EP0258289A1 - Analogues de peptides - Google Patents

Analogues de peptides

Info

Publication number
EP0258289A1
EP0258289A1 EP87900949A EP87900949A EP0258289A1 EP 0258289 A1 EP0258289 A1 EP 0258289A1 EP 87900949 A EP87900949 A EP 87900949A EP 87900949 A EP87900949 A EP 87900949A EP 0258289 A1 EP0258289 A1 EP 0258289A1
Authority
EP
European Patent Office
Prior art keywords
loweralkyl
boc
mmol
gave
hydroxy
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.)
Withdrawn
Application number
EP87900949A
Other languages
German (de)
English (en)
Other versions
EP0258289A4 (en
Inventor
Joseph Dellaria
Anthony K. L. Fung
Dale J. Kempf
Jay Richard Luly
Jacob John Plattner
Saul Howard Rosenberg
Hing L. Sham
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
Priority claimed from US06/946,883 external-priority patent/US4857507A/en
Priority claimed from US06/946,881 external-priority patent/US4826815A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0258289A1 publication Critical patent/EP0258289A1/fr
Publication of EP0258289A4 publication Critical patent/EP0258289A4/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/12—Oxygen or sulfur 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • 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
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel organic compounds which inhibit renin, processes for making such compounds, synthetic intermediates employed in these processes and methods of treating hypertension with such compounds.
  • Renin is a proteolytic enzyme synthesized and stored principally in a specific part of the kidney called the juxtaglomerular apparatus. Any of three different physiologic circumstances may cause the release of renin into the circulation: (a) a decrease in the blood pressure entering or within the kidney itself; (b) a decrease in the blood volume in the body; or (c) a fall in the concentration of sodium in the distal tubules of the kidney.
  • renin When renin is released into the blood from the kidney, the renin-angiotensin system is activated, leading to vasoconstriction and conservation of sodium, both of which result in increased blood pressure.
  • the renin acts on a circulating protein, angiotensinogen, to cleave out a fragment called angiotensin I (Al).
  • Al itself has only slight pharmacologic activity but, after additional cleavage by a second enzyme, angiotensin converting enzyme (ACE), forms the potent molecule angiotensin II (All).
  • ACE angiotensin converting enzyme
  • the major pharmacological effects of AII are vasoconstriction and stimulation of the adrenal cortex to release aldosterone, a hormone which causes sodium retention.
  • AII is cleaved by an aminopeptidase to form angiotensin III (AIII), which compared to AII, is a less potent vasoconstrictor but a more potent inducer of aldosterone release.
  • AIII angiotensin III
  • Inhibitors of renin have been sought as agents for control of hypertension and as diagnostic agents for identification of cases of hypertension due to renin excess.
  • ACE angiotensin I
  • AI angiotensin I
  • kinins which cause such undesirable side effects as pain, "leaky” capillaries, prostaglandin release and a variety of behavioral and neurologic effects.
  • ACE inhibition leads to the accumulation of AI.
  • AI has much less vasoconstrictor activity than AII, its presence may negate some of the hypotensive effects of the blockade of AII synthesis.
  • A is hydrogen; loweralkyl; arylalkyl; OR 20 or SR 20 wherein R 20 is hydrogen, loweralkyl or aminoalkyl ; NR 21 R 22 wherein R 21 and R 22 are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl;
  • B is NH, alkylamino, S, O, CH 2 , NHCH 2 or CHOH and R 23 is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) amino, [(dialkylamino)alkyl](alkyl)amino, (dihydroxyalkyl) (alkyl)amino, carboxyalkyl, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, alkoxycarbonylalkyl, (N-protected) (alkyl)-aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl or a substituted or unsubstituted heterocyclic;
  • U is CH 2 or NR 2 , provided that when W is CHOH then U is CH 2 ;
  • R 1 is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, 4-hydroxybenzyl, ⁇ , ⁇ -dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R 1 is phenoxy, thiophenoxy or anilino, B is CH 2 or CHOH or A is hydrogen;
  • R 3 is loweralkyl, loweralkenyl, [(alkoxy)alkoxy]loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;
  • R 4 is
  • R 5 is hydrogen or loweralkyl ; is loweralkyl , cycloalkylmethyl , benzyl , or CH 2 R 24 , where R 24 is selected from 1,3-dioxan-2-yl; 1,3-dioxolan-2-yl, 1,3-dithiolan-2-yl or 1,3-dithian- 2-yl; R 7 , R 8 and R 9 are hydrogen or loweralkyl and may be the same or different; V is NH, O, S, SO, SO 2 , or CH 2 ; R 10 is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or an N-protecting group, or V and R 10 taken together are N 3 ; with the proviso that R 10 may be an N-protecting group only when V is NH;R 13 is CHOH or CO; R 14 is CH 2 , CF 2 or CF with the proviso that when R 13 is CO ,
  • R 14 when R 14 is CF 2 , R 15 is CH 2 ; M is O, S, SO, SO 2 , NR 26 wherein R 26 is hydrogen or loweralkyl, NR 27 SO 2 or NR 27 CO wherein
  • R 27 is hydrogen or loweralkyl, or M and R 10 taken together are N 3 ;
  • R 16 is CH 2 , CF 2 or CHR 45 where R 45 is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, alkaryloxy or thioalkyl
  • R 17 is hydrogen or loweralkyl;
  • R 18 is loweralkyl or lipophilic or aromatic amino acid side chains;
  • P is hydrogen, loweralkyl or -CH 2 OR 28 , wherein R 28 is hydrogen, loweralkyl or alkaryl;
  • R 11 is hydrogen or hydroxy; n is 0 or 1; when n is O, T is alkylidene or alkylidene oxide; when n is 1, S is hydrogen or hydroxy and T is loweralkyl, hydroxyalkyl, aminoalkyl, haloalkyl, or azidoalkyl;
  • R 19 is hydrogen or loweralkyl;
  • R 12 is hydrogen, loweralkyl, alkyl-
  • the chiral centers of the compounds of the invention may have either the “R” or “S” configuration but preferably have an “S” configuration except where noted.
  • the terms "S” and “R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, pivaloyl, t-butylacetyl, t-butyloxycarbonyl(Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or D-aminoacyl residue, which may itself by N-protected similarly.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, 2-methylhexyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
  • arylalkyl refers to an unsubstituted or substituted aromatic ring appended to an alkyl radical including but not limited to benzyl, 1- and 2-naphthylmethyl, halobenzyl and alkoxybenzyl.
  • alkylamino refers to a loweralkkyl radical appended to an NH radical.
  • cycloalkyl refers to an aliphatic ring having 4 to 7 carbon atoms.
  • cycloalkylmethyl refers to a cycloalkyl group appended to a methyl radical, including but not limited to cyclohexylmethyl.
  • aryl refers to a substituted or unsubstituted aromatic ring including but not limited to phenyl, naphthyl, halophenyl and alkoxyphenyl.
  • carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
  • alkoxy and thioalkoxy refer to R 29 O- and R 29 S-, respectively, wherein R 29 is a loweralkyl group.
  • arylalkoxy refers to an aryl appended to an alkoxy radical.
  • arylalkoxyalkyl refers to an aryalkoxy appended to a loweralkyl radical.
  • dialkylamino refers to -NR 30 R 31 wherein R 30 and R 31 are independently selected from loweralkyl groups.
  • N-protected aminoalkyl refers to NHR 32 is appended to a loweralkyl group, where R 32 is an N-protecting group.
  • heterocyclicalkyl refers to a heterocyclic group appended to a loweralkyl radical, including but not limited to imidazoylalkyl.
