WO1991016031A1 - Psoriasis treatment - Google Patents

Psoriasis treatment Download PDF

Info

Publication number
WO1991016031A1
WO1991016031A1 PCT/US1991/002698 US9102698W WO9116031A1 WO 1991016031 A1 WO1991016031 A1 WO 1991016031A1 US 9102698 W US9102698 W US 9102698W WO 9116031 A1 WO9116031 A1 WO 9116031A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
loweralkyl
alkyl
alkylamino
hydrogen
Prior art date
Application number
PCT/US1991/002698
Other languages
French (fr)
Inventor
Robert S. Boger
Steven R. Crowley
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US07/680,811 external-priority patent/US5122514A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO1991016031A1 publication Critical patent/WO1991016031A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/553—Renin inhibitors

Definitions

  • the present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treatment of psoriasis.
  • Psoriasis is a chronic skin disease which is known to be difficult to treat. Psoriasis is characterized by discrete and confluent, reddish, silvery-scaled maculopapules. These psoriatic lesions occur most often on the elbows, knees, trunk and scalp.
  • psoriasis Current treatments for psoriasis include the use of agents such as anthralin (dihydroxyanthralin), azarabine, colchicine, fluorouracil, methotrexate, methoxsalen (8-methoxypsoraien), resorcinol, retinoids (for example, retinoic acid), corticosteroids (for example, clobetasol propionate, triamcinolone acetonide and the like), cyclosporin, iodochlorhydroxyquin, salicylic acid, vitamin D, dapsone, somatostatin, sulfur, tars and zinc oxide.
  • Ultra-violet light treatment alone or in combination with other agents such as psoralen (i.e., PUVA treatment), is also used to treat psoriasis.
  • Renin is a proteolytic enzyme synthesized and stored principally in the specific part of the kidney called the juxtaglomerular apparatus. Inhibitors of renin have been disclosed as agents for the treatment of hypertension, congestive heart failure and glaucoma.
  • renin inhibitors are useful for the treatment of psoriasis.
  • renin inhibitors examples include, but are not limited to, those disclosed in the following references, which are hereby incorporated by reference.
  • 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. 4,857,507, issued August, 15, 1989; U.S. Patent No. 4,826,958, issued May 2, 1989; U.S. Patent No. 4,837,204, issued June 6, 1989; U.S. Patent No. 4,845,079 issued July 4, 1989, all of which are hereby incorporated by reference. Preferred renin inhibitors and methods for making them also include those disclosed in copending U.S.
  • 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 ⁇ wherein R ⁇ is hydrogen, or loweralkyl, -NR 21 R wherein R 21 and ⁇ - ⁇ __ are independently selected from hydrogen and loweralkyl; or A is
  • B is NH, O, CH 2 or NHCH 2 ; and R 23 is loweralkyl, alkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, carboxyalkyi, alkoxycarbonyalkyl, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;
  • U is CH 2 or NR2 wherein R 2 is hydrogen or loweralkyl, provided that when W is CHOH then U is CH 2 ;
  • R is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxy benzyl, halobenzyl, (l -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R. is phenoxy, thiophenoxy or anilino, then B is CH 2 or A is hydrogen;
  • 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, 0,S,SO,S0 2 or CH 2 ;
  • R 10 is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or V and R 10 taken together are N 3 ; with the proviso that R 10 may be an N-protecting group only when V is NH; (2).
  • a b is hydrogen, loweralkyl, arylalkyl, OR 20b or SRgo b wherein R ⁇ b is hydrogen, loweralkyl or aminoalkyi, NR 21b R ⁇ b wherein R 21b and R ⁇ b are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or A b is
  • B b is NH, alkylamino, S, O, CH 2 or CHOH; and R 23b is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, aikylaminoalkyl, carboxyalkyi, alkoxycarbonylalkyl,
  • U b is CH 2 or NR 26 wherein R 2b is hydrogen or loweralkyl, provided that when W b is
  • R 1b is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxy benzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl,
  • a b 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
  • L b and R 10b taken together can be N 3 , with the proviso that when L t , is NH then R 10b is an
  • 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 loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or R 14b and R 15b taken together can be
  • R 14b is CF 2 then R 15b is CH 2 ; l_ b is wherein R 26b is hydrogen or loweralkyl, or NR 27b C(0) wherein
  • R 27b is hydrogen or loweralkyl
  • R 23e - ⁇ m. B c - o wherein B c is NH, or CH 2 ; and R 23o is loweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic;
  • U c is NR 2c wherein R 2c is hydrogen or loweralkyl
  • R 1c is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxybenzyl, halobenzyl, (l -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl;
  • R 3c is loweralkyl, benzyl or heterocyclic ring substituted methyl; H-m is hydrogen or loweralkyl;
  • R 6c is loweralkyl, cycloalkylmethyl, benzyl, or CH 2 R 24c where R 24c is selected from 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, 1 ,3-dithiolan-2-yl and 1,3-dithian-2-yl;
  • R 16c is CH 2 , CF 2 or CHR ⁇ 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; (4).
  • a d is hydrogen, loweralkyl, arylalkyl, -OR 20d or -SRgo d wherein R ⁇ is hydrogen, loweralkyl or aminoalkyi, -NR 21d R ⁇ d wherein R 21d and R 22d are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or A d is
  • B d is NH, alkylamino, S, O, CH 2 or NHCH 2 , and
  • 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
  • R 6d is loweralkyl, cycloalkylmethyl, or benzyl
  • R 11d 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_ is hydrogen or hydroxy and T d is loweralkyl, hydroxyalkyl, aminoalkyi, haloalkyl, or azidoalkyl;
  • R 12d is hydrogen, loweralkyl, cycloalkylalkyl, arylalkyl, aminoalkyi, or dialkylaminoalkyi;
  • Ae is hydrogen, loweralkyl, arylalkyl, -OR ⁇ or -SRao ⁇ wherein R ⁇ is hydrogen, loweralkyl or aminoalkyi, -NR ⁇ R ⁇ wherein R 21e and R 22 ⁇ are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or A p 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, arylalkoxyalkyi, amino alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, (dihydroxyalkyl)(alkyl)amino aminoalkyi, N-protected aminoalkyi, alkylaminoalkyl, carboxyalkyi, alkoxycarbonylalkyl
  • U e is NR 2e wherein R 2 ⁇ is hydrogen or loweralkyl;
  • R 1e is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxy benzyl, halobenzyl (1 -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha.alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy o anilino, provided that when R 1e is phenoxy, thiophenoxy or anilino, then B e is CH 2 o CHOH or Ag is hydrogen;
  • R 3e is loweralkyl, benzyl or heterocyclic ring substituted methyl;
  • R 5 ⁇ is hydrogen or loweralkyl;
  • Re e 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 is hydrogen, loweralkyl, arylalkyl, -OR 10f or -SR 10f wherein R 10f is hydrogen, loweralkyl or aminoalkyi, -NR 11f R 12f wherein R 11f and R 12 ⁇ are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl, hydroxyalkyl, carboxyalkyi, alkoxycarbonylalkyl, (amino)carboxyalkyl, ((N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl, ((N-protected) alky I amino) carboxyalkyi, (dialkylamino) carboxyalkyi, (amino) alkoxycarbonylal yl, ((N-protected) amino) alkoxycarbonylalkyl, (alkyamino) alkoxycarbonylalkyl, ((N-protected)alkylamino)al
  • B f is NH, alkylamino, S, O, CH 2 or CHOH and R 23f is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)ami ⁇ o, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protectedaminoalkyl, alkylami ⁇ oalkyl, (N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyi, carboxyalkyi, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonyalkylamino, (am ino)
  • alkylamino)carboxyalkylamino ((N-protected)alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkylami ⁇ o, (dialkylamino)carboxyalkyl, (dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl, (amino)alkoxycarbonylalkylamino,
  • R 3f is loweralkyl, loweralkenyl,((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;
  • 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 ; and R cf is hydrogen, loweralkyl, vinyl or arylalkyl; (7).
  • a g is hydrogen, loweralkyl, aminoalkyi, (alkyl)aminoalkyl, dialkylaminoalkyi, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyi, (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, naphthylalkyi, (substituted naphthyl)alkyl wherein the naphthyl ring is substituted with one, two or three substituents independently selected from loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino,
  • R 8g and Rg g are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyi, cya ⁇ oalkyl and hydroxyalkyl; or A g is
  • B g is NH, alkylamino, S, O, CH 2 , NHCH 2 or CH(OR 52g ) wherein R 52g is hydrogen, loweralkyl or loweralkylcarbonyl, and R 10g is hydrogen, loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, alkoxy, alke ⁇ yloxy, hydroxyalkoxy, dihydroxyalkoxy, phenylalkoxy, (substituted phenyl)alkoxy wherein 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,
  • 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-methoxy benzyl, halobenzyl, 4-hydroxy benzyl, (l-naphthyl)methyl, (2-naphthyl) methyl, (unsubstituted heterocyclic) methyl, (substituted heterocyclic) methyl wherein unsubstituted or substituted heterocyclic is as defined above, phenethyl, 1-be ⁇ zyloxyethyl, phenoxy, thiophenoxy or anilino, provided that B g is CH 2 or CHOH or A g is hydrogen when R 1g is phenoxy, thiophenoxy or anilino;
  • R 3g is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyi, (thioalkoxy)alkyl, azidoalkyl, aminoalkyi, (alkyl)aminoalkyl, dialkylaminoalkyi, (alkoxy)(alkyl)aminoalkyl,
  • R 4g is loweralkyl, cycloalkylmethyl or benzyl
  • R 5g is OH or NH 2 ;
  • M g is O, S or NH
  • a h is hydrogen, loweralkyl, arylalkyl, -OR 20h or -SR 20h wherein R20h is hydrogen, loweralkyl or aminoalkyi, -NR ⁇ R ⁇ wherein R 21h and R-_, h are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or A h is
  • B h is NH, alkylamino, S, O, CH 2 NHCH 2 or CHOH; and R 23h is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, ((dialkylamino)alkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, alkyiaminoalkyl, (N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi
  • heterocyclic alkyl, or a substituted or unsubstituted heterocyclic
  • U h is CH 2 or NR 2h wherein R 2h is hydrogen or loweralkyl, provided that when W h is CHOH then U h is CH 2 ;
  • R 1h is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl
  • R 3h is loweralkyl, loweralkenyl, ((alkoxy) alkoxy) alkyl, carboxyalkyi, (thioalkoxy) alkyl benzyl or heterocyclic ring substituted methyl;
  • R 5h is hydrogen or loweralkyl
  • R 6h is loweralkyl, cycloalkylmethyl, or benzyl
  • R 5i is i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino;
  • G is i) absent, ii) CH 2 or iii)NR 19i wherein R 19i is hydrogen or loweralkyl, with the proviso that when Gj is NR 19i , then R 18i is loweralkyl or hydroxyalkyl;
  • v" is 0 or 1
  • R 21i is i) NH, ⁇ ) O, iii) S or iv) S0 2 ; or (IV) a substituted methylene group;
  • m'" is 1 to 5 and R 7j is hy ⁇ rogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected)amino, alkylamino, (N-protected) (alkyl)amino or dialkylamino; or
  • R 10j is absent or R 10j is 0, NH or S only when q'" is 1 or 2
  • Rnch j is i) aryl or ii) heterocyclic
  • Z,- is (I) hydrogen or
  • R 28j is i) NH, ii) -N(R 200j )- wherein R 200j is loweralkyl or benzyl or iii) CH 2 and
  • R 29j is i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) dialkylamino, v) aryl or vi) heterocyclic;
  • 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-methyl butyl, 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 loweralkyl 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 cyclohexylmethyl and cyclopentylmethyl.
  • 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.
  • cycloalkenylalkyi refers to a cycloalkenyl group appended to a loweralkyl radical including, but not limited to, cyclohexenylmethyl, cylcopentenylethyl and the like.
  • 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.
  • phenylalkyi 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 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 halobenzyl, alkoxybenzyl and the like.
  • naphthylalkyi refers to a naphthyl group appended to a loweralkyl radical, including, but not limited to 1-naphthylmethyl, 2-naphthylmethyl and the like.
  • (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, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halonaphthylmethyl, alkoxynaphthylmethyl and the like.
  • heterocyclic alkyl refers to an unsubstituted or substituted heterocyclic ring as defined below appended to a loweralkyl radical, including, but not limited to imidazolylmethyl, thiazolylmethyl and the like.
  • hydroxyalkyl refers to -OH appended to a loweralkyl radical.
  • alkoxyalkyl refers to an alkoxy group appended to a loweralkyl radical.
  • arylalkoxyalkyi refers to an arylalkoxy appended to a loweralkyl radical.
  • phenylaikoxyalkyl refers to a phenylalkoxy group appended to a loweralkyl radical, including, but not limited to phenylmethoxymethyl and the like.
  • (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 1-naphthylmethoxymethyl and the like.
  • (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 methoxyethoxymethoxymethyl and the like.
  • aminoalkyi refers to -NH 2 appended to a loweralkyl radical.
  • alkyiaminoalkyl refers to -NHR 70 appended to a loweralkyl radical, wherein R 70 is a loweralkyl radical.
  • dialkylaminoalkyi refers to a dialkylamino appended to a loweralkyl radical.
  • aminocycloalkyi refers to an -NH 2 appended to a cycloalkyl radical.
  • N-protected aminoalkyi refers to -NHR 71 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 7 is a loweralkyl group.
  • alkoxycarbonylalkyl refers to R 73 C(0)R 74 - wherein R 73 is an alkoxy group and R 74 is a loweralkyl radical.
  • carboxyalkyi 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(0)- group appended to a loweralkyl radical wherein R ⁇ is a loweralkyl group.
  • loweralkylsulfonylalkyl refers to a R 78 S(0) 2 - group appended to a loweralkyl radical wherein R 78 is a loweralkyl group.
  • phenylthioalkyl refers to a R 79 S- group appended to a loweralkyl radical wherein 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 radical wherein 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 naphthyl group.
  • phenylsulfonylalkyl refers to a R 83 S(0) 2 - group appended to a loweralkyl radical wherein R ⁇ is a phenyl group.
  • (substituted phenyl)sulfonylalkyl refers to a R 84 S(0) 2 - group appended to a loweralkyl radical wherein R84 is a substituted phenyl group.
  • naphthylsuifonylalkyl refers to a R 85 S(0) 2 - group appended to a loweralkyl group wherein R 85 is a naphthyl group.
  • (substituted naphthyl)sulfonylalkyl refers to a R 86 S(0) 2 - group appended to a loweralkyl group wherein Rse is a substituted naphthyl group.
  • carboxyalkoxyalkyl refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is 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 (-COOH) and an amino group (-NH ⁇ .
  • ((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 alkylamino group.
  • ((N-protected)alkylamino)-carboxyalkyP refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR g gRgo wherein R 89 is as defined above and Rgo is a loweralkyl group.
  • (dialkylamino)carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR 91 R 92 wherein R 91 and R 92 are independently selected from loweralkyl.
  • (amino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH 2 ).
  • ((N-protected)amino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR 93 wherein R g3 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.
  • ((N-protected)alkylamino)alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 94 R 95 wherein R ⁇ is an N-protecting group and R 95 is a loweralkyl group.
  • (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 selected from loweralkyl.
  • carboxyalkylamino refers to -NHR 98 wherein R 98 is a carboxyalkyi group.
  • alkoxycarbonylalkylamino refers to -NHR 99 wherein Rg 9 is an alkoxycarbonylakyl group.
  • (amino)carboxyalkylamino refers to -NHR 100 wherein R 100 is an (amino)carboxyaikyl group.
  • ((N-protected)amino)carboxyalkylamino) refers to -NHR 101 wherein R 101 is an ((N-protected)amino)carboxyalkyl group.
  • (alkylamino)carboxyalkylamino refers to -NHR 102 wherein R 102 is an (alkylamino)carboxyalkyl group.
  • ((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 (dialkylamino)carboxyalkyl group.
  • (amino)aIkoxycarbonylalkylamino refers to -NHR 105 wherein R 105 is an (amino)alkoxycarbonylalkyl group.
  • ((N-protected)amino)alkoxycarbonylalkylamino refers to -NHR 106 wherein R 106 is an ((N-protected)amino)alkoxycarbonylalkyl group.
  • (alkylamino)alkoxycarbonylalkylamino refers to -NHR 107 wherein R 107 is an (alkylamino)alkoxycarbonylalkyl group.
  • ((N-protected)alkylamino)alkoxycarbonylalkylamino) refers to -NHR 108 wherein R 108 is an ((N-protected)alkylamino)alkoxycarbonylalkyl group.
  • dialkylamino)alkoxycarbonylalkylamino 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, 1-propylidene, 1-butylidene, 1-pentylidene, 2-propylidene, 2-butylidene, 2-pentylidene, 3-pe ⁇ tylidene, 3-hexylidene, 3-heptylidene and 4-heptylidene.
  • 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 ⁇ R ⁇ wherein R ⁇ and R 112 are independently selected from loweralkyl groups.
  • arylalkyiamino refers to R ⁇ NH-, wherein R 113 is an arylalkyl residue.
  • arylalkyl (alkyl)amino refers to R 114 R 115 N-, wherein R 114 is an arylalkyl residue and R 115 is a loweralkyl residue.
  • phenylalkylamino refers to a phenylalkyi 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 naphthylalkyi group appended to an amino radical, including, but not limited to 1-naphthylmethylamino and the like.
  • (substituted naphthyl)alkylamino refers to a (substituted naphthyl)alkyl group appended to an amino radical.
  • (phenylalkyi) (alkyl)amino refers to R 116 R 117 N-, wherein R 116 is a phenylalkyi residue and R 117 is a loweralkyl residue.
  • ((substituted phenyl)alkyl)-(alkyl)amino) refers to R ⁇ i 8 R ⁇ i 9 N - wherein R 118 is a (substituted phenyl)alkyl group and R 119 is a loweralkyl group.
  • (naphthylalkyi) (alkyl)amino) refers to R ⁇ 20 R ⁇ 2 ⁇ - wherein R 120 is a naphthylalkyi group and 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 aminoalkyi residue.
  • diaIkylamino(alkyi)amino refers to R 125 R 126 N-, wherein R 125 is a dialkylamino residue appended to a loweralkyl residue and R 126 is a loweralkyl residue.
  • (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 12 is a hydroxyalkyl group and 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 ⁇ 32 N-, wherein R 131 and R 132 are hydroxyalkyl residues.
  • alkoxyalkyl(alkyl)amino refers to R 133 R ⁇ 3 N-, wherein R 133 is a loweralkyl group and R 134 is an alkoxyalkyl group.
  • di-(alkoxyalkyl)amino refers to R 135 R 136 N-, wherein R 135 and R 136 are alkoxy residues appended to loweralkyl residues.
  • 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 13 gR 1 0 N-, wherein R 139 is a polyalkoxy residue appended to a loweralkyl radical and R140 is a loweralkyl residue.
  • ((heterocyclic)alkyl)(alkyl)amino) refers to -NR 141 R 142 wherein R 141 is a heterocyclicalkyl group and R 142 is a loweralkyl group.
  • (heterocyclicalkyl)amino refers to -NHR 143 wherein R 143 is a heterocyclic alkyl group.
  • (heterocyclic) (alkyl)amino refers to -NR 144 R 145 wherein R 144 is a substituted or unsubstituted heterocyclic group and R 145 is a loweralkyl group.
  • (alkyiaminoalkyl) (alkyl)amino” as used herein refers to -NR 146 R 147 wherein R 146 is an alkyiaminoalkyl group and R 147 is a loweralkyl group.
  • dialkylaminoalkyi) (alkyl)amino refers to -NR 148 R 149 wherein R 148 is a dialkylaminoalkyi group and R 149 is a loweralkyl group.
  • ((alkoxy) (alkyl)aminoalkyl)- (alkyl)amino) refers to -NR ⁇ 50 R 151 wherein R 150 is -NR 152 R 153 appended to a loweralkyl radical wherein 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 -NHR 156 appended to a loweralkyl group and wherein R 156 is an alkoxy group and R 155 is a loweralkyl group.
  • (alkoxyalkoxyalkyl)(alkyl)amino) refers to -NR 305 R 306 wherein R 305 is an alkoxyalkoxyalkyl group and 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 group.
  • arylsulfonylamino as used herein efers to R 310 NH- wherein R 310 is an arylsulfonyl group.
  • alkylaminocarbonylamino refers to R 311 C(0)NH- wherein R 311 is an alkylamino group.
  • alkylaminocarbonyloxy refers to R 312 C(0)0- wherein R 312 is an alkylamino group.
  • alkoxycarbonyloxy refers to R 313 C(0)0- wherein R 313 is an alkoxy group.
  • loweralkylcarbonyl refers to R 157 C(0)- wherein R 157 is a loweralkyl group, including, but not limited to acetyl, propionyl and the like.
  • alkoxy and thioalkoxy refer to R 158 0- and R 158 S-, respectively, wherein R 158 is a loweralkyl group.
  • alkoxyalkoxy refers to an alkoxy group appended to an alkoxy radical including, but not limited to, methoxymethoxy and the like.
  • aryloxyalkyl refers to an aryloxy group (R 303 ⁇ - wherein R 303 is an aryl group) appended to a loweralkyl radical.
  • thioaryloxyalkyl refers to a thioaryloxy group (R ⁇ 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, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like.
  • alkenyloxy refers to R 159 0-, 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 to R 160 0- 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 4-chlorobenzyloxy and the like.
  • 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.
  • polyalkoxy refers to R 161 0-, wherein R 161 is a straight or branched chain containing 1-5, C m -0-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.
  • haloalkyi refers to a loweralkyl radical in which one or more hydrogen atomsare replaced by halogen including, but not limited to fluoromethyl, 2-chloroethyl, trifluoromethyl, 2,2-dichloroethyl and the like.
  • polyhaloalkyi 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 refers to R 30 oS(0) 2 - wherein R 300 is a loweralkyl group.
  • (aryl)sulfonyl refers to R 30 ⁇ S(O) 2 - werein R 301 is an aryl group.
  • (heterocyclic)sulfonyl refers to R 302 S(O) 2 - wherein R 3Q2 is a heterocyclic group.
  • 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 independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • 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 group 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 nitrogen atoms; or one nitrogen and one oxygen atom; or one nitrogen and one sulfur atom; 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 quatemized, and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring.
  • Heterocyciics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyciics are also preferred.
  • Preferred heterocyciics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazi ⁇ yl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazi ⁇ yl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazoiyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indoly
  • heterocyciics include imidazolyl, pyridyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, thiazoiyl, 2-aminothiazolyl, 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 S0 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. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise carbamates, amides, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivates, imine derivatives, enamine derivatives and N-heteroatom derivatives.
  • N- protecting groups include formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and the like.
  • N-protecting groups also include an L- or D- aminoacyl residue, which may itself be N-protected similarly.
  • O-protecting group refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)) and comprise substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxy methyl, 2-(trimethylsilyl)ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethyisilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene
  • aa' is 1 to 5 and R 6q and R 7q are independently selected from
  • R 8q -Z q - wherein Z q is O, S or NH and R 8q is a C to C 6 straight or branched carbon chain substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocyclic; XXV)
  • substituted methylene group refers to: HR 13q R 14q wherein i) hydrogen or ii) hydroxy and 2) R 14q is i) hydrogen, ii) loweralkyl, iii) hydroxy, iv) hydroxyalkyl, v) alkoxy, vi)alkoxyalkyl, vii) azido, viii) azidoalkyl, ix) amino, x) (N-protected)amino, xi) aminoalkyi, xii) (N-protected)aminoalkyl, xiii) alkylamino, xiv) (N-protected) (alkyl)amino, xv) alkyiaminoalkyl, xvi) (N-protected) (alkyl)-aminoalkyl, xvii) dialkylamino, xviii) dialkylaminoalkyi,
  • R 14q is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino,
  • R ⁇ sq is i) loweralkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyi, v) alkyiaminoalkyl, vi) dialkylaminoalkyi, vii) aryl, viii) heterocyclic or ix) (heterocyclic)alkyl and
  • R ⁇ 6 q is i) hydrogen, ii) loweralkyl, iii) hydroxyalkyl, iv) haloalkyi or v) azidoalkyl;
  • R 20q is i) CH 2 or ii) N and
  • R 21q is i) NH, ⁇ ) O, iii) S or iv) S0 2 , such that when t' is 0 then R 20q is CH 2 and when t' is 1 to 3 then R 20q is N, (VI) -CH 2 CH(R 22q )C(0)NHR 23q wherein
  • R 2 2q is i) loweralkyl or ii) cycloalkylalkyl and
  • R 23q is i) loweralkyl, ii) hydroxyalkyt, iii) alkoxyalkyl, iv) aminoalkyi, v) alkyiaminoalkyl, vi) dialkylaminoalkyi, vii) aryl, viii) arylalkyl ix) heterocyclic, x) (heterocyclic)alkyl or
  • R 22 q is as defined above and i) hydrogen, ii) loweralkyl, iii)an N-protecting group or iv) R 75q -C(0)-wherein R 75q is aminoalkyi or (N-protected)aminoaikyl;
  • R 26q is i) loweralkyl or ii) cycloalkylalkyl and
  • R 27q is i) loweralkyl or ii) cycloalkylalkyl; (IX) -CH 2 CH(R 81q )NHC(0)R 82q or -CH 2 CH(R 81q )NHS(0) 2 R 82q wherein i) loweralkyl or ii) cycloalkylalkyl and
  • R 82q is i) loweralkyl, ii) alkoxy, iii) alkylamino, iv) dialkylamino, v) -OR* wherein R* is aminoalkyi, alkyiaminoalkyl, dialkylaminoalkyi or (heterocyclic) alkyl or
  • R 21q is as defined above;
  • lipophilic or aromatic amino acid side chains refer to amino acid side chains selected from the group isobutyl, isopropyl, sec-butyl, benzyl, p-methoxybenzyl, imidazole-4-yl-methyl, p-hydroxybenzyl, 1- and 2-naphthylmethyl, (pyrazolyl) methyl, (thiazolyl)methyl, cyclohexylmethyl, (3-indolyl)methyl, CH 3 SCH 2 - and the like.
  • General references to amino acid side chains in both the description and claims herein is to be taken as reference to such, whether naturally occurring in proteins or not, and to both D- and L- forms.
  • Al “His”, “Leu”, Phe”, “Tyr”, “Cys”, “Gly”, “Lys”, “Sar”, “Pro”, “HomoPhe” and “norLeu” as used herein refer to alanine, histidine, leucine, phenylalanine, tyrosine, cysteine, glycine, lysine, sarcosine, proline, homophenylalanine and norleucine, respectively.
  • amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem. 1984, 158, 9-31).
  • Renin inhibitors having one asymmetric carbon atom can exist as the racemic mixture or as pure enantiomers. Renin inhibitors having two or more asymmetric carbon atoms can exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.
  • the present invention includes within its scope all of the isomeric forms.
  • the terms "S” and "R” configuration as used herein are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45. 13-30.
  • Renin inhibitors having the general structure shown in group (9) can be prepared as described in Fung, et al., PCT Patent Application WO90/03971 (PCT/US89/04385), published April 19, 1990, which is hereby incorporated by reference.
  • the syntheses of segments containing substituents D are described in the Examples or have previously been described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al., J. Med. Chem. 1987, 30, 1609; Buhlmayer, et al., U.S. Patent No. 4,727,060; Morisawa, et al., European Patent Application No. 0228192; Ten Brink, PCT Patent Application No. W087/02986).
  • Renin inhibitors having the general structure shown in group (10) can be prepared as described in De, et al., PCT Patent Application No. WO90/04917 (PCT/US89/04649), published May 17, 1990, which is hereby incorporated by reference.
  • the syntheses of segments containing substituents R 5 are described in the Examples or have previously been described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al., J. Med. Chem. 1987, 30, 1609; Buhlmayer, et al., U.S. Patent No. 4,727,060; Morisawa, et al., European Patent Application No. 0228192; Ten Brink, PCT Patent Application No. W087/02986).
  • reaction of the alcohol 15 with bromoacetic acid, optionally followed by esterification provides 16 or 17.
  • reaction with t-butyl bromoacetate provides 18.
  • Example 1 2(S 1 (SH4-(Methoxymethoxy)piperidin-1-v0carbonyl-2- phenv ⁇ ethoxyhexanoic acid amide of 3-(4- morphormvDpropyl-5fS)-amino-6-cvclohexyl-4(S)-hvdroxy-
  • Example 1 A 4(SH-Butyloxycarbonylamino-5-cvclohexyl-3( R.S)-hvdroxy-1 -pentene
  • Example 1B 3- ( t-ButyloxycarbonvD-4-(cvclohexylmethv ⁇ -2. 2-dimethyl-5-vinyloxazolidine.
  • the procedure of S. Thaisrivong J. Med. Chem. 1987, 30, 976) was employed.
  • Solid pyridinium p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After addition was complete, the reaction was stirred for 1 h and neutralized by addition of solid sodium bicarbonate.
  • PPTS Solid pyridinium p-toluenesulfonate
  • Example 1C 3-(t-ButyloxycarbonvB-4-(cvclohexylmethv ⁇ - 2.2- dimethvioxazoIidine-5-carboxaldehvde.
  • Example 1 D 3-(3(RH3-(tert-Butyloxycarbonvn-2.2 dimethyl-4fS)- cvclohexylmethyl-5(R)-oxazolidinyl)-3-hvdroxy-2(R)- isopropyl- l-oxopropyl)-4fR)-methyl-5fS)-phenyl-2-oxazolidinone.
  • the title compound was prepared in analogy to the procedure of S. Thaisrivongs, D. T. Pals, L T. Kroll, S. R. Turner and F. S. Han, J. Med. Chem. 1987, 30, 976-82, from the resultant compound of Example 1C, in 63% yield. M. p. 97°C.
  • Example 1 E 3-(3(RH3-ftert-Butyloxycarbonvn-2.2- dimethyl-4(S - cvclohexylmethyl-5(R)-oxazolidinv ⁇ -3-f(1- imidazolv ⁇ thionyloxy)-2fR)-isopropyl-1-oxopropy ⁇ -4(R)-methyl-5fS)-phenyl-2- oxazolidinone.
  • the resultant compound from Example 1 D (1.840 g, 3.136 mmol) and 1,1'-thiocarbonyldiimidazolide (1.128g, 6.330 mmol) were refluxed in 8 mL dry 1,2-dichloroethane under a nitrogen atmosphere for 24 h.
  • Example 1 F 3-(3-(3-(tertButyloxycarbonv ⁇ 2.2-dimethyl-4rS)-cvclohexylmethyl-5fS)-oxazolidinvn-2fR)-isopropyl-l- oxopropyl)-4(R -methyl-5fS)-phenyl-2-oxazolidinone.
  • a solution of the resultant product from Example 1 E (6.50 g, 9.33 mmol) in 275 ml of dry toluene was degassed with argon for 30 min, then warmed to reflux (under argon).
  • Example 1G 2(S)-f(3-(tert-Butyloxycarbonyl-2.2-dimethyl- 4(S)-cvclohexylmethyl-5(S)-oxazolidinyl methv ⁇ -3- methylbutanoic acid.
  • the resultant product from Example 1 F (6.10 g, 10.7 mmol) was hydrolyzed with aq. LiOH and hydrogen peroxide in THF.
  • Example 1 H 3-(4-Morpholinvnpropyl 2fSV((3-tert- butyloxycarbonvn-2.2-dimethyl-4(S)-cvclohexylmethyl-5fSVoxazolidinv ⁇ methv ⁇ -3- methylbutanamide.
  • the procedure of P. Buhlmayer, et. al., J. Med. Chem. 1988, 31 (9), 1839-46 was adapted.
  • the resultant compound from Example 1G 75 mg, 0.182 mmol), HOBT (42.0 mg, 0.274 mmol) and N-methylmorpholine (55 mg, 0.55 mmol) were dissolved in 1.0 ml dry DMF, and the solution was cooled to -20°C (under nitrogen).
