Claims
- 1. A compound of the formula: ##STR6## wherein A is hydrogen; C.sub.1 -C.sub.6 loweralkyl; arylalkyl; OR.sub.10 wherein R.sub.10 is hydrogen or C.sub.1 -C.sub.6 loweralkyl; NR.sub.11 R.sub.12 wherein R.sub.11 is hydrogen or C.sub.1 -C.sub.6 loweralkyl and R.sub.12 is hydrogen or C.sub.1 -C.sub.6 loweralkyl; or R.sub.13 --CO--B wherein B is NH, O, CH.sub.2, or HNCH.sub.2 and R.sub.13 is C.sub.1 -C.sub.6 loweralkyl, alkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, N-protected aminoalkyl, hydroxylated dialkylamino, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic having one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, carboxyalkyl or C.sub.1 -C.sub.6 lower alkyl carboxyalkyl esters; W is N or CH; U,V is H,OH; OH,H; or H,H; or when taken together as O is a carbonyl group with the provisos that when U,V is H,OH, or OH,H tyhen W is CH, and when U,V is O then W is N; R.sub.1 is C.sub.1 -C.sub.6 loweralkyl, benzyl, beta-naphthylmethyl or 4-methoxybenzyl, R.sub.3 is C.sub.1 -C.sub.6 loweralkyl, hydroxy substituted C.sub.1 -C.sub.6 loweralkyl, benzyl, 4-hydroxybenzyl or 4-imidazolylmethyl, R.sub.5 is C.sub.1 -C.sub.6 loweralkyl or cycloalkyl methyl; R.sub.2, R.sub.4, R.sub.7, R.sub.8 and R.sub.9 are independently selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 loweralkyl; X is NH, O, S, SO, SO.sub.2, or CH.sub.2 ; and R.sub.6 is C.sub.1 -C.sub.6 loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an N-protecting group, with the proviso that R.sub.6 is an N-protecting group only when X is NH.
- 2. A compound of claim 1 wherein R.sub.1 and R.sub.5 are benzyl, beta-naphthylmethyl or 4-methoxybenzyl in the definition of R.sub.1 and cycloalkyl methyl for R5.
- 3. A compound of claim 2 wherein R.sub.2, R.sub.4, R.sub.7, R.sub.8 and R.sub.9 are hydrogen.
- 4. A compound of claim 3 wherein R.sub.1 is benzyl or betanaphthylmethyl.
- 5. A compound of claim 4 wherein R.sub.3 is methyl.
- 6. A compound of claim 4 wherein R.sub.3 is imidazol-4-yl-methyl.
- 7. A compound of claim 4 wherein R.sub.5 is isobutyl.
- 8. A compound of claim 4 wherein R.sub.5 is cyclohexylmethyl.
- 9. A compound of claim 4 wherein X is S or SO.sub.2.
- 10. A compound of claim 4 wherein R.sub.6 is cyclohexyl or isopropyl.
- 11. A compound of claim 4 wherein X is oxygen.
- 12. A compound of claim 4 wherein X is NH.
- 13. A compound of claim 3 wherein X is S, R.sub.1 is benzyl, R.sub.3 is imidazole-4-yl-methyl, R.sub.5 is cyclohexylmethyl and R.sub.6 is isopropyl or cyclohexyl.
- 14. A compound of claim 3 wherein X is S, R.sub.1 is .beta.-naphthylmethyl, R.sub.3 is imidazole-4-yl-methyl, R.sub.5 is cyclohexylmethyl or isobutyl and R.sub.6 is cyclohexyl.
- 15. A compound of claim 3 wherein X is SO.sub.2, R.sub.1 is benzyl, R.sub.3 is imidazole-4-yl-methyl, R.sub.5 is cyclohexylmethyl and R.sub.6 is cyclohexyl or isopropyl.
- 16. A pharmaceutical composition for treating hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
- 17. A method of treating hypertension comprising administering to a host a therapeutically effective amount of a compound of claim 1.
