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WO1990005531A1 - Procede de traitement de maladies vasculaires - Google Patents

Procede de traitement de maladies vasculaires Download PDF

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Publication number
WO1990005531A1
WO1990005531A1 PCT/US1989/005248 US8905248W WO9005531A1 WO 1990005531 A1 WO1990005531 A1 WO 1990005531A1 US 8905248 W US8905248 W US 8905248W WO 9005531 A1 WO9005531 A1 WO 9005531A1
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WIPO (PCT)
Prior art keywords
amino
alkyl
loweralkyl
substituted
hydrogen
Prior art date
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PCT/US1989/005248
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English (en)
Inventor
Hollis D. Kleinert
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Abbott Laboratories
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Publication date
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Publication of WO1990005531A1 publication Critical patent/WO1990005531A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—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
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • the present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treating, inhibiting, relieving or reversing vascular diseases with respect to functional and/or anatomical abnormalities, and in particular peripheral vascular diseases and microvascular diseases associated with diabetes, especially diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
  • vascular diseases are often the result of decreased perfusion in the vascular system or physical or biochemical injury to the blood vessel.
  • One disease in which vascular diseases and their complications are very common is diabetes mellitus.
  • Diabetes mellitus causes a variety of physiological and anatomical irregularities, the most prominent of which is the inability of the body to utilize glucose normally, which results in
  • vascular system which include atherosclerosis, abnormalities involving large and medium size blood vessels (macroangiopathy) and
  • microangiopathy such as arterioles and capillaries.
  • the thickening and leakage of capillaries caused by diabetes are also associated with skin disorders and disorders of the nervous system (neuropathy).
  • the eye diseases are also associated with skin disorders and disorders of the nervous system (neuropathy).
  • diabetes associated with diabetes are nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic maculopathy, glaucoma and cataracts. It is estimated that up to 50% of diabetics will develop diabetic nephropathy, and ultimately renal failure, between 10 and 30 years from the time of onset of the diabetes.
  • renin-angiotensin-aldosterone system renin-angiotensin-aldosterone system
  • Prorenin may be converted to the proteolytic enzyme renin by renal proteases or may change
  • Renin is a highly specific enzyme which acts on only one naturally
  • angiotensinogen which is a
  • Renin acts on angiotensinogen to cleave out a fragment called angiotensin I (Al).
  • Al itself has only slight pharmacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (All).
  • ACE angiotensin converting enzyme
  • the maj or pharmacological effects of All are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention. Vasoconstriction and sodium retention, which cause blood volume to increase, lead to hypertension. All is cleaved by an aminopeptidase to form angiotensin III (AIII), which, compared to All, is a less potent vasoconstrictor but a more potent inducer of aldosterone release.
  • AIII angiotensin III
  • an angiotensin converting enzyme (ACE) inhibitor has been shown to be effective in reducing albuminuria and lowering glomerular
  • ACE inhibitors have a protective and corrective effect on adverse histologic effects on blood vessels following balloon angioplasty and, therefore, inhibiting the renin-angiotensin- aldosterone system may be useful for preventing and/or reversing biochemical or physical injury to blood vessels.
  • ACE acts on several substrates other than angiotensin I (Al), most notably the kinins which cause such undesirable side effects as pain, "leaky” capillaries, prostaglandin release and a variety of behavorial and neurologic effects. Further, ACE inhibition leads to the accumulation of Al. Although Al has much less vasoconstrictor activity than All, its presence may negate some of the hypotensive effects of the blockade of All synthesis.
  • Renin inhibitors have been disclosed as agents for treating systemic hypertension and there are no known side effects which result when renin is inhibited from acting on its substrate.
  • renin inhibitors are useful for the prevention, treatment, inhibition or reversal of vascular diseases including those vascular diseases associated with functional and/or anatomical abnormalities, and in particular peripheral vascular diseases and microvascular diseases associated with diabetes, especially diabetic
  • renin inhibitors examples include, but are not limited to, those disclosed in the following references, which are hereby incorporated by reference.
  • Preferred renin inhibitors and methods for making them include those disclosed in U.S. Patent No. 4,826,815, issued May 2, 1989; U.S. Patent No.