  • Example 11 1 (S)-(4-(Methoxymethoxyl)piperidin-1-yl- carbonyl)-2-phenylethanol.
  • Example U 2(S)-(1 (SH4-(Methoxymethoxy)piperidin-1-yl- carbonvP-2-ohenylethoxy)hexanoic acid.
  • the resultant compound of Example 11 (1.45 g, 4.95 mmol), in 10 ml THF was added dropwise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (0-5°C). The suspension was stirred for 20 mins at 0-5° C and then warmed up to room temperature and stirred for additional 1 h. Solution of D-2-bromohexanoic acid in 6 ml THF was added dropwise to the cooled suspension (0-5° C) under N 2 atmosphere.
  • Example 1 K 2(SH1 (SH4-(Methoxymethoxy)piperidin-1- ylcarbonyl-2-phenyl ethoxyhexanoic acid amide of 3-(4- morpholinv ⁇ propyl 5(SVamino-6-cvclohexyl-4fS)-hvdroxy-
  • the resultant compound from Example 1 H (0.161 mmol) was deprotected by dissolving in 1.0 ml dry CH 2 CI 2 , cooling the solution to -10°C (under nitrogen), and treating with 1.0 ml of trifluoroacetic acid. The resulting solution was stirred at -10 to 0°C for 4 h. The solvents were largely removed with a stream of nitrogen, and the residue (as a concentrated solution in trifluoroacetic acid) was dissolved in 1.0 ml THF and 0.3 ml water at 0°C. The solution was allowed to warm slowly to ambient temperature over 18 h. The crude aminoalcohol was isolated by basifying the reaction with an excess of 1.0 M aq.
  • Example 2A 2(S)-Cvclohexylalanine methyl ester, hvdrochloride salt L-Phenylalanine (215 g, 1.3 mole) was hydrogenated over Pd/C in HOAc, filtered and concentrated. The resulting cyclohexylalanine was taken up in MeOH (1200 mL). Thionyl chloride (427 g, 3.59 mole) was slowly added to the slurry, which eventually became homogeneous. The reaction was cooled in an ice/water bath and addition of thionyl chloride was continued. The reaction mixture was heated to reflux for 2h, cooled and concentrated to afford a solid, which was taken up in ether and filtered.
  • Example 2B 2(S -N- ⁇ " riphenylmethyl)cvclohexylalanine methyl ester Cyclohexylalanine methyl ester, HCI salt (88 g, 398 mmol) was taken up in chloroform (400 ML). Triethylami ⁇ e (84.6 g, 836 mmol) was then added in one portion to the slurry and stirred five minutes. Triphenylmethylchloride (111 g, 398 mmol) was then added, and the reaction was stirred for 5h at ambient temperature.
  • the internal temperature of the reaction reached 50°C, however, external cooling was not employed.
  • the reaction mixture was washed with 1M KHS0 4 solution (2 x 100 mL), saturated NaHC0 3 (200 mL), brine (100 mL), then dried over MgS0 4 .
  • the solution was then concentrated to give 200 g of residue which was filtered through 900-1000 g of silica gel (elution gradient hexane-10:1 hexane: ethyl acetate) affording 157 g of product (93%), which could be crystallized from hexanes: ethyl acetate to afford large white crystals, m.p. 86-87°C.
  • Example 2C Dimethyl 3(S)-4-Cyclohexyl-(N-triphenylmethyl)amino-2-oxobutylphosphonate To a -78°C solution of dimethyl methyl phosphonate (272.5 g, 2.2 mol) in 1.6L THF was added n-BuLi (2.5 M, 800 mL, 2.0 mmol) and stirred 45 minutes. The product of Example 2B (156 g, 366 mmol) in 40 mL THF was then added dropwise. This reaction mixture was stirred at -50°C for 3 h, then at -40°C for 6h then finally warmed to ambient temperature overnight.
  • n-BuLi 2.5 M, 800 mL, 2.0 mmol
  • Example 2D 6(S -7-Cvclohexyl-2-methyl-6-(N-triphenylmethv ⁇ -amino-5-oxohept-2-ene-3-oic acid
  • the product of Example 2C (117.2 g, 229 mol) was dissolved in 600 ml THF and cooled to 0°C.
  • This material (123 g) was taken up in 460 ml THF, 229 ml MeOH, cooled to 0°C then 18.86 g of LiOH-H 2 0 in 229 ml of distilled water was added. This solution was allowed to warm to room temperture and stirred for 3 days. Volatiles were removed at reduced pressure and the resulting aqueous solution was washed with ether (100 ml x2) then acidified to pH 3 with 6N HCI. The aqueous solution was then extracted with EtOAc (300 ml x2), washed with brine, dried (MgS0 4 ) and concentrated to give 116 g of a yellow foam. This material was recrystallized from 525 ml of hot hexanes/EtOAc (12/1) to give 72.4 g of a white solid (62% for three steps), m.p. 97-98°C.
  • Example 2E (5S.6S)-6-Cvclohexylmethyl-3-isopropylidene-5- hvdroxypiperidine-2-one
  • This homogeneous solution was cooled to 0°C, then DCC (1.25 g, 12 mmol) in 5 ml THF was added. The cooling bath was removed and the reaction was stirred for 2h. At this time, an additional 1.25 g of DCC was added. After 5h of total reaction time, the mixture was filtered, concentrated and dissolved in either.
  • Example 2E To a 0°C slurry of the above-mentioned white solid resulting from the first part of Example 2E (1.2 g, 3.0 mmol) in 20 ml CH 2 CI 2 was added imidazole (204 mg, 3.0 mmol). The resulting reaction mixture was stirred for 1 h, then washed with 20 ml of KHS0 4 , water, saturated NaHC0 3 , and brine. The organic portion was dried over MgS0 4 , filtered and cooled to -78°C. To the cold solution was added L-Selectride® (Aldrich, 1.0 M, 5.0 ml, 5.0 mmol) and stirred for 10 min.
  • L-Selectride® Aldrich, 1.0 M, 5.0 ml, 5.0 mmol
  • reaction mixture was then warmed to -40° C and quenched with 20% citric acid solution.
  • the organics were washed with 20 ml of water, saturated NaHC0 3 solution, brine, dired over MgS0 4 , and concentrated to afford a clear oil.
  • This residue was purified on silica gel (50% hexanes/ethyl acetate) to give an oil which was triturated with ether to afford a white solid, 545 mg, 72% yield from active ester, m.p. 128-130°C.
  • Example 2F The product of Example 2F was reacted with N- (benzyloxycarbonyloxy)succinimide to provide the N-Cbz protected amino lactone. Reaction of the N-Cbz protected amino lactone with 3-amino-1-(morpholin-4- yl)propane provided 3-(4-morpholinyl)propyl 5(S)-benzyloxycarbonylamino-6- cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide. This product can be N- deprotected and coupled with the product of Example U according to the procedure of Example IK to provide the desired compound.
  • Example 3A Methyl 3-Hvdroxy-2-methylene-3-phenyl propionate
  • benzaldehyde 82.1 mL, 0.81 mol
  • methyl acrylate 109.1 mL, 1.211 mol
  • 1,4- diazabicyclo(2,2,2)octane 13.6 g, 0.12 mol
  • acetic acid 1.mL, 0.024 mol
  • Methyl acrylate (20.9 mL, 0.23 mol) was then added and the solution was allowed to react at 35°C for an additional 48 h.
  • Example 3B fZ)-1-Bromo-2-carbomethoxy-3-ohenyl-2-propene To a 2 L, 3-neck Morton flask fitted with a thermometer, a mechanical stirrer, and an addition funnel was added the resultant compound from Example 3A (305.9 g, 1.585 mol) followed by addition of 48% HBr (505 mL, 4.46 mol) in one portion. The flask was immersed in an ice-water bath, at which time concentrated sulfuric acid (460 mL, 8.62 mol) was added dropwise over 90 min and the internal temperature of the reaction mixture was maintained at 23-27°C throughout the addition process. After removal of the ice-water bath, the mixture was allowed to stir at ambient temperature overnight.
  • concentrated sulfuric acid 460 mL, 8.62 mol
  • the solution was then transferred to a separatory funnel and the organic layer was allowed to separate from the acid layer.
  • the acids were drained and the organic layer was diluted with 2 L of a 1 :1 ethyl acetate/hexane solution, washed with saturated aqueous sodium bicarbonate solution (1 L), dried over sodium sulfate, and concentrated to yield 400 g (99%) of the desired product as a light yellow oil, which was used without any additional purification: b.p.
  • the compound can be isolated by concentration to an amorphous powder, which is contaminated with an equivalent of sodium bromide: IR (KBr) 1711 , 1628, 1215 cm “1 ; 1 H NMR (DMSO D-6) delta 3.70 (s, 3H), 3.77 (s, 2H). 7.33-7.41 (m, 3H), 7.48 (s, 1H), 7.87-7.89 (m, 2H); 13 C NMR (75 MHz, DMSO D-6) delta 49.88, 51.93, 127.36, 128.33, 128.91 , 129.82, 134.75, 139.06, 168.60.
  • Example 3D 2-Carbomethoxy-3-phenylpropane-1-sulfonic Acid Sodium To the 8 L of 1 :1 methanol/water mixture containing the resultant compound from Example 3C was added 60 g of W-24 ra ⁇ ey nickel. The resulting suspension was pressurized under 50 psi of hydrogen and was allowed to shake on a Parr shaker for 24 h, at which time an additional 20 g of raney nickel catalyst was added. After 6 h under 50 psi of hydrogen, the catalyst was removed by filtration and the solution was concentrated to dryness. To the dry white solid was added ethyl acetate (6 L) and heptane (4 L) and the solution was vigorously stirred with a a mechanical stirrer overnight.
  • ethyl acetate 6 L
  • heptane 4 L
  • the white suspension was removed by filtration yielding 530 g (88%) of the desired product as an amorphous powder that was contaminated with approximately one equivalent of NaBr.
  • the comound was used without any additional purification: IR (KBr) 1740, 1215, 1050 cm- 1 .
  • Example 3E 2-Carbomethoxy-3-phenyl-l -propanesulfonyl Chloride To a 3 L round bottom flask was added the resultant compound from example 3D (530 g, 1.39 mol) and toluene (520 mL) followed by the addition of PCI 5 (317 g, 1.52 mol). The mixture was warmed to 50°C with stirring for 45 min. It was then diluted with toluene (1 L) and was filtered through DCite.
  • Example 3F Methyl 2-Benzyl-3-M -methyl-piperazin-4- ylsulfonyl) propionate
  • dichloromethane 305 mL
  • N-methyl piperazine 35.5 mL, 32.1 g
  • dichloromethane 305 mL
  • the resultant racemic ester from Example 3F (135 g, 397 mmol) was suspended in acetone (300 mL) and water (900 mL). While being stirred vigorously at a temperature of 35°C, a crude preparation fo Subtilisin Carlsberg (10 mL, Alcalase 2.4L, Novo Laboratories) was added. Sodium hydroxide solution (6 M) was used to maintain the reaction at pH 7.5-8.0. After 3 days, the acetone was removed under reduced pressure and the aqueous phase was extracted with CHCI 3 (1 L) to remove the unreacted ester.
  • Example 3I Diethyl (3-Bromo-2-oxo-propy ⁇ acetamidomalonate To a cold (0°C), stirred solution of the resultant compound from Example 3H (280 g, 0.83 mol) in a mixture of 2:1 acetonitrile/water (1.68 L) was added solid N- bromosuccinimide (193 g, 1.08 mol) in three portions over a period of 15 min. The resultant orange mixture was stirred at 0°C for an additional period of 1 h and then was allowed to warm to room temperature.
  • reaction mixture was treated with 10% aqueous sodium thiosulfate, diluted with ethyl acetate, and washed sequentially with water, 10% aqueous NaHS0 4 (3 X), water, and brine. Drying (MgS0 4 ) and concentration afforded a yellow solid which was recrystallized from a mixture of ethyl acetate and hexane to give 247 g (85%) of the desired compound as a white solid: m.p. 97-98.5°C.
  • Example 3J Diethyl (4-Thiazolylmethyl)acetamidomalonate A 5 L, 3-neck round bottom flask equipped with a mechanical stirrer, stopper and a drying tube was charged with the resultant compound from Example 31 (325 g, 0.92 mol) and flushed with nitrogen. A freshly prepared solution of thioformamide in tetrahydrofura ⁇ (0.8 M, 1.25 L) was added in one portion. The reaction mixture was stirred at room temperature for 4 h. The resultant slurry was then diluted with ether (1.25 L) and cooled to 0°C. The solid was then collected by suction filtration and washed with cold ether (3 X) to give the title compound as the hydrochloride salt.
  • Example 3K N-Acetyl-3-(4-thiazolv ⁇ -DL-alanine Ethyl Ester
  • aqueous 2 M LiOH 325 mL, 0.65 mol
  • reaction mixture was then extracted with chloroform (4 x 1.5 L), the aqueous phase was carefully acidified to pH 4 with 2 M HCL and then was concentrated under reduced pressure. Residual water was removed by consecutive evaporation of portions of toluene (3 x 500 mL) and ethanol (3 x 500 mL). The residue was taken up in warm ethanol and suction filtered to remove inorganic salts. The solids were washed with warm ethanol (3 x 400 mL). The residue was taken up in warm ethanol and suction filtered to remove inorganic salts.
  • Example 3M Epimerization of N-Acetyl-3-(4-thiazolv ⁇ -D-alanine Ethyl Ester
  • the resultant solution of sodium ethoxide was cooled slightly, and N-acetyl-3-(4-thiazolyI)-D-alanine ethyl ester from Example 3L (102 g, 0.42 mol) was added. The reaction mixture was then heated to reflux.
  • Example 3N 3-(4-ThiazolyO-L-alanine Dihvdrochloride
  • a 2 L round bottom flask equipped with a magnetic stirrer was charged with N- acetyl-3-(4-thialzoyl)-L-alanine from Example 3L (92.6 g, 0.43 mol) and 6 M HCl (1 L).
  • the resultant solution was heated to reflux. After 3 h the mixture was allowed to cool to room temperature.
  • the solution was then concentrated under reduced pressure, evaporated from toluene (3 x 200 mL), and dried under vacuum overnight to give 120 g of a slightly wet solid. This material was used in the next reaction without further purification.
  • Trifluoroacetic acid 50 mL was slowly added via cannula to a solution of the resultant compound from Example 3P (6.27 g, 12.6 mmol) in methylene chloride (50 mL) at 0°C.
  • the reaction was stirred 3 h at 0°C and concentrated in vacuo (40°C bath) to an oil which was basified to pH 10-11 with aqueous K 2 C0 3 .
  • the product was extracted into chloroform, dried over Na 2 S0 4 , filtered, and concentrated to a foam. Recrystallization from 1 :4 (v/v) methylene chloride/hexane gave 5.00 g (100%) of the desired product as a fluffy white solid: m.p.
  • Example 3R (2S)-2-Benzyl-3-(4-methylpiperazin-1- ylsulfonv ⁇ propionyl-(LH4-ThiazolvOAla Amide of f2S.3R,4S)-2-Amino-1-cvclohexyl-3,4-dihvdroxy-6- methylheptane
  • the resultant acid from Example 3G 1.000 g, 3.064 mmol
  • the resultant amine from Example 3Q (1.110 g, 2.792 mmol)
  • 1-hydroxybenzotriazole 1.022 g, 7.563 mmol
  • dimethylformamide 20 mL
  • Example 4A Ethyl (2-BromoallvDacetamidoacetate To a solution of the product of Example 3H (3.36 g, 10.0 mmol) in dimethylformamide (10 mL) was added sodium chloride (586 mg, 10.0 mmol), water (360 microliters, 20 mmol) and 4N hydrochloric acid in dioxane (0.12 mL, 0.5 mmol). The reaction vessel was Firestone purged three times and placed under a positive nitrogen pressure. The reaction mixture was heated at reflux for 24 hours and then concentrated in vacuo. The residue obtained was diluted with water (5 mL) and extracted with ether (3 x 15 mL).
  • Example 4B N-Boc-(2-Bromoallv ⁇ lvcine A slurry of the product of Example 4A in 0.1 N potassium chloride solution (300 mL) containing 0.2 M pH 7.0 phosphate buffer (30 mL) was treated with a solution of Subtiiisin Carlsberg (4 mg) in 0.1 N potassium chloride solution (3 mL). The pH was maintained between 6.50 and 7.25 by addition of 2.0 N sodium hydroxide solution via a pH-Stat. After 25 minutes, the rate of hydrolysis noticeably slowed; and the unreacted D-ester was extracted with methylene chloride (3 x 150 mL).
  • the resulting aqueous phase was treated with cobalt(ll) acetate (6 mg) and Acylase I (80 mg). The reaction mixture was stirred for 4 hours and determined to be complete.
  • the pH of the reaction mixture was adjusted to 10 by the addition of solid sodium carbonate.
  • the resulting solution was treated with di-tert-butyl dicarbonate (6.55 g, 30 mmol) dissolved in THF (100 mL) and vigorously stirred for 16 hours.
  • the aqueous solution was washed with hexane (200 mL) to remove any unreacted protecting-reagent.
  • the aqueous layer was adjusted to pH 2.5 by the addition of solid potassium hydrogen sulfate and extracted with ethyl acetate (2 x 200 mL).
  • Example 4C (2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic Acid
  • a solution of the product of Example 4B (2.00 g, 6.80 mmol) in water (30 mL) and tetrahydrofuran (15 mL) cooled to 0 °C was added N-bromosuccinimide (1.45 g, 8.16 mmol) in three portions over twenty minutes. After the addition was complete, the ice bath was removed and the solution was stirred for four hours. The tetrahydrofuran was removed in vacuo and the product was extracted with ethyl acetate (3 x 35 mL).
  • Example 4D ( , 2R)-N-Boc-2-Amino-3-(4-thiazolyl)propanoic Acid To a solution of the producut of Example 4C (91 mg, 0.293 mmol) in tetrahydrofuran (5 mL) was added thioformamide (17.7 mg, 0.29 mmol). [Thioformamide was prepared by reacting a slight excess of phosphorus pentasulfide with formamide in tetrahydrofuran.
  • Example 5A Diethyl (2-Chloroallyl)acetamidomalonate To a suspension of 95% sodium hydride (17.2 g, 680 mmol) in tetrahydrofun (1.2 L) was added 2,3-dichloropropene (100 g, 900 mmol), diethylacetamidomalonate (146 g, 672 mmol) and tetrabutylammonium bromide (6.00 g). The resulting thick suspension was warmed at reflux under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (200 mL) and a mixture of ether (300 mL) and methylene chloride (100 mL).
  • Example 5B Ethyl f2-Chloroallv0acetamidoacetate
  • the product of Example 5A (137 g, 500 mmol) was hydroiyzed and decarboxylated by the procedure described in Example 4A to afford the title compound (105.4 g, 96%) as a pale yellow oil which crystallized upon standing.
  • Example 5C f2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic acid
  • the product of Example 5B is treated according to the procedure of Examples 4B and 4C to provide the desired product.
  • Example 6A 2-Carbomethoxy-3-phenylpropane-1-sulfonic acid Sodium salt
  • (Z)-l-bromo- 2-carbomethoxy-3-phenyl-2-propene, (0.98 molar equivalents) was added over one hour at 50 °C a 1.4M aqueous solution of sodium sulfite (1.0 molar equivalent).
  • the mixture was stirred for 10 hours at 50 °C, and then the ethanol was removed under reduced pressure at 50 °C.
  • Ethyl acetate (3 kg per 1 kg of bromide) was added and the mixture stirred for an additional 15 minutes and let stand for 10 minutes. The layers were separated and the aqueous layer was washed as above with two additional aliquots of ethyl acetate (1 kg per 1 kg of bromide).
  • Raney nickel (1 kg per 10 kg of aqueous solution) was added to the aqueous solution which was then evacuated and purged with nitrogen followed by hydrogen (3x) and placed under 40 psi of hydrogen for 6.5 to 9.5 hours.
  • the Raney nickel was removed by filtration using nitrogen pressure, and the filtrate was concentrated under reduced pressure at 55 °C.
  • a 10% aqueous acetone solution (0.3 kg per 1 kg of starting bromide) was added to the residue obtained, and the mixture was warmed at 50 °C for 30 minutes. Additional acetone (3 kg per 1 kg of starting bromide) was slowly added over one hour to effect crystallization of the product. After stirring for one hour, the product was removed by filtration and washed with acetone to afford the title compound in 60-65%.
  • Example 6B Methyl 2-Benzyl-3-(4-methyl-piperazin-1-ylsulfonv ⁇ propionate
  • the product of Example 6A (1 molar equivalent) was mixed with phosphorus pentachloride (1.5 molar equivalents) and warmed at 70-75 °C for 3-4 hours.
  • the reaction mixture was cooled to room temperature and then diluted with toluene (16.7 molar equivalents) and added to 10% aqueous sodium chloride solution (4 kg per 1 kg of phosphorus pentachloride) while maintaining the temperature below 40 °C.
  • the mixture was stirred for 5 minutes, allowed to settle for 15 minutes, and then the phases were separated.
  • the sodium chloride wash was repeated as described above.
  • the toluene phase was cooled to 5 °C and N-methylpiperazine (3 molar equivalents in 3 molar equivalents of toluene) was added maintaining the temperature below 15 °C.
  • the mixture was stirred for 4-6 hours and then washed with 8% aqueous sodium hydroxide (2 x 3.4 kg per 1 kg of phosphorus pentachloride).
  • the combined basic washes were re-extracted with toluene (0.25 kg per 1 kg of sodium hydroxide solution).
  • Example 6B The product of Example 6B (69 kg, 20 mol) in acetone (420 kg)/water (960 kg) was adjusted to pH 8.0 using 1N sodium hydroxide.
  • AlcalaseTM Subtilisin
  • the pH was maintained between 7.9 and 8.4 by the addition of 1N sodium hydroxide.
  • 80% of the theoretical amount of sodium hydroxide had been consumed the reaction was quenched by the addition of ethyl acetate.
  • the reaction mixture was concentrated to half the original volume under reduced pressure and then washed with ethyl acetate (2 x 700 kg). The volume of the aqueous phase was concentrated by half and the pH adjusted to 5.2.
  • Example 7A f2S.3R.4S)-2-Amino-1-cvclohexyl-3.4-dihvdroxy-6-methylheptane-
  • a 3.5% solution of 2S-Boc-amino-1-cyclohexyl-3R,4S- dihydroxy-6-methylheptane in 4N hydrochloric acid gas in anhydrous ethanol was prepared at 0-5 °C. After 4 hours at 0-5 °C, nitrogen was bubbled through the reaction mixture to remove dissolved hydrochloric acid gas. The solvent was removed under reduced pressure at 50 °C to afford a solid which was dissolved in ethyl acetate and water.
  • Potassium carbonate was added to bring the pH of the mixture to between 10 and 11 , and the layers were separated. The aqueous layer was extracted with additional portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure at 50 °C to afford a solid. The solid was crystallized by dissolving in a minimum amount of ethanol at 40 °C and then water was slowly added until the ratio of ethanol to water was 40/60 (w/w). The solution was cooled to 0-5 °C at a rate of 5 °C per hour. The cooled mixture was stirred for not less than 2 hours prior to removal of the solid by filtration.
  • Example 7B Boc-L-(4-Thiazo )-Ala Amide of (2S,3R,4S)-2-Amino-1- cvclohexyl-3,4-dihvdroxy-6-methylheptane
  • N-Boc- L-(4-Thiazolyl)Alanine 17.45 g, 64.4 mmol
  • HOBT 1-hydroxybenzotriazole hydrate
  • Example 7C H-L-(4-Thiazolv ⁇ Ala Amide of (2S.3R.4S -2-Amino-1-cvclohexyl-3,4-dihvdroxy-6-methylheptane
  • a 12% solution of the product of Example 7B at 15-25 °C in 3N hydrochloric acid was prepared. After 4 hours at 15-25 °C, the reaction mixture was quenched by pouring it into a mixture of 4% sodium hydroxide/15% sodium chloride/ethyl acetate. The pH of the mixture was brought up to 10-12 by the addition of 10% sodium hydroxide. The layers were separated and the aqueous layer extracted with ethyl acetate (2x).
  • the combined organic extracts were washed with 25% sodium chloride (2x), dried over magnesium sulfate, treated with activated carbon at 50 °C for 1 hour, and filtered through Ceiite.
  • the filtrate was concentrated to a solid under reduced pressure at 45 °C.
  • the solid was crystallized by dissolving in a minimum amount of ethyl acetate (5x by weight) and triturating with heptane until the ratio of ethyl acetate to heptane was 30/70 (w/w).
  • the solution was cooled to 0-5 °C and stirred for two hours and then filtered.
  • the solid was dried in a vacuum oven at 45 °C for 60 hours or until the loss on dryng was less than 0.1%.
  • Example 7D (2S)-2-Benzyl-3-f4-methylpiperazin-1-yl sulfonv ⁇ propionyl -L-(4-Thiazolvn Ala Amide of (2S.3R.4S)-2-Amino-1-cvclohexyl- 3,4-dihvdroxy-6-methylheptane
  • the product of Example 7C (3.00 g, 7.6 mmol), the product of Example 6C, 2S-benzyl-3(4-methyl-piperazin-1-yl sulfonyl)propionic acid, (2.59 g, 7.9 mmol), and HOBT (1.27 g, 8.3 mmol) were dissolved in DMF (30 mL).
  • reaction mixture After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0-5 °C in an ice bath and treated with the dropwise addition over a 30 minute period of a solution of DCC (1.72 g, 8.3 mmol) dissolved in DMF (8 mL). After 1 hour, the reaction mixture was allowed to warm to ambient temperature and stirred for 24 hours. The reaction mixture was quenched with citric acid (0.15 g, 0.26 mmol) and ethanol (0.17 mL, 3.04 mmol) and stirred for 1 hour. Ethyl acetate (60 mL) was added and the mixture was stirred for an additional hour. The by-product was removed by filtration and washed with ethyl acetate (10 mL).
  • the filtrate was diluted with ethyl acetate (400 mL) and washed with 5% sodium bicarbonate solution (2 x 100 mL), 1% sodium chloride solution (100 mL), and 20% sodium chloride solution (100 mL).
  • the solvent was removed under reduced pressure to afford an off-white solid.
  • the solid was dissolved in isopropanol (80 mL) with warming, treated with decolorizing carbon at 55 °C for 1 hour, filtered through Ceiite, and stirred at ambient temperature with a mechanical stirrer for 12 hours.
  • the white solid suspension was cooled to 0-5 °C in an ice bath for 3 hours and filtered cold.
  • Example 8 N-(4-MorpholinylsulfonylHL)-Phenylalanyl-(L)- 2-amino-4-thiazolvnAlanyl Amide of (2S.3R.4S)-2-Amino-1 -cvclohexyl-3,4-dihvdroxy-6-methylheptane
  • the title compound can be prepared according to the procedure disclosed in European Patent Application No. EP 399556, published November 28, 1990.
  • a renin inhibitor invention to treat psoriasis is demonstrated as follows.
  • a 62-year-old woman patient with documented psoriasis received 0.1 mg/kg of e ⁇ alkiren (H-((beta,beta-dimethyl)-beta-Ala)-(4-OCH 3 )Phe-His amide of 2(S)-amino- 1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane diacetic acid salt)(enalkiren 5.0 mg/5 ml (0.1% concentration), glacial acetic acid 0.91 mg/5 ml and sodium chloride 43.9 mg/5 ml in water for injection) intravenously over a 5 minute period, followed 40 minutes later by administration of an additional 0.3 mg/kg of enalkiren intravenously over a 5 minute period.
  • the psoriatic lesions on the patient's elbow, face and scalp were graded prior to treatment and 2, 4 and 7
  • the data provided in Table 1 indicates that the renin inhibitor caused an improvement in the patient's psoriasis.
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyciopentanepropionate, dodecylsulfate, ethanesulfate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-pheny
  • the basic nitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such as
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid, and phosphoric acid and such organic acids as oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
  • the compounds of the present invention can also be used in the form of prodrugs which include esters.
  • esters include a hydroxyl-substituted compound of the invention which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue.
  • the amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used.
  • Other esters include the compounds of the invention wherein a carboxylic acid group has been esterified to provide esters which include, but are not limited to, methyl, ethyl or benzyl esters. These esters serve as prodrugs of the compounds of the present invention.
  • the prodrugs are metabolicaliy converted in vivo to parent compound.
  • the preparation of the pro-drug esters is carried out by reacting a hydroxyl-substituted renin inhibitor with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired pro-drug ester.
  • Prodrugs which are esters of carboxylic acid group containing renin inhibitors are prepared by methods known in the art.
  • the novel method of this invention is directed to the use of a renin inhibitor for treatment of psoriasis in a human or other mammal.
  • This invention is also directed to renin inhibitor compositions useful for treating psoriasis.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the renin inhibitor may be administered orally, parenterally, by inhalation spray, by nasal spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Topical compositions comprising the renin inhibitor can be in the form of shampoos, salves, powders, sprays, ointments, lotions, creams, solutions, suspensions and the like. These topical compositions can be prepared by mixing the renin inhibitor with non-toxic, inert solid or liquid carriers which are suitable for topical administrtion. Topical administration may also involve the use of transdernnal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular injection, intraster ⁇ al injection, intradermal injection, intralesional injection, or infusion techniques.
  • injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, dextrose solution, mannitol solution, Ringer's solution, and isotonic sodium chloride solution
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables. Injectable preparations can be in ready to use form or reconstituted from a lyophilized powder.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Solid dosage forms can also comprise agents for enhancing oral absorption.
  • Solid dosage forms can also comprise liquid filled capsules, for example PEG solutions of the active compound in a soft elastic gelatin capsule.
  • a typical tablet dosage form comprises the active ingredient (no more than 35% by weight of the tablet), citric acid (5-15% by weight of the tablet), a filler such as microcrystalline cellulose (for example, Avicel* PH101), a disintegrant (8-12% by weight of the tablet, for example, crospovidone) and a lubricant (0.5-1.5% by weight of the tablet, for example, magnesium stearate.
  • a tablet can also comprise one or more surfactants (for example, Tween 80, Brij*35, Emulphor 719 and the like), with the total amount of surfactants being 2-3% by weight of the tablet.
  • the tablet dosage form is prepared by blending the active ingredient, 50% of the citric acid and the Avicel*. Ethanol (200 proof) is added and the mixture is granulated. If surfactants are included, they are added as a solution in the ethanol during the granulation step. The granules are dried overnight and screened through a 14 mesh screen. The remaining 50% of the citric acid, the crospovidone and the magnesium stearate are blended with the granules and then compressed into tablets.
  • the composition of two typical tablet dosage forms (100 mg of active ingredient) is shown below.
  • citric Acid 50.1 14.3 AviceP PH101 150.0 42.8 crospovidone 40.0 11.4 magnesium stearate 3.0 0.9
  • a typical capsule dosage form comprises a soft elastic gelatin capsule filled with a solution comprising the active ingredient dissolved in a solvent comprising a mixture of PEG 400 (98% volume/volume) and glycerin (2% volume/volume).
  • a typical soft elastic gelatin capsule has a composition comprising gelatin NF (38.3% by weight), glycerin (96% active; 29.0% by weight) and water (32.7%).
  • the capsule dosage form is prepared by mixing appropriate volumes of PEG 400 and glycerin to give a mixture which is 98% by volume PEG 400 and 2% by . volume glycerin. Nitrogen is bubbled through the mixture for several hours. While maintaining the mixture under a nitrogen atmosphere, the mixture is heated to about 40°C and then the desired amount of the active ingredient is dissolved. The solution of active ingredient is then filled into soft elastic gelatin capsules. The filling operation is conducted under a nitrogen atmosphere.
  • soft elastic gelatin capsules can be prepared which contain 0.1 ml of a PEG 400/glycerin (98%/2% by volume) solution of the compound of Example 3 (hydrochloride) at concentrations of 0.7 mg/ml, 7 mg/ml and 21 mg/ml.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • a renin inhibitor can be administered in combination with one or more other agents known to be useful for treating psoriasis.
  • agents include anthralin (dihydroxyanthralin), azarabine, colchicine, fluorouracil, methotrexate, methoxsalen (8- methoxypsoralen), resorcinol, retinoids (for example, retinoic acid), corticosteroids (for example, clobetasol propionate, triamcinolone acetonide and the like), cyclosporin, lipoxygenase inhibitors, cyclooxyge ⁇ ase inhibitors, leukotriene synthesis inhibitors, iodochlorhydroxyquin, salicylic acid, vitamin D, dapsone, somatostatin, sulfur, tars, zinc oxide, ultra-violet light treatment (UVA or UVB) and PUVA treatment.
  • UVA or UVB ultra-violet light treatment

