EP0437508A1 - Non-peptide renin inhibitors - Google Patents

Non-peptide renin inhibitors

Info

Publication number
EP0437508A1
EP0437508A1 EP19890911665 EP89911665A EP0437508A1 EP 0437508 A1 EP0437508 A1 EP 0437508A1 EP 19890911665 EP19890911665 EP 19890911665 EP 89911665 A EP89911665 A EP 89911665A EP 0437508 A1 EP0437508 A1 EP 0437508A1
Authority
EP
European Patent Office
Prior art keywords
amino
loweralkyl
alkyl
heterocyclic
iii
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP19890911665
Other languages
German (de)
French (fr)
Other versions
EP0437508A4 (en
Inventor
Anthony K. L. Fung
William R. Baker
Yoek-Lin Armiger
Saul H. Rosenberg
Biswanath De
Jacob J. Plattner
Steven A. Boyd
Dale J. Kempf
Hing Leung Sham
Hollis D. Kleinert
Robert A. Mantei
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
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
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0437508A1 publication Critical patent/EP0437508A1/en
Publication of EP0437508A4 publication Critical patent/EP0437508A4/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/16—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms
    • C07D203/18—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with acylated ring nitrogen atoms by carboxylic acids, or by sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the presentinvention relates to novel compounds and compositions which inhibit renin, processes for making such compounds, synthetic intermediates employed in these processes, and a method of treating hypertension or congestive heart failure with such compounds or in
  • the presentinvention also relates to compositions and a method for treating glaucoma with such compounds and a method of inhibiting retroyiral proteases and treating a retroviral infection with such compounds.
  • Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different
  • renin a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood yolume in the body; or (c) a fall in the
  • angiotensin I angiotensin I
  • Al angiotensin I
  • ACE angiotensin conyerting enzyme
  • aldosterone a hormone which causes sodium retention.
  • angiotensin III (AIII), which, compared to All, is a less potent yasoconstrictor but a more potent inducer of aldosterone release.
  • Angiotensinogen the natural substrate for human renin has the following amino acid sequence.
  • Compounds which are inhibitors of renin generally comprise two parts. One part of the compound mimics the first 9 amino acid residues of angiotensinogen. The other part mimics the Leu-Val cleavage site of angiotensinogen and is designed to be non-cleayable by renin. When these two parts are combined in one compound, the compound binds to renin but is not cleayed. Thus, renin is inhibited from acting on its natural substrate angiotensinogen.
  • Inhibitors of renin haye been sought as agents for control of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
  • ACE angiotensin I
  • Al angiotensin I
  • ACE inhibition leads to the accumulation of Al.
  • Al has much less yasoconstrictor activity than All, its presence may negate some of the hypotensiye effects of the blockade of All synthesis.
  • the following references disclose peptide renin inhibitors which incorporate hydroxyl, substituted amide and heterocyclic deriyatiyes of statine and statine
  • Buhlmayer et al., U.S. Patent No. 4,727,060, issued
  • Buhlmayer et al., U.S. Patent No. 4,758,584, issued July 19, 1988;
  • EP0311012 published April 12, 1989, discloses renin inhibitors having a diol substituent which are antiglaucoma agents.
  • Peptidyl inhibitors of HIV protease are disclosed by Moore, Biochem. Biophys. Res. Commun., 159 420 (1989); Billich, J. Biol. Chem., 263 1790S (1988); and Richards, FEBS Lett., 247 113 (1989).
  • T is a mimic of the Leu-Val cleavage site of angiotensinogen.
  • the term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein includes
  • R 18 is loweralkyl
  • mic of the Leu-Val cleavage site of angiotensinogen as used herein also includes the
  • angiotensinogen having the formula
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined therein;
  • R 3 is as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • R 3 , R 4 and R 5 are as defined therein;
  • angiotensinogen having the formula
  • R 4 , R 5 , R 6 , R 7 and X are as defined therein;
  • R 4 , R 5 , R 6 , R 7 , R 9 and X are as defined therein;
  • angiotensinogen having the formula
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and E are as defined therein;
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and X are as defined therein;
  • R 1 , J, L, M and Q are as defined therein;
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined therein;
  • angiotensinogen having the formula
  • R 2 , R 3 and R 4 are as defined therein;
  • Buhlmayer et al., U.S. Patent No. 4,727,060, issued February 23, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined therein;
  • Buhlmayer et al., U.S. Patent No. 4,758,584, issued July 19, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
  • angiotensinogen having the formula
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • n, X and R 2 are as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • R 1 , R 2 , m, W 2 , R 3 and R 4 are as defined therein;
  • angiotensinogen having the formula
  • Bindra et al., U.S. Patent No. 4,749,687, issued June 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • R 1 , R 2 and R 3 are as defined therein;
  • angiotensinogen having the formula
  • R 3 and X are as defined therein;
  • angiotensinogen having the formula
  • Statyli, Ala, Statyl 2 and R' are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 , R 5 , n and R 6 are as defined therein;
  • R 2 is as defined therein;
  • R 4 , n and R 5 are as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • R 1 , R 2 , R 3 , q, R 9 and R 10 are as defined therein;
  • R 1 , R 2 , R 3 and R 9 are as defined therein;
  • R 1 , R 2 , R 3 , R 4 and A are as defined therein;
  • angiotensinogen having the formula
  • R 1 , R 2 , R 3 , R 4 and A are as defined therein;
  • angiotensinogen having the formula
  • R 1 and R 3 are as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • T, C, W, D, V, E, U and n are as defined therein;
  • angiotensinogen having the formula
  • T, U, V and W are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 , q, B, D and E are as defined therein;
  • R 3 , R 4 , m', E, B and F are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 , m' and E are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 and E are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 , R 5 , B and E are as defined therein;
  • R 1 , R 2 , R 3 , R 4 and B are as defined therein;
  • R 4 , R 5 , B and C are as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • R 3 , R 4 , R 5 , m and F are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 , R 4a , B and E are as defined therein;
  • angiotensinogen having the formula
  • R 3 , R 4 , R 5 , m and F are as defined therein;
  • angiotensinogen having the formula
  • angiotensinogen having the formula
  • R 2 , R 3 , R 4 , R 5 , n, B and D are as defined therein;
  • R, R 1 , R 2 , n and Y are as defined therein;
  • angiotensinogen having the formula
  • R 1 , E, G and Y are as defined therein;
  • R4, R5, Q and X are as defined therein; lizuka, et al., U.S. Patent No. 4,841,067, issued June 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • n and X are as defined therein;
  • n, s, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E and D are as defined therein;
  • R 4 , R 5 , R 6 and R 7 are as defined therein including R 4 is hydrogen or loweralkyl; R 5 is hydrogen, loweralkyl or an amino acid residue; R 6 is loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl and R 7 is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or an N- heterocycle;
  • R 5 , R 6 , R 7 and R 8 are as defined therein including R 5 is hydrogen or loweralkyl; R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an amino acid residue; and R 7 and R 8 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl;
  • R 5 , R 6 and A are as defined therein including R5 is hydrogen or loweralkyl; R 6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or
  • A is -CH (OH) - (CH) q -R 7 wherein q is 0-5 and R 7 is hydrogen, loweralkyl, cycloalkyl,
  • substituted thioalkyl substituted sulfone, substituted sulfoxide, substituted amine, quaternized amine,
  • heterocyclic carboxyalkyl, alkoxycarbonylalkyl or amidoalkyl;
  • R 4 is as defined therein including R 4 is
  • R 4 is as defined therein including R 4 is
  • R 2 , R 3 and R 4 are as defined therein including R 2 is hydrogen, alkyl, cyclcoalkyl, cycloalkylalkyl, aryl or arylalkyl; R 3 is hydrogen, alkyl or arylalkyl; and R 4 is -X-(CH 2 ) n '-R 7 wherein X is absent, O or S, n' is 0-4 and R 7 is hydrogen, hydroxy, amino, heteroaryl or -CH(R 9 )-(CH 2 ) p - Y-(CH 2 ) q -R 10 wherein p, q, Y and R10 are as defined therein;
  • EP0230242 published July 29, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • alkylaminoalkyl alkoxycarbonylaminoalkyl or
  • R 2 , R 3 , R 4 and R 9 are as defined therein including R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R 3 is hydrogen, alkyl, aryl or arylalkyl; R 9 is hydroxy or fluoro; and R 4 is - (CH 2 ) p -X-(CH 2 ) q -R 7 wherein p is 0-4, q is 0-4, X is -CF 2 -, -C (O) - or -CH(R 8 )- wherein R 8 is alkyl, alkoxy, thioalkoxy, alkylamino, hydroxy, azido or halo and R 7 is hydrogen, hydroxy, amino, aryl or heteroaryl;
  • R 2 is hydrogen, alkyl, cycloalkyl,
  • R 13 is hydrogen, alkyl or substituted alkyl
  • R 3 and R 4 are independently selected from hydrogen, alkyl or aryl
  • the boron containing substituent is a boron containing cyclic group
  • Noyember 14, 1988 discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • Y and R are as defined therein including Y is O or NH and R is alkyl, cycloalkyl or halogenated alkyl; European Patent Application No. EP0244083, published
  • X is as defined therein including X is alkoxy, alkyalamino, cycloalkyloxy, morpholino and haloalkoxy.
  • n, Y and R 2 are as defined therein including n is 0-1, Y is O or NH and R 2 is alkyl;
  • n, Z and R are as defined therein including n is 0- 1, Z is 0 or NH and R is alkyl;
  • n and X' are as defined therein including n is 0-1 and X 1 is alkoxycarbonyl, aralkoxycarbonyl, or -C(O)NR 1 R 2 wherein R 1 is hydrogen, alkyl or aralkyl and R 2 is alkyl or -CH 2 -Y-R wherein Y is O or NH and R is alkyl or aralkyl;
  • EP0181110 published May 14, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • R 3 and R 4 are as defined therein including R 3 is -CHO or -CH 2 OH and R 4 is isobutyl or benzyl; European Patent Application No. EP0297816, published
  • n, R 1 and R 2 are as defined therein including n is 0-1, R 1 is -NH 2 , alkylamino, alkoxy, or
  • 2-alkoxycarbonylpyrrolidin-1-yl and R 2 is alkyl, alkenyl, haloalkenyl or azide substituted alkenyl;
  • Y and R 2 are as defined therein including Y is -CH(OH)- or -C(O)- and R 2 is -CF 2 C (O)NHCH 3 , -CF 3 or
  • m, R 1 , R 2 , R 3 , R 4 and W 2 are as defined therein including m is 0-1, R 1 and R 2 are independently selected from hydrogen, alkyl, alkenyl, phenyl, naphthyl,
  • R 3 and R 4 are independently selected from alkyl, phenyl, naphthyl, cycloalkyl, adamantyl, phenylalkyl, naphthylalkyl,
  • R 7 and R 8 are independently selecterd from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl; or R 3 and R 4 taken together with the nitrogen to which they are attached form a pyrrole, indoline,
  • n, Y and D are as defined therein including n is 0- 1, Y is isobutyl, allyl or benzyl and D is 2- carboxypyrrolidin-1-yl or -ZR wherein Z is O or NH and R is alkyl, phenyl or substituted alkyl or substituted phenyl;
  • German Patent Application No. DE3725137 published August 6, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the .formula
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , B and Y are as defined therein including R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
  • R 1 is hdyroxy, alkoxy or aryloxy
  • R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, fluoro, chloro, alkyl, cycloalkyl, cycloalkylalkyl, aryl,
  • arylalkyl, heteroaryl and heteroarylalkyl B is a peptide chain containin ⁇ from 1 to 10 amino acid residues and Y is hydroxy or a protecting group for the peptide carboxy group;
  • R 1 , R 2 , R 3 , R 4 and B are as defined therein
  • R 1 is a hdyrophobic or hydrophilic side chain
  • R 2 is hydroxy or amino
  • R 4 is a hydrophobic or hydrophilic side chain and B is
  • R 6 is R 1 , R 7 and R 8 are the same as R 2 and R 3 , R 9 and R 10 are
  • R 11 and R 12 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and -CH (R 13 ) C (O) R 14 wherein R 13 is alkyl or hydroxyalkyl and R 14 is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , D and Y are as defined therein
  • R 1 is hydrogen or alkyl
  • R 2 is an amino acid side chain
  • R 3 is hydrogen, hydroxy, aryloxy or amino
  • R 4 and R 5 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and -CH (R 12 ) C (O) R 13 wherein R 12 is alkyl or hydroxyalkyl and R 13 is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl; or -NR 4 R 5 represents
  • D is a bond, O, -N(R 1 )- or
  • Y is -C(O)-, -S(O) 2 - or -P(O)-;
  • R 11 is alkyl or hydroxyalkyl and R 12 is hdyroxy, alkoxy, amino, alkylamino, aminomthylpyridyl, benzyl or -NH- (CH 2 CH 2 O) m -R 1 wherein m is 1-20 and R 1 is as defined therein; and X is a bond or O, NH or -C(R 13 ) (R 14 )- wherein R 13 and R 14 are independently selected from
  • m, R 4 and R 5 are as defined therein including m is 0-1, R 4 is alkyl, cycloalkyl or phenyl and R 5 is alkyl or substituted alkyl as defined therein;
  • R 4 and R 5 are as defined therein including R 4 is alkyl, hydroxyalkyl, (heterocyclic) alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and R 5 is hydrogen or alkyl;
  • R 5 is alkyl, cycloalkyl or phenyl
  • R 6 is alkyl
  • R 7 is alkyl or substituted alkyl as defined therein;
  • R 5 , R 6 and Y are as defined therein including R 5 is alkyl or cycloalkyl, R 6 is hydrogen or alkyl and Y is -SCH(CH 3 ) 2 or -S(O) 2 CH(CH 3 ) 2 ;
  • R 1 , R 5 and R 7 are as defined therein including R 1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
  • R 5 is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
  • R 1 , R 5 and R 7 are as defined therein including R 1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
  • R 5 is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
  • R 1 , R 5 and R 7 are as defined therein including R 1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
  • R 1 , R 5 and R 7 are as defined therein including R 1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
  • R 5 is hydrogen or alkyl and R 7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
  • R 1 , R 5 and R 6 are as defined therein including R 1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
  • R 5 is hydrogen or alkyl and R 6 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
  • EP0296581 published December 28, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • R 1 and R 3 are as defined therein including R 1 is hydrogen, arylalkyl, aryl, (heterocyclic) alkyl or
  • R 3 is hydrogen, alkyl, haloalkyl
  • arylalkyl (heterocyclic) alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, thioalkoxyalkyl,
  • hydroxythioalkoxyalkyl carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl;
  • R 1 and R 3 are as defined therein including R 1 is an N-heterocyclic ring and R 3 is hydrogen, alkyl,
  • cycloalkylalkyl haloalkyl, arylalkyl, (heterocyclic) alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, tioalkoxyalkyl, hydroxyalkoxyalkyl,
  • R 1 is hydrogen, alkyl, aryl, cycloalkyl
  • R 11 is hydrogen, alkyl benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,
  • arylalkyl (heterocyclic) alkyl, alkoxyalkyl or
  • R 22 is hydrogen or alkyl and R 23 is hydroxyalkyl, aminoalkyl, aryl or alkyl, G 12 is absent or an amino acid residue, H 13 is absent or an amino acid residue, I 14 is absent or an amino acid residue and Z is hydroxy, substituted alkoxy, substituted amino or cyclic amino;
  • R 1 is hydrogen, alkyl, aryl, cycloalkyl
  • R 11 is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,
  • arylalkyl (heterocyclic) alkyl, alkoxyalkyl or
  • R 21 is hydroxy or amino
  • R 22 is hydrogen or alkyl
  • R 23 is hydroxy, amino, hydroxyalkyl
  • G 12 is absent or an amino acid residue
  • H 13 is absent or an amino acid residue
  • I 14 is absent or an amino acid residue and Z is hydroxy
  • R 2 , R 4 , R 5 , X, Y and Z are as defined therein including R 2 is hydrogen or alkyl, R 4 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, hydroxyalkyl or aminoalkyl, R 5 is hydrogen, alkyl, arylalkyl, (heterocyclic) alkyl or cycloalkyl, X is -CH(OH)-, -CH(NH 2 )-, -C(O)-,
  • A is hydroxy or amino and B is absent, O, NH or CH 2 , Y is absent or
  • r, t, R 90 , R 100 , R 110 , R 111 , G 12 , H 13 , I 14 and Z are as defined therein including r is 0-3, t is 0-3, R 90 is hydrogen or alkyl, R 100 is hydrogen, alkyl, aryl,
  • R 110 and R 111 are independently selected from hydrogen, alkyl, aryl, arylalkyl and halo, G 12 is absent, an amino acid residue or
  • R 50 is hydrogen, alkyl, arylalkyl
  • R 60 and R 61 are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R 60 and R 61 taken together form a carbocyclic or heterocyclic
  • H 13 is absent an amino acid residue
  • R 50 is hydrogen, alkyl, arylalkyl
  • R 60 and R 61 are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R 60 and R 61 taken together form a carbocyclic or heterocyclic
  • I 14 is absent an amino acid residue or wherein R 50 is hydrogen, alkyl, arylalkyl,
  • R 60 and R 61 are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R 60 and R 61 taken together form a carbocyclic or heterocyclic
  • spirocycle and Z is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or cyclic amino;
  • R and R 1 are independently selected from alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy or thioalkoxy
  • R 11 is alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy, thioalkoxy, hydrogen, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic) alkyl, alkoxyalkyl and thioalkoxyalkyl
  • R 22 is hydrogen or alkyl
  • R 23 is hydroxy, hydroxyalkyl, amino, aminoalkyl, aryl or alkyl
  • R 24 is aryl, amino, alkylamino, dialkylamino, trialkylamino, heterocyclic, hydroxy, alkoxy, alkanoyloxy, mercapto, carboxy, alkoxycarbonyl, dialkylaminoalkoxycarbony1, aminocarbonyl,
  • alkylaminocarbonyl dialkylaminocarbonyl, cyclicamino, cycloalkylamino, guanidinyl, cyano, N-cyanoguanidinyl, cyanoamino, hydroxyalkylamino, di(hydroxyalkyl) amino, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, heterocyclicalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, mercaptoalkyl,
  • dialkylaminoalkoxycarbonylalkyl aminocarbonylalkyl, alkylaminocarbonylalkyl, diaIkylaminocarbonylalkyl, cyclicaminoalkyl, cycloalkylaminoalkyl, guanidinylalkyl, cyanoalkyl, N-cyanoguanidinylalkyl, cyanoaminoalkyl, hydroxyalkylaminoalkyl or di (hydroxyalkyl) aminoalkyl, W 1 and W 2 are independently selected from hydroxy and amino, W 3 and W 4 are independently selected from hydrogen and fluoro, W is as defined therein, Y is O, S, NH or
  • G 121 is absent or an amino acid residue
  • H 131 is absent or an amino acid residue
  • I 14 is absent or an amino acid residue
  • R 10a is hydrogen or alkyl
  • R 10b is alkyl
  • -CH(NH 2 )- and W 1 and W 2 are independently selected from hydrogen, fluoro, chloro and bromo, G is absent or an amino acid residue, H is absent or an amino acid residue and Z is hydroxy, thiol, amino, substituted alkoxy, substituted thioalkoxy, substituted alkylamino, Lys-OH, Lys-NH 2 , Ser-OH or Ser-NH 2 ;
  • Y, W and U are as defined therein including Y is Sta, Cysta or PhSta, W is Leu, lie, N-MeLeu, Val or absent and U is -NHCH 2 CH (CH 3 ) CH 2 CH 3 , -NHCH 2 Ph,
  • W is Sta, PhSta or Cysta
  • U is absent, Leu, lie, Val, N-MeLeu or N-Melle
  • V is -NHCH 2 Ph, -NHCH 2 -cyclohexyl
  • T is Sta, PhSta, Cysta, Leu,
  • CyclohexylAla or Phe W is absent, Leu, Gly or lie, V is absent, Leu or lie, C is -CH 2 NH-, -CH (OH) CH 2 - or
  • -CH 2 N(Cbz)- and U is -NHCH 2 Ph, -NHCH 2 -cyclohexyl, -NH 2 , -NH (piperidin-4-yl), -NHCH 2 (pyrid-2-yl),
  • EP0314060 published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • W and U are as defined therein including W is Sta, Cysta, PhSta, ChSta, DFKSta, DFKCys, DFKChs, ASta or ACys and U is -NHCH 2 CH 2 (morpholin-1-yl), -NHCH 2 CH (CH 3 ) CH 2 CH 3 , -NHCH (CH 2 OH) CH (CH 3 ) CH2CH3, -LeuNHCH 2 Ph,
  • R 3 and R 4 are as defined therein including R 3 is isobutyl, cyclohexylmethyl or benzyl and R 4 is phenyl, furyl, yinyl, ethyl or 1, 2-dihydroxyethyl;
  • R, U and B are as defined therein including R is hydrogen or hydroxyalkyl, U is Leu, Ala, Val or lie and B is pyridyl;
  • X is as defined therein including X is isobutyl or benzyl;
  • R 3 , R 4 and R 5 are as defined therein including R 3 is allyl, cyclohexyl or phenyl, R 4 is nitromethyl, alkoxycarbonyl or -CH 2 S (O) n -R d wherein n is 0-2 and R d is heterocyclic and R 5 is hydrogen or alkyl;
  • R 3 and Z are as defined therein including R 3 is hydroxy or amino and Z is substituted carbonyl, substituted thiocarbonyl, substituted iminocarbonyl or unsubstituted or substituted phosphono, aminomethyl, thiomethyl,
  • EP0275101 published July 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • R 2 , R 3 , R a , R b , n, X and Q are as defined therein including R 2 is an amino acid side chain, R 3 is hydrogen, alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl,
  • R a is an amino acid side chain
  • R b is hydrogen or alkyl or R a and R b taken together are -CH 2 -CH 2 -, n is 1-10
  • X is hydrogen, CH 2 , alkoxy, substituted alkoxy, alkyl, phenyl, benzyl,
  • R 1 is hydrogen, alkyl, aryl, cycloalkyl
  • R 11 is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,
  • arylalkyl (heterocyclic) alkyl, alkoxyalkyl or
  • R 21 is hydroxy or amino
  • R 22 is hydrogen or alkyl
  • R 23 is hydroxy, amino, hydroxyalkyl
  • R 24 is R 1 hydroxy, amino, hydroxyalkyl or aminoalkyl
  • G 12 is absent or an amino acid residue
  • H 13 is absent or an amino acid residue
  • I 14 is absent or an amino acid residue and Z is hydroxy
  • EP0275101 published July 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • R 1 , G 12 , H 13 and X are as defined therein including R1 is hydrogen, alkyl, aryl, cycloalkyl, heterocyclic, alkoxy or thioalkoxy, G 12 is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O, H 13 is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O and X is hydrogen, alkyl or substituted alkyl as defined therein;
  • R 1 , Y, X and E are as defined therein including R 1 is hydrogen, alkyl, aryl, cycloalkyl, 1,3-dithiolan-2-yl or 1, 3-dithian-2-yl, X is -CH 2 -C(R 13 ) (R 14 )- wherein R 13 and R 14 are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl,
  • R1, X and E are as defined therein including R 1 is hydrogen, alkyl, aryl, cycloalkyl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl, X is -CH 2 -C(R 13 ) (R 14 )- wherein R 13 and R 14 are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl,
  • dialkylamino or heterocyclic and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl;
  • R 7 , R 4 , R 10 , R 9 , R 10a , Q and J are as defined therein including r is 1-4, R 7 is alkyl, aryl or cycloalkyl, R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, R 10 and R 10a are independently selected from hydrogen and alkyl, R 9 is - (CH 2 ) s -NR 11 R 12 wherein s is 1-2 and R 11 and R 12 are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic) alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl
  • Q is -CH(OH)-, -CH(N(R 8 ))-, -CH(OH)CH 2 - or -CH (N (R 8 ) ) CH 2 - wherein R 8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino or substituted alkoxy;
  • r, R 7 , R 4 , R 10 , R 9 , R 10a , Q and J are as defined therein including r is 1-4, R 7 is alkyl, aryl or
  • R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl
  • R 10 and R 10a are independently selected from hydrogen and alkyl
  • R 9 is - (CH 2 ) s -NR 11 R 12 wherein s is 1-2 and R 11 and R 12 are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic) alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl substituted by -SO 3 H, aminocarbonylalkyl,
  • Q is -CH(OH)-, -CH(N(R 8 ))-, -CH(OH)CH 2 - or -CH(N(R 8 ))CH 2 - wherein R 8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino, substituted alkoxy,
  • r, R 7 , R 4 , Q and J are as defined therein including r is 1-4, R 7 is alkyl, aryl or cycloalkyl, R 4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, Q is -CH(OH)-, -CH(N(R 8 ))-, -CH(OH)CH 2 - or -CH (N (R 8 ) ) CH 2 - wherein R 8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is amino, hydroxy, substituted alkylamino or substituted alkoxy;
  • angiotensinogen having the formula NH— (alkyl, or amino acid alkylamide)
  • R' and R" are as defined therein including R' is fluoro and R" is hydrogen or fluoro;
  • n, R 2 , R 10 and E are as defined therein including n is 0-5, R 2 is hydrogen or alkyl, R 10 is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic) alkyl,
  • alkoxyalkyl, thioalkoxyalkyl, hydroxyalkyl or aminoalkyl and E is -CH (W) -G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is -Q-C(O)-T-U-V wherein Q is a bond or -CH(R 13 )- wherein R 13 is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, substituted alkoxy, amino or substituted amino;
  • n, R 7 , R 10 and E are as defined therein including n is 0-3, R 7 is alkyl or substituted alkyl, R 10 is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl,
  • E is -CH (W) -G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is -Q-C(O) -T-U-V wherein Q is a bond or -CH(R 13 )- wherein R 13 is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, s.ubstituted alkoxy, amino or substituted amino;
  • n is 1-2
  • R 2 is hydrogen or alkyl
  • R 3 is hydrogen, alkyl, aryl, arylalkyl, (heterocyclic) alkyl, cycloalkyl, alkoxy or cycloalkylalkyl
  • R 4 is (H,OH)
  • R 5 is hydrogen or alkyl
  • R 6 is hydrogen or alkyl
  • E is 0-2 amino acid residues
  • D is
  • sulfonylalkyl substituted carbonyl, substituted phosphonyl, phenyl, phenylalkyl, furyl, furylalkyl, thienyl, thienylalkyl, pyridyl, pyridylalkyl or other (heterocyclic) alkyl;
  • EP0309841 published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • n is 1-2, R 3 is hydrogen or alkyl, R 4 is
  • R 5 is (H,OH), (K,NH 2 ) or O
  • R 6 is
  • E is -SR 7 , -SOR 7 , -SO 2 R 7 , -SO 2 OR 7 or -SO 2 NR 7 R 8 wherein R 7 and R 8 are independently selected from R 4 ;
  • EP0292800 published Noyember 30, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
  • n, R 3 , R 4 , R 5 , R 6 , E, Q and Y are as defined therein including n is 1-2, R 3 is hydrogen or alkyl, R 4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R 5 is (H,OH), (H,NH 2 ), or O, R 6 is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl;
  • n, R 3 , R 4 , R 5 , R 6 , E, Q and Y are as defined therein including n is 1-2, R 3 is hydrogen or alkyl, R 4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic,
  • R 5 is (H,OR 12 ), (H,NR 12 R 13 ), or O wherein R 12 and R 13 are independently selected from hydrogen and alkyl, R 6 is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl; and
  • n, R2, R3, R4, E and Y are as defined therein including n is 1-2, R2 is hydrogen or alkyl, R3 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic,
  • R4 is hydrogen or alkyl
  • E is -C(O)NH-, -C(S)NH-, -C(O)O-, -SO2-, -SO2NH-, or -PO (OA) O- wherein A is
  • alkoxycarbonylalkyl substituted alkoxycarbonylalkyl, aminocarbonyl, substituted aminocarbonyl,
  • aminocarbonylalkyl substituted aminocarbonylalkyl
  • E-Y is pyrrolidinocarbonyl
  • substituted amino refers to:
  • Z is O, S or NH and R 8 is a C 1 to C 6 straight or branched carbon chain
  • aminoalkyl (N-protected) aminoalkyl, 1- amino-2-phenylethyl or 1-(N- protected) amino-2- phenylethyl.
  • substituted methylene group refers to:
  • R 13 is hydroxy then R 1 4 is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected) amino, (N- protected) (alkyl) amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R 13 is hydrogen then R 1 4 is not hydrogen or loweralkyl;
  • R 20 is N, (VI) -CH 2 CH(R 22 )C(O)NHR 23 wherein
  • R 24 is CH 2 or N and c) R 25 is NH, O, S or
  • R 22 is as defined above and
  • R 82 is i) loweralkyl
  • alkylaminoalkyl dialkylaminoalkyl or (heterocyclic) alkyl or
  • heterocyclic or (heterocyclic) alkyl wherein
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to preyent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, piyaloyl, t-butylacetyl, trichloroethoxycarbonyl, t- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or Daminoacyl residue, which may itself be N-protected similarly.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • loweralkenyl refers to a loweralkyl radical which contains at least one carbon- carbon double bond.
  • aminoalkyl refers to -NH 2 appended to a loweralkyl radical.
  • hydroxyalkyl refers to -OH appended to a loweralkyl radical.
  • alkylamino refers to a loweralkyl radical appended to an NH radical.
  • cycloalkyl refers to an aliphatic ring having 3 to 7 carbon atoms.
  • cycloalkylalkyl refers to an cycloalkyl group appended to a loweralkyl radical
  • cycloalkenyl refers to an aliphatic ring having 3-7 carbon atoms and also having at least one carbon-carbon double bond including, but not limited to, cyclohexenyl and the like.
  • cycloalkenylalkyl refers to a cycloalkenyl group appended to a loweralkyl radical.
  • alkoxy and thioalkoxy refer to R 30 O- and R 30 S-, respectiyely, wherein R 30 is a loweralkyl group or a cycloalkyl group.
  • alkoxyalkoxy refers to an alkoxy group appended to an alkoxy radical, including, but not limited to methoxymethoxy and the like.
  • alkoxyalkyl refers to an alkoxy group appended to a loweralkyl radical.
  • (thioalkoxy) alkyl refers to thioalkoxy appended to a loweralkyl radical.
  • dialkylamino refers to - NR 31 R 32 wherein R 31 and R 32 are independently selected from loweralkyl groups.
  • ((alkoxy) alkoxy) alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
  • (hydroxyalkyl) (alkyl) amino refers to -NR 33 R 34 wherein R 33 is hydroxyalkyl and R 34 is loweralkyl.
  • (N-protected) (alkyl) amino refers to -NR 34 R 35 wherein R 34 is a loweralkyl group and R 35 is an N-protecting group.
  • N-protected aminoalkyl refers to NHR 35 appended to a loweralkyl group, wherein R 35 is an N-protecting group.
  • alkylaminoalkyl refers to NHR 36 appended to a loweralkyl radical, wherein R 36 is a loweralkyl group.
  • (N-protected) (alkyl) aminoalkyl refers to NR 35 R 36 , which is appended to a loweralkyl radical, wherein R 35 and R 36 are as defined above.
  • dialkylaminoalkyl refers to NR 39 R 40 is appended to a loweralkyl radical wherein R 39 and R 40 are independently selected from loweralkyl.
  • carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
  • alkoxycarbonylalkyl refers to R 41 COR 42 - wherein R 41 is an alkoxy group and R 42 is a loweralkyl radical.
  • (amino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH 2 ).
  • ((N-protected) amino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR 43 wherein R 43 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) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR 43 R 44 wherein R 43 is as defined above and R 44 is a loweralkyl group.
  • (dialkylamino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR 45 R 46 wherein R 45 and R 4 6 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 43 wherein R 43 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 43 R 44 wherein R 43 and R 44 are as defined above.
  • (dialkylamino) alkoxycarbonyalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 43 R 44 wherein R 43 and R 44 are as defined above.
  • carboxyalkylamino refers to -NHR 47 wherein R 47 is a carboxyalkyl group.
  • alkoxycarbonylalkylamino refers to -NHR 48 wherein R 48 is an alkoxycarbonylakyl group.
  • (amino) carboxyalkylamino refers to -NHR 49 wherein R 49 is an (amino) carboxyalkyl group.
  • ((N-protected) amino) carboxyalkylamino) refers to -NHR 50 wherein R 50 is an ( (N- protected) amino) carboxyalkyl group.
  • (alkylamino) carboxyalkylamino refers to -NHR 51 wherein R 51 is an (alkylamino) carboxyalkyl group.
  • ((N-protected) alkylamino)- carboxyalkylamino) refers to -NHR 52 wherein R 52 is an ( (N-protected) alkylamino) carboxyalkyl group.
  • dialkylamino carboxyalkylamino refers to -NHR 53 wherein R 53 is a
  • ((N-protected) amino) alkoxycarbonylalkylamino) refers to -NHR 55 wherein R 55 is an ( (N-protected) amino) alkoxycarbonylalkyl group.
  • (alkylamino) alkoxycarbonylalkylamino refers to -NHR 56 wherein R 56 is an
  • ((N-protected) alkylamino) alkoxycarbonylalkylamino) refers to -NHR 57 wherein R 57 is an ((N-protected) alkylamino) alkoxycarbonylalkyl group.
  • dialkylamino alkoxycarbonylalkylamino refers to -NHR 58 wherein R 58 is a (dialkylamino) alkoxycarbonylalkyl group.
  • polyalkoxy refers to -OR 59 wherein R 59 is a straight or branched chain containing 1-5, C gg -O-C hh linkages wherein gg and hh are independently selected from 1 to 3, including, but not limited to methoxyethoxymethoxy, ethoxyethoxymethoxy and the like.
  • (dihydroxyalkyl) (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 ⁇ NR 60 R 61 wherein R 60 and R 61 are hydroxyalkyl residues.
  • alkoxyalkyl (alkyl) amino refers to -NR 62 R 63 wherein R 62 is an alkoxyalkyl group and
  • R 63 is a loweralkyl group.
  • di-(alkoxyalkyl) amino refers to -NR 64 R 65 wherein R 64 and R 65 are alkoxyalkyl groups.
  • (alkoxyalkoxyalkyl) (alkyl) amino refers to -NR 66 R 67 wherein R 66 is an
  • R 67 is a loweralkyl group.
  • di-(alkoxyalkoxyalkyl) amino refers to -NR 68 R 69 wherein R 68 and R 69 are
  • heterocyclic) alkyl) (alkyl) amino refers to an amino radical substituted by a loweralkyl group and an (unsubstituted heterocyclic) alkyl group or a (substituted heterocyclic) alkyl group, respectiyely.
  • heterocyclic alkyl or “heterocyclic ring substituted alkyl” as used herein refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to imidazolylmethyl and thiazolylmethyl.
  • alkyl refers to -N 3 appended to a loweralkyl radical.
  • alkylsulfonyl refers to R 70 S(O) 2 - wherein R 70 is a loweralkyl residue.
  • alkylsulfonylalkyl refers to an alkylsulfonyl group appended to a loweralkyl radical.
  • aryl refers to a monocyclic 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 below.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
  • arylalkyl refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, naphthylmethyl and the like.
  • aryloxy and thioaryloxy refer to R 71 O- or R 71 S-, respectiyely, wherein R 71 is an aryl group.
  • aryloxyalkyl and thioaryloxyalkyl refer to an aryloxy group or a thioaryloxy group, respectiyely, appended to a loweralkyl radical.
  • arylalkoxy and arylthioalkoxy refer to an aryl group appended to an alkoxy radical or a thioalkoxy radical, respectiyely, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like.
  • arylalkoxyalkyl and “arylthioalkoxyalkyl” as used herein refer to an arylalkoxy group or an
  • arylsulfonyl refers to arylsulfonyl
  • R 72 S(O) 2 - wherein R 72 is an aryl group.
  • arylsulfonylalkyl refers to an arylsulfonyl group appended to a loweralkyl radical.
  • alkylsulfonylamino refers to R 76 NH- wherein R 76 is an alkylsulfonyl group.
  • arylsulfonylamino refers R 77 NH- wherein R 77 is an arylsulfonyl group.
  • (heterocyclic) sulfonyl refers to R 72a S (O) 2- wherein R 72a is a heterocyclic group.
  • alkylaminocarbonylamino refers to R 78 NHCONH- wherein R 78 is a loweralkyl group.
  • alkylaminocarbonyloxy refers to R 79 NHC(O)O- wherein R 79 is a loweralkyl group.
  • alkoxycarbonyloxy refers to R 80 OC(O)O- wherein R 80 is a loweralkyl group.
  • halo or halogen as used herein refers to Cl, Br, F or I substituents.
  • haloalkyl refers to a loweralkyl radical in which one or more hydrogen atoms are replaced by halogen including, but not limited to,
  • O-protecting group refers to a substituent which protects hydroxyl groups and includes but is not limited to substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2- methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and tehahydropyranyl; substituted ethyl ethers, for example, 2,2,2-trichloroethyl, t-butyl, benzyl and triphenylmethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal,
  • cyclic ortho esters for example, methoxymethylene
  • cyclic carbonates for example, cyclic carbonates
  • cyclic boronates for example, methoxymethylene
  • heterocyclic group refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms may optionally be oxidized; wherein the nitrogen heteroatom may optionally be quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring
  • heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocyclics include: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl,
  • piperazinyl N-methyl piperazinyl, azetidinyl, N-methyl azetidinyl, pyrimidinyl, pyridazinyl, oxazolyl,
  • oxazolidinyl isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.
  • heterocyclics include imidazolyl, pyridyl, piperazinyl, N-methyl piperazinyl, azetidinyl, N- methyl azetidinyl, thiazolyl, thienyl, triazolyl and the following:
  • b is 1 or 2 and W is N, NH, O, S, provided that W is the point of connection only when T is N,
  • Y is NH, N-loweralkyl, O, S, or SO 2 , or
  • His refers to histidine, phenylalanine, homophenylalanine, alanine, leucine and norleucine,
  • each of the diastereomers is hydrolyzed and coupled to the amine (VI) using standard peptide coupling reagents such as N- methylmorpholine (NMM), 1-hydroxybenzotriazole (HOBT) and N-ethyl-N'-(3-dimethylamino ⁇ ropyl) carbodiimide (EDAC) to giye the desired compound (VII).
  • NMM N- methylmorpholine
  • HOBT 1-hydroxybenzotriazole
  • EDAC N-ethyl-N'-(3-dimethylamino ⁇ ropyl) carbodiimide
  • (VIII) is based on the fact that the compound deriyed from the L-isomer is generally a more potent renin inhibitor than the compound deriyed from the corresponding D-isomer.
  • Scheme III illustrates the preparation of compounds (XI). Reductiye amination of (IX,
  • R 2 loweralkyl
  • compound (VIII) can be coupled to amine (VI) to provide (XXII).

Abstract

L'invention concerne un composé d'inhibition de la rénine ayant la formule (I), dans laquelle A est un substituant; R1 représente hydrogène, alkyl inférieur, alkyl inférieur substitué ou alkényl inférieur; X représente CH2, CHOH, C(O), O, S, S(O), SO2, NH, N(O) ou -P(O)O-; R3 représente un alkyl inférieur, un alkényl inférieur ou un alkyl inférieur substitué; et T est une mimique du site de clivage Leu-Val de l'angiotensinogène; ou un sel, un ester ou un promédicament pharmaceutiquement acceptable de celui-ci.The invention relates to a renin inhibiting compound having the formula (I), wherein A is a substituent; R1 represents hydrogen, lower alkyl, substituted lower alkyl or lower alkenyl; X represents CH2, CHOH, C (O), O, S, S (O), SO2, NH, N (O) or -P (O) O-; R3 represents lower alkyl, lower alkenyl or substituted lower alkyl; and T is a mimicry of the Leu-Val cleavage site of angiotensinogen; or a pharmaceutically acceptable salt, ester or prodrug thereof.