  • renin inhibitors and methods for making them also include those disclosed in copending U.S. patent applications, USSN 403,906, filed September 1, 1989; USSN 231,869, filed August 16, 1988 (EP0307837, published March 22, 1989); USSN
  • the preferred renin inhibiting compounds of this invention are selected from the group consisting of compounds of the formula:
  • A is hydrogen, loweralkyl, arylalkyl, -OR 20 wherein R 20 is hydrogen, or loweralkyl, -NR 21 R 22 wherein R 21 and R 22 are independently selected from hydrogen and loweralkyl;
  • B is NH, O, CH 2 or NHCH 2 ; and R 23 is
  • alkoxycarbonyalkyl (dihydroxyalkyl) (alkyl) amino, aminoalkyl, N-protected aminoalkyl, (heterocyclic) alkyl, or a substituted or unsubstituted heterocyclic;
  • U is CH 2 or NR 2 , wherein R 2 is hydrogen or loweralkyl, provided that when W is CHOH then U is CH 2 ;
  • R 1 is loweralkyl, eyeloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,
  • R 3 is loweralkyl, (thioalkoxy) alkyl, benzyl or heterocyclic ring substituted methyl;
  • R 5 is hydrogen or loweralkyl
  • R 6 is loweralkyl, cycloalkylmethyl, or benzyl
  • R 7 , R 8 and R 9 are hydrogen or loweralkyl and may be the same or different;
  • V is NH, O, S, SO, SO 2 ' or CH 2 ;
  • R 10 is loweralkyl, cycloalkyl
  • a b is hydrogen, loweralkyl, arylalkyl; OR 20b or SR 20b wherein R 20b iS hydrogen, loweralkyl or aminoalkyl, NR 21b R 22b wnerein R 21b and R 22b are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;
  • B b is NH, alkylamino, S, O, CH 2 , or CHOH; and E 23b is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) amino, (dihydroxyalkyl) (alkyl) amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, carboxyalkyl,
  • alkoxycarbonylalkyl (N-protected) (alkyl) aminoalkyl, dialkylaminoalkyl, (heterocyclic) alkyl, or a substituted or unsubstituted heterocyclic;
  • U b is CH 2 or NR 2b , wherein R 2b is
  • R 1b is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,
  • B b is CH 2 or CHOH or
  • A is hydrogen
  • R 3b is loweralkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl
  • R 5b is hydrogen or loweralkyl
  • R 6b is loweralkyl, cycloalkylmethyl, or benzyl
  • R 10b is loweralkyl, cycloalkyl
  • R 13b is CHOH or CO
  • R 14b is CH 2 , CF 2 or CF with the Proviso that when R 13b is CO then R 14b is CF 2 ;
  • R 15b is CH 2 , CHR 25b wherein R 25b is
  • R 14b and R 1 5 b taken together can be with the proviso that when R 14 is CF 2 then R 15 is
  • L b is O, S, SO, SO 2 , NR 26b wherein R 26b
  • R 27b is hydrogen or loweralkyl, or NR 27b C(O) wherein R 27b is hydrogen or loweralkyl;
  • B is NH, or CH 2 ; and -R 23c is loweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic;
  • U c is NR 2c , wherein R 2c is hydrogen or
  • R 1c is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,
  • R 3c is loweralkyl, benzyl or heterocyclic ring substituted methyl
  • R 5c is hydrogen or loweralkyl
  • R 6c is loweralkyl, cycloalkylmethyl, benzyl, or CH 2 R 24 , where R 24c is selected from
  • R 16c is CH 2 , CF 2 or CHR 63c where R 63c is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl;
  • R 17c is hydrogen or loweralkyl
  • R 18c is loweralkyl or lipophilic or aromatic amino acid side chain
  • D c is hydrogen, loweralkyl or -CH 2 OR 28c , wherein R 28c is hydrogen, loweralkyl or arylalkyl;
  • a d is hydrogen, loweralkyl, arylalkyl,
  • R 21d and R 22d are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;
  • B d is NH, alkylamino, S, O, CH 2 , or NHCH 2
  • -R 23d is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino,
  • alkoxycarbonylalkyl (N-protected) ( alkyl) aminoalkyl, dialkylaminoalkyl, (heterocyclic) alkyl, or a substituted or unsubstituted heterocyclic;
  • U d is CH 2 or NR 2d , wherein R 2d is
  • R 1d is CHR 24d wherein R 24d is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,
  • R 3d is loweralkyl, alkenyl, benzyl or heterocyclic ring substituted methyl
  • R 5d is hydrogen or loweralkyl
  • ⁇ 6d is loweralkyl, cycloalkylmethyl, or benzyl
  • R 11 d is hydrogen or hydroxy
  • n is 0 or 1; when n is 0 then T d is alkylidene or alkylidene oxide; and when n is 1 then Z d is hydrogen or hydroxy and T d is loweralkyl, hydroxyalkyl, aminoalkyl, haloalkyl, or azidoalkyl;
  • R 12d is hydrogen, loweralkyl
  • a e is hydrogen, loweralkyl, arylalkyl,
  • R 21e and R 22e are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A e is
  • B e is NH, alkylamino, S, O, CH 2 , or CHOH; and R 23e is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino,
  • alkoxycarbonylalkyl (N-protected) (alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic) alkyl, or a substituted or unsubstituted heterocyclic;
  • U e is NK 2e , wherein R 2e is hydrogen or loweralkyl
  • R 1e is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,
  • B e is CH 2 or CHOH or
  • a e is hydrogen
  • R 3e is loweralkyl, benzyl or heterocyclic ring substituted methyl
  • R 5e is hydrogen or loweralkyl
  • R 6e is loweralkyl, cycloalkylmethyl, or benzyl
  • M e is O, NH or S
  • R 10e is hydrogen, loweralkyl , cycloalkyl , (cycloalkyl) alkyl , aryl , arylalkyl or an N-protecting group; ( 6 )
  • a f is hydrogen, loweralkyl, arylalkyl.
