Claims
- 1. A heterocyclic amide of the formula I wherein R.sup.1 is (1-8C)alkyl or phenyl;
- R.sup.2 is phenyl or pyridyl, the latter optionally bearing a (1-4C)alkyl substituent;
- R.sup.3 is hydrogen or a group of the formula Q.sup.1 A.sup.1 -in which Q.sup.1 is selected from pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A.sup.1 is methylene or ethylene;
- R.sup.4 is (1-8C)alkyl or (3-8C)cycloalkyl-(1-4C)alkyl;
- R.sup.5 is hydrogen or (1-4C)alkyl;
- R.sup.6 is hydrogen, (1-6C)alkyl, (1-4C)alkoxy, hydroxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, or a group of the formula Q.sup.2 A.sup.2 - in which Q.sup.2 is selected from (1-4Calkoxy, (2-4C)alkenyl, phenyl and hydroxy, and A.sup.2 is (1-4C)alkylene;
- or R.sup.5 and R.sup.6 together form (2-4C)alkylene;
- and wherein R.sup.7 is hydrogen, (1-4C)alkyl or hydroxy(2-4C)alkyl; and
- R.sup.8 is hydrogen, (1-4Calkyl in which 2 or 3 carbon atoms may bear a hydroxy substituent, (1-8C)alkyl, a group of the formula Q.sup.3 A.sup.3 - in which Q.sup.3 is selected from (1-4C)alkoxy, morpholino, thiomorpholino, piperidino, pyrrolidino, N-(1-4C)piperazinyl, pyridyl (itself optionally bearing a (1-4C)alkyl substituent) and phenyl (itself optionally bearing 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy, amino(1-4Calkyl), and A.sup.3 is (1-4C)alkylene; or R.sup.8 is a group of the formula Q.sup.4 A.sup.4 -in which Q.sup.4 is selected from amino, hydroxy and N,N-di-(1-4C)alkylamino, and A.sup.4 i (1-8C)alkylene;
- or R.sup.7 and R.sup.8 together with the adjacent nitrogen complete a morpholino, thiomorpholino, piperidino, pyrrolidino or N-(1-4C)piperazinyl moiety;
- and wherein a phenyl moiety of R.sup.1, R.sup.2 or Q.sup.2, may optionally bear 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, (1-4C)alkyl and (1-4C)alkoxy;
- or a pharmaceutically acceptable salt thereof when R.sup.2, R.sup.3, or R.sup.8, or R.sup.7 and R.sup.8 contain a basic group.
- 2. A heterocyclic amide as claimed in claim 1 wherein
- R.sup.1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, 1-methylpentyl, 1,1-dimethylbutyl and phenyl;
- R2 is selected from phenyl and 3-pyridyl, the latter optionally bearing a methyl or ethyl substituent;
- R.sup.4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, 1-methylpentyl, 1,1-dimethylbutyl, cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl;
- R.sup.5 is selected from hydrogen, methyl, ethyl, isopropyl and isobutyl;
- R.sup.6 is selected from hydrogen, methyl, ethyl, isopropyl, isobutyl, methoxy, ethoxy, propoxy, hydroxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulphonyl, ethylsulphonyl and a group of the formula Q.sup.2 A.sup.2 - in which Q.sup.2 is selected from methoxy, ethoxy, isopropoxy, isobutoxy, vinyl, 1-propenyl, allyl, 1-butenyl, phenyl and hydroxy, and A.sup.2 is selected from methylene, ethylene and trimethylene;
- or R.sup.5 and R.sup.6 together form ethylene, propylene or tetramethylene; and wherein R.sup.7 is selected from hydrogen, methyl, ethyl, isopropyl, isobutyl, 2-hydroxyethyl and 2-hydroxypropyl; and R.sup.8 is selected from hydrogen, 2-hydroxy-(hydroxymethyl)ethyl, 2-hydroxy-1,1-di(hydroxymethyl)ethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, 1-methylpentyl, 1,1-dimethylbutyl and a group of the formula Q.sup.3 A.sup.3 - in which Q.sup.3 is selected from methoxy, ethoxy, isopropoxy, isobutoxy, morpholino, thiomorpholino, piperidino, pyrrolidino, N-methylpiperazinyl, N-ethylpiperazinyl, N-propylpiperazinyl, pyridyl (itself optionally bearing a methyl or ethyl substituent) and phenyl (itself optionally bearing 1 or 2 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, isppropyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, aminomethyl, 2-aminoethyl and 3-aminopropyl, and A.sup.3 is selected from methylene, ethylene and trimethylene; or R.sup.8 is a group of the formula Q.sup.4 A.sup.4 -in which Q.sup.4 is selected from amino, hydroxy, dimethylamino and diethylamino, and A.sup.4 is selected from methylene, ethylene, trimethylene and tetramethylene in any of which an individual methylene may optionally bear a methyl, ethyl, isopropyl or isobutyl substituent; or R.sup.7 and R.sup.8 together with the adjacent nitrogen complete a morpholino, thiomorpholino, piperidino, pyrrolidino, N-methylpiperazinyl, N-ethylpiperazinyl or N-propylpiperazinyl moiety; and wherein a phenyl moiety of R.sup.1, R.sup.2 or Q.sup.2 may optionally bear 1 or 2 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, isopropyl, butyl, methoxy, ethoxy, propoxy and isopropoxy;
- or a pharmaceutically acceptable salt thereof when R.sup.2, R.sup.3 or R.sup.8, or R.sup.7 and R.sup.8 contain a basic group.
