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WO2001062242A1 - Promedicaments de composes cyclopentane et cyclopentene substitues utiles comme inhibiteurs de neuraminidase - Google Patents

Promedicaments de composes cyclopentane et cyclopentene substitues utiles comme inhibiteurs de neuraminidase Download PDF

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WO2001062242A1
WO2001062242A1 PCT/US2001/005862 US0105862W WO0162242A1 WO 2001062242 A1 WO2001062242 A1 WO 2001062242A1 US 0105862 W US0105862 W US 0105862W WO 0162242 A1 WO0162242 A1 WO 0162242A1
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reacting
compound
product
ethyl
amino
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Yarlagadda S. Babu
Pooran Chand
John A. Montgomery
Karen Bush Watts
Dennis J. Hlasta
Gary W. Caldwell
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Biocryst Pharmaceuticals Inc
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Biocryst Pharmaceuticals Inc
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    • 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
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
    • C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • 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
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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

Definitions

  • This invention relates to novel and useful prodrugs of substituted cyclopentane and cyclopentene compounds which are useful as neuraminidase inhibitors, to pharmaceutical compositions containing said compounds useful for the prevention, treatment or amelioration of viral, bacterial and other infections, and to methods of using said compounds.
  • the present invention is also concerned with methods for producing the novel compounds of the present invention.
  • 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 glycoprotems 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.
  • This invention is directed to novel compounds which are useful in inhibiting the viral surface enzyme NA.
  • NA-possessing organisms are also major pathogens of man and/or mammals, including Vibrio cholerae, Clostridium perfringen, Streptococcus pneumoniae, Arthrobacter si ⁇ lophilas, and other viruses, such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague vims, and Sendai virus.
  • viruses such as parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague vims, 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 DC rauy-aiiacne ⁇ s ⁇ a ⁇ containing a ny ⁇ ropnooic region by wnicn 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.
  • NA 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. 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.
  • Analogs of neuraminic acid such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives are known to inhibit HA in vitro; however, these compounds are inactive in vivo.
  • DANA 2-deoxy-2,3-didehydro-N-acetylneuraminic acid
  • 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.
  • A is O, C or S in Formula (a), and N or C in Formula (b);
  • R 1 is CO2H, PO3H2, NO2, SO 2 H, SOaH, tetrazolyl-, CH2CHO, CHO, or CH(CHO) 2 ;
  • R 2 is H, OR 6 , F, Cl, Br, CN, NHR 6 , SR 6 or CH2X, where X is NHR 6 halogen, OR 6 ;
  • R 4 is NHR 6 , SR 6 , OR 6 , CO2R 6 , NO2, C(R 6 )s, CH2CO2R 6 , CH2NO2 or CH2NHR 6 ;
  • R 5 is CH2YR 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 O, 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.
  • WO 99/14191 to BioCryst Pharmaceuticals, Inc. the assignee of the present application, and WO 99/582999 to Abbott Laboratories, Inc. describe various pyrrolidine compounds as possible inhibitors of neuraminidase.
  • WO 95/54290 to Abbott Laboratories, Inc. describes certain cyclopentane or cyclopentene derivatives as possible inhibitors of neuraminidase.
  • An aspect of the present invention relates to compounds represented by the formulae:
  • each R2 and R3 individually is H, (CH2)mOH, -C(O)OR, -C(O)R_, -C(O)SR, (CH_)m-C(O)- NRsR's, -O-C(O)-O-R5, an amino acid and/or a dipeptide;
  • R is Rs, H, (CH 2 ) m -
  • R 4 is H, OH, -OC(O)-Rs, -OC(O)-N-Rs(R' 5 ), -O-C(O)-O-Rs;
  • each Rs, R'5 and Rs" is independently H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, alkynyl, substituted alkenyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or -CH2CO2 alkyl; and wherein Rs can also be (dialkyl)CO alkyl;
  • each R7 and R'7 individually is alkyl, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl;
  • Rs is alkyl, or halo substituted alkyl
  • the present invention is also concerned with compositions for inhibiting influenza virus neuraminidase comprising a pharmaceutically acceptable carrier and an amount effective for inhibiting influenza virus neuraminidase of a compound as defined above.