  • alkenyl and alkenyloxy refer to R 35 - and R 35 O-, respectively wherein R 35 is an unsaturated alkyl group.
  • hydroxyalkoxy refers to -OH appended to alkoxy radical.
  • dihydroxyalkoxy refers to an alkoxy radical which is disubstituted with -OH radicals.
  • (hydroxyalkyl) (alkyl) amino refers to -NR 36 R 37 wherein R 36 is hydroxyalkyl and R 37 is loweralkyl.
  • (dihydroxyalkyl)(alkyl)amino refers to -NR 38 R 39 wherein R 38 is dihydroxyalkyl and R 39 is loweralkyl.
  • dihydroxyalkyl refers to a loweralkyl radical which is disubstituted with -OH radicals.
  • (dialkylamino)alkyl)(alkyl)amino refers to -NR 40 R 41 wherein R 40 is an alkyl radical which is substituted with a dialkylamino radical and R 41 is loweralkyl.
  • carboalkoxyalkyl refers to a loweralkyl radical which is substituted at any position with one or more carboalkoxy groups and includes but is not limited to carboalkoxymethyl, carboalkoxyethyl, carboalkoxypropyl, carboalkoxybutyl and carboalkoxypentyl.
  • carboalkoxy group refers to an acyl radical which has appended to it an alkoxy group and includes but is not limited to methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl and t-butyloxycarbonyl.
  • alkylaminoalkyl refers to NHR 42 appended to a loweralkyl radical, wherein R 42 is a loweralkyl group.
  • (N-protected)(alkyl)aminoalkyl refers to NR 32 R 42 , which is appended to a loweralkyl radical, wherein R 32 and R 42 are as defined above.
  • dialkylaminoalkyl refers to NR 43 R 44 appended to a loweralkyl radical wherein R 43 and R 44 are independently selected from loweralkyl.
  • (thioalkoxy)alkyl refers to thioalkoxy appended to a loweralkyl radical.
  • aminoalkyl as .used, herein refers to -NH 2 appended to a loweralkyl radical.
  • heterocyclic ring or “heterocyclic” as used herein refers to any 5-, 6-, 9- or 10-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; having various degrees of unsaturation; wherein the nitrogen and sulfur heteroatoms may optionally be quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred.
  • Preferred heterocyclics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiazolidinyl, thiazolyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
  • Saturated heterocyclics may be unsubtituted or mono- or di-substituted with hydroxy, oxo, amino, alkylamino, dialkylamino or loweralkyl.
  • Unsaturated heterocyclics may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino or loweralkyl.
  • the most preferred heterocyclics are as follows:
  • n 1 or 2 and X is N, NH, O, S, provided that X is the point of connection only when X is N,
  • Y is NH, N-loweralkyl, O, S, or SO 2 , or
  • Z ⁇ is N, O, or S and not the point of connection and Z 2 is N when it is the point of connection and NH, O or S when it is not the point of connection.
  • lipophilic or aromatic amino acid side chains refers to those amino acid side chains which have an affinity for lipids or have an aromatic ring and include but are not limited to benzyl, isobutyl, isopropyl, sec-butyl, imidazol-4-yl- methyl, p-hydroxybenzyl, 1- and 2-naphthylmethyl, (pyrazolyl)-methyl, (thiazolyl)methyl, and cyclohexylmethyl.
  • hydrophilic amino acid side chain refers to those amino acid side chains which have an affinity for water and include but are not limited to, those of serine, threonine, allothreonine, homoserine, cysteine, ornithine, arginine, and glutamine.
  • General reference to amino acid side chains in both the description and claims herein is to be taken as reference to such, whether naturally occurring in protein or not, and to both D- and L-forms.
  • alkylidene refers to a straight or branched chain alkyl radical which is attached via a carbon-carbon double bond and includes but is not limited to methylidene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 2-propylidene, 2-butylidene, 2-pentylidene, 3-pentylidene, 3-hexylidene, 3-heptylidene, and 4-heptylidene.
  • alkylidene oxide refers to an epoxide moiety which is derived from an alkylidene group.
  • thioalkyl, haloalkyl or azidoalkyl used herein refer to an alkyl radical which has appended to it a thio, halo or azido radical, respectively.
  • Al “His”, “Leu”, “Phe”, “Tyr”, “Cys”, “Gly”, “Lys”, Sar”, “Ser”, “Thr” and “Pro” as used herein refer to alanine, histidine, leucine, phenylalanine, tyrosine, cysteine, glycine, lysine, sarcosine, serine, threonine, and proline, respectively.
  • Example 5 4(S)-Isobutyl-5(S)-[2-(isoamylmercapto)ethyl]- 2-oxazolidinone Using the procedure of Example 4 but changing phenethyl mercaptan to isoamyl mercaptan, gave the desired compound in 95% yield.
  • Example 6 4( S)-Isobutyl-5(S)-[2-(isobutylmercapto)ethyl]- 2-oxazolidinone Using the procedure of Example 4 but changing phenethyl mercaptan to isobutyl mercaptan, gave the desired compound in 96% yield.
  • Example 7 (S)-Isobutyl-5(S)-[2-(isopropylmercapto)ethyl]- 2-oxazolidinone Using the procedure of Example 4 but changing phenethyl mercaptan to isopropyl mercaptan, gave the desired compound in 93% yield.
  • Example 8 4(S)-Isobutyl-5(S)-[2-(phenethylsulfonyl)ethyl]- 2-oxazolidinone
  • methylene chloride 6 mL
  • m-chloroperoxybenzoic acid 0.756 g (3.5 mmol)
  • the methylene chloride solution was washed successively with aqueous NaHSO 3 and aqueous NaOH.
  • the organic layer was dried and evaporated to a solid product. Trituration with hexane/ether (50/50) gave 495 mg (92%) of product, m.p.
  • Example 11 (3S,4S)-4-Amino-3-hydroxy-1-isoamylmercapto- 6-methylheptane Using the procedure of Example 10 with the resultant compound of Example 5, gave the desired compound, m.p. 64-65°C.
  • Example 12 ( 3S,4S)-4-Amino-3-hydroxy-6-methyl- 1-phenethylsulfonyIneptane Using the procedure of Example 10 with the resultant compound of Example 8, gave the desired compound, m.p. 153-154°C.
  • Example 13 (3S , 4S)-4-Amino-3-hydroxy- 1-isoamylsulfonyl-6-methylheptane Using the procedure of Example 10 with the resultant compound of Example 9, gave the desired compound, m.p. 125-126°C.
  • Example 16 Using the procedure of Example 16 with the resultant compound of Example 11, gave the desired compound, m.p. 137-138°C.
  • Example 8 Using the procedure of Example 8 with the resultant compound of Example 16, gave the desired compound, m.p. 186-187°C. Anal. calcd. for C 33 H 49 N 3 O 7 S: C, 62.74; H, 7.82; N, 6.65.
  • Example 17 Using the procedure of Example 8 but, using only one molar equivalent of m-chloroperoxybenzoic acid and conducting the reaction at 0°C, the resultant compound from Example 17 was converted to the desired compound.
  • Example 21 Boc-Phe-Ala Amide of (3S,4S)-4-Amino- 3-hydroxy-6-methyl-1-phenoxyheptane Using the procedure of Example 16 with the resultant compound from Example 15, gave the desired compound.
  • Example 22 Boc-Phe-His Amide of (3S,4S)-4-Amino-3-hydroxy- 1-isoamylsulfonyl-6-methylheptane
  • Boc-Phe-His-OH 153 mg, 0.38 mmol
  • dimethylformamide 3 mL
  • Hydroxybenzotriazole HOBT, 77 mg, 0.57 mmol
  • DDC dicyclohexylcarbodiimide
  • Example 10 Using the procedure of Example 10 with the resultant compound of Example 28, gave the desired compound in 73% yield, m.p. 26°C.
