C-terminal amide cyclic renin inhibitors containing peptide isosteres

Claim 2

A cyclic peptide of the formula: ##STR73## wherein: A is hydrogen or ##STR74## where X is --O--, --O--CH--, --CH--O--, --CH--, --NH--CH--, or --S--CH--; and R a 1 and R b 1 may be the same or different and are hydrogen; W--(CH 2 ) p -- or W--(CH 2 ) p , --CH═CH--(CH 2 ) p" , where W is C 1 -C 4 -alkyl; hydrogen; phenyl; naphthyl; C 3 -C 7 -cycloalkyl; or C 3 -C 7 -cycloalkyl, phenyl or naphthyl substituted with up to five members independently selected from the group consisting of C 1 -C 8 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy, and halo; p is 0 to 5; and p' and p" are independently 0 to 2; except that where X is --O--, only one of R a 1 or R b 1 is present; B is absent, glycyl, sarcosyl, or ##STR75## where R 2 is hydrogen; C 1 -C 4 -alkyl; hydroxy-C 1 -C 4 -alkyl; methylthiomethyl; indolyl; 4-imidazolyl; amino-C 2 -C 4 alkyl; ##STR76## where R 8 is hydrogen, C 1 -C 4 -alkyl, hydroxy, or C 3 -C 7 -cycloalkyl; quanidyl-C 2 -C 3 -alkyl; or unsubstituted or mono- or disubstituted phenyl or naphthyl, where the substituent(s) is/are independently selected from the group consisting of C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy, and halo; D is absent, --S-- or ##STR77## where Z is --(CH 2 ) m -- and m is 1 or 2; E is absent or ##STR78## where k is 1 to 4; and R 3 is hydrogen; C 1 -C 4 -alkyl; indolyl; or unsubstituted or mono-, or disubstituted phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl, or naphthyl-C 1 -C 4 -alkyl where the substituent(s) is/are independently selected from the group consisting of C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy, and halo; F is absent, --CH 2 --, --S--, or --0--; n is 0 to 3; G is ##STR79## where R 6 is C 3 -C 6 -alkyl; or unsubstituted or mono-, or disubstituted C 3 -C 7 -cycloalkyl, phenyl or naphthyl, where the substituent(s) is/are independently selected from the group consisting of C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 -alkoxy, and halo; q is 1 to 4; R 4 is hydrogen; or ##STR80## where R 3 is hydrogen; C 1 -C 4 -alkyl; indolyl; unsubstuted or mono-, or disubstituted phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl, or naphthyl-C 1 -C 4 -alkyl, where the substituents(s) on the phenyl or naphthyl is/are independently selected from the group consisting of C 1 -C 4 alkyl,, trifluoromethyl, hydroxy, C 1 -C 4 alkoxy, and halo; and R a 8 is hydrogen; C 1 -C 4 -alkyl; hydroxy; or C 3 -C 7 -cycloalkyl; and Y is ##STR81## wherein X' is hydroxy; amino; or mono- or di-C 1 -C 4 -alkylamino; and W' is absent; --O--, --NH--, or --CH 2 --; ##STR82## where X" and X"' are independently absent or ##STR83## and W" is absent, --CH 2 --, or ##STR84## where R 8 is hydrogen or C 1 -C 3 -alkyl; ##STR85## wherein R is hydrogen; C 1 -C 4 -alkyl; formyl; C 1 -C 4 -alkanoyl; phenoyl; C 1 -C 4 -alkoxy-carbonyl; or phenoxy-carbonyl; R 5 is hydrogen; ##STR86## where R 3 and R a 8 are as defined above; or --(CH 2 ) n' --R 9 , where n' is 0 to 4, and R 9 is guanidyl-C 2 -C 3 -alkyl; amino-C 1 -C 4 -alkyl; or an unsubstituted or mono or disubstituted heterocycle, wherein the heterocycle represents a 5- or 6- membered ring or benzofused 5- or 6-membered ring, where the one or two heteroatoms are independently selected from N, O, S, NO, SO, or quaternized N, and the substitutent(s) is/are independently selected from the group consisting of C 1 -C 6 alkyl, hydroxy, trifluoromethyl, C 1 -C 4 alkoxy, halo, phenyl, naphthyl, phenyl-C 1 -C 4 -alkyl, naphthyl-C 1 -C 4 -alkyl, amino, and mono- or di-C 1 -C 4 -alkylamino; J is absent or glycyl; and wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D and Y portion of G substituents, which may have either an S or an R configuration; and pharmaceutically-acceptable salts thereof.

Claim 3

A cyclic peptide according to claim 1 selected from the group consisting essentially of: ##STR87##

Claim 4

A pharmaceutical composition for treating renin-associated hypertension or renin-associated hyperaldosteronism, comprising a pharmaceutical carrier and a therapeutically-effective amount of a cyclic peptide or pharmaceutically-acceptable salt thereof according to claim 1.

Claim 5

A pharmaceutical composition according to claim 3, wherein the cyclic peptide is a member selected from the group consisting essentially of: ##STR88##

Claim 6

A method of treating renin-associated hypertension or renin-associated hyperaldosteronism, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a cyclic peptide or pharmaceutically-acceptable salt thereof according to claim 1.