Abstract

The present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treatment of psiorasis.

Description

PSORIASIS TREATMENT
This is a continuation-in-part of U.S. Patent Application Serial No. 678,111, filed April 4, 1991 , which is a continuation-in-part of U.S. Patent Application Serial No.513,367, filed April 23, 1990. Technical Field
The present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treatment of psoriasis.
Background Art
Psoriasis is a chronic skin disease which is known to be difficult to treat. Psoriasis is characterized by discrete and confluent, reddish, silvery-scaled maculopapules. These psoriatic lesions occur most often on the elbows, knees, trunk and scalp. Current treatments for psoriasis include the use of agents such as anthralin (dihydroxyanthralin), azarabine, colchicine, fluorouracil, methotrexate, methoxsalen (8-methoxypsoraien), resorcinol, retinoids (for example, retinoic acid), corticosteroids (for example, clobetasol propionate, triamcinolone acetonide and the like), cyclosporin, iodochlorhydroxyquin, salicylic acid, vitamin D, dapsone, somatostatin, sulfur, tars and zinc oxide. Ultra-violet light treatment, alone or in combination with other agents such as psoralen (i.e., PUVA treatment), is also used to treat psoriasis.
There are reports that the activity of the renin-angiotensin-aldosterone system is enhanced in patients with psoriasis (Ena, et al., Acta Cardiologica XL 199 (1985); Ryder, et al., Clin. Chem. Acta 153 143 (1985)). However, there is no established cause and effect relationship between the renin-angiotensin-aldosterone system and psoriasis.
Renin is a proteolytic enzyme synthesized and stored principally in the specific part of the kidney called the juxtaglomerular apparatus. Inhibitors of renin have been disclosed as agents for the treatment of hypertension, congestive heart failure and glaucoma.
Disclosure of the Invention
It has now been discovered that renin inhibitors are useful for the treatment of psoriasis.
Examples of renin inhibitors and the methods for preparing the renin inhibitors include, but are not limited to, those disclosed in the following references, which are hereby incorporated by reference.
References Disclosing Renin Inhibiting Compounds
1. Luly, et al., U.S. Patent No. 4,652,551 , issued March 24, 1987.
2. Luly, et al., U.S. Patent No. 4,645,759, issued February 24, 1987.
3. Luly, et al., U.S. Patent No. 4,680,284, issued July 14, 1987.
4. Luly, et al., U.S. Patent No. 4,725,583, issued February 16, 1988.
5. Luly, et al., U.S. Patent No. 4,725,584, issued February 16, 1988.
6. Riniker, et al., U.S. Patent No. 4,595,677 issued June 17, 1986. 7. Fuhrer, et al., U.S. Patent No. 4,613,676, issued September 23, 1986.
8. Buhlmayer, et al., U.S. Patent No. 4,727,060, issued February 23, 1988.
9. Buhlmayer, et al., U.S. Patent No. 4,758,584, issued July 19, 1988.
10. lizuka, et al., U.S. Patent No. 4,656,269, ssued April 7, 1987.
11. lizuka, et al., U.S. Patent No. 4,711,958, ssued December 8, 1987.
12. Veber, et al., U.S. Patent No. 4,384,994, ssued May 24, 1983.
13. Boger, et al., U.S. Patent No. 4,470,971, ssued September 11 , 1984.
14. Boger, et al., U.S. Patent No. 4,477,440, ssued October 16, 1984.
15. Boger, et al., U.S. Patent No. 4,477,441 , ssued October 16, 1984.
16. Veber, et al., U.S. Patent No. 4,479,941 , ssued October 30, 1984.
17. Boger, et al., U.S. Patent No. 4,485,099, ssued November 27, 1984.
18. Boger, et al., U.S. Patent No. 4,668,663, ssued May 26,1987.
19. Boger, et al., U.S. Patent No. 4,665,052,issued May 12,1987.
20. Bock, et al., U.S. Patent No. 4,636,491, issued November 3, 1987.
21. Boger, et al., U.S. Patent No. 4,661,473, issued April 28, 1987.
22. Bock, et al., U.S. Patent No. 4,663,310, issued May 5, 1987.
23. Evans, et al., U.S. Patent No. 4,609,641, issued September 2, 1986.
24. Evans, et al., U.S. Patent No. 4,665,055, issued May 12, 1987.
25. Boger, et al., U.S. Patent No. 4,668,770, issued May 26, 1987.
26. Boger, U.S. Patent No. 4,743,584, issued May 10, 1988.
27. Raddatz, et al., U.S. Patent No. 4,666,888, issued May 19, 1987.
28. Holzemann, et al., U.S. Patent No. 4,709,010, issued November 24, 1987.
29. Raddatz, et al., U.S. Patent No. 4,721 ,776, issued January 26, 1988.
30. Raddatz, et al., U.S. Patent No. 4,755,592, issued July 5, 1988.
31. Hoover, U.S. Patent No. 4,599,198, issued July 8, 1986.
32. Bindra, et al., U.S. Patent No. 4,729,985, issued March 8, 1988. 33. Hoover, U.S. Patent No. 4,668,769, issued May 26, 1987.
34. Bindra, et al., U.S. Patent No. 4,749,687, issued June 7, 1988.
35. Matsueda, et al., U.S. Patent No. 4,548,926, issued October 22, 1985.
36. Matsueda, et al., U.S. Patent No.4, 698,329, issued October 6, 1987.
37. Cazaubon, et al., U.S. Patent No. 4,481,192, issued November 6, 1984.
38. Wagnon, et al., U.S. Patent No.4,725,580, issued February 16, 1988.
39. Hansen, et al., U.S. Patent No. 4,510,085, issued April 9, 1985.
40. Hansen, et al., U.S. Patent No. 4,514,332, issued April 30, 1985.
41. Baran, et al., U.S. Patent No. 4,657,931 , issued April 14, 1987.
42. Hansen, et al., U.S. Patent No. 4,722,922, issued February 2, 1988.
43. Ryono, et al., U.S. Patent No. 4,616,088, issued October 7, 1986.
44. Ryono, et al., U.S. Patent No. 4,665,193, issued May 12, 1987.
45. Ryono, et al., U.S. Patent No. 4,629,724, issued December 16, 1986.
46. Natarajan, et al., U.S. Patent No.4,757,050, issued July 12, 1988.
47. Gordon, U.S. Patent No. 4,749,781, issued June 7, 1988.
48. Szelke, et al., U.S. Patent No.4,609,643, issued September 2, 1986.
49. Szelke, et al., U.S. Patent No. 4,650,661, issued March 17, 1987.
50. Szelke, et al., U.S. Patent No. 4,713,445, issued December 15, 1987.
51. Thaisrivongs, U.S. Patent No. 4,705,846, issued November 10, 1987.
52. Hudspeth, et al., U.S. Patent No. 4,735,933, issued April 5, 1988.
53. Hudspeth, et al., U.S. Patent No. 4,743,585, issued May 10, 1988.
54. Sham, U.S. Patent No. 4,826,958, issued May 2, 1989.
55. Rosenberg, et al., U.S. Patent No. 4,857,507, issued August 15, 1989.
56. Luly, et al., U.S. Patent No. 4,826,815, issued May 2, 1989.
57. Rosenberg, et al., U.S. Patent No. 4,837,204, issued June 6, 1989.
58. Luly, et al., U.S. Patent No. 4,845,079, issued July 4, 1989. 59. Bender, et al., U.S. Patent No. 4,818,748, issued April 4, 1989.
60. Kleinman, et al., U.S. Patent No. 4,729,985, issued March 8, 1988.
61. Hoover, et al., U.S. Patent No. 4,814,342, issued March 21 , 1989.
62. Wagnon, et al., U.S. Patent No. 4,746,648, issued May 24, 1988.
63. Natarajan, et al., U.S. Patent No. 4,757,050, issued July 12, 1988.
64. Patel, U.S. Patent No. 4,820,691 , issued April 11, 1989.
65. Kaltenbronn, et al., U.S. Patent No. 4,804,743, issued February 14, 1989.
66. Pinori, et al., U.S. Patent No. 4,560,505, issued December 24, 1985.
67. Yamato, et al., U.S. Patent No. 4,683,220, issued July 28, 1987.
68. Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989.
69. Patchett, et al., U.S. Patent No. 4,839,357, issued June 13, 1989.
70. Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989.
71. Veber, et al., U.S. Patent No. 4,478,826, issued October 23, 1984.
72. Raddatz, et al., U.S. Patent No. 4,812,555, issued March 14, 1989.
73. Wagnon, et al., U.S. Patent No. 4,840,935, issued June 20, 1989.
74. lizuka, et al., U.S Patent No. 4,841,067, issued June 20, 1989.
75. Raddatz, et al., U.S. Patent No. 4,829,053, issued May 9, 1989.
76. Huang, et al., U.S. Patent No. 4,874,745, issued October 17, 1989.
77. Wagner, et al., U.S. Patent No. 4,855,286, issued August 8, 1989.
78. Hoover, U.S. Patent No. 4,855,303 issued August 8, 1989.
79. lizuka, et al., U.S. Patent No. 4,853,463 issued August 1 , 1989.
80. Hoover, et al., U.S. Patent No. 4,859,654, issued August 22, 1989.
81. Fuhrer, et al., U.S. Patent No. 4,863,903, issued September 5, 1989.
82. lizuka, et al., U.S. Patent No. 4,863,904, issued September 5, 1989.
83. Hudspeth, et al., U.S. Patent No. 4,863,905, issued September 5, 1989.
84. Thaisrivongs, U.S. Patent No. 4,864,017, issued September 5, 1989. 85. Hudspeth, et al., U.S. Patent No. 4,895,834, issued January 23, 1990.
86. Hester, et al., U.S. Patent No. 4,880,781 , issued November 14, 1989. 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. 4,857,507, issued August, 15, 1989; U.S. Patent No. 4,826,958, issued May 2, 1989; U.S. Patent No. 4,837,204, issued June 6, 1989; U.S. Patent No. 4,845,079 issued July 4, 1989, all of which are hereby incorporated by reference. Preferred 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 132,356, filed December 18, 1987 (WO88/05050, published July 14, 1988); PCT/US89/04385, filed October 3, 1989 (WO90/03971 , published April 19, 1990); PCT/US89/04649, filed October 18, 1989 (WO90/04917, published May 17, 1990); and USSN 564,925, filed August 9, 1990 all of which are hereby incorporated by reference.
The preferred renin inhibiting compounds of this invention are selected from the group consisting of compounds of the formula:
Figure imgf000008_0001
wherein A is hydrogen, loweralkyl, arylalkyl, -OR^ wherein R^ is hydrogen, or loweralkyl, -NR21 R wherein R21 and \-\__ are independently selected from hydrogen and loweralkyl; or A is
Figure imgf000009_0001
wherein B is NH, O, CH2 or NHCH2; and R23 is loweralkyl, alkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, carboxyalkyi, alkoxycarbonyalkyl, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;
W is C = 0, CH2 or CHOH;
U is CH2 or NR2 wherein R2 is hydrogen or loweralkyl, provided that when W is CHOH then U is CH2;
R, is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxy benzyl, halobenzyl, (l -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R. is phenoxy, thiophenoxy or anilino, then B is CH2 or A is hydrogen;
R3 is loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R5 is hydrogen or loweralkyl; R6 is loweralkyl, cycloalkylmethyl, or benzyl;
R7, R8 and R9 are hydrogen or loweralkyl and may be the same or different; V is NH, 0,S,SO,S02 or CH2;
R10 is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or V and R10 taken together are N3; with the proviso that R10 may be an N-protecting group only when V is NH; (2).
Figure imgf000010_0001
wherein Ab is hydrogen, loweralkyl, arylalkyl, OR20b or SRgob wherein R^b is hydrogen, loweralkyl or aminoalkyi, NR21b R^b wherein R21b and R^b are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or Ab is
Figure imgf000010_0002
wherein Bb is NH, alkylamino, S, O, CH2 or CHOH; and R23b is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, aikylaminoalkyl, carboxyalkyi, alkoxycarbonylalkyl,
(N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi, (heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;
Wb is C = O or CHOH;
Ub is CH2 or NR26 wherein R2b is hydrogen or loweralkyl, provided that when Wb is
CHOH then Ub is CH2;
R1b is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxy benzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl,
(4-imidazolyl)methyi, (alpha,alpha)-dimethylbeπzyl,
1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R1b is phenoxy, thiophenoxy or anilino, then Bb is CH2 or CHOH or
Ab is hydrogen;
R3b is loweralkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl;
R5b is hydrogen or loweralkyl;
R6b is loweralkyl, cycloalkylmethyl, or benzyl;
R10b is loweralkyl, cycloalkyl,
(cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group, or Lb and R10b taken together can be N3, with the proviso that when Lt, is NH then R10b is an
N-protecting group;
R13b is CHOH or CO;
R14b is CH2, CF2 or CF with the proviso that when R13b is CO then R14b is CF2;
R15b is CH2, CHR25b wherein R25b is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or R14b and R15b taken together can be
Figure imgf000011_0002
with the proviso that when R14b is CF2 then R15b is CH2; l_b is
Figure imgf000011_0001
wherein R26b is hydrogen or loweralkyl, or NR27bC(0) wherein
R27b is hydrogen or loweralkyl;
(3)-
Figure imgf000012_0001
wherein A is
R23e -^ m. Bc- o wherein Bc is NH, or CH2; and R23o is loweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic;
Wc is C=0;
Uc is NR2c wherein R2c is hydrogen or loweralkyl;
R1c is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxybenzyl, halobenzyl, (l -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl;
R3c is loweralkyl, benzyl or heterocyclic ring substituted methyl; H-m is hydrogen or loweralkyl;
R6c is loweralkyl, cycloalkylmethyl, benzyl, or CH2R24c where R24c is selected from 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl, 1 ,3-dithiolan-2-yl and 1,3-dithian-2-yl; R16c is CH2, CF2 or CHR^ where R63c is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl; R17c is hydrogen or loweralkyl;
R18c is loweralkyl or lipophilic or aromatic amino acid side chain; Dc is hydrogen, loweralkyl or -CH2OR28c wherein R28c is hydrogen, loweralkyl or arylalkyl; (4).
Figure imgf000013_0001
wherein Ad is hydrogen, loweralkyl, arylalkyl, -OR20d or -SRgod wherein R^ is hydrogen, loweralkyl or aminoalkyi, -NR21d R^d wherein R21d and R22d are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or Ad is
*23d .B, o r ?23d . ^, Bd- o
wherein Bd is NH, alkylamino, S, O, CH2 or NHCH2, and
R23d is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, ((dialkylamino)alkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, alkylaminoalkyl, carboxyalkyi, alkoxycarbonylalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyi, (heterocyclic) alkyl, or a substituted or unsubstituted heterocyclic; Wd is C = O or CHOH; Ud is CH2 or NR2d wherein R2d is hydrogen or loweralkyl, provided that when Wd is
CHOH then Ud is CH2;
R1d is CHR24d wherein R24d is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,
4-hydroxybenzyl,halobenzyl,(1-naphthyl)methyl,(2-naphthyl)methyl,(4-imidazoyl)methyl,
(alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl, or R1d is C=CHR25d wherein R25d is aryl;
R3d is loweralkyl, alkenyl, benzyl or heterocyclic ring substituted methyl;
R5d is hydrogen or loweralkyl;
R6d is loweralkyl, cycloalkylmethyl, or benzyl;
R11d is hydrogen or hydroxy; n is 0 or 1 ; when n is 0 then Td is alkylidene or alkylidene oxide; and when n is 1 then
Z_ is hydrogen or hydroxy and Td is loweralkyl, hydroxyalkyl, aminoalkyi, haloalkyl, or azidoalkyl;
R12d is hydrogen, loweralkyl, cycloalkylalkyl, arylalkyl, aminoalkyi, or dialkylaminoalkyi;
Figure imgf000014_0001
wherein Ae is hydrogen, loweralkyl, arylalkyl, -OR^ or -SRaoβ wherein R^ is hydrogen, loweralkyl or aminoalkyi, -NR^R^ wherein R21e and R22β are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or Ap is
Figure imgf000015_0001
wherein Be is NH, alkylamino, S, O, CH2 or CHOH; and R23e is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, (dihydroxyalkyl)(alkyl)amino aminoalkyi, N-protected aminoalkyi, alkylaminoalkyl, carboxyalkyi, alkoxycarbonylalkyl
(N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi, (heterocyclic)alkyl, or a substituted o unsubstituted heterocyclic;
WeisC=0;
Ue is NR2e wherein R2θ is hydrogen or loweralkyl; R1e is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxy benzyl, 4-hydroxy benzyl, halobenzyl (1 -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha.alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy o anilino, provided that when R1e is phenoxy, thiophenoxy or anilino, then Be is CH2 o CHOH or Ag is hydrogen;
R3e is loweralkyl, benzyl or heterocyclic ring substituted methyl; R5β is hydrogen or loweralkyl; Ree is loweralkyl, cycloalkylmethyl, or benzyl; Me is O, NH or S;
R10e is hydrogen, loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or an N-protecting group; (6).
Figure imgf000016_0001
wherein A, is hydrogen, loweralkyl, arylalkyl, -OR10f or -SR10f wherein R10f is hydrogen, loweralkyl or aminoalkyi, -NR11f R12f wherein R11f and R12{ are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl, hydroxyalkyl, carboxyalkyi, alkoxycarbonylalkyl, (amino)carboxyalkyl, ((N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl, ((N-protected) alky I amino) carboxyalkyi, (dialkylamino) carboxyalkyi, (amino) alkoxycarbonylal yl, ((N-protected) amino) alkoxycarbonylalkyl, (alkyamino) alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonylalkyl and (dialkylamino)alkoxycarbonylalkyl; or A, is
Figure imgf000016_0002
wherein Bf is NH, alkylamino, S, O, CH2 or CHOH and R23f is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amiπo, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protectedaminoalkyl, alkylamiπoalkyl, (N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyi, carboxyalkyi, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonyalkylamino, (am ino) carboxyal kyl , (amino) carboxyal kylam ino ,
((N-protected)amino)carboxyalkyl, ((N-protected) amino) carboxyalkyamino, (alkylamino)carboxyalkyl,
(alkylamino)carboxyalkylamino, ((N-protected)alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkylamiπo, (dialkylamino)carboxyalkyl, (dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl, (amino)alkoxycarbonylalkylamino,
( ( N - p rote cted ) am in o ) al koxycar bo ny l al ky l , ( ( N - p rote cte d ) a m i n o) - alkoxycarbonylalkylamino,(alkylamino)alkoxycarbonylalkyl, (alkylamino)alkoxycarbonylalkylamino, ((N-protected)alkylamino)- alkoxycarbonylalkyl,
((N-protected)alkylamino)alkoxycarbonyl-alkylamino, (dialkylamino)alkoxycarbonylalkyl, (dialkylamino)alkoxycarbonylalkylamino, aminocycloalkyl, aminoalkylamino, dialkylaminoalkyi (alkyl)amino, arylalkylamino, arylalkyl (alkyl)amino, alkoxyalkyl(alkyl)amino, (polyalkyoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyaikoxy)alkyl)amino, polyalkoxy, (polyalkoxy) alkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic wherein saturated heterocyciics may be unsubstituted, monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyciics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; Wf is C = O or CHOH; U{ is CH2 or NR^ provided that when Wf is CHOH then Uf is CH2 ; R1f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxy benzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl) methyl, (aipha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R1f is phenoxy, thiophenoxy or anilino, then Bf is CH2 or CHOH or A, is hydrogen; R_i is hydrogen or loweralkyl;
R3f is loweralkyl, loweralkenyl,((alkoxy)alkoxy)loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R6f is loweralkyl, cycloalkylmethyl or benzyl; Raf is vinyl, formyl, hydroxymethyl or hydrogen; Rdf is hydrogen or loweralkyl;
Rbf and Ref are independently selected from OH and NH2; and Rcf is hydrogen, loweralkyl, vinyl or arylalkyl; (7).
Figure imgf000018_0001
wherein Ag is hydrogen, loweralkyl, aminoalkyi, (alkyl)aminoalkyl, dialkylaminoalkyi, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyi, (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, naphthylalkyi, (substituted naphthyl)alkyl wherein the naphthyl 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, substituted or unsubstituted heterocyclic, where saturated heterocyciics may be unsubstituted, monosubsituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweralkyl, haloalkyi or polyhaloalkyi; unsaturated heterocyciics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweraklyl, haloalkyi or polyhaloalkyi, or Ag is (unsubstituted heterocyclic) alkyl or (substituted heterocyclic)alkyl wherein unsubstituted or substituted heterocyclic is as defined above, or Ag is -OR7g or -SR7g wherein R7g is hydrogen, loweralkyl, aminoalkyi, (alkyl)aminoalkyl, dialkylaminoalkyi, (alkoxy)aminoalkyl, (alkoxy) (alkyl)aminoalkyl, phenylalkyi, (substituted phenyl) alkyl wherein substituted phenyl is as defined above, naphthylalkyi, (substituted naphthyl)alkyl wherein the substituted naphthyl is as defined above, substituted or unsubstituted heterocyclic as defined above, (unsubstituted heterocyclic) alkyl or (substituted heterocyclic) alkyl wherein unsubstituted or substituted heterocyclic is as defined above, (unsubstituted heterocyclic) C(O)- or (substituted heterocyclic)C(0)wherein unsubstituted or substituted heterocyclic is as defined above; or Ag is
-NR8gR9g wherein R8g and Rgg are independently selected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyi, cyaπoalkyl and hydroxyalkyl; or Ag is
Figure imgf000019_0001
wherein Bg is NH, alkylamino, S, O, CH2, NHCH2 or CH(OR52g) wherein R52g is hydrogen, loweralkyl or loweralkylcarbonyl, and R10g is hydrogen, loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, alkoxy, alkeπyloxy, hydroxyalkoxy, dihydroxyalkoxy, phenylalkoxy, (substituted phenyl)alkoxy wherein 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 naphthyI)alkoxyalkyl wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl,loweralkylsulfonylalkyl,pheπylthioalkyl,(substitutedphenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyi)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) amino, (dihydroxyaikyl)(alkyl)amino,aminoalkyl,alkoxycarbonylalkyl,carboxyalkyl,(N-protected)- aminoalkyl, alkyiaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyi, (heterocyclic) alkyl, a substituted or unsubstituted heterocyclic as defined above, aminocycloalkyl, aminoalkyiamino, (dialkylaminoalkyi) (alkyl)amino, phenylalkylamino, (substituted phenyl)aIkylamino wherein substituted phenyl is as defined above, naphthylalkylamino, (substituted naphthyl) alkylamino wherein substituted naphthyl is as defined above, (phenylalkyi) (alkyl)amino, ((substituted phenyl)alkyl)(alkyl)amino wherein substituted phenyl is as defined above, (naphthylalkyi) (alkyl)amino, ((substituted naphthyl)alkyl)(alkyl)amino wherein substituted naphthyl is as defined above, alkoxyalkyl(alkyl)amino, (polyalkoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, ((heterocyclic)alkyl)(alkyl)amino, ((heterocyclic)alkyl)amino, (heterocyclic) (alkyl)amino, ( al kyi am i n o al kyl ) (al ky I ) am i n o , (d i al kyl am i n o al ky i ) (al yl ) am i n o , ((alkoxy)(aikyl)aminoalkyl)(alkyl)amino, ((alkoxy)aminoalkyl)(alkyl)amino, polyalkoxy or (polyalkoxy)alkyl; or Ag is R41gCH(OH)CH2- or R41gCH(OH)CH(OH)- wherein R41g is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, phenylalkyi, (substituted phenyl)alkyl wherein substituted phenyl is as defined above, naphthylalkyi, (substituted naphthyl)alkyl wherein substituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl)aikoxyalkyl wherein substituted phenyl is as defined above, naphthylalkoxyalkyl, (substituted naphthyl) alkoxyalky I wherein substituted naphthyl is as defined above, thioalkoxyalkyl, loweralkylsulfinylalkyl,loweralkylsulfoπylalkyl,phenylthioalkyl,(substitutedphenyl)thioalkyl wherein substituted phenyl is as defined above, naphthylthioalkyl, (substituted naphthyl)thioalkyl wherein substituted naphthyl is as defined above, phenylsulfonylalkyl, (substituted phenyl)sulfonylalkyl wherein substituted phenyl is as defined above, naphthylsulfonylalkyl, (substituted naphthyl)sulfonylalkyl wherein substituted naphthyl is as defined above, aminoalkyi, alkoxycarbonylalkyl, carboxyalkyi, (N-protected)aminoalkyl, alkyiaminoalkyl, (N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi, heterocyclicalkyl, a substituted or unsubstituted heterocyclic as defined above, aminocycloalkyi or (polyalkoxy) alky I;
Wg is C = 0, CHOH or NR2g wherein R2g is hydrogen or loweralkyl;
Ug is C = 0, CH2 or NR2g wherein R2g is hydrogen or loweralkyl, with the proviso that when Wg is CHOH then Ug is CH2 and with the proviso that Ug is C = 0 or CH2 when Wg is NR2g;
Vg is CH, C(OH) or C(halogen) with the proviso that Vg is CH when Ug is NR2g;
R1g is loweralkyl, cycloalkylalkyl, benzyl, (alpha, alpha)-dimethylbenzyl, 4-methoxy benzyl, halobenzyl, 4-hydroxy benzyl, (l-naphthyl)methyl, (2-naphthyl) methyl, (unsubstituted heterocyclic) methyl, (substituted heterocyclic) methyl wherein unsubstituted or substituted heterocyclic is as defined above, phenethyl, 1-beπzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that Bg is CH2 or CHOH or Ag is hydrogen when R1g is phenoxy, thiophenoxy or anilino;
R3g is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyi, (thioalkoxy)alkyl, azidoalkyl, aminoalkyi, (alkyl)aminoalkyl, dialkylaminoalkyi, (alkoxy)(alkyl)aminoalkyl,
(alkoxy)aminoalkyl, benzyl or heterocyclic ring substituted methyl;
R4g is loweralkyl, cycloalkylmethyl or benzyl;
R5g is OH or NH2; and
Zg is
Figure imgf000022_0001
wherein Mg is O, S or NH, Tg is C = 0, C = S, S, S(O),
S(0)2 or CH2, Eg is O, S, NReg wherein Rgg is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, or alkylamino, or Eg is CR6gR42g wherein R^ is as defined above and R42g is hydrogen or loweralkyl or Eg is C = CR43gR44g wherein R^ and R44g are independently selected from hydrogen and loweralkyl, Gg is absent, CH2 or NR11g wherein R11g is hydrogen or loweralkyl, with the proviso that when Gg is NR11g then R^ is loweralkyl or hydroxyalkyl, Qg is CR45gR46g wherein R45g and R46g are independently selected from hydrogen and loweralkyl or Qg is C = CR47gR48g wherein R47g and R48g are independently selected from hydrogen and loweralkyl, and R49g is -CH2OH, carboxy, alkoxycarbonyl or -CONR50gR51g wherein R50g is hydrogen or loweralkyl and R51g is hydrogen, loweralkyl, aminoalkyi, alkyiaminoalkyl, dialkylaminoalkyi or alkoxyalkyl;
Figure imgf000023_0001
Figure imgf000023_0003
wherein Ah is hydrogen, loweralkyl, arylalkyl, -OR20h or -SR20h wherein R20h is hydrogen, loweralkyl or aminoalkyi, -NR^R^ wherein R21h and R-_,h are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl and hydroxyalkyl; or Ah is
Figure imgf000023_0002
wherein Bh is NH, alkylamino, S, O, CH2 NHCH2 or CHOH; and R23h is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, ((dialkylamino)alkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyi, N-protected aminoalkyi, alkyiaminoalkyl, (N-protected) (alkyl)aminoalkyl, dialkylaminoalkyi
(heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;
WhisC = OorCHOH;
Uh is CH2 or NR2h wherein R2h is hydrogen or loweralkyl, provided that when Wh is CHOH then Uh is CH2;
R1h is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl
(1 -naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl
(alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy o anilino, provided that when R1h is phenoxy, thiophenoxy or anilino, then Bh is CH2 o
CHOH or Ah is hydrogen;
R3h is loweralkyl, loweralkenyl, ((alkoxy) alkoxy) alkyl, carboxyalkyi, (thioalkoxy) alkyl benzyl or heterocyclic ring substituted methyl;
R5h is hydrogen or loweralkyl;
R6h is loweralkyl, cycloalkylmethyl, or benzyl;
(9).
Figure imgf000024_0001
wherein Aj is
(I) R5iC(0)-(CH2)w- wherein 1) w" is 0 to 4 and
2) R5i is i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino;
(II) alkylsulfonyl, (aryl)sulfonyl or (heterocycl ic) sulf onyl ;
(III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyl; or
(IV) Rgor or R90iNHC(O)- wherein R^ is a C, to C4 straight or branched carbon chain substituted by a substituent selected from
1) carboxy,
2) alkoxycarbonyl,
3) alkylsulfonyl,
4) aryl,
5) arylsulfonyl,
6) heterocyclic or
7) (heterocyclic)sulfonyl); R1f is
(I) hydrogen
(II) loweralkyl,
(III) loweralkenyl,
Figure imgf000026_0001
Figure imgf000027_0002
Figure imgf000027_0001
wherein R4i is
(I) loweralkyl,
(II) cycloalkylalkyl
(III) cycloalkenylalkyi or (IV) arylalkyl; and
Figure imgf000028_0001
Figure imgf000028_0002
c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and
4) G, is i) absent, ii) CH2 or iii)NR19i wherein R19i is hydrogen or loweralkyl, with the proviso that when Gj is NR19i, then R18i is loweralkyl or hydroxyalkyl;
(III)
Figure imgf000029_0001
wherein
1) v" is 0 or 1 and
2) R21i is i) NH, ϋ) O, iii) S or iv) S02; or (IV) a substituted methylene group; and
Figure imgf000029_0002
Figure imgf000030_0001
xii) substituted loweralkyl wherein the substituent is selected from alkoxy, thioalkoxy, halogen, alkylamino, (N-protected) (alkyl)amino and dialkylamino,
Figure imgf000031_0001
wherein m'" is 1 to 5 and R7j is hyαrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected)amino, alkylamino, (N-protected) (alkyl)amino or dialkylamino; or
Figure imgf000031_0002
wherein R8j is O, S, S02, 0 = C or R9jN wherein R9j is hydrogen, loweralkyl or an N-protecting group; and 2) Qj is i) C = O or ii) CH2. with the proviso that Xs is N when R^ is an N-protecting group; (VII) R54jS(0)2- wherein R54j is
1) amino
2) alkylamino,
3) dialkylamino,
4) loweralkyl,
5) haloalkyi,
6) aryl,
7) p-biphenyl,
8) heterocyclic or
VIII) (R55j)2P(0)- wherein R55j is
Figure imgf000032_0001
(I) hydrogen,
(II) loweralkyl, (lll)cycloalkylalkyl,
(IV) -CH2-R10j-(CH2)q."-R11j wherein
1) q'" is 0, 1 or 2,
2) R10j is absent or R10j is 0, NH or S only when q'" is 1 or 2, and
3) R„j is i) aryl or ii) heterocyclic;
Z,- is (I) hydrogen or
(II) -R28jC(0)R29j. -R28jS(0)2R29j or -R28jC(S)R29j wherein
1) R28j is i) NH, ii) -N(R200j)- wherein R200j is loweralkyl or benzyl or iii) CH2 and
2) R29j is i) alkoxy, ii) benzyloxy, iii) alkylamino, iv) dialkylamino, v) aryl or vi) heterocyclic;
R3j is
(I) hydrogen,
(II) loweralkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyi, (Vl)alkoxyalkyl (Vll)thioalkoxyalkyl, (VIII)(alkoxyalkoxy)alkyl,
(IX) (polyalkoxy)alkyl,
(X) arylalkyl or
(XI) (heterocyclic)alkyl;
Figure imgf000034_0001
iii)CHR61j wherein R61j is
Figure imgf000035_0001
(IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof.
The term "loweralkyl" as used herein 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-methyl butyl, 2,2-dimethylpropyl, n-hexyl, 2-methyl-pentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl and the like.
The term "loweralkenyl" as used herein refers to a straight or branched chain loweralkyl radical which contains at least one carbon-carbon double bond.
The term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon atoms.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl residue appended to a loweralkyl radical and includes but is not limited to cyclohexylmethyl and cyclopentylmethyl.
The term "cycloalkenyl" as used herein 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.
The term "cycloalkenylalkyi" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical including, but not limited to, cyclohexenylmethyl, cylcopentenylethyl and the like.
The term "arylalkyl" as used herein 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.
The term "phenylalkyi" as used herein refers to a phenyl group appended to a loweralkyl radical, including, but not limited to benzyl, phenethyl and the like.
The term "(substituted phenyl)alkyl" as used herein refers to a substituted phenyl group appended to a loweralkyl radical wherein the phenyl ring is 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 halobenzyl, alkoxybenzyl and the like.
The term "naphthylalkyi" as used herein refers to a naphthyl group appended to a loweralkyl radical, including, but not limited to 1-naphthylmethyl, 2-naphthylmethyl and the like.
The term "(substituted naphthyl)alkyl" as used herein 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, loweralkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to halonaphthylmethyl, alkoxynaphthylmethyl and the like.
The term "(heterocyclic) alkyl" as used herein refers to an unsubstituted or substituted heterocyclic ring as defined below appended to a loweralkyl radical, including, but not limited to imidazolylmethyl, thiazolylmethyl and the like.
The term "hydroxyalkyl" as used herein refers to -OH appended to a loweralkyl radical.
The term "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical.
