Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • 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
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P31/12—Antivirals
• • 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
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/006—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length of peptides containing derivatised side chain amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
  • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
• • 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
  • C07K5/08—Tripeptides
  • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
• • 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 macrocyclic compounds of the following formula (I) and methods for their preparation are known from: Tsantrizos et al., U.S. Pat. No. 6,608,027 B1; Llinas Brunet et al, U.S. Application Publication No. 2003/0224977 A1; Llinas Brunet et al, WO 2004/037855; Llinas Brunet et al, U.S. application Ser. No. 10/945,518, filed Sep. 20, 2004; Brandenburg et al., WO 2004/092203 and Mull et al., U.S. Application Publication No. 2004/0248779 A1: wherein Q is a substituent of the following formula: and the other variables are as defined herein.
• C 1-6 alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• the last named group is the radical attachment point, for example, “thioalkyl” means a monovalent radical of the formula HS-Alk-. Unless otherwise specified below, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups.
• C 3-6 cycloalkoxy as used herein, either alone or in combination with another substituent, means the substituent C 3-6 cycloalkyl-O— containing from 3 to 6 carbon atoms.
• haloalkyl as used herein means as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents having one or more hydrogens substituted for a halogen selected from bromo, chloro, fluoro or iodo.
• C 6 or C 10 aryl as used herein, either alone or in combination with another substituent, means either an aromatic monocyclic system containing 6 carbon atoms or an aromatic bicyclic system containing 10 carbon atoms.
• aryl includes a phenyl or a naphthyl ring system.
• esters may be a C 1-16 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro or trifluoromethyl.
• the compounds of formula (II) used as starting material are either commercially available, e.g., Boc-4(R)-hydroxyproline, or can be prepared from known materials using conventional techniques.
• the compounds of formula (II) may be prepared by amino-protection of the 4-hydroxyproline compounds of formula (X):
• hydroxyl-susbtituted quinoline compounds of formula (III′) can be synthesized from commercially available materials using the techniques described in WO 00/59929, WO 00/09543 and WO 00/09558, U.S. Pat. No. 6,323,180 B1, U.S. Pat. No. 6,608,027 B1 and U.S. Patent Application Publication No. 2005/0020503 A1.
• Step (ii) is directed to a process for preparing a compound of formula (VI) said process comprising reacting a compound of the formula (IV) with a compound of the formula (V): wherein A is an amide of formula —C(O)—NH—R 11 , wherein R 11 is selected from the group consisting of: C 1-8 alkyl, C 3-6 cycloalkyl, C 6 or C 10 aryl; C 7-16 aralkyl and SO 2 R 11A wherein R 11A is C 1-8 alkyl, C 3-7 cycloalkyl or C 1-6 alkyl-C 3-7 cycloalkyl; or A is a protected carboxylic acid group;
• the compounds of formulas (IV) and (V) may be linked together by well known peptide coupling techniques. See, for example, the techniques disclosed in WO 00/09543, WO 00/09558 and U.S. Pat. No. 6,608,027 B1.
• Peptide coupling between compounds of formula (IV) and (V) could be obtained, for example, under a variety of conditions known in the art using conventional peptide coupling reagents such as DCC, EDC, TBTU, HBTU, HATU, DMTMM, HOBT, or HOAT in aprotic solvents such as dichloromethane, chloroform, THF, DMF, NMP, DMSO.
• the compounds of formula (V) are known from WO 00/09543, WO 00/09558 and U.S. Pat. No. 6,608,027 B 1, and may be prepared by techniques as described therein.
• Step (iii) is directed to a process for removing the nitrogen protecting group in the compound of formula (VI) to obtain a compound of the formula (VII):
• step (ii) the compounds of formulas (VII) and (VIII) may be linked together by the same well known peptide coupling techniques as described above in step (ii) for the peptide coupling of formulas (IV) and (V).
• Examplary conditions are the same as described above for step (ii).
• the substituted acid compound of formula (VIII) used as a starting material are known from U.S. Pat. No. 6,608,027 B1 and may be obtained from commercially available materials using the techniques as described therein.
• Suitable ruthenium catalysts for the cyclization step include, for example, the compounds of formula A, B, C, D or E: wherein
• the ruthenium catalyst is a compound of formula (A-1) or (A-2): wherein:
• the ruthenium catalyst is selected from: where Ph is phenyl and Mes is 2,4,6-trimethylphenyl.
• Ruthenium-based catalysts useful for the metathesis cyclization step are all known catalysts that may be obtained by known synthetic techniques. For example, see the following references for examples of suitable ruthenium-based catalysts:
• the ring-closing reaction of step (v) is carried out in the presence of a diluent in a temperature range from about 30° to about 120° C., preferably from about 90° to about 108° C., in particular at about 100° C.
• the ring-closing reaction of step (v) is carried out in the presence of a diluent selected from alkanes, such as n-pentane, n-hexane or n-heptane, aromatic hydrocarbons, such as benzene, toluene or xylene, chlorinated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane or dichloroethane, ether solvents, such as tetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether or dioxane and methyl alcohol.
