[go: up one dir, main page]

EP1189862A1 - Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates - Google Patents

Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates

Info

Publication number
EP1189862A1
EP1189862A1 EP00946871A EP00946871A EP1189862A1 EP 1189862 A1 EP1189862 A1 EP 1189862A1 EP 00946871 A EP00946871 A EP 00946871A EP 00946871 A EP00946871 A EP 00946871A EP 1189862 A1 EP1189862 A1 EP 1189862A1
Authority
EP
European Patent Office
Prior art keywords
formula
substituted
compound
carbon atoms
alkyl
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Withdrawn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
EP00946871A
Other languages
German (de)
French (fr)
Inventor
Pooran Chand
Arthur J. Elliott
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.)
Biocryst Pharmaceuticals Inc
Original Assignee
Biocryst Pharmaceuticals Inc
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 Biocryst Pharmaceuticals Inc filed Critical Biocryst Pharmaceuticals Inc
Publication of EP1189862A1 publication Critical patent/EP1189862A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • This invention relates to methods for preparing certain substituted cyclopentane compounds and certain intermediates thereof.
  • the present invention is also concerned with novel intermediates or precursors for producing the substituted cyclopentane compounds.
  • Substituted cyclopentane compounds prepared according to the present invention are useful as neuraminidase inhibitors, and especially in pharmaceutical composition for preventing, treating or ameliorating viral, bacterial and other infections.
  • influenza remains a potentially devastating disease of man, lower mammals, and birds. No effective vaccine exists and no cure is available once the infection has been initiated.
  • Influenza viruses consist of eight pieces of single stranded RNA, packaged in orderly fashion within the virion. Each piece codes for one of the major viral proteins.
  • the replication complex is enclosed with a membrane composed of matrix protein associated with a lipid bilayer. Embedded in the lipid bilayer are two surface glycoprotein spikes, hemagglutinin (HA) and the enzyme neuraminidase (NA) . All of the viral genes have been cloned and the three- dimensional structures of the surface glycoproteins have been determined.
  • HA hemagglutinin
  • NA neuraminidase
  • Influenza viruses continually undergo antigenic variation in the two surface antigens, HA and NA, toward which neutralizing antibodies are directed. For this reason, vaccines and a subject's natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents acting at other sites of the virion.
  • NA-possessing organisms are also major pathogens of man and/or mammals, including Vijbraeo cholerae, Clostridium perfringes, Streptococcus pneumonia, Arthrobacter sialophilas, and other viruses, such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus.
  • viruses such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus.
  • Compounds of this invention are also directed to inhibiting NA of these organisms.
  • NA exists as a tetramer made of four roughly spherical subunits and a centrally-attached stalk containing a hydrophobic region by which it is embedded in the organism's membrane.
  • the enzyme catalyzes cleavage of the ⁇ -ketosidic linkage between terminal sialic acid and an adjacent sugar residue. Removal of the sialic acid lowers the viscosity and permits access of the virus to the epithelial cells.
  • NA also destroys the HA receptor on the host cell, thus allowing elution of progeny virus particles from infected cells .
  • influenza neuraminidase remains substantially unchanged for the major strains of influenza. For example, a comparison of sequences from influenza A subtypes and influenza B shows conserved residues with crucial structural and functional roles. Even though the sequence homology is only about 30%, many of the catalytic residues are conserved. Furthermore, the three-dimensional structures of influenza A and B neuraminidases have been determined. Superposition of the various structures shows remarkable structural similarity of the active site.
  • an inhibitor that is effective against different strains of influenza A and/or B neuraminidase can be designed based on the three-dimensional structure of a neuraminidase.
  • the role of NA is thought to be for the mobility of the virus both to and from the site of infections.
  • Compounds that inhibit neuraminidase ' s activity may protect a subject from infection and/or cure a subject once infection has set in.
  • A is 0, C or S in Formula (a) , and N or C in Formula (b) ;
  • R 1 is C0 2 H, P0 3 H 2 , N0 2 , S0 2 H, SO 3 H, tetrazolyl-, CH 2 CHO, CHO, or CH (CHO) 2 ;
  • R 2 is H, OR 6 , F, Cl, Br, CN, NHR 6 , SR 6 or CH 2 X, where X is NHR 6 halogen, or OR 6 ;
  • R 4 is NHR 6 , SR 6 , OR 6 , C0 2 R 6 , N0 2 , C (R 6 ) 3 ., CH 2 C0 2 R 6 , CH 2 N0 2 or CH 2 NHR S ;
  • R 5 is CH 2 YR 6 , CHYR 6 CH 2 YR 6 or CHYR 6 CHYR 6 CH 2 YR 6 ;
  • R 6 is H, acyl, alkyl, allyl, or aryl;
  • Y is 0, S, NH, or H; and pharmaceutical salts thereof, useful as antiviral agents .
  • WO 96/26933 to Gilead Sciences, Inc. describes certain 6-membered ring compounds as possible inhibitors of neuraminidase. More recently, there have been disclosed new cyclopentane derivatives that are useful as neuraminidase inhibitors. For example, see WO 96/30329, assigned to BioCryst Pharmaceuticals, Inc., the assignee of the present application, the entire disclosure of which being incorporated herein by reference.
  • the present invention relates to methods for preparing certain substituted cyclopentane compounds that are useful as inhibitors of the enzyme neuraminidase. Moreover, the present invention is concerned with a method for preparing certain precursors of the substituted cyclopentane compounds.
  • each Ri individually is alkyl or substituted alkyl, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R 2 and R 3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R 2 and R 3 is other than H;
  • A is H, F, ORi, OCORi, -OOCNHRi, NHR X , or NHCOOR ⁇ ; and pharmaceutically acceptable salts thereof.
  • the precursors according to the present invention are isoxazoline derivatives represented by the following formula 4 :
  • R 2 and R 3 are the same as defined above and wherein each of Y and Z individually is COORi or H provided that at least one of Y and Z is other than H.
  • the isoxazoline derivatives according to formula 4 are prepared according to the following procedure:
  • R 2 , R 3 , Y and Z are the same as defined above.
  • the cyclopentane compounds of formula la can be prepared from the above isoxazoline derivatives by reducing the isoxazoline derivatives of formula 4 to form an aminoalcohol derivative according to formula 5. Reacting the aminoalcohol compound of formula 5 with an anhydride or acid halide of a carboxylic acid of the formula: RiCOOH to produce the acylated compounds represented by formula 6. Next, the alcohol group of the acylated compounds is converted into a leaving group which in turn is displaced by ammonia or guanidine to produce compounds of formula la or the leaving group is displaced by an azide ion which in turn is converted to the guanidine using NH 2 compound. In an alternative process for preparing the cyclopentane compounds of formula la, an isoxazoline compound of formula 4 is converted to ketone according to formula 7
  • R is H or a substituted benzyl.
  • R is a substituted benzyl, such is removed to give the aminoalcohol compounds of formula 5.
  • the aminoalcohols are then converted to the final product as discussed above.
  • cyclopentane derivatives of formula 9 can be reacted with a nitrile oxide of formula 2 to give the isoxazoline derivatives 10 as shown in Scheme 2.
  • Such isoxazolines may be converted to compounds 12 and may further be dehydrated to give the unsaturated compounds 13.