  • a further aspect of the present invention involves a method for inhibiting influenza virus that comprises administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus neuraminidase.
  • a still further aspect of the present invention is concerned with treating influenza virus infection comprising administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus neuraminidase.
  • process 1 A process (referred to as process 1) aspect of the present invention for preparing compounds represented by formula A comprising the following steps:
  • step 6 Hydrolyzing the product from step 6 to obtain the corresponding acid.
  • a further aspect of the present invention (referred to as process 2) relates to preparing compounds represented by formula B comprising the following steps:
  • process 3 relates to forming ester prodrugs of structure A or structure B which comprises:
  • process 4 Another aspect of the present invention (referred to as process 4) relates to forming ester prodrugs of structure A or structure B which comprises:
  • a still further aspect of the present invention (referred to as process 5) relates to forming ester prodrugs of structure A or structure B which comprises: 1. Converting a compound obtained from step 4 of process 1 above or step 6 of process 2 above to the corresponding acid;
  • process 6 Another aspect of the present invention (referred to as process 6) relates to forming ester prodrugs of structure A or structure B which comprises: 5
  • a further aspect of the present invention (referred to as process 7) related to forming ester prodrugs of structure A or structure B which comprises:
  • a still further aspect of the present invention (referred to as process 8) relates to forming esters of prodrugs of structure A or structure B which comprises:
  • process 9 Another process aspect of the present invention (referred to as process 9) relates to preparing prodrugs of formula A or formula B which comprises:
  • process 10 Another process aspect of the present invention (referred to as process 10) relates to preparing prodrugs of formula A or formula B which comprises:
  • process 11 Another process of the present invention (referred to as process 11) relates to preparing compounds represented by formula A or formula B which comprises:
  • a still further process of the present invention relates to preparing compounds represented by formula A or formula B which comprises: 1. Converting the product from step 1 of process 10 to an amide; and
  • step 2 Reacting the product from step 1 with an amino acid. Furthermore, when disubstituted guanidine and ester prodrugs of structures A and B are desired, about 2 equivalents of the reactive reagents are employed.
  • the present invention relates to compounds represented by the formulae:
  • each Ri and Rs individually is H, (CH 2 )mOH, -C(O)OR, -C(O)Rs, -C(O)SR, (CH 2 )m-C(O)- NRsR'5, -O-C(O)-O-R5, an amino acid and/or a dipeptide; R 5 Rs
  • R is Rs, H,
  • R4 is H, OH, -OC(O)-Rs, -OC(O)-N-Rs(R's), -O-C(O)-O-Rs; each Rs , R'5 and R " s is independently H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, alkynyl, substituted alkenyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or -CH2CO2 alkyl; and wherein Rs can also be (dialkyl)CO alkyl;
  • each R7 and R'7 individually is alkyl, araalkyl, substituted araalkyl, cycloalkyl, substituted cycloalkyl;
  • alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms.
  • lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
  • substituted alkyl refers to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substututed alkanoylamino, substituted arylamino, substituted a
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
  • aralkyl or “alkylaryl” refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
  • substituted aryl or “substituted alkylaryl” refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryl
  • the substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
  • substituted benzyl refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
  • cycloalkyl refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl.
  • substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,
  • bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benz
  • Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
  • heteroatoms shall include oxygen, sulfur and nitrogen.
  • amino acid means any naturally occurring amino acid including D and L amino acids.
  • dipeptide means a di-amino acid containing two linked naturally occurring amino D and L acids.
  • Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
  • suitable alkyl groups include methyl, ethyl and propyl.
  • Examples of branched alkyl groups include isopropyl and t-butyl.
  • An example of a suitable alkylaryl group is phenethyl.
  • suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C1-3 alkyl such as benzyl.
  • the N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring.