  • R 11f and R 12f are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, ( amino) carboxyalkyl,
  • B f is NH, alkylamino, S, O, CH 2 or CHOH and R 13f is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino,
  • carboxyalkyl carboxyalkylamino, alkoxycarbonylalkyl,alkoxycarbonyalkylamino, (amino)carboxyalkyl,
  • dialkylamino alkoxycarbonylalkylammo, ammocycloalkyl, aminoalkylamino, dialkylaminoalkyl(alkyl)amino,
  • alkoxyalkyl(alkyl)amino (polyalkyoxy)- alkyl(alkyl)amino, di-(alkoxyalkyl)amino,
  • heterocyclic di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy, (polyalkoxy) alkyl, (heterocyclic) alkyl or a substituted or unsubstituted heterocyclic wherein saturated heterocyclics may be unsubstituted. monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyclics may be
  • U f is CH 2 or NR 2 , provided that when W f is CHOH then U f is CH 2 ;
  • R 1f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl,
  • R 2f is hydrogen or loweralkyl
  • R 3f is loweralkyl, loweralkenyl
  • R 6f is loweralkyl, cycloalkylmethyl or benzyl
  • R af is vinyl, formyl, hydroxymethyl or hydrogen
  • R df is hydrogen or loweralkyl
  • R bf and R ef are independently selected from OH and NH 2 ;
  • R cf is hydrogen, loweralkyl, vinyl or arylalkyl; wherein A g is hydrogen, loweralkyl, aminoalkyl,
  • phenylalkyl (substituted phenyl)alkyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, naphthylalkyl, (substituted naphthyl) alkyl wherein the naphthyl ring is substituted with one, two or three substituents
  • heterocyclics may be unsubstituted, monosubsituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweralkyl, haloalkyl or polyhaloalkyl; unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy,
  • R 7g is hydrogen, loweralkyl
  • aminoalkyl aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl,
  • substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl) alkyl wherein the substituted naphthyl is as defined above, substituted or
  • a g is -NR 8g R 9g wnerein R 8g and
  • R 9g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl, cyanoalkyl and
  • B g is NH, alkylamino, S, O, CH 2 , NHCH 2 or
  • R 52g is hydrogen, loweralkyl or loweralkylcarbonyl
  • R 10g is hydrogen, loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy,
  • substituted phenyl is as defined above, naphthylalkoxy, (substituted naphthyl)alkoxy wherein substituted naphthyl is as defined above, phenylalkoxyalkyl,
  • substituted phenyl alkoxyalkyl wherein substituted phenyl is as defined above, naphthylalkoxyalkyl,
  • substituted naphthyl alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl,
  • naphthylthioalkyl (substitutednaphthyl)thioalkylwherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above,
  • naphthyl sulfonylalkyl wherein substituted naphthyl is as defined above, amino, alkylamino, dialkylamino,
  • alkoxycarbonylalkyl carboxyalkyl, (N-protected)- aminoalkyl, alkylaminoalkyl,
  • heterocyclic alkyl a substituted or unsubstituted heterocyclic as defined above, ammocycloalkyl,
  • naphthylalkylamino (substituted naphthyl) alkylamino wherein substituted naphthyl is as defined above,
  • alkoxyalkyl(alkyl) amino (polyalkoxy)alkyl(alkyl) amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino,
  • a g is R 41g CH(OH)CH 2 - or
  • R 41g CH(OH)CH(OH)- wherein R 41g is loweralkyl
  • substituted phenyl is as defined above, naphthylalkyl, (substituted naphthyl) alkyl wherein substituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl) alkoxyalkyl wherein substituted phenylis as defined above, naphthylalkoxyalkyl, (substituted
  • naphthyl alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl, loweralkylsulfonylalkyl, phenylthioalkyl, (substituted phenyl )thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted
  • naphthyl is as defined above, phenylsulfonylalkyl, (substituted
  • V g is CH, C(OH) or C(halogen) with the proviso that
  • V g is CH when U g is NR 2g :
  • R 1g is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, ( 1-naphthyl)methyl, (2-naphthyl)methyl, (unsubstituted heterocyclic)methyl, (substituted
  • heterocyclic)methyl wherein unsubstituted or substituted heterocyclicis as defined above, phenethyl,
  • R 3g is loweralkyl, loweralkenyl
  • dialkylaminoalkyl (alkoxy) (alkyl)aminoalkyl
  • R 4g is loweralkyl, cycloalkylmethyl or benzyl;
  • R 5g is OH or NH 2 ;
  • M g is O, S or NH
  • C S, S, S(O)
  • Eg is O, S, NR 6g wherein R 6g is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or E g is CR 6g R 42g wherein
  • R 44g are independently selected from hydrogen and loweralkyl, G is absent, CH 2 , or NR 11g wherein
  • R 11g is hydrogen or loweralkyl , with the proviso that when G g is NR 11g then R 6g is loweralkyl or
  • Q g is CR 45g R 46g wherein R 45g and
  • alkoxycarbonyl or -CONR 50g R 51g wherein R 50g is hydrogen or loweralkyl and R 51g is hydrogen
  • a h is hydrogen, loweralkyl, arylalkyl,
  • R 21h and R 22h are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A h is
  • B h is NH, alkylamino, S, O, CH 2 , NHCH 2 or
  • R 23h is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy,
  • heterocyclic alkyl, or a substituted or unsubstituted heterocyclic
  • U h is CH 2 or NR 2h , wherein R 2h is
  • R 1h is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl,
  • B is CH 2 or CHOH or
  • a h is hydrogen
  • R 3h is loweralkyl, loweralkenyl
  • R 5h is hydrogen or loweralkyl
  • R 6h is loweralkyl, cycloalkylmethyl, or benzyl
  • v" is 0 or 1
  • R 6 j is
  • alkylamino (N-protected) (alkyl) amino and dialkylamino
  • m''' is 1 to 5 and R 7 j is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected) amino, alkylamino, (N-protected) (alkyl) amino or
  • a j and L j are independently selected from (I) absent,
  • R 200j is loweralkyl or benzyl or
  • R 4 j is
  • R 5 j is
  • R 73 j is loweralkyl
  • R 18 j is loweralkyl or hydroxyalkyl
  • v''' is 0 or 1
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methyl-pentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl and the like.