- 3. A heterocyclic amide as claimed in claim 1 wherein R.sup.8 is selected from methyl, ethyl, propyl, butyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 2-hydroxy-1,1-di(hydroxymethyl)ethyl, methoxyethyl, ethoxyethyl, 2-(N-morpholino)ethyl, 2(N-piperazinyl)ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-(3-pyridyl)ethyl, benzyl, chlorobenzyl, bromobenzyl, cyanobenzyl, 1-phenylethyl, 2-phenylethyl, 2-(hydroxymethyl)-3-methylbutyl, 2-(aminomethyl)-3-methylbutyl, 2-hydroxy-1,1-dimethylethyl, 2-(dimethylamino)ethyl, 2-(N-piperazinyl)ethyl, 2-hydroxyethyl and 4-hydroxybutyl; and R.sup.7 is selected from hydrogen, methyl, ethyl and 2-hydroxyethyl; or R.sup.7 and R.sup.8 together with the adjacent nitrogen complete a morpholino, piperidino, pyrrolidino or N-methylpiperazino moiety.
- 4. A heterocyclic amide of the formula II ##STR6## wherein R.sup.11 is (1-6C)alkyl and R.sup.2, R.sup.5, R.sup.6, R.sup.7 and .sup.8 have any of the meanings defined in claim 1; or a pharmaceutically acceptable salt thereof.
- 5. A heterocyclic amide of the formula II according to claim 4 wherein R.sup.11 is propyl or isobutyl; R.sup.2 is 3-pyridyl or phenyl; R.sup.5 is hydrogen or methyl; R.sup.6 is methyl, propyl, isopropyl, butyl, 2-methylpropyl or methoxymethyl; R.sup.7 is hydrogen; and R.sup.8 is methyl, butyl, methoxyethyl, 2-(dimethylamino)ethyl, 3-pyridylmethyl, 2-(N-morpholino)ethyl; or a pharmaceutically acceptable salt thereof.
- 6. A heterocyclic amide of the formula IIa ##STR7## wherein R.sup.8 has any of the meanings as claimed in claim 5; or a pharmaceutically acceptable salt thereof.
- 7. (2S,4S,5S)-N-Butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[(2R S)-2-(8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a]pyrazin-3-yl)-3-(3-pyridyl)propionamido]hexanamide; or a pharmaceutically acceptable salt thereof.
- 8. A pharmaceutically acceptable salt as claimed in claim 1, 4 or 6 selected from acid-addition salts with hydrogen halides, sulphuric acid, phosphoric acid and organic acids affording physiologically acceptable anions.
- 9. A pharmaceutical composition for inhibiting the catalytic action of renin in a warm-blooded animal which comprises a therapeutically effective amount of a compound of the formula I, II or IIa, or a pharmaceutically acceptable salt thereof, as defined in claim 1, 4 or 6, together with a pharmaceutically acceptable diluent or carrier.
- 10. A method of inhibiting the catalytic action of renin in the formation of angiotensins in a warm blooded animal requiring such treatment which comprises administering to said animal a therapeutically effective amount of a compound of the formula I, II or IIa, or a pharmaceutically acceptable salt thereof, as defined in claim 1, 4, or 6.
- 11. A method of producing a hypotensive effect in a warm blooded animal requiring such treatment which comprises administering to said animal an effective amount of a compound of the formula I, II or IIa, or a pharmaceutically acceptable salt thereof, as defined in claim 1, 4 or 6.