  • suitable preferred heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2- ethylpiperidino.
  • the above substitutions can include halo such as F, Cl, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
  • suitable amino acids are L-Ala, L-Val, L-Isoleu, L-Phe, Gly and L-Leu.
  • Examples of suitable dipeptides are L-Ala-L-Ala and Gly-Gly.
  • R7 and R'7 are CH3, C2H5, n-CsHz and 11-C4H9 and most preferred groups for R7 and R'7 are C2H5 and n-C3H7.
  • Preferred groups for Rs are CH3, C2H5 and C3H7 and most preferred is CH3.
  • 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, gly collie, lactic, salicyclic, succinic, toluene-p-sulphonic, 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. It is of course understood that the compounds of the present invention relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule.
  • Lactam (1, -, + , or racemic mixture) is heated at reflux temperature with methanolic HCI. The solvent is evaporated' and the residue is washed with ether to give methyl 4-amino-2-cyclopenten- 1-carboxylate hydrochloride, which is further reacted with di- tert-butyl dicarbonate and triethylamine to give methyl 4-t-rt-butoxycarbonylamino-2- cyclopenten- 1-carboxylate (2).
  • Compound (2) is reacted with 2-ethyl-l- nitrobutane/triethylamine and phenylisocyanate to give the cycloadduct (3).
  • Cycloadduct (3) may also be obtained by the reaction of (2) with 2-ethylbutyrohydroximinoxyl chloride and triethylamine. The desired isomer is separated and is hydrogenated in the presence of a catalyst to give the corresponding amine, which is acetylated with acetic anhydride to give methyl 3- (1 '-acetylamino-2'-ethyl)butyl-4-tert-butoxycarbonylamino-2-hydroxycyclopentane- 1-carboxylate (4). Cycloadduct (3) can be converted to the amine using chemical reduction also.
  • Some catalyst such as acetic acid, HgCh, ZnCb, etc. may be desirable for the reaction.
  • the ester is hydrolyzed to acid (21), and converted to ester (22) following one of the above mentioned methods. Removal of Cbz group is achieved by hydrogenation and the target (11) is obtained.
  • Any other standard method for converting acid to ester may be used for these reactions.
  • the desired RiX or RiOH are either commercially available, or are prepared according to the literature procedures.
  • Compound (25) is prepared from either (5) by reacting with a guanylating agent, such as pyrazole carboxamidine, triazole carboxamidine, 4-nitropyazole carboxamidine or amino-iminomethanesulphonic acid or by esterification of compound (6) with methanol.
  • Compound (25) further reacts with 1 equivalent of R9OC(O)Cl or R9 ⁇ C(O)OC ⁇ H4-N ⁇ 2(p) in the presence of a base to give the desired target (26).
  • ii) Compound (26) is prepared from (5) also by reacting with one equivalent of appropriately substituted guanylating agent as shown in Scheme 4.
  • Substituted guanylating agents are prepared from the literature procedures. In some cases, a catalyst, such as HgCk, ZnCk, acetic acid, etc. may be desired for the reaction.
  • These compounds (27) are prepared from the standard methods of amides preparation from amine (25) and the desired amino acid in the presence of a coupling agent.
  • any other ester also can be used for the preparation of the desired targets.
  • alkyl group containing compounds may be prepared using the same methods.
  • esters obtained are hydrolyzed with a base, acid, methanol/water/triethylamine mixture or any otlier appropriate saponification reagent.
  • Reagent R 9 OC(0)CI, or R 9 OC(0)OC 6 H 4 -N0 2 (p))
  • 2A l-Benzyloxycarbonyl-3-tert-butoxycarbonyl-2-methyl-2-thiopseudourea
  • l-benzyloxycarbonyl-2 ⁇ methyl-2-thiopseudourea IA, 5.0 g, 22.0 mmol
  • dichloromethane 100 mL
  • triethylamine 9 mL, 66.0 mmol
  • di- tert-butyl dicarbonate (14.4 g, 66.0 mmol
  • the solution was washed with water; the organic layer was separated, concentrated and purified on silica gel column using hexane: ethyl acetate as an eluent to give 3.8 g (53 %) of 2A.