Description

NON-PEPTIDE RENIN INHIBITORS
This is a continuation-in-part of U.S. Patent
Application Serial No. 393,721, filed August 14, 1989, which is a continuation-in-part of U.S. Patent Application Serial No. 253,282, filed October 4, 1988.
Technical Field
The presentinvention relates to novel compounds and compositions which inhibit renin, processes for making such compounds, synthetic intermediates employed in these processes, and a method of treating hypertension or congestive heart failure with such compounds or in
combination with another antihypertensive agent. The presentinvention also relates to compositions and a method for treating glaucoma with such compounds and a method of inhibiting retroyiral proteases and treating a retroviral infection with such compounds. Background Art
Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different
physiologic circumstances may cause the release of renin into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood yolume in the body; or (c) a fall in the
concentration of sodium in the distal tubules of the kidney.
When renin is released into the blood from the kidney, the renin-angiotensin system is actiyated, leading to yasoconstriction and conseryation of sodium, both of which result in increased blood pressure. The renin acts on a circulating protein, angiotensinogen, to cleaye out a fragment called angiotensin I (Al). Al itself has only slight pharamacologic activity but, after additional cleavage by a second enzyme, angiotensin conyerting enzyme (ACE), forms the potent molecule angiotensin II (All). The major pharmacological effects of All are yasoconstriction and stimulation of the adrenal cortex to release
aldosterone, a hormone which causes sodium retention.
Sodium retention causes blood yolume to increase, which leads to hypertension. All is cleayed by an aminopeptidase to form angiotensin III (AIII), which, compared to All, is a less potent yasoconstrictor but a more potent inducer of aldosterone release.
Angiotensinogen, the natural substrate for human renin has the following amino acid sequence. H2N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Protein 1 2 3 4 5 6 7 8 9 10 11 12 13
(Angiotensinogen)
RENIN
H2N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-OH (Al )
Renin cleayes angiotensinogen at the amide bond between amino acid residues 10 and 11 to giveangiotensin I (Al).
Compounds which are inhibitors of renin generally comprise two parts. One part of the compound mimics the first 9 amino acid residues of angiotensinogen. The other part mimics the Leu-Val cleavage site of angiotensinogen and is designed to be non-cleayable by renin. When these two parts are combined in one compound, the compound binds to renin but is not cleayed. Thus, renin is inhibited from acting on its natural substrate angiotensinogen.
Inhibitors of renin haye been sought as agents for control of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
With these objectiyes in mind, the renin-angiotensin system has been modulated or manipulated, in the past, with ACE inhibitors. Howeyer, ACE acts on seyeral substrates other than angiotensin I (Al), most notably the kinins which cause such undesirable side effects as pain, "leaky" capillaries, prostaglandin release and a yariety of behayorial and neurologic effects. Further, ACE inhibition leads to the accumulation of Al. Although Al has much less yasoconstrictor activity than All, its presence may negate some of the hypotensiye effects of the blockade of All synthesis.
Inhibition of other targets in the renin-angiotensin system such as All with compounds such as saralasin can block All actiyity, but would leaye unimpaired and perhaps enhance the hypertensiye effects of AIII.
On the other hand, there are no known side effects which result when renin is inhibited from acting on its substrate. Considerable research efforts haye thus been carried out to deyelop useful inhibitors of renin. Past research efforts haye been directed to renin antibodies, pepstatin, phospholipids and substrate analogs such as tetrapeptides and octapeptides to tridecapeptides. These inhibitors either demonstrate poor activity in inhibiting renin production or poor specificity for inhibiting renin only. Howeyer, Boger et al. haye reported that statinecontaining peptides possess potent and specific renininhibiting activity (Nature, Vol. 303, p. 81, 1983). In addition, Szelke and co-workers haye described polypeptide analogs containing a non-peptide link (Nature, Vol. 299, p. 555, 1982) which also cause potent renin inhibition and show a high specificity for this enzyme. Recent patents haye disclosed novel small peptide renin inhibitors which contain novel dipeptide isosteres as transition state analogs (Szelke, et al., U.S. Patent No. 4,609,643; Boger, et al., U.S. Patent No. 4,668,770; Baran, et al., U.S.
Patent No. 4,657,931; Matsueda, et al., U.S. Patent No. 4,548,926; Luly, et al., U.S. Patent No. 4,645,759; and Luly, et al., U.S. Patent No. 4,680,284). The following references disclose peptide renin inhibitors which incorporate hydroxyl, substituted amide and heterocyclic deriyatiyes of statine and statine
analogs:
Luly, et al., U.S. Patent No. 4,845,079, issued July 4, 1989;
Fung, et al., PCT Patent Application No. WO88/05050, published July 14, 1988;
Luly, et al., U.S. Patent No. 4,725,584, issued February 16, 1988;
Luly, et al., U.S. Patent No. 4,680,284, issued July 14, 1987;
Rosenberg, et al., U.S. Patent No. 4,837,204, issued June 6, 1989;
Baran, et al., U.S. Patent No. 4,657,931, issued April 14, 1987;
Matsueda, et al., U.S. Patent No. 4,548,926, issued October 22, 1985;
Morisawa, et al., European Patent Application No. 0228192, published July 8, 1987;
Ten Brink, PCT Patent Application No. WO87/02986, published May 21, 1987;
Buhlmayer, et al., U.S. Patent No. 4,727,060, issued
February 23, 1988;
Buhlmayer, et al., U.S. Patent No. 4,758,584, issued July 19, 1988;
Szelke, et al., U.S. Patent No. 4,713,445, issued December 15, 1987;
Raddatz, et al., U.S. Patent No. 4,755,592, issued July 5, 1988; Raddatz, et al., Australian Patent Application No. AU
76222/87, published February 4, 1988;
Ryono, et al., European Patent Application No. EP 0231919, published August 12, 1987;
Hanson, Biochem. Biophys. Res. Commun. 132155 (1985);
Luly, European Patent Application No. EP0189203, published
July 30, 1986;
Hanson, et al., European Patent Application No. EP0310070, published April 5, 1989;
Hanson, et al., European Patent Application No. EP0310071, published April 5, 1989;
Hanson, et al., European Patent Application No. EP0310072, published April 5, 1989;
Hanson, et al., European Patent Application No. EP0310073, published April 5, 1989; and
Gante, et. al., German Patent Application No. DE3721855, published September 22, 1988.
Boger, et al., U.S. Patent No. 4,782,043, issued Noyember 1, 1988, discloses cyclic peptide renin inhibitors in combination with other antihypertensive agents.
Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989, discloses tripeptide renin inhibitors in
combination with other antihypertensive agents.
Watkins, PCT Patent Application No. WO87/02581, published May 7,1987, discloses the use of renin inhibitors for the treatment of glaucoma.
Stein, et al., European Patent Application No.
EP0311012, published April 12, 1989, discloses renin inhibitors having a diol substituent which are antiglaucoma agents. Peptidyl inhibitors of HIV protease are disclosed by Moore, Biochem. Biophys. Res. Commun., 159 420 (1989); Billich, J. Biol. Chem., 263 1790S (1988); and Richards, FEBS Lett., 247 113 (1989).
Disclosure of the Invention
In accordance with the presentinvention, there are renin inhibiting compounds of the formula:
(1)
or a pharmaceutically acceptable salt, ester or prodrug thereof.
A is
(I) R5C(O)-(CH2)w- wherein
1) w is 0 to 4 and
2) R5 is
i) hydroxy,
ii) alkoxy,
iii) thioalkoxy,
iy) amino or
y) substituted amino;
(II) alkylsulfonyl, (aryl) sulfonyl or
(heterocyclic) sulfonyl;
(III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyl; or
(IV) R90- or R90NHC(O)- wherein R90 is a C1 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).
R1 is
(I) hydrogen,
(II) loweralkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) aryloxyalkyl,
(VII) thioaryloxyalkyl,
(VIIII) arylalkoxyalkyl,
(IX) arylthioalkoxyalkyl or
(X) a C1 to C3 straight or branched
carbon chain substituted by a substituent selected from
1) alkoxy,
2) thioalkoxy,
3) aryl and
6) heterocyclic.
X is
(I) CH2,
(II) CHOH,
(III) C(O),
(IV) NH, (V) O,
(VI) S,
(VII) S(O),
(VIII) SO2,
(IX) N(O) or
(X) -P(O)O-.
R3 is
(I) loweralkyl,
(II) haloalkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) alkoxyalkyl,
(VII) thioalkoxyalkyl,
(VIII) (alkoxyalkoxy) alkyl,
(IX) hydroxyalkyl,
(X) -(CH2)eeNHR12
wherein
1) ee is 1 to 3 and
2) R12 is
i) hydrogen,
ii) loweralkyl or
iii) an N-protecting group;
(XI) arylalkyl or
(XII) (heterocyclic) alkyl.
T is a mimic of the Leu-Val cleavage site of angiotensinogen. The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein includes
wherein R4 is
(I) loweralkyl,
(II) cycloalkylalkyl
(III) cycloalkenylalkyl or
(III) arylalkyl; and
D is
(I) wherein R73 is loweralkyl,
(II)
w herein
1) M is
i) O,
ii) S or
iii) NH;
2 ) . Q is i) O or
ii) S;
3) E is
i) O,
ii) S,
iii) CHR73 wherein R73 is
loweralkyl,
iy) C=CH2 or
y) NR18 wherein R18 is
a) hydrogen,
b) loweralkyl,
c) hydroxyalkyl,
d) hydroxy,
e) alkoxy,
f) amino or
g) alkylamino;
and
4) G is
i) absent,
ii) CH2 or
iii) NR19 wherein R19 is
hydrogen or loweralkyl,
with the proyiso that when G is NR19, then R18 is loweralkyl or
hydroxyalkyl;
(III) wherein
1) y is 0 or 1 and
2) R21 is
i) NH,
ii) O,
iii) S or
iy) SO2; or
(IV) a substituted methylene group.
The term "mimic of the Leu-Val cleavage site of angiotensinogen" as used herein also includes the
substituents (T) disclosed in the following references:
Luly, et al., U.S. Patent No. 4,645,759, issued February 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R4, R5, R6 , R7, R8 , R9 and X are as defined therein;
Luly, et al., U.S. Patent No. 4,652,551, issued March 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula wherein R4, R5, R6, R7, R8, R9 and X are as defined therein;
Luly, et al., U.S. Patent No. 4,680,284, issued July 14, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula .
wherein R3 is as defined therein;
Luly, et al., U.S. Patent No. 4,725,584, issued February 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3 and R4 are as defined therein; Luly, et al., U.S. Patent No. 4,725,583, issued February 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4 and R5 are as defined therein;
Rosenberg, et al., U.S. Patent No. 4,837,204, issued June 6, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R4, R5, R6, R7 and X are as defined therein;
Luly, et al., U.S. Patent No. 4,845,079, issued July 4, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, R6, R7, R8 and R9 are as defined therein; 8. Sham, U.S. Patent No. 4,826,958, issued May 2, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, R6, R7, R9 and X are as defined therein;
Rosenberg et al., U.S. Patent No. 4,857,507, issued August 15, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R4, R5, R6, R7, R8, R9 and E are as defined therein;
Luly, et al., U.S. Patent No. 4,826,815, issued May 2, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, R6, R7, R8, R9 and X are as defined therein;
Bender, et al., U.S. Patent No. 4,818,748, issued April 4, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, J, L, M and Q are as defined therein;
Fuhrer, et al., U.S. Patent No. 4,613,676, issued
September 23, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R3, R4, R5 and R6 are as defined therein;
Riniker, et al., U.S. Patent No. 4,595,677, issued June 17, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R2, R3 and R4 are as defined therein;
Buhlmayer, et al., U.S. Patent No. 4,727,060, issued February 23, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R3, R4, R5 and R6 are as defined therein;
Buhlmayer, et al., U.S. Patent No. 4,758,584, issued July 19, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R2, R3, R4, R5 and R6 are as defined therein;
Szelke, et al., U.S. Patent No. 4,609,643, issued
September 2, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-A-B-Z-W
wherein A, B, Z and W are as defined therein;
Szelke, et al., U.S. Patent No. 4,650,661, issued March 17, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
-A-B-Z-W
wherein A, B, Z and W are as defined therein;
Szelke, et al., U.S. Patent No. 4,713,445, issued December 15, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
-A-B-Z-W
wherein A, B, Z and W are as defined therein;
Iizuka, et al., U.S. Patent No. 4,656,269, issued April 7, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, X and R2 are as defined therein;
Iizuka, et al., U.S. Patent No. 4,711,958, issued Decembe: 8, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein X is as defined therein;
Kleinman, et al., U.S. Patent No. 4,729,985, issued March 8, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R1, R2, m, W2, R3 and R4 are as defined therein;
Hooyer, U.S. Patent No. 4,668,769, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein X and R2 are as defined therein;
Hooyer, et al., U.S. Patent No. 4,814,342, issued March 21, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein X, W and Z1 are as defined therein;
Bindra, et al., U.S. Patent No. 4,749,687, issued June 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R2 and R3 are as defined therein;
Hooyer, et al., U.S. Patent No. 4,814,342, issued March 21, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein X, W and Z1 are as defined therein;
Matsueda, et al., U.S. Patent No. 4,698,329, issued
October 6, 1987, which is hereby incorporated by
reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3 and X are as defined therein;
Matsueda, et al., U.S. Patent No. 4,548,926, issued
October 22, 1985, which is hereby incorporated by
reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein But and X are as defined therein;
Wagnon, et al., U.S. Patent No. 4,725,580, issued February 16, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein Z1, X, Y and R4 are as defined therein;
Wagnon, et al., U.S. Patent No. 4,746,648, issued May 24, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein Z1 , X, Y and R4 are as defined therein;
Cazaubon, et al., U.S. Patent No. 4,481,192, issued
Noyember 6, 1984, which is hereby incorporated by
reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-Statyl1-Ala-Statyl2-R'
wherein Statyli, Ala, Statyl2 and R' are as defined therein;
Hansen, et al., U.S. Patent No. 4,722,922, issued February 2, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4, R5, n and R6 are as defined therein;
Hansen, et al., U.S. Patent No. 4,510,085, issued April 9, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2 is as defined therein;
Baran, et al., U.S. Patent No. 4,657,931, issued April 14, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, n and R5 are as defined therein;
Hansen, et al., U.S. Patent No. 4,514,332, issued April 30, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
Natarajan, et al., U.S. Patent No. 4,757,050, issued July 12, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R1, R2, R3, q, R9 and R10 are as defined therein;
Gordon, U.S. Patent No. 4,749,781, issued June 7, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R2, R3 and R9 are as defined therein;
Ryono, et al., U.S. Patent No. 4,665,193, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R2, R3, R4 and A are as defined therein;
Ryono, et al., U.S. Patent No. 4,616,088, issued October 7, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R1, R2, R3, R4 and A are as defined therein;
Ryono, et al., U.S. Patent No. 4,629,724, issued December 16, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R1, R2, R3, R4, R, R12 and A are as defined therein; Patel, U.S. Patent No. 4,820,691, issued April 11, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1 and R3 are as defined therein;
Thaisriyongs, U.S. Patent No. 4,705,846, issued Noyember 10, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
-E10-F11-G12-H13-I14-Z
wherein E10, F11, G12, H13, I14 and Z are as defined therein;
Hudspeth, et al., U.S. Patent No. 4,743,585, issued May 10, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
-T-(C)n-W-(D)n-V-(E)n-U
wherein T, C, W, D, V, E, U and n are as defined therein;
Hudspeth, et al., U.S. Patent No. 4,735,933, issued April 5, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
-Y-W-U
wherein Y, W and U are as defined therein;
Kaltenbronn, et al., U.S. Patent No. 4,804,743, issued February 14, 1989, which is hereby incorporated by
reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-T-U-V-W
wherein T, U, V and W are as defined therein;
Pinori, et al., U.S. Patent No. 4,560,505, issued December 24, 1985, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein Tyr and Lys are as defined therein;
Yamato, et al., U.S. Patent No. 4,683,220, issued July 28, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
Boger, et al., U.S. Patent No. 4,668,770, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3, R4, q, B, D and E are as defined therein;
Boger, U.S. Patent No. 4,668,663, issued May 26, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3, R4, m', E, B and F are as defined therein;
Bock, et al., U.S. Patent No. 4,636,491, issued January 13, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4, m' and E are as defined therein;
Eock, et al., U.S. Patent No. 4,663,310, issued May 5, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein G, R4, J, B and L are as defined therein;
Boger, et al., U.S. Patent No. 4,661,473, issued April 28, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein G, R4, J, B and L are as defined therein; Veber, et al., U.S. Patent No. 4,479,941, issued October 30, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4 and E are as defined therein;
Boger, et al., U.S. Patent No. 4,470,971, issued September 11, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4, R5, B and E are as defined therein;
Veber, et al., U.S. Patent No. 4,384,994, issued May 24, 1983, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R2, R3, R4 and B are as defined therein;
Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-G-J
wherein G and J are as defined therein;
Eyans, U.S. Patent No. 4,665,055, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, B and C are as defined therein;
Eyans, et al., U.S. Patent No. 4,609,641, issued September 2, 1986, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R1, R2, X, Y, B and C are as defined therein; Patchett, et al., U.S. Patent No. 4,839,357, issued June 13, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
-G-J
wherein G and J are as defined therein;
Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-G-J
wherein G and J are as defined therein;
Boger, U.S. Patent No. 4,665,052, issued May 12, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3, R4, R5, m and F are as defined therein;
Veber, et al., U.S. Patent No. 4,478,826, issued October; 23, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4, R4a, B and E are as defined therein;
Boger, et al., U.S. Patent No. 4,485,099, issued Noyember 27, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4, R5, m and F are as defined therein;
Boger, et al., U.S. Patent No. 4,477,440, issued October 16, 1984, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R3, R4 , m", E, F and G are as defined therein; Raddatz, et al., U.S. Patent No. 4,721,776, issued January 26, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
3
wherein R2, R3, R4, R5, n, B and D are as defined therein;
Holzemann, et al., U.S. Patent No. 4,709,010, issued Noyember 24, 1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R, R1, R2, n and Y are as defined therein;
Raddatz, et al., U.S. Patent No. 4,812,555, issued March 14, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of
angiotensinogen having the formula
wherein R2, R3, R4, n and E are as defined therein; Raddatz, et al., U.S. Patent No. 4,755,592, issued July 5, 1988, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-W-E-W'-Y
wherein W, E, W and Y are as defined therein;
Raddatz, et al., U.S. Patent No. 4,666,888, issued May 19,
1987, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, E, G and Y are as defined therein;
Wagnon, et al., U.S. Patent No. 4,840,935, issued June 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, Q and X are as defined therein; lizuka, et al., U.S. Patent No. 4,841,067, issued June 20, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n and X are as defined therein;
Raddatz, et al., U.S. Patent No. 4,829,053, issued May 9, 1989, which is hereby incorporated by reference, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-N(R2)-CH(R3)-CR4-(CHR5)n-C(O)-E-N(R6)-(CH(R7))s-D wherein n, s, R2, R3, R4, R5, R6, R7, E and D are as defined therein;
European Patent Application No. EP0264106, published April 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, R6 and R7 are as defined therein including R4 is hydrogen or loweralkyl; R5 is hydrogen, loweralkyl or an amino acid residue; R6 is loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl and R7 is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or an N- heterocycle;
European Patent Application No. EP0272583, published June 29, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R5, R6, R7 and R8 are as defined therein including R5 is hydrogen or loweralkyl; R6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an amino acid residue; and R7 and R8 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl or arylalkyl;
European Patent Application No. EP0309766, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R5, R6 and A are as defined therein including R5 is hydrogen or loweralkyl; R6 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl or
heterocyclic; and A is -CH (OH) - (CH)q-R7 wherein q is 0-5 and R7 is hydrogen, loweralkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclic,
substituted thioalkyl, substituted sulfone, substituted sulfoxide, substituted amine, quaternized amine,
heterocyclic, carboxyalkyl, alkoxycarbonylalkyl or amidoalkyl;
European Patent Application No. EP0300189, published January 25, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4 is as defined therein including R4 is
loweralkyl;
European Patent Application No. EP0283970, published September 28, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4 is as defined therein including R4 is
loweralkyl;
European Patent Application No. EP0255082, published
February 3, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R3 and R4 are as defined therein including R2 is hydrogen, alkyl, cyclcoalkyl, cycloalkylalkyl, aryl or arylalkyl; R3 is hydrogen, alkyl or arylalkyl; and R4 is -X-(CH2)n'-R7 wherein X is absent, O or S, n' is 0-4 and R7 is hydrogen, hydroxy, amino, heteroaryl or -CH(R9)-(CH2)p- Y-(CH2)q-R10 wherein p, q, Y and R10 are as defined therein;
European Patent Application No. EP0230242, published July 29, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R3 and R4 are as defined therein including R2 is hydrogen, alkyl, cycloalkylalkyl, aryl or arylalkyl; R3 is hydrogen, alkyl or alkenyl; and R4 is -N (R5) -CH (R6) - (CH2)n-Ar or -N (R5) -CH (R6) -CH=CH- (CH2) m-Ar wherein n is 0- 6, m is 0-4, R5 is hydrogen or alkyl and R6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, thioalkoxyalkyl,
carboxyalkyl, alkoxycarbonylalkyl, haloalkyl,
alkylaminoalkyl, alkoxycarbonylaminoalkyl or
arylalkoxycarbonylaminoalkyl;
European Patent Application No. EP0310015, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R3, R4 and R9 are as defined therein including R2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl; R3 is hydrogen, alkyl, aryl or arylalkyl; R9 is hydroxy or fluoro; and R4 is - (CH2)p-X-(CH2)q-R7 wherein p is 0-4, q is 0-4, X is -CF2-, -C (O) - or -CH(R8)- wherein R8 is alkyl, alkoxy, thioalkoxy, alkylamino, hydroxy, azido or halo and R7 is hydrogen, hydroxy, amino, aryl or heteroaryl;
European Patent Application No. EP0315574, published May 10, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
(B is a boron atom) wherein R2, X, Y, R3 and R4 are as defined therein
including R2 is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, aryl or heterocyclic; X and Y are
independently selected from O or -N(R13)- wherein R13 is hydrogen, alkyl or substituted alkyl; and R3 and R4 are independently selected from hydrogen, alkyl or aryl; or the boron containing substituent is a boron containing cyclic group;
Japanese Patent Application No. J63275552, published
Noyember 14, 1988 discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
European Patent Application No. EP0252727, published
January 13, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein Y and R are as defined therein including Y is O or NH and R is alkyl, cycloalkyl or halogenated alkyl; European Patent Application No. EP0244083, published
Noyember 4, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein X is as defined therein including X is alkoxy, alkyalamino, cycloalkyloxy, morpholino and haloalkoxy.
European Patent Application No. EP0216539, published April 1, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, Y and R2 are as defined therein including n is 0-1, Y is O or NH and R2 is alkyl;
European Patent Application No. EP0206807, published December 30, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, Z and R are as defined therein including n is 0- 1, Z is 0 or NH and R is alkyl;
European Patent Application No. EP0190891, published
August 13, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n and X' are as defined therein including n is 0-1 and X1 is alkoxycarbonyl, aralkoxycarbonyl, or -C(O)NR1R2 wherein R1 is hydrogen, alkyl or aralkyl and R2 is alkyl or -CH2-Y-R wherein Y is O or NH and R is alkyl or aralkyl;
European Patent Application No. EP0181110, published May 14, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3 and R4 are as defined therein including R3 is -CHO or -CH2OH and R4 is isobutyl or benzyl; European Patent Application No. EP0297816, published
January 4, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R1 and R2 are as defined therein including n is 0-1, R1 is -NH2, alkylamino, alkoxy, or
2-alkoxycarbonylpyrrolidin-1-yl and R2 is alkyl, alkenyl, haloalkenyl or azide substituted alkenyl;
European Patent Application No. EP0297815, published
January 4, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein Y and R2 are as defined therein including Y is -CH(OH)- or -C(O)- and R2 is -CF2C (O)NHCH3, -CF3 or
-CF2C (CH2CH (CH3) 2) CO2C2H5;
European Patent Application No. EP0212903, published March 4, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein m, R1, R2, R3, R4 and W2 are as defined therein including m is 0-1, R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, phenyl, naphthyl,
cycloalkyl, cycloalkenyl, phenylalkyl, naphthylalkyl, cycloalkylalkyl and cycloalkenylalkyl, R3 and R4 are independently selected from alkyl, phenyl, naphthyl, cycloalkyl, adamantyl, phenylalkyl, naphthylalkyl,
cycloalkylalkyl and adamantylalkyl; or R3 is hydrogen and R4 is -CH(R7) (CH2)P(Q)rCH(R8) (CH2)q-Y wherein p and q are independently selected from 0,1,2,3,4,5 and 6, r is 0-1, Q is -CH2-, -CH=CH-, -O-, -NH-, -CH(OH)- or -C (O) -, Y is methyl, phenyl, -C(O)OR9, -C(O)NR9R10, -C (O) NHC (O) OCH2C6H5, -NH2, -NHC(O)CH2C6H5, -NHCH (CH2C6H5) C (O) OR9 or
-NHCH (CH2C6H5)C (O)NR9R10 wherein R9 and R10 are
independently selecterd from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl, and R7 and R8 are independently selecterd from hydrogen, alkyl, phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl or adamantyl; or R3 and R4 taken together with the nitrogen to which they are attached form a pyrrole, indoline,
isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydroazepine or
morpholine ring; and W2 is -NHCH ( (CH2)3R6) -C (O) - wherein R6 is -NH2, -NHC(=NH)NH2 or -CH2NH2; PCT Patent Application No. WO 88/03022, published May 5, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, Y and D are as defined therein including n is 0- 1, Y is isobutyl, allyl or benzyl and D is 2- carboxypyrrolidin-1-yl or -ZR wherein Z is O or NH and R is alkyl, phenyl or substituted alkyl or substituted phenyl;
German Patent Application No. DE3725137, published August 6, 1986, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the .formula
wherein R, R1, R2, R3, R4, R5, R6, B and Y are as defined therein including R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl, R1 is hdyroxy, alkoxy or aryloxy, R2 is hydrogen or R1 and R2 taken together is oxo (=O), R3, R4, R5 and R6 are independently selected from hydrogen, fluoro, chloro, alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heteroaryl and heteroarylalkyl, B is a peptide chain containinσ from 1 to 10 amino acid residues and Y is hydroxy or a protecting group for the peptide carboxy group;
British Patent Application No. GB2203740, published
October 26, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R2, R3, R4 and B are as defined therein
including R1 is a hdyrophobic or hydrophilic side chain, R2 is hydroxy or amino, R3 is hydrogen or R2 and R3 taken together is oxo (=O), R4 is a hydrophobic or hydrophilic side chain and B is
-NHCH (R6) C (R7) (R8)C(R9) (R10) CH2C(O)NR11R12 wherein R6 is R1, R7 and R8 are the same as R2 and R3, R9 and R10 are
independently selected from hydrogen and fluoro and R11 and R12 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and -CH (R13) C (O) R14 wherein R13 is alkyl or hydroxyalkyl and R14 is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl;
British Patent Application No. GB2200115, published July 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
R1, R2, R3, R4, R5, D and Y are as defined therein
including R1 is hydrogen or alkyl, R2 is an amino acid side chain, R3 is hydrogen, hydroxy, aryloxy or amino, R4 and R5 are independently selected from hydrogen, alkyl, arylalkyl, heteroarylalkyl and -CH (R12) C (O) R13 wherein R12 is alkyl or hydroxyalkyl and R13 is hydroxy, alkoxy, amino, alkylamino, aminomethylpyridyl or benzyl; or -NR4R5 represents
pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or substituted piperazinyl; D is a bond, O, -N(R1)- or
-CH(R1)- and Y is -C(O)-, -S(O)2- or -P(O)-;
German Patent Application No. DE3830825, published March 23, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4, R5, R6, R7, R8, R9, R10 and X are as defined therein including R4 is a hydrophilic or hydrophobic amino acid side chain, R5 is hydroxy or amino, R6 is hydrogen or R5 and R6 taken together are oxo (=O), R7 and R8 are independently selected from hydrogen and fluoro, R9 and R10 are independently selected from hydrogen, alkyl and
-CH(R11) C (O)R12 wherein R11 is alkyl or hydroxyalkyl and R12 is hdyroxy, alkoxy, amino, alkylamino, aminomthylpyridyl, benzyl or -NH- (CH2CH2O)m-R1 wherein m is 1-20 and R1 is as defined therein; and X is a bond or O, NH or -C(R13) (R14)- wherein R13 and R14 are independently selected from
hydrogen, fluoro or R4; Japanese Patent Application No. J62246546, published
October 27, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein m, R4 and R5 are as defined therein including m is 0-1, R4 is alkyl, cycloalkyl or phenyl and R5 is alkyl or substituted alkyl as defined therein;
European Patent Application No. EP0274259, published July 13, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R4 and R5 are as defined therein including R4 is alkyl, hydroxyalkyl, (heterocyclic) alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl and R5 is hydrogen or alkyl;
European Patent Application No. EP0228192, published July 8, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein m, n, R5, R6 and R7 are as defined therein
including m and n are independently selected from 0 and 1, R5 is alkyl, cycloalkyl or phenyl, R6 is alkyl and R7 is alkyl or substituted alkyl as defined therein;
European Patent Application No. EP0273893, published July 6, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R5, R6 and Y are as defined therein including R5 is alkyl or cycloalkyl, R6 is hydrogen or alkyl and Y is -SCH(CH3)2 or -S(O)2CH(CH3)2;
European Patent Application No. EP0310070, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
OH
wherein R1, R5 and R7 are as defined therein including R1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
alkylcycloalkenyl or alkoxycarbonyl, R5 is hydrogen or alkyl and R7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
European Patent Application No. EP0310071, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R5 and R7 are as defined therein including R1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
alkylcycloalkenyl or alkoxycarbonyl, R5 is hydrogen or alkyl and R7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
European Patent Application No. EP0310072, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R5 and R7 are as defined therein including R1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
alkylcycloalkenyl or alkoxycarbonyl, R5 is hydrogen or alkyl and R7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl; European Patent Application No. EP0310073, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R5 and R7 are as defined therein including R1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
alkylcycloalkenyl or alkoxycarbonyl, R5 is hydrogen or alkyl and R7 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
European Patent Application No. EP0313847, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, R5 and R6 are as defined therein including R1 is hydrogen, alkyl, haloalkyl, alkylcycloalkyl,
alkylcycloalkenyl or alkoxycarbonyl, R5 is hydrogen or alkyl and R6 is cycloalkyl, phenyl, cycloalkylalkyl or phenylalkyl;
European Patent Application No. EP0296581, published December 28, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1 and R3 are as defined therein including R1 is hydrogen, arylalkyl, aryl, (heterocyclic) alkyl or
heterocyclic and R3 is hydrogen, alkyl, haloalkyl,
arylalkyl, (heterocyclic) alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, thioalkoxyalkyl,
hydorxyalkoxyalkyl, aminoalkoxyalkyl,
hydroxythioalkoxyalkyl, carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl;
European Patent Application No. EP0231919, published
August 12, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1 and R3 are as defined therein including R1 is an N-heterocyclic ring and R3 is hydrogen, alkyl,
cycloalkylalkyl, haloalkyl, arylalkyl, (heterocyclic) alkyl, hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, tioalkoxyalkyl, hydroxyalkoxyalkyl,
aminoalkoxyalkyl, hydroxythioalkoxyalkyl, carboxyalkyl, aminothioalkoxyalkyl, guanidinoalkyl, aminocarbonylalkyl or imidazolylalkyl; PCT Patent Application No. WO 87/05302, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-E10-F11-G12-H13-I14-Z wherein Eio, F11, G12, H13, I14 and Z are as defined therein including -E10-F11- is
wherein R1 is hydrogen, alkyl, aryl, cycloalkyl,
heterocyclic, alkoxy or thioalkoxy, R11 is hydrogen, alkyl benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,
arylalkyl, (heterocyclic) alkyl, alkoxyalkyl or
thioalkoxyalkyl, R22 is hydrogen or alkyl and R23 is hydroxyalkyl, aminoalkyl, aryl or alkyl, G12 is absent or an amino acid residue, H13 is absent or an amino acid residue, I14 is absent or an amino acid residue and Z is hydroxy, substituted alkoxy, substituted amino or cyclic amino;
PCT Patent Application No. WO 87/02986, published May 21, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-E10-F11-G12-H13-I14-Z wherein E10, F11, G12, H13, I14 and Z are as defined therein including -E10-F11- is
wherein R1 is hydrogen, alkyl, aryl, cycloalkyl,
heterocyclic, alkoxy or thioalkoxy, R11 is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,
arylalkyl, (heterocyclic) alkyl, alkoxyalkyl or
thioalkoxyalkyl, R21 is hydroxy or amino, R22 is hydrogen or alkyl and R23 is hydroxy, amino, hydroxyalkyl,
aminoalkyl, aryl or alkyl, G12 is absent or an amino acid residue, H13 is absent or an amino acid residue, I14 is absent or an amino acid residue and Z is hydroxy,
substituted alkoxy, substituted amino or cyclic amino;
PCT Patent Application No. WO 89/00161, published January 12, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R4, R5, X, Y and Z are as defined therein including R2 is hydrogen or alkyl, R4 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclic, hydroxyalkyl or aminoalkyl, R5 is hydrogen, alkyl, arylalkyl, (heterocyclic) alkyl or cycloalkyl, X is -CH(OH)-, -CH(NH2)-, -C(O)-,
-CH(OH)CH(OH)-, -CH(OH)CH2-, -CH (NH2) CH2-, -C(O)-CH2-, -CH2-NH-, -CH2-O- or -P(O) (A)B- wherein A is hydroxy or amino and B is absent, O, NH or CH2, Y is absent or
-NHCH (R5) C (O)- and Z is hydroxy,- substituted alkoxy, substituted amino or N-heterocyclic;
PCT Patent Application No. WO 88/07053, published
Septmeber 22, 1988, discloses mimics of the Leu-Val
cleavage site of angiotensinogen having the formula
wherein r, t, R90, R100, R110, R111, G12, H13, I14 and Z are as defined therein including r is 0-3, t is 0-3, R90 is hydrogen or alkyl, R100 is hydrogen, alkyl, aryl,
cycloalkyl, heterocyclic, alkoxy or thioalkoxy, R110 and R111 are independently selected from hydrogen, alkyl, aryl, arylalkyl and halo, G12 is absent, an amino acid residue or
wherein R50 is hydrogen, alkyl, arylalkyl,
(heterocyclic) alkyl, cycloalkylalkyl or adamantyl, and R60 and R61 are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R60 and R61 taken together form a carbocyclic or heterocyclic
spirocycle, H13 is absent an amino acid residue or
wherein R50 is hydrogen, alkyl, arylalkyl,
(heterocyclic) alkyl, cycloalkylalkyl or adamantyl, and R60 and R61 are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R60 and R61 taken together form a carbocyclic or heterocyclic
spirocycle, I14 is absent an amino acid residue or wherein R50 is hydrogen, alkyl, arylalkyl,
(heterocyclic) alkyl, cycloalkylalkyl or adamantyl, and R60 and R61 are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl and adamantyl; or R60 and R61 taken together form a carbocyclic or heterocyclic
spirocycle and Z is hydroxy, alkoxy, substituted alkoxy, amino, substituted amino or cyclic amino;
PCT Patent Application No. WO 88/02374, published April 7, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula a) -E10-F11-C(=Y)-G12-H13-Z,
b) -E10-F11-W,
c) -E10-F11-G12-H13-W or
d) -E10-F11-G121-H131-I14-Z wherein E10, F11, G12, H13, G121, H131, I14, W, Y and Z are as defined therein including -E10-F11- is
wherein R and R1 are independently selected from alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy or thioalkoxy, R11 is alkyl, cycloalkyl, aryl, substituted alkyl as defined therein, alkoxy, thioalkoxy, hydrogen, hydroxyalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic) alkyl, alkoxyalkyl and thioalkoxyalkyl, R22 is hydrogen or alkyl, R23 is hydroxy, hydroxyalkyl, amino, aminoalkyl, aryl or alkyl, R24 is aryl, amino, alkylamino, dialkylamino, trialkylamino, heterocyclic, hydroxy, alkoxy, alkanoyloxy, mercapto, carboxy, alkoxycarbonyl, dialkylaminoalkoxycarbony1, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl, cyclicamino, cycloalkylamino, guanidinyl, cyano, N-cyanoguanidinyl, cyanoamino, hydroxyalkylamino, di(hydroxyalkyl) amino, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl, heterocyclicalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, mercaptoalkyl,
carboxyalkyl, alkoxycarbonylalkyl,
dialkylaminoalkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, diaIkylaminocarbonylalkyl, cyclicaminoalkyl, cycloalkylaminoalkyl, guanidinylalkyl, cyanoalkyl, N-cyanoguanidinylalkyl, cyanoaminoalkyl, hydroxyalkylaminoalkyl or di (hydroxyalkyl) aminoalkyl, W1 and W2 are independently selected from hydroxy and amino, W3 and W4 are independently selected from hydrogen and fluoro, W is as defined therein, Y is O, S, NH or
-N (alkyl)-, Z is as defined therein, G12 is absent or an amino acid residue, H13 is absent or an amino acid
residue, G121 is absent or an amino acid residue, H131 is absent or an amino acid residue and I14 is absent or an amino acid residue;
PCT Patent Application No. WO 86/06379, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-E-F-G-H-Z wherein E, F, G, H and Z are as defined therein including -E-F- is
wherein R10a is hydrogen or alkyl, R10b is alkyl,