  • the OH may be converted to NH 2 or F by conventional methods known in the art to afford compounds 14 and 15 respectively.
  • each Ri individually is alkyl or substituted alkyl of 1-6 carbon atoms, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R 2 and R 3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R 2 and R 3 is other than H;
  • A is H, F, ORi, OCOR 1( -OOCNHRi, NHRi, or NHCOORi; and pharmaceutically acceptable salts thereof .
  • the alkyl groups contain 1 to about 8 carbon, and preferably 1 to about 3 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups .
  • alkyl groups examples include methyl, ethyl and propyl .
  • branched alkyl groups include isopropyl and t-butyl.
  • suitable cyclic aliphatic groups typically contain 4-8 carbon atoms and include cyclopentyl and cyclohexyl.
  • the aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C ⁇ - 3 alkyl such as benzyl.
  • substituted cycloalkyl groups include cyclic aliphatic groups typically containing 4-8 carbon atoms in the ring substituted with alkyl groups typically having 1-6 carbon atoms and/or hydroxy group. Usually 1 or 2 substituted groups are present.
  • the lower alkylene group can be straight, branched chain or cyclic unsaturated hydrocarbon group and contains 2-8 carbon atoms and preferably 2-3 carbon atoms.
  • alkylene groups are vinyl, 1-propenyl, allyl, isopropenyl, 2-methyl-2-propenyl and cyclopentenyl .
  • Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable, inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, p-toluenesulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
  • Salts derived from appropriate bases include alkali such as sodium and ammonia .
  • Examples of some specific compounds within the scope of the present invention are: t-3 - (l-Acetylamino-2-ethyl) butyl-c-4- (aminoimino) methylamino-t-2-hydroxycyclopentane-r-l- carboxylic acid;
  • Ri, R 2 and R 3 are the same as defined above and wherein each of Y and Z individually is COORi or H provided that at least one of Y and Z is other than H.
  • the isoxazoline derivatives according to formula 4 are prepared according to scheme 1 illustrated below.
  • R 2 , R 3 Y and Z are the same as defined above.
  • nitrile oxides are conveniently prepared in si tu by the method of Mukaiyama et al [J. Amer. Chem. Soc . , Vol. 82, pp. 5339-5342 (1960) ] .
  • the derivatives obtained are cis/trans mixtures which optionally may be separated by conventional means such as chromatography or crystallization.
  • one of the carboxyl groups may be removed by selective hydrolysis and subsequent decarboxylation. Such selective hydrolysis may be achieved either chemically or enzymatically.
  • the product may be further separated, by conventional means, into its two enantiomers in order to obtain an optically pure compound, if desired.
  • the cycloaddition reaction may be achieved with enrichment of the desired enantiomer .
  • the cyclopentane compounds of formula la as illustrated in scheme 1 can be prepared from the above isoxazoline derivatives by reducing the isoxazoline derivatives of formula 4 to form an aminoalcohol derivative according to formula 5.
  • the isoxazoline derivatives 4 can be reduced to form the aminoalcohol derivatives 5 directly by catalytic hydrogenation using catalysts such as Raney nickel or precious metal catalysts such as palladium or platinum. Alternatively, the reduction may be achieved with a chemical reducing agent such as a hydride reagent. If desired, by the choice of suitable reducing agents, such reductions may be done stereospecifically to obtain a single isomer. If a mixture of isomers is obtained, then separation of the isomers may be achieved by conventional separation techniques .
  • the aminoalcohol compound of formula 5 is reacted with an anhydride or acid halide, e.g. acid chloride, of a carboxylic acid of the formula: RiCOOH to produce the acylated compounds represented by formula 6.
  • an anhydride or acid halide e.g. acid chloride
  • a carboxylic acid of the formula: RiCOOH e.g. carboxylic acid of the formula: RiCOOH
  • the alcohol group of the acylated compounds is converted into a leaving group by conventional means.
  • suitable leaving groups are tosylate and mesylate.
  • the leaving group in turn, is displaced by ammonia or guanidine to produce compounds of formula la.
  • the leaving group can be displaced by an azide ion which in turn is converted to the guanidine using NH 2 compound.
  • the ring can be opened by hydrolysis .
  • the ketone of formula 7 is subjected to reductive amination to form a compound according to formula 8
  • R 4 is H or a benzyl group optionally substituted with an ⁇ -alkyl group of 1-3 carbon atoms.
  • the reduction may be done stereospecifically. Further, the optical resolution may conveniently be performed at this stage.
  • R 4 is a substituted benzyl, such is removed, for example by catalytic hydrogenation to give the aminoalcohol compounds of formula 5.
  • the aminoalcohols are then converted to the final product as discussed above.
  • cyclopentane derivatives of formula 9 can be reacted with a nitrile oxide of formula 2 to give the isoxazoline derivatives 10 as shown in Scheme 2.
  • Such isoxazolines may be converted to compounds 12 and may further be dehydrated to give the unsaturated compounds 13.
  • the OH may be converted to NH 2 or F by conventional methods known in the art to afford compounds 14 and 15 respectively.
  • OH may be reacted with a carboxylic acid derivative RiCOOH, for example an acid anhydride to produce the esters -OCORi.
  • the NH 2 compound may be reacted with a carboxylic acid derivative to give HNCORi or with an alkyl chloroformate derivative, RiOCOCl, to give the carbamates NHCOORi .
  • Phosphorus tribromide (33.3 g, 0.123 mol) was added dropwise to 2 -propyl-1-pentanol (40 g, 0.307 mol) at -10°C to maintain the temperature below 0°C and the mixture was stirred overnight at room temperature.
  • the reaction mixture was heated at 100°C for 1 h, cooled to room temperature, and poured into ice water (250 ml) . The organic layer was separated, washed with cone. H 2 S0 4 (25 ml) followed by saturated K 2 C0 3 (25 ml) , dried and distilled in vacuo (80°C/15 mm Hg) to furnish 40 g (83%) of l-bromo-2- propylpentane .
  • the antiviral compounds prepared by the processes of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent's site of action with the viral neuraminidase in the body of a human, mammal, bird, or other animal. They can be administered by an conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • a daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.
  • Dosage forms contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. The active ingredient can also be administered intranasally (nose drops) or by inhalation. Other dosage forms are potentially possible such as administration transdermally, via a patch mechanism or ointment .
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract .
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract .
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol .
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • Useful pharmaceutical dosage forms for administration of the compounds prepared according to the present invention can be illustrated as follows:
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mu of the active ingredient.
  • the capsules are washed and dried.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose.
  • Appropriate coatings may be applied to increase palatability or delay absorption.
  • the compounds of the present invention can be administered in the form of nose drops or a nasal inhaler.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to methods for preparing substituted cyclopentene compounds, their intermediates and use as neuraminidase inhibitors.

