WO2001005817A1 - Analogues amides et esters de pseudomycine - Google Patents

Analogues amides et esters de pseudomycine Download PDF

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Publication number
WO2001005817A1
WO2001005817A1 PCT/US2000/015021 US0015021W WO0105817A1 WO 2001005817 A1 WO2001005817 A1 WO 2001005817A1 US 0015021 W US0015021 W US 0015021W WO 0105817 A1 WO0105817 A1 WO 0105817A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
aromatic ring
membered aromatic
hydrogen
Prior art date
Application number
PCT/US2000/015021
Other languages
English (en)
Inventor
Shu Hui Chen
Christopher Stanley Galka
Sarah Lynne Hellman
John Leonard Krstenansky
Michael John Rodriguez
Xicheng Sun
Alexander Ya. Usyatinsky
Venkatraghavan Vasudevan
Mark James Zweifel
Original Assignee
Eli Lilly And Company
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 Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to EA200200165A priority Critical patent/EA200200165A1/ru
Priority to MXPA02000312A priority patent/MXPA02000312A/es
Priority to BR0013163-6A priority patent/BR0013163A/pt
Priority to JP2001511474A priority patent/JP2003505399A/ja
Priority to EP00942656A priority patent/EP1198473A1/fr
Priority to AU57250/00A priority patent/AU5725000A/en
Priority to CA002379321A priority patent/CA2379321A1/fr
Publication of WO2001005817A1 publication Critical patent/WO2001005817A1/fr
Priority to NO20020186A priority patent/NO20020186L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • R 1 is a hydrogen, halogen, or C 5 -C 8 alkoxy, and m is 1, 2 or 3 ; R is
  • R 1 is independently -NH 2 or -NHp-Pg, where p is 0 or 1;
  • a prodrug of a pseudomycin compound having structure I represented above wherein R 2 and R 3 are represented by -OR a , where R a is C ⁇ -C 3 alkyl.
  • a 3-amido derivative of a pseudomycin compound is provided where the compound is prepared by the steps of (i) providing a compound having structure I above wherein R 1 is -NH 2 and R 2 and R 3 are both -OH; (ii) protecting the amino groups, R 1 , at positions 2, 4 and 5 with an amino-protecting group; (iii) forming an amide linkage at position 3 using an o- Benzotriazol-l-yl-N,N,N' ,N' -tetramethyluronium tetrafluoroborate as a coupling agent; and (iv) removing the amino-protecting groups.
  • An 8-amido derivative is also provided where the derivative is prepared using the steps described above except using benzotria
  • amino protecting group refers to a substituent of the amino group (Pg) commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
  • the amino protecting group when taken with the nitrogen to which it is attached, forms a cyclic imide, e.g., phthalimido and tetrachlorophthalimido .
  • the protecting group when taken with the nitrogen to which it is attached, can form a carbamate, e.g., methyl, ethyl, and 9-fluorenylmethylcarbamate; or an amide, e.g., N-formyl and N-acetylamide .
  • animal refers to humans, companion animals (e.g., dogs, cats and horses), food-source animals (e.g., cows, pigs, sheep and poultry) , zoo animals, marine animals, birds and other similar animal species.
  • companion animals e.g., dogs, cats and horses
  • food-source animals e.g., cows, pigs, sheep and poultry
  • zoo animals e.g., marine animals, birds and other similar animal species.
  • a bulky amine enhances the ratio of monoamides at residue 3.
  • the ratio of amidation at residue 3 vs . residue 8 increased from about 1:1 to about 6:1 and the amount of bis-amides was reduced through the addition of a bulky amine.
  • the term "bulky amine” refers to an amine having multiple and/or large substituents on the nitrogen atom. Any tertiary amine may be used that is compatible with the reaction conditions.
  • Preferred bulky amines include N,N-diisopropylethylamine (DIEA) and N-ethyldicyclohexylamine.
  • the amido or ester derivative can be formed from an N-acyl semi-synthetic compound.