- 12. A compound of formula VIII ##STR8## wherein R.sup.1 is (1-8C)alkyl or phenyl;
- R.sup.2 isphenyl or pyridyl, the latter optionally bearing a (1-4C)alkyl substituent;
- R.sup.3 is hydrogen or a group of the formula Q.sup.1 A.sup.1 -in which Q.sup.1 is selected from pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A.sup.1 is methylene or ethylene;
- R.sup.4 is (1-8C)alkyl or (3-8C)cycloalkyl-(1-4C)alkyl;
- R.sup.5 is hydrogen or (1-4C)alkyl;
- R.sup.6 is hydrogen, (1-6C)alkyl, (1-4C)alkoxy, hydroxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, or a group of the formula Q.sup.2 A.sup.2 - in which Q.sup.2 is selected from (1-4C)alkoxy, (2-4C)alkenyl, phenyl and hydroxy, and A.sup.2 is (1-4C)alkylene;
- or R.sup.5 and R.sup.6 together form (2-4C)alkylene;
- and wherein a phenyl moiety of R.sup.1, R.sup.2 or Q.sup.2, may optionally bear 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, (1-4C)alkyl and (1-4C)alkoxy;
- or a pharmaceutically acceptable salt thereof when .sup.2 or R.sup.3 contains a basic group.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 8826930 |
Nov 1988 |
GBX |
|
| 8912080 |
May 1989 |
GBX |
|
Parent Case Info
This invention contains novel heterocyclic amides and, more particularly, it concerns novel 5-(heterocyclylalkanoyl)amino-4-hydroxypentanamides which are inhibitors of the catalytic action of renin, pharmaceutical compositions containing said amides and processes for their manufacture.
Renin is a proteolytic enzyme component of the renin-angiotensinaldosterone cascade system which is closely involved, inter alia, with the maintenance of normal blood pressure in warm-blooded animals such as man. Renin is produced and stored in the juxtaglomerular apparatus of the kidney and may be released into the blood circulation in response to various physiological stimuli such as a decrease in the pressure of the blood entering or within the kidney, a fall in total body blood volume or a reduction in renal distal tubular sodium ion concentration. Once released into the circulation, renin acts on its specific natural substrate, the circulating protein angiotensinogen, to liberate the decapeptide, angiotensin I, which is subsequently cleaved by angiotensin converting enzyme (ACE) to the potent vasoconstrictor and aldosterone releasing peptide, angiotensin II. The latter is further cleaved by an aminopeptidase to give a further pressor substance, angiotensin III, which has potent aldosterone releasing properties on the adrenal cortex and is a moderate vasoconstrictor. Aldosterone itself promotes retention of sodium ions and fluid retention. Accordingly, the release of renin into the circulation tends to produce a hypertensive effect. Inhibitors of the action of renin have therefore been sought for use in the general control of hypertension and congestive heart failure as well as agents for use in the diagnosis of hypertension due to excessive renin levels. The specificity of renin for its substrate angiotensinogen provides a pharmacologically specific means of modifying the renin-angiotensin-aldosterone system.
It has now been discovered that the novel heterocyclic amides of formula I below have surprisingly good inhibitory effects on the action of renin, of value in treating diseases and medical conditions where amelioration of the vasoconstrictor and fluid retaining properties of he renin-angiotensin-aldosterone system is desirable, for example, in treating hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals including man.
According to the invention there is provided a heterocyclic amide of the formula I (set out hereinafter) wherein:
R.sup.1 is (1-8C)alkyl or phenyl;
R.sup.2 is phenyl or pyridyl, the latter optionally bearing a (1-4C)alkyl substituent;
R.sup.3 is hydrogen or a group of the formula Q.sup.1.A.sup.1 --in which Q.sup.1 is selected from pyridyl, imidazolyl, thiazolyl and pyrazolyl, and A.sup.1 is methylene or ethylene;
R.sup.4 is (1-8C)alkyl or (3-8C)cycloalkyl-(1-4C)alkyl;
R.sup.5 is hydrogen or (1-4C)alkyl;
R.sup.6 is hydrogen, (1-6C)alkyl, (1-4C)alkoxy, hydroxy, (1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, or a group of the formula Q.sup.2.A.sup.2 --in which Q.sup.2 is selected from (1-4C)alkoxy, (2-4C)alkenyl, phenyl and hydroxy, and A.sup.2 is (1-4C)alkylene; or R.sup.5 and R.sup.6 together form (2-4C)alkylene;
and wherein R.sup.7 is hydrogen, (1-4C)alkyl or hydroxy(2-4C)alkyl; and
R.sup.8 is hydrogen, (1-4C)alkyl in which 2 or 3 carbon atoms may bear a hydroxy substituent, (1-8C)alkyl, a group of the formula Q.sup.3.A.sup.3 --in which Q.sup.3 is selected from (1-4C)alkoxy, morpholino, thiomorpholino, piperidino, pyrrolidino, N-(1-4Cpiperazinyl, pyridyl (itself optionally bearing a (1-4C)alkyl substituent) and phenyl (itself optionally bearing 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy, amino(1-4C)alkyl), and A.sup.3 is (1-4C)alkylene; or R.sup.8 is a group of the formula Q.sup.4.A.sup.4 --in which Q.sup.4 is selected from amino, hydroxy and N,N-di(1-4C)-alkylamino, and A.sup.4 is (1-8C)alkylene; or R.sup.7 and R.sup.8 together with the adjacent nitrogen complete a morpholino, thiomorpholino, piperidino, pyrrolidino or N-(1-4C)piperazinyl moiety; and wherein a phenyl moiety of R.sup.1, R.sup.2 or Q.sup. 2, may optionally bear 1 or 2 substituents independently selected from halogeno, trifluoromethyl, cyano, (1-4C)alkyl and (1-4C)alkoxy; or a pharmaceutically acceptable salt thereof when R.sup.2, R.sup.3, or R.sup.8, or R.sup.7 and R.sup.8 contain a basic group.