cycloalkyl, cycloalkylalkyl, arylalkyl,
(heterocyclic) alkyl, cycloalkenyl or cycloalkenylalkyl, R10c is hydrogen or alkyl, U is -C(O)-, -CH(OH)- or
-CH(NH2)- and W1 and W2 are independently selected from hydrogen, fluoro, chloro and bromo, G is absent or an amino acid residue, H is absent or an amino acid residue and Z is hydroxy, thiol, amino, substituted alkoxy, substituted thioalkoxy, substituted alkylamino, Lys-OH, Lys-NH2, Ser-OH or Ser-NH2;
European Patent Application No. EP0271862, published June 22, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-Y-W-U wherein Y, W and U are as defined therein including Y is Sta, Cysta or PhSta, W is Leu, lie, N-MeLeu, Val or absent and U is -NHCH2CH (CH3) CH2CH3, -NHCH2Ph,
-NHCH (CH2OH) CH (CH3) CH2CH3, -NHCH2CH (OH) CH2SCH (CH3)2 ,
-NHCH2CH (OH) CH2S (O) CH (CH3) 2, -NHCH2CH (OH) CH2S (O)2CH (CH3)2, -NHCH2CH2Ph, -NHCH2(pyrid-2-yl), -NH2, -NHCH2CH=CH2, -OEt, /
European Patent Application No. EP0275480, published July 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-W-U-V wherein W, U and V are as defined therein including W is Sta, PhSta or Cysta, U ie absent, Leu, lie, Val, N-MeLeu or N-Melle and V is -NHCH2Ph, -NHCH2-cyclohexyl,
-NH (piperidin-4-yl), -NHCH2 (pyrid-2-yl),
-NHCH2CH(CH3)CH2CH3, -OMe, -OEt, -NHCH (CH2OH) CH (CH3) CH2CH3, -NHCH2CH2 (morpholin-1-yl),
^
PCT Patent Application No. WO 88/03927, published June 2, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-T-(C)n-W-(D)n-V-(E)n-U wherein T, C, W, D, V, E, U and n are as defined therein including nis 0-1, T is Sta, PhSta, Cysta, Leu,
CyclohexylAla or Phe, W is absent, Leu, Gly or lie, V is absent, Leu or lie, C is -CH2NH-, -CH (OH) CH2- or
-CH(OH)-CH=CH-C(O)-, D is -CH2NH-, E is -CH2NH- or
-CH2N(Cbz)- and U is -NHCH2Ph, -NHCH2-cyclohexyl, -NH2, -NH (piperidin-4-yl), -NHCH2 (pyrid-2-yl),
-NHCH2CH(CH3)CH2CH3, -OMe, -OEt,
European Patent Application No. EP0314060, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-W-U wherein W and U are as defined therein including W is Sta, Cysta, PhSta, ChSta, DFKSta, DFKCys, DFKChs, ASta or ACys and U is -NHCH2CH2 (morpholin-1-yl), -NHCH2CH (CH3) CH2CH3, -NHCH (CH2OH) CH (CH3) CH2CH3, -LeuNHCH2Ph,
-LeuNHCH2-cyclohexyl, -LeuNH (piperidin-4-yl),
-LeuNHCH2(pyrid-2-yl) or
European Patent Application No. EP0310918, published April 12, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3 and R4 are as defined therein including R3 is isobutyl, cyclohexylmethyl or benzyl and R4 is phenyl, furyl, yinyl, ethyl or 1, 2-dihydroxyethyl;
French Patent Application No. FR8700560, published July 22, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R, U and B are as defined therein including R is hydrogen or hydroxyalkyl, U is Leu, Ala, Val or lie and B is pyridyl;
European Patent Application No. EP0236948, published
September 16, 1987, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein X is as defined therein including X is isobutyl or benzyl;
European Patent Application No. EP0281316, published
September 7, 1988, discloses mimics of the Leu-Val
cleavage site of angiotensinogen having the formula
wherein R3, R4 and R5 are as defined therein including R3 is allyl, cyclohexyl or phenyl, R4 is nitromethyl, alkoxycarbonyl or -CH2S (O)n-Rd wherein n is 0-2 and Rd is heterocyclic and R5 is hydrogen or alkyl;
German Patent Application No. DE3825242, published
February 9, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R3 and Z are as defined therein including R3 is hydroxy or amino and Z is substituted carbonyl, substituted thiocarbonyl, substituted iminocarbonyl or unsubstituted or substituted phosphono, aminomethyl, thiomethyl,
sulfinylmethyl, sulfonylmethyl or phosphonomethyl;
European Patent Application No. EP0275101, published July 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R2, R3, Ra, Rb, n, X and Q are as defined therein including R2 is an amino acid side chain, R3 is hydrogen, alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl,
2-pyridylmethyl or an amino acid side chain, Ra is an amino acid side chain, Rb is hydrogen or alkyl or Ra and Rb taken together are -CH2-CH2-, n is 1-10, X is hydrogen, CH2, alkoxy, substituted alkoxy, alkyl, phenyl, benzyl,
cyclohexyl, cyclohexylmethyl or 2-pyridylmethyl and Q is hydrogen, alkyl, arylakyl, alkoxycarbonyl or an amino acid residue; PCT Patent Application No. WO 89/01488, published February 23, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
-E10-F11-G12-H13-I14-Z wherein E10, F11 , G12, H13, I14 and Z are as defined therein including -E10-F11- is
wherein R1 is hydrogen, alkyl, aryl, cycloalkyl,
heterocyclic, alkoxy or thioalkoxy, R11 is hydrogen, alkyl, benzyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl,
arylalkyl, (heterocyclic) alkyl, alkoxyalkyl or
thioalkoxyalkyl, R21 is hydroxy or amino, R22 is hydrogen or alkyl and R23 is hydroxy, amino, hydroxyalkyl,
aminoalkyl, aryl or alkyl, R24 is R1 hydroxy, amino, hydroxyalkyl or aminoalkyl, G12 is absent or an amino acid residue, H13 is absent or an amino acid residue, I14 is absent or an amino acid residue and Z is hydroxy,
substituted alkoxy, substituted amino or cyclic amino;
European Patent Application No. EP0275101, published July 20, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, G12, H13 and X are as defined therein including R1 is hydrogen, alkyl, aryl, cycloalkyl, heterocyclic, alkoxy or thioalkoxy, G12 is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O, H13 is absent, an amino acid residue or an amino acid residue wherein the alpha-amino group has been replaced by O and X is hydrogen, alkyl or substituted alkyl as defined therein;
European Patent Application No. EP0312291, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, Y, X and E are as defined therein including R1 is hydrogen, alkyl, aryl, cycloalkyl, 1,3-dithiolan-2-yl or 1, 3-dithian-2-yl, X is -CH2-C(R13) (R14)- wherein R13 and R14 are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl,
substituted alkyl, alkanoyloxy, substituted
aminocarbonyloxy, substituted carbonylamino, substituted aminocarbonylamino, substituted sulfinyl, substituted sulfonyl, substituted sulfide, amino, alkylamino,
dialkylamino or heterocyclic, Y is CH2, O, S, SO or SO2 or X and Y taken together is -(CH2)4- and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl; European Patent Application No. EP0312283, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein R1, X and E are as defined therein including R1 is hydrogen, alkyl, aryl, cycloalkyl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl, X is -CH2-C(R13) (R14)- wherein R13 and R14 are independently selected from hydrogen, alkyl, alkenyl, carboxy, aminocarbonyl, substituted aminocarbonyl,
substituted alkyl, alkanoyloxy, substituted
aminocarbonyloxy, substituted carbonylamino, substituted aminocarbonylamino, substituted sulfinyl, substituted sulfonyl, substituted sulfide, amino, alkylamino,
dialkylamino or heterocyclic and E is hydrogen, aryl, heterocyclic, alkyl, cycloalkyl or substituted alkyl;
European Patent Application No. EP0312158, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein r, R7, R4, R10, R9, R10a, Q and J are as defined therein including r is 1-4, R7 is alkyl, aryl or cycloalkyl, R4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, R10 and R10a are independently selected from hydrogen and alkyl, R9 is - (CH2)s-NR11R12 wherein s is 1-2 and R11 and R12 are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic) alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl
substituted by -SO3H, aminocarbonylalkyl,
alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, Q is -CH(OH)-, -CH(N(R8))-, -CH(OH)CH2- or -CH (N (R8) ) CH2- wherein R8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino or substituted alkoxy;
European Patent Application No. EP0312157, published April 19, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein r, R7, R4, R10, R9, R10a, Q and J are as defined therein including r is 1-4, R7 is alkyl, aryl or
cycloalkyl, R4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, R10 and R10a are independently selected from hydrogen and alkyl, R9 is - (CH2)s-NR11R12 wherein s is 1-2 and R11 and R12 are independently selected from hydrogen, heterocyclic, aryl, cycloalkyl, alkyl, arylalkyl, (heterocyclic) alkyl, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, alkyl substituted by -SO3H, aminocarbonylalkyl,
alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, Q is -CH(OH)-, -CH(N(R8))-, -CH(OH)CH2- or -CH(N(R8))CH2- wherein R8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is substituted alkylamino, substituted alkoxy,
heterocyclic, heterocyclicamino or substiute guanidino;
European Patent Application No. EP0314239, published May 3, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein r, R7, R4, Q and J are as defined therein including r is 1-4, R7 is alkyl, aryl or cycloalkyl, R4 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl or substituted alkyl, Q is -CH(OH)-, -CH(N(R8))-, -CH(OH)CH2- or -CH (N (R8) ) CH2- wherein R8 is hydrogen, alkyl, formyl, alkanoyl, aroyl, alkoxycarbonyl, aryloxycarbonyl or araylalkoxycarbonyl and J is amino, hydroxy, substituted alkylamino or substituted alkoxy;
South African Patent Application No. 866642, published February 24, 1987, discloses mimics of the Leu-Val
cleavage site of angiotensinogen having the formula NH— (alkyl, or amino acid alkylamide)
wherein R' and R" are as defined therein including R' is fluoro and R" is hydrogen or fluoro;
European Patent Application No. EP0273696, published July 6, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R2, R10 and E are as defined therein including n is 0-5, R2 is hydrogen or alkyl, R10 is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (heterocyclic) alkyl,
alkoxyalkyl, thioalkoxyalkyl, hydroxyalkyl or aminoalkyl and E is -CH (W) -G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is -Q-C(O)-T-U-V wherein Q is a bond or -CH(R13)- wherein R13 is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, substituted alkoxy, amino or substituted amino;
European Patent Application No. EP0278158, published
August 17, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R7, R10 and E are as defined therein including n is 0-3, R7 is alkyl or substituted alkyl, R10 is alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl,
(heterocyclic) alkyl, alkoxyalkyl, thioalkoxyalkyl,
hydroxyalkyl or aminoalkyl and E is -CH (W) -G wherein W is hydroxy, amino, alkanoyloxy or alkanoyloxyalkyloxy and G is -Q-C(O) -T-U-V wherein Q is a bond or -CH(R13)- wherein R13 is hydrogen, aryl, alkyl, cycloalkyl or substituted alkyl, T and U are independently absent or selected from an amino acid residue and V is hydroxy, s.ubstituted alkoxy, amino or substituted amino;
German Patent Application No. DE3721855, published
September 22, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R2, R3, R4, R5, R6, E and D are as defined therein including n is 1-2, R2 is hydrogen or alkyl, R3 is hydrogen, alkyl, aryl, arylalkyl, (heterocyclic) alkyl, cycloalkyl, alkoxy or cycloalkylalkyl, R4 is (H,OH),
(H,NH2) or O, R5 is hydrogen or alkyl, R6 is hydrogen or alkyl, E is 0-2 amino acid residues and D is
-CH2CHOHCH2OH, substituted sulfonyl, substituted
sulfonylalkyl, substituted carbonyl, substituted phosphonyl, phenyl, phenylalkyl, furyl, furylalkyl, thienyl, thienylalkyl, pyridyl, pyridylalkyl or other (heterocyclic) alkyl;
European Patent Application No. EP0309841, published April 5, 1989, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R3, R4, R5, R6 and E are as defined therein including n is 1-2, R3 is hydrogen or alkyl, R4 is
hydrogen, alkyl, aryl, arylalkyl, heterocyclic,
(heterocyclic) alkyl, cycloalkyl, alkoxy or
cycloalkylalkyl, R5 is (H,OH), (K,NH2) or O, R6 is
hydrogen, alkyl or alkenyl and E is -SR7, -SOR7, -SO2R7, -SO2OR7 or -SO2NR7R8 wherein R7 and R8 are independently selected from R4;
European Patent Application No. EP0292800, published Noyember 30, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R3, R4, R5, R6, E, Q and Y are as defined therein including n is 1-2, R3 is hydrogen or alkyl, R4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R5 is (H,OH), (H,NH2), or O, R6 is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl;
European Patent Application No. EP0249096, published
December 16, 1987, discloses mimics of the Leu-Val
cleavage site of angiotensinogen having the formula
wherein n, R3, R4, R5, R6, E, Q and Y are as defined therein including n is 1-2, R3 is hydrogen or alkyl, R4 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic,
(heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl or alkoxy, R5 is (H,OR12), (H,NR12R13), or O wherein R12 and R13 are independently selected from hydrogen and alkyl, R6 is hydrogen or alkyl, E is 0-2 amino acid residues, Q is O or NH and Y is H or substituted alkyl; and
European Patent Application No. EP0264795, published April 27, 1988, discloses mimics of the Leu-Val cleavage site of angiotensinogen having the formula
wherein n, R2, R3, R4, E and Y are as defined therein including n is 1-2, R2 is hydrogen or alkyl, R3 is hydrogen, alkyl, aryl, arylalkyl, heterocyclic,
(heterocyclic) alkyl, cycloalkyl, cycloalkylalkyl or
alkoxy, R4 is hydrogen or alkyl, E is -C(O)NH-, -C(S)NH-, -C(O)O-, -SO2-, -SO2NH-, or -PO (OA) O- wherein A is
hydrogen or alkyl and Y is carboxy, carboxyalkyl,
substituted carboxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, substituted alkoxycarbonylalkyl, aminocarbonyl, substituted aminocarbonyl,
aminocarbonylalkyl, substituted aminocarbonylalkyl,
hydrogen, alkyl, aryl, arylalkyl, cycloalkyl or
cycloalkylalkyl; or E-Y is pyrrolidinocarbonyl,
piperidinocarbonyl, morpholinocarbonyl,
pyrrolidinosulfonyl, piperidinosulfonyl or
morpholinosulfonyl.
The term "substituted amino" as used herein refers to:
I) alkylamino,
II) dialkylamino,
III) (hydroxyalkyl) (alkyl) amino,
IV) (dihydroxyalkyl) (alkyl) amino,
V) alkoxycarbonylalkylamino,
VI) carboxyalkylamino,
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) alkylamino) alkoxycarbonyl- alkylamino,
XVI) (dialkylamino)alkoxycarbonylalkylamino,
XVII) (alkoxyalkyl) (alkyl)amino,
XVIII) (alkoxyalkoxyalkyl) (alkyl)amino,
XIX) di-(alkoxyalkyl)amino,
XX) di-(alkoxyalkoxyalkyl)amino,
XXI) di-(hydroxyalkyl)amino,
XXII) ((unsubstituted heterocyclic)alkyl) (alkyl)- amino,
XXIII) ((substituted heterocyclic)alkyl) (alkyl)- amino,
XXIV)
wherein aa is 1 to 5 and R6 and R7 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)
wherein dd is 1 to 5,
and
18) R8-Z- wherein
Z is O, S or NH and R8 is a C1 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) whe rein R9 is
1) O,
2 ) S,
3 ) SO2 or
4 ) C=O; or wherein R1 0 is
1) hydrogen,
2) loweralkyl,
3) an N-protecting group or
4) R1 1-C(O)- wherein R1 1 is
aminoalkyl, (N-protected) aminoalkyl, 1- amino-2-phenylethyl or 1-(N- protected) amino-2- phenylethyl.
The term "substituted methylene group" as used herein refers to:
(I) -CHR13R14 wherein
1) R13 is
i) hydrogen or
ii) hydroxy
and
2) R14 is
i) hydrogen,
ii) loweralkyl,
iii) hydroxy,
iv) hydroxyalkyl,
v) alkoxy,
vi) alkoxyalkyl,
vii) azido,
viii) azidoalkyl,
ix) amino, x) (N-protected)amino,
xi) aminoalkyl,
xii) (N-protected)aminoalkyl,
xiii) alkylamino,
xiv) (N-protected) (alkyl)amino,
xv) alkylaminoalkyl,
xvi) (N-protected)(alkyl)- aminoalkyl,
xvii) dialkylamino,
xviii) dialkylaminoalkyl,
xix) carboxyalkyl,
xx) thioalkoxy,
xxi) thioalkoxyalkyl,
xxii) alkylsulfonyl,
xxiii) alkylsulfonylalkyl,
xxiv) thioaryloxy,
xxv) thioaryloxyalkyl,
xxvi) arylsulfonyl,
xxvii) arylsulfonylalkyl,
xxviii) (unsubstituted
heterocyclic) alkyl or xxvix) (substituted
heterocyclic) alkyl
such that when R13 is hydroxy then R1 4 is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, (N-protected) amino, (N- protected) (alkyl) amino, thioalkoxy, alkylsulfonyl or arylsulfonyl, and such that when R13 is hydrogen then R1 4 is not hydrogen or loweralkyl;
(II) -C(=CH2)C(O)NHR15,
(III) -C(OH) (R16)C(O)NHR15 or (IV) -CH(R16)C(O)NHR15 wherein
1) R15 is
i) loweralkyl,
ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl,
v) alkylaminoalkyl, vi) dialkylaminoalkyl, vii) aryl,
viii) heterocyclic or ix) (heterocyclic) alkyl and
2) R16 is
i) hydrogen,
ii) loweralkyl,
iii) hydroxyalkyl, iv) haloalkyl or v) azidoalkyl;
(V)
-CH2C(O)NH-(CH2)t- wherein
1) t is 0 to 3,
2) R20 is
i) CH2 or
ii) N and
3) R21 is
i) NH,
ii) O,
iii) S or iv) SO2,
such that when t is 0 then R20 is CH2 and
when t is 1 to 3 then R20 is N, (VI) -CH2CH(R22)C(O)NHR23 wherein
1) R22 is
i) loweralkyl or
ii) cycloalkylalkyl
and
2) R23 is
i) loweralkyl,
ii) hydroxyalkyl,
iii) alkoxyalkyl,
iv) aminoalkyl,
v) alkylaminoalkyl,
vi) dialkylaminoalkyl,
vii) aryl,
viii) arylalkyl
ix) heterocyclic,
x) (heterocyclic) alkyl or
xi)
wherein
a) u is 0 to 3,
b) R24 is CH2 or N and c) R25 is NH, O, S or
SO2,
such that when u is 0 then R24 is CH2 and when u is 1 to 3 then R24 is N; (VII)
-CH2CH(R22)-C(O)- -R74
wnerem
1) R22 is as defined above and
2) R74 is
i) hydrogen,
ii) loweralkyl,
iii) an N-protecting group or iy) R75-C(O)- wherein R75 is
aminoalkyl or (N-protected)- aminoalkyl;
(VIII)
-CH2CH(R26)C(O)NHCH(R27)C(O)NHCH2 N wherein
1) R26 is
i) loweralkyl or
ii) cycloalkylalkyl and 2) R27 is
i) loweralkyl or
ii) cycloalkylalkyl;
(IX) -CH2CH(R81)NHC(O)R82 or
-CH2CH(R81)NHS(O)2R82 wherein
1) R81 is
i) loweralkyl or
ii) cycloalkylalkyl and
2) R82 is i) loweralkyl,
ii) alkoxy,
iii) alkylamino,
iy) dialkylamino,
y) -OR* wherein R* is aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl or (heterocyclic) alkyl or
wherein R21 is
as defined above;
(X) -CH2NHC(O)R82 or -CH2NHS (O)2R82 wherein R82 is as defined above; or
(XI) -CF2CH(OH)R83 wherein R83 is
loweralkyl, loweralkenyl, cycloalkyl,
cycloalkenyl, cycloalkylalkyl,
cycloalkenylalkyl, aryl, arylalkyl,
heterocyclic or (heterocyclic) alkyl.
The chiral centers of the compounds of theinvention may haye either the "R", "S" or "R,S" configuration. The terms "R" and "S" configuration are as defined by IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to preyent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, piyaloyl, t-butylacetyl, trichloroethoxycarbonyl, t- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or Daminoacyl residue, which may itself be N-protected similarly.
The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "loweralkenyl" as used herein refers to a loweralkyl radical which contains at least one carbon- carbon double bond.
The term "aminoalkyl" as used herein refers to -NH2 appended to a loweralkyl radical.
The term "hydroxyalkyl" as used herein refers to -OH appended to a loweralkyl radical.
The term "alkylamino" as used herein refers to a loweralkyl radical appended to an NH radical.
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 an cycloalkyl group appended to a loweralkyl radical,
including, but not limited to cyclohexylmethyl and the like.
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 "cycloalkenylalkyl" as used herein refers to a cycloalkenyl group appended to a loweralkyl radical. The terms "alkoxy" and "thioalkoxy" as used herein refer to R30O- and R30S-, respectiyely, wherein R30 is a loweralkyl group or a cycloalkyl 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 "alkoxyalkyl" as used herein refers to an alkoxy group appended to a loweralkyl radical.
The term "(thioalkoxy) alkyl" as used herein refers to thioalkoxy appended to a loweralkyl radical.
The term "dialkylamino" as used herein refers to - NR31 R32 wherein R31 and R32 are independently selected from loweralkyl groups.
The term "((alkoxy) alkoxy) alkyl" refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
The term "(hydroxyalkyl) (alkyl) amino" as used herein refers to -NR33R34 wherein R33 is hydroxyalkyl and R34 is loweralkyl.
The term "(N-protected) (alkyl) amino" as used herein refers to -NR34 R35 wherein R34 is a loweralkyl group and R35 is an N-protecting group.
The term "N-protected aminoalkyl" as used herein refers to NHR35 appended to a loweralkyl group, wherein R35 is an N-protecting group.
The term "alkylaminoalkyl" as used herein refers to NHR36 appended to a loweralkyl radical, wherein R36 is a loweralkyl group.
The term "(N-protected) (alkyl) aminoalkyl" as used herein refers to NR35R36, which is appended to a loweralkyl radical, wherein R35 and R36 are as defined above. The term "dialkylaminoalkyl" as used herein refers to NR39R40 is appended to a loweralkyl radical wherein R39 and R40 are independently selected from loweralkyl.
The term "carboxyalkyl" as used herein refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
The term "alkoxycarbonylalkyl" as used herein refers to R41COR42- wherein R41 is an alkoxy group and R42 is 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 (-NH2).
The term "((N-protected) amino) carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR43 wherein R43 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) carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR43R44 wherein R43 is as defined above and R44 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 -NR45R46 wherein R45 and R 4 6 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 -NHR43 wherein R43 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 -NR43R44 wherein R43 and R44 are as defined above.
The term "(dialkylamino) alkoxycarbonyalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR43R44 wherein R43 and R44 are as defined above.
The term "carboxyalkylamino" as used herein refers to -NHR47 wherein R47 is a carboxyalkyl group.
The term "alkoxycarbonylalkylamino" as used herein refers to -NHR48 wherein R48 is an alkoxycarbonylakyl group.
The term "(amino) carboxyalkylamino" as used herein refers to -NHR49 wherein R49 is an (amino) carboxyalkyl group.
The term "((N-protected) amino) carboxyalkylamino" as used herein refers to -NHR50 wherein R50 is an ( (N- protected) amino) carboxyalkyl group. The term" (alkylamino) carboxyalkylamino" as used herein refers to -NHR51 wherein R51 is an (alkylamino) carboxyalkyl group.
The term "((N-protected) alkylamino)- carboxyalkylamino" as used herein refers to -NHR52 wherein R52 is an ( (N-protected) alkylamino) carboxyalkyl group.
The term "(dialkylamino) carboxyalkylamino" as used herein refers to -NHR53 wherein R53 is a
(dialkylamino) carboxyalkyl group.
The term" (amino) alkoxycarbonylalkylamino" as used herein refers to -NHR54 wherein R54 is an
(amino) alkoxycarbonylalkyl group.
The term "((N-protected) amino) alkoxycarbonylalkylamino" as used herein refers to -NHR55 wherein R55 is an ( (N-protected) amino) alkoxycarbonylalkyl group.
The term "(alkylamino) alkoxycarbonylalkylamino" as used herein refers to -NHR56 wherein R56 is an
(alkylamino) alkoxycarbonylalkyl group.
The term "((N-protected) alkylamino) alkoxycarbonylalkylamino" as used herein refers to -NHR57 wherein R57 is an ((N-protected) alkylamino) alkoxycarbonylalkyl group.
The term "(dialkylamino) alkoxycarbonylalkylamino" as used herein refers to -NHR58 wherein R58 is a (dialkylamino) alkoxycarbonylalkyl group.
The term "polyalkoxy" as used herein refers to -OR59 wherein R59 is a straight or branched chain containing 1-5, Cgg-O-Chh linkages wherein gg and hh are independently selected from 1 to 3, including, but not limited to methoxyethoxymethoxy, ethoxyethoxymethoxy and the like. The term "(dihydroxyalkyl) (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 ~NR60R61 wherein R60 and R61 are hydroxyalkyl residues.
The term "alkoxyalkyl (alkyl) amino" as used herein refers to -NR62R63 wherein R62 is an alkoxyalkyl group and
R63 is a loweralkyl group.
The term "di-(alkoxyalkyl) amino" as used herein refers to -NR64R65 wherein R64 and R65 are alkoxyalkyl groups.
The term "(alkoxyalkoxyalkyl) (alkyl) amino" as used herein refers to -NR66R67 wherein R66 is an
alkoxyalkoxyalkyl group and R67 is a loweralkyl group.
The term "di-(alkoxyalkoxyalkyl) amino" as used herein refers to -NR68R69 wherein R68 and R69 are
alkoxyalkoxyalkyl groups.
The terms "((unsubstituted
heterocyclic) alkyl) (alkyl) amino and ((substituted
heterocyclic) alkyl) (alkyl) amino" as used herein refer to an amino radical substituted by a loweralkyl group and an (unsubstituted heterocyclic) alkyl group or a (substituted heterocyclic) alkyl group, respectiyely.
The term "(heterocyclic) alkyl" or "heterocyclic ring substituted alkyl" as used herein refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to imidazolylmethyl and thiazolylmethyl.
The term "azidoalkyl" as used herein refers to -N3 appended to a loweralkyl radical. The term "alkylsulfonyl" as used herein refers to R70S(O)2- wherein R70 is a loweralkyl residue.
The term "alkylsulfonylalkyl" as used herein refers to an alkylsulfonyl group appended to a loweralkyl radical.
The term "aryl" as used herein refers to a monocyclic 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 below. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.
The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical including, but not limited to, benzyl, naphthylmethyl and the like.
The terms "aryloxy" and "thioaryloxy" as used herein refer to R71O- or R71S-, respectiyely, wherein R71 is an aryl group.
The terms "aryloxyalkyl" and "thioaryloxyalkyl" as used herein refer to an aryloxy group or a thioaryloxy group, respectiyely, 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, respectiyely, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like.
The terms "arylalkoxyalkyl" and "arylthioalkoxyalkyl" as used herein refer to an arylalkoxy group or an
arylthioalkoxy group, respectiyely, appended to a
loweralkyl radical. The term "arylsulfonyl" as used herein refers to
R72S(O)2- wherein R72 is an aryl group.
The term "arylsulfonylalkyl" as used herein refers to an arylsulfonyl group appended to a loweralkyl radical.
The term "alkylsulfonylamino" as used herein refers to R76NH- wherein R76 is an alkylsulfonyl group.
The term "arylsulfonylamino" as used herein refers R77NH- wherein R77 is an arylsulfonyl group.
The term "(heterocyclic) sulfonyl" as used herein refers to R72aS (O) 2- wherein R72a is a heterocyclic group.
The term "alkylaminocarbonylamino" as used herein refers to R78 NHCONH- wherein R78 is a loweralkyl group.
The term "alkylaminocarbonyloxy" as used herein refers to R79 NHC(O)O- wherein R79 is a loweralkyl group.
The term "alkoxycarbonyloxy" as used herein refers to R80OC(O)O- wherein R80 is a loweralkyl group.
The term "halo" or "halogen" as used herein refers to Cl, Br, F or I substituents.
The term "haloalkyl" as used herein refers to a loweralkyl radical in which one or more hydrogen atoms are replaced by halogen including, but not limited to,
fluoromethyl, 2-chloroethyl, trifluoromethyl, 2,2- dichloroethyl and the like.
The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups and includes but is not limited to substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2- methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and tehahydropyranyl; substituted ethyl ethers, for example, 2,2,2-trichloroethyl, t-butyl, benzyl and triphenylmethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal,
acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates.
The term "heterocyclic group" or "heterocyclic" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms may optionally be oxidized; wherein the nitrogen heteroatom may optionally be quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring
independently as defined above. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred. Preferred heterocyclics include: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl,
piperazinyl, N-methyl piperazinyl, azetidinyl, N-methyl azetidinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl. Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substitutents independently selected from hydroxy, halo, oxo (=O), alkylimino (R*N= wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or haloalkyl.
The most preferred heterocyclics include imidazolyl, pyridyl, piperazinyl, N-methyl piperazinyl, azetidinyl, N- methyl azetidinyl, thiazolyl, thienyl, triazolyl and the following:
wherein b is 1 or 2 and W is N, NH, O, S, provided that W is the point of connection only when T is N,
wherein Y is NH, N-loweralkyl, O, S, or SO2, or
wherein the symbols (i), (ii) and (iii) represent 5- membered heterocycles containing one or more heteroatoms and containing 2 double bonds; wherein Z1 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.
The terms "His", "Phe", "HomoPhe", "Ala", "Leu" and "norLeu" as used herein refer to histidine, phenylalanine, homophenylalanine, alanine, leucine and norleucine,
respectiyely.
The compounds of theinvention may be prepared as shown in Schemes I-XXIII. The syntheses of segments
containing substituents D are described in the Examples or haye preyiously 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. WO87/02986).
In particular, the process shown in Scheme I discloses the preparation of compounds of theinvention having the general structure (1) wherein A is carboxy or
alkoxycarbonyl and X is NH. As illustrated in Scheme I, reductiye amination of an amino acid ester (I) with an alpha-keto ester (II, R=loweralkyl) provides a
diastereomeric mixture which is separated. Each of the diastereomers is hydrolyzed and coupled to the amine (VI) using standard peptide coupling reagents such as N- methylmorpholine (NMM), 1-hydroxybenzotriazole (HOBT) and N-ethyl-N'-(3-dimethylaminoρropyl) carbodiimide (EDAC) to giye the desired compound (VII).
Compound (VII) can also be prepared using the
following method. After reductiye amination of (II) with (I), the diastereomeric mixture is hydrolyzed to give(III) and then coupled to amine (VI) as described above. The mixture of diastereomers is then separated, proyiding two separate isomers. Compound (VII) may be further hydrolyzed to the acid (VIII). The assignment of R or S configuration to the carbon bearing the R3 substitutent in compound
(VIII) is based on the fact that the compound deriyed from the L-isomer is generally a more potent renin inhibitor than the compound deriyed from the corresponding D-isomer.
The stereochemistry at the chiral carbons of (VIII) can also be established by using chiral starting materials. As illustrated in Scheme II, chiral amino acid ester (XV, R=loweralkyl) is reacted with chiral D-trifluorosulfonyloxy ester (XVI) to givethe single isomer (XVII) which is then hydrolyzed and coupled to (VI) to obtain the desired compound (XVIII).
Alternatiyely, Scheme III illustrates the preparation of compounds (XI). Reductiye amination of (IX,
R2=loweralkyl) by (X) provides a mixture of diastereomers which can be separated.
A further alternatiye illustrated by Scheme III inyolyes reductiye amination of (IX, R2=loweralkyl) by (XII) followed by separation of the diastereomers (XIII). Each of the diastereomers is then debenzylated and coupled to (VI) as preyiously described. The methods of Scheme III provide compound (XI) having unknown stereochemistry at the carbon bearing the R1 substituent.
The process of Scheme IV discloses the preparation of compounds of the general structure (1) wherein A is a carboxy derivativeR5CO- wherein R5 is an amine and X is NH. Selectiye hydroysis of one of the diastereomers (IV) giyes the acid derivative(XIX). The acid (XIX) is coupled to the amine R5-H and the resulting amide-ester is
hydrolyzed to give(XXI). The acid (XXI) is coupled to amine (VI) to give(XXII).
Alternatiyely, compound (VIII) can be coupled to amine (VI) to provide (XXII).
The process in Scheme V discloses the preparation of compounds of the general structure (XXV) wherein R28 is a C1 to C4 straight or branched carbon chain substituted by a substituent selected from carboxy, alkoxycarbonyl,
alkylsulfonyl or a substituted or unsubstituted
heterocylic. A reaction sequence similar to that used in Scheme I is followed except that compound (XXIII) is employed instead of the amino acid ester (I).
The process in Scheme VI discloses the preparation of compounds of general structure (XXIX) wherein A is
alkoxycarbonyl or R5CO- wherein R5 is a substituted amine and X is O or S. The reaction of an alcohol or thiol
(XXVI) with the bromo-acid (XXVII) provides a single diastereomer (XXVIII) which is then coupled to the amine
(VI) using standard peptide coupling conditions to givethe desired product (XXIX). If the racemic form of the bromo- acid (XXVII) is used, diastereomer separation can take place with compound (XXVIII) or (XXIX). Scheme VII discloses the preparation of compounds of general structure (1) wherein X is CH2 and A is R5CO- wherein R5 is hydroxy, alkoxy, thioalkoxy or an amine.
Compound (XXX) (J. Med. Chem. 26 1277 (1983)) is coupled to amine (VI) to provide the amide ester (XXXI) which is hydrolyzed to givethe carboxylic acid (XXXII). Coupling to the appropriate amine provides (XXXIII) wherein R5 is a substituted amine.
The process in Scheme VIII discloses the preparation of compounds of the general structure (1) wherein X is CHOH. Aldol condensation of an aldehyde (XXXIV) (J. Am. Chem. Soc. 103 2876 (1981)) with the chiral oxazolidinone imide (XXXV) (J. Am. Chem. Soc. 103 2127 (1981)) provides (XXXVI). After protection of the secondary alcohol, the benzyl group is removed and the primary alcohol oxidized to the carboxylic acid (XXXVII). The acid is coupled to the appropriate amine R5-H, the imide is hydrolyzed, the resulting acid is coupled to the amine (VI) and the alcohol is deprotected proyiding the desired compound (XXXVIII).
Schemes IX-XIII disclose the preparation of
intermediates used in Schemes I, V and VI, respectiyely. In Scheme X, R is loweralkyl. In Scheme XI, R is
loweralkyl, Ts is p-toluenesulfonyl and P is an N- protecting group. In Scheme XII, R is loweralkyl, R5-H is an amine and X is 0 or S. In Scheme XIII, R5-H is an amine.
The process in scheme XIV describes the preparation of compounds of the general structure XLII wherein R3 is a C1 to C6 straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by O, S, N or substituted by a substitutent selected from a heterocycle or substituted heterocycle. R1 is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl,
alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. R5 is a cyclic amine, substituted amine, substituted cyclic amine, aryl, substituted aryl, heterocycle, substituted heterocycle. The synthesis of intermediate XL begins by the metalation of the sulfonyl deriyatiye XXXIX with alkyl lithium reagents in THF or THF/HMPA at low temperature according to the procedure sited in European Patent Application No. EP0309841, published April 5, 1989. The subsequent anion is trapped with the appropriate 2-substituted-3-benzyloxypropyl iodide (prepared from the alcohl-ol by the procedure of M . Holladay; J. Med. Chem. 1983, 26, 1277 ),
p-toluenesulfonyl chloride and sodium iodide. The
resulting diastereomeric sulfonyl ethers XL are
deprotected ( H2 Pd/C or PdOH) and oxidized to the
corresponding carboxylic acids XLI using a yariety of oxidants (KMnO4, Jones, PDC, RUO4, Pt/O2). Coupling of the acids with mimics of the Leu-Val cleavage site of
angiotensinogen (T-H) using standard coupling procedures giyes the diastereomeric amides XLII and XLIII which are separated to giveoptically actiye inhibitors.
Scheme XV outlines the synthesis of carboxylic acids of the general formula XLIX wherein R1 is a C1 to C6 straight or branched alkyl/alkenyl carbon chain or
heteroatom substituted carbon chain substituted by O, S, N. or substituted by a substitutent selected from a heterocycle or substituted heterocycle. R is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl,
alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a C1 to C6
straight or branched alkyl/alkenyl carbon chain or
heteroatom substituted carbon chain substituted by O, S, N. The synthesis begins by esterificaton followed by allylation of the 2S-hydroxyacid XLIV. Ester XLV is reduced with lithium aluminum hydride and the resulting alcohol is reacted with ozone. Reductiye workup of the ozonide and Collins oxidation (CrO3.2Pyr) givse the optically pure lactone XLVI. Reaction of the lactone with LiHMDS in THF or THF/HMPA followed by the addition of P1-I or R1-Br (i.e., an alkyl io-dide or arylalkyl iodide or bromide) givse the disubstituted lactone XLVII. The lactone XLVII is reacted with the amino aluminum reagent which is prepared from the secondary amine and
trimethylaluminum according to the procedure of Weinreb et. al. Org. Syn. 1980, 59, 49, to givethe alcohol
XLVIII. Oxidation of the alcohol using a yariety of oxidants (KMnO4, Jones, PDC, RuO4, Pt/O2) givse the acid XLIX which is ready for coupling to T-H using known methods.
An alternatiye synthesis of the disubstituted lactone LIII and related lactone LVII is shown in scheme XVI. The 2 (S) -hydroxyacid L is first conyerted to the ethyl ester by Fisher esterification. Trans esterification with the Z- allylic alcohol and titanium isopropoxide (using the procedure of Seebach et. al. Org. Syn. 1986, 65, 230) givse the hydroxy ester LI. Halo ( I2 or NBS) or mercuric trifluoroacetate cyclization of the hydroxy olefin givse the disubstituted lactone LII. Reduction of LII with tributyltinhydride or sodium borohydride affords the reduced lactone intermediate LIII.
Scheme XVII discloses an alternatiye synthesis of carboxylic acids LVIII and LIX wherin R1 is a C1 to C6 straight or branched alkyl/alkenyl carbon chain or
heteroatom substituted carbon chain substituted by O, S, N or substituted by a substitutent selected from a
heterocycle or substituted heterocycle. R is selected from aryl, substituted aryl, heterocycle, substituted heterocycle, cycloalkyl, unsaturated cycloalkyl,
alkylaryl, alkylheterocycle, alkyl cycloalkyl, alkyl unsaturated cycloalkyl. The cyclic amine (n" = 1 to 7) is substituted with groups V selected from a C1 to C6
straight or branched alkyl/alkenyl carbon chain or heteroatom substituted carbon chain substituted by O, S, N. The synthetic strategy is similar to that outlined in scheme XV. The lactone LV is prepared from the
corresponding amino alcohol LIV. Alkylation of LV with NaHMDS and alkyl iodide or bromide givse the disubstituted lactone LVI. The lactone LVI is hydrolyzed and esterified to hydroxy ester LVII which is conyerted to the acid LIX as shown in the scheme. Alternatiyely, LVI is transformed to the acid LVIII. Carboxylic acids LVIII and LIX are conyerted to final inhibitor compounds LVIIIa and LIXa as preyiously described.
Scheme XVIIa discloses a synthetic route to
inhibitors containing esters of the general formula LVIb and LVIIb wherein R and R1 are the same as preyiously described for scheme XVII and R2 is selected from C1 to C6 straight or branched carbon chain. T is selected from a yariety of mimics of the Leu-Val cleavage site of
angiotensinogen. The fiye step sequence from LVI to LVIb prepares the key acid intermediate from permanganate oxidation which is coupled to givefinal products. The seyen step sequence from LVI to LVIlb produces a similar final product with the R and R1 substituents reyersed.
The syntheses of hydroxyethylene dipeptide isosteres are depicted in Schemes XVIII and XIX. The chirality of the yaline-mimic isopropyl group is established via a highly diastereoselectiye aldol condensation. Scheme XVIII details the use of technology deyeloped by D. A.
Eyans and coworkers (see D. A. Eyans, J. Bartroli and T. L. Shih, J. Am . Chem . Soc . 1981, 103, 2127), in which the aldehyde LX (synthesized in anal-ogy to the isobutylsubstituted aldehyde described by S. Thaisriyongs, D. T. Pals, L. T. Kroll, S. R. Turner and F.-S. Han, J. Med.
Chem . 1987, 30, 976) is condensed with the norephedrinederiyed acyloxazolidinone to produce the aldol product
LXI. Barton deoxygenation (D. H. R. Barton and S. W.
McCombie, J. Chem . Soc , Perkin Trans . 1 , 1975, 1574) provides the diprotected hydroxyethylene dipeptide
isostere LXIII. Remoyal of the chiral auxiliary with basic peroxide (D. A. Eyans, T. C. Britton and J. A.
Ellman, Tetrahedron Lett. 1987, 28(49), 6141) affords the intermediate carboxylic acid LXTV, which is then coupled to the desired amines (RNH2) to yield amides LXV.
An alternatiye strategy is outlined in Scheme XIX. Employment of the cysteine-deriyed thiazolidinethione (C. N. Hsiao, L. Liu and M. J. Miller, J. Org. Chem . 1987, 52, 2201) as chiral auxiliary allows the direct conyersion of aldol adduct LXVI I to the hydroxy amide LXVlll, thereby ayoiding the hydrolysis step in Scheme XVIII. The
secondary hydroxyl group is deoxygenated to produce the same protected amides LXV.