• alkanes such as n-pentane, n-hexane or n-heptane
• aromatic hydrocarbons such as benzene, toluene
• the ring-closing reaction of step (v) is carried out at a ratio of the diene compound of formula IX to diluent in the range from 1:400 by weight to 1:25 by weight, preferably from 1:200 by weight to 1:50 by weight, in particular from 1:150 by weight to 1:75 by weight.
• One skilled in the art can readily optimize the cyclization step by selecting and adjusting appropriate conditions suitable for the particular ring-closing catalyst selected. For example, depending upon the catalyst selected it may be preferable to run the cyclization step at high temperature, e.g., higher than 90° C., although lower temperatures may also be possible with the addition of an activator such as copper halide (CuX, where X is halogen) to the reaction mixture.
• an activator such as copper halide (CuX, where X is halogen)
• this ring-closing reaction of step (v) is performed using the 2 nd generation Hoveyda's catalyst, in a temperature range of from about 90° to about 108° C., for example at about 100° C., in the presence of an aromatic hydrocarbon diluent, for example toluene, using portionwise addition of the catalyst in the range from 2 to 6 portions, for example from 3-5 portions, in particular 4 portions.
• this ring-closing reaction of step (v) is performed using the 2 nd generation Hoveyda's catalyst, in a temperature range of from about 30° to about 45° C., for example at about 40° C., in the presence of a suitable activator such as copper iodide, in a chlorinated hydrocarbon diluent or an aromatic hydrocarbon diluent, for example dichloromethane, using a one-pot addition or a portionwise addition of the catalyst in the range from 2 to 4 portions, in particular a one-pot addition.
• a suitable activator such as copper iodide
• chlorinated hydrocarbon diluent or an aromatic hydrocarbon diluent for example dichloromethane
• the compound of formula (IX) is dissolved in a degassed organic solvent (such as toluene or dichloromethane) to a concentration below about 0.02M, then treated with a ruthenium-based catalyst such as Hoveyda's catalyst, at a temperature from about 40° C. to about 110° C. until completion of the reaction.
• a ruthenium-based catalyst such as Hoveyda's catalyst
• Some or all of the ruthenium metal may be removed from the reaction mixture by treatment with a suitable heavy metal scavenger, such as THP or other agents known to scavenge heavy metals.
• the reaction mixture is washed with water, followed by partial concentration of the organic solution (e.g., by distillation process).
• the organic solution may be decolorized, such as by the addition of activated charcoal with subsequent filtration, and then is added to a suitable solvent at a suitable temperature, such as pre-cooled methylcyclohexane, which causes precipitation of the product compound of formula (I) that is collected by filtration.
• a suitable solvent such as pre-cooled methylcyclohexane
• the esterified compound of formula (I) can optionally be subjected to hydrolysis conditions to obtain the corresponding free carboxylic acid compound.
• Hydrolysis can be carried out using conventional hydrolysis conditions known in the art.
• the esterified compound of formula (I) is dissolved in an organic solvent such as THF, and a suitable hydrolyzing agent such as lithium hydroxide monohydrate (LiOH.H 2 O) is added followed by the addition of water.
• a suitable hydrolyzing agent such as lithium hydroxide monohydrate (LiOH.H 2 O) is added followed by the addition of water.
• the resultant solution is stirred at a temperature from about 35° C. to about 50° C.
• the solution is cooled, and the organic layer collected.
• a suitable solvent such as ethanol is added to the organic layer and the pH is adjusted to from about pH 5 to about pH 6.
• the mixture is then warmed to a temperature from about 40° C. to about 50° C. at which point water is added and solution is stirred whereupon the compound of formula (I) begins to precipitate.
• the solution is cooled to ambient temperature and the compound of formula (I) is collected by filtration, washed and dried.
• the olefin group is in the configuration syn to the A group as represented by structure (ii) above;
• L 0 , L 1 , L 2 and R 2 are as defined below: Cpd # L 2 L 0 L 1 R 2 101 H —OMe Me 102 H —OMe Me 103 H —OMe Me 104 H —OMe Me 105 H —OMe Br 106 H —OMe Br 107 H —OMe Cl 108 H —OMe Cl 109 Me —OMe Me 110 Me —OMe Me 111 H —OMe F 112 H —OMe F 113 H —OMe Cl 114 H —OMe Br 115 H —OMe Br 116 H —OMe Br
• R 13 , R 4 and R 2 are defined as follows: Cpd # R 13 : R 4 : R 2 : 201 H 202 H 203 H 204 H OEt; 205 H OEt; 206 H 207 H 208 H 209 H 210 H 211 H 212 H 213 H 214 H 215 H 216 H 217 H 218 H 219 H 220 10-(R)Me OEt; 221 H 222 H 223 H and 224 H

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• 2005
  • 2005-03-11 RU RU2006136084/04A patent/RU2006136084A/ru not_active Application Discontinuation
  • 2005-03-11 EP EP05725498A patent/EP1730166B1/en active Active
  • 2005-03-11 DE DE602005019700T patent/DE602005019700D1/de active Active
  • 2005-03-11 JP JP2007503990A patent/JP4654239B2/ja active Active
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  • 2005-03-11 US US11/078,074 patent/US20050209135A1/en not_active Abandoned
  • 2005-03-11 WO PCT/US2005/008366 patent/WO2005090383A2/en active Application Filing
  • 2005-03-11 AU AU2005224092A patent/AU2005224092A1/en not_active Abandoned
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