  • the desired deketalized product was obtained as follows. A solution of the ketal (400 mg) was stirred for 24 h in 37 mL acetic acid/water/tetrahydrofuran (3/1/1). The solvents were evaporated under reduced pressure and the residue was triturated with hexaneether (65:35) to give 280 mg (76%) of product; m.p. 137-138°C.
  • Example 32 [(4-Morpholinyl)carbonyl]-Phe Methyl Ester A suspension of L-phenylalanine methyl ester hydrochloride (6 g) in toluene (125 mL) was heated to 100°C while phosgene gas was bubbled into the reaction mixture. After approximately 1.5-2 h, the mixture became homogeneous. The passage of phosgene was continued for an additional 15 min, keeping the temperature at 90-100°C. The toluene was then evaporated and the residue chased several times with benzene.
  • Example 33 [(4-Morpholinyl)carbonyl]-Phe-OH
  • a solution of lithium hydroxide (0.174 g, 4.15 mmol) in water (7.5 mL).
  • the reaction mixture was diluted with cold water and extracted 2X with ether.
  • the aqueous portion was acidified with 6N HCl and extracted with ether.
  • the organic extract was washed with brine and evaporated to give an 87% yield of product as a viscous liquid.
  • Example 35 [(4-Morpholinyl)carbonyl]-Phe-(Me)His Amide of (3S,4S)-4-Amino-3-hydroxy- 6-methyl-1-phenethylsulfonylheptane
  • the product from Example 34 was deprotected with trifluoroacetic acid/methylene chloride (1:1) and the resultant amine coupled to the product from Example 33 using the method of Example 34. There was obtained a 50% yield of the title compound.
  • Example 36 3-3enzyloxycarbonylamino-3-methylbutanoic Acid
  • Example 38 Cbz-[(ß,ß-di-Me)-ß-Ala]-Phe-OH
  • a solution of Cbz-[( ⁇ ,ß-di-Me)-ß-Ala]-Phe-OMe 1.5 g, 3.63 mmol
  • lithium hydroxide 0.174 g, 4.15 mmol
  • water 7.5 mL
  • the reaction mixture was diluted with cold water and extracted 2X with ether.
  • the aqueous portion was acidified with 6N HCl and extracted with ether.
  • the organic extract was washed with brine and evaporated to give an 87% yield of product as a viscous liquid.
  • Example 38 The product from Example 38 was coupled to the product from Example 31 using the procedure described in Example 22. There was obtained a 50% yield of the title compound.
  • Example 40 H-[(ß,ß-di-Me)-ß-Ala]-Phe-His Amide of (3S,4S)- 4-Amino-3-hydroxy-6-methyl-1-phenethylsulfonylheptane
  • acetic acid 5 mL
  • Pd/C 0.1 g
  • Fi ltration , extraction of the catalyst with acetic acid, and evaporation of the combined acetic acid solutions gave a residue which was dissolved in H 2 O (10 mL) and lyopholized to provide 75% of the desired product.
  • Example 42 Cbz-[( ⁇ , ⁇ -di-Me)-ß-Ala]-(OMe)Tyr-OCH 3
  • oxalyl chloride 0.757 g, 5.97 mmol
  • dimethylformamide 30 uL
  • the reaction mixture was cooled to 0°C and treated successively with OMe-tyrosine methyl ester hydrochloride (1.465 g, 5.97 mmol) and N-methylmorpholine (1.81 g, 17.9 mmol).
  • Example 44 H-[( ⁇ , ⁇ -di-Me)-ß-Ala]-(OMe)Tyr-His Amide of (3S,4S)- 4-Amino-3-hydroxy-6-methyl-1-phenethylsulfonylheptane Using the procedures described in Examples 39 and 40, the product from Example 43 was converted to the desired product.
  • Example 45 2(S)-[[(4-Morpholinyl)carbonyl]oxy]- 3-phenylpropionic Acid Methyl Ester
  • L-phenyllactic acid methyl ester 3.2 g
  • 150 mL of 12.5% phosgene in toluene 25 drops of dimethylformamide.
  • the solvent was evaporated and the residue chased several times with benzene.
  • the resulting product was dissolved in methylene chloride (50 mL), cooled to 0°C and treated by dropwise addition with 3.86 g (0.044 mol) of morpholine.
  • Example 46 2(S)-[(4-Morpholinyl)carbonyl]oxy-3-phenylpropionic Acid Using the hydrolysis procedure of Example 33, the title compound was obtained in 90% yield.
  • Example 48 3-t-Butyloxycarbonylamino-5-methylhex-1-ene
  • methyltriphenyl phosphonium bromide 10.97 g, 30.70 mmol
  • n-butyl lithium (19.8 mL of a 1.55 M hexane solution) dropwise over the course of 5 min.
  • the -78°C bath was replaced with a 0°C bath for .5 h, at which time the resulting orange solution was cooled again to -78°C.
  • Example 51 3-Amino-1-cyclohexylmercapto-2-hydroxy- 5-methylhexane Hydrochloride To a stirred solution of approximately 0.25 mmol of the resultant compound of Example 50 in methanol was added methanolic HCl (10 mL of approximately 0.75 M HCl). After 8 to 12 h, the solvent was evaporated, and the desired compound was used without further purification.
  • HOBT Hydroxybenzotriazole
  • DCC N,N'-dicyclohexylcarbodiimide
  • Example 52 The resultant compound of Example 52 was treated with methanolic HCl according to the procedure used in Example 51, yielding the corresponding deprotected HCl salt which was used as described below without further purification.
  • methanolic HCl methanolic HCl according to the procedure used in Example 51, yielding the corresponding deprotected HCl salt which was used as described below without further purification.
  • N-methylmorpholine 8.0 1, 0.0725 mmol
  • isobutylchloroformate 9.4 1, 0.0725 mmol
  • Example 57 Benzyl (2R)-2-acetyl-3-phenylpropionate
  • Example 52 The resultant compound from Example 52 was treated with ethanolic HCl according to the procedure in Example 51, yielding the corresponding HCl salt which was used as described below without further purification. Coupling of the resultant compound from Example 60 with the above salt was performed, in analogy to the procedure of Example 52, to provide the desired compound.
  • Example 64 Using the procedure from Example 64 with the resultant compound from Example 63 provided the desired compound.
  • Example 70 Boc-His Amide of 3-Amino-4-cyclohexyl- 2-hydroxy-1-isopropylsulfonylbutane
  • the resultant compound of Example 69 was deprotected in analogy to Example 51 and coupled to Boc-His OH according to Example 52 to provide the desired compound.
  • Mass spectrum: (M) + 514.
  • Example 71 Boc-Leu Amide of 3-Amino-4-cyclohexyl-2-hydroxy-1- isopropylsulfonylbutane
  • the resultant compund of Example 69 was deprotected in analogy to Example 51 and coupled to BocLeuOH in analogy to Example 53 to provide the desired compound.
  • Mass spectrum: (M+H) + 491.
  • Example 73 (2R)-2-Benzyl-3-(morpholinocarbonyl)- propionyl-Leu Amide of3-Amino-4-cyclohexyl- 2-hydroxy-1-isopropylsulfonylbutane Using the procedure of Example 65 with the resultant compound of Example 71 provided the desired compound.
  • Example 74 Using the procedure of Example 74 with the resultant compound of Example 71 in lieu of the resultant compound from Example 70, provided the desired compound.