The chemical structures referred to herein by Roman numerals are set out together at the end of the specification. The generic term "(1-8C)alkyl" in this specification means an alkyl group of 1 to 8 carbon atoms and includes both straight chain and branched alkyl groups of 3 to 8 carbon atoms. Other generic terms such as "alkylene" are to be interpreted similarly. However, the term "butyl" means the "n-butyl" group, with isomeric groups such as t-butyl, sec- butyl and i-butyl being referred to specifically as necessary. Other specific terms such as "propyl" are to be interpreted similarly. It will be appreciated that the compounds of formula I possess at least 3 chiral centres (shown with an asterisk *) and may therefore exist in racemic or optically active form, or other stereoisomeric mixtures thereof. This invention includes any optical isomer or racemate of formula I, or any other stereoisomeric mixture thereof, which inhibits renin, it being well known in the art how to prepare optical isomers, for example by resolution of the racemic form or by synthesis from optically active starting materials, how to separate stereoisomeric mixtures and how to show their renin inhibitory activity, for example using the standard tests referred to hereinafter. In general, it is preferred that the chiral centres in the fragment of the structure--CO.NH.CH(R.sup.4).CH(OH).CH.sub.2 - in formula I have the S-configuration.
A particular value for R.sup.1, R.sup.4 or R.sup.8 when it is (1-8C)alkyl is, for example, (1-6C)alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, 1-methylpentyl or 1,1-dimethylbutyl.
A particular value for R.sup.4 when it is (3-8C)cycloalkyl(1-4)alkyl is, for example, (3-8C)cycloalkylmethyl such as cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl.
A particular value for R.sup.2 when it is pyridyl is, for example, 3-pyridyl) and a particular value for an optional (1-4C)alkyl substituent is, for example, methyl or ethyl.
A particular value for R.sup.5 or R.sup.7 when it is (1-4C)alkyl is, for example, methyl, ethyl, isopropyl or isobutyl.
A particular value for A.sup.2 or A.sup.3 is, for example, methylene, ethylene, ethylidene or trimethylene, of which values methylene is generally preferred.
A particular value for R.sup.6 when it is (1-6C)alkyl is, for example, (1-4C)alkyl such as methyl, ethyl, isopropyl or isobutyl.
A particular value for R.sup.6 when it is (1-4C)alkoxy is, for example, methoxy, ethoxy or propoxy.
A particular value for R.sup.6 when it is (1-4C)alkylthio is for example, methylthio or ethylthio; when it is (1-4C)alkylsulphinyl is, for example, methylsulphinyl or ethylsulphinyl; and when it is (1-4C)alkylsulphonyl is, for example, methylsulphonyl or ethylsulphonyl.
A particular value for Q.sup.2 or Q.sup.3 when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, isopropoxy or isobutoxy; and when it is (3-8C)cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
A particular value for Q.sup.2 when it is (2-4C)alkenyl is, for example, vinyl, 1-propenyl, allyl or 1-butenyl.
A particular value for R.sup.5 and R.sup.6 when together they form (2-4C)alkylene is, for example, ethylene, propylene or tetramethylene.
A particular value for R.sup.7 when it is hydroxy(2-4C)alkyl is, for example, 2-hydroxyethyl or 2-hydroxypropyl.
A particular value for R.sup.8 when it is (2-4C)alkyl in which 2 or 3 carbon atoms bear a hydroxy substituent is, for example, 2-hydroxy-(hydroxymethyl)ethyl or 2-hydroxy-1,1-di(hydroxymethyl)ethyl.
A particular value for Q.sup.3 when it is N-(1-4C)alkyl-piperazinyl, or for R7 and R8 when together with the adjacent nitrogen they complete a N-(1-4C)alkylpiperazinyl moiety, is, for example, N-methyl-, N-ethyl or N-propylpiperazinyl.