Description

PREPARATION OF SUBSTITUTED CYCLOPENTANE AND
CYCLOPENTENE COMPOUNDS AND CERTAIN INTERMEDIATES
DESCRIPTION
Technical Field
This invention relates to methods for preparing certain substituted cyclopentane compounds and certain intermediates thereof. The present invention is also concerned with novel intermediates or precursors for producing the substituted cyclopentane compounds. Substituted cyclopentane compounds prepared according to the present invention are useful as neuraminidase inhibitors, and especially in pharmaceutical composition for preventing, treating or ameliorating viral, bacterial and other infections.
Background of the Invention
Despite the wealth of information available, influenza remains a potentially devastating disease of man, lower mammals, and birds. No effective vaccine exists and no cure is available once the infection has been initiated.
Influenza viruses consist of eight pieces of single stranded RNA, packaged in orderly fashion within the virion. Each piece codes for one of the major viral proteins. The replication complex is enclosed with a membrane composed of matrix protein associated with a lipid bilayer. Embedded in the lipid bilayer are two surface glycoprotein spikes, hemagglutinin (HA) and the enzyme neuraminidase (NA) . All of the viral genes have been cloned and the three- dimensional structures of the surface glycoproteins have been determined.
Influenza viruses continually undergo antigenic variation in the two surface antigens, HA and NA, toward which neutralizing antibodies are directed. For this reason, vaccines and a subject's natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents acting at other sites of the virion.
Furthermore, many other organisms carry NA. Many of these NA-possessing organisms are also major pathogens of man and/or mammals, including Vijbraeo cholerae, Clostridium perfringes, Streptococcus pneumonia, Arthrobacter sialophilas, and other viruses, such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, and Sendai virus. Compounds of this invention are also directed to inhibiting NA of these organisms.
In viruses, NA exists as a tetramer made of four roughly spherical subunits and a centrally-attached stalk containing a hydrophobic region by which it is embedded in the organism's membrane. Several roles have been suggested for NA. The enzyme catalyzes cleavage of the α-ketosidic linkage between terminal sialic acid and an adjacent sugar residue. Removal of the sialic acid lowers the viscosity and permits access of the virus to the epithelial cells. NA also destroys the HA receptor on the host cell, thus allowing elution of progeny virus particles from infected cells .
Research indicates that the active site for influenza neuraminidase remains substantially unchanged for the major strains of influenza. For example, a comparison of sequences from influenza A subtypes and influenza B shows conserved residues with crucial structural and functional roles. Even though the sequence homology is only about 30%, many of the catalytic residues are conserved. Furthermore, the three-dimensional structures of influenza A and B neuraminidases have been determined. Superposition of the various structures shows remarkable structural similarity of the active site. Since the active site amino acid residues are conserved in all known influenza A neuraminidases that have been sequenced so far, an inhibitor that is effective against different strains of influenza A and/or B neuraminidase can be designed based on the three-dimensional structure of a neuraminidase. In general, the role of NA is thought to be for the mobility of the virus both to and from the site of infections. Compounds that inhibit neuraminidase ' s activity may protect a subject from infection and/or cure a subject once infection has set in.
Analogs of neuraminic acid, such as 2-deoxy-2,3- didehydro-N-acetylneuraminic acid (DANA) and its derivatives are known to inhibit HA in vi tro; however, these compounds are inactive in vivo . Palese and Schulman, in
CHEMOPROPHYLAXIS AND VIRUS INFECTION OF THE UPPER RESPIRATORY TRACT, Vol. 1 (J.S. Oxford, Ed.), CRC Press, 1977, at PS 189-205.
Von Itzstein et al . describes cyclohexane analogs of α-
D-neuraminic acid of the formula
00 ()
wherein: A is 0, C or S in Formula (a) , and N or C in Formula (b) ; R1 is C02H, P03H2, N02, S02H, SO3H, tetrazolyl-, CH2CHO, CHO, or CH (CHO) 2 ;
R2 is H, OR6, F, Cl, Br, CN, NHR6, SR6 or CH2X, where X is NHR6 halogen, or OR6;
R3 and R3 ' are H, CN, NHR6, SR6, =NOR6, OR6, guanidino, NR6; R4 is NHR6, SR6, OR6, C02R6, N02 , C (R6) 3., CH2C02R6, CH2N02 or CH2NHRS ;
R5 is CH2YR6, CHYR6CH2YR6 or CHYR6CHYR6CH2YR6 ; R6 is H, acyl, alkyl, allyl, or aryl; Y is 0, S, NH, or H; and pharmaceutical salts thereof, useful as antiviral agents .
In addition, certain benzene derivatives are suggested in U.S. patent 5,453,533 as being inhibitors of influenza virus neuraminidase and various others are disclosed in U.S. patent application serial number 08/413,886. Yamamoto et al . describe various sialic acid isomers as having inhibitory activity against neuraminidase in Synthesis of Siali c Acid Isomers Wi th Inhibi tory Activi ty Against Neuraminidase, TETRAHEDRON LETTERS, Vol. 33, No. 39, pp. 5791-5794, 1992.
WO 96/26933 to Gilead Sciences, Inc. describes certain 6-membered ring compounds as possible inhibitors of neuraminidase. More recently, there have been disclosed new cyclopentane derivatives that are useful as neuraminidase inhibitors. For example, see WO 96/30329, assigned to BioCryst Pharmaceuticals, Inc., the assignee of the present application, the entire disclosure of which being incorporated herein by reference.
Summary of Invention
The present invention relates to methods for preparing certain substituted cyclopentane compounds that are useful as inhibitors of the enzyme neuraminidase. Moreover, the present invention is concerned with a method for preparing certain precursors of the substituted cyclopentane compounds.