The synthesis of P2, retro-inyerted amine deriyatiyes is described in Scheme XX. The intermediate carboxylic acid LXIV is transformed into isocyanate LXX by the action of diphenylphosphorylazide, and the isocyanate is trapped with a range of nucleophiles, including, but not limited to primary and secondary amines, alcohols, thiols and organomagnesium halides. Scheme XX illustrates the synthesis of retro-inyerted amides LXXI, ureas LXXII and carbamates LXXITI.
These yarious hydroxyethylene dipeptide isosteres are then deprotected under the conditions listed in Scheme XXI. The resulting free-base forms of the aminoalcohols LXXIV and LXXV are then ayailable for standard peptide couplings.
Scheme XXII outlines a method for producing analogs of P2'-retro-inyerted statine isosteres (an extension of the preyious work of S. H. Rosenberg, J. J. Plattner, K. W. Woods, H. H. Stein, P. A. Marcotte, J. Cohen and T. J. Perun, J. Med. Chem. 1987, 30, 1224), in which the protected amino-epoxide LXXVI (J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist and N. Yi, J. Org. Chem . 1987, 52, 1487) is opened with a primary amine to provide aminoalcohols LXXVII. These compounds are then
deriyatized as sulfonamides, sulfamides, ureas,
carbamates, amides or other amine deriyatiyes. Scheme XXII details the example of a sulfonamide or sulfamide. The free aminoalcohol (LXXIX) is provided by simple deprotection of the Boc-group. Scheme XXIII depicts an alternatiye strategy for the production of the P2, retro-inyerted amide deriyatiyes. Intermediate aldehyde LX is condensed with a primary amine under standard reductiye alkylation conditions, and the resulting amine LXXX is deriyatized to the desired
protected amine derivativeLXXXII. This has been
accomplished by the use of the appropriate sulfonyl or sulfamoyl chloride, to yield, respectiyely, the
corresponding sulfonamide or sulfamide. In addition, the catechol sulfamate ester LXXXI can be employed to produce sulfamide deriyatiyes. Deprotection produces aminoalcohols LXXXIII, ayailable for coupling reactions.
In the above schemes, optically actiye or racemic starting materials can be used to obtain products of known or mixed stereochemistry.
Particularly useful intermediates for the preparation of the novel compounds of thisinvention are compounds of the formula:
or an acid halide or activated ester derivativethereof.
A is
(I) R5C(O)-(CH2)w- wherein
1) w is 0 to 4 and
2) R5 is
i) hydroxy,
ii) alkoxy,
iii) thioalkoxy,
iy) amino or
y) substituted amino;
(II) alkylsulfonyl, (aryl) sulfonyl or
(heterocyclic) sulfonyl;
(III) aryl, arylalkyl, heterocyclic or
(heterocyclic) alkyl; or
(IV) R90- or R90NHC(O)- wherein R90 is a C1 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)
R1 is
(I) hydrogen,
(II) loweralkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) aryloxyalkyl,
(VII) thioaryloxyalkyl,
(VIIII) arylalkoxyalkyl-,
(IX) arylthioalkoxyalkyl or
(X) a C1 to C3 straight or branched
carbon chain substituted by a substituent selected from
1) alkoxy,
2) thioalkoxy,
3) aryl and
6) heterocyclic.
X is
(I) CH2,
(II) CHOH,
(III) C(O),
(IV) NH,
(V) O,
(VI) S,
(VII) S(O),
(VIII) sO2, (IX) N(O) or
(X) -P(O)O-.
R3 is
(I) loweralkyl,
(II) haloalkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) alkoxyalkyl,
(VII) thioalkoxyalkyl,
(VIII) (alkoxyalkoxy) alkyl,
(IX) hydroxyalkyl,
(X) -(CH2)eeNHR12
wherein
1) ee is 1 to 3 and
2) R12 is
i) hydrogen,
ii) loweralkyl or
iii) an N-protecting group;
(XI) arylalkyl or
(XII) (heterocyclic) alkyl.
Acid halide deriyatiyes of the above intermediates include the acid chloride. Actiyated ester deriyatiyes of the above intermediates include activated esters commonly used by those skilled in the art for actiyating carboxylic acid groups for coupling with an amine to form a peptide bond, including, but not limited to formic and acetic acid deriyed anhydrides, anhydrides deriyed from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinimide deriyed esters, N-hydroxyphthalimide deriyed esters, N-hydroxybenzotriazole deriyed esters, N- hydroxy-5-norbornene-2,3-dicarboxamide deriyed esters, 4- nitrophenol deriyed esters, 2,4,5-trichlorophenol deriyed esters and the like.
Compounds of theinvention include the following.
Preferred compounds of theinvention include:
2 (S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethoxyhexanoic acid amide of 3-(1-imidazolyl)propyl 5 (S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide;
2 (S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethoxyhexanoic acid amide of 3-(dimethylamino)propyl 5 (S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide;
2 (S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethoxyhexanoic acid amide of 3-(4-morpholinyl)propyl 5 (S) -amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide;
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethyl-L-norleucyl amide of 3-(1-imidazolyl)propyl 5(S)-amino-6-cyclohexyl-4 (S)-hydroxy-2 (S)- isopropylhexanamide; and
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl) carbonyl)-2- phenylethyl-L-norleucyl amide of 3-(4-morpholinyl)propyl 5 (S) -amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide.
The following examples will serve to further illustrate preparation of the novel compounds of the invention.
Example 1
4-Methyl-2-oxo-pentanoic acid, benzyl ester.
A mixture of 2-0xo-4-methyl pentanoic acid sodium salt (10 g, 65.7 mmol) and benzyl chloride (8 g, 63 mmol) in 300 ml DMF was stirred at 40-50°C for 5 h. It was filtered, and the filtrate was evaporated under reduced pressure to provide an oil. The oil was dissolved in chloroform, wasned with water, dried, filtered, and eyaporated to provide the desired product (13 g, 94%) 1 1H NMR (CDCl3, TMS) δ 0.95 (d,6H), 2.15 (m,1H), 2.7 (d,2H), 5.28 (s,2H), 7.4 (m,5H). Mass spectrum: (M+H)+ = 221.
Example 2
Pyruvic acid, benzyl ester.
Using the procedure of Example 1, but replacing 2-Oxo-4- methyl pentanoic acid sodium salt with pyruvic acid sodium salt gave the desired compound. 1H NMR (CDCl3, TMS) δ 2.4 (s,3H), 5.3 (s,2H). Mass spectrum: (M+H)+ = 179.
Example 3
Hexanoic acid, benzyl ester.
Using the procedure of Example 1, but replacing 2-Oxo-4- methyl pentanoic acid sodium salt with 2-oxo-hexanoic acid sodium salt gave the desired compound. 1H NMR (CDCl3, TMS) δ 0.91 (t,3H), 1.35 (m,2H), 1.6 (m,2H), 2.85 (t,2H), 5.29 (s,2H), 7.4 (m,5H). Mass spectrum: (M+H)+ = 221. Example 4
o-Phenylalanine, tert-butyl ester'HCl. 6.07 ml of concentrated sulfuric acid was added to a solution of 5 g (0.03 mol) of u-phenylalanline in 80 ml of dioxane. The solution was saturated with isobutylene.
After 18 h at room temperature the solution was added to 500 ml of ice water containing sodium hydroxide sufficient to neutralize all acids. The aqueous dioxane solution was extracted with a large quantity of ether. The ether portion was washed with water, saturated sodium chloride, dried, and filtered. The filtrate was evaporated to an oil. Hexane and etherial hydrogen chloride were added sequentially. A white solid precipitated out to give the desired compound in 65% yield. 1H NMR (CDCl3, TMS) δ 1.29 (s,9H), 3 (dd-1H), 3.25 (dd,1H), 4.1 (dd,1H), 7.4 (m,5H). Mass spectrum:
(M+H)+ = 222. Example 5
L-Homoohenylalanine, tert-butyl ester'HCl. Using the procedure of Example 4, but replacing D-Phe with L-HomoPhe gave the desired compound. H NMR (DMSO, TMS) δ 1.5 (s,9H), 2.05 (m,2H), 2.75 (m,2H), 3.9 (t,1H), 7.3 (m,5H). Mass spectrum: M+ = 235, Rf = 0.6 (5 CHCl3: 1 CH3OH) .
Example 6
D-Homophenylalanine, tert-butyl ester'HCl. Using the procedure of Example 4, but replacing D-Phe with D-HomoPhe gave the desired compound. H NMR (DMSO, TMS) δ 1.5 (s,9H), 2.05 (m,2H), 2.75 (m,2H), 3.89 (t,1H), 7.25 (m,5H). Rf = 0.6 (5 CHCl3: 1 CH3OH). Example 7
N- (1 (S)- ( tert-Butyloxycarbonyl )-2-phenyl ethy l ) -
L-leucine, benzyl ester.
TEA (triethylamine) (140 ul, 0.94 rnrno1) was added to the cooled suspension of L-Phe-t-Bu ester°HCl (0.243 g,
0.94 mmol) in 3 ml of methylene chloride at 0°C and the mixture was stirred at 0-5°C for a half hour. The mixture was added to a solution of 4-methyl-2(R)-(trifluoro- sulfonyloxy)-pentanoic acid, benzyl ester (0.288 g,
0.81 mmol) and TEA (120 μl, 0.82 mmol) in 2 ml of methylene chloride and the mixture was allowed to stir at 15°C for 2 h, then warmed to room temperature and stirred for one hour. The clear liquid was then allowed to stand in a refrigerator for 18 h and then concentrated. The clear liquid was dissolved in EtOAc and washed with H2O, dried, and filtered. The filtrate was evaporated to an oil which v/as chromatographed, eluting with ether:hexane (1:9) to obtain the desired product in 255. yield. 1H NMR (CDCl3, TMS) δ 0.87 (t,6H), 1.33 (s,9H), 1.46 (d,2H), 1.67 (m,1H), 2.89 (bd,2H), 3.37 (bt,1H), 3.41 (bt,1H), 5.11 (d,2H). Mass spectrum: (M+H)+ = 426.
Example 8
N-(1(S)-(tert-Butyloxycarbony1)-2-phenylethyl)- L-leucine, benzyl ester and its D-leucine isomer.
To L-Phe-t-Bu ester°HCl (0.25 g, 0.96 rnrnol) in 10 ml of absolute ethanol, 2-oxo-4-methyl pentanoic acid benzyl ester (0.25 g, 1.15 mmol) and sodium acetate (0.16 g, 1.92 mmol) were added sequentially at 5°C. The suspension was cooled at 5°C for 30 min, followed by dropwise addition of sodium cyanoborohydride (0.07 g, 1.15 mmol) in 6 ml of absolute ethanol. The reaction mixture was stirred at 0-5°C for 1 h and at room temperature for 15 h. The mixture was filtered and the filtrate was evaporated under reduced pressure to give a solid which was taken up into chloroform and washed with 5% sodium bicarbonate, water, and brine. The organic phase was dried and evaporated to a yellow oil. The crude product was chromatographed on silica gel eluting with ether: hexane (1:9) to give two separate diastereomers (26% total yield).
Less polar (S,R) isomer: 1H NMR (CDCl3, TMS) δ 0.8 (dd,6H), 1.33 (2,9H) 1.43 (bt,2H), 1.62 (m,1H), 2.87
(bt,2H), 3.22 (bt,1H), 3.37 (bt,1H), 5.1 (s,2H). Mass spectrum: (M+H)+ = 426.
More polar (S,S) isomer: 1H NMR (CDCl3, TMS) δ 0.S7 (t,6H); 1.33 (s,9H), 1.46 (d,2H), 1.67 (m,1H), 2.89 (bd,2H), 3.37 (bt,1H), 3.41 (bt,1H), 5.11- (d,2H). Mass spectrum: (M+H)+ = 426. Rf value is identical to the resultant compound of Example 7.
Example 9
N- ( 1 (R)- ftert-Butyloxycarbonyl)-3-phenylpropyl)-
L-leucine, benzyl ester and its D-leucine isomer.
Using the procedure of Example 8, but replacing L-Phe-t-
Bu ester°HCl with D-HomoPhe-t-Bu ester°HCl gave a mixture of two diastereomers which were separated by chromatography on silica gel eluting with ethyl acetate: hexane (1:4).
Less polar (R,S) isomer: 1H NMR (CDCl3, TMS) δ 0.89 (d,3H), 0.91 (d,3H), 1.45 (s,9H), 1.85 (m,3H), 2.7 (m,2H), 3.15 (t,1H), 3.3 (t,1H), 5.1 (q,2H), 7.3 (m,5H). Mass spectrum: (M+H)+ = 440.0 More polar (R,R) isomer: 1H NMR (CDCl3, TMS) δ 0.89 (d,3H), 0.91 (d,3H), 1.45 (s,9H), 2.65 (m,2H), 3.15 (t,1H), 3.36 (t,1H), 5.15 (s,2H), 7.2 (m,5H). Mass spectrum:
(M+H)+ = 440.
Example 10
N-(1(S)-(tert-Butyloxycarbonyl)-3-phenylpropyl)-
L-leucine, benzyl ester and its D-leucine isomer.
Using the procedure of Example 8, but replacing L-Phe-t-
Bu ester°HCl with L-HomoPhe-t-Bu ester°HCl gave a mixture of two diastereomers which were separated by chromatography to give the desired compounds.
Less polar (S,R) isomer: 1H NMR (CDCl3, TMS) δ 0.9 (dd,6H), 1.45 (s,9H), 1.8 (dd,1H), 1.9 (m,2H), 2.69 (m,2H), 3.25 (t,1H), 3.39 (t,1H), 5.11 (d,2H), 7.27 (m,5H). Mass spectrum: (M+H)+ = 440.
More polar (S ,S) isomer: 1H NMR (CDCH, TMS) δ 0.89 (d,3H), 0.92 (d,3H), 1.46 (s,9H), 2.64 (m,2H), 3.15 (t,1H), 3.36 (dd,1H), 7.26 (m,5H). Mass spectrum: (M+H)+ = 440.
Example 11
N-(1(S)-(tert-Butyloxycarbonyl)-2-phenylethyl)- L-alanine benzyl ester and its D-alanine isomer.
Using the procedure of Example 8, but replacing 2-oxo-4- methyl pentanoic acid benzyl ester with pyruyic acid benzyl ester gaye the desired compounds.
Less polar (S,S) isomer: 1H NMR (CDCl3, TMS) δ 1.27 (d,3H), 1.33 (s,9H), 2.91 (dd,2H), 3.35 (dd,1H), 3.45 (bt,1H), 5.12 (d,2H). Mass spectrum: (M+H)+ = 384.
More polar (S,R) isomer: 1H NMR (CDCl3, TMS) δ 1.3 (d,3H), 1.34 (s,9H), 2.91 (d,2H), 3.44 (dd,1H), 3.42
(bt,1H), 5.12 (s,2H). Mass spectrum: (M+H)+ = 384. Example 12
Hexanoic acid, benzyl ester.
Alternatively, the compound of Example 3 was prepared by the Grignard reaction of n-butylmagnesium chloride with excess benzyloxalate to obtain desired product in 27% yield. 1H NMR (CDCl3, TMS) δ 0.91 (t,3H), 1.35 (m,2H), 1.6 (m,2H), 2.85 (t, 2H ) , 5.29 (s ,2H) , 7.4 (m,5H) . Rf value i s i denti cal to Example 3.
Example 13
N-( 1(R))-ftert-Butyloxycarbonyl)-2-ohenylethyl)- L-alanine benzyl ester and its D-alanine isomer.
Using the procedure of Example 11, but replacing L-Phe- t-Bu ester°HCl with D-Phe-t-Bu ester°HCl gave tne desired compounds.
Less polar isomer: 1H NMR (CDCl3, TMS) δ 1.27 (d,3H),
1.32 (s,9H), 2.91 (dd,2H), 3.34 (dd,1H), 3.45 (t,1H), 5.12 (d,2H). Mass spectrum: (M+H)+ = 384.
More polar isomer: 1H NMR (CDCl3, TMS) δ 1.3 (d,3H),
1.33 (s,9H), 2.91 (d,2H), 5.12 (s,2H). Mass spectrum:
(M+H)+ = 384.
Example 14
N-(1(S)-ftert-Butyloxycarbonyl)-2-phenylethyl)-
L-norleucine, benzyl ester and its
D-norleucine isomer.
Using the procedure of Example 8, but replacing the
2-oxo-4-methyl pentanoic acid benzyl ester with 2-oxo- hexanoic acid benzyl ester gave the desired compounds. Less polar (S,R) isomer: 1H NMR (CDCl3, TMS) δ 0.8 (bt,3H), 1.18 (m,2H), 1.34 (s,9H), 2.89 (bt,2H), 3.19
(t,1H), 3.37 (t-1H), 5.12 (d,2H). Mass spectrum: (M+H)+ = 426.
More polar (S,S) isomer: 1H NMR (CDCl3, TMS) δ 0.85 (m,3H), 1.33 (s,9H), 2.9 (d,2H), 3.31 (t,1H), 3.41 (t,1H), 5.11 (s,2H). Mass spectrum: (M+H)+ = 426.
Example 15
N- (1(R)-t(ert-Butyloxycarbonyl)-2-phenvlethyl)- L-leucine. benzyl ester.
Using the procedure of Example 8, but replacing the L- Phe-t-Bu ester°HCl with D-Phe-t-Bu ester°HCl to give the desired less polar L-isomer. 1H NMR (CDCl3, TMS) δ 0.8 (dd-6H), 1.34 (s,9H), 1.42 (t,2H), 2.88 (t,2H), 3.21
(bt,1H), 3.48 (bt,1H), 5.1 (s,2H). Mass spectrum: (M+H)+ = 426.
Example 16
N-(1( S)-(tgrt-Butyloxycarbonyl)- 3-phenylpropyl)-L-leucine.
A solution of the more polar (S, S) diastereomer (45 mg, 0.1 rnrnol) of Example 10 in 2 ml of methanol was treated with 20 mg of 10% palladium on carbon and stirred under a hydrogen atmosphere for 2 h. After filtration through celite, the solution was concentrated under reduced pressure to give the desired product (35 mg, 98%). 1H NMR (CDCl3, TMS) δ 0.92 (dd,6H), 1.49 (s,9H), 2.68 (m,2H), 3.19 (dd,1H), 3.28 (t,1H), 7.24 (m,5H) . Mass spectrum: (M+H)+ = 350. Example 17
4(S)-t-Butyloxycarbonylamino-5-cyclohexyl- 3 (R,S)-hydroxy-1-pentene.
To a stirred -78°C solution of Boc-cyclohexylalanine methyl ester (10.2 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, yinyl 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 H2O), 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 (60%) of the desired product.
Anal. Calcd. for C16H29NO3°¼ H2O: C, 66.8; H, 10.3; N, 4.9.
Found: C, 66.9; H, 10.2; N, 4.7.
Example 18
4(S)-Cyclohexylmethyl-5(R,S)-vinyl-2-oxazolidinone. The resultant product of Example 17 (2.80 g, 9.88 mmol) in dry dimethylformamide (DMF) (50 ml) was added to a stirred suspension of NaH (593 mg of a 60% dispersion in oil, 14.8 mmol, hexane washed) in dry DMF (50 ml). After 3 h, the mixture was quenched (750 ml water + 100 ml brine) and extracted with ether (5 x 100 ml). The combined organic phase was washed with brine (3 x 50 ml), dried (MgSO4), filtered and eyaporated to an oil (2.23 g). The NMR spectrum of the crude product revealed an 82:18 mixture of 5S:5R diastereomers. Silica gel chromatography gave 80% recovery of pure diastereomers. 5S:
Anal. Calcd. for C12H19NO2: C, 68.9; H, 9.1; N, 6,7. Found: C, 68.4; H, 9.2; N, 6.5. Mass spectrum:
(M+l)+ = 210. 5R: Mass spectrum: (M+1)+ = 210.
Example 19
(3S.4S)-3-Hydroxy-4-amino-5-cyclohexyl-1-pentene.
To the resultant 5S-diastereomer from Example 18
(2.06 g, 9.84 mmol) in dioxane (180 ml) and water (120 ml) was added barium hydroxide octahydrate (6.24 g,
19.8 mmol). The mixture was refluxed for 18 h, cooieo, filtered, concentrated, taken up in water and extracted with ethyl acetate which was dried over Na2SO4 and evaporated to afford 1.64 g (91%) of the desired product, m.p.: 59-61°C.
Anal. Calcd. for C11H21NO: C, 72.08; H, 11.55; N, 7.64.
Found: C, 71.67; H, .11.68; N, 7.36.
Example 20
(3S,4S)-3-Hydroxy-4-tert-butyloxycarbonylamino- 5-cyclohexyl-1-oentene.
To the resultant compound from Example 19 (1.62 g, 8.84 mmol) in methylene chloride (20 ml) was added di-tert- butyldicarbonate (1.93 g, 8.84 mmol). The mixture was stirred for 14 h, diluted with ethyl acetate, washed sequentially with 0.5 M H3PO4, saturated NaHCO3 solution and brine, then dried over Na2SO4 and eyaporated to afford 2.51 g (100%) of the desired compound. Example 21
(3S,4S)-3-Methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexyl-1-pentene.
To the resultant compound from Example 20 (2.51 g, 8.84 mmol) in methylene chloride (20 ml) was added
diisopropylethylamine (4.60 ml, 26.4 mmol) and methoxy- ethoxychloromethane (3.00 ml, 26.3 mmol). After stirring at room temperature for 24 h the mixture was concentrated, diluted with ethyl acetate, washed with 0.5 M H3PO4, saturated NaHCO3 solution, then brine, dried over Na2SO4, and evaporated. Chromatography on silica gel with ethyl acetate/ hexane mixtures afforded 2.63 g (80%) of the desired product as an oil. EI-MS: M+ = 371.
Example 22
(2RS,3R,4S)-3-Methoxyethoxymethoχy-4-tert- butyloxycarbonylamino-5-cyclohexyl-1,2-oxopentane. To the resultant compound from Example 21 (5.41 g, 14.56 rnrnol) in methylene chloride (50 ml) was added 3- chloroperbenzoic acid (6.28 g). After stirring at room temperature for 60 h the mixture was concentrated, diluted with ethyl acetate, washed with cold 1:1 15% aαueous Na2SO3 solution/saturated NaHCO3 solution (2 x 200 ml), saturated NaHCO3 solution (3 x 100 ml) then brine (1 x 100 ml), dried over Na2SO4, and evaporated to afford 4.57 g (81%) product as an oil. EI-MS: M+ = 387.
Example 23
(2'S,1'R.5S)-3-Ethyl-5-(1'-methoxyethoxymethoxy-
2'-tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- oxazolidin-2-one.
To the resultant compound from Example 22 (310 mg, 0.80 mmol) in isopropanol (5 ml) was added ethylamine (200 mg, 4 mmol). The mixture was heated at 70°C for 48 h, evaporated and dissolved in methylene chloride (5 ml). To this solution was added triethylamine (0.34 ml, 2.4 mmol) and phosgene in toluene (1.0 ml, 1.2 mmol, 12.5% solution). After 2 h the mixture was diluted with ethyl acetate, washed with 0.5 M H3PO4, saturated NaHCO3 solution then brine, dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 1:1 ethyl acetate/ hexane provided 14.3 mg (4%) of the 5R isomer followed oy 63.0 mg (17%) of the desired 5S isomer, both as oils.
5S-Isomer: 1H-NMR (CDCL3,TMS) δ 4.33 (d,1H), 4.80 (d,1H), 4.58 (m,1H), 3.49. (s,3H), 1.43 (s,9H), 1.15 (t,3H).
5R-Isomer: MS (M+H)+ = 459.
Example 24
(2'S.1'R.5S)-3-Methoxy-5-(1'-methoxyethoxymethoxy-
2'-tert-butyloxycarbonylamino-3'-cyclohexylprcpyl)- oxazolidin-2-one.
Using the procedure of Example 23 but replacing the ethyl amine with equal parts of methoxyamine hydrochloride and sodium bicarbonate gives the desired compound.
Example 25
(2RS,3R,4S)-1.2-Dihydroxy-3-methoxyethoxymethoxy- 4-tert-butyloxycarbonylamino-5-cyclohexylpentane.
To the resultant compound from Example 21 (1.00 g, 2.69 mmol) in tetrahydrofuran (20 ml) at 0°C was added osmium tetroxide (0.75 ml of a 2.5% solution in tertbutanol) and N-methylmorpholine N-oxide (347 mg, 2.95 mmol). The mixture was stirred at room temperature 16 h, diluted with ethyl acetate, washed with NaHSO3 solution, saturated NaHCO3 solution and brine, then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with methanol/methylene chloride mixtures provided 887 mg (81%) of the desired product.
Anal. Calcd. for C20H39NO7O.3 H2O: C, 58.46; H, 9.71; N, 3.41.
Found: C, 58.69; H, 9.53; N, 3.41.
Example 26
(2' S.1'R,5S)-2-Oxo-4-(1'-methoxyethoxymethoxy-
2'-tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- dioxolane.
The resultant compound of Example 25 in methylene chloride at 0°C was treated with triethylamine then phosgene in toluene. The mixture was stirred at 0°C for 1 h, then at room temperature for 3 h, poured into ethyl acetate, washed with 0.5 M H3PO4, saturated NaHCO3 solution and brine, then dried over Na2SO4 and evaporated to afford the desired product as an oil. Example 27
(2R.3R,4S)-1-Benzyloxycarbonylethylamino-2-hydroxy-
3-metnoxyethoxymethoxy-4-tert-butyloxycaroonylamino- 5-cyclohexylpentane.
Using the procedure of Example 23 with the resultant compound from Example 22 and replacing the phosgene with benzyl chl oroformate provided the desired 2R isomer preceded by the 2S isomer.
2R-Isomer: 1H-NMR (CDCL3,TMS) δ 7.34 (m,5H), 5.13 (s,2H), 4.95 (d,1H), 4.79 (m,2H), 3.37 (s,3H), 1.43 (s,9H), 1.14 (m,3H).
2S-Isomer: 1H-NMR (CDCL3,TMS) δ 7.35 (m,5H), 5.14 (d,1H), 5.12 (d,1H), 4.93 (d,1H), 4.80 (m,2H), 3.38 (s,3H), 1.43 (s,9H), 1.13 (t,3H).
Example 28
(2S.3R,4S)-1-Benzyloxycarbony!ethylamino-2-azigo-
3-methoxyethoxymethoxy-4-tert-butyloxycarponylamino- 5-cyclohexylpentane.
To triphenylphosphine (100.0 mg, 0.381 mmol) in tetrahydrofuran (THF, 0.6 ml) at -78°C was added diethyl azodicarboxylate (60 μl, 0.38 mmol) in THF (1 ml). To thi s mixture was added a solution of hydrazoic acid (0.46 mmol) in benzene (1 ml) then the resultant compound from Example 27 (180.0 mg, 0.318 mmol) in THF (1.4 ml) was added. After one hour the mixture was warmed to room temperature, stirred for 16 h, eyaporated and chromatographed on silica gel with 20% ethyl acetate in hexane to afford 103.5 mg (55%) of the desired product as an oil. 1H-NMR (CDCL3,TMS) δ 7.35 (m,5H), 5.15 (m,2H), 3.38 (s,3H), 1.45 (s,9H), 1.15 (m,3H). Example 29
(2'S,1'R,5S)-3-Ethyl-5-(1'-methoxyethoxymethoxy-
2'-tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- imidazolidin-2-one.
To the resultant compound from Example 28 (99.0 mg, 0.167 rnrnol) in methanol (2 ml) was added triethylamine (75 μl, 0.54 mmol) and propane 1,3-dithiol (50 μl,
0.50 mmol). After 72 h the mixture was filtered and evaporated, and the crude amino compound was dissolved in toluene (5 ml) and heated to reflux for 72 h. Evaporation and chromatography on silica gel with ethyl acetate/hexane mixtures provided the desired product as an oil. 1H NMR (CDCl3) δ 1.12 (t,3H), 1.43 (s,9H), 3.23 (m,2H), 3.39
(s,3H), 3.64 (m,1H), 3.78 (m,1H), 3.94 (m,1H), 4.58 (d,1H), 4.74 (d,1H), 5.47 (s,1H).
Example 30
(3S, 4S)-3-tert-Butyldimethylsilyloxy-4-tert- butoxycarbonylamino-5-cyclohexyl-l-pentene. To the resultant compound from Example 20 (0.264 g, 0.932 rnrnol) in DMF (4 ml) was added tert-butyldimethylsilyl chloride (0.300 g, 1.99 rnrnol) and imidazole (0.269 g, 3.95 mmol). The mixture was stirred at room temperature for 12 hours, poured into ethyl acetate and washed sequentially with 0.5 M H3PO4, saturated NaHCO3 solution and brine, then dried oyer Na2SO4 and eyaporated to afford 0.355 g (96%) of the desired compound. Mass spectrum: (M+H)+ = 398.
Example 31
(2RS,3R,4S)-3-tert-Butyldimethylsilyloxy-4-tert- butoxycarbonylamino-5-cyclohexy1-l,2-oxopentane.
The resultant compound from Example 30 (0.355 g,
0.893 rnrnol) in methylene chloride (8 ml) was treated with m-chloroperbenzoic acid (0.758 g, 3.51 mmol) and stirred at ambient temperature for 14 hours. The mixture was concentrated, dissolved in ethyl acetate, washed sequentially with cold 10% aqueous Na2SO3 solution, saturated NaHCO3 solution and brine, and then dried oyer Na2SO3 and eyaporated to afford 0.374 g ( 100%) of the des ired compound . Mass spectrum: (M+H)+ = 404.
Example 32
(2RS.3R,4S)-3-Hydroxy-4-tert-butoxycarbonylamino- 5-cycl ohexyl-1,2-oxopentane.
The resultant compound from Example 31 (2.10 g,
5.07 mmol) was treated with 1 M tetrabutyl ammonium fluorine in tetrahydrofuran (10 ml). The mixture was stirred at O°C for 1 hour, poured into ethyl acetate, washed with water and brine, then dried over Na2SO4 and evaporated. Chromatography on silica gel (0.5% methanol in chloroform) afforded 1.3 gg (74%) of the desired compound. Mass spectrum: (M+H)+ = 300.
Example 33
(2S.3R,4S)-1-Azido-2,3-dihydroxy-4-tert- butoxycarbonylamino-5-cyclohexylpentane. The resultant compound from Example 32 (1.12 g,
3.74 mmol), ammonium chloride (0.374 g, 6.98 mmol) and sodium azide (0.580 g, 8.92 rnrnol) were refluxed in methanol (25 ml) for 12 hours. The mixture was concentrated, then taken up in ethyl acetate, washed with water and brine, dried over Na2SO4 and evaporated. Chromatography on silica gel (20% ether in hexane) afforded 0.461 g (36%) of the desired compound followed by 0.323 g (25%) of the 4-R isomer. 4S-Diasteriomer: m.p. 93-94°C. 4R-Diasteriomer: mass spectrum: (M+H)+ = 343.
Example 34
N-(3-Methylbutyl)-4-hydroxy-
5-t-butv -loxvcarbonvlamino-
6-cyclohexylhex-1-ene-2-carboxamide. A solution of N-(3-methylbutyl)-2-methylpropenamide (643 mg, 4.15 mmol) in 25 ml of dry tetrahydrofuran was cooled unoer an N2 atmosphere to -78°C and treated dropwise with 3.28 ml (8.5 mmol) of n-butyllithium in hexane. The resulting solution was warmed to 0°C for 20 min, recooled to -78°C and treated with 6.2 ml (6.2 mmol) of chlorotitanium triisoproooxide in hexane. After again warming to 0°C for 5 min, the dark solution was recooled to -78°C treated with a solution of N-t-butyloxycarbonylcyclohexylal ininal (670 mg, 2.3 rnrnol) in 5 ml of tetrahydrofuran, stirred for 5 min at -78°C, warmed to 0°C for 20 min and quenched with saturated aqueous ammonium chloride. The resulting suspension was treated with ca. 50 ml of ether, stirred until the salts became white, extracted with two 100 ml portions of ether, dried over MgSO4 and concentrated in vacuo. The crude mixture was separated by flash column chromatography using 4:1 chloroform/ethyl acetate to give 249 mg (26%) of the (4S,5S) product (Rf .44), 292 mg (31%) of the (4R,5S) product (Rf .36, 3:2 chloroform/ethyl acetate) and 184 mg (20%) of a ca. 1:1 mixture of the two products. (4S,5S)-Isomer: 1H NMR (CDCl3) δ 0.8-1.9 (m,16H), 0.94 (d,J=6Hz,6H), 1.43 (s,9H), 2.42 (m,2H), 3.32
(br q,J=7Hz,2H), 3.62 (m,1H), 3.68 (m,1H), 4.79
(br d,J=9Hz,1H), 5.08 (br s,1H), 5.43 (s,1H), 5.56 (s,1H), 6.03 (br t,1H). Mass spectrum: M+ = 410.
Example 35
2(S)-t-Butyloxycarbonylamino-1-cyclohexyl-
6-methyl heot-3-ene.
To a stirred -78°C solution of Boc-cyclohexylalanine methyl ester (40 g, 140 mmol) in anhydrous toluene (250 ml) was added diisobutylaluminum hydride (130 M%, 1.5 M solution in toluene, 121.4 ml) at a rate to keep the internal temperature below -60°C. After stirring for an additional 20 minutes at -78°C, the aldehyde solution is used immeoiately as described below.
To a potassium hydride (35% dispersion in oil, 32.09 g) suspension in a 0°C mixture of anhydrous THF/DMSO (1000 ml/200 ml) under dry N2 was added 1,1,1,3,3,3-hexamethyl- disilazane (209 M%, 49.07 g) dropwise. After stirring at 0°C for 1 hour, the resulting solution was added via cannula to a 0°C flask containing isopentyltriphenylphosphonium bromide (209 M%, 125.66 g). The mixture was stirred vigorously for 1 hour at which time it was cooled to -78°C. The -78°C aldehyde solution prepared aboye was then added yia cannula. After stirring at -78°C for 15 minutes, the mixture was allowed to slowly warm to room temperature and then heated to 40°C for 12 hours. The mixture was then cooled to room temperature and quenched with methanol (7.65 ml) followed by aqueous Rochelle salts (100 ml saturated solution and 500 ml H2O). The mixture was then extracted with ethyl acetate (2x). The combined extracts were washed with water and brine. Drying (MgSO4) and evaporating provided crude alkene which was chromatographed on silica gel (ether/ hexane) to give 16.5 g (38%) of the desired compound as an 85:15 mixture of cis:trans isomers. Mp = 53-55°C. Mass spectrum: M+ = 309.
Anal. Calcd. for C19H35NO2: C, 73.7; H, 11.4; N, 4.5.
Found: C, 73.8; H, 11.4; N, 4.5.
Example 36
2 (S)-t-Butvloxycarbonylamino-1-cvclohexyl- 3,4-dihydroxy-6-methylheptane:
The 3(R)4(S). 3(S)4(S), 3(R)4(R), and 3(S)4(R)
Diastereomers.
To a solution of the resultant compound of Example 35 (8.50, 27.5 mmol) in dry THF (150 ml) were added OsO4
(2.8 ml of a 2.5% solution in t-butanol and N-methylmoroholine N-oxide (9.28 g, 68.7 mmol). After 4 days the mixture was partitioned between ether (200 ml) and orine (100 ml). The aqueous layer was back-extracted witn ether (2 x 100 ml), and the combined organic phase was washed with 10% Na2SO3, 0.1 M H3PO4, and brine. Drying (MgSO4) and eyaporating proyided a residue (10.81 g) which was
chromatographed on silica gel to elute a 60% yield of the 4 diols in the following order.
3(R),4(S) Mass spectrum: (M+H)+ = 344.
Anal Calcd. for C19H37NO4: C, 66.4; H, 10.9; N, 4.1.
Found: C, 66.4; H, 10.8; N, 3.9.
3(S),4(S) Mass spectrum: (M+H)+ = 344.
Anal Calcd. for C19H37NO4: C, 66.4; H, 10.9; N, 5.1.
Found: C, 66.4; H, 11.1; N, 4.0.
3(R),4(R) Mass spectrum: (M+H)+ = 344. 3(S),4(R) Mass spectrum: (M+H)+ = 344.
Anal Calcd. for C19H37NO4: C, 66.4; H, 10.9; N, 4.1.
Found: C, 66.0; H, 10.7; N, 4.0.
Example 37
2-t-Butyloxycarbonylamino-1-cyclohexylbut-3-ene.
To a stirred suspension of methyltriphenyl phosphonium bromide (10.97 g, 30.70 rnrnol) in anhydrous tetrahydrofuran (200 ml) at -78°C (dry ice/acetone bath) under an argon atmosphere, was added n-butyl lithium (19.8 ml of a 1.55 M hexane solution) dropwise over the course of 5 min. After 10 min, the -78°C bath was replaced with a 0°C bath for .5 h, at which time the resulting orange solution was cooied again to -78°C. The solution was then added dropwise by cannula to a stirred -78°C solution of Boc-cyclohexylalaninal (27.91 mmol) in anhydrous tetrahydrofuran (30 ml) over the course of .5 h. The mixture was then allowed to warm to room temperature during a 3 h period after wnich water (150 ml) was added. Extraction with hexane (4 x 100 ml) provided a combined organic phase which was wasned with brine (100 ml), dried (Na2SO3), and concentrated.
Chromatography with ether/hexane (1/9) provided the desired compound. Mass spectrum: (M+H)+ = 254.
Example 38
3-t-Butyloxycarbonylamιno-4-cyclohexyl- 1,2-oxobutane.
To a stirred solution of the resultant compound of Example 37 (2.0 rnrnol) in dichloromethane (20 ml) was added m-chlorooeroenzoic acid (MCPBA, 1.51 g of 80% MCPBA, 7.0 mmol). After 68 h the reaction mixture was cooled to 0°C, and 0°C 10% Na2SO3 (5 ml) was added with stirring. After 15 min, the solid was filtered off and extracted with dichloromethane. The combined organic phase was washed sequentially with 0°C 10% Na2SO3 (6 ml), saturated NaHCO3 (2 x 6 ml), and water (5 ml). Drying (MgSO4), filtering, concentrating and chromatography on 50 g of SiO2 (hexane/ ether, 3/1) gave the desired compound. Mass spectrum:
(M+H)+ = 270.
Example 39
3-t-Butyloxycarbonylamino-4-cyclohexyl-
2-hydroxy-1-isopropylmercabtobutane. To a stirred solution of the resultant compound of Example 33 (0.37 mmol) in methanol (3.7 ml) was acded isopropyl mercaotan (0.87 mmol) and triethylamine
(0.87 mmol). The resultant solution was refluxed for 2 h and then evaporated to give a residue which was cnromatograohed on 15 g of 40 μ SiO2 (7/3, hexane/ether) to give the desired compound. Mass spectrum: (M+H)+ = 346.
Example 40
3-t-Butyloxycarbonylamino-4-cyclohexyl- 2-hydroxy-1-isopropylsulfonylbutane. Treating the resultant compound of Example 39 with 2.5 equivalents of 3-chloroperoxybenzoic acid in dichloromethane, gave the desired compound after work-up as described in Example 38. Mass spectrum: (M+H)+ = 418.
Anal Calcd. for C21H33NO5S°0.5 H2O: C, 59.10; H, 9.45; N, 3.28.
Found: C, 58.90; H, 9.46; N, 3.03. Examαle 41
2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane Hydrochloride.
To 0.17 g (0.50 rnrnol) of the resultant compound of Example 36 was added 5 ml of 4 M HCl in dioxane. After being allowed to stand for 1 h at ambient temperature, the solution was concentrated with two chloroform chasers to give a white solid which was used without further purification.