The term "arylalkoxyalkyi" as used herein refers to an arylalkoxy appended to a loweralkyl radical.
The term "phenylaikoxyalkyl" as used herein refers to a phenylalkoxy group appended to a loweralkyl radical, including, but not limited to phenylmethoxymethyl and the like. The term "(substituted phenyl)alkoxyalkyl" as used herein refers to a (substituted phenyl)alkoxy group appended to a loweralkyl radical, including, but not limited to 4-chlorophenylmethoxymethyl.
The term "naphthylalkoxyalkyl" as used herein refers to a naphthylalkoxy group appended to a loweralkyl radical, including, but not limited to 1-naphthylmethoxymethyl and the like.
The term "(substituted naphthyl)alkoxyalkyl" as used herein refers to a (substituted naphthyl) alkoxy group appended to a loweralky radical, including, but not limited to halonaphthylmethoxymethyl and the like.
The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group appended to a loweralkyl radical.
The term "((alkoxy)alkoxy)alkyl" as used herein 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.
The term "polyalkoxyalkyl" as used herein refers to a polyalkoxy residue appended to a loweralkyl radical, including, but not limited to methoxyethoxymethoxymethyl and the like.
The term "aminoalkyi" as used herein refers to -NH2 appended to a loweralkyl radical.
The term "alkyiaminoalkyl" as used herein refers to -NHR70 appended to a loweralkyl radical, wherein R70 is a loweralkyl radical.
The term "dialkylaminoalkyi" as used herein refers to a dialkylamino appended to a loweralkyl radical.
The term "aminocycloalkyi" as used herein refers to an -NH2 appended to a cycloalkyl radical.
The term "N-protected aminoalkyi" as used herein refers to -NHR71 appended to a loweralkyl group, wherein R71 is an N-protecting group.
The term " (N-protected) (alkyl)amino alkyl" as used herein refers to -NR71R72 which is appended to a loweralkyl radical, wherein R71 is defined as above and R7 is a loweralkyl group.
The term "alkoxycarbonylalkyl" as used herein refers to R73C(0)R74- wherein R73 is an alkoxy group and R74 is a loweralkyl radical.
The term "carboxyalkyi" as used herein refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
The term "cyanoalkyl" as used herein refers to -CN appended to a loweralkyl radical.
The term "azidoalkyl" as used herein refers to -N3 appended to a loweralkyl radical.
The term "(alkoxy)aminoalkyl" as used herein refers to an alkoxy group appended to an amino group which in turn is appended to a loweralkyl radical.
The term " (alkoxy) (alkyl)aminoalkyl" as used herein refers to an -NR75R76 group appended to a loweralkyl radical wherein R75 is an alkoxy group and R76 is a loweralkyl group.
The term "loweralkylsulfinylalkyl" as used herein refers to a R77S(0)- group appended to a loweralkyl radical wherein R^ is a loweralkyl group.
The term "loweralkylsulfonylalkyl" as used herein refers to a R78S(0)2- group appended to a loweralkyl radical wherein R78 is a loweralkyl group.
The term "phenylthioalkyl" as used herein refers to a R79S- group appended to a loweralkyl radical wherein R79 is a phenyl group.
The term "(substituted phenyl)thioalkyl" as used herein refers to a R80S- group appended to a loweralkyl radical wherein R80 is a substituted phenyl group.
The term "naphthyl thioalkyl" as used herein refers to a R81S- group appended to a loweralkyl radical wherein R81 is a naphthyl group.
The term "(substituted naphthyl)thioalkyl" as used herein refers to a R82S- group appended to a loweralkyl radical wherein R82 is a substituted naphthyl group.
The term "phenylsulfonylalkyl" as used herein refers to a R83S(0) 2- group appended to a loweralkyl radical wherein R^ is a phenyl group.
The term "(substituted phenyl)sulfonylalkyl" as used herein refers to a R84S(0)2- group appended to a loweralkyl radical wherein R84 is a substituted phenyl group.
The term "naphthylsuifonylalkyl" as used herein refers to a R85S(0)2- group appended to a loweralkyl group wherein R85 is a naphthyl group.
The term "(substituted naphthyl)sulfonylalkyl" as used herein refers to a R86S(0)2- group appended to a loweralkyl group wherein Rse is a substituted naphthyl group.
The term "carboxyalkoxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.
The term "alkoxycarbonylalkoxyalkyl" as used herein refers to an alkoxycarbonyl group (R87CO- wherein R87 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
The term "(amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH^.
The term "((N-protected)amino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR88 wherein R88 is an N-protecting group. The term "(alkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an alkylamino group.
The term "((N-protected)alkylamino)-carboxyalkyP as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NRggRgo wherein R89 is as defined above and Rgo is a loweralkyl group.
The term "(dialkylamino)carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR91R92 wherein R91 and R92 are independently selected from loweralkyl.
The term "(amino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH2).
The term "((N-protected)amino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR93 wherein Rg3 is as defined above.
The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
The term "((N-protected)alkylamino)alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR94R95 wherein R^ is an N-protecting group and R95 is a loweralkyl group.
The term "(dialkylamino)alkoxycarbonyalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR96R97 wherein R96 and R97 are independently selected from loweralkyl.
The term "carboxyalkylamino" as used herein refers to -NHR98 wherein R98 is a carboxyalkyi group.
The term "alkoxycarbonylalkylamino" as used herein refers to -NHR99 wherein Rg9 is an alkoxycarbonylakyl group.
The term "(amino)carboxyalkylamino" as used herein refers to -NHR100 wherein R100 is an (amino)carboxyaikyl group.
The term "((N-protected)amino)carboxyalkylamino" as used herein refers to -NHR101 wherein R101 is an ((N-protected)amino)carboxyalkyl group.
The term" (alkylamino)carboxyalkylamino" as used herein refers to -NHR102 wherein R102 is an (alkylamino)carboxyalkyl group.
The term "((N-protected)alkylamino)-carboxyalkylamino" as used herein refers to -NHR103 wherein R103 is an ((N-protected)alkylamino)carboxyalkyl group.
The term "(dialkylamino)carboxyalkylamino" as used herein refers to -NHR104 wherein R104 is a (dialkylamino)carboxyalkyl group.
The term"(amino)aIkoxycarbonylalkylamino" as used herein refers to -NHR105 wherein R105 is an (amino)alkoxycarbonylalkyl group.
The term "((N-protected)amino)alkoxycarbonylalkylamino" as used herein refers to -NHR106 wherein R106 is an ((N-protected)amino)alkoxycarbonylalkyl group.
The term "(alkylamino)alkoxycarbonylalkylamino" as used herein refers to -NHR107 wherein R107 is an (alkylamino)alkoxycarbonylalkyl group.
The term "((N-protected)alkylamino)alkoxycarbonylalkylamino" as used herein refers to -NHR108 wherein R108 is an ((N-protected)alkylamino)alkoxycarbonylalkyl group.
The term "(dialkylamino)alkoxycarbonylalkylamino" as used herein refers to -NHR109 wherein R109 is a (dialkylamino)alkoxycarbonylalkyl group.
The term "alkylidene" as used herein 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, 1-propylidene, 1-butylidene, 1-pentylidene, 2-propylidene, 2-butylidene, 2-pentylidene, 3-peπtylidene, 3-hexylidene, 3-heptylidene and 4-heptylidene. The term "alkylidene oxide" as used herein refers to an epoxide moiety which is derived from an alkylidene group.
The term "amino" as used herein refers to an -NH2 substituent.
The term "alkylamino" as used herein refers to -NHR110, wherein R110 is a loweralkyl group.
The term "dialkylamino" as used herein refers to -NR^R^ wherein Rι and R112 are independently selected from loweralkyl groups.
The term "arylalkyiamino" as used herein refers to R^NH-, wherein R113 is an arylalkyl residue.
The term "arylalkyl (alkyl)amino" as used herein refers to R114R115N-, wherein R114 is an arylalkyl residue and R115 is a loweralkyl residue.
The term "phenylalkylamino" as used herein refers to a phenylalkyi group appended to an amino radical, including, but not limited to benzylamino and the like.
The term "(substituted phenyl)alkylamino" as used herein refers to a (substituted phenyl)alkyl group appended to an amino radical, including, but not limited to 4-chlorobenzylamino and the like.
The term "napthylalkylamino" as used herein refers to a naphthylalkyi group appended to an amino radical, including, but not limited to 1-naphthylmethylamino and the like.
The term "(substituted naphthyl)alkylamino" as used herein refers to a (substituted naphthyl)alkyl group appended to an amino radical.
The term " (phenylalkyi) (alkyl)amino" as used herein refers to R116R117N-, wherein R116 is a phenylalkyi residue and R117 is a loweralkyl residue.
The term "((substituted phenyl)alkyl)-(alkyl)amino" as used herein refers to Rιi8 Rιi9 N- wherein R118 is a (substituted phenyl)alkyl group and R119 is a loweralkyl group. The term " (naphthylalkyi) (alkyl)amino" as used herein refers to Rι20Rι2ι - wherein R120 is a naphthylalkyi group and R121 is a loweralkyl group.
The term "((substituted naphthyl)alkyl)(alkyl)amino" as used herein refers to R122R123N- wherein R122 is a (substituted naphthyl) alkyl group and R123 is a loweralkyl group.
The term "aminoalkylamino" as used herein refers to R124NH- where R124 is an aminoalkyi residue.
The term "diaIkylamino(alkyi)amino" as used herein refers to R125R126N-, wherein R125 is a dialkylamino residue appended to a loweralkyl residue and R126 is a loweralkyl residue.
The term "((dialkylamino)alkyl)(alkyl)amino" as used herein refers to -NR127R128 wherein R127 is a dialkylamino residue appended to a loweralkyl residue and R128 is a loweralkyl residue.
The term "(hydroxyalkyl) (alkyl)amino" as used herein refers to -NR129 R130 wherein R12 is a hydroxyalkyl group and R130 is a loweralkyl group.
The term "(di-hydroxyalkyl)(alkyl)amino" as used herein 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.
The term "di-(hydroxyalkyl)amino" as used herein refers to R131Rι32N-, wherein R131 and R132 are hydroxyalkyl residues.
The term "alkoxyalkyl(alkyl)amino" as used herein refers to R133Rι3 N-, wherein R133 is a loweralkyl group and R134 is an alkoxyalkyl group.
The term "di-(alkoxyalkyl)amino" as used herein refers to R135R136N-, wherein R135 and R136 are alkoxy residues appended to loweralkyl residues.
The term "di-(polyalkoxyalkyl)amino" as used herein refers to R137 R138N-, wherein R137 and R138 are polyalkoxy residues appended to loweralkyl residues. The term "((polyalkoxy)alkyl)(alkyl)amino" as used herein refers to R13gR1 0N-, wherein R139 is a polyalkoxy residue appended to a loweralkyl radical and R140 is a loweralkyl residue.
The term "((heterocyclic)alkyl)(alkyl)amino" as used herein refers to -NR141R142 wherein R141 is a heterocyclicalkyl group and R142 is a loweralkyl group.
The term "(heterocyclicalkyl)amino" as used herein refers to -NHR143 wherein R143 is a heterocyclic alkyl group.
The term " (heterocyclic) (alkyl)amino" as used herein refers to -NR144R145 wherein R144 is a substituted or unsubstituted heterocyclic group and R145 is a loweralkyl group. The term " (alkyiaminoalkyl) (alkyl)amino" as used herein refers to -NR146R147 wherein R146 is an alkyiaminoalkyl group and R147 is a loweralkyl group.
The term " (dialkylaminoalkyi) (alkyl)amino" as used herein refers to -NR148R149 wherein R148 is a dialkylaminoalkyi group and R149 is a loweralkyl group.
The term "((alkoxy) (alkyl)aminoalkyl)- (alkyl)amino" as used herein refers to -NRι50 R151 wherein R150 is -NR152R153 appended to a loweralkyl radical wherein R152 is an alkoxy group and R153 is a loweralkyl group and R151 is a loweralkyl group.
The term "((alkoxy)aminoalkyl)(alkyl)amino" as used herein refers to -NR154R155 wherein R154 is -NHR156 appended to a loweralkyl group and wherein R156 is an alkoxy group and R155 is a loweralkyl group.
The term "(alkoxyalkoxyalkyl)(alkyl)amino" as used herein refers to -NR305R306 wherein R305 is an alkoxyalkoxyalkyl group and R306 is a loweralkyl group.
The term "di(alkoxyalkoxyalkyl)amino" as used herein refers to -NR307R308 wherein R307 and R308 are alkoxyalkoxyalkyl groups.
The term "alkylsulfonylamino" as used herein refers to R309NH- wherein R309 is an alkylsulfonyl group.
The term "arylsulfonylamino" as used herein efers to R310NH- wherein R310 is an arylsulfonyl group.
The term "alkylaminocarbonylamino" as used herein refers to R311C(0)NH- wherein R311 is an alkylamino group.
The term "aikylaminocarbonyloxy" as used herein refers to R312C(0)0- wherein R312 is an alkylamino group.
The term "alkoxycarbonyloxy" as used herein refers to R313C(0)0- wherein R313 is an alkoxy group.
The term "loweralkylcarbonyl" as used herein refers to R157C(0)- wherein R157 is a loweralkyl group, including, but not limited to acetyl, propionyl and the like.
The terms "alkoxy" and "thioalkoxy" as used herein refer to R1580- and R158S-, respectively, wherein R158 is a loweralkyl group.
The term "alkoxyalkoxy" as used herein refers to an alkoxy group appended to an alkoxy radical including, but not limited to, methoxymethoxy and the like.
The term "aryloxyalkyl" as used herein refers to an aryloxy group (R303θ- wherein R303 is an aryl group) appended to a loweralkyl radical.
The term "thioaryloxyalkyl" as used herein refers to a thioaryloxy group (R^S- wherein R304 is an aryl group) appended to a loweralkyl radical.
The terms "arylalkoxy" and "arylthioalkoxy" as used herein refer to an aryl group appended to an alkoxy radical or a thioalkoxy radical, respectively, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like.
The terms "arylalkoxyalkyi" and arylthioalkoxyalkyi" as used herein refer to an arylalkoxy group or an arylthioalkoxy group, respectively, appended to a loweralkyl radical.
The term "alkenyloxy" as used herein refers to R1590-, wherein R159 is an alkyl group of 1 to 7 carbon atoms which contains at least one carbon-carbon double bond. The term "hydroxyalkoxy" as used herein refers to -OH appended to an alkoxy radical.
The term "dihydroxyalkoxy" as used herein refers to an alkoxy radical which is disubstituted with -OH radicals.
The term "arylalkoxy" as used herein refers to an aryl group appended to an alkoxy radical.
The term "alkylaryloxy" as used herein refers to R1600- wherein R160 is an alkylaryl group.
The term "phenylalkoxy" as used herein refers to a phenyl group appended to an alkoxy radical, including, but not limited to benzyloxy and the like.
The term "(substituted phenyl)alkoxy" as used herein refers to a substituted phenyl group appended to an alkoxy radical, including, but not limited to 4-chlorobenzyloxy and the like.
The term "naphthylalkoxy" as used herein refers to a naphthyl group appended to an alkoxy radical.
The term "(substituted naphthyl)alkoxy" as used herein refers to a substituted naphthyl group appended to an alkoxy radical.
The term "polyalkoxy" as used herein refers to R1610-, wherein R161 is a straight or branched chain containing 1-5, Cm-0-Cm. linkages where m and m' are independently 1 to 3.
The terms "halo" or "halogen" as used herein refer to Cl, Br, F or I substituents.
The term "haloalkyi" as used herein refers to a loweralkyl radical in which one or more hydrogen atomsare replaced by halogen including, but not limited to fluoromethyl, 2-chloroethyl, trifluoromethyl, 2,2-dichloroethyl and the like.
The term "polyhaloalkyi" as used herein refers to a loweralkyl radical substituted with two or more halogens, including, but not limited to trifluoromethyl, 2,2-dichloroethyl and the like.
The term "halobenzyl" as used herein refers to a halo substituent appended to the phenyl ring of a benzyl radical.
The term "halophenyl" as used herein refers to a halo substituent appended to a phenyl radical.
The term "alkylsulfonyl" as use dherein refers to R30oS(0)2- wherein R300 is a loweralkyl group.
The term " (aryl)sulfonyl" as used herein refers to R30ιS(O)2- werein R301 is an aryl group.
The term "(heterocyclic)sulfonyl" as used herein refers to R302S(O)2- wherein R3Q2 is a heterocyclic group.
The term "arylsulfonylalkyl" as used herein refers to an arylsulfonyl group appended to a loweralkyl radical.
The term "aryl" as used herein 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 independently selected from loweralkyl, haloalkyi, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The term "substituted phenyl" as used herein 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. The term "substituted naphthyl" as used herein 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.
The term "alkylaryl" as used herein refers to a loweralkyl group appended to an aryl radical.
The term "heterocyclic group" or "heterocyclic" as used herein 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 nitrogen atoms; or one nitrogen and one oxygen atom; or one nitrogen and one sulfur atom; 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 quatemized, and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring.
Heterocyciics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyciics are also preferred. Preferred heterocyciics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperaziπyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridaziπyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazoiyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, beπzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.
Heterocyciics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo ( = 0), alkylimino (RN = wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, haloalkyi or cycloalkyl. The most preferred heterocyciics include imidazolyl, pyridyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, thiazoiyl, 2-aminothiazolyl, thienyl, triazolyl and the following:
Figure imgf000050_0001
wherein 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,
Figure imgf000050_0002
wherein Y is NH, N-loweralkyl, O, S, or S02, or
Figure imgf000050_0003
wherein the symbols (i), (ii) and (iii) represent 5-membered heterocycles containing one or more heteroatoms and containing 2 double bonds; wherein Z-, is N, O, or S and not the point of connection and Z2 is N when it is the point of connection and NH, O or S when it is not the point of connection; with the proviso that when Z2 is the point of connection, then Z, is N.
The term "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. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise carbamates, amides, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivates, imine derivatives, enamine derivatives and N-heteroatom derivatives. In particular, N- protecting groups include formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and the like. N-protecting groups also include an L- or D- aminoacyl residue, which may itself be N-protected similarly.
The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)) and comprise substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxy methyl, 2-(trimethylsilyl)ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethyisilyl, 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; cyclic boronates and the like. The term "substituted amino" as used herein refers to:
I) alkylamino,
II) dialkylamino,
III) (hydroxyalkyl) (alkyl)amino, IV) (dihydroxyalkyl) (alkyl)amino,
V) alkoxycarbonylalkylamino,
VI) carboxyalkyiamino,
VII) (amino)carboxyalkylamino,
VIII) ((N-protected)amino)carboxyalkylamino,
IX) (alkylamino)carboxyalkylamino,
X) ((N-protected)alkylamino)carboxyalkylamino,
XI) (dialkylamino)caboxyalkylamino,
XII) (amino)alkoxycarbonylalkylamino,
XIII) ((N-protected)amino)alkoxycarbonylalkylamino,
XIV) (alkylamino)alkoxycarbonylalkylamino,
XV) ((N-protected)alkyiamino)alkoxycarbonylalkylamino,
XVI) (dialkylamino)alkoxycarbonylalkylamino,
XVII) (alkoxyalkyl) (alkyl) amino,
XVIII) (alkoxyalkoxyalkyl) (alkyl)amino,
XIX) di-(aikoxyalkyl)amino,
XX) di-(alkoxyalkoxyalkyl)amiπo,
XXI) di-(hydroxyalkyl)amino,
XXII) ((unsubstituted heterocyclic)alkyl)(alkyI)amino,
XXIII) ((substituted heterocyclic)alkyl)(alkyl)amino, XXIV)
(-H2 )._ N—
wherein aa' is 1 to 5 and R6q and R7q are independently selected from
1) hydrogen,
2) hydroxy,
3) alkoxy,
4) thioalkoxy,
5) alkoxyalkoxy,
6) carboxy,
7) alkoxycarbonyl,
8) halogen,
9) amino,
10) alkylamino,
11) dialkylamino,
12) alkylsulfonylamino,
13) arylsulfonylamino,
14) alkylaminocarbonylamino,
15) alkylaminocarbonyloxy,
16) alkoxycarbonyloxy,
17)
Figure imgf000053_0001
wherein dd' is 1 to 5, and 18) R8q-Zq- wherein Zq is O, S or NH and R8q is a C to C6 straight or branched carbon chain substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocyclic; XXV)
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0003
1) hydrogen,
2) loweralkyl,
3) an N-protecting group or
4) R11q- C(0)- wherein R11q is aminoalkyi, (N-protected)aminoalkyl, 1-amino-2-phenylethyl or 1-(N-protected)amino-2- phenylethyl.
The term "substituted methylene group" as used herein refers to: HR13qR14q wherein
Figure imgf000055_0001
i) hydrogen or ii) hydroxy and 2) R14q is i) hydrogen, ii) loweralkyl, iii) hydroxy, iv) hydroxyalkyl, v) alkoxy, vi)alkoxyalkyl, vii) azido, viii) azidoalkyl, ix) amino, x) (N-protected)amino, xi) aminoalkyi, xii) (N-protected)aminoalkyl, xiii) alkylamino, xiv) (N-protected) (alkyl)amino, xv) alkyiaminoalkyl, xvi) (N-protected) (alkyl)-aminoalkyl, xvii) dialkylamino, xviii) dialkylaminoalkyi, xix) carboxyalkyi, xx) thioalkoxy, xxi) thioalkoxyalkyl, xxii) alkylsulfonyl, xxiii) alkylsulfonylalkyl, xxiv) thioaryloxy, xxv) thioaryloxyalkyl, xxvi) arylsulfonyl, xxvii) aryisulfonylalkyl, xxviii) (unsubstituted heterocyclic) alkyl or xxvix) (substituted heterocyclic)alkyl such that when R13q is hydroxy then
R14q is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino,
(N-protected)amino, (N-protected) (alkyl)amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R13q is hydrogen then R14q is not hydrogen or loweralkyl;
(II) -C( = CH2)C(0)NHR15q;
(III) -C(OH)(R16q)C(0)NHR15q or
(IV) -CH(R16q)C(0)NHR15q wherein
1) Rιsq is i) loweralkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyi, v) alkyiaminoalkyl, vi) dialkylaminoalkyi, vii) aryl, viii) heterocyclic or ix) (heterocyclic)alkyl and
2) Rι6q is i) hydrogen, ii) loweralkyl, iii) hydroxyalkyl, iv) haloalkyi or v) azidoalkyl;
(V)
CH2C(0)NH - (CH2)t. -
Figure imgf000056_0001
wherein
1) f is 0 to 3,
2) R20q is i) CH2 or ii) N and
3) R21q is i) NH, ϋ) O, iii) S or iv) S02, such that when t' is 0 then R20q is CH2 and when t' is 1 to 3 then R20q is N, (VI) -CH2CH(R22q)C(0)NHR23q wherein
1)R22q is i) loweralkyl or ii) cycloalkylalkyl and
2) R23q is i) loweralkyl, ii) hydroxyalkyt, iii) alkoxyalkyl, iv) aminoalkyi, v) alkyiaminoalkyl, vi) dialkylaminoalkyi, vii) aryl, viii) arylalkyl ix) heterocyclic, x) (heterocyclic)alkyl or
Figure imgf000058_0001
a) u' is 0 to 3, b) R2 q is CH2 or N and c) R25q is NH, O, S or S02, such that when u' is 0 then R24q is CH2 and when u' is 1 to 3 then R24q is N; (VII)
Figure imgf000058_0002
wherein
1) R 22q is as defined above and
Figure imgf000058_0003
i) hydrogen, ii) loweralkyl, iii)an N-protecting group or iv) R75q-C(0)-wherein R75q is aminoalkyi or (N-protected)aminoaikyl;
(VIII)
Figure imgf000058_0004
wherein
1) R26q is i) loweralkyl or ii) cycloalkylalkyl and
2) R27q is i) loweralkyl or ii) cycloalkylalkyl; (IX) -CH2 CH(R81q)NHC(0)R82q or -CH2CH(R81q)NHS(0)2R82q wherein
Figure imgf000059_0001
i) loweralkyl or ii) cycloalkylalkyl and
2) R82q is i) loweralkyl, ii) alkoxy, iii) alkylamino, iv) dialkylamino, v) -OR* wherein R* is aminoalkyi, alkyiaminoalkyl, dialkylaminoalkyi or (heterocyclic) alkyl or
Figure imgf000059_0002
wherein R21q is as defined above;
(X) -CH2NHC(0)R82q or -CH2NHS(0)2R82q wherein R82q is as defined above; or (XI) -CF2CH(OH)R83q wherein R^ is loweralkyl, loweralkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyenylalkyl, aryl, aryalkyl, heterocyclic or (heterocyclic)alkyl.
The terms "lipophilic or aromatic amino acid side chains" as used herein refer to amino acid side chains selected from the group isobutyl, isopropyl, sec-butyl, benzyl, p-methoxybenzyl, imidazole-4-yl-methyl, p-hydroxybenzyl, 1- and 2-naphthylmethyl, (pyrazolyl) methyl, (thiazolyl)methyl, cyclohexylmethyl, (3-indolyl)methyl, CH3SCH2- and the like. General references to amino acid side chains in both the description and claims herein is to be taken as reference to such, whether naturally occurring in proteins or not, and to both D- and L- forms.
The terms "Ala", "His", "Leu", Phe", "Tyr", "Cys", "Gly", "Lys", "Sar", "Pro", "HomoPhe" and "norLeu" as used herein refer to alanine, histidine, leucine, phenylalanine, tyrosine, cysteine, glycine, lysine, sarcosine, proline, homophenylalanine and norleucine, respectively. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem. 1984, 158, 9-31).
Renin inhibitors having one asymmetric carbon atom can exist as the racemic mixture or as pure enantiomers. Renin inhibitors having two or more asymmetric carbon atoms can exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention includes within its scope all of the isomeric forms. The terms "S" and "R" configuration as used herein are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45. 13-30.
Renin inhibitors having the general structure shown in group (9) can be prepared as described in Fung, et al., PCT Patent Application WO90/03971 (PCT/US89/04385), published April 19, 1990, which is hereby incorporated by reference. The syntheses of segments containing substituents D are described in the Examples or have previously been described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al., J. Med. Chem. 1987, 30, 1609; Buhlmayer, et al., U.S. Patent No. 4,727,060; Morisawa, et al., European Patent Application No. 0228192; Ten Brink, PCT Patent Application No. W087/02986).
Renin inhibitors having the general structure shown in group (10) can be prepared as described in De, et al., PCT Patent Application No. WO90/04917 (PCT/US89/04649), published May 17, 1990, which is hereby incorporated by reference. The syntheses of segments containing substituents R5 are described in the Examples or have previously been described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al., J. Med. Chem. 1987, 30, 1609; Buhlmayer, et al., U.S. Patent No. 4,727,060; Morisawa, et al., European Patent Application No. 0228192; Ten Brink, PCT Patent Application No. W087/02986).
An intermediate useful in the preparation of certain renin inhibitors is compound 8 (Scheme I). Scheme I outlines a process for the preparation of 8. D- Isoascorbic acid (I) can be converted to the known lactol 3 (J.Am.Chem.Soc.105 3661 (1983)). Reaction with 2-isopropylidene triphenylphosphorane provides alcohol 4. Oxidation to aldehyde 5, followed sequentially by reaction with benzylamine and cyclohexylmagnesium bromide/CeCI3, provides amine 7. Deprotection of the amino group, reduction of the olefin and removal of the acetonide protecting group provides
8.
An alternative preparation of the reduced form of compounds 5 (i.e., 13) is shown in Scheme II. Epoxyalcohol 10 (J.Am.Chem.Socl09 1525 (1987)) can be protected and then reacted with isopropyl grignard to provide H. Reaction with camphorsulfonic acid (CSA), followed by ozonolysis, gives the aldehyde 13.
Scheme
1. H 2,O^2-
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0003
= benzyl
Scheme II
Figure imgf000063_0001
Figure imgf000063_0002
1 2
1 3
Another intermediate useful in the preparation of certain renin inhibitors is compound 21 (Scheme III). Reaction of aldehyde 14 with n-butyl magnesium bromide, followed by oxidative resolution, provides 15 as a single enantiomer.
Reaction of the alcohol 15 with bromoacetic acid, optionally followed by esterification provides 16 or 17. Alternatively, reaction with t-butyl bromoacetate provides 18.
Alkylation with benzylbromide provides a mixture of 19 and the desired 20, which can be separated from the mixture. Hydrogenoiysis or hydrolysis of the ester, coupling with 4-methoxymethoxypiperidine and oxidation provides the desired carboxylic acid
£1-
Scheme III
Figure imgf000064_0001
16 R = H
17 R = CH(P )2
1 8 R « t-Butyl
σ"f
Figure imgf000064_0002
DBU. acloπitnla oV 2 1
1 9 - 2 0
1 : 2
Reagents: a) π-BuMgBr, b) (-) DIPT t-BuOOH Ti(OCH(CH3)2)4, c) NaH BrCH2C02H, d) CH2N2 or C(Ph)2N2, e) KN(TMS)2 BrCH2CO2t-Bu, f) NaN(TMS)2 BnBr, g) when R = CH(Ph)2
H2 Pd/C, when R = t-Bu HCI methanol, h) EDC 4-methoxymethoxypiperidine, i) O3 or NaiO
RuCI3 The following examples will serve to further illustrate preparation of the compounds of the invention.
Example 1 2(S 1 (SH4-(Methoxymethoxy)piperidin-1-v0carbonyl-2- phenvπethoxyhexanoic acid amide of 3-(4- morphormvDpropyl-5fS)-amino-6-cvclohexyl-4(S)-hvdroxy-
2(S)-isopropylhexanamide
Example 1 A: 4(SH-Butyloxycarbonylamino-5-cvclohexyl-3( R.S)-hvdroxy-1 -pentene
To a stirred -78° C solution of Boc-cyclohexylalanine methyl ester ( 0.2 g, 35.8 mmol) in dry toluene (60 ml) was added diisobutylaluminum hydride (34 ml of a 1.5 M solution in toluene). After 30 min, vinyl magnesium bromide (108 ml of 1 M solution in tetrahydrofuran (THF)) was added. After stirring for 15 h at 0°c, the mixture was carefully quenched with methanol, treated with Rochelle salts (22 ml of saturated aqueous solution in 140 ml H20), and filtered. After extracting the solids 5 times with ethyl acetate, the extracts and filtrate were combined and the organic phase was washed with brine, dried, filtered and evaporated to an oil (10.2 g). Chromatography on silica gel eluting with hexane/ethyl acetate mixtures provided 6.1 g of the desired product. Anal, calcd. for C^H∞NOg .1/4 H20: C, 66.8; H, 10.3; N, 4.9. Found: C, 66.9; H, 10.2; N, 4.7.
Example 1B: 3-(t-ButyloxycarbonvD-4-(cvclohexylmethvπ-2. 2-dimethyl-5-vinyloxazolidine. The procedure of S. Thaisrivong (J. Med. Chem. 1987, 30, 976) was employed. A solution of 40 g of the resultant compound of Example 1A and 102 g of 2-methoxy- propene in 250 ml of dichloromethane was stirred at room temperature. Solid pyridinium p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After addition was complete, the reaction was stirred for 1 h and neutralized by addition of solid sodium bicarbonate. The solids were filtered and the filtrate was concentrated. Flash chromatography on silica gel gave 57 g of the desired compound. IR(CDCl 3 ) 1690 (C = 0 carbamate)cm"1; 1HNMR (CDCI3) 5.95 (m,IH), 5.32 (m,IH), 5.20 (dt,IH), 4.27 (dd,IH), 1.47 (s,9H). Anal. Calcd. for C19H33 N03 C, 70.55; H, 10.28; N, 4.33. Found: C, 70.47; H, 10.27; N, 4.09.
Example 1C: 3-(t-ButyloxycarbonvB-4-(cvclohexylmethvπ- 2.2- dimethvioxazoIidine-5-carboxaldehvde. A solution of 10 g of the resultant compound of Example 1B in 150 ml of 2:1 dichloromethane: methanol was cooled in an dry-ice acetone bath. Ozone was bubbled through the solution until a blue color persisted (1 h). Dry nitrogen was then bubbled through the reaction mixture to remove excess dissolved ozone. The reaction mixture was caπnulated into a suspension of 8 g zinc dust, 8 ml glacial acetic acid, 200 ml water, and 200 ml of methanol cooled to -45° C. After 5 min the bath was removed and the mixture allowed to warm to room temperature overnight. 100 ml of saturated sodium chloride was added and the entire reaction mixture extracted with two 300 ml portions of dichloromethane. The combined dichloromethane extracts were decanted, dried (MgSO 4 ), filtered, and evaporated. The crude aldehyde was purified by flash chromatography (1 :4) ethyl acetate:hexane to give 9.7 g of the desired compound as a mixture of diastereomers (3:1 trans:cis) as judged by the integrated resonances of the two aldehyde protons.