A particular value for a (1-4C)alkyl substituent which may be present when Q.sup.3 is pyridyl is, for example, methyl or ethyl.
Particular values for optional substituents which may be present as defined above on phenyl include, for example: for halogeno: fluoro, chloro and bromo; for (1-4C)alkyl: methyl, ethyl, isopropyl and butyl; and for (1-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy.
Particular values for optional amino(1-4C)alkyl substituents which may be present when Q.sup.3 is phenyl in addition include, for example, aminomethyl, 2-aminoethyl and 3-aminopropyl.
A particular value for Q.sup.4 when it is N,N-di[(1-4C)alkyl]amino is, for example, dimethylamino or diethylamino.
A particular value for A.sup.4 is, for example, methylene, ethylene, trimethylene or tetramethylene, is any of which an individual methylene may optionally bear a methyl, ethyl, isopropyl or isobutyl substituent.
Specific combinations of values for R.sup.7 and R.sup.8 include, for example:
(1), when R8 is methyl, ethyl, propyl, butyl, 2-hydroxy-1-(hydroxymethyl)ethyl, 2-hydroxy-1,1-di(hydroxymethyl)ethyl, methoxyethyl, ethoxyethyl, 2-(morpholino)ethyl, 2-pyridylmethyl, 2-(3-pyridyl)ethyl, benzyl, chlorobenzyl, bromobenzyl, cyanobenzyl, 1-phenylethyl, 2-phenylethyl, 2-(hydroxymethyl)-3-methylbutyl, 2-(aminomethyl)-3-methylbutyl, or 2-hydroxy-1,1-dimethylethyl; and R.sup.7 is hydrogen, methyl, ethyl or 2-hydroxyethyl; and
(2), when R.sup.7 and R.sup.8 together with he adjacent nitrogen complete a morpholino, piperidino, pyrrolidino or N-methylpiperazino moiety.
A particular group of compounds of the invention of special interest comprise, for example those heterocyclic amides of the formula II wherein R.sup.11 is (1-6C)alkyl; and R.sup.2, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 have any of the meanings defined above; together with the pharmaceutically acceptable salts thereof.
A preferred value for R.sup.1 or R.sup.11 is, for example, propyl or isobutyl.
A preferred value for R.sup.2 is, for example, 3-pyridyl.
A preferred value for R.sup.3 is, for example, hydrogen or pyridylmethyl (especially 3-pyridylmethyl).
A preferred value for R.sup.4 is, for example, cyclohexylmethyl.
A preferred value for R.sup.5 is, for example, hydrogen or methyl and for R.sup.6 is methyl or isopropyl.
Suitable pharmaceutically acceptable salts of heterocyclic amides of formula I which contain a basic group include, for example, salts with inorganic acids such as with hydrogen halides (especially hydrochloride or hydrobromide salts), or with sulphuric or phosphoric acids, and salts with organic acids affording physiologically acceptable anions, for example, salts with acetic, citric, gluconic, tartaric, p-toluenesulphonic or trifluoroacetic acids.
Particular compounds of the invention are described in the accompanying Examples, which compounds are provided together with their appropriate pharmaceutically acceptable salts, as a further feature of the invention. A compound of particular interest is described hereinafter in Example 6.
The heterocyclic amides of formula I may be made by analogy with any process known in the art for the production of structurally related compounds, for example by analogy with the many different procedures known in standard text-books for the formation of amide bonds. Such processes for the production of heterocyclic amides of formula I and pharmaceutically acceptable salts thereof are provided as a further feature of the invention and are illustrated by the following preferred procedures in which R.sup.1 -R.sup.8, Q.sup.1 -Q.sup.4, and A.sup.1 -A.sup.4 have any of the meanings stated above:
a) A carboxylic acid of the formula III, in free acid form or as its alkali metal salt, or a reactive derivative thereof, is reacted with the appropriate amine of the formula IV.
When a free acid of formula III is used, the process is preferably carried out in the presence of a suitable condensing agent, for example, a carbodiimide such as 1,3-dichyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide optionally together with an N-hydroxytriazole such as 1-hydroxybenzotriazole and in a suitable solvent or diluent, for example, methylene chloride or dimethylformamide, and at a temperature in the range, for example, -20.degree. to -35.degree. C. and, preferably, at or near ambient temperature. When 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide is used as condensing agent, it is conveniently used in the form of a hydrohalide (such as the hydrochloride) salt and, preferably, in the presence of a suitable organic base, for example, triethylamine. When an alkali metal salt, for example, the sodium salt, of an acid of formula III is used, a condensing agent such as a carbodiimide optionally together with an N-hydroxytriazole is used as described above. However, in this case, when a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrohalide is used as the condensing agent, no added organic base is required.