  • Example 76 (3S,4S)-3-hydroxy-4-t-butyloxycarbonyl- amino-5-cyclohexylpentanenitrile
  • acetonitrile (0.25 mL, 4.4 mmol).
  • 2(S)-t-butyloxycarbonylamino3-cyclohexylpropanal (0.76 g, 2.98 mmol) in tetrahydrofuran (5 mL) pre-cooled to -78°C.
  • Example 78 The resultant compound from Example 78 (36.9 mg, 0.0926 mmol) was stirred for 1 h in 4 M HCl in dioxane. The solvent was removed and dimethylformamide (0.5 mL) and N-methylmorpholine (23 uL, 0.21 mmol) were added.
  • Example 80 Boc-His Amide of (3S,4S)-1-(3-Methylbutylcarbonylamino)- 3-hydroxy-4-amino-5-cyclohexylpentane Using the procedure of Example 79 with the resultant compound of Example 78 and Boc-His-OH rather than Boc-Phe-His-OH, gave the desired compound.
  • Example 81 (3S,4S)-1-(2-Propylsulfonylamino)-3-hydroxy-4-t- butyloxycarbonylamino-5-cyclohexylpentane Using the procedure of Example 78 employing the resultant compound from Example 77 and isopropylsulfonyl chloride instead of 4-methylpentanoyl chloride afforded the desired compound.
  • Example 82 Boc-Phe-His Amide of (3S,4S)-1-(2-Propylsulfonylamino)- 3-hydroxy-4-amino-5-cyclohexylpentane Using the procedure of Example 79 employing the resultant compound from Example 81 gave the desired compound, m.p. 174-177°C.
  • Boc-Phe-dl-3-pyrazolylalanine methyl ester (0.210 g, 0.505 mmol) in dioxane (1.5 mL) and water (1.0 mL) was treated with lithium hydroxide monohydrate (0.0272 g, 0.648 mmol), stirred at 25°C for 30 min and quenched with 0.32 mL 2 M HCl. The mixture was poured into chloroform, washed with water, dried over Na 2 SO 4 and evaporated to afford 0.184 g (91%) of the desired compound.
  • Example 79 Using the procedure of Example 79 with the resultant compound from Example 78 and using the resultant compound from Example 84 rather than Boc-Phe-His-OH afforded the desired compound.
  • Example 91 (3R,4S)-4-Cyclohexylmethyl-5-(2-isopropylmercapto-1,1- difluoroethyl)-2-oxazolidinone
  • NaH 85.0 mg, 2.22 mmol, 60% in oil, hexane washed
  • DMF 4 mL
  • isopropylmercaptan (0.40 mL, 4.3 mmol).
  • the resultant compound from Example 89 373.4 mg, 1.09 mmol
  • DMF 4 mL
  • Example 93 (3R,4S)-3-Hydroxy-4-amino-2,2-difluoro- 1-azido-5-cyclohexyIpentane
  • dioxane 4.5 mL
  • water 3 mL
  • Ba(OH) 2 8 H 2 O 0.25 g, 0.79 mmol
  • the mixture was heated at reflux for 13 h.
  • the mixture was filtered, and the filtrate was concentrated, partitioned between water and ether, and extracted with ether.
  • the organic extract was dried over Na 2 SO 4 and evaporated to afford 108 mg (100%) product as an oil.
  • Mass spectrum: FAB, (M+H) + 263.
  • Example 94 (3R,4S)-3-Hydroxy-4-amino-2,2-difluoro-1-isopropyloxy- 5-cyclohexylpentane Using the procedure of Example 93 with the resultant compound from Example 92 afforded the desired compound.
  • Example 96 Boc-Phe-Leu Amide of (3R,4S)-3-hydroxy- 4-amino-2,2-difluoro-1-isopropyloxy-5-cyclohexylpentane Using the procedure of Example 95 with the resultant compound from Example 94 afforded the desired product.
  • Example 95 Using the procedure of Example 95 and the resultant compound from Example 91 which had been hydrolyzed to the free amine according to the procedure in Example 93 afforded the desired product.
  • Example 97 To the resultant compound from Example 97 (50.0 mg, 0.0762 mmol) in CH 2 Cl 2 (2 mL) was added m-chloroperbenzoic acid (42.0 mg, 0.20 mmol, 80% pure). After 1 h the mixture was diluted with ethyl acetate, washed sequentially with cold 10% aqueous Na 2 SO 3 solution, saturated aqueous NaHCO 3 solution and brine, then dried over Na 2 SO 4 and evaporated. Chromatography on silica gel with ethyl acetate/ hexane mixtures provided 42.4 mg (81%) product as a solid.
  • Example 101 Using the procedure of Example 101 with the resultant compound from Example 100 afforded the desired product as a solid.
  • Example 101 Using the procedure of Example 101 with the resultant compound from Example 96 provided the desired product.
  • Example 104 Boc-Phe-Leu Amide of (4S)-3-oxo-4-amino-2,2-difluoro- 1-isopropylmercapto-5-cyclohexylpentane Using the procedure of Example 101 with the resultant compound from Example 97 provided the desired product as a solid.
  • Example 105 Boc-Phe-Leu Amide of (4S)-3-oxo-4-amino-2,2-difluoro-1- isopentylcarbonylamino-5-cyclohexylpentane Using the procedure of Example 101 with the resultant compound from Example 99 provided the desired product as a solid.
  • Example 106 (2S,3S)-1-Azido-3-t-butyloxycarbonylamino- 2-hydroxy-5-methylhexane
  • methanol 10 mL
  • sodium azide 2.4 mmol
  • ammonium chloride 1.8 mmol
  • the solvent was evaporated, and the residue was extracted with several portions of hot chloroform.
  • Example 107 (2S,3S)-1-Azido-3-t-butyloxycarbonylamino- 2-hydroxy-5-methylhexane
  • Example 106 The resultant compound of Example 106 (400 mg) dissolved in methanol containing added CHCl 3 was hydrogenated over 10% Pd/C (40 mg) with 3 atmospheres hydrogen. Filtration and evaporation gave the desired compound (305 mg).
  • Example 107 (1.0 mmol) and triethyl amine (2.0 mmol) in chloroform (10 mL) cooled to 0°C was added isovaleryl chloride (1.0 mmol) in CHCl 3 (2 mL). After 3 h, the solution was washed sequentially with 10% citric acid, saturated NaHCO 3 , and brine. Drying and evaporating provided the desired compound.
  • Example 67 The resultant compound from Example 67 was treated according to the procedure of Example 106 to give the desired compound.
  • Example 79 Using the procedure of Example 79 with the resultant compound from Example 108 gave the desired compound.
  • Example 109 Using the procedure of Example 79 with the resultant compound from Example 109 gave the desired compound.
  • Example 112 The resultant product of Example 112 (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 (MgSO 4 ), filtered and evaporated 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.
  • DMF dry dimethylformamide
  • Example 114 To the resultant compound from Example 114 (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 H 3 PO 4 , saturated NaHCO 3 solution and brine, then dried over Na 2 SO 4 and evaporated to afford 2.51 g (100%) of the desired compound.
  • Example 116 (3S,4S)-1,3-Dihydroxy-4-t-butyloxycarbonylamino- 5-cyclohexylpentane
  • THF tetrahydrofuran
  • 9-borabicyclo(3.3.1)nonane 4 mL, 2.3 mmol in THF
  • NaOH 280 mg, 7.0 mmol
  • 30% H 2 O 2 0.70 mL, 6.9 mmol
  • Example 118 (3S,4S)-1-Azido-3-hydroxy-4-t-butyloxycarbonylamino- 5-cyclohexylpentane
  • the resultant compound from Example 117 was reacted according to the procedure in Example 90 to give the desired compound.