IR(CDCI 3 ) 1735 (C = 0 aldehyde), 1690 (C = 0 carbamate)cm'1; 1 HNMR (CDCI3 9.83
(S,1H,CH0), 9.73
(d,IH,CHO cis diastereomer), 4.14 (m,IH), 1.46 (s,9H).
Anal. Calcd. for C 18H31 N04 C, 66.43; H, 9.60; N, 4.30.
Found: C, 65.27; H, 9.79; N, 4.20.
Equilibration of Aldehyde Isomers
A suspension of 25 g of the above aldehyde in 300 mi of methanol and powdered potassium carbonate (10.7 g) was stirred at room temperature for 6 h. The reaction mixture was cooled in an ice-water bath and treated with 9.3 g of glacial acetic acid for 5 min. A solution of 0.5 M_sodium dihydrogen phosphate (300 ml) was added to the mixture. After 30 min, the solution was concentrated to one-half the volume under reduced pressure and extracted with ether (600 ml). The combined ether extracts were dried (MgS04), filtered, and concentrated. The aldehyde was purified by flash chromatography using (1 :4) ethyl acetate:hexane to give 19.5 g of the desired compound as an 8:1 mixture of trans:cis diastereomers.
Example 1 D: 3-(3(RH3-(tert-Butyloxycarbonvn-2.2 dimethyl-4fS)- cvclohexylmethyl-5(R)-oxazolidinyl)-3-hvdroxy-2(R)- isopropyl- l-oxopropyl)-4fR)-methyl-5fS)-phenyl-2-oxazolidinone. The title compound was prepared in analogy to the procedure of S. Thaisrivongs, D. T. Pals, L T. Kroll, S. R. Turner and F. S. Han, J. Med. Chem. 1987, 30, 976-82, from the resultant compound of Example 1C, in 63% yield. M. p. 97°C. 1HNMR (CDCI3) 0.91 (d, 3H), 1.06 (d, 3H), 1.1 (d, 3H), 1.48 (s, 9H), 0.9-1.9 (several bm, 12 H total), 2.12 (bd, 1H), 2.3 (m, 1H), 3.81 (dd, 1H), 3.94 (td, 1H), 4.04 (bm, 1H), 4.22 (dd, 1 H), 4.84 (dq, 1 H), 5.61 (d, 1 H), 7.31-7.45 (m, 5H). High resolution mass spectrum. Calcd. for (M + H) + Of C33H5lN207: 587.3698. Found: 587.3696.
Analysis. Calcd. for C∞HsoN^: C, 67.55; H, 8.59; N, 4.77. Found: C, 67.41 ; H, 8.61 ; N, 4.77.
Example 1 E: 3-(3(RH3-ftert-Butyloxycarbonvn-2.2- dimethyl-4(S - cvclohexylmethyl-5(R)-oxazolidinvπ-3-f(1- imidazolvπthionyloxy)-2fR)-isopropyl-1-oxopropyπ-4(R)-methyl-5fS)-phenyl-2- oxazolidinone. The resultant compound from Example 1 D (1.840 g, 3.136 mmol) and 1,1'-thiocarbonyldiimidazolide (1.128g, 6.330 mmol) were refluxed in 8 mL dry 1,2-dichloroethane under a nitrogen atmosphere for 24 h. The mixture was concentrated and the residue purified by flash chromatography (2.5% MeOH-CH2CI2) to afford 1.896 g (87%) of the title compound. 1H NMR(CDCI3) 0.93 (d, 3H),1.04 (d, 3H), 1.08 (d, 3H), 1.5 (bs, 9H), 0.9-1.9 (several bm, 13H total), 2.05 (m, 1H), 4.13 (bm, 1H), 4.23 (dd,1H), 4.81 (dd, 1H), 4.94 (dq, 1H), 5.70 (d, 1 H), 6.33 (dd,IH), 7.06 (bs, 1H), 7.3-7.5 (m, 5H), 7.61 (bs, 1H), 8.40 (bs, 1H). High resolution mass spectrum. Calcd. for (M + H) + of C37H53N407S: 697.3635. Found: 697.3629. Analysis. Calcd. for C37H52N407S: C, 63.77; H, 7.52; N, 8.04. Found: C, 63.58; H, 7.44; N, 7.94.
Example 1 F: 3-(3-(3-(tertButyloxycarbonvπ 2.2-dimethyl-4rS)-cvclohexylmethyl-5fS)-oxazolidinvn-2fR)-isopropyl-l- oxopropyl)-4(R -methyl-5fS)-phenyl-2-oxazolidinone. A solution of the resultant product from Example 1 E (6.50 g, 9.33 mmol) in 275 ml of dry toluene was degassed with argon for 30 min, then warmed to reflux (under argon). A solution of tri-n-butyltin hydride (5.43 g, 18.6 mmol) in 75 ml of dry, degassed toluene was added dropwise over 15 min. After an additional 2 h of reflux, the reaction was cooled, concentrated and purified by flash chromatography (5% EtOAc-hexanes) to afford 4.82 g (90%) of the title compound as a white foam. 1H NMR(CDC13) 0.90 (d, 3H), 0.92 (d, 3H), 0.9-1.1 (bm, 3H), 1.06 (d, 3H), 1.15-1.35 (bm, 3H), 1.51 (s, 9H), 1.57-2.14 (several bm, 16H total), 3.84 (m, 1 H), 3.97 (m, 1 H), 4.85 (dq, 1 H), 5.68 (d, 1 H), 7.3-7.46 (m, 5H). Mass spectrum: (M + H) + = 571.
Analysis. Calcd. for C33H50N206: C, 69.44; H, 8.83; N, 4.91. Found: C, 69.31 ; H, 8.82; N, 4.89.
Example 1G: 2(S)-f(3-(tert-Butyloxycarbonyl-2.2-dimethyl- 4(S)-cvclohexylmethyl-5(S)-oxazolidinyl methvπ-3- methylbutanoic acid. Using the procedure of D. A. Evans, T. C. Britton and J. A. Ellman, Tetrahedron Lett. 1987, 28(49), 6141-44, the resultant product from Example 1 F (6.10 g, 10.7 mmol) was hydrolyzed with aq. LiOH and hydrogen peroxide in THF. The crude material was purified by flash chromatography (15% EtOAc-0.5% HOAc-hexanes) to provide 3.53 g (90%) of the title αo ' riund as a viscous colorless oil. 1H NMR(CDC13) 0.96 (d, 3H), 1.00 (d, 3H), 1.1-1.3 (bm, 5H), 1.48 (s, 9H), 1.5-1.9 (several bm, 15H total), 2.0 (m, 1 H), 2.66 (m, 1 H), 3.7 (bm, 1 H), 3.90 (m, 1 H). Mass spectrum: (M + H) + = 412. Analysis. Calcd. for C23H41NO5.0.25 H20: C, 66.39; H, 10.05; N, 3.37. Found: C, 66.46; H, 9.84; N, 3.36.
Example 1 H: 3-(4-Morpholinvnpropyl 2fSV((3-tert- butyloxycarbonvn-2.2-dimethyl-4(S)-cvclohexylmethyl-5fSVoxazolidinvπmethvπ-3- methylbutanamide. The procedure of P. Buhlmayer, et. al., J. Med. Chem. 1988, 31 (9), 1839-46 was adapted. The resultant compound from Example 1G (75 mg, 0.182 mmol), HOBT (42.0 mg, 0.274 mmol) and N-methylmorpholine (55 mg, 0.55 mmol) were dissolved in 1.0 ml dry DMF, and the solution was cooled to -20°C (under nitrogen). EDAC (53 mg, 0.28 mmol) was added as a solid, and the resulting mixture was stirred at -20 to 0°C for 1 h. The mixture was sealed, and allowed to react at 0°C (in refrigerator) for 48 h. To the resulting solution was added 4-(3-aminopropyl)morpholine (0.23 mmol). The resulting solution was stirred at 0°C for 4 h, and for a further 20 h, allowing it to warm slowly to room temperature. The volatiles were removed by high vacuum distillation, and the residue was partitioned between CH2CI2 and aq. NaHC03. The aqueous phase was extracted 3X with CH2CI2, and the combined organic phases were washed with brine, dried (Na2S04) and concentrated. Purification by flash chromatography (4% MeOH-CH^y provided the desired compound.
1H NMR(CDCI3) 0.92 (d, 3H), 0.95 (d, 3H), 1.46 (s) and 1.48 (s, 12H total), 1.57 (bs, 3H), 0.8-1.8 (several bm, 18H total), 2.01 (m, 1H), 2.46 (bm, 6H), 3.37 (m, 2H), 3.64 (bm, 1H), 3.75 (bm, 5H), 6.80 (bt, 1H). High resolution mass spectrum. Calcd. for (M + H) + of C3oH56N305: 538.4220. Found: 538.4220.
Example 11: 1 (S)-(4-(Methoxymethoxyl)piperidin-1-yl- carbonyl)-2-phenylethanol.
A solution of 176 g (1.3 mol) of Ihydroxybenzotriazole (Aldrich), 80 g (0.48 mol) of L-3-phenyllactic acid (prepared from L-phenylalanine), 76 g (0.52 mol) of 4-(methoxymethoxy)piperidine in 800 mL of DMF was cooled to -25° C (internal temperature) while 132 g EDC HCI (Saber Labs) was added (mechanical stirring). After addition, the reaction was stirred to rt over 24 h. Excess DMF was removed under high vacuum and the residue dissolved into 1.5 L of ethyl acetate. The ethyl acetate solution was washed with 4 L of saturated sodium bicarbonate. The ethyl acetate layer was separated, dried (MgS04) and evaporated to give approximately 138 g of crude amide. The product was isolated by silica gel chromatography using ethyl acetate/hexane as eluant. Yield 120 g (79%).
1H NMR(CDCI3, TMS) 1.61 (m,2H), 1.81 (m,2H), 2.89 (m,2H), 3.38 (s,3H), 3.5 (m,2H), 3.79 (m,2H), 3.96 (m,1H), 4.62 (t, 1H) , 4. 68 (s, 2H).
Example U: 2(S)-(1 (SH4-(Methoxymethoxy)piperidin-1-yl- carbonvP-2-ohenylethoxy)hexanoic acid. The resultant compound of Example 11 (1.45 g, 4.95 mmol), in 10 ml THF was added dropwise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (0-5°C). The suspension was stirred for 20 mins at 0-5° C and then warmed up to room temperature and stirred for additional 1 h. Solution of D-2-bromohexanoic acid in 6 ml THF was added dropwise to the cooled suspension (0-5° C) under N2 atmosphere. It was then allowed to warm up to room temperature and stirred overnight, quenched with cold H20 and extracted with ethylacetate to remove undesired starting material. It was acidified with 1 M sodium hydrogen sulfate and extracted with chloroform. After filtration and evaporation, the crude product was purified on silica gel, eluted with CH2Ci2: CH3OH:AcOH (19.4: 0.3:0.3) to obtain 0.79 g of desired acid (43 % yield).
1H NMR(CDCI3, TMS) 0.88 (t,3H), 3.35 (s,3H), 3.98 (bt,IH), 4.6 (m,IH), 4.64 (s,2H), 7.38 (m,5H). Mass spectrum: (M + H) + = 408.
Example 1 K: 2(SH1 (SH4-(Methoxymethoxy)piperidin-1- ylcarbonyl-2-phenyl ethoxyhexanoic acid amide of 3-(4- morpholinvπpropyl 5(SVamino-6-cvclohexyl-4fS)-hvdroxy-
2fS isopropylhexanamide.
The resultant compound from Example 1 H (0.161 mmol) was deprotected by dissolving in 1.0 ml dry CH2CI2, cooling the solution to -10°C (under nitrogen), and treating with 1.0 ml of trifluoroacetic acid. The resulting solution was stirred at -10 to 0°C for 4 h. The solvents were largely removed with a stream of nitrogen, and the residue (as a concentrated solution in trifluoroacetic acid) was dissolved in 1.0 ml THF and 0.3 ml water at 0°C. The solution was allowed to warm slowly to ambient temperature over 18 h. The crude aminoalcohol was isolated by basifying the reaction with an excess of 1.0 M aq. Na2C03, saturating the solution with NaCI, and extracting with 5 x 10 ml of 5% EtOH-CHCI3. The combined organic phases were washed with brine, dried (Na2S04), concentrated, and the residue placed under high vacuum overnight to yield 66.2 mg (100%) of yellow viscous oil.
Coupling was acheived by combining the resultant compound from Example U (72 mg, 0.177 mmol), the above aminoalcohol (0.168 mmol), HOBT (34 mg, 0.22 mmol) and N-methylmorpholine (25 mg, 0.25 mmol) in 1.0 ml dry DMF. The resulting solution was cooled to -20°C (under argon), and EDAC (45 mg, 0.23 mmol) was added. The reaction was allowed to slowly warm to room temperature as the ice bath melted, for a total of 24 h. The solvent was removed by high vacuum distillation, and the residue was partitioned between 15 ml CH2CI2, 9 ml sat. aq. NaHC03 and 1 ml H20. The aqueous phase was further extracted (3 X 10 ml CHsCy, and the combined organic phases were washed with 10 ml brine, dried (Na2S04) and concentrated. Purification by flash chromatography yielded the title compound as a hygroscopic glassy solid, m.p. 49-51°C. 1H NMR(CDCI3) 0.90 (m), 0.91 (d) and 0.92 (d, 9H total), 0.65-1.90 (several bm, approx. 28H total), 2.02 (m, 1H), 2.45 (bm, 6H), 2.95 (m, 1H), 3.05 (dd, 1H), 3.20 (bm, 2H), 3.36 (s, 3H), 3.45 (m, 2H), 3.6-4.0 (several bm) and 3.71 (m, 10H total), 4.48 (dd, 1H), 4.68 (s, 2H), 5.80 (d) and 5.88 (d, 1H total), 6.87 (bt, IH), 7.3 (bm, 5H). Mass spectrum: (M + H) + = 787.
Example 2
2(SH1(SH4-Methoxymethoxy)piperidin-l-yl)carbonyl-2- phenvDethoxyhexanoic acid amide of 3-(4-morpholinyl)propyl-
5(S)-amino-6-cvclohexyl-4(S)-hvdroxy-2(S)- isopropylhexanamide (Alternate Preparation)
Example 2A 2(S)-Cvclohexylalanine methyl ester, hvdrochloride salt L-Phenylalanine (215 g, 1.3 mole) was hydrogenated over Pd/C in HOAc, filtered and concentrated. The resulting cyclohexylalanine was taken up in MeOH (1200 mL). Thionyl chloride (427 g, 3.59 mole) was slowly added to the slurry, which eventually became homogeneous. The reaction was cooled in an ice/water bath and addition of thionyl chloride was continued. The reaction mixture was heated to reflux for 2h, cooled and concentrated to afford a solid, which was taken up in ether and filtered. The white solid was washed with ether in the filter funnel and dried in vacuo to give 271 g of product, 94% yield over two steps, m.p. 150-150°C. Example 2B 2(S -N-π"riphenylmethyl)cvclohexylalanine methyl ester Cyclohexylalanine methyl ester, HCI salt (88 g, 398 mmol) was taken up in chloroform (400 ML). Triethylamiπe (84.6 g, 836 mmol) was then added in one portion to the slurry and stirred five minutes. Triphenylmethylchloride (111 g, 398 mmol) was then added, and the reaction was stirred for 5h at ambient temperature. The internal temperature of the reaction reached 50°C, however, external cooling was not employed. The reaction mixture was washed with 1M KHS04 solution (2 x 100 mL), saturated NaHC03 (200 mL), brine (100 mL), then dried over MgS04. The solution was then concentrated to give 200 g of residue which was filtered through 900-1000 g of silica gel (elution gradient hexane-10:1 hexane: ethyl acetate) affording 157 g of product (93%), which could be crystallized from hexanes: ethyl acetate to afford large white crystals, m.p. 86-87°C.
Example 2C Dimethyl 3(S)-4-Cyclohexyl-(N-triphenylmethyl)amino-2-oxobutylphosphonate To a -78°C solution of dimethyl methyl phosphonate (272.5 g, 2.2 mol) in 1.6L THF was added n-BuLi (2.5 M, 800 mL, 2.0 mmol) and stirred 45 minutes. The product of Example 2B (156 g, 366 mmol) in 40 mL THF was then added dropwise. This reaction mixture was stirred at -50°C for 3 h, then at -40°C for 6h then finally warmed to ambient temperature overnight. The reaction mixture was concentrated, taken up in ether, washed with 1 M KHS04, saturated NaHC03 (twice) and brine, dried and concentrated. The residue (200g) was filtered through 1000 g silica gel, (1:1 hexanes:ethyl acetate) to give 135 g of beta-keto phosphonate (72%) as an oil. Example 2D 6(S -7-Cvclohexyl-2-methyl-6-(N-triphenylmethvπ-amino-5-oxohept-2-ene-3-oic acid The product of Example 2C (117.2 g, 229 mol) was dissolved in 600 ml THF and cooled to 0°C. To this solution was added hexanes washed NaH (60%, 9.6 g(wet), 240 mmol) and the mixture was stirred 30 min. Next was added methyl 3- methyl-2-oxobutyrate (29.8 g, 229 mmol) in 100 ml THF and stirred at 0°C for 4 h. Volatiles were removed at reduced pressure, the residue was disolved in 1 :1 hexanes: ether (500 ml) and washed with water (100 ml), NaHC03 (200 ml), brine (200 ml), dried (MgS04) and concentrated to afford 129 g of the desired ester as an oil. This material (123 g) was taken up in 460 ml THF, 229 ml MeOH, cooled to 0°C then 18.86 g of LiOH-H20 in 229 ml of distilled water was added. This solution was allowed to warm to room temperture and stirred for 3 days. Volatiles were removed at reduced pressure and the resulting aqueous solution was washed with ether (100 ml x2) then acidified to pH 3 with 6N HCI. The aqueous solution was then extracted with EtOAc (300 ml x2), washed with brine, dried (MgS04) and concentrated to give 116 g of a yellow foam. This material was recrystallized from 525 ml of hot hexanes/EtOAc (12/1) to give 72.4 g of a white solid (62% for three steps), m.p. 97-98°C.
Example 2E (5S.6S)-6-Cvclohexylmethyl-3-isopropylidene-5- hvdroxypiperidine-2-one A solution of 3.06 g (6.0 mmol) of the product of Example 2D in 50 ml THF was added to 6.8 g (60 mmol) of N-hydroxysuccinimide. This homogeneous solution was cooled to 0°C, then DCC (1.25 g, 12 mmol) in 5 ml THF was added. The cooling bath was removed and the reaction was stirred for 2h. At this time, an additional 1.25 g of DCC was added. After 5h of total reaction time, the mixture was filtered, concentrated and dissolved in either. The organics were washed with NaHC03 (aq, 50 ml x2), brine, dried (MgS04) and concentrated at reduced pressure to give 5.2 g of product as an oil, which was dissolved in 20 ml ether. A 1 N solution of HCI/Ether (30ml) was added. A gummy solid immediately precipitated out of solution; CH2CI2 (25 ml) was added and the clear reaction mixture was stirred overnight. After 12 h, the product which precipitated from the mixture was collected by filtration and washed with ether to give, after drying, 2.1 g of a white solid in 87% yield for two steps, which was taken on in the following step.
To a 0°C slurry of the above-mentioned white solid resulting from the first part of Example 2E (1.2 g, 3.0 mmol) in 20 ml CH2CI2 was added imidazole (204 mg, 3.0 mmol). The resulting reaction mixture was stirred for 1 h, then washed with 20 ml of KHS04, water, saturated NaHC03, and brine. The organic portion was dried over MgS04, filtered and cooled to -78°C. To the cold solution was added L-Selectride® (Aldrich, 1.0 M, 5.0 ml, 5.0 mmol) and stirred for 10 min. The reaction mixture was then warmed to -40° C and quenched with 20% citric acid solution. The organics were washed with 20 ml of water, saturated NaHC03 solution, brine, dired over MgS04, and concentrated to afford a clear oil. This residue was purified on silica gel (50% hexanes/ethyl acetate) to give an oil which was triturated with ether to afford a white solid, 545 mg, 72% yield from active ester, m.p. 128-130°C.
Example 2F (2S,4S,5S)-5-Amino-6- cvclohexyl-2-isopropyl-4-hexaπolide
A solution of the product of Example 2E (24.7 g, 98.4 mmol) in 500 ml of ethyl acetate was treated with 2.5 g of dry Pd/C and hydrogenated at 4 atm for 4h at ambient temperature. The reaction mixture was filtered and concentrated to a white foamy solid which was taken on without further purification.
The resulting saturated lactam was dissovled in 200 ml of 6N HCI and 50 ml of ethanol then heated to reflux for 14h. The reaction mixture was concentrated at reduced pressure and azeotropically dried with toluene to afford a pale oil. This material was taken up in water and extracted with hexane, then made basic by addition of a solution of NaHC03. Extraction with ethyl acetate followed by drying (MgS04) and removal of volatiles afforded a yellowish oil which solidified to a white solid upon standing. Recrystallization from hexane gave 20.7 g (90%) of product as white needles, m.p. 49-50°C.
Example 2G
2(S)-(1 (SH4-Methoxymethoxy)piperidin-1-vPcarbonyl- 2-phenvπethoxyhexanoic acid amide of 3-(4-morpholinvπpropyl-5(S)-amino-6-cvclohexyl-4(S)-hvdroxy-2(S)- isopropylhexanamide
The product of Example 2F was reacted with N- (benzyloxycarbonyloxy)succinimide to provide the N-Cbz protected amino lactone. Reaction of the N-Cbz protected amino lactone with 3-amino-1-(morpholin-4- yl)propane provided 3-(4-morpholinyl)propyl 5(S)-benzyloxycarbonylamino-6- cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide. This product can be N- deprotected and coupled with the product of Example U according to the procedure of Example IK to provide the desired compound.
Example 3 f2S -2-Benzyl-3-(1-methylpiperazin-4-ylsulfonvπpropionyl-(L)-f4-ThiazolvπAla Amide of f2S.3R,4S)-2-Amino-1-cvclohexyl- 3.4-dihvdroxy-6-methylheptane
Example 3A Methyl 3-Hvdroxy-2-methylene-3-phenyl propionate A mixture of benzaldehyde (82.1 mL, 0.81 mol), methyl acrylate (109.1 mL, 1.211 mol), 1,4- diazabicyclo(2,2,2)octane (13.6 g, 0.12 mol), and acetic acid (1.4mL, 0.024 mol) was allowed to stir at 35°C for 60 h, at which point the reaction was determined to have proceeded to 70% completion by 1H NMR. Methyl acrylate (20.9 mL, 0.23 mol) was then added and the solution was allowed to react at 35°C for an additional 48 h. The mixture was diluted with diethyl ether (1.0 L) and was washed with 2 x 200 mL portions of a pH 7 phosphate buffer. After concentration in vacuo, the remaining mixture was distilled at reduced pressure (12 mm) to afford 6.5 g of unreacted benzaldehyde and 130.0 g (90%) of the desired product as a colorless oil: b.p. 130°C (12 mm); IR (film) 1718, 1440 cm'1; 1H NMR (CDCI3) delta 3.67 (s, 3H), 5.52 (br s, 1H), 5.83-5.85 (m, 1H), 6.29-6.31 (m, 1H), 7.23-7.39 (m,5H); 13C NMR (75 MHz, CDCI3) delta 51.8, 72.9, 125.8, 126.5, 127.7, 128.3, 141.2, 141.9, 166.6.
Example 3B fZ)-1-Bromo-2-carbomethoxy-3-ohenyl-2-propene To a 2 L, 3-neck Morton flask fitted with a thermometer, a mechanical stirrer, and an addition funnel was added the resultant compound from Example 3A (305.9 g, 1.585 mol) followed by addition of 48% HBr (505 mL, 4.46 mol) in one portion. The flask was immersed in an ice-water bath, at which time concentrated sulfuric acid (460 mL, 8.62 mol) was added dropwise over 90 min and the internal temperature of the reaction mixture was maintained at 23-27°C throughout the addition process. After removal of the ice-water bath, the mixture was allowed to stir at ambient temperature overnight. The solution was then transferred to a separatory funnel and the organic layer was allowed to separate from the acid layer. The acids were drained and the organic layer was diluted with 2 L of a 1 :1 ethyl acetate/hexane solution, washed with saturated aqueous sodium bicarbonate solution (1 L), dried over sodium sulfate, and concentrated to yield 400 g (99%) of the desired product as a light yellow oil, which was used without any additional purification: b.p. 180°C (12 mm); IR (film) 1718, 712 cm-1; 1H NMR (CDC13) delta 3.89 (s, 3H), 4.40 (s, 2H), 7.38- 7.45 (M, 3H), 7.56-7.60 (m, 2H), 7.83 (s, 1 H); 13C NMR (75 MHz, CDCI3) delta 26.77, 52.47, 128.63, 128.87, 129.61, 134.20, 142.95, 166.62.
Example 3C (Z)-2-Carbomethoxy-3-phenyl-2-propene-1 -sulfonic Acid
Sodium Salt To a 12 L, 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and an addition funnel was added the resultant product from Example 3B (400 g, 1.57 mol) and methanol (4 L). The mixture was warmed to 50°C and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4 L) was added over 75 min while the internal temperatue of the flask was maintained at 50°C. After the addition was complete, the clear solution was allowed to stir at 50°C for an additional 45 min. The reaction mixture in solution was taken to the next step without additional purification. The compound can be isolated by concentration to an amorphous powder, which is contaminated with an equivalent of sodium bromide: IR (KBr) 1711 , 1628, 1215 cm"1; 1H NMR (DMSO D-6) delta 3.70 (s, 3H), 3.77 (s, 2H). 7.33-7.41 (m, 3H), 7.48 (s, 1H), 7.87-7.89 (m, 2H); 13C NMR (75 MHz, DMSO D-6) delta 49.88, 51.93, 127.36, 128.33, 128.91 , 129.82, 134.75, 139.06, 168.60.
Example 3D 2-Carbomethoxy-3-phenylpropane-1-sulfonic Acid Sodium To the 8 L of 1 :1 methanol/water mixture containing the resultant compound from Example 3C was added 60 g of W-24 raπey nickel. The resulting suspension was pressurized under 50 psi of hydrogen and was allowed to shake on a Parr shaker for 24 h, at which time an additional 20 g of raney nickel catalyst was added. After 6 h under 50 psi of hydrogen, the catalyst was removed by filtration and the solution was concentrated to dryness. To the dry white solid was added ethyl acetate (6 L) and heptane (4 L) and the solution was vigorously stirred with a a mechanical stirrer overnight. The white suspension was removed by filtration yielding 530 g (88%) of the desired product as an amorphous powder that was contaminated with approximately one equivalent of NaBr. The comound was used without any additional purification: IR (KBr) 1740, 1215, 1050 cm-1. 1H NMR (DMSO D-6) delta 2.48-2.54 (m, 1H), 2.74-2.87 (m, 2H), 2.91-3.04 (m, 2H), 3.48 (s, 3H), 7.12-7.32 (m, 5H); 13C NMR (75 MHz, D20/DMSO D-6) delta 38.18, 44.80, 52.67, 52.82, 127.42, 129.13, 129.34, 138.14, 176.84.
Example 3E 2-Carbomethoxy-3-phenyl-l -propanesulfonyl Chloride To a 3 L round bottom flask was added the resultant compound from example 3D (530 g, 1.39 mol) and toluene (520 mL) followed by the addition of PCI5 (317 g, 1.52 mol). The mixture was warmed to 50°C with stirring for 45 min. It was then diluted with toluene (1 L) and was filtered through ceiite. After concentration in vacuo, 371 g (96%) of the desired product was obtained as a light brown oil: IR (film); 1740, 1380, 1170 cm"1; H NMR (CDC13); delta 2.92 (dd, 1H, J = 8.1, 14.0), 3.17 (d, 1 H, J = 6.6, 14.0), 3.41-3.50 (m, 1H), 3.67 (dd, 1 H, J = 3.3, 14.3), 3.72 (s, 3H), 4.20 (dd, 1H, J = 8.8, 14.3), 7.15-7.18 (m, 2H), 7.25-7.35 (m, 3H); 13C NMR (75 MHz, CDC13) delta 37.26, 42.88, 52.65, 64.89, 127.49, 128.87, 128.92, 135.61, 171.79.
Example 3F Methyl 2-Benzyl-3-M -methyl-piperazin-4- ylsulfonyl) propionate To a 1 L round bottom flask was added the resultant compound from Example 3E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0°C in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed,the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 crτϊ1; 1H NMR (CDC13) delta 2.30 (s, 3H), 2.42 (t, 4H, J = 4.8), 2.88 (dd, 1 H, J = 7.7, 14.0), 2.93 (dd, 1 H, J = 3.7, 14.0), 3.06 (dd, 1H, J = 7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1 H, J = 8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDC13) delta 37.91 , 42.22, 45.36, 45.83, 49.61 , 52.21 , 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.
Example 3G
(2S 2-Benzyl-3-(4-methyl-piperazin-1 - ylsulfonyOpropionic Acid.
The resultant racemic ester from Example 3F (135 g, 397 mmol) was suspended in acetone (300 mL) and water (900 mL). While being stirred vigorously at a temperature of 35°C, a crude preparation fo Subtilisin Carlsberg (10 mL, Alcalase 2.4L, Novo Laboratories) was added. Sodium hydroxide solution (6 M) was used to maintain the reaction at pH 7.5-8.0. After 3 days, the acetone was removed under reduced pressure and the aqueous phase was extracted with CHCI3 (1 L) to remove the unreacted ester. The aqueous phase was adjusted to pH 7 with 3 M HCl and was desalted by eluting through a column of Amberiite XAD-16(2 kg, prewashed sequentially with water, methanol, and water) using a water to water/methanol gradient. Evaporation of the solvent afforded 46 g (70%) of a white solid: mp 184.5°C; TLC (25% ethyl acetate/25% water/25% acetic acid/25% n-butanol) Rf = 0.43; anal. (C15H22N204S 0.25 H20)
Calcd: C, 54.44; H, 6.85; N, 8.47.
Found: C, 54.77; H, 6.53; N, 8.39.
Example 3H Diethyl f2-BromoallvPacetamidomalonate To a stirred mixture of diethyl acetaminomalonate (217 g, l .Omol) and 2,3- dibromopropene (240 g, 1.2 mol) in dry tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at room temperature for 30 min, then heated to reflux. After heating for 18 h, the resultant slurry was cooled to room temperature and suction filtered through a short pad of silica gel. The solid residue as washed with tetrahydrofuraπ (2 x 50 mL), and the filtrates were combined and concentrated. The residue was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over MgS04. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85-87°C.
Example 3I Diethyl (3-Bromo-2-oxo-propyπacetamidomalonate To a cold (0°C), stirred solution of the resultant compound from Example 3H (280 g, 0.83 mol) in a mixture of 2:1 acetonitrile/water (1.68 L) was added solid N- bromosuccinimide (193 g, 1.08 mol) in three portions over a period of 15 min. The resultant orange mixture was stirred at 0°C for an additional period of 1 h and then was allowed to warm to room temperature. After 4 h, the reaction mixture was treated with 10% aqueous sodium thiosulfate, diluted with ethyl acetate, and washed sequentially with water, 10% aqueous NaHS04 (3 X), water, and brine. Drying (MgS04) and concentration afforded a yellow solid which was recrystallized from a mixture of ethyl acetate and hexane to give 247 g (85%) of the desired compound as a white solid: m.p. 97-98.5°C.
Example 3J Diethyl (4-Thiazolylmethyl)acetamidomalonate A 5 L, 3-neck round bottom flask equipped with a mechanical stirrer, stopper and a drying tube was charged with the resultant compound from Example 31 (325 g, 0.92 mol) and flushed with nitrogen. A freshly prepared solution of thioformamide in tetrahydrofuraπ (0.8 M, 1.25 L) was added in one portion. The reaction mixture was stirred at room temperature for 4 h. The resultant slurry was then diluted with ether (1.25 L) and cooled to 0°C. The solid was then collected by suction filtration and washed with cold ether (3 X) to give the title compound as the hydrochloride salt. This material was transferred to a 4 L separatory funel, slurried with ethyl acetate (2 L) and basified by the careful addition of 2 M NaOH. The organic layer was separated, washed with water and brine, and then dried over MgS04. Filtration and concentration afforded a pale yellow oil which solidified upon drying to give 242 g of the desired compound. This material was recrystallized from an ethyl acetate/hexane mixture to afford 185.6 g (64%) of pure material: m.p. 104-106°C.
Example 3K N-Acetyl-3-(4-thiazolvπ-DL-alanine Ethyl Ester To a stirred solution of the resultant compound from Example 3J (185.6 g, 0.59 mol) in a mixture of tetrahydrofuran (620 mL) and ethanol (310 mL) was added aqueous 2 M LiOH (325 mL, 0.65 mol) dropwise over 20 min. After stirring at room temperature for 2.5 hr the reaction mixture was concentrated and the resultant aqueous mixture was extracted with ether (3 x 200 mL), adjusted to pH 3 with 3 M HCl, and concentrated under reduced pressure. Residual water was removed by evaporating portions of toluene (2 x 200 mL). The residue was diluted with toluene (1.5 L) and the resultant slurry was heated to reflux with separation of water (Dean- Stark trap). After 3 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate (1.5 L) and suction filtered through Si02 (60 g). The solids were washed with additional ethyl acetate (4 x 500 mL) and the combined organics were concentrated to afford a pale yellow oil which solidified on drying (0.5 torr) to afford 119.6 g (84%) of the desired compound: m.p. 58-62°C.
Example 3L
N-Acetyl-3-(4-thiazolyl)-L-alanine and N-Acetyl-3-(4- thiazolvπ-D-alanine Ethyl Ester
A 5 L, 3-neck round bottom flask equipped with a mechanical stirrer was charged with the resultant compound from Example 3K (210 g, 0.87 mol), distilled water (1.6 L), and 1 M aqueous KCI (0.8 L). The homogeneous solution was adjuted to pH 7.0 with 0.1 M NaOH and then was treated with Subtilisin Carlsberg (1.8 g) dissolved in 0.1 M aqueous KCI (25 mL). The reaction mixture was stirred at room temperature with 1.0 M NaOH added as required to maintain the pH at 6.25-7.25. After 4 h, 430 mL of base had been consumed and the reaction was judged to be complete. The reaction mixture was then extracted with chloroform (4 x 1.5 L), the aqueous phase was carefully acidified to pH 4 with 2 M HCL and then was concentrated under reduced pressure. Residual water was removed by consecutive evaporation of portions of toluene (3 x 500 mL) and ethanol (3 x 500 mL). The residue was taken up in warm ethanol and suction filtered to remove inorganic salts. The solids were washed with warm ethanol (3 x 400 mL). The residue was taken up in warm ethanol and suction filtered to remove inorganic salts. The solids were washed with warm ethanol (3 x 400 mL) and the filtrates were concentrated to afford 92.6 g (50%) of N-acetyl-3-(4-thiazolyl)-L-alanine as a white solid: m.p. 186°C.
The combined chloroform fractions from the extractions were washed with saturated aqueous NaHC03, water, and brine and then were dried over MgS04. Filtration and concentration gave 103 g (49%) of N-acetyl-3-(4-thiazolyl)-D-alanine ethyl ester. This material could be further purified by recrystallization from ethyl acetate/hexane: m.p. 79-80.5°C. Example 3M Epimerization of N-Acetyl-3-(4-thiazolvπ-D-alanine Ethyl Ester A 2 L round bottom flask equipped with a magnetic stirrer, reflux condenser, and nitrogen inlet was charged with sodium (0.96 g, 0.045 mol) and ethanol (900 mL) and the mixture was allowed to reflux until the sodium was consumed. The resultant solution of sodium ethoxide was cooled slightly, and N-acetyl-3-(4-thiazolyI)-D-alanine ethyl ester from Example 3L (102 g, 0.42 mol) was added. The reaction mixture was then heated to reflux. After 3 h the solution was cooled to room temperature, quenched with glacial acetic acid (0.045 mol) and concentrated to remove ethanol. The residue was diluted with ethyl acetate, washed with water and brine and dried over MgS04. Filtration and concentration gave a yellow oil which was purified by recrystallizing from a mixture of hot ethyl acetate and hexane to yield 89 g (87%) of material identical to that obtained from Example 3L
