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WO2008143996A1 - Nouveaux procédés chimiques - Google Patents

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Publication number
WO2008143996A1
WO2008143996A1 PCT/US2008/006325 US2008006325W WO2008143996A1 WO 2008143996 A1 WO2008143996 A1 WO 2008143996A1 US 2008006325 W US2008006325 W US 2008006325W WO 2008143996 A1 WO2008143996 A1 WO 2008143996A1
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Prior art keywords
group
cyclosporin
process according
alkyl
substituted
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Application number
PCT/US2008/006325
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English (en)
Inventor
Keqiang Li
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Scynexis Inc
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Scynexis Inc
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to new methods for the preparation of 3 -substituted cyclosporin derivatives. These compounds are useful as pharmaceuticals or as intermediates in the preparation of biologically active compounds.
  • Cyclosporins are a group of non-polar cyclic oligopeptides with immunosuppressant, anti-inflammatory, and anti-parasitic properties.
  • 3 -Ether substituted cyclosporin derivatives are known from European Patent No. EP 1086124, WO2006/039668 and WO2007/041631 and are described as having various pharmaceutical properties.
  • EP 1086124 describes processes for the preparation of compounds of formula (I) that involve the treatment of a 3-sulfide substituted cyclosporin derivative with a suitably protected amino alcohol which result in a diastereomeric mixture of 3-ether cyclosporins that are frequently difficult to purify.
  • a cyclosporin derivative substituted in the 3-position by an ether group -OR 1 wherein R 1 is an amine-bearing alkyl group, which comprises the reductive amination of a cyclosporin derivative bearing an ether group in the 3-position, wherein said 3-substituted ether contains a carbonyl group, e.g., a cyclosporin derivative substituted in the 3-position by an ether group -OR 11 , wherein R 11 is an alkyl group substituted by a carbonyl group.
  • the invention provides a process for the preparation of a cyclosporin derivative of general formula (I):
  • R 5 and R 6 are each independently hydrogen or straight- or branched- chain alkyl comprising from one to six carbon atoms; alkylaryl; alkylheteroaryl; aryl; heteroaryl; or R 5 and R , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from four to six ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by one to four groups which may be the same or different selected from alkyl, hydroxyl, amino, N-alkylamino and N,N-dialkylamino;
  • R 2 is isobutyl or 2-methyl-2-(OR 12 )propyl, where R 12 is hydrogen or a protecting group;
  • R 3 is (E)-2-butenyl-l or n-butyl
  • R 4 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
  • R 10 is hydrogen or a protecting group
  • Cyclosporin refers to any cyclosporin compound known to those of skill in the art, or a derivative thereof. See, e.g., Ruegger et al., 1976, HeIv. Chim. Acta. 59:1075-92; Borel et al., 1977, Immunology 32:1017-25; the contents of which are hereby incorporated by reference in their entireties. Exemplary compounds for use in the methods provided herein are cyclosporin derivatives. Unless noted otherwise, a cyclosporin described herein is a cyclosporin A, and a cyclosporin derivative described herein is a derivative of cyclosporin A.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups, particularly having up to about 11 carbon atoms, more particularly as a lower alkyl, from 1 to 8 carbon atoms and still more particularly, from 1 to 6 carbon atoms.
  • the hydrocarbon chain may be either straight-chained or branched. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like.
  • the term "lower alkyl” refers to alkyl groups having 1 to 6 carbon atoms.
  • Alkylene refers to divalent saturated aliphatic hydrocarbyl groups particularly having up to about 1 1 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Aryl refers to a mono or bicyclic aromatic ring which can be optionally substituted by alkyl, halo, hydroxyl, amino or carboxyl groups. Preferred aryl groups are phenyl and naphthyl.
  • Heteroaryl refers to a mono or bicyclic aromatic group containing 5-9 atoms in which at least one of the atoms is nitrogen, sulfur or oxygen.
  • preferred heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, indole, benzothiophene and the like.
  • Amino refers to the radical -NH 2 .
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, for example, heteroalkyl, aryl, for example, heteroaryl, and the like, having from 1 to 5, and especially from 1 to 3 heteroatoms.
  • Heterocycle or “heterocyclic ring” refers to any heterocycle known to those of skill in the art.