  • loweralkenyl refers to a straight or branched chain loweralky radical which contains at least one carbon-carbon double bond.
  • cycloalkyl refers to an aliphatic ring having 3 to 7 carbon atoms.
  • cycloalkylalkyl refers to a cycloalkyl residue appended to a loweralkyl radical and includes but is not limited to
  • cycloalkenyl refers to an aliphatic ring having 3-7 carbon atoms and also having at least one carbon-carbon double bond including, but not limited to, cyclohexenyl and the like.
  • cycloalkenylalkyl refers to a cycloalkenyl group appended to a loweralkyl radical including, but not limited to,
  • arylalkyl refers to an aryl group as defined herein appended to a loweralkyl radical including but not limited to benzyl, 1- and 2-naphthylmethyl, halobenzyl, and alkoxybenzyl.
  • phenylalkyl refers to a phenyl group appended to a loweralkyl radical, including, but not limited to benzyl, phenethyl and the like.
  • substituted phenyl) alkyl refers to a substituted phenyl group appended to a loweralkyl radical wherein the phenyl ring is
  • naphthylalkyl refers to a naphthyl group appended to a loweralkyl radical, including, but not limited to 1-naphthylmethyl,
  • (substituted naphthyl)alkyl refers to a substituted naphthyl group appended to a loweralkyl radical wherein the naphthyl ring is substituted with one, two or three substituents chosen from the group loweralkoxy, loweralkyl, amino,
  • thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide including, but not limited to
  • heterocyclic alkyl refers to an unsubstituted or substituted heterocyclic ring as defined below appended to a loweralkyl radical, including, but not limited to imidazolyImethyl,
  • hydroxyalkyl refers to -OH appended to a loweralkyl radical.
  • alkoxyalkyl refers to an alkoxy group appended to a loweralkyl radical.
  • arylalkoxyalkyl refers to an arylalkoxy appended to a loweralkyl radical.
  • phenylalkoxyalkyl refers to a phenylalkoxy group appended to a loweralkyl radical, including, but not limited to
  • (substituted phenyl) alkoxyalkyl refers to a (substituted phenyl) alkoxy group appended to a loweralkyl radical, including, but not limited to 4-chlorophenylmethoxymethyl.
  • naphthylalkoxyalkyl refers to a naphthylalkoxy group appended to a
  • loweralkyl radical including, but not limited to
  • (substituted naphthyl) alkoxyalkyl refers to a (substituted naphthyl) alkoxy group appended to a loweralky radical, including, but not limited to halonaphthylmethoxymethyl and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
  • ((alkoxy) alkoxy) alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical, including, but not limited to methoxymethoxymethyl and the like.
  • polyalkoxyalkyl refers to a polyalkoxy residue appended to a loweralkyl radical, including, but not limited to
  • aminoalkyl refers to -NH 2 appended to a loweralkyl radical.
  • alkylaminoalkyl refers to -NHR 70 appended to a loweralkyl radical, wherein R 70 is a loweralkyl radical.
  • dialkylaminoalkyl refers to a dialkylamino appended to a loweralkyl radical.
  • ammocycloalkyl refers to an -NH 2 appended to a cycloalkyl radical.
  • N-protected aminoalkyl refers to -NHR-, appended to a loweralkyl group, wherein R 71 is an N-protecting group.
  • (N-protected) (alkyl) amino alkyl refers to NR 71 R 72 which is appended to a loweralkyl radical, wherein R 71 is defined as above and R 72 is a loweralkyl group.