  • Semi- synthetic pseudomycin compounds may be synthesized by exchanging the N-acyl group on the L-serine unit. Examples of various N-acyl derivatives are described in PCT Patent Application Serial No. , Belvo, et al . , filed evendate herewith entitled "Pseudomycin N-Acyl Side-Chain Analogs" and incorporated herein by reference.
  • the acid-modification of the protected N-acyl semi- synthetic compound is then accomplished by reacting at least one of the pendant carboxyl groups attached to the aspartic or hydroxyaspartic peptide units of the N-acyl modified semi-synthetic pseudomycin compound to form the desired amide or ester linkage (s).
  • the protecting groups are then removed as described earlier.
  • the formulations are typically diluted or reconstituted (if freeze-dried) and further diluted if necessary, prior to administration.
  • An example of reconstitution instructions for the freeze-dried product are to add ten ml of water for injection (WFI) to the vial and gently agitate to dissolve. Typical reconstitution times are less than one minute.
  • WFI water for injection
  • the resulting solution is then further diluted in an infusion solution such as dextrose 5% in water (D5W) , prior to administration.
  • Torulopus spp. i.e., T. glabrata
  • a method for inhibiting fungal activity comprising contacting the pseudomycin compound of the present invention with a fungus.
  • a preferred method includes inhibiting Candida albicans or Aspergillus fumigatus activity.
  • the term "contacting" includes a union or junction, or apparent touching or mutual tangency of a compound of the invention with a fungus. The term does not imply any further limitations to the process, such as by mechanism of inhibition.
  • the methods are defined to encompass the inhibition of fungal activity by the action of the compounds and their inherent antifungal properties.
  • R 2 -OCH 2 CH 2 CH 3
  • R 3 -OCH 2 CH 2 CH 3
  • the protected amido compound (60 mg) was dissolved in 6 ml of 1% AcOH in methanol and 60 mg of 10% Pd/C was added. The mixture was stirred for 30 minutes under hydrogen at room temperature. After filtering, the solution was concentrated in vacuo. The residue was dissolved in 50% ACN/water and lyophilized to yield 45 mg (90%) yield of Compound 5-1.
  • Compound 6-1 can also be made from the Alloc-protected pseudomycin B using the following procedures.
  • Example 7 The same general procedures as described in Example 7 may be used. When no base is added, a mixture of 8 and 3 amido substituted compounds are observed.
  • Example 11 The same general procedures as described in Example 7 are used to synthesize Compound 10-1 using the appropriate corresponding amine starting material .
  • Example 11 The same general procedures as described in Example 7 are used to synthesize Compound 10-1 using the appropriate corresponding amine starting material .
  • Example 7 The same general procedures as described in Example 7 are used to synthesize Compound 11-1 using 4- (aminomethyl) pyridine as the amine starting material.
  • Examples 14-16 illustrate the synthesis of amide derivatives at residue 8.
  • the deprotection of the alloc groups was performed by adding Bu 3 SnH( 0.648 g, 2.23 mmol), and (Ph 3 P) 2 PdCl 2 (0.009g, 0.013 mmol) to a 1% acetic/ dichloromethane solution of alloc-protected Psuedomycin B Morpholine derivative (10 mg/mL) . Reaction time was 30 minutes. Reaction was monitored by HPLC. The solution was concentrated down, and the product was isolated by reverse phase HPLC prep, and lyophilized to yield 38 mg, 32% of Compound 16-1. MS data: Calculated for C57 H99 CI N14 019 Mol. Wt. 1318.7 Found ES+ 1320.0, ES- 1318.0
  • the 3-amido derivatives demonstrated a similar trend as observed with the 8-amido derivatives in comparison with the parent natural product (e.g., amide substituents at R 2 having shorter alkyl chains were more active than longer alkyl chains) .