  • Example 15 Ethyl (lS,25,3R,4R4' ⁇ -(-)-3-(l'-acetylammo-2'-ethyl)butyl-4-[N-(2'-L-amino-3'- phenylpropanoyIamino)-imino]methylarnino-2-hydroxycyclopentan-l-carboxylate 15A: Ethyl (15,2S,3__,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)butyl-4-[N-(2'-L-amino-3'- phenyl)propanoylamino)-N'-(benzyloxycarbonylimino)methyl]amino-2-hydroxy- cyclopentan-1-carboxylate To a solution of N-benzyloxycarbonyl L-phenylalanine (0.26 g, 0.87 mmol) in ethyl
  • N- hydroxysuccinimide 0.1 g, 0.87 mmol
  • the reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0.34 g of N-benzyloxycarbonyl L-phenylalanine succinimido ester.
  • N-benzyloxycarbonyl L-alanine (0.23 g, 1.0 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0.16 g, 1.0 mmol) and the mixture was stirred for 0.25 h.
  • N- hydroxysuccinimide (0.12 g, 1.0 mmol) and stirred for 2 h.
  • the reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0.32 g of N-benzyloxycarbonyl L-alanine succinimido ester.
  • N-benzyloxycarbonyl L-phenylalanine (0.0.3 g, 1.0 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0.16 g, 1.0 mmol) and the mixture was stirred for 0.25 h.
  • N- hydroxysuccinimide (0.12 g, 1.0 mmol) and stirred for 2 h.
  • the reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0.39 g of N-benzyloxycarbonyl L-phenylalanine succinimido ester.
  • 26B Benzyl (15,25,3R,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)butyl-4-[(N-benzyl- oxycarbonylamino-N'-tof-butoxycarbonylimino)methyl]amino-2-hydroxycyclo- pentan-1- carboxylate
  • 26D Benzyl (1S,2S,3R,4R, 1 '5)-(-)-3-(l '-acetylamino-2'-ethyl)butyl-4-[(N-benzyloxy carbonylamino-N' -acetyloxymethoxycarbonylimino)methyl]amino-2-hydroxycyclo- pentan- 1-carboxylate
  • N-benzyloxycarbonyl L-phenylalanine (0.26 g, 0.87 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0.14 g, 0.87 mmol) and the mixture was stirred5 for 0.25 h.
  • N- hydroxysuccinimide 0.1 g, 0.87 mmol
  • the reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0.34 g of N-benzyloxycarbonyl L-phenylalanine succinimido ester.
  • N-benzyloxycarbonyl L-alanine (0.22 g, 1.0 mmol) in ethyl acetate (20 mL) was added 1, l'-carbonyldiimidazole (0.16 g, 1.0 mmol) and the mixture was stirred for 0.255 h.
  • N- hydroxysuccinimide (0.11 g, 1.0 mmol) and stirred for 2 h.
  • the reaction mixture was washed with water and the organic layer separated, dried, filtered and concentrated to give 0.32 g of N-benzyloxycarbonyl L-alanine succinimido ester.
  • 35A Benzyl (15,25,3R,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)butyl-4-[(N-acetyloxy- methoxycarbonylamino-N'-acetyloxymethoxycarbonylimino)methyl]amino-2- l o hydroxycyclopentan-1-carboxylate
  • 35 To a solution of benzyl (15,25,3R,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)butyl-4-[(N- acetyloxymethoxycarbonylamino-N'-acetyloxymethoxycarbonylimino)methyl]- amino-2- hydroxycyclopentan- 1-carboxylate (35A, 0.15 g, 0.23 mmol) in ethanol (16 mL) and water (4 mL) was added 10% Pd/C (50 mg) and the mixture was hydrogenated at 40 psi for 1 h. The 25 mixture was passed through a pad of Celite and silica gel, and the filtrate was concentrated and dried to give 0.056g (42%) of 35.