  • alkoxycarbonylalkyl refers to R 73 COR 74 -, wherein R 73 is an alkoxy
  • R 74 is a loweralkyl radical.
  • carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
  • cyanoalkyl refers to -CN appended to a loweralkyl radical.
  • azidoalkyl refers to -N 3 appended to a loweralkyl radical.
  • (alkoxy) aminoalkyl refers to an alkoxy group appended to an amino group which in turn is appended to a loweralkyl radical.
  • (alkoxy) (alkyl) aminoalkyl refers to an -NR 75 R 76 group appended to a loweralkyl radical wherein R 75 is an alkoxy group and R 76 is a. loweralkyl group.
  • loweralkylsulfinylalkyl refers to a R 77 S(O)- group appended to a
  • loweralkyl radical wherein R 77 is a loweralkyl group.
  • loweralkylsulfonylalkyl refers to a R 78 S(O) 2 - group appended to a
  • R 78 is a loweralkyl radical wherein R 78 is a loweralkyl group.
  • phenylthioalkyl refers to a R 79 S- group appended to a loweralkyl
  • R 79 is a phenyl group.
  • (substituted phenyl)thioalkyl refers to a R 80 S- group appended to a loweralkyl radical wherein R 80 is a substituted phenyl group.
  • naphthyl thioalkyl refers to a R 81 S- group appended to a loweralkyl
  • R 81 is a naphthyl group.
  • (substituted naphthyl)thioalkyl refers to a R 82 S- group appended to a loweralkyl radical wherein R 82 is a substituted
  • phenylsulfonylalkyl refers to a R 83 S(O) 2 - group appended to a loweralkyl radical wherein R 83 is a phenyl group.
  • (substituted phenyl)sulfonylalkyl refers to a R 84 S(O) 2 - group appended to a loweralkyl radical wherein R 84 is a substituted phenyl group.
  • naphthylsulfonylalkyl refers to a R 85 S(O) 2 - group appended to a loweralkyl group wherein R 85 is a naphthyl group.
  • (substituted naphthyl)sulfonylalkyl refers to a R 86 S(O) 2 - group appended to a loweralkyl group wherein R 86 is a substituted naphthyl group.
  • carboxyalkoxyalkyl refers to a carboxylic acid group (-COOH) appended to an alkoxy group whichis appended to a loweralkyl radical.
  • alkoxycarbonylalkoxyalkyl refers to an alkoxycarbonyl group (R 87 CO- wherein R 87 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
  • (amino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-C00H) and an amino group
  • ((N-protected) amino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR 88 wherein R 88 is an N-protecting group.
  • (alkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an
  • ((N-protected) alkylamino)- carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR 89 R 90 wherein R 89 is as defined above and R 90 is a loweralkyl group.
  • (dialkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and
  • (amino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended.an alkoxycarbonyl group as defined above and an amino group (-NH-).
  • ((N-protected) amino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR 93 wherein R 93 is as defined above.
  • (alkylamino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
  • (dialkylamino)alkoxycarbonyalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 96 R 97 wherein R 96 and R 97 are independently
  • carboxyalkylamino refers to -NHR 98 wherein R 98 is a carboxyalkyl group.
  • alkoxycarbonylalkylammo refers to -NHR 99 wherein R 99 is an
  • (amino)carboxyalkylamino refers to -NHR 100 wherein R 100 is an
  • R 101 is an C(N-Protected)-amino)carboxyalkyl group.
  • alkylamino (alkylamino)carboxyalkylamino" as used herein refers to -NHR 102 wherein R 102 is an
  • ((N-protected)alkylamino)- carboxyalkylamino) refers to -NHR 103 wherein R 103 is an ( (N-protected) alkylamino ) - carboxyalkyl group .
  • dialkylamino ) carboxyalkylamino refers to -NHR 104 wherein R 104 is a
  • ((N-protected)amino)alkoxy- carbonylalkylamino refers to -NHR 105 wherein R 106 is an ((N-protected) amino)- alkoxycarbonylalkyl group.
  • (alkylamino) alkoxycarbonylalkylammo refers to -NHR 107 wherein R 107 is an (alkylamino) alkoxycarbonylalkyl group.
  • ((N-protected) alkylamino) alkoxycarbonylalkylammo) refers to -NHR 108 wherein R 108 is an ((N-protected)alkylamino)- alkoxycarbonylalkyl group.
  • dialkylamino)alkoxycarbonylalkylammo refers to -NHR 109 wherein R 109 is a (dialkylamino)alkoxycarbonylalkyl group.
  • alkylidene refers to a straight or branched chain alkyl radical which is attached via a carbon-carbon double bond and includes but is not limited to methylidene, ethylidene,
  • alkylidene oxide refers to an epoxide moiety which is derived from an alkylidene group.
  • amino refers to an -NH 2 substituent.
  • alkylamino refers to -NHR 110 , wherein R 110 is a loweralkyl group.
  • dialkylamino refers to -NR 111 R 112 , wherein R 111 and R 112 are
  • arylalkylamino refers to R 1 13 NH-, wherein R 11 3 is an arylalkyl residue.