Claim 7

A method according to claim 5, wherein the cyclic peptide is a member selected from the group consisting essentially of: ##STR89##

Claim 8

A method of determining the presence of renin-associated hypertension in a patient, comprising administering to such a patient, in a single dose at a hypotensive dosage level, a cyclic peptide or pharmaceutically-acceptable salt thereof according to claim 1, followed by monitoring of the blood pressure of the patient, with a transitory fall in the patient's blood pressure indicating supranormal plasma renin levels in the patient.

Claim 9

A composition for treating hypertension comprising a cyclic peptide or pharmaceutically-acceptable salt thereof according to claim 1. and one or more antihypertensive agents selected from the group consisting essentially of: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respectively); metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironolactone; tricrynafen; triamterene; trichlormethiazide; α-Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; tolazoline; β-Adrenergic Blocking Agents: atenolol; metoprolol; nadolol; propranolol; timolol; ((±)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-2-furan-anilide) (ancarolol); (2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran HCl) (befunolol); ((±)-1-(isopropylamino)-3-(p-(2-cyclopropylmethoxyethyl)-phenoxy)-2-propranol HCl) (betaxolol); (1-[(3,4-dimethoxyphenethyl)amino]-3-(m-tolyloxy)-2-propanol HCl) (bevantolol); (((±)-1-(4-((2-isopropoxyethoxy)methyl)phenoxy)-3-isopropylamino-2-propanol)fumarate) (bisoprolol); (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidino]propoxy)-indole); (carbazolyl-4-oxy-5,2-(2-methoxyphenoxy)-ethylamino-2-propanol); (1-((1,1-dimethylethyl)amino)-3-((2-methyl-1H-indol-4-yl)oxy)-2-propanol benzoate) (bopindolol); (1-(2-exobicyclo[2.2.1]-hept-2-ylphenoxy)-3-[(1-methylethyl)- amino]-2-propanol HCl) (bornaprolol); (o-[2-hydroxy-3-[(2-indol-3-yl-1,1-dimethylethyl)amino]propoxy]benzonitrile HCl) (bucindolol); (α-[(tert.butylamino)methyl]-7-ethyl-2-benzofuranmethanol) (bufuralol); (3-[3-acetyl-4-[3-(tert.butylamino)-2-hydroxypropyl]phenyl]-1,1-diethylurea HCl) (celiprolol); ((±)-2-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenoxy]-N-methylacetamide HCl) (cetamolol); (2-benzimidazolyl-phenyl(2-isopropylaminopropanol)); ((±)-3'-acetyl-4'-(2-hydroxy-3-isopropylaminopropoxy)acetanilide HCl) (diacetolol); (methyl-4-[2-hydroxy-3-[(1-methylethyl)aminopropoxy]]benzenepropanoate HCl) (esmolol); (erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol); (1-(tert.butylamino)-3-[O-(2-propynyloxy)phenoxy]-2-propanol (pargolol); (1-(tert.butylamino)-3-[o-(6-hydrazino-3-pyridazinyl)phenoxy]-2-propanol diHCl) (prizidilol); ((-)-2-hydroxy-5-[(R)-1-hydroxy-2-[(R)-(1-methyl-3-phenylpropyl)amino]ethyl]benzamide); (4-hydroxy-9-[2-hydroxy-3-(isopropylamino)-propoxy]-7-methyl-5H-furo[3,2-g][1]-benzopyran-5-one) (iprocrolol); ((-)-5-(tert.butylamino)-2-hydroxypropoxy]-3,4-dihydro-1-(2H)-naphthalenone HCl) (levobunolol); (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole HCl); (4-[3-(tert.butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril HCl); ((±)-N-2-[4-(2-hydroxy-3-isopropyl aminopropoxy)phenyl]ethyl-N'-isopropylurea) (pafenolol); (3-[[(2-trifluoroacetamido)ethyl]amino]-1-phenoxypropan-2-ol); (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-(4'-chloro2,3-dihydro-3-oxo-5-pyridazinyl)ethylenediamine); ((±)-N-[3-acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]phenyl]butanamide) (acebutolol); ((±)-4'-[3-(tert-butylamino)-2-hydroxypropoxy]spiro[cyclohexane-1,2'-indan]-1'-one) (spirendolol); (7-[3-[[2-hydroxy-3-[(2-methylindol-4-yl)oxy]propyl]amino]butyl]thiophylline) (teoprolol); ((±)-1-tert.butylamino-3-(thiochroman-8-yloxy)-2-propanol) (tertatolol); ((±)-1- tert.butylamino-3-(2,3-xylyloxy)-2-propanol HCl) (xibenolol); (8-[3-(tert.butylamino)-2-hydroxypropoxy]-5-methylcoumarin) (bucumolol); (2-(3-(tert.butylamino)-2-hydroxy-propoxy)benzonitrile HCl) (bunitrolol); ((±)-2'-[3-(tert-butylamino)-2-hydroxypropoxy-5'-fluorobutyrophenone](butofilolol); (1-(carbazol-4-yloxy)-3-(isopropylamino)-2-propanol) (carazolol); (5-(3-tert.butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril HCl) (carteolol); (1-(tert.butylamino)-3-(2,5-dichlorophenoxy)-2-propanol) (cloranolol); (1-(inden-4(or 7)-yloxy)-3-(isopropylamino)-2-propanol HCl) (indenolol); (1-isopropylamino-3-[(2-methylindol-4-yl)oxy]-2-propanol) (mepindolol); (1-(4-acetoxy-2,3,5-trimethylphenoxy)-3-isopropylaminopropan-2-ol) (metipranolol); (1-(isopropylamino)-3-(o-methoxyphenoxy)-3-[(1-methylethyl)amino]-2-propanol) (moprolol); ((1-tert.butylamino)-3-[(5,6,7,8-tetrahydro-cis-6,7-dihydroxy-1-naphthyl)oxy]-2-propanol) (nadolol); ((S)-1-(2-cyclopentylphenoxy)-3-[(1,1-dimethylethyl)-amino]-2-propanol sulfate (2:1)) (penbutolol); (4'-[1-hydroxy-2-(amino)ethyl]methanesulfonanilide) (sotalol); (2-methyl-3-[4-(2-hydroxy-3-tert.butylaminopropoxy)phenyl]-7-methoxy-isoquinolin-1-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)-3-isopropylamino-2-propanol HCl); ((-)-p-[3-[(3,4-dimethoxyphenethyl)amino]-2-hydroxypropoxy]-β-methylcinnamonitrile) (pacrinolol); ((±)-2-(3'-tert.butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thienyl)thiazole HCl) (arotinolol); ((±)-1-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy]-3-(isopropylamino)-2-propanol) (cicloprolol); ((±)-1-[(3-chloro-2-methylindol-4-yl)oxy]-3-[(2-phenoxyethyl)amino]-2propanol) (indopanolol); ((±)-6-[[2-[[3-(p-butoxypheboxy)-2-hydroxypropyl]amino]ethyl]amino]-1,3-dimethyluracil) (pirepolol); (4-(cyclohexylamino)-1-(1-naphtholenyloxy)-2-butanol); (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxypropyl]-aminoethyl]hydantoin HCl); (3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran) (nipradolol); α and β-Adrenergic Blocking Agents: ((±)-1-tert-butylamino)-3-[o-[2-(3-methyl-5-isoxazolyl)vinyl]phenoxy]-2-propanol) (isoxaprolol); (1-isopropylamino-3-(4-(2-nitroxyethoxy)phenoxy)-2-propanol HCl); (4-hydroxy-α-[[3-(4-methoxyphenyl)-1-methylpropyl]aminomethyl]-3-(methylsulfinyl)-benzmethanol HCl) (sulfinalol); (5-[1-hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]ethyl]-2-methylbenzenesulfonamide HCl); (5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]salicylamide HCl) (labetalol); (1-((3-chloro-2-methyl-1H-indol-4-yl)oxy)-3-((2-phenoxyethyl)amino)-2-propanol- hydrogenmalonate) (ifendolol); (4-(2-hydroxy-3-[(1-methyl-3-phenylpropyl)amino]propoxy)benzeneacetamide); (1-[3-[[3-(1-naphthoxy)-2-hydroxypropyl]-amino]-3,3-dimethyl-propyl]-2-benzimidazolinone); (3-(1-(2-hydroxy-2-(4-chlorophenylethyl)-4-piperidyl)-3,4-dihydroxy)quinoxolin-2(1H)-one); CNS-Acting Agents: clonidine; methyldopa; Adrenergic Neuron Blocking Agents: quanethidine; reserpine and other rauwolfia alkaloids such as rescinnamine; Vasodilators: diazoxide; hydralazine; minoxidil; Angiotensin I Converting Enzyme Inhibitors: 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2,4(R,R)-dimethylbutanoyl)indoline-2(S)-carboxylic acid); (2-[2-[[1-(ethoxycarbonyl)-3-phenyl-propyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid); ((S)-1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid HCl); (N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxopropyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid) (1-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)cis, syn-octahydroindol-2(S)-carboxylic acid HCl); ((-)-(S)-3-mercapto-2-methyl-1-oxopropyl]indoline-2-carboxylic acid); ([1(S),4S]-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-phenylthio-L-proline; (3 -([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1-acetic acid HCl); (N-(2-benzyl-3-mercaptopropanoyl)-S-ethyl-L-cysteine) and the S-methyl analogue; (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate) (enalapril); N-[1-(S)-carboxy-3-phenylpropyl]-L-alanyl-1-proline; N 2 -[1-(S)-carboxy-3-phenylpropyl]-L-lysyl-L-proline (lysinopril); Other Antihypertensive Agents: aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; trimethaphan camsylate; including pharmaceutical salt and ester forms thereof.

Claim 10

A method according to claim 7, wherein the hypotensive dosage level is from 0.1 to 10 mg per kg of body weight, and the cyclic peptide or pharmaceutically-acceptable salt thereof is administered by intravenous injection.