Example 3N 3-(4-ThiazolyO-L-alanine Dihvdrochloride A 2 L round bottom flask equipped with a magnetic stirrer was charged with N- acetyl-3-(4-thialzoyl)-L-alanine from Example 3L (92.6 g, 0.43 mol) and 6 M HCl (1 L). The resultant solution was heated to reflux. After 3 h the mixture was allowed to cool to room temperature. The solution was then concentrated under reduced pressure, evaporated from toluene (3 x 200 mL), and dried under vacuum overnight to give 120 g of a slightly wet solid. This material was used in the next reaction without further purification. 85
Example 30 N-Boc-3-(4-thiazolvπ-L-alanine
A 4 L Erlenmeyer flask equipped with a mechanical stirrer was charged with the resultant compound from Example 3N (125.9 g) and tetrahydrofuran (1.5 L) and the mixture was adjusted to pH 6.6 with saturated aqueous sodium bicarbonate. The resultant solution was then adjusted to pH 8.9 with 3.0 M NaOH and a solution of di- tert-butyldicarbonate (117.8 g, 0.51 mol) in tetrahydrofuran (150 mL) as added. The reaction mixture was vigorously stirred at room temperature for 40 h. The tetrahydrofuran was removed under vacuum, the pH of the residue was adjusted to 2.0 with 3.0 M HCl and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined extracts were dried over MgS04, filtered, and concentrated to give 150 g of a white solid. Recrystallization from hot 1:1 ethyl acetate/hexane (1.06 L) gave 107.6g (82% from the resultant compound of Example 3M) of the desired compound: m.p. 115 °C; [alpha]D = + 129.8 (c = 1.04, CHCI3). Anal. (CnH^N^a).
Calcd: C, 48.53; H, 5.88; N, 10.29.
Found: C, 48.58; H, 5.91; N, 10.17.
Example 3P Boc-L-(4-Thiazolyl)Ala Amide of (2S. 3R. 4S)-2-Amino-1- cvclohexyl-3,4-dihvdroxy-6-methylheptane (2S,3R,4S)-2-[(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6- methylheptane (5.05 g, 14.7 mmol, Luly et al., J. Org. Chem. 1988, 53, 6109) was stirred for 90 min in 4 M HCl in ethanol and then evaporated. Ether was added and evaporated 3 times and the residue was dried under high vacuum. To this residue was added 1-hydroxybenzotriazole (5.57 g, 41.2mmol), the resultant acid from Example 30 (4.00 g, 14.7 mmol), dimethylformamide (60 mL) and N- methylmorpholine (3.40 mL, 30.9 mmol). The mixture was cooled to -23 °C, treated with l-(3-dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride (4.03 g, 21.0 mmol). After 2 h at -23 °C and 21 h at ambient temperature the mixture was poured into saturated NaHC03 solution and extracted into ethyl acetate. The organic layer was washed with water and brine, then dried over Na2S04 and evaporated to a white solid which was recrystallized from 1 :15 (v/v) methylene chloride/ether (multiple crops) affording 6.28 g (86%) of the desired product as a flaky white solid: m.p. 159- 160 °C; TLC (15% CH3OH/85% CHCI3) Rf = 0.63; 1H NMR (CDC13) delta 8.78 (1 H,d), 7.14 (1 H, d), 6.18 (2H, br d), 4.44 (1 H, dd), 4.27 (1 H, m), 4.10 (1 H, m), 3.37 (1 H, dd), 3.30-3.12 (3H,m), 1.89 (1 H, septet), 1.46 (9H, s), 0.94 (3H, d), 0.88 (3H, d). Anal. (C25H43N305S).
Calcd: C, 60.33; H, 8.71 ; N, 8.44.
Found: C, 60.43; H, 8.68; N, 8.51.
Example 3Q
H-L-(4-ThiazolvnAla Amide of (2S.3R.4S)-2-Amino-1- cvclohexyl-3.4-dihvdroxy-6-methylheptane
Trifluoroacetic acid (50 mL) was slowly added via cannula to a solution of the resultant compound from Example 3P (6.27 g, 12.6 mmol) in methylene chloride (50 mL) at 0°C. The reaction was stirred 3 h at 0°C and concentrated in vacuo (40°C bath) to an oil which was basified to pH 10-11 with aqueous K2C03. The product was extracted into chloroform, dried over Na2S04, filtered, and concentrated to a foam. Recrystallization from 1 :4 (v/v) methylene chloride/hexane gave 5.00 g (100%) of the desired product as a fluffy white solid: m.p. 111-112°C; TLC (15% CH30H/85% CHCI3) Rf = 0.46; 1H NMR (CDCl3) delta 8.77 (1 H, d), 7.40 (1 H, br d), 7.13 (1 H, d), 4.54 (1 H, m), 4.25 (1 H, m), 3.80 (1 H, dd), 3.33 (1 H, dd), 3.25-3.12 (3H, m), 0.95 (3H, d), 0.86 (3H, d). Anal (C20H35N3O3S)
Calcd: C, 60.42; H, 8.87; N, 10.57.
Found: C, 60.05; H, 8.65; N, 10.42.
Example 3R (2S)-2-Benzyl-3-(4-methylpiperazin-1- ylsulfonvπpropionyl-(LH4-ThiazolvOAla Amide of f2S.3R,4S)-2-Amino-1-cvclohexyl-3,4-dihvdroxy-6- methylheptane To the resultant acid from Example 3G (1.000 g, 3.064 mmol), the resultant amine from Example 3Q (1.110 g, 2.792 mmol), and 1-hydroxybenzotriazole (1.022 g, 7.563 mmol) in dimethylformamide (20 mL) was added N-methylmorpholine (0.35 mL, 3.2 mmol). The mixture was cooled to -23°C and treated with 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.760 g, 3.96 mmol). After 2 h at -23 °C and 14 h at ambient temperature, the reaction was poured into saturated NaHC03 solution (100 mL) and extracted into ethyl acetate (2 x 50 mL) which was washed with water (2 x 50 mL) and brine (50 mL) and then was dried over Na S04 and evaporated to afford 1.94 g. Recrystallization from ethanol (15 mL)/hexane (90 mL) afforded 1.559g (79%) of a white solid: m.p. 169-170°C; TLC (10% CH3OH/90% CHCI3) Rf = 0.40; 1H NMR (CDCI3) delta 8.73 (1 H, d), 7.43 (1 H, d), 7.37-7.16 (6H, m), 6.23 (1 H, d), 4.63 (1 H, dd), 2.30 (3H, s), 0.95 (3H, d), 0.87 (3H, d). Anal. (C35H55N506S2O.75 H20)
Calcd: C, 58.43; H, 7.91 ; N, 9.73. Found: C, 58.51; H, 7.74; N, 9.60. Example 4
Alternative Preparation of
N-Boc-3-f4-thiazolvπ-L-alanine
Example 4A Ethyl (2-BromoallvDacetamidoacetate To a solution of the product of Example 3H (3.36 g, 10.0 mmol) in dimethylformamide (10 mL) was added sodium chloride (586 mg, 10.0 mmol), water (360 microliters, 20 mmol) and 4N hydrochloric acid in dioxane (0.12 mL, 0.5 mmol). The reaction vessel was Firestone purged three times and placed under a positive nitrogen pressure. The reaction mixture was heated at reflux for 24 hours and then concentrated in vacuo. The residue obtained was diluted with water (5 mL) and extracted with ether (3 x 15 mL). The combined organic extracts were decolorized with charcoal (0.5 g), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product (2.51 g, 95%) as a pale yellow oil. 1H NMR (300 MHz, CDC!3) 1.29 (t, 3H), 2.04 (s, 3H), 2.99 (m, 2H),
4.22 (q, 2H), 4.79 (m, 1 H), 5.53 (d, 1 H), 5.68 (m, 1H), 6.44 (d, 1H); IR (film) 1195, 1220, 1370, 1540, 1660, 1740, 2990, 3050, and 3300 cm-1. MS (DCI/NH3) m/e 264/266 (M + H) -, 281/283 (M + H + NH3) -". Anal. Calcd. for C9H14N03Br: C, 40.92; H, 5.34; N, 5.30. Found: C, 42.04; N, 5.48; N, 5.26.
Example 4B N-Boc-(2-Bromoallvπαlvcine A slurry of the product of Example 4A in 0.1 N potassium chloride solution (300 mL) containing 0.2 M pH 7.0 phosphate buffer (30 mL) was treated with a solution of Subtiiisin Carlsberg (4 mg) in 0.1 N potassium chloride solution (3 mL). The pH was maintained between 6.50 and 7.25 by addition of 2.0 N sodium hydroxide solution via a pH-Stat. After 25 minutes, the rate of hydrolysis noticeably slowed; and the unreacted D-ester was extracted with methylene chloride (3 x 150 mL).
The resulting aqueous phase was treated with cobalt(ll) acetate (6 mg) and Acylase I (80 mg). The reaction mixture was stirred for 4 hours and determined to be complete.
The pH of the reaction mixture was adjusted to 10 by the addition of solid sodium carbonate. The resulting solution was treated with di-tert-butyl dicarbonate (6.55 g, 30 mmol) dissolved in THF (100 mL) and vigorously stirred for 16 hours. The aqueous solution was washed with hexane (200 mL) to remove any unreacted protecting-reagent. The aqueous layer was adjusted to pH 2.5 by the addition of solid potassium hydrogen sulfate and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo to give the title compound (7.30 g, 81%) as a pale yellow crystalline solid. [alpha]D at 25°C = -9.86° (MeOH), c = 1.085. H NMR (300 MHz, CDCI3) 1.48 (s, 9H), 2.91 (m, 2H), 4.52 (m, 1H), 5.19 (d, 0.5H), 5.53 (m, 1H), 5.71 (s, 1H), 6.79 (d, 0.5H), 11.3 (s, 1H); IR (CDCI3) 1150, 1250, 1400, 1500, 1620, 1640, 1710, 3000, 3350, and 3520 cm-1. (DCI/NH3) m/e 311/313 (M + H + NH3)*. Anal. Calcd. for C10H16NO4Br: C, 42.12; H, 5.66; N, 4.91. Found: C, 41.38; H, 5.59; N, 4.75.
Example 4C (2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic Acid To a solution of the product of Example 4B (2.00 g, 6.80 mmol) in water (30 mL) and tetrahydrofuran (15 mL) cooled to 0 °C was added N-bromosuccinimide (1.45 g, 8.16 mmol) in three portions over twenty minutes. After the addition was complete, the ice bath was removed and the solution was stirred for four hours. The tetrahydrofuran was removed in vacuo and the product was extracted with ethyl acetate (3 x 35 mL). The organic extracts were combined and washed with 5% sodium chloride solution (25 mL) and brine (25 mL), dried over magnesium sulfate, and concentrated in vacuo to afford the title compound (1.70 g, 81%). 1H NMR (300 MHz, CDCI3) 1.45 (s, 9H), 3.30 (m, 2H), 3.93 (s, 2H), 4.61 (m, 1 H), 5.51 (d, IH). MS (DCI/NHg) m/e 310/312 (M + H)*, 327/329 (M + H + NH3)^.
Example 4D (,2R)-N-Boc-2-Amino-3-(4-thiazolyl)propanoic Acid To a solution of the producut of Example 4C (91 mg, 0.293 mmol) in tetrahydrofuran (5 mL) was added thioformamide (17.7 mg, 0.29 mmol). [Thioformamide was prepared by reacting a slight excess of phosphorus pentasulfide with formamide in tetrahydrofuran. The resulting solution was diluted with hexanes and filtered through a silica gel plug and stored at -25 °C] The resulting solution was allowed to stand for sixteen hours and then concentrated in vacuo to afford a residue which was partitioned between diethyl ether and aqueous sodium bicarbonate. The aqueous layer was washed with ether (2 x 10 mL) and methylene chloride (10 mL), adjusted to pH 2.3 with solid potassium hydrogen sulfate, and extracted with ether (3 x 20 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white crystalline solid (55 mg, 71%). 1H NMR (300 MHz, CDCI3) 1.48 (s, 9H), 3.48 (m, 2H), 4.52 (m, 1H), 5.61 (m, 1H), 7.18 (d, 1 H), 8.91 (d, 1H).
Example 5
Alternative Preparation of f2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic acic
Example 5A Diethyl (2-Chloroallyl)acetamidomalonate To a suspension of 95% sodium hydride (17.2 g, 680 mmol) in tetrahydrofun (1.2 L) was added 2,3-dichloropropene (100 g, 900 mmol), diethylacetamidomalonate (146 g, 672 mmol) and tetrabutylammonium bromide (6.00 g). The resulting thick suspension was warmed at reflux under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (200 mL) and a mixture of ether (300 mL) and methylene chloride (100 mL). The organic phase was washed with 5% sodium chloride solution (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid (195 g) was dissolved in hot hexanes (1300 mL) and allowed to cool to room temperature and sit overnight to afford the title compound as a crystalline solid (157 g, 80%). mp 76.3 °C. 1H NMR (300 MHz, CDCI3) 1.29 (t, 6H), 2.05 (s, 3H), 3.48 (s, 2H), 4.28 (m, 4H), 5.18 (m, 1 H), 5.29 (m, 1 H), 6.92 (bs, 1 H); IR (CDCI3) 1140, 1180, 1200, 1240, 1270, 1300, 1500, 1630, 1680, 1740, 2950, 2990, and 3300 cm-1. MS (DCI/NH3) m/e 292/294 (M + H) *, 309/311 (M + H + Nhy*. Anal. Calcd. for C12H18N05CI: C, 49.41 ; H, 6.22; N, 4.80. Found: C, 49.18; H, 6.29; N, 4.75.
Example 5B Ethyl f2-Chloroallv0acetamidoacetate The product of Example 5A (137 g, 500 mmol) was hydroiyzed and decarboxylated by the procedure described in Example 4A to afford the title compound (105.4 g, 96%) as a pale yellow oil which crystallized upon standing. 1H NMR (300 MHz, CDCI3) 1.31 (t, 3H), 2.05 (s, 3H), 2.79 (m, 2H), 4.22 (q, 2H), 4.79 (m, 1H), 5.23 (m, 1 H), 5.29 (m, 1H), 6.61 (m, 1 H); IR 1200, 1220, 1280, 1300, 1370, 1440, 1550, 1638, 1659, 1740, 2890, 2990, 3050, and 3300 cm-1. MS (DCI/NH3) m/e 220/222 (M + H)*, 237/239 (M + H + NH3)~. Anal. Calcd. for C9H14N03CI: C, 49.21 ; H, 6.42; N, 6.38. Found: C, 46.58; H, 6.05; N, 6.02.
Example 5C f2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic acid The product of Example 5B is treated according to the procedure of Examples 4B and 4C to provide the desired product.
Example 6
Alternative Preparation of
2(S 2-Benzyl-3-(4-methyl-piperazin-1-ylsulfonvπ propionic acid
Example 6A 2-Carbomethoxy-3-phenylpropane-1-sulfonic acid Sodium salt To a 0.3M ethanolic solution of the product of Example 3B, (Z)-l-bromo- 2-carbomethoxy-3-phenyl-2-propene, (0.98 molar equivalents) was added over one hour at 50 °C a 1.4M aqueous solution of sodium sulfite (1.0 molar equivalent). The mixture was stirred for 10 hours at 50 °C, and then the ethanol was removed under reduced pressure at 50 °C. Ethyl acetate (3 kg per 1 kg of bromide) was added and the mixture stirred for an additional 15 minutes and let stand for 10 minutes. The layers were separated and the aqueous layer was washed as above with two additional aliquots of ethyl acetate (1 kg per 1 kg of bromide).
Raney nickel (1 kg per 10 kg of aqueous solution) was added to the aqueous solution which was then evacuated and purged with nitrogen followed by hydrogen (3x) and placed under 40 psi of hydrogen for 6.5 to 9.5 hours. The Raney nickel was removed by filtration using nitrogen pressure, and the filtrate was concentrated under reduced pressure at 55 °C. A 10% aqueous acetone solution (0.3 kg per 1 kg of starting bromide) was added to the residue obtained, and the mixture was warmed at 50 °C for 30 minutes. Additional acetone (3 kg per 1 kg of starting bromide) was slowly added over one hour to effect crystallization of the product. After stirring for one hour, the product was removed by filtration and washed with acetone to afford the title compound in 60-65%. m.p. 255 °C dec. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. A second crop was obtained by adding additional acetone (2.5 kg per 1 kg of starting bromide) and cooling to -20 °C for 10-12 hours and removing the second crop by filtration. An additonal 13-40% yield of title compound was obtained in that way.
Example 6B Methyl 2-Benzyl-3-(4-methyl-piperazin-1-ylsulfonvπ propionate The product of Example 6A (1 molar equivalent) was mixed with phosphorus pentachloride (1.5 molar equivalents) and warmed at 70-75 °C for 3-4 hours. The reaction mixture was cooled to room temperature and then diluted with toluene (16.7 molar equivalents) and added to 10% aqueous sodium chloride solution (4 kg per 1 kg of phosphorus pentachloride) while maintaining the temperature below 40 °C. The mixture was stirred for 5 minutes, allowed to settle for 15 minutes, and then the phases were separated. The sodium chloride wash was repeated as described above. The toluene phase was cooled to 5 °C and N-methylpiperazine (3 molar equivalents in 3 molar equivalents of toluene) was added maintaining the temperature below 15 °C. The mixture was stirred for 4-6 hours and then washed with 8% aqueous sodium hydroxide (2 x 3.4 kg per 1 kg of phosphorus pentachloride). The combined basic washes were re-extracted with toluene (0.25 kg per 1 kg of sodium hydroxide solution). The combined toluene extracts were washed with water (1 kg per 1 kg of phosphorus pentachloride), and the toluene was removed by distillation at reduced pressure to afford the title compound (65-70%) as a viscous oil which crystallized on standing. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 341 (M + H)~.
Example 6C (2S)-2-Benzyl-3-(4-methylpiperazin-1-yl sulfonvQpropionic
Acid The product of Example 6B (69 kg, 20 mol) in acetone (420 kg)/water (960 kg) was adjusted to pH 8.0 using 1N sodium hydroxide. Alcalase™ (Subtilisin) was added and the pH was maintained between 7.9 and 8.4 by the addition of 1N sodium hydroxide. When 80% of the theoretical amount of sodium hydroxide had been consumed, the reaction was quenched by the addition of ethyl acetate. The reaction mixture was concentrated to half the original volume under reduced pressure and then washed with ethyl acetate (2 x 700 kg). The volume of the aqueous phase was concentrated by half and the pH adjusted to 5.2. The reaction mixture was treated with XAD-16 resin (50 kg), stirred for 18 hours, and applied to an XAD-16 resin column (50 kg). The column was eluted with water (500 kg) and then 35% ethanol in water (1000 kg) to afford a residue which was treated with isopropanol (270 kg) and warmed to 75 °C. Upon cooling to room temperature and subsequently to -5 °C, crystalline material was obtained. The solid was removed by filtration, washed with cold isopropanol (30 kg) and dried at 50 °C to afford the title compound (13 kg, 49%). The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 327 (M + H) "\ This compound could be recrystallized from 1 :1 isopropanol/water.
Example 7
Alternative Preparation of 2fS)-2-Benzyl-3-(4- methylpiperazin-1-ylsulfonv0propionyl-L-(4-thiazolvπ
Ala Amide of (2S. 3R. 4S)-2-Amino-1-Cvclohexyl
-3.4-dihvdroxy-6-methylheptane
Example 7A f2S.3R.4S)-2-Amino-1-cvclohexyl-3.4-dihvdroxy-6-methylheptane- A 3.5% solution of 2S-Boc-amino-1-cyclohexyl-3R,4S- dihydroxy-6-methylheptane in 4N hydrochloric acid gas in anhydrous ethanol was prepared at 0-5 °C. After 4 hours at 0-5 °C, nitrogen was bubbled through the reaction mixture to remove dissolved hydrochloric acid gas. The solvent was removed under reduced pressure at 50 °C to afford a solid which was dissolved in ethyl acetate and water. Potassium carbonate was added to bring the pH of the mixture to between 10 and 11 , and the layers were separated. The aqueous layer was extracted with additional portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure at 50 °C to afford a solid. The solid was crystallized by dissolving in a minimum amount of ethanol at 40 °C and then water was slowly added until the ratio of ethanol to water was 40/60 (w/w). The solution was cooled to 0-5 °C at a rate of 5 °C per hour. The cooled mixture was stirred for not less than 2 hours prior to removal of the solid by filtration. The solid was dried in a vacuum oven at 45 °C until a loss on drying was less than 0.1%. The title compound was obtained as a white crystalline solid in 65-72%. m.p. 106-108 °C. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 244 (M + H)~.
Example 7B Boc-L-(4-Thiazo )-Ala Amide of (2S,3R,4S)-2-Amino-1- cvclohexyl-3,4-dihvdroxy-6-methylheptane To a solution of the product of Example 7A (14.25 g, 58.5 mmol), N-Boc- L-(4-Thiazolyl)Alanine (17.45 g, 64.4 mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (9.86 g, 64.4 mmol) dissolved in dimethylformamide (DMF) (33 mL) and cooled to 0-5 °C in an ice bath was added dropwise over 30 minutes, a solution of 1 ,3-dicyclohexylcarbodiimide (DCC) (14.5 g, 70.3 mmol) dissolved in DMF (27 mL). After one hour, the reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction was quenched by the addition of citric acid (1.14 g, 6.0 mmol) and ethanol (1.31 mL, 1.05 g, 22.0 mmol). The mixture was stirred for 1 hour and then ethyl acetate was added (285 mL). After an additional 30 minutes, the solid by-product was removed by filtration and washed with ethyl acetate (48 mL). Additional ethyl acetate (1.9 L) was added and the organic phase was washed with 1% sodium chloride (713 mL), 5% citric acid containing 1% sodium chloride (2 x 713 mL), 8% sodium bicarbonate (2 x 713 mL) and 20% sodium chloride (2 x 713 mL) and concentrated under reduced pressure to afford an off-white solid. The solid was dissolved in isopropanol (200 mL) with warming, treated with decolorizing carbon at 50 °C for one hour, and filtered through Ceiite. The filtrate was diluted with isopropanol (50 mL) and stirred at room temperature with a mechanical stirrer for 15 hours. The solid suspension was cooled to 0-5 °C with an ice bath and stirred at this temperature for 3 hours. The solid was removed by cold filtration, washed with cold 1:1 isopropanol/heptane (100 mL), and dried in a vacuum oven at 50 °C for 48 hour to afford the title compound as a white solid in 85% yield, m.p. 156-158 °C. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 498 (M + H) + .
Example 7C H-L-(4-ThiazolvπAla Amide of (2S.3R.4S -2-Amino-1-cvclohexyl-3,4-dihvdroxy-6-methylheptane A 12% solution of the product of Example 7B at 15-25 °C in 3N hydrochloric acid was prepared. After 4 hours at 15-25 °C, the reaction mixture was quenched by pouring it into a mixture of 4% sodium hydroxide/15% sodium chloride/ethyl acetate. The pH of the mixture was brought up to 10-12 by the addition of 10% sodium hydroxide. The layers were separated and the aqueous layer extracted with ethyl acetate (2x). The combined organic extracts were washed with 25% sodium chloride (2x), dried over magnesium sulfate, treated with activated carbon at 50 °C for 1 hour, and filtered through Ceiite. The filtrate was concentrated to a solid under reduced pressure at 45 °C. The solid was crystallized by dissolving in a minimum amount of ethyl acetate (5x by weight) and triturating with heptane until the ratio of ethyl acetate to heptane was 30/70 (w/w). The solution was cooled to 0-5 °C and stirred for two hours and then filtered. The solid was dried in a vacuum oven at 45 °C for 60 hours or until the loss on dryng was less than 0.1%. The title compound was obtained as a white crystalline solid in 70-82%. yield, m.p. 109-112 °C. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 398 (M + H)~.
Example 7D (2S)-2-Benzyl-3-f4-methylpiperazin-1-yl sulfonvπpropionyl -L-(4-Thiazolvn Ala Amide of (2S.3R.4S)-2-Amino-1-cvclohexyl- 3,4-dihvdroxy-6-methylheptane The product of Example 7C (3.00 g, 7.6 mmol), the product of Example 6C, 2S-benzyl-3(4-methyl-piperazin-1-yl sulfonyl)propionic acid, (2.59 g, 7.9 mmol), and HOBT (1.27 g, 8.3 mmol) were dissolved in DMF (30 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0-5 °C in an ice bath and treated with the dropwise addition over a 30 minute period of a solution of DCC (1.72 g, 8.3 mmol) dissolved in DMF (8 mL). After 1 hour, the reaction mixture was allowed to warm to ambient temperature and stirred for 24 hours. The reaction mixture was quenched with citric acid (0.15 g, 0.26 mmol) and ethanol (0.17 mL, 3.04 mmol) and stirred for 1 hour. Ethyl acetate (60 mL) was added and the mixture was stirred for an additional hour. The by-product was removed by filtration and washed with ethyl acetate (10 mL). The filtrate was diluted with ethyl acetate (400 mL) and washed with 5% sodium bicarbonate solution (2 x 100 mL), 1% sodium chloride solution (100 mL), and 20% sodium chloride solution (100 mL). The solvent was removed under reduced pressure to afford an off-white solid. The solid was dissolved in isopropanol (80 mL) with warming, treated with decolorizing carbon at 55 °C for 1 hour, filtered through Ceiite, and stirred at ambient temperature with a mechanical stirrer for 12 hours. The white solid suspension was cooled to 0-5 °C in an ice bath for 3 hours and filtered cold. The solid obtained was washed with cold 1 :1 heptane/isopropanol (25 mL) and dried in a vacuum oven at 55 °C for 48 hours to afford the title comound (4.32 g, 81%) as a white solid, m.p. 169-170 °C. The 300 MHz 1H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 706 (M + H)~.
Example 8 N-(4-MorpholinylsulfonylHL)-Phenylalanyl-(L)- 2-amino-4-thiazolvnAlanyl Amide of (2S.3R.4S)-2-Amino-1 -cvclohexyl-3,4-dihvdroxy-6-methylheptane The title compound can be prepared according to the procedure disclosed in European Patent Application No. EP 399556, published November 28, 1990.
The ability of a renin inhibitor invention to treat psoriasis is demonstrated as follows. A 62-year-old woman patient with documented psoriasis received 0.1 mg/kg of eπalkiren (H-((beta,beta-dimethyl)-beta-Ala)-(4-OCH3)Phe-His amide of 2(S)-amino- 1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane diacetic acid salt)(enalkiren 5.0 mg/5 ml (0.1% concentration), glacial acetic acid 0.91 mg/5 ml and sodium chloride 43.9 mg/5 ml in water for injection) intravenously over a 5 minute period, followed 40 minutes later by administration of an additional 0.3 mg/kg of enalkiren intravenously over a 5 minute period. The psoriatic lesions on the patient's elbow, face and scalp were graded prior to treatment and 2, 4 and 7 days following treatment. The results are shown in Table 1.
Table 1
Figure imgf000102_0001
1 Minimal: poorly defined scales, possibly dusty appearance
2 Moderate: defined scales, flat surface edges
3 Severe: well defined, raised and lifted scales, possible yellow/brown color
4 Extreme: scales totally cover plaque, raised edges, may be pigmented, possible "crusty" fissures may be present
Figure imgf000103_0001
Figure imgf000103_0002
The data provided in Table 1 indicates that the renin inhibitor caused an improvement in the patient's psoriasis.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyciopentanepropionate, dodecylsulfate, ethanesulfate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid, and phosphoric acid and such organic acids as oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
The compounds of the present invention can also be used in the form of prodrugs which include esters. Examples of such esters include a hydroxyl-substituted compound of the invention which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used. Other esters include the compounds of the invention wherein a carboxylic acid group has been esterified to provide esters which include, but are not limited to, methyl, ethyl or benzyl esters. These esters serve as prodrugs of the compounds of the present invention. The prodrugs are metabolicaliy converted in vivo to parent compound. The preparation of the pro-drug esters is carried out by reacting a hydroxyl-substituted renin inhibitor with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired pro-drug ester. Prodrugs which are esters of carboxylic acid group containing renin inhibitors are prepared by methods known in the art.
The novel method of this invention is directed to the use of a renin inhibitor for treatment of psoriasis in a human or other mammal.
This invention is also directed to renin inhibitor compositions useful for treating psoriasis.
Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
The renin inhibitor may be administered orally, parenterally, by inhalation spray, by nasal spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
Topical compositions comprising the renin inhibitor can be in the form of shampoos, salves, powders, sprays, ointments, lotions, creams, solutions, suspensions and the like. These topical compositions can be prepared by mixing the renin inhibitor with non-toxic, inert solid or liquid carriers which are suitable for topical administrtion. Topical administration may also involve the use of transdernnal administration such as transdermal patches or iontophoresis devices.
The term parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular injection, intrasterπal injection, intradermal injection, intralesional injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, dextrose solution, mannitol solution, Ringer's solution, and isotonic sodium chloride solution, in addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Injectable preparations can be in ready to use form or reconstituted from a lyophilized powder.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Solid dosage forms can also comprise agents for enhancing oral absorption. Solid dosage forms can also comprise liquid filled capsules, for example PEG solutions of the active compound in a soft elastic gelatin capsule.
A typical tablet dosage form comprises the active ingredient (no more than 35% by weight of the tablet), citric acid (5-15% by weight of the tablet), a filler such as microcrystalline cellulose (for example, Avicel* PH101), a disintegrant (8-12% by weight of the tablet, for example, crospovidone) and a lubricant (0.5-1.5% by weight of the tablet, for example, magnesium stearate. A tablet can also comprise one or more surfactants (for example, Tween 80, Brij*35, Emulphor 719 and the like), with the total amount of surfactants being 2-3% by weight of the tablet.
The tablet dosage form is prepared by blending the active ingredient, 50% of the citric acid and the Avicel*. Ethanol (200 proof) is added and the mixture is granulated. If surfactants are included, they are added as a solution in the ethanol during the granulation step. The granules are dried overnight and screened through a 14 mesh screen. The remaining 50% of the citric acid, the crospovidone and the magnesium stearate are blended with the granules and then compressed into tablets. The composition of two typical tablet dosage forms (100 mg of active ingredient) is shown below.
Figure imgf000108_0001
citric Acid 50.1 14.3 AviceP PH101 150.0 42.8 crospovidone 40.0 11.4 magnesium stearate 3.0 0.9
Tablet Composition B
Amount Per Tablet
Ingredient
Compound of Example 3 hydrochloride salt citric acid
AviceP PH101
Brij*35
Tween 80 crospovidone magnesium stearate
Figure imgf000108_0002
A typical capsule dosage form comprises a soft elastic gelatin capsule filled with a solution comprising the active ingredient dissolved in a solvent comprising a mixture of PEG 400 (98% volume/volume) and glycerin (2% volume/volume).
A typical soft elastic gelatin capsule has a composition comprising gelatin NF (38.3% by weight), glycerin (96% active; 29.0% by weight) and water (32.7%).
The capsule dosage form is prepared by mixing appropriate volumes of PEG 400 and glycerin to give a mixture which is 98% by volume PEG 400 and 2% by . volume glycerin. Nitrogen is bubbled through the mixture for several hours. While maintaining the mixture under a nitrogen atmosphere, the mixture is heated to about 40°C and then the desired amount of the active ingredient is dissolved. The solution of active ingredient is then filled into soft elastic gelatin capsules. The filling operation is conducted under a nitrogen atmosphere.
Using the method described above, soft elastic gelatin capsules can be prepared which contain 0.1 ml of a PEG 400/glycerin (98%/2% by volume) solution of the compound of Example 3 (hydrochloride) at concentrations of 0.7 mg/ml, 7 mg/ml and 21 mg/ml.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
In addition to being used as the sole active ingredient for treating psoriasis, a renin inhibitor can be administered in combination with one or more other agents known to be useful for treating psoriasis. Such other agents include anthralin (dihydroxyanthralin), azarabine, colchicine, fluorouracil, methotrexate, methoxsalen (8- methoxypsoralen), resorcinol, retinoids (for example, retinoic acid), corticosteroids (for example, clobetasol propionate, triamcinolone acetonide and the like), cyclosporin, lipoxygenase inhibitors, cyclooxygeπase inhibitors, leukotriene synthesis inhibitors, iodochlorhydroxyquin, salicylic acid, vitamin D, dapsone, somatostatin, sulfur, tars, zinc oxide, ultra-violet light treatment (UVA or UVB) and PUVA treatment. The renin inhibitor and the other agent for treating psoriasis can be administered as part of the same composition or as separate compositions.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, method and compositions. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