Example -2
Boc-His Amide of 2(S)-Aminc-1-cvclonexyl-
3(R) ,4(S)-dihydroxy-6-methylheptane.
To a stirred suspension of Boc-His-OH (72 mg, 0.23 mmol) in dry dimethylformamide (3 ml) at -23°C was adαed a solution of the resultant compound of Example 41 (0.23 mmol) in dry dimethyl formamide (2 ml) containing N-methyimorpnoline (29 mg, 0.28 mmol). Hydroxybenzotriazole (HOBT, 53 mg, 0.43 mmol) and N,N'-dicyclohexylcarbodi imide (DCC, 59 mg, 0.23 rnrnol) were then added sequentially. After 2 h the mixture was allowed to warm to room temperature. After 22 h the mixture was filtered, eyaporated, and partitioned between ethyl acetate (18 ml) and saturated aqueous NaHCO3 (6 ml). The layers were separated, and the organic phase was washed with brine (5 ml), dried (Na2SO4), filtered, and evaporated to a solid which was chromatographed on SiO2 to giye the desired compound. Mass spectrum: M+ = 480.
Anal Calcd. for C25H44N4O5º3/4 H2O: C, 60.8; H, 9.1; N, 11.3.
Foundd C, 60.9; H, 9.2; N, 11.0. Examole 43
3-Amino-4-cyclohexyl-2-hvdroxy-1-isopropyl- sulfonylbutane Hydrochloride.
Using the procedure of Example 41 with the resultant compound of Example 40 gave the desired compound which was used without further purification.
Example 44
His Amide of 2(S)-Amino-1-cyclohexyl-3-(R),4(S)- dihydroxy-5-methylheptane Dihydrochloride.
Using the procedure of Example 41 with the resultant compound of Example 42 gave the desired compound wnich was used without further purification.
Example 45
(4S.5S)-N-(3-Methylbutyl)-5-amino-4-hvdroxy-
6-cyclohexylhex-1-ene-2-carboxamide Hydrocnlorlge.
Using the procedure of Example 41 with the resultant compound of Example 34 gave the desired ccmoounα wnicn was used without further purification.
Example 46
(2S,3R.4S)-1-Azido-2.3-dihydroxy-4-amino-
5-cyclohexylpentane Hydrochloride.
Using the procedure of Example 41 with the resultant compound of Example 33 gave the desired compound which was used without further purification.
Example 47
(2'S,1'R.5S)-3-Ethyl-5-(2'-amino-3-cyclohexyl-
1'-hydroxypropyl)imidazolidin-2-one Hydrochloride.
Using the procedure of Example 41 with the resultant compound of Example 29 gave the desired compound which was used without further purification.
Example 48
(2' S.1 R, 5S)-2-Oxo-4-(2'-amino-3'-cyciohexyl-
1'-hydroxypropyl)dioxolane Hydrocholpride.
Using the procedure of Example 41 with the resultant compound of Example 26 gaye the desired compound wnich was used without further purification.
Example 49
(2 'S.1'R,5S)-3-Methoxy-5-(1'-hvdroxy-2'-amino- 3'-cyclohexysoropylloxazolidin-2-one Hydrocnloride. Using the procedure of Example 41 with the resultant compound of Example 24 gave the desired compound which was used without further purification/
Example 50
(2 ' S .1 ' R .5S) -3-Ethyl-5-('1-hydroxy-2'-amino-
3'-cyclohexylpropyl)oxazolidin-2-one Hydrochloride.
Using the procedure of Example 41 with the resultant compound of Example 23 gave the desired compound which was used without further purification.
Example 51
N-(1(S)-(tert-Butyloxycarbonyl1-3-ohenyloropyl)- L-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R) .4 (S)-dihydroxy-6-methylheotane. To a mixture of the resultant compound of Example 16 (33.2 mg, 0.095 rnrnol) and 2(S)-amino-1-cyclohexyl-3(R),4(S)- dihydroxy-6-methyl heptane hydrochloride (26.6 mg,
0.095 rnrnol, Example 41) in 2 ml of anhydrous DMF was added 1-hydroxybenzotriazole hydrate (38.5 mg, 0.285 mmol), N-methyl morpholine (11 mg, 0.114 rnrnol) and EDAC (21.9 mg, 0.114 mmol) seαuentially at -23°C. After stirring for 2 h, the mixture was allowed to warm to room temperature. After another 17 h, the mixture was poured into ethyl acetate, wasned with dilute sodium bicarbonate, water, and brine. The organic phase was dried and concentrated under reduced pressure to a crude product which was chromatograpned on silica gel eluting with ethyl acetate: hexane (1.5:3.5) to obtain the desired compound (29.2 mg, 54%) as a wnite solid. 1H NMR (CDCl3, TMS) δ 0.9 (d,3H), 0.94 (d,2H), 0.95 (d,3H), 0.97 (d,3H), 1.49 (s,9H), 2.73 (m,2H), 3.05
(br t,1H), 3.11 (dd.1H), 3.20 (m,2H), 4.31 (m.1H). 7.22 (m,5H). Mass spectrum: (M+H)+ = 575.
Example 52
N-(1(S)-(tert-Butyloxycarbonyl)-3-Dhenylpropyl)- D-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane. The resultant less polar (S,R) diastereomer of Example 10 was hydrogenated using the procedure of Example 16. The resultant product was coupled to the resultant product of Example 41 according to the procedure of Example 51 to give the desired compound. 1H NMR (CDCl3, TMS) δ 0.9 (dd,6H), 0.95 (dd,6H), 1.59 (s,9H), 1.94 (m,3H) , 2.6 (m,2H), 3.2 (m,4H), 4.29 (m,1H), 7.24 (m,5H). Mass spectrum: (M+H)+ = 575.
Example 53
N-(1(R)-(tert-Butyloxycarbonyl)-3-phenylpropyl)- D,L-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S oxy-6-methylheptane. The resultant di eric mixture of Example 9 was hydrogenated accordi g e procedure of Example 16. The resultant acid was coupled to the resultant product of Example 41 according to the procedure of Example 51 to give the desired compound. 1H NMR (CDCl3, TMS) δ 0.85 (dd, 6H), 0.95 (dd,6H), 1.5 (2s,9H), 3.1 (m,2H), 7.2 (m,5H). Mass spectrum: (M+H)+ = 575.
Example 54
N- (1 (S)-(tert-Butyloxycarbonyl)-2-ohenylethyl)- L-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane. The resultant more polar diastereomer of Example 8 was hydrogenated according to the procedure of Example 16. The resultant acid was coupled to the resultant product of Example 41 according to the procedures of 51 to giye the desired compound. 1H NMR (CDCl3, TMS) δ 0.83 (dd,6H), 0.89 (dd,6H), 1.37 (s,9H), 1.93 (m,1H), 2.45 (d,2H), 4.28 (br dd,1H), 4.52 (br dd,1H), 7.24 (m,5H), 7.41 (br d,1H). Mass spectrum: (M+H)+ = 561. Examole 55
N- (1 (S)-(tert-Butyloxycarbonyl)-2-phenylethyl)- D-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane.
Using the procedure of Example 54, but replacing the resultant more polar diastereomer of Example 8 with the less polar diastereomer of Example 8 gave the desired compound. 1H NMR (CDCl3, TMS) 6 0.91 (dd,6H), 0.96 (dd,6H), 1.38 (s-9H). 2.83 (br dd,2H), 4.16 (brm,1H), 4.5 (br,1H), 6.8 (br.1H), 7.28 (m,5H). Mass spectrum: (M+H)+ = 561. N- (1 (S)-(tert-Butyloxycarbonyl)-2-phenylethyl)- D-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane. Using the procedure of Example 52, but replacing the resultant (S,R) less polar diastereomer of Example 10 with the resultant product of Example 15 gave the desired compound.
lH NMR (CDC!3, TMS) δ 0.73 (dd,6H), 0.88 (dd,6H), 1.41 (s,9H), 2.8 (dd,1H), 2.97 (dd,1H), 3.12 (bm,3H), 3.43
(dd,1H), 4.3 (m,1H), 4.86 (bm,1H), 7.95 (bd,1H). Mass spectrum: (M+H)+ = 561.
Example 57
N-(1-(Ethoxycarbonyl)-3-phenylpropyl)-
L-alanine, benzyl ester.
(More polar and Less polar isomers)
2-0xo-4-phenylbutyric acid, ethyl ester (Syn. Comm.,
11(12), 943-946, 1981) was treated with L-Ala benzyl ester°HCl according to the procedure of Example 3. The crude product was chromatographed eluting with 15% EtOAc/Hex to give two separate diastereomers. Less polar isomer (18% yield). 1H NMR (CDCl3, TMS) δ 1.25 (t,3H), 1.32 (d,3H), 1.94 (m,2H), 2.37 (bs,1H), 2.71 (t,2H), 3.27 (bt,1H), 3.38 (q,1H), 4.12 (m,2H), 5.13 (dd,2H). Mass spectrum: (M+H)+ = 370.
More polar isomer (20% yield) 1H NMR (CDCl3, TMS) δ 1.28 (t,3H), 1.35 (d,3H), 1.93 (m,2H), 2.71 (m,2H), 3.35 (dd,1H), 3.43 (q,1H), 4.15 (m,2H), 5.15 (dd,2H). (M+H)+ = 370.
Example 58
N- ( 1 ( R or S)-(Ethoxycarbonyl)-3-Phenylpropyl)- L-alanyl Amide of 2(S)-Amino-1-cyclonexyl- 3(R),4(S)-dihydroxy-6-methylheptane.
The more polar resultant product of Example 57 was hydrogenated according to the procedure of Example 16. The resultant acid was coupled to the resultant product of Example 41 according to the procedure of Example 51 to give the desired compound in 80% yield. 1H NMR (CDCl3, TMS) δ 0.9 (dd,6H), 1.27 (t,3H), 1.29 (d,3H), 2.3 (bd,1H), 2.59 (bt,2H), 3.12 (m,3H), 3.34 (t,1H), 4.15 (m,2H) , 4.3 (m,1H), 4.63 (b,1H), 7.67 (bd,1H). Mass spectrum: (M+H)+ = 505.
Example 59
N-(1(R or S)-(Ethoxycarbonyl)-3-Phenylpropyl)- L-alanyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane. Using the procedure of Example 58, but replacing the more polar resultant product of Example 57 with the less polar product of Example 57 gaye the desired compound. 1H NMR (CDCl3, TMS) δ 0.9 (dd,6H), 1.26 (t,3H), 1.23 (d,3H), 2.3 (bd,1H), 2.68 (t,2H), 2.12 (m,3H), 4.17 (q,2H), 4.3 (m,1H), 7.67 (bd,1H). Mass spectrum: (M+H)+ = 505, Example 60
N-(1(R or S)-(Ethoxycarbonyl)-3-phenylpropyl)- L-His Amide of 2(S)-Amino-1-cyclohexyl-3(R), 4 (S ) - dihydroxy-6-methylheptane and its isomer. Using the procedure of Example 57, but replacing L-Ala benzyl ester'HCl with the resultant compound of Example 44 gave a mixture of two diastereomers which were separated on silica gel chromatography eluting with 5% CH3OH/CHCI3 Less polar isomer (a) 1H NMR (CDCl3, TMS) δ 0.9 (dd,6H), 1.25 (t,3H), 1.1-1.9 (m,19H), 2.6 (bt,3H), 3.1 (m,3H), 4.1 (m,2H), 4.3 (m,1H), 6.9 (s.1H), 7.2 (m,5H), 7.58 (s,1H). Mass spectrum: (M+H) = 571. More polar isomer (b) 1H NMR (CDC13. TMS) δ 0.9 (dd,6H), 1.2 (t,2H), 4.1 (q,2H), 4.3 (m,1H), 5.9 (s,1H), 7.3 (m,5H), 7.6 (s,1H). Mass
spectrum: (M+H)+ = 571.
Example 61
N-(1 (R)-(4-Morpholinylcaroonyl)-3-pnenyl propyl)-L-leucine benzyl ester.
The resultant less polar (S ,S) isomer of Example 9 (770 mg, 1.76 rnrnol) was stirred in 7 ml of 4 M HCl/dioxane for 16 h. The solvent was evaporated off under reduced pressure to proyide a solid. The residual solid (400 mg, 0.95 mmol) was coupled to morpholine (0.96 mmol) using NMM, HOBT, and EDAC according to the procedure of Example 51 to give the desired compound in 70% overall yield. 1H NMR (CDCl3, TMS) δ 0.9 (dd,6H), 2.75 (m,2H), 3.2 (t,2H), 3.35 (t,2H), 3.5 (m,2H), 3.6 (m,2H), 5.05 (s,2H), 7.4 (m,5H). Example 62
N-(1(S)- (4-Morpholinylcarbonyl)-2-phenylethyl)- L-alanine. benzyl ester.
Using the procedure of Example 61, the resultant less polar isomer of Example 11 was hydrolyzed and coupled to morpholine to giye the desired compound. 1H NMR (CDCl3, TMS) δ 1.35 (d,3H), 2.5 (m,2H), 2.8 (m,2H), 3.1 (m,1H), 3.3 (m,2H), 3.5 (m,2H), 3.8 (q,1H), 5.2 (s,2H), 7.25 (m,5H).
Example 63
N-(1(R)-(4-Morpholinylcarbonyl)-2-Phenylethyl)- L-alanine, benzyl ester.
Using the procedure of Example 61, the resultant less polar iscmer of Examole 13 was hydrolyzed and coubled to morpholine to giye the desired Compound in 32% yield. 1H NMR (CDCl3, TMS) δ 0.82 (d,3H), 2.73 (m,3H), 3.02 (m,2H), 3.36 (m,4H), 3.56 (m,1H), 3.64 (m,1H), 3.78 (dd, 1H), 5.12 (s,2H). Mass spectrum: (M+H)+ = 397.
Example 64
N- (1(S)-(4-Morpholinylcarbonyl)-2-Phenylethyl) - L-norLeu, benzyl ester.
Using the procedure of Example 61, the resultant more polar (S ,S ) isomer of Example 14 was hydrolyzed and coupled to morpholine to give the desired compound in 65% yield. 1H NMR (CDCl3, TMS) δ 0.86 (m,3H), 1.27 (m,4H), 2.44 (m,2H), 2.77 (m,2H), 2.99 (dd,1H), 3.13 (m,2H), 3.32 (m,2H), 3.53 (m,2H), 3.7 (dd,1H), 5.18 (s,2H). Mass spectrum: (M+H)+ = 439. Example 65
N-(1(S)- (-4Morpholinylcarbonyl)-2-ohenylethyl)- L-leucyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane.
Using the procedure of Example 61, but replacing the resultant product of Example 9 with the more polar (S ,S) resultant product of Example 54 gave the desired compound in 71% yield. 1H NMR (CDCl3, TMS) δ 0.87 (dd,6H), 0.93
(dd,6H), 2.88 (m,6H), 3.16 (m,4H), 3.62 (m,4H), 4.22
(bm,1H), 4.52 (bd,1H), 7.09 (bd,1H). Mass spectrum: (M+H)+ = 574.
Example 66
N- (1(S)-(tert-Butyloxycarbonyl)-2-Phenylethyl)- L-alanyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane.
Using the procedure of Example 58, but replacing the more polar resultant product of Example 57 with tne less polar (S ,S ) resultant product of Example 11 gave the desired compound in 76% yield. 1H NMR (CDCl3, TMS) δ 0.92 (dd,6H), 1.42 (d,2H), 1.42 (s,9H), 1.4 (m,1H), 2.72 (dd,2H), 2.95 (dd,1H), 3.09 (m,3H), 4.11 (m,1H), 4.45 (b,1H), 6.73
(bd,1H). Mass spectrum: (M+H)+ = 519.
Example 67
N- (1(S) -(3-(Ethoxycarbonyl)propylcarbamoyl)- 2-phenylethyl)-L-alanyl Amide of 2(S)-Amino- 1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane.
Using the procedure of Example 61, the resultant compound of Example 66 was hydroyzed and coupled to 3-(ethoxycarbonyl)-propyl amine according to the procedure of
Example 51 gave the desired compound in 33% yield. 1H NMR (CD3OD, TMS) δ 0.92 (dd,6H), 1.24 (d,3H), 1.25 (t,3H), 2.15 (t,2H), 2.83 (m,2H), 4.12 (q,2H), 7.23 (m,5H). Mass spectrum: (M+H)+ = 576.
Example 68
N-(1(S)-(4-Morpholinylcarbonyl)-2-phenylethyl)- L-alanyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane.
Using the procedure of Example 52, but replacing the resultant (S,R) less polar product of Example 10 with the resultant product of Example 62 gave the desired compound. 1H NMR (CDCl3, TMS) δ 0.3 (d,3H), 0.95 (d,2H), 1.25 (t,3H), 2.7-3.0 (m,4H), 3.15 (m,2H), 3.5 (m,2H), 3.7 (m,2H), 7.3 (m,5H). Mass spectrum: (M+H)+ = 532.
Example 69
N-(1(S)-(4-Morpholinylcarbonyl)-2-phenyletnyl)-
L-norleucyl Amide of 2(S)-Amino-1-cycloriexyi-
3(R),4(S)-dihvdroxy-6-methylheptane.
Using the procedure of Example 52, but replacing the resultant (S,R) less polar product of Example 10 with the resultant product of Example 64 gaye the desired compound in 50% yield. 1H NMR (CDCl3, TMS) δ 0.88 (dd,6H), 0.9 (t,3H), 1.87 (m,1H) 2.85(m,5H), 3.15 (m,3H), 3.4 (m,2H), 3.62 (m,3H), 4.24 (bt,1H), 4.51 (bd,1H), 7.06 (bd,1H). Mass spectrum: (M+H)+ = 574.
Example 70
N-(1(R)-(4-Moroholinylcarbonyl)-2-phenylethyl)- L-alanyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S4-dihydroxy-6-methylheptane.
Using the procedure of Example 52, but replacing the resultant (S,R) less polar product of Example 10 with the resultant product of Example 63 gave the desired compound in 57% yield. 1H NMR (CDCl3, TMS) . 0.9 (dd,6H), 1.3 (d,3H), 2.92 (m,4H), 3.2 (m,3H), 3.37 (m,3H), 3.64 (m,2H), 3.88 (b dd.1H), 4.3 (m,1H), 4.74 (bd,1H), 7.8 (bd,1H). Mass spectrum: (M+H)+ = 532.
Example 71
N-(1(R)-(4-Moroholinylcarbonyl)-2-phenylethyl)- L-alanyl Amide of 2(S)-Amino-1-cyclohexyl- 3(R),4(S)-dihydroxy-6-methylheptane. Using the procedure of Example 52, but replacing the resultant (S,R) less polar product of Example 10 with tne resultant product of Example 61 gave the desired compound. 1 H NMR (CDCl3, TMS) δ 0.8-1.0 (3d,12H), 2.6-3.6 (m,10H), 7.3 (m,5H). Mass spectrum: (M+H)+ = 572.
Example 72
tert-Butyl (2(S)-2-(tert-butyloxycarbamoyl)- 3-phenyl propyl)sulfide.
Tert-butyl mercaptan (0.52 ml, 416 mg, 4.61 rnrnol) was added to a suspension of sodium hydride (111 mg, 4.62 mmol) in 8 ml of THF, cooled to 0°C under a nitrogen atmosphere. The resulting suspension was stirred at 0°C for 1 h, and for an additional 3 h at room temperature. To the resulting thick white suspension, cooled to 0°C, was added dropwise via cannula, a solution of 1-phenyl-3-p-toluenesulfonyloxy- 2(S)-t-butyloxyamidopropane (1.63 g, 4.02 rnrnol) in 10 ml of THF. The resultant mixture was allowed to stir and slowly warm to room temperature over 18 h. The mixture was partitioned between 75 ml Et2O and 50 ml water. The organic phase was extracted with 50 ml saturated NaHCO3, then the combined aqueous phases were extracted with 2 x 50 ml
Et2O. All organic phases were combined, washed with 50 ml brine, dried (MgSO4), and the filtrate concentrated under reduced pressured to afford 1.40 g of orangish solid.
Purification by recrystallization (hexanes, three crops) gave 1.15 g (89%) of white crystals; m.p. 67-69°C. 1H NMR (CDCl3) δ 1.31 (s,9H), 1.43 (s,9H), 2.57 (dd,1H), 2.55 (dd-1H), 2.84 (m,2H), 4.04 (bm,1H), 4.79 (bm.1H), 7.10-7.4 (m,5H).
Example 73
tert-Butyl (2(S)-2-(tert-buty1oxycarbamoyl)- 3-phenyl propyl)sulfide.
The resultant compound from Example 72 (863 mg,
2.67 mmol) was dissolved in 5 ml absolute ethanol and 5 ml THF, and 2.5 ml water and 5 ml pH 4.5 aqueous phospnate buffer was added. The mixture was cooled in ice ana treated with OXONE (2.45 g, 8.00 mmol KHSO5). The mixture was stirred and allowed to warm*to room temperature. After 60 h, the mixture was partitioned between 50 ml water and 50 ml CH2Cl2. The aqueous phase was further extracted with 3 x 50 ml CH2Cl2, and the combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to give 942 mg of white solid. Recrystallization from CH2Cl2/Et2O (three crops) afforded 839 mg (88%) of white crystals; m.p. 169-170.5°C. 1H NMR (CDCl3) δ 1.38 (s,9H), 1.42 (s,9H), 3.1-3.3 (m,4H), 4.30 (bm,1H), 5.26 (bs,1H), 7.21-7.42 (m,5H). High resolution mass spectrum; calcd. for C1 3H30NO4S (M+H)+:
356.1895. Found: 356.1894.
Example 74
tert-butyl (2(S)-2-amino-3-phenylpropyl)
sulfone hydrochloride.
The resultant compound from Example 73 (741 mg,
2.09 mmol) was treated with 2.5 ml of 4.5 M HCl in dioxane at room temperature. After 24 h the volatiles were removed unαer reduced pressure, and the residue placed under high vacuum overnignt, to afford 614 mg (100%) of the cesired compound; m.p. >220°C. 1H NMR (CDCl3) δ 1.34 (s,9H), 2.2C (dd.1H), 3.25 (dd.1H), 3.70 (dd.1H), 3.89 (dd,1H), 4.25 (bm,1H), 7.25-7.35 (m,5H), 8.7 (bs,1H + H2O) .
Examole 75
N-(1(S)-(tert-Butylsulfonylmetnyl)-2- phenylethyl)-D,L-alanine ethyl ester.
A suspension of the resultant compound from Example 74 (200 mg, 0.685 mmol) in 5 ml of isopropanol was cooled to 0°C, then ethyl pyruvate (96 mg, 0.822 mmol) and sodium acetate (140 mg, 1.03 mmol) were added. Sodium cyanoborohydride (49 mg, 0.780 mmol) was added as a solution in 1.2 ml of isopropanol, and the reaction mixture was allowed to warm slowly to room temperature and stir for 48 h. The mixture was stirred with 5 ml of 1 M sodium carbonate for 1 h at room temperature, then the mixture was concentrated under reduced pressure. The residue was partitioned between 40 ml of water and 50 ml of CH2Cl2. The aqueous phase was further extracted (4 x 25 ml CH2Cl2), then the combined organic phases were washed (50 ml sat. aq. NaHCO3, 50 ml brine), dried (Na2SO3), and the filtrate concentrated under reduced pressure. Purification by column chromatography (Et2O-hexanes 5:1) gave the two isomeric products, 70 mg (29%) of the less polar isomer, and 124 mg (51%) of the more polar isomer, as colorless, viscous oils.
Data for the less polar isomer: 1H NMR (CDCl3) δ 1.27 (dd,3H), 1.3 (d,3H), 1.57 (bm,1H), 2.74-3.04 (m,4H), 3.50 (b q,1H), 3.62 (m,1H), 4.20 (qd,2H), 7.2-7.33 (m,5H).
Data for more polar isomer: 1H NMR (CDCl3) δ 1.23 (t,3H), 1.30 (d,3H), 2.39-3.16 (m,4H), 3.54 (q.1H), 3.53 (m.1H), 4.12 (qd,2H), 7.21-7.35 (m,5H).
Example 76
N-(1(S)-(tert-ButYlsulfonyimethyl)-
2-ohenylethyl)-L-alanyl Amide of 2(S)-Amino- 1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylneptane.
The resultant compound from Example 75 (51 mg,
0.143 rnrnol, more polar isomer) was treated with lithium hycroxide (160 m1, 1.0 M in H2O, 0.160 mmol) in 1.0 ml of THF. After 20 h, the solution was concentrated under reduced pressure and the residue was placed under high yacuum, affording 49.3 mg of the corresponding lithium carboxylate. The carboxylate salt was then suspended in 1.4 ml of dry DMF, cooled to 0°C, and hydroxybenzotriazole monohydrate (22.6 mg, 0.148 mmol), ethyl (dimethyl amino- propyl)carbodi imide hydrochloride (38 mg, 0.198 rnrnol) and N- methylmorpholine (36 mg, 0.355 mmol) were added. After stirring for 5 min, the resultant compound from Example 41 (40.2 mg, 0.144 rnrnol) was added, and the resulting mixture allowed to slowly warm to room temperature and stir for 48 h. Concentration under high vacuum was followed by partitioning of the residue between 15 ml of EtOAc, 5 ml of sat. aqueous NaHCO3 and 2 ml of water. The aqueous phase was further extracted with 2 x 10 ml of EtOAc, and the ccmpined organic extracts were washed with 10 ml of brine, dried (Na2SO3), and the filtrate was concentrated under reduced pressure to give 69.3 mg of yellow oil. Column chromatography on silica gel (EtOAc-hexane 5:2) afforded 33.8 mg (69%) of the desired product as a glassy solid. 1H NMR (CDCl3) δ 0.74 (d,3H), 0.90 (d,3H +m,4H), 1.1-1.75 (several m,HH), 1.32 (s,9H), 1.39 (d,3H), 1.87 (m,1H), 2.74 (dd.1H), 2.78 (dd,1H), 3.06 (m,2H), 3.17 (bs,1H), 3.43 (bq-1H), 3.55 (bm,1H), 4.2 (bm,2H), 4.57 (bm,1H), 7.18-7.23 (m,5H), 7.52 and 7.71 (2m, 1H). High resolution mass spectrum; calcd. for C30H53N2O5S (M+H)+: 553.3575.
Found: 553.2677.
Example 77
1(S)-(4-Morpholinylcarbonyl)-2-phenyletnanol.
Morpholine (0.48 ml, 5.47 mmol) was aαceo to a mixture of L-pnenyllactic acid (1 g, 6.02 rnrnol) and HOBT (2 g, 14.77 mmoi) in DMF (30 ml). The clear solution was cooled to -23°C and then treated with EDAC (1.648 g, 6.02 mmol). The mixture was stirred at -23°C for 2 h and then allowed to warm to room temperature and stirred for another 18 h. The resultant yellow liquid was concentrated and then taken up into EtOAc, washed consecutively with 5% NaHCO3, H2O, and brine. The crude product obtained after concentration was chromatographed on SiO2 column, eluted with 50% EtOAc/ Hexane. The desired product was obtained as white needles (1.0972 g, 85%). 1H NMR (CDCl3, TMS) δ 1.59 (b,1H), 2.93 (t,2H), 3.07 (dd,1H), 3.3 (b dd,2H), 3.58 (m,4H), 4.59 (bt,1H). Mass spectrum: (M+H)+ = 236. Analogous to the preparation of Example 77 the following compounds were prepared.
Example 78
1 (S)-(N-Αzetidinylcarbonyl)-
2-phenylethanol (60%).
1H NMR (CDCI3, TMS) δ 2.19 (m, 2H) , 2.91 (dd, 2H), 3.42 (m, 1H), 4.03 (m,3H), 4.22 (t,1H). Mass spectrum: (M+H)+ = 206.
Example 79
1(S)-(N-Pyrolidlnylcarbonyl)- 2-ohenylethanol.
iH NMR (CDCl3, TMS) δ 1.82 (m,4H), 2.91 (m, 3H), 3.4 (m, 1H), 3.56 (m,2H), 4.39 (t,1H). Mass spectrum: (M+H)+ = 220.
Example 80
1(S)-(N-Piperidinylcarbonyl)- 2-phenylethanol, (84% yield) .
1H NMR (CDCl3, TMS) δ 1.52 (m, 6H) , 2.88 (dd,2H), 3.16 (m, 1H), 3.31 (m, 1H), 3.5 (m, 1H), 3.64 (m, 1H), 3.82 (b, 1H) , 4.59 (b dd, 1H) . Mass spectrum: (M+H)+ = 234.
Example 81
1(S)-(4-(Methoxycarbonyl)pipeririin-1-yl-carhonyl)- 2-phenylethanol (84% yield) .
1H NMR (CDCl3, TMS) δ 0.9 (m, 1H), 1.64 (m,1H), 1.88 (m,2H), 2.52 (m, 1H), 2.88 (d,2H), 2.92 (m,2H), 3.64
(m,2H), 3.7 (s,3H), 4.35 (m,1H), 4.6 (dd, 1H) . Mass spectrum: (M+H)+ = 292. Example 82 (a )
4-(Methoxymethoxy)-piperidine
A solution of 200 g (1.98 mol) of 4-hydroxypiperidine
(Aldrich) and 160 mL (2.59 mol) was allowed to stir first at ice-water bath temperature for 30 min then at rt for 2 h. Excess methyl formate and methanol were removed by rotary eyaporation under yacuum then submitted to high yacuum (0.5 mm Hg) for 18 h. The crude formamide was used without further purification.
The crude formamide was dissolyed into 1 L
dichloromethane, 700 mL of diisopropylethylamine, and cooled in an ice-water bath. MOMC1 (200 g) was added dropwise and the reaction stirred to rt oyer 8 h. Another 250 mL portion of diisopropylethylamine was added and the reaction mixture recooled in an ice-water bath. MOMCl (100 g) was added dropwise and the reaction mixture stirred to rt oyer 18 h. TLC (2% CH3OH/EtOAc) showed complete reaction. Saturated sodium bicarbonate solution was added (2 L) and the dichloromethane layer separated. The aqueous layer extracted once with dichloromethane. The combined dichloromethane solutions were combined, dried (MgSO4) and eyaporated at 65 0∞C using a rotary eyaporator to remove excess diisopropylethylamine, then kept at rt (0.5 mm Hg) for 1 h. The crude ether was used in the next step without purification.
The crude residue was stirred rapidly at rt for 24 h with a solution of 300 g KOH (85%) in 1.5 L of water. The aqueous suspension was extracted four times with diethyl ether, dried (MgSO4) and concentrated under reduced pressure. The product was isolated by short path
distillation as a water white liquid. Yield
190 g (66% from 4-hydroxypiperidine): bp 68-70°C at 0.7 mm Hg. 1H NMR (CDCI3, TMS) δ 1.65 (m, 2H), 1.95 (m, 2H), 2.8 (m,2H), 3.15 (m, 2H) , 3.4 (s,3H), 4.7 (s,2H). Mass
spectrum : (M+H) + = 146.
Example 82 (b)
1(S)-(4-Methoxymethoxyl)piperidin-1-yl-carbonyl)-
2-phenylethanol.
A solution of 176 g (1.3 mol) of 1- hydroxybenzotriazole (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 0°C (internal temperature) while 132 g EDC HCl (Saber Labs) was added (mechanical stirring). After addition the reaction was stirred to rt oyer 24 h. Excess DMF was removed under high yacuum and the residue dissolyed 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 (MgSO4) and eyaporated to giveapproximately
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 (CDCl3 , TMS) δ 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 83
2(S)-(1(S) - ( 4 -(Methoxymethoxy)piperidin-1-yl-carbonyl)- 2-phenylethoxy)hexanoic acid.
The resultant compound of Example 82(b) (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 (0-5oC). The suspension was stirred for 20 mins at 0-5oC 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 (0-5oC) at N2 atmosphere. It was then allowed to warm up to room temperature and stirred oyernight. Quenched with cold H2O 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
eyaporation, the crude product was purified on silica gel, eluted with CH2Cl2: CH3OH: AcOH (19.4 = 0.3:0.3) to obtain 0.79 g of desired acid (43 % yield).
1H NMR (CDCl3 , TMS) δ 0.88 (t,3H), 3.35 (s,3H), 3.98 (bt,1H), 4.6 (m, 1H), 4.64 (s,2H), 7.38 (m, 5H). Mass spectrum: (M+H)+ = 408.
Example 84 (Method A)
2(S)-(1(S)-(4-Morphollnycarbonyl)- 2-phenylethoxy)hexanoic acid Amide of 2 (S)-Amino- 1-cyclohexyl-3(R),4( S )-dihydroxy-6-methylheptane.
The resultant compound of Example 77 (110 mg,
0.468 mmol), in 5 ml of dry THF, was added dropwise to sodium hydride (60% dispersion in oil, 39 mg, 0.93 mmol) in 6 ml of dry THF at 5°C. The mixture was stirred at 5°C for half hour and at room temperature for another half hour. Then the mixture was cooled to 5°C and
D-2-bromohexanoic acid (91 mg, 0.468 mmol) in 5 ml of dry THF was added dropwise. The mixture was stirred at 5°C for 5 h and at room temperature for 16 h. 3 ml of dry DMF was added and the mixture was stirred for another day. The mixture was eyaporated to provide a solid which was partitioned between ethyl acetate and water. The aqueous portion was acidified with citric acid and extracted with ethyl acetate. The organic portion was dried and
filtered, and the filtrate was eyaporated to a solid which, without purification, was coupled to the
aminoglycol of Example 41 according to the procedure of Example 51 (except that only one equiyalent of HOBT was used). After isolation, the crude product was
chromatographed eluting with ethyl acetate:hexane (5:2) to obtain the desired compound in 37% yield.
1H NMR (CDCl3 , TMS) δ 0.8 (d-3H), 0.95 (m, 5H), 1.2-1.9
(m, 22H) , 3.0 (q, 2H), 3.2 (m, 4H) , 3.55 (m, 2H) , 3.65 (m, 2H), 3.8 (t,1H), 4.4 (q,1H), 7.3 (m, 5H). Rf = 0.30
(EtOAc 5:Hexane 2).
Example 84 (Method B)
2(S)-(1(S)-(4-Morpholinylcarbonyl)- 2-phenylethoxy)hexanoic acid Amide of 2(S)-Amino- 1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane and the 2(R) isomer.
The resultant compound of Example 77 (1.1 g,
4.68 mmol), in 10 ml of dry THF, was added dropwise into sodium hydride (60% dispersion in oil, 390 mg, 9.3 mmol) in 6 ml of dry THF at 5°C. The mixture was stirred at 5°C for a half hour and at room temperature for another half hour. Then the mixture was cooled to 5°C and D,L-2- bromohexanoic acid (910 mg, 4.68 mmol) in 10 ml of dry THF was ad.ded dropwise. The mixture was stirred at 5°C for 5 h and at room temperature for 16 h. 3 ml of dry DMF was added and the mixture was stirred for another day. The mixture was eyaporated to a solid which was partitioned between ethyl acetate and water. The aqueous portion was acidified with citric acid and extracted with ethyl acetate. The organic portion was dried and filtered, and the filtrate was eyaporated to a solid which, without purification, was coupled to the aminoglycol of Example 41 according to the procedure of Example 51 (except that only one equiyalent of HOBT was used). After isolation, the crude product was chromatographed eluting with ethyl acetate:hexane (5:2) to obtain two compounds: the less polar diastereomer (150 mg, 22.4% (2 steps)) and the more polar diastereomer (130 mg, 19.4% (2 steps)).
Less polar 1(S),2(R) isomer (a) 1H NMR (CDCl3 , TMS) δ 0.85 (m,5H), 0.95 (d,3H), 1.2-1.9 (m,22H), 3.0 (q,3H), 3.2
(m,4H), 3.5 (m,2H), 3.65 (m, 2H) , 4.2 (m, 1H), 4.45 (t, 1H), 7.25 (m,5H). Mass spectrum: (M+H)+ = 575.
More polar 1(S),2(S) isomer (b) 1H NMR (CDCl3 , TMS) δ 0.8 (d,3H), 0.95 (m,5H), 1.2-1.9 (m, 22H) , 3.0 (1,2H), 3.2
(m,4H), 3.55 (m,2H), 3.65 (m,2H), 3.8 (t,1H), 4.4 (q, 1H), 7.3 (m,5H). Mass spectrum: (M+H)+ = 575. Rf = 0.30
(EtOAc 5:Hexane 2).
Example 85
2(S)-(1(S)-(4-Morpholinylcarbonyl)- 2-phenγlethoxy)octannic arid Amide of 2(S)-Amino- 1-cyclohexyl-3 (R),4(S)-dihydroxy-6- methylheptane and the 2(R) isomer.
The resultant compound of Example 77 (0.2 g,
0.85 mmol), in 10 ml of dry THF, was added dropwise into sodium hydride (60% dispersion in oil, 0.04 g, 0.85 mmol) in 6 ml of dry THF at 5°C. The mixture was stirred at 5°C for a half hour and at room temperature for another half hour. Then the mixture was cooled to 5°C and D,L-2- bromooctanoic acid (0.19 g, 0.85 mmol) in 10 ml of dry THF was added dropwise. The mixture was stirred at 5°C for 5 h and at room temperature for 16 h. 3 ml of dry DMF was added and the mixture was stirred for another day.
Without isolation, the resultant crude product in the mixture was coupled to the aminoglycol of Example 41 according to the procedure of Example 51 (except that only one equiyalent of HOBT was used). After isolation, the crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (3:1) to obtain two separate diastereomers. Total yield of the two isσmers = 26.5% (two steps).
Less polar 1(S),2(R) isomer: 1H NMR (CDCl3 , TMS) δ 0.9 (m,5H), 0.95 (d,3H), 1.2-1.9 (m,26H), 3.0 (q,2H), 3.2 (m, 4H), 3.5 (m,2H), 3.7 (m, 2H) , 4.25 (bq, 1H), 4.45 (t,1H), 7.3 (m, 5H). Mass spectrum: (M+H) + = 603.
More polar 1(S),2(S) isomer: 1H NMR (CDCl3, TMS) δ 0.8 (d,3H), 0.9 (t,3H), 0.95 (d, 3H) , 1.1-1.9 (m,26H), 3.0 (q,2H), 3.1 (m, 4H), 3.5 (m,2H), 3.6 (m, 2H) , 3.8 (t, 1H), 3.9 (g,1H), 7.3 (m,5H). Mass spectrum: (M+H)+ = 603.
Analogous to the preparation of Example 83 the
following compounds were prepared.
Example 86
2(S)-(1(S)-(4-Morpholinylcarbonyl)- 2-phenylethoxy)propionic acid Amide of 2(S)-Αmino- 1-cyclohexyl-3(R),4(S)-dihydrocy- 6-methylheptane (30% yield).
1H NMR (CDCl3 , TMS) δ 0.89 (dd, 6H), 1.43 (d,3H), 1.87 (m,1H), 3.04 (dd,2H), 3.1 (m,2H), 3.3 (bm,2H), 3.44
(m,1H), 3.61 (m, 6H), 3.89 (q, 1H), 4.14 (m, 2H), 4.42
(dd,1HH, 6.01 (bd, 1H). Mass spectrum: (M+H)+ = 533.
Example 87
2(S)-(1(S)-(N-Azetidinylcarbonyl)-
2-phenylethoxy)propionic acid Amide of 2(S)-Amino-
1-cyclohexyl-3(R),4(S)-dihydroxy-
6-methylheptane (26% yield).
1H NMR (CDCl3 , TMS) δ 0.9 (dd,6H), 1.43 (d,3H), 1.88
(m,1H), 2.2 (m,2H), 3.02 (m, 2H) , 3.78 (m, 1H) , 3.9 (q, 1H),
4.07 (m,5H), 6.03 (bd, 1H). Mass spectrum: (M+H) + = 503.