TECHNICAL FIELD
This application is continuation-in-part of U.S. patent application Ser. No. 735,491, filed May 17, 1985 now U.S. Pat. No. 4,645,759, which is a continuation in part of U.S. application, Ser. No. 623,807 filed June 22, 1984.
The present invention relates to novel organic compounds which inhibit renin, processes for making such compounds, synthetic intermediates employed in these processes and methods of treating hypertension with such compounds.
Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different physiologic circumstances may cause the release of renin into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood volume in the body; or (c) a fall in the concentration of sodium in the distal tubules of the kidney.
When renin is released into the blood from the kidney, the renin angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure. The renin acts on a circulating protein, angiotensinogen, to cleave out a fragment called angiotensin I (AI). AI itself has only slight pharmacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (AII). The major pharmacological effects of AII are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention. AII is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to AII, is a less potent vasoconstrictor but a more potent inducer of aldosterone release.
Inhibitors of renin have been sought as agents for control of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
With these objectives in mind, the renin angiotension system has been modulated or manipulated, in the past, with ACE inhibitors. However, ACE acts on several substrates other than angiotensin I (AI), most notably the kinins which cause such undesirable side effects as pain, "leaky" capillaries, prostaglandin release and a variety of behavioral and neurologic effects. Further, ACE inhibition leads to the accumulation of AI. Although AI has much less vasoconstrictor activity than AII, its presence may negate some of the hypotensive effects of the blockade of AII synthesis.
Inhibition of other targets in the renin-angiotensin system such as AII with compounds such as saralasin can block AII activity, but would leave unimpaired and perhaps enhance the hypertensive effects of AIII.
On the other hand, there are no known side effects which result when renin is inhibited from acting on its substrate. Considerable research efforts have thus been carried out to develop useful inhibitors of renin. Past research efforts have been directed to renin antibodies, pepstatin, phospholipids and substrate analogs such as tetrapeptides and octapeptides to tridecapeptides. These inhibitors either demonstrate poor activity in inhibiting renin production or poor specificity for inhibiting renin only. However, Boger et al. have reported that statine-containing peptides possess potent and specific renin-inhibiting activity (Nature, Vol. 303, p. 81, 1983). In addition, Szelke and co-workers have described polypeptide analogs containing a non-peptide link (Nature, Vol. 299, p. 555, 1982) which also cause potent renin inhibition and show a high specificity for this enzyme.
In accordance with the present invention, there are renin inhibiting compounds of the formula ##STR2## wherein A is hydrogen; loweralkyl; arylalkyl; OR.sub.10 wherein R.sub.10 is hydrogen or loweralkyl; NR.sub.11 R.sub.12 wherein R.sub.11 and R.sub.12 are independently selected from hydrogen and loweralkyl; or R.sub.13 --CO--B wherein B is NH, O, CH.sub.2, HNCH.sub.2 and R.sub.13 is loweralkyl, alkoxy, aryl alkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, N-protected aminoalyl, hydroxylated dialkylamino, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic, carboxyalkyl, or lower alkyl carboxyalkyl esters; W is N or CH; U,V may be the following combinations H,OH; OH,H; H,H; or when taken together as O represents a carbonyl group with the provisos that if U,V.dbd.H,OH, or OH,H then W.dbd.CH, and if U,V.dbd.0 then W.dbd.N; R.sub.1, R.sub.3 and R5 are loweralkyl, or hydro-philic, lipophilic or aromatic amino acid side chains and may be the same or different; R.sub.2, R.sub.4, R.sub.7, R.sub.8 and R.sub.9 are hydrogen or loweralkyl and may be the same or different; X is NH, O, S, SO, SO.sub.2, or CH.sub.2 ; and R.sub.6 is loweralkyl cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an N-protecting group, with the proviso that R.sub.6 may be an N protecting group when X is NH.
The preferable compounds are when R.sub.2, R.sub.4, R.sub.7, R.sub.8 and R.sub.9 are hydrogen, R.sub.1 is benzyl, 1- or 2-naphthylmethyl and R.sub.5 is isobutyl or cyclohexyl methyl. The most preferable compounds are when R.sub.3 is imidazol 4 yl methyl, X is SO.sub.2, or O and R.sub.5 is cyclohexylmethyl.