  • reaction mixture was added portion wise, over a period of 1 h, to a stirred mixture of 2-methyl-2-thiopseudourea sulfate (2.0 g, 7.2 mmol) in dichloromethane (100 mL) and aqueous sodium bicarbonate (100 mL), while maintaining the pH of the mixture basic by adding 40% sodium hydroxide.
  • the reaction mixture was further stirred for 1 h and the organic layer was separated. After drying, it was filtered and the filtrate was concentrated and the residue was purified on silica gel column using hexane: ethyl acetate as an eluent to give 0.4 g (16%) of 36A.
  • reaction mixture was concentrated and the residue was suspended in a mixture of chloroform: methanol (1: 1).
  • the solid was removed by filtration, the filtrate concentrated and the residue was purified by silica gel column using chloroform (80): methanol (18): ammonium hydroxide (2) mixture as an eluent to give 0.2 g (23 %) of 39B.
  • Methyl chloroformate (1.8 mL, 23.3 mmol) was added to a mixture of N- benzyloxycarbonylglycine (5.0 g, 23.9 mmol) and triethylamine (3.35 mL, 24.2 mmol) in THF (60 mL) at -20 °C over a period of 10 min. and further stirred for 20 min. To this mixture was then added, a solution of 4-aminobenzoic acid (3.28 g, 23.9 mmol) and triethylamine (3.35 mL, 24.2 mmol) in THF (45 mL) drop wise and stirred at the same temperature for 1 h.
  • Antibiotics 1987, XL, 370-384) was added to a mixture of (15,25,322,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)- butyl-4-tert- butoxycarbony lamin)-2-hy droxy cy clopentan- 1 -carboxylic acid (20B, 1.0 g, 2.6 mmol) and diisopropylamine (0.0.53 g, 5.2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate.
  • reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate.
  • Organic layer was separated, aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane: ethyl acetate as eluent to give 0.7 g (57%) of 45A.
  • 45B ⁇ -Acetyloxyethyl (15,25,3R,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)butyl-4-(N- benzyloxycarbonylamino-N'-benzyloxycarbonylimino)methyl]amino-2-hydroxy- cyclopentan-1-carboxylate
  • 46 tert-Butylcarbonyloxomethyl (15,25,322,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)- butyl- 4-(amino-imino)methyl]amino-2-hydroxycyclopentan-l-carboxylate 46A: tert-Butylcarbonyloxymethyl (15,25,322,4R,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)- butyl- 4-tert-butoxycarbonylamino-2-hydroxycyclopentan-l-carboxylate
  • reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate.
  • Organic layer was separated, aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with sodium bicarbonate, water and brine and dried. After filtration, the filtrate was concentrated, and the residue was purified on silica gel column using hexane: ethyl acetate as eluent to give 0.7 g (59%) of 46A.
  • antibiotics 1987, XL, 370- 384) was added to a mixture of (15,25,322,422, l'5)-(-)-3-(l ' -acetylamino-2 ' -ethyl)butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l -carboxylic acid (20B, 1.0 g, 2.6 mmol) and dusopropylamine (0.53 g, 5.2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate.
  • antibiotics 1987, XL, 370- 384) was added to a mixture of (15,25,3R,422,l'5)-(-)-3-(l'-acetylamino-2'-ethyl)butyl-4-tert- butoxycarbonylamino-2-hydroxycyclopentan-l -carboxylic acid (20B, 1.0 g, 2.6 mmol) and dusopropylamine (0.53 g, 5.2 mmol) in dimethyl acetamide (30 mL) at 0 °C. The reaction mixture was further stirred for 2 h at this temperature and diluted with water and ethyl acetate. Organic layer was separated, aqueous layer was extracted with ethyl acetate.
  • Compounds of the present invention are useful as prodrugs for substituted cyclopentane and substituted cyclopentene compounds which are useful as neuraminidase inhibitors, or as active neuraminidase inhibitors themselves.