  • arylalkyl(alkyl)amino refers to R 114 R 115 N-, wherein R 1 1 4 is an arylalkyl residue and -R 115 is a loweralkyl residue.
  • phenylalkylamino refers to a phenylalkyl group appended to an amino radical, including, but not limited to benzylamino and the like.
  • (substituted phenyl)alkylamino refers to a (substituted phenyl)alkyl group appended to an amino radical, including, but not limited to 4-chlorobenzylamino and the like.
  • naphylalkylamino refers to a naphthylalkyl group appended to an amino radical, including, but not limited to
  • (substituted naphthyl) alkylamino refers to a (substituted naphthyl) alkyl group appended to an amino radical.
  • (phenylalkyl) (alkyl) amino refers to R 116 R 117 N-, wherein R 116 is a
  • R 117 is a loweralkyl residue.
  • ((substituted phenyl) alkyl)- (alkyl) amino refers to R 118 R 119 N- wherein R 118 is a (substituted phenyl)alkyl group and R 119 is a loweralkyl group.
  • (naphthylalkyl) (alkyl) amino refers to R 120 R 121 N- wherein R 120 iS a
  • R 121 is a loweralkyl group.
  • ((substituted naphthyl) alkyl)- (alkyl)amino refers to R 122 R 123 N- wherein R 122 is a (substituted naphthyl) alkyl group and R 123 is a loweralkyl group.
  • aminoalkylamino refers to R 124 NH- where R 124 is an aminoalkyl
  • dialkylamino( alkyl) amino refers to R 125 R 126 N-, wnerein R 125 is a
  • ((dialkylamino) alkyl) (alkyl) amino refers to -NR 127 R 128 wherein R 127 is a dialkylamino residue appended to a loweralkyl residue and R 128 is a loweralkyl residue.
  • (hydroxyalkyl) (alkyl) amino refers to -NR 129 R 130 wherein R 129 is a
  • R 130 is a loweralkyl group.
  • (di-hydroxyalkyl) (alkyl) amino refers to a loweralkyl group which is disubstituted with -OH radicals appended to an amino group, which amino group also has appended another loweralkyl group.
  • di-(hydroxyalkyl) amino refers to R 131 R 132 N-, wherein R 131 and
  • R 132 are hydroxyalkyl residues.
  • alkoxyalkyl(alkyl) amino refers to R 133 R 134 N-, wherein R 133 is a
  • R 134 is an alkoxyalkyl group.
  • di-(alkoxyalkyl) amino refers to R 135 R 136 N-, wherein R 135 and R 136 are
  • di-(polyalkoxyalkyl) amino refers to R 137 R 138 N-, wherein R 137 and
  • R 138 are polyalkoxy residues appended to loweralkyl residues.
  • ((polyalkoxy) alkyl) (alkyl)amino) refers to R 139 R 140 N-, wherein R 139 is a polyalkoxy residue appended to a loweralkyl radical and R 140 is a loweralkyl residue.
  • (heterocyclic) alkyl) (alkyl)amino refers to -NR 141 R 142 wherein R 141 isa heterocyclicalkyl group and R 142 is a loweralkyl group.
  • (heterocyclicalkyl) amino refers to -NHR 143 wherein R 143 is a
  • (heterocyclic) (alkyl) amino refers to -NR 144 R 145 wherein R 144 is a
  • R 145 is a loweralkyl group.
  • (alkylaminoalkyl) (alkyl) amino refers to -NR 146 R 147 wherein R 146 is an alkylaminoalkyl group and R 147 is a loweralkyl group.
  • dialkylaminoalkyl (alkyl)amino” refers to -NR 148 R 149 wherein R 148 is a dialkylaminoalkyl group and R 149 is a loweralkyl group.
  • (alkoxy) (alkyl)aminoalkyl)- (alkyl)amino refers to -NR 150 R 151 wherein R 150 is -NR 152 R 153 appended to a
  • R 152 is an alkoxy group and R 153 is a loweralkyl group and R 151 is a loweralkyl group.
  • ((alkoxy) aminoalkyl) (alkyl) amino refers to _ NR 154 R 155 wherein R 154 is
  • R 156 is an alkoxy group and R 155 is a loweralkyl
  • (alkoxyalkoxyalkyl) (alkyl) amino refers to -NR 305 R 306 wherein R 305 is
  • R 306 is a loweralkyl group.
  • di( alkoxyalkoxyalkyl)amino refers to -NR 307 R 308 wherein R 307 and
  • R 308 are alkoxyalkoxyalkyl groups.
  • alkylsulfonylamino refers to R 309 NH- wherein R 309 is an alkylsulfonyl gorup .
  • arylsulfonylamino refers to R 310 NH- wherein R 310 is an arylsulfonyl group.
  • alkylaminocarbonylamino refers to R 311 C(O)NH- wherein R 311 is an
  • alkylammocarbonyloxy refers to R 312 C(O)O- wherein
  • R 312 is an alkylamino group.