Example 88
2 (S)-(1(S)-(N-Pyrolidinylrarbonyl)-
2-phenylethoxy)propionic acid Amide of 2(S)-Amino-
1-cyclohexyl-3(R),4(S)-dihydroxy-
6-methylheptane (26% yield).
1H NMR (CDCl3 , TMS) δ 0.9 (dd, 6H), 1.44 (d,3H), 3.02
(m, 5H), 3.37 (m, 1H), 3.51 (m,2H), 3.89 (q,1H), 4.24
(dd,lH), 6.01 (bd,1H). Mass spectrum: (M+H)+ =
517.Example 89
2(S)-(1(S)-(N-Piperidinylcarbonyl)-
2-phenylethoxy)propionic acid Amide of 2(S)-Amino-
1-cyclohexyl-3(R),4(S)-dihydroxy- 6-methylheptane (39% yield).
1H NMR (CDCl3 , TMS) δ 0.89 (dd, 6H), 1.43 (d,3H), 1.86 (m,1H), 3.0 (m,2H), 3.05 (m, 2H) , 3.38 (m,2H), 3.87 (q, 1H), 4.43 (dd, 1H), 5.94 (bd, 1H). Mass spectrum: (M+H) + = 531.
Example 90
2(S)-(1(S)-(4-(Methoxycarbonyl)Piperidin-1-yl-carbonyl)- 2-phenylethoxy)propionic acid Amide of 2(S)-Amino- 1-cyclohexyl-3(R),4(S)-dihydroxy- 6-methylheptane (16% yield).
1H NMR (CDCl3 , TMS) δ 0.89 (dd, 6H), 1.42 (d-3H), 2.53 (m,1H), 3.7 (s,3H), 3.86 (q, 1H), 4.42 (m, 1H). Mass spectrum: (M+H)+ = 589. Example 91
2(S)-(1(S)-(4-MorphPlinylcarbonyl)- 2-phenylethoxy) propionic acid Amide of 2 (S) -A-mino- 1-cyclohexyl-3(S)-hydroxy-5(S)- n-butylcarbamoyl-6-methylheptane.
The title compound was prepared using the method of Example 84 (method A) 3ut replacing the D-2-bromohexanoic acid and amino glycol of Example 41 with the D-2- bromopropionic acid and the appropriate amino deriyatiye (Buhlmayer, et al., U.S. Patent No. 4,727,060, issued February 23, 1988).
1H NMR (CDCl3 , TMS) δ 0.9 (m, 9H), 1.43 (d, 3H), 0.7-1.9 (seyeral bm,20H) , 2.01 (m, 1H), 2.9-3.25 (seyeral m, 4H), 3.35 (q,2H), 3.45 (bm, 3H), 3.55-3.62 (bm, 5H) , 3.79 (q, 1H), 4.49 (dd,1H), 5.72 (bt, 1H), 5.82 (bd, 1H), 7.33 (bm, 5H); 13C NMR (CDCl3 , TMS) 13.78, 19.84, 20.13, 21.24, 26.11, 26.43, 30.22, 31.71, 32.21, 33.82, 34.16, 34.34, 37.15, 39.11, 39.25, 42.55, 45.79, 51.16, 52.30, 66.55, 66.89, 71.11, 76.09, 76.83, 77.22, 77.88, 127.47, 128.92, 129.81, 136.59, 169.36, 173.82, 175.36.. Analysis Calcd. for
C35H57N3O6 0.5 H2O: C, 67.28; H, 9.36; N, 6.73. Found C, 67.44; H, 9.28; N, 6.91.
Example 92
2(S)-((Ethoxγcarbonyl)methylthio)propionic acid
Amide of 2 (S) -Amino-1-cyclohexyl- 3(R)-4(S)-dihydroxy-6-methylpeptane.
The title compound was prepared using the method of Example 86, but replacing the resultant compound of
Example 77 with commercially ayailable ethylthioacetate.
1H NMR (CDCl3 , TMS) 8 0.9 (dd, 6H), 1.28 (t,3H), 1.49 (d,3H), 1.92 (m,1H), 3.35 (dd, 2H), 3.59 (q, 1H), 4.2 (m, 2H), 4.34 (m, 1H), 6.84 (bd, 1H). Mass spectrum: (M+H)+ = 418.
Example 93
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2- phenylethoxy)hexanoic acid Amide of 2 (S) -Amino-1- cyclohexyl-3(R),4(S)-dihvdroxy-6-methylheptane (41% yield).
The resultant compound of Example 83 was coupled to the aminoglycol of Example 41 according to the procedure of Example 51 to obtain the desired compound in 41% yield.
1H NMR (CDCl3 , TMS) δ 0.89 (dd, 6H), 0.9 (t,3H), 2.98 (m,2H), 3.08 (m, 2H), 3.35 (s,3H), 4.44 (m, 1H), 4.66
(s,2H), 5.98 (dd, 1H). Mass spectrum: (M+H)+ = 633.
Similarly, the following compound was prepared.
Example 94
2(S)-(1(S)-(4-(Methoxymethoxy)piperidinyl-1-yl-carbonyl)- 2-phenvlethoxy) propionic acid Amide of 2(S)-Amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane (16%) vield).
1H NMR (CDCI3, TMS) δ 0.9 (dd, 6H), 1.44 (d, 3H), 3.04 (m,4H), 3.37 (s,3H) 3.88 (m, 1H), 4.43 (m, 1H), 4.6 (s,2H),
6.0 (dd,1H). Mass spectrum: (M+H)+ = 591.
Example 95
2(R)-Methyl-4(R)-(4-(methoxymethoxy)- piperidin-1-yl-carbonyl)-6-phenylhexanoic acid
Amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)-dihydroxy-
6-methylheptane.
The title compound can be prepared according to the procedure of Scheme VII in which R5 is
4- (methoxymethoxy) piperidin-1-yl R1 is benzyl, R3 is methyl, and (VI) is the aminoglycol of Example 41. As illustrated in Scheme VII), compound (XXX) (J. Med. Chem. 1983, 26, 1277) is coupled to the aminoglycol of Example 41 according to the procedure of Example 51 to afford the amide (XXXI) which is hydrolyzed to the acid (XXXII) with LiOH/H2O/dioxane. The resulting acid is then coupled to 4-(methyoxymethoxy) piperidine (HOBT, EDAC) to obtain the desired compound (XXXIII).
Example 96
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)- 2-phenylethoxy)hexanoic acid Amide of 2(S)-Amino- 1-cyclohexyl-3(S)-hydroxy-5(S)-n-butylcarbamoyl-
6-methγlheptane.
Using the procedure of Example 93, but replacing the resultant glycol of Example 41 with 2(S)-amino-1- cyclohexyl-3(S)-hydroxy-5(S)-n-butylcarbamoyl-6- methylheptane (see Example 93) gave the desired product.
1H NMR (CDCl3 , TMS) 52.04 (m, 1H), 2.97 (m, 1H),
3.17 (m,2H), 3.38 (s,3H), 3.4 (m, 4H), 3.84 (m, 4H), 4.47 (m,1H), 4.68 (s,1H), 5.7 (bm, 1H), 5.8 (bd, 1H). Mass spectrum: (M+H)+ = 716. Example 97
2(R)-Methyl-3(R )-hydroxy-4(R)-(4- (methoxymethoxy)piperidin-1-yl- carbonyl)pentanoic
acid Amide of 2(S)-Amino-1-cyclohexyl-3(R),4(S)- dihydroxy-6-methylheptane.
The title compound can be prepared according to the process of Scheme VIII in which R5 is 4-(methoxymethoxy)- piperidin-1-yl, R1 and R3 are methyl and (VI) is the aminoglycol of Example 41. The dibutylboryl enolate
(XXXV) (Eyans, D.A., Bartroli, J., Shih, T., J. Am. Chem. Soc. 1981, 103, 2127-2129) undergoes condensation with the aldehyde (XXXIV) (Eyans D.A., McGee, L.R., J. Am. Chem. Soc. 1981, 103, 2876. Also Tetrahedron Lett. 1980, 21, 3975) under standard conditions (see references above) to provide a diastereomeric adduct. The secondary alcohol is conyerted to the silyl ether (Me3SiNEt2, DMAP, CH2Cl2) followed by debenzylation with palladium/carbon in an nitrogen atmosphere and Jones' oxidation to provide an acid (XXXVII). The resulting acid is then coupled to 4- (methoxymethoxy)piperidine and the chiral auxiliary is removed by hydrolysis (LiOH/H2O). The resulting acid is then coupled to the aminoglycol (VI) of Example 41 according to the procedure of Example 51 to provide a product which is deprotected (oxalic acid, NaOH, r.t.) to afford the desired compound.
Example 98
3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-
2,2-dimethyl-5-vinyloxazolidine.
The procedure of S. Thaisriyong (J. Med. Ctiem. 1987, 30, 976) was employed. A solution of 40 g of the
resultant compound of Example 17 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 (CDCl3) 1690 (C=O
carbamate) cm-1; 1H NMR (CDCl3) 55.95 (m, 1H), 5.32
(m,1H), 5.20 (dt,1H), 4.27 (dd, 1H), 1.47 (s, 9H).
Anal. Calcd. for C19H33NO3: C , 70.55; H, 10.28;
N, 4.33.
Found: C, 70.47; H, 10.27; N, 4.09.
Example 99
3-(t-Butyloxycarbonyl)-4-(cyclohexγlmethyl)-2,2- dimethyloxayzolidine-5-carboxaldehyde.
A solution of 10 g of the resultant compound of Example 98 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 dissolyed ozone. The reaction mixture was
cannulated 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 oyernight.
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 (MgSO4), filtered, and eyaporated. The crude aldehyde was purified by flash chromatography (1:4) ethyl acetate:hexane to give9.7 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 (CDCl3) 1735 (C=O aldehyde), 1690 (C=O carbamate) cm-1; 1H NMR (CDCl3) δ 9.83 (s,1H,CHO), 9.73 (d, 1H,CHO cis diastereomer), 4.14 (m, 1H), 1.46 (s,9H).
Anal. Calcd. for C18H31NO4: 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 ml 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 yolume under reduced pressure and extracted with ether (600 ml). The combined ether extracts were dried (MgSO4), filtered, and concentrated. The aldehyde was purified by flash chromatography using (1:4) ethyl acetate:hexane to give19.5 g of the desired compound as an 8:1 mixture of trans: cis diastereomers.
Example 100
(5S,4'S,5'R)-5-(3-(t-Butvloxycarbonyl)- 4-(cyclohexylmethyl)-2,2-dimethyloxazolidin-5-yl)- 3-methylenedihydrofuran-2(4H)-one.
A solution of 16.52 g (51 mmol) of the resultant compound of Example 99 in 15 ml of anhydrous
tetrahydrofuran was treated with 3.98 g (61 mmol) of freshly activated zinc dust. With yigorous stirring, the mixture was treated with 10 g (56 mmol) of methyl 2- (bromomethyl) aerylate at a rate which maintained the temperature at 50-60°C. Upon completion of the addition, the mixture was stirred at 50°C for 1 h. After being allowed to cool, the mixture was poured into 100 ml of cold 1 M HCl and extracted with dichloromethane (3 X
100 ml). The combined organic layers were washed
successiyely with saturated aqueous NaHCO3, and H2O, dried oyer Na2SO4, and concentrated. Silica gel chromatography using 9:1 hexane:ethyl acetate provided 10.83 g (61%) of the desired compound.
1H NMR (CDCl3) δ 0.8-2.0 (br enyelope), 1.49 (s,9H), 1.54 (s,3H), 1.57 (s,3H), 2.93 (ddt, J=18, 6, 3Hz, 1H), 3.05 (m, 1H), 3.70 (m, 1H), 4.07 (m, 1H), 4.47
(ddd, J=13,9,6Hz,1H), 5.70 (br t, J=3Hz, 1H), 6.28
(t, J=3Hz,1H). Mass spectrum: (M+H) + = 394.
Anal. Calcd. for C22H35NO5: C, 67.15; H, 8.96; N, 3.56.
Found: C, 67.66; H, 9.11; N, 3.60.
Example 101
(3S,5S,4'S,5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2,2-dimethyloxazolidin-5-yl)- 3-methyldihydrofuran-2(3H)-one.
A mixture of 8.03 g (20 mmol) of the resultant compound of Example 100 and 0.81 g of 10% palladium on carbon in 200 ml of ethyl acetate was shaken under 4 atmospheres of H2. After filtration, concentration of the filtrate gave 7.58 g (94%) of the desired compound.
1H NMR (CDCl3) δ 0.8-2.0 (br enyelope), 1.31 (s,3H), 1.48 (s,9H), 1.54 (s,3H), 1.58 (s,3H), 2.57 (m, 1H), 2.68 (m,1H), 3.74 (m, 1H), 4.04 (m, 1H), 4.31
(ddd, J=13,9,6Hz,1H). Mass spectrum: (M+H)+ = 396. Example 102
3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5- (1,4-dihydroxy-3-methylbutyl)-2,2-dimethyloxazolidine. A mixture of 0.50 g (1.26 mmol) of the resultant compound of Example 101 and 0.15 g (4 mmol) of sodium borohydride in 50 ml of tetrahydrofuran was heated at reflux under N2 atmosphere for 48 h. After being allowed to cool, the mixture was treated cautiously with aqueous NH4Cl, extracted with ether, washed with saturated brine, dried oyer MgSO4, and concentrated in vacuo. Silica gel chromatography using 2:1 chloroform/ethyl acetate gave 0.37 g (73%) of the desired compound.
1H NMR (CDCl3) δ 0.7-2.0 (br enyelope), 0.94
(d, J=7Hz,3H), 1.49 (s,9H), 1.52 (s,3H), 1.55 (s,3H), 3.43 (dd, J=11,8Hz,1H), 3.55-3.7 (m,3H), 4.09 (br d, 1H). Mass spectrum: (M+H) + = 400.
Example 103
3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)- 2,2-dimethyl-5-(4-methyltetrahydrofuran-
2-yl)oxazolidine
A solution of 51 mg (0.13 mmol) of the resultant compound of Example 102 and 0.037 ml (0.27 mmol) of triethylamine in 2 ml of dichloromethane was cooled to 0°C under N2 atmosphere and treated with 0.012 mol (0.15 mmol) of methanesulfonyl chloride. After 1 h, the solution was diluted with dichloromethane, washed successiyely with 10% citric acid, water and saturated aqueous NaHCO3, dried oyer Na2SO4, and concentrated in vacuo. The crude
mesylate thus produced (59 mg) was taken up in 8 ml of dry detrahydrofuran, treated with 20 mg (0.50 mmol) of sodium hydride (60% dispersion in oil), and heated at reflux for 2 h. After being allowed to cool, the solution was treated cautiously with saturated aqueous NH4Cl, extracted with ether, dried oyer MgSO4 and concentrated. Silica gel chromatography using 9:1 hexane/ethyl acetate gave 30 mg (75%) of the desired compound.
1H NMR (CDCl3) δ 0.7-2.4 (br enyelope), 1.06
(d, J=7Hz,3H),1.48 (s,9H),1.52 (s,3H), 1.56 (s,3H),3.30 (t, J=9Hz,1H), 3.66 (m, 1H), 3.9-4.0 (m, 3H). Mass spectrum: (M+H)+ = 382.
Example 104
2(S)-(1(S)-(4-(Methoxymethoxy)pjperidin-1-yl-carbonyl)- 2-phenylethoxy)hexanoic acid Amide of 2(S)-(2(S)- Amino-3-cyclohexyl-1(R)-hydroxy)propyl-4(S)- methyltetrahydrofuran.
Using the procedure of Example 93, but replacing the resultant glycol of Example 41 with 2(S)-(2(S)-amino-3- cyclohexyl-1(R)-hydroxy) propyl-4(S)-methyltetrahydrofuran (obtained from deprotection of the resultant compound of Example 103 according to the procedure of Example 41) gave the desired compound in 30% yield.
1 H NMR (CDCl3 , TMS) δ 0.9 (t,3H), 1.02 (d,3H), 1 99
(m,1H), 2.3 (m,1H), 3.31 (t, 1H), 3.37 (s,3H), 3.9 (t,2H), 4.5 (m,1H), 4.67 (S,2H). Mass spectrum: (M+H) + = 631.
Example 105
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2- phenylenhyl-L-norleucyl Amide of 2(S)-Amino-1- cvclohexvl-3(R),4(S)-dihydroxy-6-methylheptane.
Using the procedure of Example 64, but replacing the morpholine with 4-(methoxymethoxy) piperidine gave the desired- intermediate. The resultant benzyl ester was hydrogenated using the procedure of Example 16 and
followed by coupling to the resultant product of Example 41 according to the procedure of Example 51 to givethe desired compound in 69% yield. 1H NMR (CDCl3, TMS) δ 0.9 (dd, 6H), 0.9, (t,3H) , 2.81 (m,2H), 3.1(m,2H), 3.35 (s,3H), 3.67 (b, 1H), 4.63 (s,2H) . (M+H)+ = 632.
Example 106
N-(1 (S)-4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2- phenylethyl)-L-norleucyl Amide of 2(S)-amino-
1-cyclohexyl-3(S)-hydroxy-5(S)-n-butylcarbamoyl-
6-methylheptane.
The title compound can be obtained according to the procedure of Example 105, but replacing the resultant product of Example 41 with 2(S)-amino-1-cyclohexyl-3(S)- hydroxy-5(S)-n-butylcarbamoyl-6-methylheptane.
Example 107
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-
2-phenylethyl)-L-norleucyl Amide of 2(S)-(2(S)-
Amino-3-cyclohexyl-1(R)-hydroxy)propyl-4(S)- methyltetrahydrofuran.
The title compound can be obtained according to the procedure of Example 105, but replacing the resultant product of Example 41 with 2 (S) - (2 (S) -amino-3-cyclohexyl- 1 (R) -hydroxy) propyl-4 (S) -methyltetrahydrofuran (see
Example 104).
Example 108
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-
2-phenylethoxy)hexanoic acid Amide of
(2's,1'R,5S)-3-Ethyl-5-(1'-hydroxy-2'-amino- 3'-cvclohexylpropyl)oxazolidin-2-one.
Using the procedure of Example 93, but replacing the resultant glycol of Example 41 with the resultant compound of Example 50 gave the desired product. 1H NMR (CDCl3 , TMS) δ 0,9 (t,3H) 1.18 (t,3H), 1.3-1.7
(m,22H), 3.4 (s,3H), 4.7 (s,3H), 7.4 (m, 5H). Mass
spectrum: (M+H) + = 660.
Example 109
3-(3(R)-(3-(tert-Bntyloxycarbonyl)-2.2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-3-hydroxy-2(R)- isopropyl- 1-oxopropyl)-4(R)-methyl-5(S)-phenyl-2-oxazolidinone.
The title compound was prepared in analogy to the procedure of S. Thaisriyongs, 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 99, in 63% yield. M. p. 97 °C. 1H NMR (CDCl3) δ 0.91 (d, 3H), 1.06 (d, 3H),
1.1 (d, 3H), 1.48 (s, 9H), 0.9-1.9 (seyeral 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, 1H), 4.84 (dq, 1H), 5.61 (d, 1H), 7.31-7.45 (m, 5H). High resolution mass spectrum. Calcd. for (M+H)+ of C33H51N2O7: 587.3698. Found: 587.3696.
Analysis. Calcd. for C33H50N2O7: C, 67.55; H, 8.59; N, 4.77. Found: C, 67.41; H, 8.61; N, 4.77.
Example 110
3-(3(R)-(3-(tert-Butyloxycarbonyl)-2.2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-3-((1- imidazolyl)thionyloxy)-2(R)-isopropyl-1-oxopropyl)-4(R)- methyl-5(S)-phenyl-2-oxazolidinone.
The resultant compound from Example 109 (1.840 g,
3.136 mmol) and 1,1'-thiocarbonyldiimidazolide (1.128 g, 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-CH2Cl2) to afford 1.896 g (87%) of the title compound. 1H NMR (CDCl3) δ 0.93 (d, 3H),
1.04 (d, 3H), 1.08 (d, 3H), 1.5 (bs, 9H), 0.9-1.9 (seyeral 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, 1H), 6.33 (dd, 1H), 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 C37H53N4O7S: 697.3635. Found: 697.3629.
Analysis. Calcd. for C37H53N4O7S: C, 63.77; H, 7.52; N, 8.04. Found: C, 63.58; H, 7.44; N, 7.94.
Example 111
3-(3-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)-2(R)-isopropyl-1- oxopropyl)-4(R)-methyl-5(S)-phenyl-2-oxazolidinone.
A solution of the resultant product from Example 110 (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 oyer 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 (CDCI3) δ 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 (seyeral bm, 16H total), 3.84 (m, 1H), 3.97 (m, 1H), 4.85 (dq, 1H), 5.68 (d, 1H), 7.3-7.46 (m, 5H). Mass spectrum: (M+H)+ = 571.
Analysis. Calcd. for C33H50N2O6: C, 69.44; H, 8.83; N, 4.91. Found: C, 69.31; H, 8.82; N, 4.89.
Example 112
2(S)-((3-(tert-Butyloxyoarbonyl-2,2-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)methyl)-3- methylbntanoic acid.
Using the procedure of D. A. Eyans, T. C. Britton and J. A. Ellman, Tetrahedron Lett . 1987, 28(49), 6141-44, the resultant product from Example 111 (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 compound as a yiscous colorless oil. 1H NMR(CDCI3) δ 0.96 (d, 3H), 1.00 (d, 3H) , 1.1-1.3 (bm, 5H),
1.48 (s, 9H), 1.5-1.9 (seyeral bm, 15H total), 2.0 (m, 1H), 2.66 (m, 1H), 3.7 (bm, 1H), 3.90 (m, 1H). Mass spectrum: (M+H) + = 412.
Analysis. Calcd. for C23H41NO5.0.25 H2O: C, 66.39; H, 10.05; N, 3.37. Found: C, 66.46; H, 9.84; N, 3.36.
Example 113
3-(1-Imidazolyl)proPyl 2(S)-((3-(tert-bntyloxycarhonyl)- 2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)- oxazolidinvl)methyl)-3-methylbutanamide. The procedure of P. Buhlmayer, et. al., J. Med. Chem . 1988, 31 ( 9) , 1839-46 is adapted. The resultant compound from Example 112 (75 mg, 0.182 mmol), HOBt (42.0 mg, 0.274 mmol) and N-methylmorpholine (55 mg, 0.55 mmol) were dissolyed 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 1- (3-aminopropyl) imidazole (28 mg, 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 yolatiles were removed by high yacuum distillation, and the residue was partitioned between CH2Cl2 and aq. NaHCO3. The aqueous phase was extracted 3X with CH2Cl2, and the combined organic phases were washed with brine, dried (Na2SO4) and concentrated to a yiscous oil. Purification by flash chromatography (4% MeOH-CH2Cl2) provided 90.2 mg (95%) of a colorless glass. 1H NMR (CDCl3) δ 0.93 (d, 3H), 0.95 (d, 3H), 1.48 (s, 9H),
1.58 (s, 6H), 0.8-1.9 (seyeral bm, 16H total), 2.05 (m, 2H), 3.28 (ddd, 2H), 3.64 (bm, 1H), 3.72 (m, 1H), 4.01 (t, 1H), 5.70 (bt, 1H), 6.96 (t, 1H), 7.08 (s, 1H), 7.58 (s, 1H). High resolution mass spectrum. Calcd. for (M+H)+ of C29H51N4O4: 519.3910. Found: 519.3915.
Example 114
3- (Dimethylamino) propyl 2 (S) - ( (3- (tert-butyloxycarbonyl) -
2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)- oxazolidinγl)methyl)-3-methylbutanamide. The procedure of Example 113 is followed,
substituting 3-dimethylaminopropyl amine for 1-(3- aminopropyl) imidazole, which provided the title compound in 97% yield. 1H NMR (CDCl3) δ 0.93 (d, 3H), 0.935 (d,
3H), 1.48 (s, 12H), 1.58 (bs, 3H), 0.8-1.8 (seyeral bm, 18H total), 2.05 (m, 1H), 2.37 (bs, 6H), 2.53 (bm, 2H), 3.3.7 (2 x dd, 2H), 3.63 (bm, 1H), 3.75 (m, 1H), 6.60 (bm, 1H). Mass spectrum: (M+H)+ = 496.
Analysis. Calcd. for C28H53N3O4Η2O: C, 65.46; H, 10.79; N, 8.18. Found: C, 65.6; H, 10.18; N, 8.23.
Example 115
3- (4-Morpholinyl)propyl 2(S)-((3-(tert-butyloxycarbonyl)- 2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)- oxazolidinyl)methyl)-3-methylbutanamide. Using the procedure of Example 113, substituting 4- (3-aminopropyl) morpholine for 1-(3-aminopropyl) imidazole, the title compound was obtained in 96% yield. 1H NMR (CDCl3) δ 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 (seyeral 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 C30H56N3O5:
538.4220. Found: 538.4220.
Example 116
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbnnyl-2- phenyl)ethoxyhexanoic acid amide of 3-(1-imidazolyl)propyl
5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide.
The resultant compound from Example 113 (83.5 mg, 0.161 mmol) was deprotected by dissolying in 1.0 ml dry CH2Cl2, 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 solyents were largely removed with a stream of nitrogen, and the residue (as a concentrated solution in trifluoroacetic acid) was dissolyed in 1.0 ml THF and 0.3 ml water at 0 °C. The solution was allowed to warm slowly to ambient temperature oyer 18 h. The crude aminoalcohol was isolated by basifying the reaction with an excess of 1.0 M aq. Na2CO3, saturating the solution with NaCl, and extracting with 5 x 10 ml of 5% EtOH-CHCl3. The combined organic phases were washed with brine, dried (Na2SO4), concentrated, and the residue placed under high yacuum oyernight to yield 66.2 mg (>100%) of yellow yiscous oil.
Coupling was acheiyed by combining the resultant compound from Example 83 (72 mg, 0.177 mmol), the above aminoalcohol (63.8 mg, 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 solyent was removed by high yacuum distillation, and the residue was partitioned between 15 ml CH2Cl2, 9 ml sat. aq. NaHCO3 and 1 ml H2O. The aqueous phase was further extracted (3 X 10 ml CH2Cl2), and the combined organic phases were washed with 10 ml brine, dried (Na2SO4) and concentrated.
Purification by flash chromatography (6% MeOH-0.5% cone, aq. NH4OH-CH2Cl2) yielded 92.3 mg (72%) of the title compound as a hygroscopic glassy solid, m.p. 49-56 °C. 1H NMR (CDCl3) δ 0.9 (m, 9H), 1.97 (m, 3H), 0.65-1.9 (seyeral bm, approx. 26H total), 2.88-3.07 (m, 2H), 3.13 (bm, 1H), 3.25 (m, 2H), 3.37 (s, 3H), 3.2-3.5 (bm, 3H), 3.6-3.9 (bm, 4H), 4.0 (bm, 3H), 4.50 (m, 1H), 4.68 (s, 2H), 5.70 (m, 1H), 5.78 (d) and 5.85 (d, 1H total), 6.96 (s, 1H), 7.08 (s, 1H), 7.3 (m, 5H), 7.58 (m, 1H). Mass spectrum:
(M+H)+ = 768.
Analysis. Calcd. for C43H69N5O7 .1.25 H2O: C, 65.33; H, 8.86; N, 8.86. Found: C, 65.28; H, 8.78; N, 8.91.
Example 117
2( S )-(1 (S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of 3- (dimethylamino)prooyl 5(S)-amino-6-cyclohexyl-4(S)- hydroxy-2(S)-isopropylhexanamide.
The procedure of Example 116 was used, with the substitution of the resultant compound from Example 114 for the resultant compound from Example 113, to provide the title compound in 77% yield as a white foamy solid, m. p. 49-54 °C. 1H NMR (CDCl3) δ 0.90 (m), 0.92 (d) and
0.94 (d, 9H total), 0.65-1.95 (seyeral bm, approx. 28H total), 2.02 (m, 1H), 2.26 (bs, 6H), 2.42 (m, 2H), 2.96 (m, 1H), 3.05 (dd, 1H), 3.1-3.48 (seyeral bm) and 3.36 (s, 8H total), 3.54 (bm, 1H), 3.60-4.0 (seyeral bm, 5H total), 4.52 (dd, 1H), 4.67 (s, 2H), 5.83 (d) and 5.90 (d, 1H total), 6.93 (bm, 1H), 7.30 (bm, 5H). High resolution mass spectrum. Calcd. for C42H73N4O7: 745.5479. Found: 745.5471.
Example 118
2(S)-(1(S)-(A-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenvl)ethoxyhexanoic acid amide of 3-(4- morPholinyl)propyl 5(S)-amino-6-cyolnhexyl-4(S)-hydroxy-
2(S)-isopropylhexanamide.
The procedure of Example 116 was used, substituting the resultant product from Example 115 for the resultant compound from Example 113, to provide the title compound in 68% yield as a hygroscopic glassy solid, m.p. 49-51 °C. 1H NMR (CDCl3) δ 0.90 (m), 0.91 (d) and 0.92 (d, 9H total), 0.65-1.90 (seyeral 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 (seyeral 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, 1H), 7.3 (bm, 5H). Mass spectrum: (M+H) + = 787.
Example 119
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)rarbonyl-2- phenyl)ethyl-L-norleucyl amide of 3-(1-imidazolyl)propyl
5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide.
The procedure of Example 116 was followed, with the substitution of the intermediate amino acid from Example 105 for the resultant compound from Example 83, proyiding the title compound in 89% yield as a hygroscopic foamy solid, m.p. 66-71 °C. 1H NMR (CDCl3) δ 0.90 (d) and 0.91
(d) and 0.93 (d, 9H total), 0.65-1.90 (seyeral bm, approx. 26H total), 2.0 (bm, 3H), 2.22 (m, 1H), 2.29 (bm, 2H), 2.35 (bm, 1H), 3.25 (m, 2H), 3.36 (s, 3H), 2.9-3.5
(seyeral bm, 4H total), 3.5-4.0 (seyeral bm, 6H total), 4.0 (m, 2H), 4.66 (2 s, 2H), 5.70 (m, 1H), 6.96 (m, 1H), 7.07 (s, 1H), 7.2-7.35 (bm, 5H), 7.57 (d, 1H), Mass spectrum: (M+H)+ = 767.
Analysis. Calcd. for C43H70N6O6Η2O: C, 65.79; H, 9.24; N, 10.70. Found: C, 65.46; H, 8.95; N, 10.54. Example 120
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethyl-L-norlencyl amide of 3-(4-morpholinyl)propyl
5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide.
The procedure of Example 118 was used, with the substitution of the intermediate amino acid from Example 105 for the resultant compound from Example 83, proyiding the title compound in 81% yield as a hygroscopic foamy solid, m.p. 60-65 °C. 1H NMR (CDCl3) δ 0.89 (t), 0.93 (d,
9H total), 0.65-1.94 (seyeral bm, approx. 28H total), 2.06 (m, 1H), 2.33 (bm, 1H), 2.46 (bm, 6H), 2.67-2.85 (m, 3H),
3.0 (bm, 1H), 3.25 (m, 3H), 3.35 (s, 3H), 3.35-3.60 (bm,
3H), 3.71 (bm, 4H), 3.6-3.9 (seyeral bm, 5H total), 4.65 (2 s, 2H), 6.75 (m, 1H), 6.80 (d) and 6.87 (d, 1H total),
7.2-7.4 (bm, 5H). Mass spectrum: (M+H)+ = 786.
Example 121
(2S,3S)-3-((tert-Butyloxycarbonyl)amino)-4-cyclohexyl-2- hydroxy-1-(methyl(methylsulfamoyl)amino)butane.
A solution of (1R,S)-(1'S-((tert-Butyloxycarbonyl)- amino)-1-cyclohexylmethyl) oxirane (1.29 g, 4.79 mmol, prepared according to J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Spderquist and N. Yi, J. Org. Chem . 1987, 52, 1487) in 20 ml methanol was treated with 40% aq.
methylamine (4.1 ml, 1.48 g, 47.6 mmol). After 24 h at ambient temperature, the solyent was removed in yacuo to provide 1.53 g (100%) of (2S,3S)-3-((tert- butyloxycarbonyl)- amino)-4-cyclohexyl-2-hydroxy-1- (methylamino) butane as a yiscous oil. 1H NMR (CDCl3) δ
0.75-1.57 (seyeral bm) and 1.45 (s, approx. 17H total), 1.66 (bm, 5H), 1.86 (bd, 1H), 1.9-2.5 (ybm, 2H), 2.42 (s, 3H), 2.5-2.68 (m, 2H), 3.6 (bm, 2H), 4.70 (bd, 1H), Mass spectrum: (M+H)+ = 301.
A sample of the crude N-methylamine above (896 mg, 2.98 mmol) was dissolyed in 13 ml CH2Cl2 and treated sequentially with triethylamine (602 mg, 5.93 mmol) and methylsulfamoyl chloride (450 mg, 3.46 mmol) at -35 °C. The resulting solution was stirred at -35 °C for 3 h, at which time tlc (15% MeOH-CH2Cl2) indicated complete consumption of starting amine. The reaction was quenched with 20 ml of sat. aq. NaHCO3 and extracted with 3 x 30 ml CH2Cl2. The combined organic extracts were combined, washed with brine, dried (Na2SO4) and concentrated in yacuo. The crude was purified by column chromatography (EtOAc-hexane-toluene 4:4:1) to provide 534 mg (49%) of the title compound as glassy solid; 1H NMR (CDCl3) δ 0.75-1.90 (seyeral bm) and 1.45 (s, 22H total), 2.74 (d, 3H), 2.86 (m, 1H), 2.93 (s, 3H), 3.14 (dd, 1H), 3.38 (dd, 1H), 3.64 (m, 1H), 3.79 (m, 1H), 4.33 (m, 1H), 4.69 (m, 1H), Mass spectrum: (M+H)+ = 394; (M+NH4)+ = 411.
Example 122
(2S,3S)-3-((tert-Butyloxycarbonyl)amino)-4-cyclohexyl-2- phenyl)ethoxyhexanoic acid amide of (2S,3S)-3-amino-4- cyclohexyl-2-hydroxy-1- (methyl(methylsulfamoyl)amino)butane.
A sample of the resultant compound from Example 121 (501 mg, 1.27 mmol) was dissolyed in 3 ml CH2Cl2, cooled to 0 oC under a dry nitrogen atmosphere, and treated with 3 ml trifluoroacetic acid. The solution was stirred for 5.5 h, then the solyents were removed under reduced pressure, and the residue was basified with 1.0 M aq.
Na2CO3. The product was extracted with 4 x 20 ml CH2CI2. The combined extracts were washed with brine, dried
(Na2S04) and concentrated under reduced pressure to yield 332 mg (89%) of (2S,3S)-3-amino-4-cyclohexyl-2-hydroxy-1- (methyl (methylsulfamoyl) amino) butane as a white powder. 1H NMR (CDCl3) δ 0.8-1.45 (seyeral bm, 8H), 1.6-1.8 (bm,
5H), 1.9 (ybm, 3H), 2.75 (s, 3H), 2.85 (m, 1H), 2.94 (s, 3H), 3.21 (dd, 1H), 3.30 (dd, 1H), 3.48 (m, 1H). Mass spectrum: (M+H) + = 294.
The above crude aminoalcohol (35.4 mg, 0.121 mmol) was combined with the resultant compound from Example 83 (53.1 mg, 0.130 mmol), HOBt (23.2 mg, 0.152 mmol) and 4- methyl- morpholine (14 mg, 0.136 mmol) in 1.2 ml DMF. The solution was cooled to -15 °C and EDC (36 mg, 0.19 mmol) was added. The resulting mixture was stirred and allowed to slowly warm to room temperature (24 h total). The solyent was removed under reduced pressure, and the residue partitioned between aq. NaHCO3 and CH2CI2. The aqueous phase was extracted (3 x 10 ml CH2Cl2), and the combined organic extracts were washed with 10 ml brine, dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (3% MeOH-CH2Cl2) provided 41.3 mg
(50%) of the. title compound as a colorless solid, m.p. 55- 60 °C. 1H NMR (CDCl3) δ 0.6-1.9 (seyeral bm, approx.
26H), 2.68 (d, 3H), 2.8 (dd, 1H), 2.92 (s, 3H), 3.0-3.2 (m, 2H), 3.31 (m, 1H), 3.38 (2s, 3H), 3.4-3.6 (bm, 2H), 3.85 (bm, 4H), 3.94 (bm, 1H), 4.51 (dd, 1H), 4.69 (2s, 2H), 5.65 (bm, 1H), 5.87 (2d, 1H), 7.25-7.38 (m, 5H).
Mass spectrum: (M+H)+ = 683. Analysis. Calcd. for C34H58N408S- 0.5 H2O: C, 59.02; H, 8.59; N, 8.10. Found: C, 58.98; H, 8.31; N, 7.94.
Example 123
1-(3-(tert-Butyloxycarbonyl)-2.2-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-
((dimethylaminoethoxycarbonyl)amino)-3-methylbutane, A solution of the resultant compound from Example 112 (2.27 g, 5.52 mmol) in 17 ml dry toluene was treated with triethylamine (0.85 ml, 6.07 mmol) and diphenylphosphorylazide (1.67 g, 6.07 mmol). The solution was warmed to 65 °C for 2 h, then N,N-dimethylethanolamine (2.46 g, 27.6 mmol) was added, and the resulting solution was refluxed for 24 h. The solyent was eyaporated under reduced pressure and the residue was dissolyed in 450 ml EtOAc and extracted (1 x 400 ml of 1N HCl, 1 x 400 ml water, 1 x 400 ml sat. aq. NaHCO3, 1 x 450 ml brine). The organic phase was dried (MgSO4) and concentrated under reduced pressure. Flash chromatography (6% MeOH-CH2Cl2) provided 1.88 g
(68%) of a colorless glass.
1H NMR (CDCl3) δ 0.9 (d, 6H), 0.8-1.9 (seyeral bm) and
1.47 (s, approx. 31H total), 2.29 (s, 6H), 2.54 (bt, 2H), 3.7 (bm, 2H), 3.97 (m, 1H), 4.16 (m, 2H), 4.90 (bd, 1H). Mass spectrum: (M+H)+ = 498.
Analysis. Calcd. for C27H51N3O5.0.5 H2O: C, 64.00; H, 10.34; N, 8.29. Found: C, 64.13; H, 10.13; N, 8.35.
Example 124
1-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethvl-5(S)-oxaznlidinyl)-2(S)-((4- morpholinoethoxycarbonyl)amino)-3-methylbutane.
The procedure of Example 123 was followed, with the substitution of 2- (hydroxyethyl) morpholine for N,N- dimethylethanolamine, to provide the title compound in 65% yield. 1H NMR (CDCl3) δ 0.93 (2d, 6H), 0.8-1.9 (seyeral bm), 1.48 (s) and 1.60 (s, approx. 31H total), 2.50 (bm, SH), 2.61 (bt, 2H), 3.65 (bm) and 3.72 (m, 6H total), 3.99 (m, 1H), 4.2 (m, 2H), 4.9 (bm, 1H), Mass spectrum:
(M+H)+ = 540.
Example 125
1-(3-(tert-Butyloxycarbonyl)-2,7-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((2- pyridyl)ethoxycarbonyl)amino)-3-methylbutane. The procedure of Example 123 was followed, with the substitution of 2-(2-hydroxyethyl) pyridine for N,N- dimethylethanolamine, to provide the title compound in 64% yield after flash chromatography (3% MeOH-CH2Cl2). 1H NMR (CDCl3) δ 0.9 (bd, 6H), 1.47 (s), 1.54 (bs) and 0.75-1.85
(seyeral bm, approx. 31H total), 3.11 (bt, 2H), 3.63 (bm, 2H), 3.97 (bd, 1H), 4.45 (ra, 2H), 4.82 (bs, 1H), 7.14 (ddd, 1H), 7.19 (bd, 1H), 7.60 (td, 1H), 8.55 (ddd, 1H).