  • the term “prodrag” denotes a derivative of cyclopentane or cyclopentene, which derivative, when administered to a warm-blooded animal, "cleaves” in such a manner as to release the active drug form at its target site or sites of activity.
  • the enzymatic and/or chemical hydrolytic "cleavage" of the compounds of the instant invention occurs in a manner such that the active drag form is released while the remaining “cleaved” moiety remains nontoxic and is metabolized in such a manner that nontoxic, virologically inert products are produced.
  • the prodrug compounds of the present invention can be used to treat any condition for which the parent cyclopentane or cyclopentene containing drug, medicament or pharmaceutical is useful for.
  • the prodrugs may be administered in low amounts relative to the amounts of neuraminidase inhibitor that would ordinarily be administered.
  • the compounds 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 any 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 500 mg of prodrug per unit.
  • the compound of the present invention will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the prodrug 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 prodrug can also be administered intranasally (nose drops) or by inhalation of a drug powder mist.
  • Other dosage forms are potentially possible such as administration transdermally, via a patch mechanism or ointment.
  • Gelatin capsules contain the prodrug and powdered carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, 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, biocompatible polymers, 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
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
  • parenteral solutions 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, buffering agents.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • 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 and in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association, both standard reference texts in this field.
  • Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows: Hard Shell Capsules
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered prodrug, 150 mg of lactose, 50 mg of cellulose, and 6 5 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or0 olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix. 5 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. o Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules 5 These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the prodrug is mixed in a liquid containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the compounds may be compressed with viscoelastic and o thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers.
  • the drug is delivered from a nasal solution5 as a fine mist or from a powder as an aerosol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un composé représenté par les formules (A) or (B) dans lesquelles R1 est H, R5, (a), (b), (c), (d), (e), (f), (g), —(CH2)nOC(O)%5, —(CH2)nOR5, or —(CH2)n-N-R6; chacun des R2 et R3 Est individuellement H, (CH2)mOH, -C(O)OR, -C(O)R5, -C(O)SR, (CH2)m-C(O)-NR5R'5, -O-C(O)-O-R5, un amino acide et/ou un dipeptide; R est R5, H, (h), (i), (j), (k), (l), (m) ou (n); R4 est H, OH, -OC(O)-R5, -OC(O)-N-R5(R'5), -O-C(O)-O-R5; chacun des R5, R'5, et R5'' est indépendamment H, alkyle, alkyle substitué, aryle, aryle substitué, alkényle, alkynyle, alkényle substitué, alkynyle substitué, hétérocycle, hétérocycle substitué, alkylaryle, alkylaryle substitué, cycloalkyle, cycloalkyle substitué, ou -CH2CO2 alkyle; et dans lesquelles R5 Peut être aussi (dialkyle)CO alkyle; -NR6 est (o), (p), (q), (r) ou (s), chacun des R7 et R'7 est individuellement alkyle, alkylaryle, alkylaryle substitué, cycloalkyle, cycloalkyle substitué; R8 est alkyle, ou halo alkyle substitué; n=1-5 et m=0-4; Cette invention concerne aussi des sels pharmaceutiquement acceptables de ces composés et des techniques de préparation. Les composés des formules susmentionnées sont utiles comme promédicaments destinés à des composés utiles comme inhibiteurs de neuraminidase. Par conséquent, ils peuvent être utilisés pour la prévention, le traitement ou l'amélioration d'états infectieux à virus et à bactéries.