  • DCI-MS: (M+H) 327.
  • Example 79 Using the procedure of Example 79 with the resultant compound from Example 118 gave the desired compound.
  • Lithium aluminum hydride (7.20 g, 189 mmol) in tetrahdyrofuran (THF, 300 mL) was heated to reflux and the resultant compound from Example 120 (17.0 g, 75.5 mmol) in THF (150 mL) was added dropwise over 10 min.
  • the mixture was relfuxed for 2 h, cooled, quenched sequentially with water (10 mL), 3 M NaOH (40 mL) and water (20 mL), then filtered and concentrated. The residue was dissolved in water which was washed with ether and evaporated. Bulb to bulb distillation of the residue afforded 2.0 g (25%) of the desired compound as an oil.
  • Example 136 To the resultant compound from Example 136 (1.53 g, 6.5 mmol) in dioxane (5 mL) at 0°C was added the resultant compound from Example 121 (0.684 g, 6.5 mmol). The reaction was stirred at 0°C for 1 h then at room temperature for 1 h, evaporated and chromatographed on silica gel with 5% methanol in chloroform to afford 1.855 g (84%) of the desired product as an oil.
  • Example 123 (N-Methyl-2,3-dihydroxypropylamino)carbonyl- (O-methy1)tyrosine
  • Example 125 (2R)-3-(N-Methyl-2,3-dihydroxypropylamino)carbonyl- 2-benzylpropionic Acid
  • the resultant compound from Example 124 200 mg, 0.523 mmol
  • 10% Pd on carbon 200 mg
  • methanol 10 mL
  • the reaction was filtered and evaporated to afford 148 mg (97%) of the desired product as an oil.
  • Example 126 Dimethylaminocarbonyl-(O-methyl)tyrosine Methyl Ester Prepared from dimethyl amine and the resultant compound from Example 136 according to the procedure for Example 122.
  • Example 127 Dimethylaminocarbonyl-(O-methyl)-tyrosine Prepared according to the procedure of Example 123 from the resultant compound of Example 126 with the modification that the product was isolated by pouring the reaction mixture into 2 M HCl and extracting with ethyl acetate which was dried over Na 2 SO 4 and evaporated.
  • EI-MS: M + 266
  • Example 129 (4-t-Butyloxycarbonyl-3,3-dimethyl)butanoylphenylalanine benzyl Ester Prepared according to the procedure from Example 95 from the resultant compound from Example 128 and phenylalanine benzyl ester p-toluenesulfonic acid salt.
  • Example 130 (4-t-Butyloxycarbonyl-3,3-dimethyl)butanoylpenylalanine Using the procedure of Example 125 with the resultant compound of Example 129 gave the desired product as an oil. NMR (300 MHz, CDCl 3 , ppm) , 0 . 93 (S,3H), 0.99 (s,3H), 1.45 (s,9H), 1 . 77 (d, 1H) , 2 . 10 (d,1H), 2.19 (d,1H), 2.25 (d,1H), 3 . 02 ( dd ,1H ) , 3 . 33 (dd,1H), 4.72 (m,1H), 7.25 (m,5H).
  • Example 131 Dimethylaminocarbonyl (O-methyl)Tyr-His Amide of (3S,4S)-1-(3-Methylbutylcarbonylamino)- 3-hydroxy-4-amino-5-cyclohexylpentane Using the procedure of Example 79 with the resultant compounds from Example 127 and Example 80 gave the desired compound.
  • Example 79 Using the procedure of Example 79 with the resultant compounds from Example 122 and Example 80 gave the desired compound.
  • Example 79 Using the procedure of Example 79 with the resultant compounds from Example 130 and Example 80 gave the desired compound.
  • Example 134 The resultant compound from Example 134 was stirred in 4 M HCl/methanol for 1 h and then evaporated to provide the desired compound.
  • Example 136 ⁇ -Isocyanato-L-(O-methyl)tyrosine A suspension of (O-methyl)tyrosine methyl ester hydrochloride (6 g) in toluene (125 mL) was heated at 100°C while phosgene was bubbled into the reaction mixture. After 2 h the mixture became homogeneous and the phosgene was continued for an additional 15 min. The mixture was cooled and evaporated with several benzene chasers to provide the desired product.
  • Example 137 The resultant compound of Example 137 (320 mg, 0.977 mmol) was dissolved in 25 mL of anhydrous 1 M HCl in methanol. After 12 h, evaporation of the solvent provided the corresponding deprotected amine hydrochloride (241 mg, 93%) which was used in the below coupling without further purification.
  • Example 140 Cbz-D-Ala-Phe-His Amide of 2-Amino- 1-cyclohexyl-3-hydroxy-6-methylheptane Following the procedure of Example 138, but replacing Boc-Phe-His-OH with Cbz-D-Ala-Phe-OH and replacing the resultant compound of Example 137 with the resultant compound of Example 139 gave the desired product.
  • Example 141 D-Ala-Phe-His Amide of 2-Amino- 1-cyclohexyl-3-hydroxy-6-methylheptane
  • the resultant compound of Example 140 (1.0 g) in glacial acetic acid (20 mL) was hydrogenated with 10% Pd/C (450 mg) at 55 p.s.i. H 2 . After 3 h, the mixture was filtered and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3 for 30 min. The organic phase was washed (brine), dried (Na 2 SO 4 ), filtered, and evaporated to give the desired compound in 84% yield.
  • Example 142 D-Ser-Phe-His Amide of 2-Amino- 1-cyclohexyl-3-hydroxy-6-methylheptane Following the procedures of Examples 140 and 141, but replacing Cbz-D-Ala-Phe-OH with Cbz-D-Ser-Phe-OH, gave the desired product in 39% yield.
  • Example 143 (OCH 3 )Tyr-His Amide of 2-Amino- 1-cyclohexyl-3-hydroxy-6-methylheptane Following the procedures of Examples 140 and 141, but replacing Cbz-D-Ala-Phe-OH with Cbz-(OCH 3 )-Tyr, gave the desired product.
  • Example 138 Following the procedure of Example 138, but replacing Boc-Phe-His-OH with ( imidazol-4-yl) acetic acid, and replacing the salt derived from the resultant compound of Example 137 with the resultant compound of Example 143, gave the desired compound in 34% yield after recrystallization.
  • Example 143 The resultant compound of Example 143 (250 mg) in dry THF at 0°C was treated sequentially with 2 eq. N-methylmorpholine and 1 equivalent bromoacetyl bromide. After 1 h, imidazole (5 eq) was added. The mixture was warmed to room temperature for 6 h and then evaporated. Chromatography of the residue on silica gel (dichloromethane/isopropyl amine/methanol, 89:9:2) provided the desired product.
  • Example 148 Boc-Phe-Ala Amide of 4-Amino-3-hydroxy-6-methyl-1-(4- methylvaleryl)amino-1-phenylheptane Following the deprotection procedure of Example 138 and using the resultant compound of Example 147 gave the corresponding hydrochloride which was coupled to Boc-Phe-Ala according to the procedures of Example 16. The desired compound was obtained in 98% yield.
  • Example 151 5-t-Butyloxycarbonylamino-4-hydroxy-7-methyl- 2-phenyloctanoic Acid Isoamyl Amide Using the procedure of Example 147, but replacing 4-methylvaleric benzamide with N-isoamyl phenylacetamide gave the desired compound in 15% after chromatography.