  • a heterocycle can be a heteroaryl group or a cycloheteroalkyl group, as will be recognized by those of skill in the art.
  • heterocyclyl refers to a 4, 5, or 6 membered saturated heterocyclic ring containing one or more heteroatoms in the ring.
  • Dialkylamino means a radical -NRR' where R and R' independently represent an alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl group as defined herein.
  • Halogen or “halo” refers to chloro, bromo, fluoro or iodo.
  • “Sarcosine” refers to N-methyl glycine (CH 3 NHCH 2 CO 2 H).
  • enantiomers Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn ef ⁇ /., 1966, Angew. Chem. 78:413-447, Angew. Chem., Int. Ed. Engl. 5:385- 414 (errata: Angew.
  • the compounds for use in the methods provided herein may possess one or more asymmetric centers; such compounds can therefore be produced as the individual (R)- or (5)-enantiomer or as a mixture thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • Methods for determination of stereochemistry and separation of stereoisomers are well-known in the art.
  • provided herein are the stereoisomers of the compounds depicted herein upon treatment with base.
  • the compounds for use in the methods provided herein are "stereochemically pure.”
  • "stereochemically pure” designates a compound that is substantially free of alternate isomers.
  • the compound is 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% free of other isomers.
  • cyclosporin derivatives substituted in the 3-position by an ether group -OR 1 wherein R 1 is an amine-bearing alkyl group, such as compounds of formula (I).
  • R 1 is an amine-bearing alkyl group
  • the reaction of a compound of formula (II) with an amine under reducing conditions gives compounds of formula (I).
  • the reaction is carried out by treating the compound of formula (II) with an appropriate amine and a reducing agent, optionally in the presence of an acid catalyst such as acetic acid, in an appropriate solvent.
  • an acid catalyst is particularly desirable where the 3-substituted ether contains a carbonyl group which is not an aldehyde (e.g., compounds of formula (II) above in which R 7 is not hydrogen).
  • the reaction is performed at a temperature from about -1O 0 C to about 8O 0 C.
  • the reaction is performed at a temperature from about O 0 C to about 8O 0 C.
  • the reaction is performed at a temperature from about O 0 C to about 4O 0 C.
  • the reaction is performed at about room temperature.
  • the acid catalyst is acetic acid.
  • the acid catalyst is a Lewis acid, for example, titanium isoproxide.
  • the molar ratio of cyclosporin to reducing agent is from about 1 : 1 to about 1 :8. In another embodiment the molar ratio of cyclosporin to reducing agent is from about 1 : 1 to about 1 :2. In a still further embodiment the molar ratio of cyclosporin to reducing agent is from about 1 : 1.3 to about 1 : 1.6.
  • Ak is methylene, ethylene or propylene. In another embodiment Ak is ethylene. In another embodiment R 2 is isobutyl. In another embodiment R 2 is 2-methyl-2- hydroxypropyl. In a further embodiment R 3 is (E)-2-butenyl-l. In a still further embodiment R 4 is ethyl. In a still further embodiment R 5 and R 6 are lower alkyl, or R 5 and R 6 , together with the nitrogen to which they are attached, form a ring selected from the group consisting of azetidine, pyrrolidine, piperazine, morpholine, imidazole, said ring optionally bearing one or two groups selected from alkyl and hydroxyl. In a still further embodiment R 7 is hydrogen.
  • R 10 is a protecting group it is generally an acid stable protecting group, such as an allyl or benzyl ether, a trichloroacetate, benzoate, or methyl, allyl or benzyl carbonate.
  • the reducing agent contains boron.
  • the reducing agent is a cyanoborohydride, for example, sodium cyanoborohydride, sodium acetoxyborohydride and the like.
  • the reducing agent is selected from a borane in pyridine, titanium isoproxide with sodium cyanoborohydride, a borohydride exchange resin, zinc in acetic acid, sodium borohydride with magnesium pechlorate, and zinc tetrahydroborate with zinc chloride.
  • the solvent is an alcohol (e.g., methanol or ethanol), a chlorinated solvent (e.g., dichloromethane or dichloroethane), tetrahydrofuran or acetonitrile.
  • R 11 is a protecting group.
  • R 12 is hydroxyl.
  • each protecting group is removed by hydrolysis using an alkoxide in an alcohol under conditions typical for such a reaction, for example, an alkali metal alkoxide such as sodium methoxide in methanol; or an alkaline earth metal salt such as potassium carbonate in methanol.
  • each protecting group is an acetate.
  • each protecting group may be removed by treatment with a base.
  • the base is an alkoxide, for example, an alkali metal alkoxide such as sodium methoxide