CLAIMS What is claimed is:
1. A method for treating psoriasis comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a renin inhibitor.
2. The method Claim 1 wherein the renin inhibitor is a compound of the formula:
Figure imgf000111_0001
wherein A, is hydrogen, loweralkyl, arylalkyl, -OR10f or -SR10f wherein Rio, is hydrogen, loweralkyl or aminoalkyi, -NRn, R^ wherein R11f and Ri2, are independently selected from hydrogen, loweralkyl, aminoalkyi, cyanoalkyl, hydroxyalkyl, carboxyalkyi, alkoxycarbonylalkyl, (amino)carboxyalkyl, ((N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkyl, (dialkyiamino)carboxyalkyl, (amino)alkoxycarbonylalkyl, ((N-protected)amino)alkoxycarbonylalkyl, (alkyamiπo)alkoxycarbonylalkyl, ((N-protected)alkylamino)alkoxycarbonylalkyl and (dialkyiamino)alkoxycarbonyialkyl; or A, is
Figure imgf000112_0001
wherein B, is NH, alkylamino, S, O, CH2 or CHOH and
R23, is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyi, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyi,
N-protectedaminoalkyl, alkyiaminoalkyl, (N-protected) (alkyl) aminoalkyi, dialkylaminoalkyi, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyl, carboxyalkyi, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonyalkylamino,
(amino)carboxyalkyl, (amino)carboxyalkylamino,
((N-protected)amino)carboxyalkyl, ((N-protected)amino)carboxyalkyamino,
(alkylamino)carboxyalkyl,
(alkylamino) carboxyalkylamino, ((N-protected)alkylamino)carboxyaIkyl,
((N-protected)alkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl,
(dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl,
(amino)alkoxycarbonylalkylamino,
((N-protected)amino)alkoxycarbonylalkyl, ((N-protected)amino)- alkoxycarbonylalkylamino,(alkylamino)alkoxycarbonylalkyl,
(alkylamino)alkoxycarbonylalkylamino,
((N-protected)alkylamino)- alkoxycarbonylalkyl,
((N-protected)alkylamino)alkoxycarbonyl- alkylamino,
(dialkylamino)alkoxycarbonylalkyl, (dialkylamino)alkoxycarbonylalkylamino, aminocycloalkyi, aminoalkylamino, dialkylaminoalkyi (alkyl)amino, arylalkylamino, arylalkyi(alkyl)amiπo, alkoxyalkyl(alkyl)amino, (polyalkyoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy, (polyalkoxy)alkyl, (heterocyciic)alkyl or a substituted or unsubstituted heterocyclic wherein saturated heterocyciics may be unsubstituted, monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocyciics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl;
W, is C = O or CHOH;
U, is CH2 or NR2, provided that when W, is CHOH then U, is CH2 ; R1f is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (l-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided that when R1f is phenoxy, thiophenoxy or anilino, then B, is CH2 or CHOH or A, is hydrogen;
R2, is hydrogen or loweralkyl;
R3, is loweralkyl, loweralkenyl,((alkoxy)alkoxy)loweralkyl, (thioalkoxy) alkyl, benzyl or heterocyclic ring substituted methyl;
R6, is loweralkyl, cycloalkylmethyl or benzyl;
Raf is vinyl, formyl, hydroxymethyl or hydrogen;
Rdf is hydrogen or loweralkyl;
Rbf and R^ are independently selected from OH and NH2; and
Rc, is hydrogen, loweralkyl, vinyl or arylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof.
3. The method of Claim 1 wherein the renin inhibitor is a compound of the formula:
Figure imgf000114_0001
wherein Aj is
(I) R5iC(0)-CH2)w.- wherein
1) w" is 0 to 4 and
2) R5i is i) hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino;
(II) alkylsulfonyl, (aryi)sulfonyl or (heterocyclic)sulfonyl;
(lll)aryi, arylalkyl, heterocyclic or (heterocyclic)alkyl; or (IV) R90i- or R90iNHC(O)- wherein R90j is a C, to C4 straight or branched carbon chain substituted by a substituent selected from
1) carboxy,
2) alkoxycarbonyl,
3) alkylsulfonyl,
4) aryl,
5) arylsulfonyl,
6) heterocyclic or
7) (heterocyclic)sulfonyl);
Rιι is
(I) hydrogen
(II) loweralkyl, (lll)loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyi,
(VI) aryloxyalkyl, (Vll)thioaryloxyalkyl, (IV) arylalkoxyalkyi,
(IX) arylthioalkoxyalkyi or
(X) a C, to C3 straight or branched carbon chain substituted by a substituent selected from
1) alkoxy,
Figure imgf000116_0001
2) R12i is i) hydrogen, ii) loweralkyl or iii)an N-protecting group;
(XI) arylalkyl or
(XII) (heterocyclic)alkyl; and
Figure imgf000117_0001
Figure imgf000117_0004
Figure imgf000117_0002
wherein R73i is loweralkyl,
wherei
Figure imgf000117_0003
Figure imgf000118_0001
i) O, ii) S or iii) NH;
Figure imgf000118_0002
i) O or ϋ) S;
3) E, is i) O, ϋ) S, iii) CHR73i wherein R73i is loweralkyl, iv) C = CH2 or v) NR18i wherein R18i is a) hydrogen, b) loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and
Figure imgf000118_0003
i) absent, ii) CH2 or iii)NR19i wherein R19l is. hydrogen or loweralkyl. with the proviso that when Gj is NR19i. then R18i is loweralkyl or hydroxyalkyl;
(III)
(CH2)v.. - C(0)-N R 21 i
\ / wherein
1) v" is 0 or 1 and
2) R21i is i) NH, ϋ) O, iii) S or iv) S02; or (IV) a substituted methylene group; or a pharmaceutically acceptable salt ester or prodrug thereof.
4. The method of Claim 1 wherein the renin inhibitor is enalkiren.
5. The method of Claim 1 wherein the renin inhibitor is 2(S)-(1 (S)-(4- (Methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanoic acid amide of 3-(4- morpholinyl)propyl-5-(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide; or a pharmaceutically acceptable salt, ester or prodrug thereof.
6. The method of Claim 1 wherein the renin inhibitor is 2(S)-2-Benzyl-3-(1- methylpiperazin-4-ylsulfonyl)-propionyl-(L)-(4-thiazolyl)Ala amide of (2S,3R,4S)-2- amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
7. The method of Claim 1 wherein the renin inhibitor is N-(4- Morpholinylsulfonyl)-(L)-Phenylalanyl-(L)-(2-amino-4-thiazolyl)Alanyl amide of (2S,3R,4S)-2-amino-1 -cyclohexyl-3,4-dihydroxy-6-methylheptane: or a pharmaceutically acceptable salt, ester or prodrug thereof.
8. The method of Claim 1 wherein the renin inhibitor is administered topically.
9. A method for treating psoriasis comprising administering to a human or other mammal in need thereof a therapeutically effect amount of a renin inhibitor in combination with a therapeutically effective amount of another agent which is useful for treating psoriasis.
10. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a renin inhibitor for treating psoriasis.
PCT/US1991/002698 1990-04-23 1991-04-19 Psoriasis treatment WO1991016031A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US513,367 1983-07-13
US51336790A 1990-04-23 1990-04-23
US680,811 1990-08-15
US07/680,811 US5122514A (en) 1990-04-23 1991-04-09 Psoriasis treatment