Example 126
1-( 3(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((2-(1H- imidazolyl))methoxycarbonyl)amino)-3-methylbutane.
The procedure of Example 123 is employed, with the substitution of (2-hydroxymethyl) imidazole hydrochloride for N,N-dimethylethanolamine, and the inclusion of an additional equiyalent of triethylamine, to provide the title compound.
Example 127
1-( 3(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)-((2- methylthio)ethoxycarbonyl )amino)-3-methylbutane. The procedure of Example 123 is employed, with the substitution of 2-methylthioethanol for N,N- dimethylethanolamine, to provide the desired compound in 25% yield, after flash chromatography (10% EtOAc-hexanes). 1H NMR (CDCI3) δ 0.92 (bd) and 0.8-1.05 (bm, 8H total),
1.48 (s), 1.60 (bs) and 1.1-1.9 (seyeral bm, approx 31H total), 2.16 (s, 3H) , 2.71 (bt, 2H), 3.65 (bm, 2H), 3.99
(m, 1H), 4.23 (m, 2H) , 4.87 (bm, 1H), Mass spectrum:
(M+H)+ = 501.
Example 128
1-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(S)-oxazolidinyl)-2(S)- (pentanoyl)amino)-3-methylbutane.
A solution of the resultant compound from Example 112 (200 mg, 0.486 mmol) in 1.5 ml dry toluene was treated with triethylamine (0.075 ml, 0.54 mmol) and diphenylphosphoryl- azide (0.115 ml, 0.54 mmol) . The solution was warmed to 65 °C for 2.5 h, then was cooled to 0 °C and treated with a solution of butylmagnesium
chloride (0.668 ml, 2.0 M in THF, 1.34 mmol). The
solution was allowed to slowly warm to room temperature and stir for 14 h. The mixture was partitioned between EtOAc and water, and the organic phase was washed (1 x 25 ml IN HCl, 2 x 75 ml water, 1 x 75 ml sat. aq.NaHCO3, 1 x 100 ml brine), then concentrated in yacuo. Flash
chromatography (20% EtOAc-hexanes) gave 202 mg (84%) of the title compound as a white solid. !H NMR (CDCl3) δ
0.93 (m) and 0.8-1.05 (bm, 11H total), 1.48 (s) and 1.1- 1.9 (seyeral bm, approx. 35H total), 2.16 (dd, 2H) , 3.63 (bm, 1H), 3.95 (bm) and 4.0 (m, "2H total), 5.25 (bm, 1H). Mass spectrum: (M+H)+ = 467.
Example 129
2 (S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of 2(S)-amino-1- cvclohexyl-5(S)-(7-(dimethylamino)ethoxycarbonyl)amino- 3(S)-hydroxy-6-methylheptane.
Using the procedure of Example 116, the resultant product from Example 123 is deprotected and coupled, to provide the desired product in 68% yield after flash chromatography (5% MeOH-CH2Cl2), m.p. 55-60 °C. 1H NMR (CDCl3) δ 0.88 (m) and 0.7-1.0 (bm, approx 11H total),
1.0-1.9 (seyeral bm, approx. 24H total), 2.25 (bs, 3H), 2.31 (bs, 3H), 2.57 (bm, 2H), 2.6-3.25 (bm, 4H), 3.32 (m, 4H), 3.4-4.0 (seyeral bm, 8H), 4.2 (bm, 2H), 4.4-4.9 (bm, 4H), 6.04 (bd), 6.18 (bd) and 6.7 (2 oyerlapping bd,1H total), 7.2-7.4 (bm, 5H). Mass spectrum: (M+H)+ = 747. Analysis. Calcd. for C41H70N4O8: C, 65.92; H, 9.44; N, 7.50. Found: C, 65.77; H, 9.45; N, 7.47.
Example 130
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of 2(S)-amino-1- oyclohexyl-5(S)-((2-(4-morpholino)ethoxycarbonyl)amino- 3(S)-hydroxy-6-methylheptane.
Using the procedure of Example 116, the resultant product from Example 124 is deprotected and coupled, to provide the desired product in 73% yield after flash chromatography (3% MeOH-CH2Cl2), m.p. 57-60 °C. 1H NMR (CDCl3) δ 0.9 (oyerlapping t and 2d) and 0.6-1.05 (bm, 11K total), 1.05-1.9 (seyeral bm, approx. 24H), 2.50 (m, 4H), 2.64 (bt, 2H), 2.97-3.25 (bm, 3H), 3.34 (s) and 3.25-3.45
(bm, 4H total), 3.47 (bm), 3.75 (m) and 3.45-4.0 (12H total), 4.25 (m, 2H), 4.4-4.7 (bm) and 4.63 (s) and 4.65
(s, 3H total), 4.77 (bd, 1H), 6.02 (bd), 6.16 (bd), 6.50
(m) and 6.05 (m, 1H total), 7.28 (bm, 5H). Mass spectrum:
(M+H)+ = 789.
Analysis. Calcd. for C43H72N4O9: C, 65.45; H, 9.20; N, 7.09. Found: C, 65.10; H, 9.10; N, 7.09.
Example 131
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of 2(S)-amino-1- cyclohexyl-5(S)-((2-(2-pyridyl)ethoxycarbonyl)amino-3(S)- hydroxy-6-methylheptane.
Using the procedure of Example 116, the resultant product from Example 125 is deprotected and coupled, to provide the desired product in 64% yield after flash chromatography (3% MeOH-CH2Cl2), m.p. 51-54 °C. 1H NMR (CDCl3) δ 0.88 (oyerlapping t and 2d) and 0.6-1.0 (bm, 11H total), 1.0-1.9 (seyeral bm, approx. 24H), 3.14 (bt), 3.35 (s) and 2.96-3.4 (seyeral bm, 9H total), 3.54 (bd) , 3.73 (bt) and 3.4-4.4 (seyeral bm, approx 9H total), 4.52 (bm, 4H), 4.65 (2s, 2H), 5.99 (bd) and 6.12 (bd, 1H total), 7.1-7.3 (m, 7H), 7.61 (m, 1H), 8.56 (m, 1H), Mass
spectrum: (M+H)+ = 781.
Analysis. Calcd. for C44H68N4O80.5 H2O: C, 66.89; H, 8.80; N, 7.09. Found: C, 66.68; H, 8.59; N, 7.13.
Example 132
2( S ) -(1(S)-( 4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of 2(S)-amino-1- cyclohexyl-5(S)-(( 2-(pentanoyl)amino-3(S)-hydroxy-6- methylheptane.
Using the procedure of Example 116, the resultant product from Example 128 is deprotected and coupled, to provide the desired product in 35% yield after flash chromatography (1% MeOH-CH2Cl2), m.p. 55-65 °C. 1H NMR (CDCl3) δ 0.9 (oyerlapping t and 2d) and 0.6-1.0 (bm, 11H total), 1.0-1.9 (seyeral bm, approx. 28H), 2.27 (t, 2H), 2.9-3.6 (seyeral bm) and 3.33 (s, 10H total), 3.65 (bm, 1H), 3.72 (bt, 2H), 3.9 (bm, 3H), 4.14 (bm, 1H), 4.52 (bq, 1H), 4.64 (2s, 2H), 5.50 (dd, 1H), 6.19 (d) and 6.30 (d, 1H total), 7.28 (bm, 5H). Mass spectrum: (M+H)+ = 716.
Analysis. Calcd. for C41H69N3O7.0.75 H2O: C, 67.50; H, 9.74; N, 5.76. Found: C, 67.13; H, 9.36; N, 5.80. Example 133
2(S)-(1(S)-(4-(Mothoxvmethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of 2(S)-amino-1- cyclohexyl-5(S)-((1H-imidazol-2-yl)methoxycarbonyl)amino- 3(S)-hydroxy-6-methylheptane.
Using the procedure of Example 116, the resultant product from Example 126 is deprotected and coupled, to provide the desired product.
Example 134
2(S)-(1(S)-( 4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of 2(S)-amino-1- cyclohexyl-5(S)-(2-(methylthio)ethoxycarbonyl)amino-3(S)- hydroxy-6-methylheptane.
Using the procedure of Example 116, the resultant product from Example 127 is deprotected and coupled, to provide the desired product.
Example 135
2 ( S) - ( 1 ( S) - (4- (Methoxymethoxy) piperidin-1-yl ) carbonyl-2-
Phenyl) ethoxyhexanoic acid amide of 2(S)-amino-1- cyclohexyl-5(S)-(2-(methylsulfonyl)ethoxycarbonyl)amino- 3(S)-hydroxy-6-methylheptane.
Using the procedure of B. M. Trost and D. P. Curran, Tetrahedron Lett. 1981, 22, 1287-1290, the resultant product from Example 134 is oxidized to provide the desired product. Example 136
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of 3-(dimethyl-N- oxyamino)propyl 5 (S) -amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide.
A sample of the resultant product from Example 117
(50 mg, 0.067 mmol) was dissolyed in 0.35 ml MeOH and
treated with 30% aq. hydrogen peroxide solution (0.027 ml), added in three portions oyer 3 days. After 4 days at room temperature, the solyent was removed, and the residue purified by column chromatography (9.5% MeOH-0.5% cone, aq. NH4OH-CH2Cl2) to provide 18 mg (37%) of the desired compound. 1H NMR (CDCl3) δ 0.88 (d, 3H), 0.9 (bt, 3H),
0.93 (d, 3H), 0.65-2.7 (seyeral bm, approx. 28H total),
2.9-3.25 (seyeral bm) and 3.14 (s, 7H total), 3.25-3.6
(seyeral bm), 3.34 (s), 3.36 (s) and 3.37 (s, approx.
10H), 3.6-3.8 (bm, 4H), 3.88 (bm, 1H), 4.0-4.2 (bm, 2H), 4.62 (bm, 1H), 4.67 (2s, 2H), 5.84 (bt, 1H), 7.2-7.4 (bm, 5H), 8.28 (bm, 1H), Mass spectrum: (M+H)+ = 761.
Example 137
(2S,3R,4S)-4-(tert-Butyloxycarbonyl)amino-5-cyclohexy1-2- hydroxy-
1- (N-methoxy-N-methvlamino)-3-(methoxyethoxymethoxy)pentane.
The resultant compound from Example 22 (454.7 mg, 1.17 mmol) in dioxane (4 mL) was treated with N-methyl-O- methylhroxylamine hydrochloride (1.14 g, 11.7 mmol) in water (4 mL). Solid NaHCO3 (1.00 g, 11.9 mmol) was added, the reaction was sealed and heated at 90ºC for 60 h. The reaction was cooled, poured into saturated NaHCO3 solution and extracted into ethyl acetate which was dried oyer Na2SO4 and eyaporated. Chromatography of the residue on silica gel
(60 g) with 60% ethyl acetate in hexane afforded 306.0 mg
(58%) of the 2S-isomer (followed by the 2R-isomer). TLC (5% methanol/95% chloroform) Rf = 0.53; 1H NMR (CDCl3) δ 4.89 (d, 1H), 4.77 (s,2H), 4.02-4.12 (m, 1H), 3.02 (s, 3H), 3.39 (s, 3H), 2.91 (dd,1H ), 2.63 (s, 3H), 1.45 (s, 9H).
Example 138
(2S,3R,4S)-4-Amino-5-cyclohexyl-2,3-dihdroxy- 1-(N-methoxy-N-methylamino)pentane.
The resultant compound from Example 137 (1.00 mmol) was stirred for 1 h in 4M HCl/ethanol. The mixture was
eyaporated and the residue was dissolyed in water which was made basic with solid K2CO3 and was then saturated withNaCl .
The mixture was extracted with chloroform which was dried oyer Na2SO4 and evaporated to afford the desired product.
Example 139
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of (2S,3R,4S)-4-Amino-5- cyclohexyl-2,3-dihydroxy- 1- (N-methoxy-N-methylamino)pentane
The resultant compounds from Examples 138 and 83 were coupled according to the procedure of Example 93 to givethe desired product. High resolution mass spectrum. Calcd. for (M+H)+ of C35H6ON3O8: 650.4380. Found: 650.4388. Example 140
N-((3-(tert-Bntylovycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)methyl)isopropylamine.
The resultant aldehyde from Example 99 (479 mg, 1.47 mmol, 8:1 mixture of epimeric aldehydes) was dissolyed in 5 ml iPrOH, and isopropylamine (0.15 ml, 1.76 mmol) was added, and the pH was adjusted to 6 with acetic acid and sodium acetate as buffer. The solution was cooled in an ice bath, and a solution of sodium cyanoboro-hydride (119 mg, 1.89 mmol) in 2 ml iPrOH was added. After stirring the resultant solution at 0 °C for 6 h, it was allowed to warm to room temperature and stir an additional 0.5 h. The reaction was made basic with 1.0 M aq. Na2CO3 (5 ml) and the isopropanol was removed under reduced pressure. The residue was partitioned between water and EtOAc, and the organic extracts washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (3% MeOH-CH2Cl2) provided 262 mg (48%) of the title compound as a colorless oil, (as well as 18 mg (3%) of
diastereomeric amine). 1H NMR(CDCI3) δ 0.9-1.35 (seyeral bm) and 1.08 (2d, 13H total), 1.48 (s, 9H), 1.51 (s), 1.58 (s) and 1.35-1.86 (seyeral bm, approx. 12H total), 2.70 (m, 2H), 2.82 (m, 1H), 3.7 (bm, 1H), 4.0 (ddd, 1H), Mass spectrum: (M+H)+ = 369.
Example 141
N-((3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)methyl)-N- (methylsulfamoyl)isopropylamine.
The resultant product from Example 140 is reacted with methylsulfamoyl chloride according to the procedure of Example 121, to produce the title compound as a low melting solid in 86% after flash chromatography (EtOAc- hexanes 1:4). 1H NMR (CDCl3) δ 0.98 (bm, 2H), 1.25 (2d) and 1.1-1.35 (bm, 10H total), 1.48 (s, 9H), 1.63 (bs) and 1.37-1.87 (seyeral bm, approx. 13H total), 2.70 (d, 3H), 3.25 (m, 2H), 3.83 (dt, 1H), 4.01 (septet, 1H), 4.10 (m, 1H), 4.25 (bm, 1H), Mass spectrum: (M+H)+ = 462.
Analysis. Calcd. for C22H43N3O5S: C, 57.24; H, 9.39; N, 9.10. Found: C, 57.54; H, 9.50; N, 8.95.
Example 142
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of (2S,3S)-3-amino-4- cyolohexyl-2-hydroxy-1- (isopropyl(methylsnlfamoyl)amino)butane. The resultant compound from Example 141 was
deprotected and coupled according to the procedure of Example 116 to provide the desired product in 51% yield after preparatiye thin-layer chromatography (4% MeOH- CH2C12) as a foam, m.p. 45-52 °C. 1H NMR (CDCl3) δ 0.94
(2t, 3H), 1.21 (2d, 6H), 0.65-1.9 (seyeral bm, approx. 21H), 2.66 (2d, 3H), 2.9-3.15 (bm, 5H), 3.2-3.4 (bm, 2H), 3.37 (2s, 3H), 3.5 (bm, 3H), 3.72 (bm, 5H), 4.0 (bm oyerlapping septet, 2H), 4.55 (dd, 1H), 4.69 (2s, 2H), 5.58 (bm, 1H), 5.64 (2bd, 1H), 7.35 (bm, 5H). Mass spectrum: (M+H)+ = 711.
Analysis. Calcd. for C36H62N4O8S.0.25 H2O: C.
60.44; H, 8.80; N, 7.83. Found: C, 60.82; H, 8.57; N, 7.80. Example 143
2(S)-(1(S)- (4 -(Methoxymethoxy)oiperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of (4S,5S)-5-amino-4- hydroxy-7-methyl-2(E)-octenoic acid isobutylamide.
The title compound is prepared according to the procedure of Example 116, with the substitution of
(4S,5S)-5-amino-4-hydroxy-7-methyl-2 (E) -octenoic acid isobutylamide (prepared according to the procedure
described in Example 2, part 3, European Patent
Application EP0272583, publioshed June 29, 1988) for 2(S)- amino-1-cyciohexyl-3(R),4(S)-dihydroxy-6-methylheptane as the amine component.
Example 144
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of N-((2R,4S,5S)-5-amino- 4-hydroxy-2-isopropyloctanoyl)-isoleucylhistadinamide.
The title compound is prepared according to the procedure of Example 116, with the substitution of N- ((2R,4S,5S)-5-amino-4-hydroxy-2-isoρropyloctanoyl)- isoleucylhistadinamide (prepared according to the
procedure described in Example 1 (i), United States Patent Nb. 4,719,288, issued January 12, 1988) for 2 (S) -amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane as the amine component.
Example 145
2 (S) - ( 1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of (1R,3S,4S)-4-amino-5- cyclohexyl-3-hydrovy-1-isopropylpentanesulfonic acid morpholinoamide.
The title compound is prepared according to the procedure of Example 116, with the substitution of
(1R,3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-1- isopropylpentanesulfonic acid morpholinoamide (prepared according to the procedure described in Example 2,
European Patent Application No. EP0309841, published April 5, 1989) for 2(S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy- 6-methylheρtane as the amine component.
Example 146
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of (25)-2-amino-1- cyclohexyl-3,4-dioxoheptane.
The procedure of Example 116 is utilized, with the substitution of 2-((1RS,2S)-2-amino-3-cyclohexyl-1- hydroxypropyl)-2-propyl-1,3-dithiane hydrochloride
(prepared according to the procedure described in Example 1, European Patent Application No. EP0296581, published December 28, 1988) for 2(S)-amino-1-cyclohexyl-3(R),4(S)- dihydroxy-6-methylheptane as the amine component. The resulting amide was transformed into the title compound by hydrolysis of the thioketal and Dess-Martin oxidation of the secondary hydroxyl group according to the procedures described in the above citation. Example 147
2(S)-(1(S)-(4 -(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of 2-((1R,2S,-2-amino-3- cyclohexylpropyl)-1H-imidazole.
The procedure of Example 116 is employed, with the substitution of 1-benzyloxymethyl-2-((1R,2S)-2-amino-3- cyclohexylpropyl)-imidazole (prepared according to the procedure described in Example 1, European Patent
Application No. EP0231919, published August 12, 1987) for 2(S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane as the amine component. The title compound is then produced by hydrogenolysis of the resultant amide oyer palladium hydroxide on carbon, according to the procedure in the citation above.
Example 148
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl)ethoxyhexanoic acid amide of (4S)-N1-((2S)-(2- benzylami nocarbonyl-3-methylbutanoyl))-2,2-difluoro-3-oxo-
6-methyl-1,4-heptanediamine.
The title compound is prepared according to the procedure of Example 116, with the substitution of
(3RS,4S)-N1-((2S)-(2-benzylaminocarbonyl-3- methylbutanoyl))-2,2-difluoro-3-hydroxy-6-methyl-1,4- heptanediamine (prepared according to the procedure described in Example 32, European Patent Application No. 275101, published July 20, 1988) for 2(S)-amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane as the amine component. Subsequent Collins oxidation, according to the procedure of Example 8 of the above citation, produces the title compound. Example 149
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of (3S)-3-((1S,2S)-2- amino-3-cyclohexyl-1-hydroxypropyl)-1-(N-benzyl-2- (diethylaminoethyl))-5,5-dimethyl-2-pyrrolidinone acetate.
The procedure of Example 116 is employed, with the substitution of (3S) -3-((1S,2S)-2-amino-3-cyclohexyl-1- hydroxypropyl)-1-(2-(diethylaminoethyl))-5,5-dimethyl-2- pyrrolidinone (prepared according to the procedure
described in Examples 2 and 3, European Patent Application NO. 312283, published April 19, 1989) for 2(S)-amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methyIheptane as the amine component. The C-terminal tertiary amine is
quaternized by the action of benzyl bromide in the
presence of ethyldiisopropylamine, followed by anion exchange, according to the procedure of Example 3, part Q, of the above citation, thereby producing the desired compound.
Example 150
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid N4-amide of (3S,4S)-N1-((1S)-1-
(benzylaminocarbonyl)-3-methylbutyl)-3-hydroxy-6-methyl-
1,4-heptanediamine
The title compound is prepared according to the procedure of Example 116, with the substitution of
(3S,4S)-N1-((1S)-1-(benzylaminocarbonyl)-3-methylbutyl)-3- hydroxy-6-methy1-1,4-heptanediamine (prepared according to the procedure described in Example 2, United States Patent No. 4,609,641, issued September 2, 1986) for 2(S)-amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane as the amine component.
Example 151
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid amide of N-(N-((((2S,3S)-3- amino-2-hydroxy-5-methylhexyl)-(1- methylethyl)amino)carbonyl)-L-isoleucyl)-L-histidine methyl ester.
The title compound is prepared according to the procedure of Example 116, with the substitution of N-(N- ((((2S,3S)-3-amino-2-hydroxy-5-methylhexyl)-(1- methylethyl)- amino) carbonyl)-L-isoleucyl)-L-(Nim- benzyloxymethyl)-histidine, methyl ester (prepared
according to the procedure described in Example 4g, United States Patent No. 4,757,050, issued July 12, 1988) for 2(S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6- methylheptane as the amine component. The title compound is obtained by standard hydrogenolysis of the above resultant compound.
Example 152
2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2- phenyl) ethoxyhexanoic acid N4-amide of ((3S,4S)-3,4- diamino-6-methylheptanoyl)-L-isolenoyl-2- pyridylmethylamine.
The title compound is prepared according to the procedure of Example 116, with the substitution of
((3S,4S)-3-(4-methoxyphenyl)amino-4-amino-6- methylheptanoyl)-L-isoleucyl-2-pyridyl-methylamine
(prepared according to the procedures described in H. J. Schostarez, J. Org. Chem . 1988, 53, 3628, and S.
Thaisriyongs, H. J. Schostarez, D. T. Pals and S. R.
Turner, J. Med. Chem . 1987, 30, 1837) for 2 (S)-amino-1- cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane as the amine component. The title compound is obtained by oxidatiye deprotection of the methoxyphenyl group with eerie ammonium nitrate as described in the citations above.
Example 153
4-(tert-But-oxycarbonyl)-5S-(benzyl)-2H-1,4-oxazin-2-one To suspension of 10.0 g (66 mmol) of L-phenylalanincl in 120 mL of dry THF and 16 mL, 11.5 g (114 mmol)
triethylamine cooled in an ice-water bath was added 11 mL, 16.5 g (98 mmol) of ethyl bromoacetate (freshly filtered through basic alumina). The reaction mixture was stirred to room temperature oyer 18 h, recooled in an ice-water bath, and filtered. Remaining unfiltered solids were washed with cold THF and filtered. Di-tert-butyl
dicarbonate (20g, 92 mmol) was added to the combined filterates and the THF was slowly removed under reduced pressure (30 min) at 50-70 °C. The crude residue was dissolyed in 300 mL toluene, washed with dilute HCl, saturated sodium bisulfate, dried (MgSO4) and filtered. p-Toluenesulfonic acid monohydrate, 500 mg, was added to the toluene solution. Excess toluene (250 mL) was removed by distillation. The toluene solution was cooled, washed with saturated sodium bisulfate, dried (MgSO4) and
filtered, total yolume 100 mL. Hexane (150 mL) was added and the product crystallized at room temperature to give 10.00 g of a white solid. A second recrystallization gave 1.75 g of a white solid. The mother liquors were purified by flash chromatography using ethyl acetate:hexane (1:4) to giveanother 1.13 g. Total combined yield 12.88 g (67%): mp 98-100 °C; [a]25 D = -13.7 ° (C = 2.45 CHCl3) ;
IR (CDCl3) 1750 (lactone C=O), 1690 (carbamate C=O) cm-1; 1H NMR(CDCI3) 7.4-7.2 (m, 5H, Ph), 4.35-4.1 (m, 5H, O- CH2, COCH2 and CH-N), 3.0 (dd, 1H, J = 5 and 12 Hz, CH2- Ph), 2.82 (dd,1H , J = 10 and 12 Hz, CH2-Ph), 1.45 (s, 9H, t-butyl); MS, m/e (M+) 291; Anal. Calcd for C16H21NO4: C, 65.97; H, 7.21; N, 4.81. Found: C, 65.67; H, 7.21; N, 4.75.
Example 154
4-(tert-Butoxycarbonyl)-5S-(cyclohexylmethyl)-2H-1,4- oxazin-2-one
Using the procedure of Example 1 and 14.0 g (71 mmol) of amino alcohol hydrochloride (prepared from 20 g of L- Boc-cyclohexylalaninol and 4M HCl dioxane), 200 mL THF, 28 mL (193 mmol) triethylamine, 17.9 g (106 mmol) ethyl bromoacetate, 18.5 g (85 mmol) di-tert-butyl dicarbonate, 500 mg p-tolunesulfonic acid monohydrate gave crude lactone. Product was purified by flash chromatography using a 1:4, 3:7 and 4:6 ethyl acetate : hexane step gradient to give11.7 grams of pure lactone. Yield 55%: mp 73-74 °C; [a]25 D= +1.09 ° (C = 0.82 CHCl3); IR(CDCI3)
1750 (lactone C=O) , 1690 (carbamate C=O) cm-1; 1H NMR
(CDCl3) 4.5-4.2 (m, 4H, 0-CH2, COCH and CH-N), 3.97 (d,1H, 18 Hz, COCH), 1.9-0.9 (br m, 13H, cyclohexylmethyl), 1.49 (s, 9H, t-butyl); MS m/e (M+H) + 298; Anal. Calcd for C16H27NO4: C, 64.64; H, 9.09; N, 4.71. Found: C, 64.73; H, 9.00; N, 4.71. Example 155
4-(tert-Bntovycarbony.l)-5S-(methyl)-2H-1,4-oxazin-2-one Using the procedure of Example 1 and 9.5 g (126 mmol) of 2S-amino-1-ρropanol, 100 mL THF, 30 mL (214 mmol) triethylamine, 31 g (190 mmol) ethyl bromoacetate, 33 g (151 mmol) di-tert-butyl dicarbonate, 500 mg p- tolunesulfonic acid monohydrate gave crude lactone.
Product was purified by flash chromatography using a 1:4 and a 3:7 ethyl acetate : hexane step gradient. The lactone was obtained as a white crystalline solid (8.0 g) in 30% yield: mp 85-86 °C; [a]25D= +6.96 ° (C = 2.21 CHCl3); IR (CDCI3) 1750 (lactone C=O), 1690 (carbamate C=O) cm-1;1 H NMR (CDCl3) 4.46 (dd, 1H, J = 3 and 10 Hz, 0-
CH), 4.30 (d, 1H, 18 Hz, COCH), 4.18 (br dd, 2H, J = 3 and 12 Hz, O-CH and CH-N), 4.08 (d, 1H, J = 18 Hz, COCH), 1.48 (s, 9H, t-butyl), 1.29 (d, 3H, J = 7Hz, CH3); MS m/e (M+H)+ 216; Anal. Calcd for C10H17NO4: C, 55.81; H, 7.90; N, 6.51. Found: C, 55.98; H, 7.93; N, 6.55.
Example 156
4-(tert-Butoxycarbonyl)-5S-(n-butyl)-2H-1,4-oxazin-2-one Using the procedure of Example 1 and 16 g of 2S- amino-1-hexanol hydrochloride (prepared from 26 g ,119 mmol of L-Boc-norlucinol and 4 M HCl dioxane), 250 mL THF, 45 mL (320 mmol) triethylamine, 30 g (180 mmol) ethyl romoacetate, 31 g (142 mmol) di-tert-butyl dicarbonate, 500 mg p-tolunesulfonic acid monohydrate gave crude lactone. Product was purified by flash chromatography using a 1:4 and a 3:7 ethyl acetate : hexane step
gradient. The lactone was obtained as a clear oil (13.0 g) in 45% yield: [a]25 D= +3.45 ° (C = 2.95 CHCl3); IR
(Film) 1760 (lactone C=O), 1700 (carbamate C=O) cm-1;1H NMR (CDCl3) 4.46 (dd, 1H, J = 3 and 10 Hz, 0-CH), 4.41-
4.26 (br m, 2H, O-CH and COCH), 4.12 (br s,1H, CH-N), 4.00 1.74-1.56 (11 line m, 2H, CH2), 1.48 (s, 9H, t- butyl), 1.42-1.21 (m, 4H, CH2CH2), 0.92 (d, 3H, J = 6Hz, CH3); MS m/e (M+H) + 258; Anal. Calcd for C13H23NO4: C, 60.70; H, 8.95; N, 5.45. Found: C, 60.56; H, 8.88; N, 5.42.
Example 157
4- (tert-Butoxycarbonyl)-5S-(isopropyl)-2H-1,4-oxazin-2-one
Using the procedure of Example 1 and 10 g (97 mmol) of 2S-3-methyl-1-butanol, 100 mL- THF, 23 mL (145 mmol) triethylamine, 23 g (145 mmol) ethyl bromoacetate, 25 g (116 mmol) di-tert-butyl dicarbonate, 500 mg p- tolunesulfonic acid monohydrate gave crude lactone.
Product was purified by flash chromatography using a 1:4 and a 3:7 ethyl acetate : hexane step gradient. The lactone was obtained as a clear oil (14.9 g) which
solidified at -25 °C. Yield 66%: mp 38-40 °C [a]25 D= - 30.55 ° (C = 3.22 CHCl3); IR (Film) 1750 (lactone C=O), 1700 (carbamate C=O) cur1;1H NMR (CDCl3) 4.50 (br d, 2H, 0-CH and COCH), 4.40 (d d, 1H, J = 3 and 10 Hz, O-CH), 3.95 (br d, 2H, CH-N and COCH), 1.99 (14 line m, 1H, CH), 1.48 (s, 9H, t-butyl), 1.04 (d, 3H, J = 7Hz, CH3), 0.96 (d, 3H, J = 7Hz, CH3); MS m/e (M+H) + 244; Anal. Calcd for C12H21NO4: C, 59.25; H, 8.64; N, 5.76. Found: C, 58.88; H, 8.72; N, 5.71. Example 158
3S-(Prop-2-en-1-yl)-4-(tert-butoxycarbonyl)-5S-(benzyl)-
2H-1,4-oxazin-2-one
To a solution of 7.0 mL (1 M, 7 mmol) of sodium bis (hexamethyl-silyl) amide in THF cooled to -70 °C (limited liquid nitrogen-diethyl ether bath) was added 2.1 g (7.2 mmol) of lactone (example 1) in 10 mL THF. After addition was complete 2.5 mL of dry HMPA was added. The reaction was stirred for 15 min between -70 and -80 °C and 1.5 mL cf allyl bromide (freshly filtered through basic alumina) was added. The reaction was stirred from -80 to -50 °C oyer a 20 min period. A dilute solution of sodium
bisulfate was added and the reaction warmed to room temperature, poured into chloroform and the aqueous layer separated. The aqueous layer was extracted once with chloroform. The combined chloroform extracts were washed once with water, dried (MgSO4) and eyaporated to give2.02 g of a crystalline solid (85%). An analytical sample was prepared by recrystalization from ethyl acetate:hexane at 0 °C: mp 125-127 °C;
[a]25D = +40.1 o (C = 0.96 CHCl3); IR(CDCI3) 1750
(lactone C=O), 1690 (carbamate C=O); 1H NMR (CDCI3, 55
°C) 7.37-7.18 ( br m, 5H, C6H5), 5.90-5.74 (11 line m, 1H, CH=C) , 5.22-5.10 (m, 2H, C=CH2), 4.61-4.48 (br s, 1H,
COCH), 4.38-4.30 (m,1H , O-CH), 4.17-4.10 (br d, 2H, O-CH and CH-N), 3.13-3.00 (br d, 1H, CHPh), 2.8-2.58 (m, 3H, CH2-C=C and CHPh), 1.55 (s, 9H, t-butyl); MS m/e (M+H)+ 332; Anal. Calcd for C19H25NO4: C, 68.88; H, 7.55; N, 4.22. Found: C, 68.49; H, 7.56; N, 4.17. Example 159
3S-(Bntyl)-4-(tert-butoxycarbonyl)-5S-(benzyl)-2H-1,4- oxazin-2-one
Using the procedure in Example 6 but replacing allyl bromide with butyl iodide and raising the reaction
temperature to -60 °C gave the alkylated product in 43% yield. 1H NMR (DMSO) 7.37-7.18 ( br m, 5H, C6H5), 4.48 (dd,1H, COCH), 4.22 (dd, 1H, O-CH), 4.13-3.97 (br d, 2H, C-CH and CH-N), 2.90 (dd, 1H, CHPh), 2.65 (dd, 1H, CHPh), 1.45 (s, 9H, t-butyl), 0.86 (t, 3H, CH3); MS m/e (M+H)+ 348; Anal. Calcd for C20H29NO4: C, 69.14; H, 8.41; N,
4.03. Found: C, 69.43; H, 8.46; N, 3.89.
Example 160
Methyl 3-Aza-4(S)-benzyl-3-(tert-butoxycarbonyl)-2(S)- butyl-5-hydroxypentanoate
A solution of lithium hydroxide (966 mg, 22.8 mmol) in 7 mL water and lactone ( 2.0 g, 5.7 mmol) from example 7 in 16 mL THF were stirred at room temperature for 18 h. The reaction mixture was acidified with a saturated solution of sodium bisulfate and extracted with
dichloromethane. A solution of diazomethane in ether was added to the dichloromethane extract until the yellow color persisted. Excess diazomethane and solvent was removed under a nitrogen ebullition. The crude methyl ester was purified by column chromatrography using ethyl acetate : hexane (3:7) as eluant. The pure ester was obtained as a clear oil (2.05 g) in 94% yield.1H NMR (CDCl3) 7.26 ( br m, 5H, C6H5), 4.31 (br m, 2H, CH2OH), 3.78 (s, 3H, O-CH3),1.46 (s, 9H, t-butyl), 0.90 (t, 3H, CH3); MS m/e (M+H)+ 380.
Example 161
Methyl 3-Aza-3-(tert-bntoxycarbonyl)-2(S)-butyl-4(S)-(4- methoxymethoxypiperidinocarponyl)-5-phenyl- pentanoate The hydroxy ester from example 8 ( 600 mg, 1.58 mmol) in dichloromethane is added to a solution of oxalyl chloride (152 mcL) and DMSO (0.27 mL) at -25 °C. After stirring for 15 min, triethylamine (1.1 mL) was added and the reaction stirred to room temperature. The crude aldehyde was obtained as a yellow oil and directly
oxidized to the carboxylic acid using the procedure of Masmune et al. (Tetrahedron Letters 1986, 27, 4537) givse the carboxylic acid. The crude acid couples with the amine from example 82a using the procedure in example 93 to givethe product.
Example 162
Methyl 3-Aza-3-(tert-butoxycarbonyl)-2(S)-(prop-2-en-1- yl)-4(S)-morpholinocarbonyl-5-phenylpentanoate
The lactone from example 6 ( 520 mg, 1.5 mmol) was hydrolyzed using the procedure in example 8 to givethe hydroxy ester which was oxidized in 1.6 mL of DMF with 1.5 g of PDC. Standard workup gave the crude acid. Coupling of the crude acid with 0.6 mL morpholine, 318 mg HOBT, 450 mg EDC HCl in 5 mL DMF at -20 °C to room temperature oyer 18 h gave the amide. Mass Spectrum: (M+H)+ = 447. Example 163
3-Aza-2(S)-(prop-2-en-1-yl)-4(S)-morpholinocarbonyl-5- phenylpentanoic acid amide of 2(S)-amino-1-cyclohexyl- 3(R),4(S)-dibydroxy-6-methylheptane The ester from example 10 ( 90 mg) was hydrolyzed using 50 mg LiOH in 2.5 mL of 1.5:1 (dioxane: water) at room temperature for 2 days gave 67 mg of the crude acid which was coupled with 2(S)-amino-1-cyclohexyl-3(R),4(S)- dihydroxy-6-methylheptane using the procedure in example 93 gave the Boc amide which was. purified by silica gel chromatography. The Boc amide was stirred in TFA:
dichloromethane (1:1) for 24h. The solyents were removed under reduced presure, the residue made basic with
saturated sodium bicarbonate and the free base extracted with dichloromethane. The product was purified by
preparatiye TLC using 4:1 ethyl acetate:hexane.
Concentration of the solyent gave the product as a white solid. Mass Spectrum: (M+H)+ = 558
Example 164
2 (S) - (1 (S) - (4-Methoxymethoxypiperidin-1-yl carbonyl ) -2-
Phenylethoxy)hexanioc acic amide of 5-amino-6-cyclohexyl- 4-hydroxy-1-isopropylsulfonyl-2-methylhexane Using the acid from example 83, 5-amino-6-cyclohexyl- 4-hydroxy-1-isopropylsulfonyl-2-methylhexane (Tetrahedron Letters 1989, 30, 2653) and the procedure from exaaple 93 giyes the desired product. Example 165
2 (S) - ( 1 (S ) - (4-Methoxymethoxypi perinin-1-yl carbonyl ) -2- phenylethoxy) hexanioc acic amide of 5-amino-6-cycloh exyl-
4-hydroxy-1-is opropylsulfonyl-2-isopropvlhexane Using the acid from example 83, 5-amino-6-cyclohexyl- 4-hydroxy-1-isopropylsulfonyl-2-isopropylhexane (European Patent Application No . EP0273893, published July 6, 1988 ) and the procedure from example 93 gives the desired product .
Example 166
2(S)-(1(S)-(4-Methoxymethoxypiperidin-1-yl carbonyl)-2- phenylethoxy)hexanioc acic amide of isopropyl 3-amino-4- cyclohexyl-2-hydroxybutrate
Using the acid from example 83, 3-amino-4-cyclohexyl- 2-hydroxy-butyrate (Japanese Patent Application No.
JP63275552, published Noyember 14, 1988) and the procedure from example 93 givse the desired product.
Example 167
2 (S) - (1 (S) - (4-Methoxymethoxypiperidin-1-yl carkonyl)-2-
Phenylethoxy) hexanioc acic amide of N-(2-Morpholinoethyl)
4-Amino-5-cyclohexyl-3-hydroxypentamide Using the acid from example 83, N-(2- morpholinoethyl) 4-amino-5-cyclohexyl-3-hydroxypentamide (Japanese Patent Application No. JP62246546A, published October 27, 1987; European Patent Application No.
EP0274259, published July 13, 1988) prepared from BocACHPA amide of 2-morpholinoethylamine by acid treatment, and the procedure from example 93 gives the desired product. Example 168
2(S)-(1(S)-(4-Methoxymethoxypiρeridin-1-yl carbonyl)-2- phenylethoxy)hexanioc acic amide of 6-Amino-7-cyclohexyl-
5-hydroxy-3-isopropyl-1-heptene
Using the acid from example 83, 6-amino-7- cyclohexyl-5-hydroxy-3-iso)ropyl-1-heptene (European
Patent Application No. EP0310918, published April 12, 1989) and the procedure from example 93 givse the desired product.
Example 169
2(S)-(1(S)-(4-Methoxymethoxypiperidin-1-yl carbonyl)-2- phenylethoxy)hexanioc acic amide of N-isobutyl 4-amino-5 - cyclohexyl-2,2-diflnoro-3-hydroxypentamide Using the acid from example 83, N-isobutyl 4-amino- 5-cyclohexyl-2, 2-difluor-3-hydroxypentamide, prepared from Boc cyclomethylalinal according to the procedure of
Thaisriyong (J. Med. Chem. 1986, 29, 2080; see also U.S. Patent No. 4,857,507, issued August 15, 1989, example 69), and the procedure from example 93 givse the desired product.