A particularly suitable reactive derivative of an acid of formula III is, for example, the acid halide of the said acid, for example the acid chloride (obtainable, for example, by reaction of the acid with a chlorinating agent such as thionyl chloride), a mixed anhydride of the said acid with a (1-4C)alkanoic acid (such as formic acid) or a hemi(1-4C)alkyl carbonater [obtainable, for example, by reaction with an appropriate alkanoyl halide, a (1-45C)alkyl formate or a (1-4C)alkyl chloroformate (such as isobutyl chloroformate)], or an azide of the said acid, (obtainable, for example, by reaction of the acid with diphenylphosphoryl azide and triethylamine or from the corresponding hydrazide of the said acid by reaction with an alkyl nitrite such as t-butyl or amyl nitrite in the presence of strong acid.)
When a reactive derivative of an acid of the formula III is used in process (a), a base such as triethylamine, N-methylmorpholine, N-methylpiperidine or 4-(dimethylamino)pyridine is conveniently also present and the reaction is carried out in a suitable solvent or diluent such as dioxan, N,N-dimethylformamide or methylene chloride and a temperature in the range, for example -40.degree. to 35.degree. C.
The starting materials of formula III and IV may be made by standard procedures of organic chemistry already known for the production of structurally similar compounds and as illustrated in the accompanying Examples. For example, the acids of formula III may be obtained by the procedures shown in Scheme 1. Similarly, the amine derivatives of formula IV may be obtained, for example, by the procedures shown in Scheme 2. It will be appreciated that certain of the reaction stages and in particular the reaction of the dianion of the formula: (R.sup.5)(R.sup.6)C.sup.-.CO.sub.2.sup.- with the iodomethyloxazoline of the formula V to give the carboxylic acid of the formula VI, may give rise to diastereoisomeric mixtures which require to separated so that the desired stereoisoeric form of the amine of formula IV is obtained. This separation may be carried out, for example, by standard chromatographic procedures already generally known in the art of organic chemistry. The starting amines of the formula: (R.sup.7)(R.sup.8)NH required in Scheme 2 are either commercially available or may be obtained by analogy with well known procedures already known for the production of structurally analogous amines.
b) A lactone of the formula VIII is reacted with an amine of the formula: (R.sup.7)(R.sup.8)NH.
The process is conveniently carried out at a temperature in the range, for example, 20.degree. to 100.degree. C. and in the presence of a suitable diluent or solvent, for example, an inert solvent such as N,N-dimethylformamide, tetrahydrofuran or t-butyl methyl ether. Alternatively, where the amine of the formula: (R.sup.7)(R.sup.8)NH is an inexpensive volatile liquid, the amine may itself be used in large excess instead of most or all of he conventional solvent or diluent. Equally, where the amine is relatively unreactive, it may be used in process (b) in the form of its dimethylaluminium complex, formed by reaction of the amine with dimethylaluminium chloride or trimethylaluminium in a suitable inert solvent such as methylene chloride and in the absence of oxygen. The process may then be carried out at a temperature in the range, for example, -70.degree. to 60.degree. C.
It will be appreciated that when R.sup.8 itself contains an amino substituent, this must preferably first be protected with a suitable amine protecting group, for example, a t-butoxycarbonyl or benzyloxycarbonyl group, before the reaction with the lactone of the formula VI and then the protecting group subsequently removed. The protection of amino groups and their subsequent deprotection is well known in the organic chemical art for analogous compounds such as peptides.
The starting lactones of formula VIII may be made by standard organic chemical procedures, for example, by condensing an aminoalkyl lactone of the formula VII with a carboxylic acid of formula III, as illustrated in the accompanying Examples and as shown in Scheme 3. The aminoalkyl lactones of formula VII may also be obtained, for example, by reaction of the lithium enolate anion of a lactone of the formula IX in which P is a suitable protecting group, for example, t-butoxycarbonyl or benzyloxycarbonyl with an appropriate electrophile. Thus, for example, the following lactones (R.sup.5 =hydrogen) may be obtained by such a procedure:
The lactones of the formula IX may themselves be made by analogy with published procedures such as that described by Kleinman et alia (J. Org. Chem., 1986, 51, 4828).
Alternatively, the aminoalkyl lactones of formula VII may be obtained by reduction of an azidoalkyl lactone of the formula VIIa, for example, by palladium-on-charcoal catalyst hydrogenation at about one atmosphere pressure and ambient temperature in a suitable solvent or diluent such as ethanol or methanol. The said azidoalkyl lactones may themselves be made by analogy with published procedures such as that described in European Patent Application, Publication No. 0258183.
c) When a heterocyclic amide of formula I which contains a (1-4C)alkylsulphinyl or (1-4C)alkylsulphonyl substituent is required, the corresponding compound of the formula I containing a (1-4C)alkylthio substituent is oxidised.