  • Example 152 Boc-Phe-Ala Amide of 5-Amino-4-hydroxy-7-methyl- 2-phenyloctanoic Acid Isoamyl Amide Following the deprotection procedure of Example 138 and using the resultant compound of Example 151 gave the corresponding amine hydrochloride which was coupled to Boc-Phe-Ala according to the procedure of Example 16. The desired compound was obtained in 75% yield.
  • Example 151 The resultant compound of Example 151 was hydrogenated according to the procedure of Example 149 to give the desired compound in 68% yield.
  • Example 155 4-t-Butyloxycarbonylamino-3-hydroxy- 6-methylheptanoic Acid Ethyl Ester To diisopropylamine (7.7 g, 0.077 mol) in dry tetrahydrofuran (20 ml) cooled to -20°C under an argon atmosphere was added dropwise n-butllithium in hexane (1.46 M, 52.4 ml, 0.077 mol).
  • Example 156 4-t-Butyloxycarbonylamino-3-hydroxy- 6-methylheptanoic Acid (Boc-Statine) To 0.8 g of Boc-Sta-OEt in 24 mi of dioxane/water (2:1) was added 120 mg of lithium hydroxide at 0°C. After 10 min, the mixture was warmed to room temperature. After 1 h, the mixture was poured to a 10% solution of potassium bisulfate and extracted with ethyl acetate (3 x 100 ml). The combined organic phase was washed with a satd. NaCl solution and dried with MgSO 4 and filtered. Evaporation of the filtrate in vacuo gave 0.7 g of a white solid. Recrystallization from ether/hexane gave a solid with a m.p. of 117-118°C.
  • Boc-Sta amide of benzylamine (100 mg, 0.27 mmol) was dissolved in 3 ml of 4N HCl and stirred for 10 min. The solvent was evaporated in vacuo and the crude product, the amine hydrochloride from deprotection of the N-terminal of Boc-Sta-amide of benzylamine was dried under high vacuum for 12 h at room temperature. Likewise, the amine hydrochloride of the compounds in Example 158 to Example 161 are prepared by the same procedure.
  • Example 164 Boc-Phe-His-Sta Amide of Benzylamine
  • the solution was cooled to 0°C and Boc-Phe-His-OH was added (136 mg, 0.34 mmol), followed by 1-hydroxybenzotriazole (70 mg, 0.51 mmol) and then dicyclohexylcarbodiimide (72 mg, 0.34 mmol).
  • the solution was stirred at 0°C for 8 h and then at room temperature for 4 h.
  • Example 169 Boc-His-Sta Amide of 2-Methylbutylamine Using the procedure of Example 164, but using the amine hydrochloride of Boc-Sta amide of 2-methylbutylamine and replacing Boc-Phe-His with Boc-His-OH gave the desired compound (60% yield). m.p. 115-116°C.
  • Example 165 Using the procedure of Example 165, but using the amine hydrochloride of Example 169 and replacing Boc ( ⁇ -Naphthyl ) -Ala-Ala-OH with Boc-p-iodo-Phe-OH gave the desired compound (65% yield). m.p. 213°C
  • Example 173 4-t-Butyloxycarbonylamino-5-phenyl- 3-hydroxypentanoic Acid (Boc-F-Sta) Using the procedure of Example 156 but using the compound in Example 172 gave the desired compound (95% yield). m.p. 88°C.
  • Example 183 4-Boc-amino-2,3-dihydroxy-5-cyclohexylpentanoic Acid Amide of 2-Methylbutylamine
  • a solution of 400 mg of the compound in Example 182 in 20 ml of methanol with 200 mg of palladium black added was stirred vigorously under 3 atmosphere of hydrogen for 17 h.
  • the catalyst was filtered off and the solution was concentrated in vacuo.
  • Example 184 Amine Hydrochloride of 4-Boc-amino-2-benzyloxy- 3-hydroxy-5-cyclohexyl-pentanoic Acid Amide of 2-Methylbutylamine Using the procedure of Example 163, but replacing Boc-Sta amide of benzylamine with the compound is Example 182 gave the desired product (100% yield).
  • Example 185 Amine Hydrochloride of 4-Boc-amino-2,3-dihydroxy- 5-cyclohexylpentanoic Acid Amide of 2-Methylbutylamine Using the procedure in Example 163 but replacing Boc-Sta amide of benzylamine with the compound in Example 183 gave the desired product (100% yield).
  • Example 193 Amine Hydrochloride of 4-Boc-ammo-2-methoxy- 3-hydroxy-5-cyclohexylpentanoic Acid Amide of 2-Methylbutylamine Using the procedure of Example 163, but replacing Boc-Sta amide of benzyl amine with the compound in Example 192 gave the desired compound (100% yield) .
  • Example 212 2-t-Butyloxycarbonylamino- 3-(1',3'-dithiolan-2'-yl)-propanol
  • ethanol/water 25 ml/25 ml
  • barium hydroxide 2 equivalents
  • the suspension was heated to reflux for 16 h.
  • the solid formed was filtered and washed with methanol.
  • the solution was concentrated under reduced pressure.
  • the residue was dissolved in 20 ml of dichloromethane.
  • To this solution was added 1.5 equivalents of di-t-butyldicarbonate. After 2 h, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (CH 2 Cl 2 /EtOAc 6.4) to give 430 mg of pure product.
  • Mass spectrum: M 279.
  • Example 212 Using 110 mg of the product from Example 209 and the procedure in Example 212 gave 90 mg of the desired product.
  • Example 214 Using 300 mg of the product from Example 211 and using the procedure of Example 214 gave 280 mg of the desired product.
  • Example 221 3-Hydroxy-4-t-butyloxycarbonylamino- 5-(1',3'-dithiolan-2'-yl)-pentanoic Acid
  • Example 228 Amine Hydrochloride of 3-hydroxy- 4-t-butyloxycarbonylamino-5-(1',3'-dithiolan-2'-yl)- pentanoic Acid Amide of 2-Methylbutylamine To 0.2 g of the product from Example 224 was added 8 ml of 4N HCl in dioxane. The solution was stirred at room temperature for 30 min and the solvent was then removed under reduced pressure to give a gummy solid which was used without further purification.
  • Example 229 Amine Hydrochloride of 3-hydroxy- 4-t-butyloxycarbonylamino-5-(1',3'-dithian-2'-yl)- pentanoic Acid Amide of 2-Methylbutylamine Using the procedure described in Example 228 and using the product from Example 225 gave the desired product which was used without further purification.
  • Example 230 3-Hydroxy-4-amino-5-(1',3'-dioxolan-2'-yl)- pentanoic Acid Amide of 2-Methylbutylamine
  • 10 mg of 10% palladium on charcoal was added carefully 10 ml of methanol.
  • the suspension was stirred vigorously under a hydrogen atmosphere by attaching a 3-way stopcock with a hydrogen-filled balloon attached. Reaction was complete in 10 min as shown by the complete disappearance of the starting material on TLC analysis.
  • the suspension was filtered and the catalyst was washed with 20 ml of methanol.
  • the combined methanol solution was concentrated under pressure to give the desired product which was used without further purification.
  • Example 230 Using the procedure described in Example 230 and using the product from Example 227 as the starting material gave the desired product which was used without further purification.
  • Example 232 Boc-Phe-S-methylcysteinyl-[3-hydroxy-4-ammo- 5-(1',3'-dithiolan-2'-yl)]-pentanoic Acid Amide of 2-Methylbutylamine
  • a solution of 57 mg of Boc-Phe-S-methylcysteine in 5 ml of THF at -15°C was added 0.017 ml of N-methylmorpholine, followed by 0.020 ml of isobutylchloroformate. After 10 min, a solution of the product from Example 228 (starting with 49 mg) in 5 ml of THF with 0.016 ml of N-methylmorpholine was added.