Example 170
2(S)-(1(S)-(4-Methoxymethoxypiperidin-1-yl carbonyl)-2- phenylethoxylhexanioc acic amide of 4-amino-5-cyclohexyl- 2.2-difluoro-3-hydroxy-1-isopropylmercapto-1-pentane Using the acid from example 83, 4-amino-5- cyclohexyl-2,2-difluor-3-hydroxy-1-isopropylmercapto-1- pentane, prepared from the oxazolidinone (U.S. Patent No. 4,857,507, issued August 15, 1989, example 74, according to the procedure of example 76 in U.S. Patent No. 4,857,507, issued August 15, 1989), and the procedure from example 93 givse the desired product.
Example 171
2(S)-(1(S)-(4-Methoxymethoxypiperidin-1-yl carbonyl)-2- phenylethoxy)hexanioc acic amide of 4-amino-5-cyclohexyl-
2,2-difluoro-3-hydroxy-1-isopropylsulfonyl-1-pentane To the resultant compound from example 36 (10 mmol) in 5 mL of CH2Cl2 is added 30 mmol of m-chloroperbenzoic acid. Standard workup and chromatography on silica gel givse the title compound.
Example 172
Ethyl 4(S)-((t-butyloxycarbohyl) amino) -5-cyclohexyl-
2,2-difluoro-3(R,S)-hydroxypentanoate.
To a suspension of 1.2 g (17 mmole) of activated zinc in 5 ml of tetrahydrofuran under argon in a sonicating bath was added slowly a solution of 1.7 g (6.8 mmole) of Boc-L- cyclohexylalaninal and 2.34 ml (18.4 mmole) of ethyl bromodifluoroacetate in 30 ml of tetrahydrofuran. After complete addition, the solution was sonicated for an additional 30 min. The mixture was then added to 1 M KHSO4 and extracted with dichloromethane (3 X 100 ml), dried with Na2SO4, filtered and concentrated in yacuo. The residual oil was purified by silica gel column chromatography (15- 30% ethyl acetate in hexane) to give1.22 g (75%) of two diasteromers.
3(R) diastereomer: 1H NMR (CDCl3) δ 1.37 (t,3H, J=7.0 Hz),
1.46 (S,9H), 4.35 (q, 2H, J=7.0 Hz). m.p. 73-74.5°C.
Anal. (C18H31NO5F2)C,H,N. 3(S) diastereomer: 1H NMR (CDCI3) δ 1.37 (t,3H, J=7.5 Hz),
1.45 (S,9H), 4.31 (q,2H, J=7.5 Hz); m.p. 115º-117°C.
Anal. (C18H31NO5F2)C,H,N.
Example 173
2-Oxazolidinone deriyatiye of Ethyl 4 (S) -amino-5- cyclohexyl-2.2-difluoro-3(R)-hydroxypentanoate.
To 50 mg of the 3 (R) isomer from Example 172 was added 1 ml of 4 M HCl in dioxane. The solution was stirred at RT for 30 min. The concentrated residue was dissolyed in dichloromethane and treated with 0.1 ml of triethylamine and excess phosgene in toluene (10% solution). After stirring at RT for 1 hr, the crude product was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give32 mg of desired product. 1H NMR (CDCl3) δ
1.38 (t,3H, J=7 Hz), 4.08 (m,1H), 4.38 (q, 2H, J=7 Hz), 4.58 (ddd,1H, J=4.5, 6.0, 15 Hz), 6.05 (br S,1H).
Anal. (C14H21NO4F2)C,H,N. Example 174
2-Oxazolidinone deriyatiye of Ethyl 4(S)-amino-5- cyclohexyl-2,2-difluoro-3-(S)hydroxypentanoate.
Using the same procedure as in Example 173, and using the 3 (S) isomer from Example 1 as the starting material provided the desired product 1H NMR (CDCl3) δ 1.38
(t,3H, J=7.5 Hz), 4.28 (ddd, 1H, J=3, 7.5, 12 Hz), 4.38 (q,2H, J=7.5 Hz), 5.02 (ddd,1H,J=6, 9,19.5 Hz), 5.63 (br S,1H). Anal. (C14H21NO4F2)C,H,N. Example 175
4(S)-cyclohexylmethyl-5(R)-(4'(4',4'-difluoro-3'-oxo-2'- methyl-buthyl))-2-oxazolidinone.
The hydrolysis of 2.5 g of the product in Example 174 by lithium hydroxide in aqueous methanol provided 2.3 g of the corresponding carboxylic acid. The acid was dissolyed in 40 ml of THF and cooled to -78° C. To the yigorously stirred solution was added 18 ml of isopropyl lithium solution in pentane (12.4% by wt.). After 30 min, the solution was slowly warmed to 0°C and stirred for an
additional 30 min. The reaction was carefully quenched with water and extracted with ethyl acetate (3 X 100 ml), dried and concentrated in yacuo. The crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to give1.36 g of desired product. 1H NMR (CDCl3) δ
1.20 (t,6H, J=6.3 Hz), 3.17 (d of heptet, 1H, J-l.8,6.6 Hz), 4.06 (m,1H), 4.62 (ddd,1H , J=4.5, 6.0, 20.4 Hz), 5.63 (br S,1H). Anal. (C14H23NO3F2) C, H,N.
Example 176
4(S)-cyclohexylmethyl-5(R)(4'-(4',4'-difluoro-3(R,S.- hydroxy-2'-methylbutyl))-2-oxazolidinone. To the product of Example 175 (1.0 g, 3.4 mmole) in 20 ml of methanol at 0°C was added 125 mg of sodium
borohydride. After 10 min the reaction was quenched by addition of excess acetone. The solution was concentrated and the residual oil was dissolyed in ethyl acetate and washed with brine. The aqueous layer was extracted with ethyl acetate (2 X 50 ml). The combined ethyl acetate solution was dried with MgSO4 and concentrated to givea mixture of 3'(R) and 3'(S) diastereomers. 3'(R) isomer: 1H NMR (CDCl3): δ 1.04 (t, 6H, J=7.5 Hz), 2.12 (m,1H), 3.82 (m, 1H), 4.10 (m, 1H), 4.63 (dd1,H , J=4.5,22.5 Hz), 5.38 (br S,1H).
Anal. (C14H25NO3F2)C,H,N.
3'(S) isomer: 1H NMR (CDCl3): δ 1.01 (d, 3H, J=6Hz), 1.07 (d,3H, J= 2.10 (m,1H), 3.80 (m, 1H), 4.15 (m, 1H), 4.40 (td, 1H, J=6,15.5 Hz), 5.62 (br S,1H).
Anal. (C14H25NO3F2)C,H,N.
Example 177
2(S)-Benzyloxycarbonylamino-1-cyclohexyl-4,4-difluoro- 3 (R),5(R)-dihydroxy-6-methylheptane.
To a solution of 0.9 g (3.0 mmole) of the 3'(R) isomer in Example 176 in 50 ml of dioxane and water was added 1.05 g (2-1 eq) of barium hydroxide hydrate. The reaction mixture was heated to reflux for 18 hr. and cooled to RT and filtered. The filtrate was concentrated in yacuo and the crude product was dissolyed in 50 ml of dichloromethane and 1.0 g of N-(benzyloxycarbonyloxy) succinimide was added.
After 1 hr. at RT the solution was washed with satd. NaHCO3 and extracted with dichloromethane (3 X 50 ml), dried with Na2S04 and filtered. The filtrate was concentrated in yacuo to givea pale yellow oil which was purified by silica gel column chromatography (10% EtOAc in CH2CI2) to give900 mg of the desired product. 1H NMR(CDCI3) δ 1.01 (d,3H,
J=5Hz), 1.03 (d,3H, J=5Hz), 2.07 (m, 1H), 2.42 (br d, 1H), 3.70-3.95 (m,3H), 4.07 (m, 1H), 5.02 (br d, 1H), 5.11 (S,2H), 7.30-7.36 (m,5H).
Anal. (C22H33NO4F2)C,H,N. Example 178
2(S )-Amino-1-cyclohexyl-4,4-difluoro-3(R),5(R) -dihydroxy-6- methylheptane.
A solution of 700 mg of the product from Example 177 in 10 ml of methanol was stirred yigorously under a hydrogen atmosphere using 10% Pd/C as catalyst. After 30 min, the catalyst was filtered off and the solution concentrated to giye 470 mg the desired product. Mass spectrum: M+ = 279.
Example 179
2 (S ) - ( 1 (S ) - ( 4- (Methoxymethoxy) piperidin-1 -yl -carbonyl ) -
2-phenylethoxy) hexanoic acid Amide of
(2 (S ) -Amino-1-cyclohexyl-4. 4-difluoro-3 (R) , 5 (R) -dihydroxy-
6-methylheptane.
Using the procedure of Example 93, but replacing the resultant glycol of Example 41 with the resultant product of Example 178 gave the desired product.
1H NMR (CDCl3 , TMS) δ 0.9 (bt,1H), 1.02 (dd, 6H), 2.92 (m,2H), 3.37 (s,3H), 4.46 (dd, 1H), 4.67 (s,2H), 6.0 (bdd,1H), 7.32 (m,5H). Mass spectrum: (M+H)+ = 669.
Example 180
2(S)-(1(S)-(4-(Methoxymethoxy)pipeririin-1-yl-carbamoyl)-
2-phenylethoxy)hexanoic acid Amide of
4(S)-Amino-5(S)-hydroxy-2-methyl-6-(2(S)- methylcarbonyl)hexane.
Using the procedure of Example 93, but replacing the resultant glycol of Example 41 with 4(S)-Amino-5(S)- hydroxy-2-methyl-6-(2(S)-methylcarbamoyl) hexane
(Buhlmayer, et al., U.S. Patent No. 4,727,060, issued
February 23, 1988) gave the desired product. 1H NMR (CDCl3 , TMS) δ 0.84 (m,15H), 2.2 (m, 2H), 3.36 (s,3H), 3.77 (t,1H), 3.9 (bt,1H), 4.53 (bdd, 1h), 4.66 (s,2H), 6.08 (bdd,1H), 6.28 (bm, 1H), 7.28 (m, 5H). Mass spectrum: (M+H) + = 634.
Example 181
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2- phenyl-L-norleucyl Amide of 5 (S)-Amino-6-cyclohexyl-4(R)- hydroxy-2-isopropylhexanoyl)-L-isoleucyl)-2- pyridylmethylamine.
Using the procedure of Example 105, but replacing the resultant product of Example 41 with 5 (S) -Amino-6- cyclohexyl-4(R)-hydroxy-2-isopropylhexanoyl)-L-isoleucyl)- 2-pyridylmethylamine (PCT Patent Application No.
WO87/02986, published May 21, 1987), gave the desired product.
1H NMR (CDCl3 , TMS) δ 0.9 (m, 15H), 1.1-1.6 (m,29H), 3 (s,3H), 4.55 (d,2H), 7.4 (m, 10H). Mass spectrum: (M+H)+ = 864.
Example 182
2(R)-Butyl-4(R)-(4(Methoxymethoxy)piperidin-1-yl- sulfσnyl)-5-phenylpentanoic acid Amide of 3-(4- morpholinyl)-propyl-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-
2(S)-isopropyl hexanamide.
The title compound can be prepared according to the procedure of Scheme XIV in which R5 is 4-(methoxymethoxy)- piperidin-1-yl, R1 is phenyl, R3 is n-butyl and D is the deprotected resultant product of Example 115 .
The compounds of the presentinvention can be used in the form of salts deriyed 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, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate,
glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxy-ethanesulfonate, lactate, maleate,
methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, piyalate, propionate,
succinate, tartrate, thiocyanate, tosylate, and
undecanoate. Also, the basic nitrogen-containing groups can be quaternized 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, aralkyl 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, 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 presentinvention can also be used in the form of prodrugs which include esters.
Examples of such esters include a hydroxyl-substituted compound of formula (1) 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;
howeyer, other amino acid residues can also be used. Other esters include the compounds of formula (1) 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 serye as prodrugs of the compounds of the presentinvention and serye to increase the solubility of these substances in the gastrointestinal tract. The prodrugs are metabolically conyerted in vivo to the parent compound of formula (1). The preparation of the pro-drug esters is carried out by reacting a hydroxylsubstituted compound of formula (1) with an activated amino acyl, phosphoryl or hemisuccinyl deriyatiye. The resulting product is then deprotected to provide the desired prodrug ester. Prodrugs which are esters of carboxylic acid group containing compounds of formula (1) are prepared by methods known in the art.
The novel compounds of the presentinvention possess an excellent degree of activity and specificity in treating hypertension in a host. The novel compounds of the present inyention are also useful for treating congestive heart failure. The ability of the compounds of theinvention to inhibit human renal renin can be demonstrated in vitro by reacting a selected compound at yaried concentrations with human renal renin, free from acid proteolytic actiyity, and with renin substrate (human angiotensinogen) at 37 degrees C and pH of 6.0. At the end of the incubation, the amount of angiotensin I formed is measured by radioimmunoassay and the molar concentration required to cause 50% inhibition, expressed as the IC50 is calculated. When tested in accordance with the foregoing procedure, the compounds of theinvention demonstrated IC50's in the range of 10-7 to 10-9 M as seen in Table I.
The ability of the compounds of theinvention to decrease blood pressure and plasma renin activity in vivo can be determined using the following method.
In Vivo Activity
Male cynomolgous monkeys housed under constant temperature and lighting conditions and weighing 3-5 kg were instrumented with chronic indwelling arterial and yenous catheters. Following pretreatment by salt- depletion, the monkeys were dosed by nasogastric tube with 3 mg/kg of the compound of Example 118. The results with two monkeys are shown in Table II.
Table II
Effect of the Compound of Example 118 on Blood Pressure (BP, mmHg) and Plasma Renin Actiyity (PRA, ng/ml/hr) in TwoSalt Depleted Monkeys Following Oral Dosing (3 mg/kg)
These results indicate that the compound caused a decrease in blood pressure accompanied by suppression of PRA when administered orally.
The compounds of tϊteinvention may also be used with one or more antihypertensive agents selected from the group consisting of diuretics, and/or β-adrenergic blocking agents, central neryous system -acting agents, adrenergic neuron blocking agents, yasodilators, angiotensin I
conyerting enzyme inhibitors, and other antihypertensive agents.
Total daily dose administered to a host in single or diyided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of actiye ingredient that may be combined with the carrier materials to produce a single dosage form will yary depending upon the host treated and the
particular mode of administration.
It will be understood, howeyer, that the specific dose leyel for any particular patient will depend upon a yariety cf 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 seyerity of the particular disease undergoing therapy.
The compounds of the presentinvention may be
administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations
containing conyentional nontoxic pharmaceutically
acceptable carriers, adjuyants, and vehicles as desired. Topical administration may also inyolye the use of
transdermal administration such as transdermal patches or iontophoresis deyices. The term parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular, intrasternal 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 solyent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solyents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conyentinally employed as a solyent 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.
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 actiye 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.
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 adjuyants, such as wetting agents, emulsifying and suspending agents, and sweetening,
flayoring, and perfuming agents.
The presentinvention also relates to the use of novel compounds, pharmaceutical compositions containing the novel compounds and the use of the compounds and compositions to inhibit renin for treating glaucoma or reducing and/or controlling intraocular pressure. The present invention also relates to the use of novel compounds and
pharmaceutical compositions which inhibit renin in
combination with a beta-adrenergic antagonist agent or an angiotensin conyerting enzyme inhibiting compound for treating glaucoma or reducing and/or controlling
intraocular pressure.
The presentinvention also relates to pharmaceutical compositions for treating the increase in intraocular pressure associated with the administration of steroidal antiinflammatory agents comprising novel renin inhibiting compounds in combination with a steroidal antiinflammatory compound in a pharmaceutically acceptable vehicle.
The presentinvention also relates to a kit comprising in indiyidual containers in a single package a novel renin inhibiting compound in a suitable pharmaceutical vehicle and a steroidal antiinflammatory compound in a suitable pharmaceutical vehicle and/or a beta-adrenergic antagonist agent in a suitable pharmaceutical vehicle or an
angiotensin conyerting enzyme inhibiting compound in a suitable pharmaceutical vehicle.
The compositions of theinvention are administered as topical or systemic pharmaceutical compositions when used for treating or reducing and/or controlling intraocular pressure. These compositions are preferably administered as topical pharmaceutical compositions suitable for ophthalmic administration, in a pharmaceutically acceptable vehicle such as pharmaceutically acceptable sterile aqueous or nonaqueous solutions, suspensions, emulsions, ointments and solid inserts.
Examples of suitable pharmaceutically acceptable vehicles for ophthalmic administration are water, propylene glycol and other pharmaceutically acceptable alcohols, sesame or peanut oil and other pharmaceutically acceptable yegetable oils, petroleum jelly, water soluble
ophthalmologically acceptable non-toxic polymers such as methyl cellulose, carboxymethyl cellulose salts,
hydroxyethyl cellulose, hydroxypropyl cellulose; acrylates such as polyacrylic acid salts; ethylacrylates;
polyacrylamides; natural products such as gelatin,
alginates, pectins, tragacanth, karaya, agar, acacia;
starch deriyatiyes such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch; as well as other synthetic deriyatiyes such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, carbopol and xantham gum; and mixtures of these polymers. Such compositions may also contain adjuyants such as buffering, preserying, wetting, emulsifying, and dispersing agents. Suitable preserving agents include antibacterial agents such as quaternary ammonium compounds,
phenylmercuric salts, benzyl alcohol, phenyl ethanol; and antioxidants such as sodium metabisulfite, butylated hydroxyanisole and butylated hydroxytoluene. Suitable buffering agents include borate, acetate, gluconate and phosphate buffers. The pharmaceutical ophthalmic compositions of the inyention may also be in the form of a solid insert. A solid water soluble or water swellable polymer such as dextran, hydroxyloweralkyl dextran, carboxymethyl dextran, hydroxyloweralkyl cellulose, loweralkyl cellulose,
carboxymethyl cellulose,polyvinyl alcohol, dextrin, starch, polyvinyl pyrrolidone and polyalkylene glycols may be used as the carrier for the drug.
Dosage leyels of the actiye compound in the
compositions for treating glaucoma or reducing and/or controlling intraocular pressure may be yaried so as to obtain a desired therapeutic response to a particular composition. Generally, the actiye compound will be administered as an isotonic aqueous solution of from
0.00001 to 1.0 (w/v) percent concentration. More
preferably the actiye compound will be administered as an isotonic aqueous solution of from 0.00001 to 0.1 (w/v) percent concentration.
The term "controlling intraocular pressure" as used herein means the regulation, attenuation and modulation of increased intraocular tension. The term also means that the decrease, in the otherwise eleyated intraocular
pressure, obtained by the methods and compositions of the invention is maintained for a significant period of time as, for example, between consecutiye doses of the
composition of theinvention.
The novel renin inhibiting compounds of the invention may be the only actiye ingredient for controlling
intraocular pressure in the methods and compositions of theinvention or may be used in combination with other
ingredients which control intraocular pressure such as beta-adrenergic antagonist compounds. The term "beta- adrenergic antagonist" as used herein means a compound which by binding to betaadrenergic plasma membrane
receptors reduces or eliminates sympathetic activity or blocks the effects of exogenously adminstered
catecholamines or adrenergic drugs. Examples of beta- adrenergic antagonists are atenolol, metopropol, nadolol, propranolol, timolol, labetalol, betaxolol, carteolol and dileyalol and pharmaceutically acceptable salts thereof. Most preferably the beta-adrenergic antagonist is timolol.
Timolol is currently used for treating glaucoma or reducing and/or controlling intraocular pressure, but it has a number of adyerse side effects. Accordingly,
administration of a composition comprising a combination of a beta-adrenergic antagonist and a novel renin inhibiting compound of theinvention could produce a reduction in intraocular pressure equiyalent to that produced by a beta- adrenergic antagonist alone, but at a reduced dose leyel of the beta-adrenergic antagonist. This will result in a reduced leyel of the beta-adrenergic antagonist related adyerse side effects.
The combination composition is administered as a single dosage form containing both the novel renin
inhibitor and the beta-adrenergic antagonist. The beta adrenergic antagonist may comprise from 5 mg to about 125 mg of the composition of theinvention . The preferred ranges of the components in the composition of the
invention in unit dosage form are:
Renin inhibitor: 1 ng to 0.1 mg
Beta-adrenergic antagonist: 5 ug to 125 ug When the beta-adrenergic antagonist and the novel renin inhibitor are administered as separate compositions the presentinvention relates to a kit comprising in two separate containers a pharmaceutically acceptable beta- adrenergic antagonist composition and a pharmaceutically acceptable novel renin inhibitor composition, in a single package. A preferred kit comprises a beta-adrenergic antagonist composition and a topical novel renin inhibitor composition. A most preferred kit comprises a topical cphthalmological beta-adrenergic antagonist composition and a topical ophthalmological novel renin inhibitor
composition.
The novel renin inhibiting compounds of theinvention may also be administered in combination with an angiotensin conyerting enzyme (ACE) inhibiting compound. Examples of angiotensin conyerting enzyme inhibiting compounds are captopril and enalapril. As was preyiously mentioned, ACE inhibitors have some undesirable side effects.
Accordingly, administration of an ACE inhibitor in
combination with a renin inhibitor could produce a
reduction in intraocular pressure greater than or
equiyalent to that of an ACE inhibitor alone, but at a reduced dose leyel of the ACE inhibitor. This will result in a reduced leyel of the ACE inhibitor related adyerse side effects.
The combination composition is administered as a single dose form containing both the novel renin inhibitor and the angiotensin conyerting enzyme inhibitor. The ACE inhibitor may comprise from 5 ng to about 50 ug of the compositon of theinvention . The preferred ranges of the components in the composition of theinvention in unit dosage form are:
Renin inhibitor: 1 ng to 0.1 mg
ACE inhibitor: 5 ng to 50 ug
When the ACE inhibitor and the novel renin inhibitor are administered as separate compositions the present inyention relates to a kit comprising in two separatd containers a pharmaceutically acceptable ACE inhibitor composition and a pharmaceutically acceptable novel renin inhibitor composition, in a single package. A preferred kit comprises an ACE inhibitor composition and a topical novel renin inhibitor composition. A most preferred kit comprises a topical ophthalmological ACE inhibitor
composition and a topical novel renin inhibitor
composition.
Dosage leyels of the actiye compounds in the
compositions of theinvention may be yaried so as to obtain a desired therapeutic response depending on the route of administration, seyerity of the disease and the response of the patient.
Topical, ophthalmic and systemic administration of steroidal antiinflammatory agents can cause an increase in intraocular pressure. The increase in intraocular pressure can be reduced by the administration of a novel renin inhibiting compound of theinvention. Steroidal
antiinflammatory agents include hydrocortisone, cortisone, prednisone, prednisolone, dexamethasone,
methylprednisolone, triamcinolone, betamethasone,
alclometasone, flunisolide, beclomethasone, clorocortolone, diflorasone, halcinonide, fluocinonide, fluocinolone, desoximetasone, medrysone, paramethasone, and fluorometholone, and their pharmaceutically acceptable salts and esters. Preferred steroidal antiinflammatory agents are hydrocortisone, prednisolone, dexamethasone, medrysone and fluorometholone and their pharmaceutically acceptable salts and esters. The novel renin inhibitor is administered after use of a steroidal antiinflammatory agent or at the same time, causing reduction and/or control of intraocular pressure.
Various combinations of a topical or oral or
injectible dosage form of a steroidal antiinflammatory agent and a topical or oral dosage form of the novel renin inhibitor may be used. A preferred combination comprises a topical steroidal antiinflammatory and a topical novel renin inhibitor. More preferred- is a topical ophthalmic dosage form comprising both a steroidal antiinflammatory and a novel renin inhibitor.
When the steroidal antiinflammatory agent and the novel renin inhibitor are administered as separate
compositions the presentinvention relates to a kit
comprising in two separate containers a pharmaceutically acceptable steroidal antiinflammatory agent composition and a pharmaceutically acceptable novel renin inhibitor
composition, in a single package. A preferred kit
comprises a steroidal antiinflammatory composition and a topical novel renin inhibitor composition. A most
preferred kit comprises a topical ophthamological steroidal antiinflammatory composition and a topical ophthamological novel renin inhibitor composition.
The combination composition of theinvention may contain from about 0.00001 to 1.0 (w/v) percent of the novel renin inhibitor for combined or separate topical administration. More preferably the amount of the novel renin inhibitor is about 0.00001 to 0.1 (w/v) percent of the composition. The amount of the novel renin inhibitor in a unit dosage form for topical administration to the eye is from about 5 ng to about 0.5 mg, preferably from about 5 ng to about 25 ng. The dose required will depend on the potency of the particular novel renin inhibitor, the seyerity of the intraocular pressure increase and the response of the indiyidual patient.
The combination composition of theinvention may contain from about 0.05 to 1.5 (w/v) percent of the
steroidal antiinflammatory for combined or separate topical administration. The amount of the steroidal
antiinflammatory in a unit dosage form for topical
administration to the eye is from about 20 ug to about 600 ug. The dose required will depend on the potency of the particular steroidal antiinflammatory, the seyerity of the disease and the response of the indiyidual patient.
When the steroidal antiinflammatory agent of the combination therapeutic method of the invention is
administered other than ophthalmically, appropriate doses are well known in the art.
The compositions of theinvention may include other therapeutic agents in addition to the novel renin
inhibitor, and other agents which reduce and/or control intraocular pressure.
The effect on intraocular pressure of the novel compounds of theinvention can be determined in rabbits by using the following method. Effects of Topically Administered Renin Inhibiting Compounds on Intraocular Pressure of Rabbits a. Method The antiglaucoma activity of the compounds was tested by measuring the effect on intraocular pressure in rabbits as described by Tinjum, A.M., Acta
Ophthalmologica, 50 , 677 (1972). Male albino, New Zealand rabbits were placed in restraining deyices and the
intraocular pressure was measured with an applamatic tonometer. Exactly 0.1 ml of an isotonic saline solution containing a test compound was instilled into the
conjuctiyal sac and the intraocular pressure was measured at 5, 15, 30, 60, 90, 120 and 180 minutes afterwards.
The presentinvention is also directed to the use of compounds of the formula I in combination with one or more antihypertensive agents independently selected from
diuretics, adrenergic blocking agents, yasodilators, calcium channel blockers, angiotensin conyerting enzyme (ACE) inhibitors, potassium channel actiyators and other antihypertensive agents.
Representatiye diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacirinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
Representatiye adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof. Representatiye yasodilators include hydralazme, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof.
Representatiye calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, yerapamil,
gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
Representatiye ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
Representatiye potassium channel actiyators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
Other representatiye antihypertensive agents include sympatholytic agents such as methyldopa, clonidine,
guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
Synergistic combinations of a compound of formula I with one or more of the above-mentioned antihypertensive agents are useful for the treatment of hypertension or congestive heart failure.
The compound of formula I and the antihypertensive agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage leyels of the actiye compounds in the compositions of theinvention may be yaried so as to obtain a desired therapeutic response depending on the route of administration, seyerity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. In addition, the presentinvention is directed to the use of a compound of formula I to inhibit retroyiral proteases and in particular to inhibit HIV-1 protease and HIV-2 protease. Compounds of formula I are useful for treatment or prophylaxis of diseases caused by
retroyiruses, especially acquired immune deficiency
syndrome or an HIV infection.
The antiyiral activity of compounds of theinvention can be demonstrated using the following method.
A mixture of 0.1 ml (4 X 106 cells/ml) of H9 cells and 0.1 ml (100 infectious units) of HIV-13B was incubated on a shaker for 2 h. The resulting culture was washed three times, resuspended into 2 ml of medium, and treated with 10 μl of the compound of the invention (5 mM in
dimethylsulfoxide). The control culture was treated in an identical manner except the last step was omitted. After incubation of the culture for eight days without change of medium, an aliquot (0.1 ml) of the supernatent was
withdrawn and incubated with fresh H9 cells on a shaker for 2 h. The resulting culture was washed three times,
resuspended into 2 ml of medium, and incubated. Virus infectiyity was determined using the Abbott HTLV-III antigen E.I.A. method (Paul, et al., J. Med. Virol., 22357 (1987)).
The foregoing is merely illustratiye of the invention and is not intended to limit theinvention to the disclosed compounds. Variations and changes which are obyious to one skilled in the art are intended to be within the scope and nature of theinvention which are defined in the appended claims.

Claims

CLAIMS What is claimed is:
1. A compound of the formula:
rein A is
(I) R5C (O) - (CH2) w- wherein
1 ) w is 0 to 4 and
2) R5 is
i) hydroxy,
ii) alkoxy,
iii) thioalkoxy,
iy) amino or
y) substituted amino;
(II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl;
(III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyl; or
(IV) R90- or R90NHC(O)- wherein R90 is a C1 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);
R1 is
(I) hydrogen,
(II) loweralkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) aryloxyalkyl,
(VII) thioaryloxyalkyl,
(VIIII) arylalkoxyalkyl,
(IX) arylthioalkoxyalkyl or
(X) a C1 to C3 straight or branched
carbon chain substituted by a substituent selected from
1) alkoxy,
2) thioalkoxy,
3) aryl and
6) heterocyclic;
X is
(I) CH2,
(II) CHOH,
(III) C (O) ,
(IV) NH,
(V) O,
(VI) S, (VII) S(O),
(VIII) sO2,
(IX) N(O) or
(X) -P(O)O-;
R3 is
(I) loweralkyl,
(II) haloalkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) alkoxyalkyl,
(VII) thioalkoxyalkyl,
(VIII) (alkoxyalkoxy) alkyl,
(IX) hydroxyalkyl,
(X) -(CH2)eeNHR12
wherein
1) ee is 1 to 3 and
2) R12 is
i) hydrogen,
ii) loweralkyl or
iii) an N-protecting group;
(XI) arylalkyl or
(XII) (heterocyclic) alkyl; and
T is a mimic of the Leu-Val cleavage site of
angiotensinogen;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
2. The compound of Claim 1 wherein R1 is loweralkyl, benzyl or phenethyl; X is O or NH; R3 is loweralkyl; and T is
wherein R4 is loweralkyl or cycloalkylmethyl and D is
( I)
wherein R73 is loweralkyl,
(II)
wherein
1) M is
i) O,
ii) S or
iii) NH;
2) Q is
i) O or
ii) S;
3) E is
i) O,
ii) S,
iii) CHR73 wherein R73 is
loweralkyl. iv) C=CH2 or
v) NR18 wherein R18 is
a) hydrogen,
b) loweralkyl,
c) hydroxyalkyl.
d) hydroxy.
e) alkoxy.
f) amino or
g) alkylamino;
and
4) G is
i) absent,
ii) CH2 or
iii) NR19 wherein R19 is
hydrogen or loweralkyl,
with the proyiso that when G is NR19, then R18 is loweralkyl or
hydroxyalkyl;
(III)
wherein
1) v is 0 or 1 and
2) R21 is
i) NH,
ii) O,
iii) S or
iv) SO2; or (IV) a substituted methylene group, 3. A compound of the formula
wherein A is
(I) R5C(O) -(CH 2)w wherein
1) w is 0 to 4 and
2) R5 is
i) hydroxy,
ii) alkoxy,
iii) thioalkoxy, iy) amino or
y) substituted amino;
(II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl;
(III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyl; or
(IV) R90- or R90NHC(O)- wherein R90 is a C1 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); R1 is
(I) hydrogen,
(II) loweralkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) aryloxyalkyl,
(VII) thioaryloxyalkyl,
(VIIII) arylalkoxyalkyl,
(IX) arylthioalkoxyalkyl or
(X) a C1 to C3 straight or branched
carbon chain substituted by a substituent selected from
1) alkoxy,
2) thioalkoxy,
3) aryl and
6) heterocyclic;
X is
(I) CH2,
(II) CHOH,
(III) C(O),
(IV) NH,
(V) O,
(VI) S.
(VII) S(O),
(VIII) SO2.
(IX) N(O) or
(X) -P(O)O-;
R3 is
(I) loweralkyl.
(II) haloalkyl. (III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) alkoxyalkyl,
(VII) thioalkoxyalkyl,
(VIII) (alkoxyalkoxy)alkyl,
(IX) hydroxyalkyl,
(X) -(CH2)eeNHR12
wherein
1) ee is 1 to 3 and
2) R12 is
i) hydrogen,
ii) loweralkyl or
iii) an N-protecting group;
(XI) arylalkyl or
(XII) (heterocyclic) alkyl;
R4 is
(I) loweralkyl,
(II) cycloalkylalkyl
(III) cycloalkenylalkyl or
(III) arylalkyl; and
D is
wherein R73 is loweralkyl.
wherein
1) M is
i) O,
ii) S or
iii) NH ;
2) Q is
i) O or
ii) S;
3) E is
i) O,
ii) S,
iii) CHR73 wherein R73 is loweralkyl, iv) C=CH2 or v) NR18 wherein R18 is a) hydrogen.
b) loweralkyl.
c) hydroxyalkyl, d) hydroxy.
e) alkoxy.
f) amino or
g) alkylamino;
and
4) G is
i) absent.
ii) CH2 or iii) NR19 wherein R19 is
hydrogen or loweralkyl,
with the proyiso that when G is NR19, then R18 is loweralkyl or
hydroxyalkyl;
(III)
wherein
1) v is 0 or 1 and
2) R21 is
i) NH,
ii) O,
iii) S or
iy) SO2; or
(IV) a substituted methylene group;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
4. The compound of Claim 3 wherein D is
(a) -CH(OH)CH2CH(CH3)2,
wherein M is O, S or NH; Q is O or S; E is O, S, C=CH2, CHR73 wherein R73 is loweralkyl, or NR18 wherein R18 is hydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino or alkylamino; and G is absent, CH2 or NR19 wherein R19 is hydrogen or loweralkyl, with the proyiso that when G is NR19, then R18 is loweralkyl or hydroxyalkyl, or
(c) -CH2CH(R22) C(O)NHR23 wherein R22 is loweralkyl and R23 is (heterocyclic) alkyl; and
A is R5C(O)- wherein R5 is selected from the group
consisting of:
wherein aa is 1 to 5 and R6 and R7 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.
wherein dd is 1 to 5,
and
18) R8-Z- wherein
Z is O, S or NH and R8 is a C1 to C6 straight or branched carbon chain substituted by a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, phenyl and substituted phenyl;
wherein R9 is
1) O,
2 ) S,
3 ) SO2 or
4 ) C=O ; or
wherein R1 0 is
1 ) hydrogen,
2) loweralkyl,
3) an N-protecting group or
4) R11-C(O)- wherein R11 is
aminoalkyl, (N-protected) aminoalkyl, 1-amino-2-phenylethyl or
1-(N-protected) amino-2-phenylethyl.
5. A compound selected from the group consisting of: 2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethoxyhexanoic acid amide of 3-(1-imidazolyl) propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide;
2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethoxyhexanoic acid amide of 3-(dimethylamino) propyl 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide;
2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethoxyhexanoic acid amide of 3-(4-morpholinyl) propyl 5 (S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)- isopropylhexanamide,:
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl)-2- phenylethyi-L-norleucyl amide of 3-(1-imidazolyl) propyl 5 (S) -amino-6-cyclohexy1-4 (S) -hydroxy-2 (S) - isopropylhexanamide; and
N-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl) carbonyl) -2- phenylethyl-L-norleucyl amide of 3-(4-morpholinyl) propyl 5(S)-amino-6-cyclohexyl-4(S)-h-ydroxy-2(S)- isopropylhexanamide; or a pharmaceutically acceptable salt, ester or prodrug thereof.
6. 2(S)-(1(S)-(4-(methyoxymethoxy)piperidin-1- yl) carbonyl) -2-phenylethoxyhexanoic 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.
7. A pharmaceutical composition for inhibiting renin, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
8. A method for inhibiting renin comprising
administering to a host in need of such treatment a
therapeutically effective amount of a compound of claim 1.
9. A pharmaceutical composition for treating
hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
10. A method for treating hypertension or congestive heart failure comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1.
11. A compound of the formula:
A is
(I) R5C(O)-(CH2)w- wherein
1) w is 0 to 4 and
2) R5 is
i) hydroxy,
ii) alkoxy,
iii) thioalkoxy, iy) amino or
v) substituted amino;
(II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl;
(III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyl; or
(IV) R90- or R90NHC(O)- wherein R90 is a C1 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) . R 1 is
(I ) hydrogen,
(II) loweralkyl,
(III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) aryloxyalkyl,
(VII) thioaryloxyalkyl,
(VIIII) arylalkoxyalkyl,
(IX) arylthioalkoxyalkyl or
(X) a C1 to C3 straight or branched
carbon chain substituted by a substituent selected from
1) alkoxy,
2) thioalkoxy,
3) aryl and
6) heterocyclic.
X is
(I) CH2,
(II) CHOH,
(III) C(O),
(IV) NH,
(V) O,
(VI) s.
(VII) S(O),
(VIII) SO2,
(IX) N(O) or
(X) -P(O)O-.
R3 is
(I) loweralkyl,
(II) haloalkyl, (III) loweralkenyl,
(IV) cycloalkylalkyl,
(V) cycloalkenylalkyl,
(VI) alkoxyalkyl,
(VII) thioalkoxyalkyl,
(VIII) (alkoxyalkoxy) alkyl,
(IX) hydroxyalkyl,
(X) -(CH2)eeNHR12
wherein
1) ee is 1 to 3 and
2) R12 is
i) hydrogen,
ii) loweralkyl or
iii) an N-protecting group;
(XI) arylalkyl or
(XII) (heterocyclic) alkyl;
or an acid halide or activated ester deriyatiye thereof,
12. A compound of the formula
wherein A is 4-methoxymethoxymσrpholin-l-ylcarbonyl, R1 is arylalkyl, X is O, NH or S and R3 is loweralkyl,
cycloalkylalkyl, arylalkyl or heterocyclic alkyl; or an acid halide or activated ester derivativethereof.
13. A compound of the formula wherein A is 4-methoxymethoxymorpholin-1-ylcarbonyl, R1 is benzyl, X is O and R3 is n-butyl; or an acid halide or activated ester derivativethereof.
14.. A method for treating glaucoma or reducing and/or controlling intraocular presure, comprising
administering to a patient in need a therapeutically effective amount of a compound of Claim 1.
15. A method for inhibiting a retroyiral protease, comprising administering to a patient in need a
therapeutically effective amount of a compound of Claim 1.
16. A method for treating a retroyiral infection, comprising administering to a patient in need a
therapeutically effective amount of a compound of Claim 1.
17. A method for treating hypertension or congestive heart failure comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Claim 1 and another antihypertensive agent.
18. A pharmaceutical composition for treating hypertension or congestive heart failure, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1 and another antihypertensive agent.
19. A process for the preparation of the compound of
Claim 1 comprising coupling a carboxylic acid of the formula or an acid halide or an activated ester derivativethereof wherein A, R1, X and R3 are as defined herein with an amine represented by H-T wherein T is as defined herein.
20. The process of Claim 18 wherein H-T is
EP19890911665 1988-10-04 1989-10-03 Non-peptide renin inhibitors Pending EP0437508A4 (en)

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Title
NATURE vol. 299, 7 October 1982, pages 555-557, Basingstoke, GB; M. SZELKE et al.: "Potent new inhibitors of human renin" *
NATURE vol. 303, 5 May 1983, pages 81-84, Basingstoke, GB; J. BOGER et al.: "Novel renin inhibitors containing the amino acid statine" *
See also references of WO9003971A1 *

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AU4416389A (en) 1990-05-01
AU639212B2 (en) 1993-07-22
WO1990003971A1 (en) 1990-04-19
EP0364804A1 (en) 1990-04-25
DK59991D0 (en) 1991-04-04
IL91780A (en) 1995-08-31
IL91780A0 (en) 1990-06-10
CA1337909C (en) 1996-01-09
EP0437508A4 (en) 1991-11-06
JPH04505608A (en) 1992-10-01
KR900701759A (en) 1990-12-04
DK59991A (en) 1991-04-04
NZ230894A (en) 1991-07-26

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