Publications (1)

Publication Number Publication Date
WO1991016031A1 true WO1991016031A1 (en) 1991-10-31

Family

ID=27057843

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/002698 WO1991016031A1 (en) 1990-04-23 1991-04-19 Psoriasis treatment

Country Status (3)

Country Link
IE (1) IE911326A1 (en)
PT (1) PT97438A (en)
WO (1) WO1991016031A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2163245A1 (en) * 2008-09-10 2010-03-17 Novartis Ag Renin inhibitors for the treatment of psoriasis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906613A (en) * 1985-11-05 1990-03-06 Schering Corporation Antiglaucoma compositions and methods

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906613A (en) * 1985-11-05 1990-03-06 Schering Corporation Antiglaucoma compositions and methods

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ACTA CARDIOLOGICA, Vol. XI, issued 1985, ENA et al., "High Prevalance of Cardiovascular Diseases and Enhanced Activity of the Renin-Angio-Tensin System in Psoriatic Patients", pp. 199-205. *
NEPHRON, Vol. 44, issued 1986, MUDEDDU et al., "Captropril-Induced Proteinuria in Hypertensive Psoriatic Patients", pp. 358-360. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2163245A1 (en) * 2008-09-10 2010-03-17 Novartis Ag Renin inhibitors for the treatment of psoriasis

Also Published As

Publication number Publication date
PT97438A (en) 1992-01-31
IE911326A1 (en) 1991-10-23

Similar Documents

Publication Publication Date Title
US5122514A (en) Psoriasis treatment
US5032577A (en) Peptidylaminodiols
US5063208A (en) Peptidyl aminodiol renin inhibitors
AU639212B2 (en) Non-peptide renin inhibitors
US5164388A (en) Heterocyclic peptide renin inhibitors
AU4849390A (en) Heterocyclic peptide renin inhibitors
EP0202577A2 (en) N(Acyldipeptidyl)-aminoglycols
IE68045B1 (en) Renin inhibitors
AU624010B2 (en) Peptidyl aminodiol renin inhibitors
EP0103496A1 (en) Acylalkylaminocarbonyl substituted amino and imino acid compounds
EP0159156A1 (en) Hydroxy substituted ureido amino and imino acids
US5178877A (en) Encapsulated renin inhibitor composition
EP0158947B1 (en) Amino thiol dipeptides
US5276031A (en) Method for treating renal disease
AU632895B2 (en) Method for treating renal disease
WO1991016031A1 (en) Psoriasis treatment
US5258362A (en) Renin inhibiting compounds
WO1990005531A1 (en) Method for treating vascular diseases
US5523289A (en) Pharmaceutical composition
IE902944A1 (en) Peptidyl difluorodiol renin inhibitors
JPH0745453B2 (en) Acylaminohydroxyalkanoylamino and imino acids and esters
AU609774C (en) Peptidylaminodiols

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

WR Later publication of a revised version of an international search report
NENP Non-entry into the national phase

Ref country code: CA