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Saccharide Compounds (AREA)

Abstract

Cette invention concerne la modification acide d'unités d'acide aspartique et/ou d'acide hydro-aspartique d'un composé de pseudomycine naturel ou semi-synthétique ainsi que des méthodes de traitement antifongiques.
PCT/US2000/015021 1999-07-15 2000-06-08 Analogues amides et esters de pseudomycine WO2001005817A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EA200200165A EA200200165A1 (ru) 1999-07-15 2000-06-08 Амид псевдомицина и его эфирные аналоги
MXPA02000312A MXPA02000312A (es) 1999-07-15 2000-06-08 Analogos de amida y ester de pseudomicina.
BR0013163-6A BR0013163A (pt) 1999-07-15 2000-06-08 Análogos de amida e éster de pseudomicida
JP2001511474A JP2003505399A (ja) 1999-07-15 2000-06-08 プソイドマイシンのアミドおよびエステルアナログ
EP00942656A EP1198473A1 (fr) 1999-07-15 2000-06-08 Analogues amides et esters de pseudomycine
AU57250/00A AU5725000A (en) 1999-07-15 2000-06-08 Pseudomycin amide and ester analogs
CA002379321A CA2379321A1 (fr) 1999-07-15 2000-06-08 Analogues amides et esters de pseudomycine
NO20020186A NO20020186L (no) 1999-07-15 2002-01-14 Pseudomycin amid og ester analoger

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14398199P 1999-07-15 1999-07-15
US60/143,981 1999-07-15

Publications (1)

Publication Number Publication Date
WO2001005817A1 true WO2001005817A1 (fr) 2001-01-25

Family

ID=22506548

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/015021 WO2001005817A1 (fr) 1999-07-15 2000-06-08 Analogues amides et esters de pseudomycine

Country Status (11)

Country Link
EP (1) EP1198473A1 (fr)
JP (1) JP2003505399A (fr)
CN (1) CN1362966A (fr)
AU (1) AU5725000A (fr)
BR (1) BR0013163A (fr)
CA (1) CA2379321A1 (fr)
EA (1) EA200200165A1 (fr)
HU (1) HUP0202267A3 (fr)
MX (1) MXPA02000312A (fr)
NO (1) NO20020186L (fr)
WO (1) WO2001005817A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041534A2 (fr) * 1999-12-13 2001-06-14 Eli Lilly And Company Promedicaments de phosphate pseudomycine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5576298A (en) * 1992-11-30 1996-11-19 Research And Development Institute, Inc. At Montana State University Peptides from pseudomonas syringae possessing broad-spectrum antibiotic activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5576298A (en) * 1992-11-30 1996-11-19 Research And Development Institute, Inc. At Montana State University Peptides from pseudomonas syringae possessing broad-spectrum antibiotic activity
US5837685A (en) * 1992-11-30 1998-11-17 Research And Development Institute Inc. At Montana State University Peptides from Pseudomonas syringae possessing broad-spectrum antibiotic activity

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A BALLIO ET AL: "Novel bioactive lipodepsipeptides from Pseudomonas syringae: the pseudomycins", FEBS LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 355, no. 1, 21 November 1994 (1994-11-21), pages 96 - 100, XP002125309, ISSN: 0014-5793 *
CHEN E.A.: "Syntheses and biological evaluation of novel pseudomycin side-chain analogues. Part 2", BIOORG.MED.CHEM.LETT., vol. 10, no. 18, 2000, pages 2107 - 2110, XP004208322 *
JAMISON E.A.: "Syntheses and antifungal activity of pseudomycin side-chain analogues.Part 1", BIOORG.MED.CHEM.LETT., vol. 10, no. 18, 2000, pages 2101 - 2105, XP004208321 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001041534A2 (fr) * 1999-12-13 2001-06-14 Eli Lilly And Company Promedicaments de phosphate pseudomycine
WO2001041534A3 (fr) * 1999-12-13 2001-11-22 Lilly Co Eli Promedicaments de phosphate pseudomycine

Also Published As

Publication number Publication date
AU5725000A (en) 2001-02-05
HUP0202267A2 (en) 2002-10-28
CA2379321A1 (fr) 2001-01-25
HUP0202267A3 (en) 2002-11-28
EP1198473A1 (fr) 2002-04-24
NO20020186L (no) 2002-03-04
BR0013163A (pt) 2002-04-02
NO20020186D0 (no) 2002-01-14
EA200200165A1 (ru) 2002-06-27
JP2003505399A (ja) 2003-02-12
MXPA02000312A (es) 2002-06-21
CN1362966A (zh) 2002-08-07

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