  • Example 237 Boc-Phe-His-[3-hydroxy-4-amino- 5-(1',3'-dithiolan-2'-yl)]- pentanoic Acid Amide of 2-Methylbutylamine
  • Boc-Phe-His-OH in 5 ml of DMF at -15°C was added sequentially 45 mg of 1-hydroxybenzotriazole, 21 mg of ethyl dimethylaminopropyl carbodiimide.
  • a solution of 37 mg of the product from Example 228 in .3 ml of DMF was added. The solution was kept at -15°C for several hours and then at room temperature overnight.
  • Example 244 (3,4-cis-dihydroxypyrrolidinylcarbonyl)-Phe-methyl Ester
  • L-phenylalamine methyl ester hydrochloride 10 g
  • toluene -200 ml
  • phosgene gas was bubbled into the reaction mixture. After approximately 2 h the mixture became homogeneous. The bubbling of phosgene was continued for 15 more minutes keeping the temperature at -100°C.
  • the toluene was then evaporated and the residue chased with benzene several times.
  • the isocyanate from L-Phe-OCH 3 was then dissolved in -100 ml of methylene chloride and
  • Example 256 N-(3-MethylbutyP-4-hydroxy-5-t-butyloxycarbonylamino- 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 under an N 2 atmosphere to -78 °C and treated dropwise with 3.28 ml (8.5 mmol) of n-butyllithium in hexane.
  • N-isobutyl-2-methylpropenamide gave a ca. 1:1 mixture of the (4S,5S) product (R f .39) and (4R,5S) product (R f
  • Example 259 N-(2,2-Dimethyl-3-(N,N-dimethylamino)propyl)- 4-hydroxy-5-t-butyloxycarbonylamino- 6-cyclohexylhex-1-ene-2-carboxamide Using the procedure of Example 256, but replacing N-(3-methylbutyl)-2-methylpropenamide with N-(2,2-dimethyl-3-(N,N-dimethylamino)propyl)-2-methyl-propenamide gave a ca.
  • Example 260 N-(3-t-Butyloxycarbonylammo-2,2-dimethylpropyl)- 4-hydroxy-6-cyclohexyl-5-triphenyl- methylaminohex-1-ene-2-carboxamide
  • a solution of N-t-butyloxycarbonyl-N'-2-methylpropenoyl-2,2-dimethyl-1,3-propanediamine (270 mg, 1.0 mmol) in 10 ml of dry tetrahydrofuran was cooled under a N 2 atmosphere to -78°C, treated dropwise with 1.68 ml (3.0 mmol) of n-butyllithium in hexane, stirred at -78°C for 5 min, warmed to 0°C for 30 min, recooled to -78°C and treated with 266 mg (0.67 mmol) of N-(triphenylmethypcyclohexylalaninal in 3 ml of tetrahydrofuran
  • Example 264 (4S,5S)-N-(3-Methylbutyl)-1-acetoxy- 4-hydroxy-5-t-butyloxycarbonylamino- 6-cyclohexylhexane-2-carboxamide
  • a solution of the resultant compound of Example 263 (40.2 mg, 0.094 mmol) in 0.3 ml of dry dichloromethane was treated sequentially with 14.5 uL (0.10 mmol) of triethylamine and 9.8 uL (0.10 mmol) of acetyl chloride.
  • Example 270 The (4S,5S) diastereomer from Example 256 (31.5 mg, 0.077 mmol) was treated with 0.5 ml of a 4 M solution of HCl in dioxane and allowed to stand at ambient temperature for 1 h. After removal of the solvent in vacuo, the residue was treated twice with 0.5 ml of anhydrous ether followed each time by removal of the solvent in vacuo. The crude amine hydrochloride was used without further purification.
  • Example 270 The (4S,5S) diastereomer from Example 256 (31.5 mg, 0.077 mmol) was treated with 0.5 ml of a 4 M solution of HCl in dioxane and allowed to stand at ambient temperature for 1 h. After removal of the solvent in vacuo, the residue was treated twice with 0.5 ml of anhydrous ether followed each time by removal of the solvent in vacuo. The crude amine hydrochloride was used without further purification.
  • Example 270 The (4S,5
  • Example 269 Using the procedure of Example 269 with the resultant (4S,5S) diastereomer of Example 257 gave the desired compound.
  • Example 269 Using the procedure of Example 269 with the resultant (4S,5S) diastereomer of Example 258 gave the desired compound.
  • N-(2,2-Dimethyl-3-(N,N-dimethylamino)propyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene- 2-carboxamide dihydrochloride A solution of 45 mg (0.1 mmol) of the resultant compound of Example 259 in ca. 0.1 ml of absolute ethanol was treated with 0.6 ml of 4 M HCl in dioxane and allowed to stand at ambient temperature for 1.5 h. After removal of the solvent in vacuo, the residue was treated twice with 0.5 ml of anhydrous ether followed each time by removal of the solvent in vacuo. The crude diamine dihydrochloride was used without further purification.
  • Example 269 Using the procedure of Example 269 with the resultant compound of Example 264 gave the desired compound.
  • Example 275 (2R,4S,5S)-N-Isobutyl-5-amino-1-azido- 6-cyclohexylhexan-2,4-diol-2-carboxamide hydrochloride Using the procedure of Example 269 with the resultant compound of Example 265 gave the desired compound.
  • Example 269 Using the procedure of Example 269 with the resultant compound of Example 266 gave the desired compound.
  • Example 277 (2S, 4S , 5S)-N-Isobutyl-4-amino-1-chloro- 6-cyclohexylhexane-2,4-diol-2-carboxamide hydrochloride Using the procedure of Example 269 with the resultant (2R) diastereomer of Example 262 gave the desired compound.
  • Example 278 (4S,5S)-N-(3-Methylbutyl)-5-amino-6-cyclohexylhexane- 1,2,4-triol-2-carboxamide hydrochloride Using the procedure of Example 269 with the resultant compound of Example 267 gave the desired compound as a mixture of diastereomers.
  • Example 279 (4S,5S)-N-Isobutyl-5-ammo-6-cyclohexylhex-1-ene- 3,4-diol-2-carboxamide hydrochloride Using the procedure of Example 269 with the resultant compound of Example 268 gave the desired compound as a mixture of diastereomers.
  • Example 280 Boc-Phe-Ala amide of (4S,5S)-N-(3-methylbutyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene-2-carboxamide
  • a solution of 39 mg (0.115 mmol) of Boc-Phe-Ala-OH and 13 uL (0,12 mmol) of 4-methylmorpholine in 0.5 ml of dichloromethane and 0.1 ml of dimethylformamide was cooled to -15°C and treated with 15 uL (0.12 mmol) of isobutyl chloroformate.
  • Example 282 Boc-Phe-His amide of (4S,5S)-N-(3-methylbutyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene-2-carboxamide
  • a solution of 52 mg (0.13 mmol) of Boc-Phe-His-OH and 52 mg (0.39 mmol) of 1-hydroxybenzotriazole monohydrate in 0.6 ml of dimethylformamide was cooled to -23 °C, treated with 25 mg (0.13 mmol) of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride, and allowed to stir for 1 h.
