| GEP20063783B (en) * | 2001-03-28 | 2006-04-10 | Pfizer | N-Phenpropylcyclopentyl-Substituted Glutaramide Derivatives as Inhibitors of Neutral Endopeptidase Enzyme (NEP) for Treating Female Sexual Dysfunction (FSAD) |
| US7045653B2 (en) | 2002-12-23 | 2006-05-16 | Pfizer, Inc. | Pharmaceuticals |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR880007441A (en) * | 1986-12-11 | 1988-08-27 | 알렌 제이.스피겔 | Spiro-Substituted Glutaramide Diuretics |
| GB2218983A (en) * | 1988-05-27 | 1989-11-29 | Pfizer Ltd | Spiro-substituted glutaramides as diuretics |
| GB8812597D0 (en) * | 1988-05-27 | 1988-06-29 | Pfizer Ltd | Therapeutic agents |
| GB8820844D0 (en) * | 1988-09-05 | 1988-10-05 | Pfizer Ltd | Therapeutic agents |
-
1990
- 1990-02-26 GB GB909004260A patent/GB9004260D0/en active Pending
-
1991
- 1991-02-14 WO PCT/EP1991/000296 patent/WO1991013054A1/en not_active Application Discontinuation
- 1991-02-14 CA CA002073450A patent/CA2073450A1/en not_active Abandoned
- 1991-02-14 JP JP3503973A patent/JPH05504146A/en active Pending
- 1991-02-14 EP EP91903839A patent/EP0594588A1/en not_active Withdrawn
- 1991-02-25 PT PT96863A patent/PT96863A/en not_active Application Discontinuation
- 1991-02-25 IE IE061591A patent/IE910615A1/en unknown
-
1992
- 1992-08-21 FI FI923780A patent/FI923780A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9004260D0 (en) | 1990-04-18 |
| IE910615A1 (en) | 1991-08-28 |
| JPH05504146A (en) | 1993-07-01 |
| WO1991013054A1 (en) | 1991-09-05 |
| EP0594588A1 (en) | 1994-05-04 |
| FI923780A0 (en) | 1992-08-21 |
| PT96863A (en) | 1991-11-29 |
| FI923780A (en) | 1992-08-21 |
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