It will be appreciated that, depending on the nature and amount of oxidising agent used, it is possible to produce either the alkylsulphinyl or alkylsulphonyl compounds of formula I. When only alkylsulphonyl compounds are required, the starting material may be the corresponding alkylsulphinyl compound. Equally, by reduction or increase of the reaction temperature within the general range -10.degree. to 45.degree. C., it is possible to predispose the production of sulphinyl or sulphonyl compounds.
Suitable oxidising agents include any conventional oxidants which are compatible with the presence of other sensitive functional groups, for example, alkali metal persulphates (such as potassium peroxymonosulphate), alkali metal periodates (such as sodium or potassium periodate), alkali metal permanganates (such as potassium permanganate), organic peracids (such as perbenzoic acid) and lead tetraacetate. The solvents suitable for use in the process necessarily depend on the oxidising agent used, but include, for example, methanol, formic acid, acetic acid, dichloromethane and chloroform.
When an alkylsulphonyl compound is required, a convenient oxidising agent is, for example, an alkali metal peroxymonosulphate (such as potassium peroxymonosulphate in methanol at a temperature in the range, for example, -10.degree. to 25.degree. C.) and when an alkylsulphinyl compound is required, a convenient oxidising agent is, for example, an alkali metal periodate (such as potassium periodate in aqueous methanol or acetic acid at 10.degree. to 25.degree. C.).
d) A protected derivative of the formula X wherein P.sup.1 and P.sup.2 are suitable protecting groups, or one of P.sup.1 and P.sup.2 is hydrogen and the other is a suitable protecting group, is deprotected.
Particularly suitable values for P.sup.1 or P.sup.2 include, for example, typical hydroxy and imino protecting groups such as arylmethyl (and typically benzyl), which may be removed in process (d), for example, by palladium-on-charcoal catalysed hydrogenation at about atmospheric pressure and ambient temperature in a suitable solvent or diluent such as ethanol or methanol. Particularly suitable values for the hydroxy protecting group P.sup.2 include, for example, carbonate ester radicals, such as t-butoxycarbonyl and benzyloxycarbonyl, which may be removed by conventional procedures, such as hydrolysis, or, in the case of benzyloxycarbonyl, hydrogenation. Alternatively, P.sup.1 and P.sup.2 may conveniently be consolidated into an alkylidene or benzylidene group completing an oxazoline ring with the neighbouring nitrogen and oxygen atoms. Such a combined protecting group may be removed, for example, by mild acid hydrolysis or by using ammonium formate and palladium-on-charcoal in a suitable solvent or diluent, such as aqueous ethanol.
Whereafter, when a pharmaceutically acceptable salt is required, it may be obtained, for example, by reacting the compound of formula I with the appropriate acid or base affording a physiologically acceptable ion.
Whereafter, when a particular optically active form of a compound of formula I is required, it may be obtained, for example, by resolution of the corresponding racemic form, by using the appropriate optically active forms of the starting materials in any one of the aforesaid processes, or by separation of the diastereoisomers by physical methods well known in the art.
As stated previously, the compounds of formula I inhibit the action of renin and thereby have beneficial pharmacological effects in warm-blooded animals (including man) in diseases and medical conditions where amelioration of he vasoconstrictor and fluid retaining properties of the renin-angiotensinaldosterone system is desirable, as further set out hereinafter.
In particular, the compounds of formula I inhibit the catalytic activity of renin and hence the biosynthesis of substances known as angiotensins in warm-blooded animals (including man) and thereby minimise the pharmacological effects associated with their presence. The angiotensins, and in particular that known as angiotensin II, are potent spasmogens especially in the vasculature and are known to increase vascular resistance and blood pressure. In addition, the angiotensins are known to stimulate the release of aldosterone and hence result in vascular congestion and hypertension via sodium and fluid retention mechanisms.
The compounds of formula I will therefore be useful in the treatment of diseases or medical conditions such as hypertension, congestive heart failure and/or hyperaldosteronism in warm-blooded animals (including man), as well as in other diseases or medical conditions in which the renin-angiotensin-aldosterone system plays a significant causative role.
The inhibition of the catalytic activity of renin, and in particular of human renin, may be assessed in vitro using a routine laboratory procedure involving the incubation of a test compound initially at a concentration of 100 micromolar in a buffered mixture containing appropriate concentrations of partially purified human renin and the natural renin substrate angiotensinogen. The formation of the angiotensin known as angiotensin I (which is assayed by a standard radioimmunoassay using procedures well known in the art) is inhibited by those compounds which inhibit the action of renin and the degree of inhibition is readily determined by comparing the angiotensin I generation rate in the presence of the test compound (at the specified test concentration) with the control rate of angiotensin I generation in the absence of the test compound.