The substituted cyclopentane compounds prepared according to the present invention are represented by the following formulae la and lb:
wherein each Ri individually is alkyl or substituted alkyl, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; X is NHRi, NHC(=NH)NHR4 where R4 is H, alkyl of 1-6 carbon atoms, ORi, CORi, COORi , CN or N02 ; A is H, F, ORi, OCORi, -OOCNHRi, NHRX , or NHCOORι; and pharmaceutically acceptable salts thereof.
The precursors according to the present invention are isoxazoline derivatives represented by the following formula 4 :
wherein R2 and R3 are the same as defined above and wherein each of Y and Z individually is COORi or H provided that at least one of Y and Z is other than H.
The isoxazoline derivatives according to formula 4 are prepared according to the following procedure:
A nitrile oxide of the formula 2
is reacted with a cyclopentene derivative of the formula 3 to produce the desired isoxazoline derivative. R2, R3, Y and Z are the same as defined above.
The cyclopentane compounds of formula la can be prepared from the above isoxazoline derivatives by reducing the isoxazoline derivatives of formula 4 to form an aminoalcohol derivative according to formula 5. Reacting the aminoalcohol compound of formula 5 with an anhydride or acid halide of a carboxylic acid of the formula: RiCOOH to produce the acylated compounds represented by formula 6. Next, the alcohol group of the acylated compounds is converted into a leaving group which in turn is displaced by ammonia or guanidine to produce compounds of formula la or the leaving group is displaced by an azide ion which in turn is converted to the guanidine using NH2 compound. In an alternative process for preparing the cyclopentane compounds of formula la, an isoxazoline compound of formula 4 is converted to ketone according to formula 7
by opening its isoxazoline ring. The ketone of formula 7 is subjected to reductive amination to form a compound according to formula 8
wherein R is H or a substituted benzyl. When R is a substituted benzyl, such is removed to give the aminoalcohol compounds of formula 5. The aminoalcohols are then converted to the final product as discussed above. According to a still further aspect of the present invention, cyclopentane derivatives of formula 9 can be reacted with a nitrile oxide of formula 2 to give the isoxazoline derivatives 10 as shown in Scheme 2. Such isoxazolines may be converted to compounds 12 and may further be dehydrated to give the unsaturated compounds 13.
Alternatively, the OH may be converted to NH2 or F by conventional methods known in the art to afford compounds 14 and 15 respectively.
It is a further object of this invention to provide a method of using compounds of this invention for treating and/or curing a viral infection.
Best and Various Modes for Carrying Out Invention
The substituted cyclopentane compounds prepared according to the present invention are represented by the following formulae la and lb:
wherein each Ri individually is alkyl or substituted alkyl of 1-6 carbon atoms, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; X is NHRi, NHC(=NH)NHR4 where R4 is H, alkyl of 1-6 carbon atoms, ORi, CORi, COORi CN or N02; A is H, F, ORi, OCOR1( -OOCNHRi, NHRi, or NHCOORi; and pharmaceutically acceptable salts thereof .
The alkyl groups contain 1 to about 8 carbon, and preferably 1 to about 3 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups .
Examples of suitable alkyl groups include methyl, ethyl and propyl . Examples of branched alkyl groups include isopropyl and t-butyl. Examples of suitable cyclic aliphatic groups typically contain 4-8 carbon atoms and include cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl Cι-3 alkyl such as benzyl.
Examples of substituted cycloalkyl groups include cyclic aliphatic groups typically containing 4-8 carbon atoms in the ring substituted with alkyl groups typically having 1-6 carbon atoms and/or hydroxy group. Usually 1 or 2 substituted groups are present.
The lower alkylene group can be straight, branched chain or cyclic unsaturated hydrocarbon group and contains 2-8 carbon atoms and preferably 2-3 carbon atoms. Examples of alkylene groups are vinyl, 1-propenyl, allyl, isopropenyl, 2-methyl-2-propenyl and cyclopentenyl .
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, p-toluenesulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia .
Examples of some specific compounds within the scope of the present invention are: t-3 - (l-Acetylamino-2-ethyl) butyl-c-4- (aminoimino) methylamino-t-2-hydroxycyclopentane-r-l- carboxylic acid;
t-3- (l-Acetylamino-2-ethyl) butyl-c-4 -amino-t-2- hydroxycyclopentane-r-1-carboxylic acid;
t-3- (l-Acetylamino-2-ethyl) butyl-c-4- (aminoimino) methylaminocyclopentane-r-1 -carboxylic acid;
t-3- (1-Acetylamino-2-ethyl) butyl-c-4 -aminocyclopentane- r-1-carboxylic acid;
Ethyl t-3- (l-Acetylamino-2-ethyl) butyl-c-4-
(aminoimino) methylamino-t-2-hydroxycyclopentane-r-l- carboxylate;
Ethyl t-3- (l-Acetylamino-2-ethyl) butyl-c-4-amino-t-2- hydroxycyclopentane-r- 1-carboxylate ;
Ethyl t-3- (l-Acetylamino-2-ethyl)butyl-c-4- (aminoimino) methylaminocyclopentane-r-1-carboxylate ;
Ethyl t-3 - (l-Acetylamino-2-ethyl) butyl-c-4- aminocyclopentane-r-1-carboxylate ; t-3- (l-Acetylamino-2-propyl) pentyl-c-4- (aminoimino) methylamino-1-2 -hydroxycyclopentane-r- 1- carboxylic acid;
t-3 - (1- cetylamino-2 -propyl) pentyl-c-4 -amino-1-2- hydroxycyclopentane-r-1-carboxylic acid;
t-3- (1 -Acetylamino-2 -propyl) pentyl-c-4- (aminoimino) methylaminocyclopentane-r-1-carboxylic acid;
t-3- (1 -Acetylamino-2 -propyl) pentyl-c-4 - aminocyclopentane-r-1-carboxylic acid;
Ethyl t-3- (l-Acetylamino-2-propyl) pentyl-c-4-
(aminoimino) methylamino-t-2 -hydroxycyclopentane-r- 1- carboxylate;
Ethyl t-3- (l-Acetylamino-2-propyl) pentyl-c-4-amino-t-2- hydroxycyclopentane-r-1-carboxylate ;
Ethyl t-3- (1-Acetylamino-2-propyl) pentyl-c-4- (aminoimino)methylaminocyclopentane-r-1-carboxylate;