  • Boc-Phe-His-OH, and 3.27 g (24.2 mmol) of 1-hydroxybenzotriazole in 20 ml of dimethylformamide was treated with 750 uL (6.83 mmol) of 4-methylmorpholine, cooled to
  • Example 282 Using the procedure of Example 282 with the resultant compound of Example 274 gave, after purification by flash column chromatography using
  • Example 287 (5N)-Boc-Phe-His amide of (2R,3S,5S)-N-isobutyl- 6-cyclohexyl-1,5-diaminohexane-2,4-diol-2-carboxamide
  • Example 293 His amide of (4S,5S)-N-(3-methylbutyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene- 2-carboxamide dihydrochloride Using the procedure of Example 272 with the resultant compound of Example 292 gave the desired compound.
  • Example 294 Boc-6-aminohexanoic acid A mixture of 3.0 g (0.02 mol) of 6-aminohexanoic acid, 5.04 g (0.02 mol) of di-t-butyldicarbonate and 3.84 g (0.05 mol) of NaHCO 3 in 160 ml of 1:1 H 2 O/tetrahydrofuran was stirred vigorously for 24 h. After concentration of the solvent, the mixture was acidified with HCl, saturated with NaCl, extracted with ethyl acetate, dried over MgSO 4 and concentrated in vacuo to give the desired product (R f 0.48, 9:1 chloroform/methanol).
  • Example 295 Boc-6-aminohexanoyl-Phe benzyl ester
  • Example 296 Boc-6-aminohexanoyl-Phe-OH A mixture of 0.5 g (1.07 mmol) of the resultant compound of Example 295 and 30 mg of 10% palladium on carbon in 50 ml of methanol was stirred under an H 2 atmosphere for 3.5 h. After filtration through Celite, concentration in vacuo gave the desired compound.
  • Example 298 6-Aminohexanoyl-Phe-His amide of (4S,5S)-N-(3-methylbutyl)-5-amino-4-hydroxy- 6-cyclohexylhex-1-ene-2-carboxamide bis trifluoroacetate
  • a solution of the resultant compound of Example 297 (17 mg, 0.021 mmol) in 0.2 ml of trifluoroacetic acid was allowed to stand at ambient temperature for 40 min. After removal of the solvent in vacuo, and the residue was treated three times with 0.5 ml of ether and concentrated in vacuo to give the desired compound as a white solid.
  • Mass spectrum: (M+H) + 708.
  • Example 299 t-Butylacetyl-Phe-His amide of N-(3-t-butyloxycarbonylamino-2,2-dimethylpropyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene-2-carboxamide
  • Example 301 (4S,5S,8R,10R,11S)-N-Isobutyl-6-aza- 11-(t-butyloxycarbonylamino)-5-(cyclohexylmethyl)- 4,10-dihydroxy-8-isobutyl-7-oxo-12- phenyldodec-1-ene-2-carboxamide Using the procedure of Evans, et al, (J. Org. Chem.
  • N-Methyl-N-(2-(N,N-dimethylamino)ethyl)carbamoyl- (O-methyl)tyrosine methyl ester A solution of 0.5 g (2.1 mmol) of the resultant compound of Example 136 in 50 ml of dichloromethane was cooled to 0°C and treated with 0.3 ml (2.3 mmol) of N,N,N'-trimethylethylenediamine. After being allowed to stir for 16 h, the solution was concentrated and the desired compound was isolated by flash column chromatography using 1% methanol/2% isopropylamine in chloroform.
  • Example 304 N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl- (O-methyl)tyrosine lithium salt
  • a solution of the resultant compound of Example 303 in dioxane was cooled to 0°C, treated with 1.05 equiv. of aqueous lithium hydroxide (0.5 M) and stirred for 1.5 h.
  • the resulting solution was concentrated in vacuo to give the desired compound as a white solid.
  • Example 305 N-Methyl-N-(2-(N,N-dimethylamino)ethyl)carbamoyl- (O-methyl)Tyr-His amide of (4S, 5S)-N-(3-methylbutyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene-2-carboxamide Using the procedure of Example 283 but replacing Boc-Phe-His-OH with the resultant compound of Example 304 and replacing the resultant compound of Example 272 with the resultant compound of Example 293 gave the desired compound.
  • Example 306 5-Carbomethoxypentanoyl-(O-methyl)Tyr benzyl ester
  • Example 280 Using the procedure of Example 280 but replacing Boc-Phe-Ala-OH with adipic acid monomethyl ester and replacing the resultant compound of Example 269 with (O-methyl) tyrosine benzyl ester hydrochloride gave the desired compound.
  • Example 307 5-Carbomethoxypentanoyl-(O-methyl)Tyr-OH A solution of the resultant compound of Example 306 and 20% palladium on carbon in methanol was shaken under an H 2 atmosphere. After filtration, concentration of the solution in vacuo gave the desired compound.
  • Example 308 5-Carbomethoxypentanoyl-(O-methyl)Tyr-Leu benzyl ester Using the procedure of Example 280 but replacing Boc-Phe-Ala-OH with the resultant compound of Example 307 and replacing the resultant compound of Example 269 with leucme benzyl ester p-toluenesulfonate salt gave, after purification by flash column chromatography using 20% ethyl acetate in chloroform, the desired compound in 64% yield.
  • Example 310 5-Carbomethoxypentanoyl-(O-methyl)Tyr-Leu amide of N-(2,2-dimethyl-3-(N,N-dimethylamino)propyl)- 5-amino-4-hydroxy-6-cyclohexylhex-1-ene-2-carboxamide
  • Boc-Phe-Ala-OH with the resultant compound of Example 309
  • replacing the resultant compound of Example 269 with the resultant compound of Example 272 gave, after purification by flash column chromatography using 1.25% methanol/1% isopropylamine/chloroform, the desired compound in 57% yield (R f 0.38 (2.5% methanol/2% isopropylamine/chloroform)).
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, heptonate, glycerophosphate, hemisulfate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, oxalate, 2-naphthalenesulfonate, pamoate, pectinate, persulfate, 3-phen
  • 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.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl., and diamyl sulfates
  • novel compounds of the present invention possess an excellent degree of activity and specificity in treating renin-associated hypertension in a host.
  • the ability of the compounds of the invention to inhibit human renal renin can be demonstrated in vitro by reacting a selected compound at varied concentrations with human renal renin, free from acid proteolytic activity, and with human renin substrate (angiotensinogen) at 37°C and pH 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
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Injectable preparation for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

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Abstract

Est décrit un genre de nouveaux analogues de peptides qui possèdent une puissante activité d'inhibition de la rénine, des procédés de traitement de l'hypertension causée par la rénine au moyen de ces composés, et des compositions pharmaceutiques renfermant ces composés comme principes actifs.
EP19870900949 1986-01-16 1987-01-16 Peptide analogs Withdrawn EP0258289A4 (en)

Applications Claiming Priority (16)

Application Number Priority Date Filing Date Title
US820274 1977-07-29
US82027486A 1986-01-16 1986-01-16
US82006086A 1986-01-16 1986-01-16
US820060 1986-01-16
US85080286A 1986-04-11 1986-04-11
US86207786A 1986-05-12 1986-05-12
US94688487A 1987-01-09 1987-01-09
US94688287A 1987-01-09 1987-01-09
US06/946,883 US4857507A (en) 1986-04-11 1987-01-09 Angiotensinogen analogs
US946881 1987-01-09
US946882 1987-01-09
US946883 1987-01-09
US06/946,881 US4826815A (en) 1985-05-17 1987-01-09 Renin inhibiting compounds
US946884 1987-01-09
US850802 1997-05-02
US862077 2006-10-19

Publications (2)

Publication Number Publication Date
EP0258289A1 true EP0258289A1 (fr) 1988-03-09
EP0258289A4 EP0258289A4 (en) 1991-01-02

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WO1987004349A1 (fr) 1987-07-30
EP0258289A4 (en) 1991-01-02

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