  • alkoxycarbonyloxy refers to R 313 C(O)O- wherein R 313 is an alkoxy group.
  • loweralkylcarbonyl refers to R 157 C(O)- wherein R 157 is a loweralkyl
  • alkoxy and thioalkoxy refer to R 158 O- and R 158 S-, respectively, wherein R 158 is a loweralkyl group.
  • alkoxyalkoxy refers to an alkoxy group appended to an alkoxy radical
  • aryloxyalkyl refers to an aryloxy group (R 303 O- wherein R 303 is an aryl group) appended to a loweralkyl radical.
  • thioaryloxyalkyl refers to a thioaryloxy group (R 304 S- wherein R 304 is an aryl group) appended to a loweralkyl radical.
  • arylalkoxy and arylthioalkoxy refer to an aryl group appended to an alkoxy radical or a thioalkoxy radical, respectively,
  • arylthioalkoxyalkyl refers to an arylalkoxy group or an arylthioalkoxy group
  • alkenyloxy refers to R 159 O-, wherein R 159 is an alkyl group of 1 to 7 carbon atoms which contains at least one carbon-carbon double bond.
  • hydroxyalkoxy refers to -OH appended to an alkoxy radical .
  • dihydroxyalkoxy refers to an alkoxy radical which is disubstituted with -OH radicals.
  • arylalkoxy refers to an aryl group appended to an alkoxy radical.
  • alkylaryloxy refers te R 160 O- wherein R 160 is an alkylaryl group.
  • phenylalkoxy refers to a phenyl group appended to an alkoxy radical, including, but not limited to benzyloxy and the like.
  • (substituted phenyl)alkoxy refers to a substituted phenyl group appended to an alkoxy radical, including, but not limited to
  • naphthylalkoxy refers to a naphthyl group appended to an alkoxy radical .
  • (substituted naphthyl) alkoxy refers to a substituted naphthyl group appended to an alkoxy radical.
  • R 161 O-, wherein R 161 is a straight or branched chain containing 1-5, C m -O-C m , linkages where m and m' are independently 1 to 3.
  • halo or halogen as used herein refer to Cl , Br, F or I substituents.
  • haloalkyl refers to a loweralkyl radical in which one or more hydrogen
  • halogen including, but not limited to fluoromethyl, 2-chloroethyl, trifluoromethyl,
  • polyhaloalkyl refers to a loweralkyl radical substituted with two or more halogens, including, but not limited to trifluoromethyl, 2,2-dichloroethyl and the like.
  • halobenzyl refers to a halo substituent appended to the phenyl ring of a benzyl radical.
  • halophenyl refers to a halo substituent appended to a phenyl radical.
  • alkylsulfonyl as use dherein refers to R 300 s(o) 2 - wherein R 300 is a loweralkyl group.
  • (aryl) sulfonyl as used herein refers to R 301 S(O) 2 - werein R 301 is an aryl group.
  • (heterocyclic) sulfonyl refers to R 302 S(O) 2 - wherein R 302 is a
  • arylsulfonylalkyl refers to an arylsulfonyl group appended to a loweralkyl radical.
  • aryl refers to a monocylic or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; or "aryl” refers to a heterocyclic aromatic ring as defined herein.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents
  • substituted phenyl refers to a phenyl ring substituted with one, two or three substituents chosen from the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halophenyl, loweralkylphenyl, alkoxyphenyl and the like.
  • substituted naphthyl refers to a naphthyl ring substituted with one, two or three substituents chosen from the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halonaphthyl, alkoxynaphthyl and the like.
  • alkylaryl refers to a loweralkyl group appended to an aryl radical.
  • heterocyclic refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, sulfur and nitrogen, or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered ring has 0 to 2 double bonds and the 6-membered ring has 0 to 3 double bonds; wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, wherein the nitrogen heteroatom may optionally be guaternized, 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,
  • benzothiazolyl benzoxazolyl, furyl, thienyl, triazolyland benzothienyl.
  • heterocyclics include imidazolyl, pyridyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, thiazolyl, thienyl, triazolyl and the following:
  • k is 1 or 2 and X is N, NH, O, or S, provided that X is the point of connection only when X is N,
  • Y is NH, N-loweralkyl, O, S, or SO 2 , or
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes but is not limited to sulfonyl, acyl, acetyl, pivaloyl,
  • O-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic
  • substituted methyl ethers for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
  • triphenyImethyl triphenyImethyl
  • tetrahydropyranyl ethers substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl
  • silyl ethers for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl
  • cyclic acetals and ketals for example, methylene acetal, acetonide and benzylidene acetal
  • cyclic ortho esters for example, methoxymethylene
  • cyclic carbonates and cyclic boronates.
  • substituted amino refers to:
  • aa' is 1 to 5 and R 6 q and R 7q are independently selected from
  • Z q is O, S or NH and R 8q is a C 1 to C 6 straight or branched carbon chain
  • alkylamino dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocyclic;
  • aminoalkyl (N-protected) aminoalkyl, 1- amino-2-phenylethyl or 1- (N- protected) amino-2- phenylethyl.