Ethyl t-3- (l-Acetylamino-2-propyl) pentyl-c-4- aminocyclopentane-r-1-carboxylate ; t-3- (1-Acetylamino-3 -ethyl) pentyl-c-4- (aminoimino) methylamino-t-2 -hydroxycyclopentane-r-1- carboxylic acid;
t-3- (1-Acetylamino-3 -ethyl) pentyl-c-4 -amino-t-2- hydroxycyclopentane-r-1-carboxylic acid;
t-3- (1-Acetylamino-3 -ethyl) pentyl-c-4- (aminoimino) methylaminocyclopentane-r-1-carboxylic acid;
t-3- (1-Acetylamino- 3 -ethyl) pentyl-c-4 - aminocyclopentane-r-1-carboxylic acid;
Ethyl t-3- (l-Acetylamino-3 -ethyl) pentyl-c-
4 (aminoimino) methy1amino-1-2 -hydroxycyc1opentane-r-1- carboxylate;
Ethyl t-3- (l-Acetylamino-3-ethyl)pentyl-c-4-amino-t-2- hydroxycyclopentane-r-1-carboxylate ;
Ethyl t-3- (l-Acetylamino-3-ethyl)pentyl-c-4- (aminoimino) methylaminocyclopentane-r-1-carboxylate ;
Ethyl t-3- (1-Acetylamino-3 -ethyl) pentyl-c-4- aminocyclopentane-r-1-carboxylate . The precursors according to the present invention are isoxazoline derivatives represented by the following formulae 4 and 10
wherein Ri, R2 and R3 are the same as defined above and wherein each of Y and Z individually is COORi or H provided that at least one of Y and Z is other than H.
The isoxazoline derivatives according to formula 4 are prepared according to scheme 1 illustrated below.
In particular, nitrile oxide of the formula 2
is reacted with a cyclopentane derivative of the formula 3 to produce the desired isoxazoline derivative. R2, R3 Y and Z are the same as defined above.
The nitrile oxides are conveniently prepared in si tu by the method of Mukaiyama et al [J. Amer. Chem. Soc . , Vol. 82, pp. 5339-5342 (1960) ] .
When Y is H, the derivatives obtained are cis/trans mixtures which optionally may be separated by conventional means such as chromatography or crystallization. When Y = Z = COORi, one of the carboxyl groups may be removed by selective hydrolysis and subsequent decarboxylation. Such selective hydrolysis may be achieved either chemically or enzymatically. After separation of the stereoisomers , the product may be further separated, by conventional means, into its two enantiomers in order to obtain an optically pure compound, if desired. Alternatively, by the suitable choice of chiral auxiliaries in Y or Z, the cycloaddition reaction may be achieved with enrichment of the desired enantiomer .
The cyclopentane compounds of formula la as illustrated in scheme 1 can be prepared from the above isoxazoline derivatives by reducing the isoxazoline derivatives of formula 4 to form an aminoalcohol derivative according to formula 5. The isoxazoline derivatives 4 can be reduced to form the aminoalcohol derivatives 5 directly by catalytic hydrogenation using catalysts such as Raney nickel or precious metal catalysts such as palladium or platinum. Alternatively, the reduction may be achieved with a chemical reducing agent such as a hydride reagent. If desired, by the choice of suitable reducing agents, such reductions may be done stereospecifically to obtain a single isomer. If a mixture of isomers is obtained, then separation of the isomers may be achieved by conventional separation techniques .
The aminoalcohol compound of formula 5 is reacted with an anhydride or acid halide, e.g. acid chloride, of a carboxylic acid of the formula: RiCOOH to produce the acylated compounds represented by formula 6. Next the alcohol group of the acylated compounds is converted into a leaving group by conventional means. Examples of suitable leaving groups are tosylate and mesylate. The leaving group, in turn, is displaced by ammonia or guanidine to produce compounds of formula la. In the alternative, the leaving group can be displaced by an azide ion which in turn is converted to the guanidine using NH2 compound.
In an alternative process for preparing the cyclopentane compounds of formula la, an isoxazoline compound of formula 4 is converted to ketone according to formula 7
by opening its isoxazoline ring. The ring can be opened by hydrolysis .
The ketone of formula 7 is subjected to reductive amination to form a compound according to formula 8
8
wherein R4 is H or a benzyl group optionally substituted with an α-alkyl group of 1-3 carbon atoms.
If an optically pure benzyl derivative, e.g. (+) - or (■ ) -α-methylbenzyl is used, the reduction may be done stereospecifically. Further, the optical resolution may conveniently be performed at this stage.
When R4 is a substituted benzyl, such is removed, for example by catalytic hydrogenation to give the aminoalcohol compounds of formula 5. The aminoalcohols are then converted to the final product as discussed above.
According to a still further aspect of the present invention, cyclopentane derivatives of formula 9 can be reacted with a nitrile oxide of formula 2 to give the isoxazoline derivatives 10 as shown in Scheme 2. Such isoxazolines may be converted to compounds 12 and may further be dehydrated to give the unsaturated compounds 13. Alternatively, the OH may be converted to NH2 or F by conventional methods known in the art to afford compounds 14 and 15 respectively. Further, OH may be reacted with a carboxylic acid derivative RiCOOH, for example an acid anhydride to produce the esters -OCORi. Similarly, the NH2 compound may be reacted with a carboxylic acid derivative to give HNCORi or with an alkyl chloroformate derivative, RiOCOCl, to give the carbamates NHCOORi .
Scheme 1
8
Scheme 2
The following non-limiting examples are presented to further illustrate the present invention.
Example 1
(-) -Ethyl cis-4-tert- butoxycarbonylamino-2 -cyclopentene-1-carboxylate .
F.W. 255.313
A mixture of (-) -2-azabicyclo [2.2.1] hept-5-en-3 -one (10 g, 91.7 mmol), ethanol (200 mL) and cone. HCl (10 mL) was heated at reflux for 2h. The mixture was concentrated and the residue dried under vacuum. A white solid was obtained which was suspended in ether to give 17.5 g (100%) of (-)- ethyl cis-4-amino-2-cyclopentene-1-carboxylate hydrochloride.