PCT/US2001/005862 2000-02-24 2001-02-26 Promedicaments de composes cyclopentane et cyclopentene substitues utiles comme inhibiteurs de neuraminidase Ceased WO2001062242A1 (fr)

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CN102603577A (zh) * 2011-01-19 2012-07-25 董慧珍 一种抗流感和禽流感药物的衍生物及其用途
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WO2017051761A1 (fr) * 2015-09-25 2017-03-30 芳男 ▲浜▼田 Nouveau promédicament
CN107903302A (zh) * 2017-11-22 2018-04-13 韶远科技（上海)有限公司 一种γ‑内酰胺桥联二肽类化合物的制备方法
JP2018515614A (ja) * 2015-05-15 2018-06-14 リクスト・バイオテクノロジー，インコーポレイテッド オキサビシクロヘプタンプロドラッグ
CN115025080A (zh) * 2021-03-08 2022-09-09 合肥合源药业有限公司 一种抗流感病毒的药物组合物及其用途
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WO2002092555A1 (fr) * 2001-05-11 2002-11-21 Sankyo Company, Limited Derives d'acides sialiques
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6833140B2 (en) 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US6972341B2 (en) 2001-06-11 2005-12-06 Xeno Port, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US7423169B2 (en) 2001-06-11 2008-09-09 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
JP2007521291A (ja) * 2003-07-09 2007-08-02 パラテック ファーマシューティカルズ インコーポレイテッド ９−アミノメチルテトラサイクリン化合物のプロドラッグ
US9533943B2 (en) 2003-07-09 2017-01-03 Paratek Pharmaceuticals, Inc. Substituted tetracycline compounds
US8906412B2 (en) 2004-11-04 2014-12-09 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
CN103108861A (zh) * 2010-04-02 2013-05-15 Tsrl公司 神经氨酸酶抑制剂
WO2011123856A1 (fr) * 2010-04-02 2011-10-06 Tsrl, Inc. Inhibiteurs de la neuraminidase
CN102603577A (zh) * 2011-01-19 2012-07-25 董慧珍 一种抗流感和禽流感药物的衍生物及其用途
US11931354B2 (en) 2013-04-09 2024-03-19 Lixte Biotechnology, Inc. Formulations of oxabicycloheptanes and oxabicycloheptenes
US12343342B2 (en) 2013-04-09 2025-07-01 Lixte Biotechnology, Inc. Methods for treating soft tissue sarcoma
CN104496857A (zh) * 2014-12-10 2015-04-08 广东东阳光药业有限公司 作为神经氨酸酶抑制剂的化合物及其在药物中的应用
JP2018515614A (ja) * 2015-05-15 2018-06-14 リクスト・バイオテクノロジー，インコーポレイテッド オキサビシクロヘプタンプロドラッグ
US10618908B2 (en) 2015-05-15 2020-04-14 Lixte Biotechnology, Inc. Oxabicycloheptane prodrugs
JP2020180130A (ja) * 2015-05-15 2020-11-05 リクスト・バイオテクノロジー，インコーポレイテッド オキサビシクロヘプタンプロドラッグ
US11236102B2 (en) 2015-05-15 2022-02-01 Lixte Biotechnology, Inc. Oxabicycloheptane prodrugs
JP7187023B2 (ja) 2015-05-15 2022-12-12 リクスト・バイオテクノロジー，インコーポレイテッド オキサビシクロヘプタンプロドラッグ
JP7187023B6 (ja) 2015-05-15 2023-01-05 リクスト・バイオテクノロジー，インコーポレイテッド オキサビシクロヘプタンプロドラッグ
US11866444B2 (en) 2015-05-15 2024-01-09 Lixte Biotechnology, Inc. Oxabicycloheptane prodrugs
WO2017051761A1 (fr) * 2015-09-25 2017-03-30 芳男 ▲浜▼田 Nouveau promédicament
US12168008B2 (en) 2016-12-08 2024-12-17 Lixte Biotechnology, Inc. Oxabicycloheptanes for modulation of immune response
CN107903302B (zh) * 2017-11-22 2021-05-14 韶远科技（上海)有限公司 一种γ-内酰胺桥联二肽类化合物的制备方法
CN107903302A (zh) * 2017-11-22 2018-04-13 韶远科技（上海)有限公司 一种γ‑内酰胺桥联二肽类化合物的制备方法
CN115025080A (zh) * 2021-03-08 2022-09-09 合肥合源药业有限公司 一种抗流感病毒的药物组合物及其用途

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