In this standard test procedure, compounds which show at least 30% inhibition are retested at lower concentrations to determine their inhibitory potency. For determination of the IC.sub.50 (concentration for 50% inhibition of the renin catalysed reaction), concentrations are ordinarily chosen to allow testing over at least four orders of magnitude centred about the predicted approximate IC.sub.50, which latter is subsequently determined from a plot of percentage inhibition against concentration of the test compound. The above procedure may also be carried out using buffered human plasma in order to assess the effects of the test compound on the action of human plasma renin and involves measuring the inhibition of angiotensin I generated by the action of endogenous plasma renin on plasma-bourne angiotensinogen. In general, compounds of formula I will produce significant inhibition in the above tests at a concentration of 100 micromolar or much less. For example, the compound described in Example 6 hereinafter has an IC.sub.50 of 2.times.10.sup.-10 M.
The inhibition of renin may also be assessed in vivo using a routine laboratory procedure involving the stimulation of release of endogenous renin in the common marmoset (Callithrix jacchus) by introducing a diet of low sodium content and giving three daily oral doses of the diuretic known as frusemide at 25 mg/kg body weight. A test compound is then administered (orally or parenterally) to marmosets to which an arterial catheter has been implanted under anaesthesia and the change in blood pressure and/or plasma renin activity is determined. The determinations may be carried out in terminally anaesthetised or conscious marmosets. To ensure that the effects seen with the test compound are specific to inhibition of the action of renin, the effect of the test compound on the hypertensive response to injected human renin may be compared with its effect on the hypertensive response to injected angiotensin I in anaesthetised marmosets or in alternative animal preparations adapted for blood pressure measurements. Many of the compounds of formula I generally show specific renin inhibitory properties in the above in vivo test at a dose of 50 mg/kg body weight or much less, without any overt toxic or other untoward pharmacological effects.
The compounds of formula I (or pharmaceutically acceptable salts thereof) will generally be administered for therapeutic or prophylactic purposes to warm-blooded animals (including man) requiring such treatment in the form of a pharmaceutical composition in conjunction with a pharmaceutically acceptable diluent or carrier, as is well known in the pharmaceutical art. Such pharmaceutical compositions are provided as a further feature of the invention and will conveniently be in a form suitable for oral administration (for example, as a tablet, capsule, solution, suspension or emulsion) or parenteral administration (for example, as an injectable aqueous or oily solution, or injectable emulsion). The compounds of formula I may also be advantageously administered for therapeutic or prophylactic purposes together with one or more other pharmacological agents known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, for example, together with another anti-hypertensive agent such as a diuretic, an adrenergic blocking agent and/or a calcium channel blocking agent.
A compound of formula I will generally be administered to man so that, for example, a daily oral dose of up to 50 mg/kg body weight (and preferably of up to 5 mg/kg) or a daily parenteral dose of up to 10 mg/kg body weight (and preferably of up to 1 mg/kg) is received, given in divided doses as necessary, the precise amount of compound (or pharmaceutically acceptable salt) received and the route and form of administration depending on size, age and sex of the person being treated and on the particular disease or medical condition being treated according to principles well known in the medical arts.
The invention will now be illustrated by the following non-limiting Examples in which, unless otherwise stated:
(i) all evaporations were carried out by rotary evaporation under reduced pressure (0.1-50 mm Hg);
(ii) all operations were carried out at room temperature, that is in the general range 18.degree.-26.degree. C.;
(iii) purification by flash chromatography was performed on silica (Merck Kieselgel: Art.9385) using the procedure described in J. Org. Chem., 1978, 43, 2923, following the purification by thin layer chromatography on silica (0.25 mm, Merck Kieselgel 60F 254 plates: Art. 5715; materials available from E Merck, Darmstadt, Federal Republic of Germany);
(iv) the purity and chemical composition of products was assessed by nuclear magnetic resonance (NMR) spectroscopy, thin layer chromatographic analysis, mass spectroscopy and/or microanalysis;
(v) NMR spectra were determined at 200 MHz using tetramethyl silane (TMS) as an internal standard and are given as chemical shifts in parts per million relative to TMS, using conventional abbreviations for signals, such as: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet; br, broad; and
(vi) yields are given for illustration purposes only and are not necessarily the maximum attainable following diligent process development.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4758584 |
Buhlmayer etal. |
Jul 1988 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 0258183 |
Mar 1988 |
EPX |
| 0270234 |
Jun 1988 |
EPX |
Patent Grant
5091425