To a mixture of (-) -ethyl cis-4-amino-2-cyclopentene-l- carboxylate hydrochloride (17.5 g, 91.3 mmol), in CH2C12 (200 mL) at 0°C, was added triethylamine (26 mL, 186.5 mmol), di- tert-butyldicarbonate (26 g, 119 mmol), and 4- dimethylaminopyridine (1 g, 8.2 mmol) and the mixture was stirred at room temperature for 16h. The reaction mixture was washed with water (2 x 200 mL) , and brine (50 mL) , the organic layer was dried (MgS04) and concentrated in vacuo to furnish 21.3 g of crude product. Purification by flash column chromatography (silica gel 600 g, 20-50% ethyl acetate in hexane) gave 15.7 g (67%) of the product as a yellow oil.
Example 2
Ethyl c-4- ert-butoxycarbonylamino-t-3- (2 -propyl) butyl - 4,5,6, 6a-tetrahydro-3aH-cyclopent [d] isoxazole-6-r- carboxylate .
Phosphorus tribromide (33.3 g, 0.123 mol) was added dropwise to 2 -propyl-1-pentanol (40 g, 0.307 mol) at -10°C to maintain the temperature below 0°C and the mixture was stirred overnight at room temperature. The reaction mixture was heated at 100°C for 1 h, cooled to room temperature, and poured into ice water (250 ml) . The organic layer was separated, washed with cone. H2S04 (25 ml) followed by saturated K2C03 (25 ml) , dried and distilled in vacuo (80°C/15 mm Hg) to furnish 40 g (83%) of l-bromo-2- propylpentane .
To a solution of sodium nitrite (30.6 g, 0.43 mol) in DMSO (700 ml) was added l-bromo-2-propylpentane (49 g, 0.254 mol) . The mixture was stirred overnight at room temperature and poured into ice water (700 g) . The mixture was extracted with ether (4 x 250 ml) , the organic layers were combined, washed with water (2 x 500 ml) , brine (500 ml) , dried and concentrated in vacuo to furnish 37.4 g (93%) of l-nitro-2-propylpentane which was 85% pure based on 1H NMR data.
A mixture of l-nitro-2-propylpentane (16 g, 75.4 mmol) and Et3N (1.0 mL, 7.2 mmol) in benzene (75 ml) was added dropwise to a refluxing solution of (-) -ethyl 4-tert- butoxycarbonylaminocyclopentene-1-carboxylate (16.1 g, 62.9 mmol) and phenyl isocyanate (14.65 mL, 132.1 mmol) in benzene (125 ml) over lh. The mixture was boiled under reflux for 16 h, the solids were filtered off and washed with Et20 (20 mL) . The combined filtrates were concentrated to yield an orange oil. This crude product was purified by flash chromatography (750 g, Si02) using ethyl acetate (5%- 20%) in hexane to give 15.75 g (62%) of ethyl c-4-tert- butoxycarbonylamino- t-3- (2 -propyl) butyl-4, 5,6, 6a-tetrahydro- 2aH-cyclopent [d] isoxazole-6-r-carboxylate .
Example 3
(-) -Ethyl t-3- (l-acetylamino-2~propyl) pentyl-c-4- ert- butoxycarbonylamino- t-2 -hydroxycyclopentane-r-1-carboxylate
F.W.442.60
To a mixture of ethyl c-4- ert-butoxycarbonylamino- -3- (2-propyl) utyl-4 , 5,6, 6a-tetrahydro-2aH- cyclopent [d] isoxazole-6-r-carboxylate (15 g, 39.8 mmol) in ethanol/water/acetic acid (1:1:1, 120 mL) , was added Pt02 (1.5 g) . The reaction mixture was hydrogenated at 45 psi for 60h. The catalyst was removed by filtration and the filtrate was concentrated to give 19 g of (-) -ethyl t-3- (1- amino-2-propyl) -pentyl-c-4- tert-botoxycarbonylamino- -2- hydroxycycl open tane -r -1-carboxylate as an oil, which was used without further purification.
To a solution of the above compound (15.9 g, 39.8 mmol) in CH2C12 (200 mL) was added Ac20 (8 mL, 80 mmol) . The reaction mixture was stirred at room temperature for 2 h and poured into ice water (50 mL) . The reaction mixture was neutralized with cone. NH40H. The organic layer was separated, washed with brine (50 mL) , dried (MgS04) and concentrated in vacuo to furnish 17.6 g of crude product as an oil. Purification by flash column chromatography (silica gel 510 g, 50%, 75% and 100% EtOAc in hexane) gave 10.59 g (61%) of the product. Ether/hexane (10/50 mL) was added to the oil and stored in the freezer overnight. The crystals obtained were collected by filtration to furnish 4.0 g of the product as a white solid; mp 128-129°C.
Example 4
(-) -Ethyl t-3- (1-acetylamino-2 -propyl) pentyl-c-4- [ ( ert- butoxycarbonylamino- ert-butoxycarbonylimino) methyl] amino- -2 -hydroxycyclopentane-r-1 -carboxylate
F.W.584.75
To a solution of (-) -ethyl t-3- (l-acetylamino-2- propyl) pentyl-c-4- ert-butoxycarbonylamino- -2- hydroxycyclopentane-r-1-carboxylate (0.5 g, 1.13 mmol) in CH2C12 (10 mL) was added trifluoroacetic acid (1.75 mL, 22.6 mmol) . After stirring at room temperature for 16 h, the reaction mixture was concentrated and dried in vacuo to furnish (-) -ethyl t-3- (l-acetylamino-2-propyl) pentyl-c-4- amino- -2 -hydroxycyclopentane-r-1-carboxylate .
To the above compound dissolved in dry DMF (10 ml) was added Et3N (0.55 ml, 3.96 mmol), 1 , 3-bis ( ert- butoxycarbonyl) -2-methyl-2-thiopseudourea (0.37 g, 1.24 mmol) and HgCl2 (0.34 g, 1.24 mmol) . The reaction mixture was stirred for 16 h at room temperature and was diluted with EtOAc (50 ml) . The reaction mixture was filtered through Celite and washed with water (2 x 10 ml) , brine (10 ml), dried (MgS04) and concentrated in vacuo to furnish 0.7 g of the crude product. The crude was purified by flash column chromatography (silica gel, 33 g, 20-30% EtOAc in hexane) to furnish 0.54 g (82%) of the product as a white foam, mp 42-43°C.
Example 5
( - ) -Ethyl t-3 - ( l -acetylamino-2 -propyl ) pentyl - c-4 -
[ (aminoimino) methyl] amino- -2 -hydroxycyclopentane- r- l- carboxylate
F.W. 555.55 A mixture of (-) -ethyl t-3 - (l-acetylamino-2- propyl) pentyl-c-4- [ ( ert-butoxycarbonylamino- tert- butoxycarbonylimino) methyl] amino- t-2 -hydroxycyclopentane-r- 1-carboxylate (0.5 g, 0.85 mmol) in dichloromethane (10 mL) was stirred with trifluoroacetic acid (1.3 mL, 17.2 mmol) for 16 h at room temperature. The mixture was concentrated and co-evaporated with toluene (2X) . The residue was triturated with ether-hexane to give 0.4 g (95%) of the product as a white solid, mp 105-107°C.
Example 6
(-) - -3- (1-Acetylamino-2 -propyl) entyl-c-4- [ (aminoimino) methyl] amino- t-2- hydroxycyclopentane-r-1-carboxylic acid
F.W. 356.46