  • substituted methylene group refers to:
  • R 13q is i) hydrogen or
  • R 13q is hydroxy then R 14 q is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected) amino,
  • u' is 0 to 3
  • R 24q is CH 2 or N
  • R 25q is NH, O, S or
  • R 22q is as defined above and
  • alkylaminoalkyl dialkylaminoalkyl or (heterocyclic) alkyl or

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Abstract

L'invention concerne l'utilisation d'inhibiteurs de rénine ainsi que des compositions inhibitrices de rénine pour le traitement, l'inhibition, le soulagement ou l'inversion de maladies vasculaires parmi lesquelles les maladies vasculaires associées à des anomalies fonctionnelles et/ou biochimiques, et en particulier des maladies vasculaires périphériques, ainsi que des maladies micro-vasculaires associées au diabète, notamment à la rétinopathie diabétique, la néphropathie diabétique et la neuropathie diabétique.
PCT/US1989/005248 1988-11-21 1989-11-20 Procede de traitement de maladies vasculaires WO1990005531A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5244910A (en) * 1990-08-15 1993-09-14 Abbott Laboratories Renin inhibitors
EP0573652A4 (fr) * 1991-03-01 1994-01-12 Fujisawa Pharmaceutical Co., Ltd.
US5284849A (en) * 1990-05-11 1994-02-08 Abbott Laboratories Renin inhibitors
WO2001015674A3 (fr) * 1999-08-30 2002-03-28 Aventis Pharma Gmbh Utilisation d'inhibiteurs du systeme renine-angiotensine dans la prevention de manifestations cardio-vasculaires
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
EP2277519A3 (fr) * 1999-08-27 2011-09-07 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds

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US4812555A (en) * 1985-10-31 1989-03-14 Merck Patent Gesellschaft Mit Beschrankter Haftung Peptides possessing renin inhibitory activity

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DE3418491A1 (de) * 1984-05-18 1985-11-21 Merck Patent Gmbh, 6100 Darmstadt Diaminosaeurederivate
DE3438545A1 (de) * 1984-10-20 1986-04-24 Merck Patent Gmbh, 6100 Darmstadt Peptide
DE3626130A1 (de) * 1986-08-01 1988-02-11 Merck Patent Gmbh Aminosaeurederivate
DE3640535A1 (de) * 1986-11-27 1988-06-01 Merck Patent Gmbh Peptide
US7490044B2 (en) * 2004-06-08 2009-02-10 Bose Corporation Audio signal processing

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Publication number Priority date Publication date Assignee Title
US4812555A (en) * 1985-10-31 1989-03-14 Merck Patent Gesellschaft Mit Beschrankter Haftung Peptides possessing renin inhibitory activity

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Title
See also references of EP0444156A4 *
The New England Journal of Medicine, Volume 312, No. 22, page 1412, published May 30, 1985, J.A. LUETSCHER, "Increased Plasma Inactive Renin in Diabetes Mellitus." See page 1415 column 2 lines 3-7 and page 1416 column 1 lines 1-5. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284849A (en) * 1990-05-11 1994-02-08 Abbott Laboratories Renin inhibitors
US5310740A (en) * 1990-05-11 1994-05-10 Abbott Laboratories Renin inhibitors
US5244910A (en) * 1990-08-15 1993-09-14 Abbott Laboratories Renin inhibitors
US5389647A (en) * 1990-08-15 1995-02-14 Abbott Laboratories Renin inhibitors
EP0573652A4 (fr) * 1991-03-01 1994-01-12 Fujisawa Pharmaceutical Co., Ltd.
EP2277519A3 (fr) * 1999-08-27 2011-09-07 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
CZ300687B6 (cs) * 1999-08-30 2009-07-15 Sanofi - Aventis Deutschland GmbH Léciva s obsahem ramiprilu k ošetrování kardiovaskulárních príhod
US7368469B2 (en) 1999-08-30 2008-05-06 Sanofi-Aventis Deutschland Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
AU2009200746B2 (en) * 1999-08-30 2011-07-28 Sanofi-Aventis Deutschland Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
AU2009200746B8 (en) * 1999-08-30 2011-08-18 Sanofi-Aventis Deutschland Gmbh Use of inhibitors of the renin-angiotensin system in the prevention of cardiovascular events
WO2001015674A3 (fr) * 1999-08-30 2002-03-28 Aventis Pharma Gmbh Utilisation d'inhibiteurs du systeme renine-angiotensine dans la prevention de manifestations cardio-vasculaires
US7166586B2 (en) 2001-01-30 2007-01-23 Bristol Myers Squibb Co. Sulfonamide lactam inhibitors of FXa and method
US6555542B1 (en) 2001-01-30 2003-04-29 Bristol-Myers Squibb Company Sulfonamide lactam inhibitors of FXa and method
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds

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EP0444156A1 (fr) 1991-09-04
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EP0444156A4 (en) 1992-12-09
CA2003382A1 (fr) 1990-05-21

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