The chiral centers of the compounds of the invention may have either the "R" or "S" configuration but preferably have an "S" configuration except where noted. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 30.
The term "N protecting group" or "N-protected" as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, pivalcyl, t-butylacetyl, t-butyloxycarbonyl(Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or D- aminoacyl residue, which may itself be N-protected similarly.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "arylalkyl" as used herein refers to an unsubstituted or substituted aromatic ring appended to an alkyl radical including but not limited to benzyl, 1- and 2-naphthylmethyl, halobenzyl and alkoxybenzyl.
The term "alkylamino" as used herein refers to a loweralkyl radical appended to an NH radical.
The term "aminoalkyl" as used herein refers to --NH.sub.2 appended to a loweralkyl radical.
The term "cycloalkyl" as used herein refers to an aliphatic ring having 4 to 7 carbon atoms.
The term "cycloalkylmethyl" as used herein refers to a cycloalkyl group appended to a methyl radical, including but not limited to cyclohexylmethyl.
The term "aryl" as used herein refers to a substituted or unsubstituted aromatic ring including but not limited to phenyl, naphthyl, halophenyl and alkoxy phenyl.
The term "alkoxy" as used herein refers to R.sub.14 O-- wherein R.sub.14 is a loweralkyl group.
The term "arylalkoxy" as used herein refers to an aryl appended to an alkoxy radical.
The term "arylalkoxyalkyl" as used herein refers to an arylalkoxy appended to a loweralkyl radical.
The term "dialkylamino" as used herein refers to --NR.sub.15 R.sub.16 wherein R.sub.15 and R.sub.16 are independently selected from loweralkyl groups.
The term "N-protected aminoalkyl" as used herein refers to NHR.sub.17 is appended to a loweralkyl group, where R.sub.17 is an N-protecting group.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to imidazoylalkyl.
The term "heterocyclic ring" or "heterocyclic" as used herein refers to any 5-, 6-, 9- or 10-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; having various degrees of unsaturation; wherein the nitrogen and sulfur heteroatoms may optionally be quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocyclics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolidinyl, thiazolyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
Saturated heterocyclics may be unsubtituted or mono- or di- substituted with hydroxy, oxo, amino, alkylamino, dialkylamino or loweralkyl. Unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino or loweralkyl.
The most preferred heterocyclics are as follows: ##STR3## wherein n is 1 or 2 and X is N, NH, O, S, provided that X is the point of connection only when X is N, ##STR4## wherein Y is NH, N-loweralkyl, O, S, or SO.sub.2, or ##STR5## wherein Z.sub.1 is N, O, or S and not the point of connection and Z.sub.2 is N when it is the point of connection and NH, O or S when it is not the point of connection.
The terms "lipophilic or aromatic amino acid side chains" as used herein refer to those amino acid side chains which have an affinity for lipids or have an aromatic ring and include but are not limited to benzyl, isobutyl, isopropyl, sec-butyl, imidazol-4-yl- methyl, p-hydroxybenzyl, 1- and 2-naphthylmethyl, (pyrazolyl)methyl, (thiazolyl)methyl, and cyclohexylmethyl. The term "hydrophilic amino acid side chain" as used herein refers to those amino acid side chains which have an affinity for water and include but are not limited to, those of serine, threonine, allothreonine, homoserine, cysteine, ornithine, arginine, and glutamine. General reference to amino acid side chains in both the description and claims herein is to be taken as reference to such, whether naturally occurring in protein or not, and to both D- and L-forms.
The terms "Ala", "His", "Leu" and "Phe" as used herein refer to alanine, histidine, leucine and phenylalanine.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 4609641 |
Evans et al. |
Sep 1986 |
|
| 4645759 |
Luly et al. |
Feb 1987 |
|
Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 0045665 |
Feb 1982 |
EPX |
Continuation in Parts (2)
|
Number |
Date |
Country |
| Parent |
735491 |
May 1985 |
|
| Parent |
623807 |
Jun 1984 |
|
Patent Grant
4826815