A mixture of (-) -ethyl t-3- (l-acetylamino-2- propyl) pentyl-c-4- [(aminoimino) methyl] amino-t-2 - hydroxycyclopentane-r-1-carboxylate (10.1 mg, 18 μmol), IN sodium hydroxide (0.1 mL) and water (0.2 mL) was stirred at room temperature for 2 h, and neutralized with IN HCl. The volume was adjusted to 1.0 mL with water to give 18.0 mmolar solution of the product.
Example 7
(-) -Ethyl t-3- (l-acetylamino-2-propyl) pentyl-c-4- ert- botoxycarbonylamino- -2- (1- imidazolythiocarbonyl) oxycyclopentane-r-1-carboxylate
F.W.552.73
To a mixture of (-) -ethyl t-3 - (l-acetylamino-2- propyl) pentyl-c-4- ert-butoxycarbonylamino- t-2- hydroxycyclopentane-r-1-carboxylate (3.43 g, 7.76 mmol) in CHC12 (50 mL) was added thiocarbonyldiimidazole (3.45 g, 19.41 mmol) and the mixture was heated under reflux for 16 h. The reaction mixture was cooled, washed with 0.25 N HCl (2.50 mL) , water (50 mL) and brine (50 mL) . The organic layer was dried (MgSo4) and concentrated in vacuo to furnish 4.9 g of crude product. Purification by flash column chromatography (silica gel 295 g, 40-90% EtOAc in hexane) gave 1.23 g (29%) of the product as a white foam, mp 58- 60°C.
Example 8
(-) -Ethyl t-3- (l-acetylamino-2-propyl) pentyl-c-4- tert-butoxycarbonylaminocyclo-pentane-r-1-carboxylate
ACHN / ,,, ' C02C2H5
NHBoc
F.W. 426.56
To a solution of (-) -ethyl t-3- (l-acetylamino-2- p opyl) pentyl-c-4- ert-butoxycarbonylamino- -2- (1- imidazolylthiocarbonyl) oxycyclopentane-r-1-carboxylate (1.2 g, 2.17 mmol) in toluene (20 mL) at 70°C was added AIBN (0.39 g, 2.39 mmol) followed by tributyltin hydride (0.64 mL, 2.39 mmol) . The reaction mixture was heated at reflux for 5 minutes and concentrated in vacuo . The residue obtained was dissolved in EtOAc (20 mL) and was washed with 0.25 N HCl (2x20 mL) , water (20 mL) and brine (20 mL) . The organic layer was dried and concentrated in vacuo to furnish crude product as an oil. Purification by flash column chromatography (silica gel 46 g, hexane (2 L) to remove excess tributyltin hydride and 40-50% EtOAc in hexane) gave 0.84 g (91%) of the product as a white foam, mp 81-83°C.
Example 9
( - ) -Ethyl t-3 - ( l-acetylamino-2 -propyl ) pentyl - c-4 - [ ( tert- butoxycarbonylamino- tert-butoxycarbonylimino) methyl] aminocyclopentane-r- 1 - carboxylate hydrate [4 : 1]
F.W. 573.25
To a solution of (-) -ethyl t-3- (l-acetylamino-2- propyl) pentyl-c-4- tert-butoxycarbonylaminocyclopentane-r-1- carboxylate (0.84 g, 1.97 mmol) in CH2C12 (20 mL) was added trifluoroacetic acid (2.28 mL, 29.6 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated and dried in vacuo to furnish (-) -ethyl t-3-(l- acetylamino-2 -propyl) pentyl-c-4-aminocyclopentane-r-1- carboxylate .
To the above compound dissolved in dry DMF (20 ml) was added Et3N (0.97 ml, 6.9 mmol), 1, 3-bis ( tert- butoxyearbonyl) -2-methyl-2-thiopseudourea (0.64 g, 2.17 mmol) and HgCl2 (0.59 g, 2.17 mmol) . The reaction mixture ■ was stirred for 16 h at room temperature and was diluted with EtOAc (50 ml) . The reaction mixture was filtered through Celite and the filtrate was washed with water (2 x 10 ml) , brine (10 ml) , dried (MgS04) and concentrated in vacuo to furnish 1.27 g of the crude product. The crude was purified by flash column chromatography (silica gel 56 g, 30-40% EtOAc in hexane) to furnish 0.82 g (73%) of the product as a white foam, mp 42-43°C.
Example 10
(-) -Ethyl t-3- (l-acetylamino-2-propyl) pentyl-c-4-
[ (aminoimino) methyl] aminocyclopentane-r-1-carboxylate
F.W.491.55
To a solution of (-) -ethyl t-3- (l-acetylamino-2- propyl) pentyl-c-4- [ ( tert-butoxycarbonylamino- ert- butoxycarbonylimino) methyl] aminocyclopentane-r-1 -carboxylate (0.8 g, 1.4 mmol) in CH2C12 (15 mL) was added (2.2 mL, 28.2 mmol) of trifluoroacetic acid and stirred at room temperature for 16 h. The reaction mixture was concentrated and co-distilled with toluene (2x) in vacuo to furnish product as a white residue. The residue was triturated with ether/hexane to furnish 0.5 g (72%) of the product as a white solid, mp 56-58°C.
Examp1e 11
(-) - t-3- (l-Acetylamino-2-propyl) pentyl-c-4- [ (amino- imino) methyl] aminocyclopentane-r-1-carboxylic acid
F.W.340.47
A mixture of (-) -ethyl t-3- (l-acetylamino-2- propyl) pentyl-c-4- [ (amino-imino) -methyl] aminocyclopentane-r- 1-carboxylate (10.2 mg, 21 μmol), IN sodium hydroxide (0.1 mL) and water (0.2 mL) was stirred at room temperature for 2 h and neutralized with IN HCl. The volume was then adjusted to 1.0 mL with water to give a 14.9 mmolar solution of the product . Dosage and Formulation
The antiviral compounds prepared by the processes of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent's site of action with the viral neuraminidase in the body of a human, mammal, bird, or other animal. They can be administered by an conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg. Dosage forms (compositions suitable for administration) contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. The active ingredient can also be administered intranasally (nose drops) or by inhalation. Other dosage forms are potentially possible such as administration transdermally, via a patch mechanism or ointment .
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract .
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol .
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Useful pharmaceutical dosage forms for administration of the compounds prepared according to the present invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mu of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption. Moreover, the compounds of the present invention can be administered in the form of nose drops or a nasal inhaler.
Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims .
The foregoing disclosure includes all the information deemed essential to enable those skilled in the art to practice the claimed invention. Because the cited applications may provide further useful information, these cited materials are hereby incorporated by reference in their entirety.

Claims

Claims :What is claimed is:
1. A method for preparing isoxazoline compounds represented by the formula 4 :
wherein each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; each of Y and Z individually is COORi or H provided that at least one of Y and Z is other than H; which comprises reacting a nitrile oxide of the formula 2
with a cyclopentane derivative of the formula 3
to produce said isoxazoline compound.
2. A method for preparing a substituted cyclopentane compound represented by formula la:
wherein each Rλ individually is alkyl or substituted alkyl, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R and R3 is other than H; X is NHRi, NHC(=NH)NHR4 where R4 is H, alkyl of 1-6 carbon atoms, ORi, CORi, COORi CN or N02; A is H; and pharmaceutically acceptable salts thereof; which comprises: obtaining an isoxazoline compound of formula 4 according to the process of claim 1; reducing said isoxazoline compound of formula 4 to form an aminoalcohol derivative according to formula 5; reacting said aminoalcohol compound of formula 5 with an anhydride or acid halide of a carboxylic acid of the formula: RiCOOH to produce an acylated compound represented by formula 6; converting the alcohol group of said acylated compound into a leaving group; displacing said leaving group with ammonia or guanidine to obtain said compound of formula la; or displacing said leaving group with an azide ion and then converting to a guanidine with a NH2 compound to obtain said compound of formula la.
3. A method for preparing a substituted cyclopentane compound represented by formula la:
wherein each Ri individually is alkyl or substituted alkyl, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; X is NHRi, NHC(=NH)NHR4 where R4 is H, alkyl of 1-6 carbon atoms, ORi, CORi, COORi CN or N02; A is H; and pharmaceutically acceptable salts thereof; which comprises: obtaining an isoxazoline compound of formula 4 according to the process of claim 1 ; converting said isoxazoline compound of formula 4 to a ketone according to formula 7
by opening its isoxazoline ring; subjecting said ketone of formula 7 to reductive amination to thereby form a compound according to formula 8
wherein R4 is H or a substituted benzyl; when R4 is a substituted benzyl, R4 is removed to give the aminoalcohol compound of formula 5 ;
reacting said aminoalcohol compound of formula 5 with an anhydride or acid halide of a carboxylic acid of the formula: RiCOOH to produce an acylated compound represented by formula 6;
converting the alcohol group of said acylated compound into a leaving group; displacing said leaving group with ammonia or guanidine to obtain said compound of formula la; or displacing said leaving group with an azide ion and then converting to a guanidine with a NH2 compound to obtain said compound of formula la.
4. A method for preparing isoxazoline compounds represented by the formula 10 :
wherein each R individually is alkyl or substituted alkyl, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; which comprises reacting a nitrite oxide of formula 2
with a cyclopentane derivative of the formula 9
to produce said isoxazoline compound.
5. A method for preparing a substituted cyclopentane compound represented by formulae la or lb
wherein each Ri individually is alkyl or substituted alkyl, alkenyl or substituted alkenyl of 1-6 carbon atoms, or H; each of R2 and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, aryl or substituted aryl, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; X is NHRi, NHC(=NH)NHR4 where R4 is H, alkyl of 1-6 carbon atoms, ORi, CORi, COORi CN or N02; A is H, F, ORi, OCORi, -OOCNHRi, NHRi, or NHCOORi; and pharmaceutically acceptable salts thereof; which comprises: obtaining an isoxazoline compound of formula 10 according to claim 4; converting said isoxazoline to a compound of formula 12
and dehydrating said compound of formula 12 to produce a compound of formula 13
or converting the OH groups of said compound of formula 12 to a group selected from the group of F, OR, OCOR, NHRi or NHCOOR, except when said grop is ORx, Rx is other than H.
6. An isoxazoline derivative represented by the following formula 4:
wherein each of R and R3 individually is alkyl or alkenyl of 1-8 carbon atoms, cycloalkyl or substituted cycloalkyl of 4-8 carbon atoms, arylalkyl or substituted arylalkyl, or H provided at least one of R2 and R3 is other than H; each of Y and Z individually is COORx or H provided that at least one of Y and Z is other than H.
EP00946871A 1999-06-28 2000-06-28 Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates Withdrawn EP1189862A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14084099P 1999-06-28 1999-06-28
US140840P 1999-06-28
PCT/US2000/017685 WO2001000558A1 (en) 1999-06-28 2000-06-28 Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates

Publications (1)

Publication Number Publication Date
EP1189862A1 true EP1189862A1 (en) 2002-03-27

Family

ID=22493015

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00946871A Withdrawn EP1189862A1 (en) 1999-06-28 2000-06-28 Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates

Country Status (6)

Country Link
EP (1) EP1189862A1 (en)
JP (1) JP2003530306A (en)
AR (1) AR024600A1 (en)
AU (1) AU6056600A (en)
CA (1) CA2377287A1 (en)
WO (1) WO2001000558A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062242A1 (en) * 2000-02-24 2001-08-30 Biocryst Pharmaceuticals, Inc. Prodrugs of substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
WO2002092555A1 (en) * 2001-05-11 2002-11-21 Sankyo Company, Limited Sialic acid derivatives
CN101367750B (en) * 2007-08-14 2012-05-23 中国人民解放军军事医学科学院毒物药物研究所 (1S,2S,3S,4R)-3-[(1S)-1-acet-ammonia-2-ethyl-butyl]-4- guanidino-2-hydroxyl-cyclopentyl-1-carboxylic acid aqua compound and medical uses thereof
CN102584637B (en) * 2011-01-17 2014-07-09 天津药物研究院 Peramivir hydrate crystal, preparation method, medical compound and usage thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1040094T3 (en) * 1997-12-17 2009-06-02 Biocryst Pharm Inc Substituted cyclopentane and cyclopenten compounds useful as neuraminidase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0100558A1 *

Also Published As

Publication number Publication date
WO2001000558A1 (en) 2001-01-04
AR024600A1 (en) 2002-10-16
AU6056600A (en) 2001-01-31
CA2377287A1 (en) 2001-01-04
JP2003530306A (en) 2003-10-14

Similar Documents

Publication Publication Date Title
EP1040094B9 (en) Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
US6410594B1 (en) Substituted cyclopentane compounds useful as neuraminidase inhibitors
KR101535691B1 (en) Synthesis of oseltamivir containing phosphonate congeners with anti-influenza activity
WO1999014191A1 (en) Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors
US20110065762A1 (en) Methods of use of antiviral compounds
JPS6323897A (en) Taftsin analog, manufacture and medicinal composition
JP2005255690A (en) Conformationally restricted polyamines
WO2001062242A1 (en) Prodrugs of substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
US6762316B1 (en) Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates
EP1189862A1 (en) Preparation of substituted cyclopentane and cyclopentene compounds and certain intermediates
CN116947681B (en) Intermediates of pharmaceutical salts of polyamine derivatives, preparation methods and applications thereof
CA1126296A (en) R-n-(2-phenyl-2-hydroxyethyl)-3-phenylpropyl amines, formulations and method of treatment
AU2003212040B2 (en) Substituted Cyclopentane And Cyclopentene Compounds Useful As Neuraminidase Inhibitors
CA3180417A1 (en) Synthesis of (2s,5r)-5-(2-chlorophenyl)-1-(2'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid
US20040133001A1 (en) Peptide deformylase inhibitors
JPS5934175B2 (en) N,N-disubstituted aminomethyl phenyl ethanolamines
US20230137160A1 (en) Large scale process for preparing 1,2,4, 6-tetra-o-acetyl-3-azido-3-deoxy-d-galactopyranoside
MXPA00005890A (en) Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
AU6613690A (en) Anti-viral compounds that bind the active site of influenza neuramidase and display (in vivo) activity against orthomyxovirus and paramyxovirus
CZ20002119A3 (en) Substituted cyclopentanes and cyclopentenes effective as neuraminidase inhibitors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20011227

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL PAYMENT 20011227;LT PAYMENT 20011227;LV PAYMENT 20011227;MK PAYMENT 20011227;RO PAYMENT 20011227;SI PAYMENT 20011227

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20030122