  • the solvent is an alcohol, for example, methanol, as described in the reaction sequence below for the conversion of a compound of formula (III) into a compounds of formula (Ia), which is a compound of formula (I) above in which R 10 is hydrogen.
  • the acetate protecting group may be replaced with a different group that is compatible with the conditions described in these procedures.
  • R 22 CH 2 CH(CH 3 ) 2 or CH 2 C(OH)(CH 3 ) 2
  • Compounds of formula (III) can be prepared by treating an alcohol compound of formula (IV) with an oxidizing agent known by those of skill in the art to convert an alcohol to an aldehyde or a ketone. Typically the reaction is carried out by treating the alcohol of formula (IV) with an oxidant, such as Dess-Martin periodinane, in a suitable solvent, such as dichloromethane or dichloroethane. A molar excess of oxidizing agent is generally used, for example, up to five molar equivalents of oxidizing agent or more preferably up to two molar equivalents. The reaction is generally performed at a temperature from O 0 C to 4O 0 C. The reaction scheme is illustrated for compounds of formula (III) [i.e., a compound of formula (II) in which R 7 is hydrogen]:
  • Compounds of formula (IV) in which R 10 is a protecting group can be obtained by treatment of the diastereomeric mixture of an acetate compound of formula (V) with an appropriate alcohol in a solvent, optionally in the presence of an acid catalyst, and heating.
  • the alcohol is a dihydroxy compound such as 1 ,2-dihydroxyethane, 1,3-dihydroxypropane, 1,4- dihydroxybutane and the like.
  • the acid catalyst can be a sulfonic acid, such as camphorsulfonic acid and toluenesulfonic acid; hydrochloric acid, sulphuric acid and the like.
  • the preferred solvents include, but are not limited to, tetrahydrofuran, 1,4-dioxane, and 1 ,2-dimethoxyethane, and the reaction is preferably heated to 50 to 80 0 C.
  • Compounds of formula (IV) are isolated completely, or substantially as a single isomer with stereochemistry as indicated.
  • Compounds of formula (V) can be prepared from compounds of formula (VI) by treatment of said mixture with an acetate salt in acetic acid with optional heating.
  • the acetate salt is preferably mercury acetate and the reaction is heated at about 40 to 80 0 C.
  • Compounds of formula (VI) are described in EP 1086124.
  • the cyclosporin derivative in which the 3-position is a carbonyl-bearing alkyl group may be prepared by the reaction of the corresponding cyclosporin derivative in which the 3-position is substituted by a sulfide with an acetate salt, followed by treatment with a dihydroxy compound.
  • cyclosporin compounds listed below. Note that in general the process of the invention is performed on the corresponding compound bearing a protecting group on the hydroxyl present in the 1 -position of the cyclosporin ring, and this protecting group is subsequently removed.
  • Example 1 The compound obtained in Example 1 above was de-protected as follows: to a solution of [3'-acetoxy-N-MeBmt] l [(R)-2'-(2-pyrrolidin-l-yl)ethoxy-Sar] 3 cyclosporin A (150 mg) in methanol (10 mL) was added 25 wt % sodium methoxide in methanol (0.04 mL) and the resulting mixture was stirred at room temperature for 24 hours under nitrogen. Methanol was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with saturated ammonium chloride, brine, and dried over anhydrous sodium sulfate.
  • the compounds prepared by the processes of the present invention are useful either as pharmaceutical compounds, as intermediates in the preparation of biologically active compounds (e.g., protected intermediate forms of pharmaceutically active compounds), for example, as described in European Patent No. EP 1086124, and International Patent Publication No. WO2006/039668 and WO2007/041631.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention a pour objet des procédés de préparation d'un dérivé de cyclosporine substitué en position 3 par un groupe éther -OR1, où R1 représente un groupe alkyle portant une amine, qui comprennent l'amination réductrice d'une cyclosporine substituée en position 3 par un groupe éther -OR11, où R11 représente un groupe alkyle substitué par un groupe carbonyle. Ces composés sont utiles en tant que médicaments pharmaceutiques ou en tant qu'intermédiaires dans la préparation de composés actifs sur le plan biologique.
PCT/US2008/006325 2007-05-18 2008-05-16 Nouveaux procédés chimiques Ceased WO2008143996A1 (fr)

Applications Claiming Priority (2)

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US93102407P 2007-05-18 2007-05-18
US60/931,024 2007-05-18

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WO2008143996A1 true WO2008143996A1 (fr) 2008-11-27

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007136759A3 (fr) * 2006-05-19 2009-04-16 Scynexis Inc Procédé de traitement et de prévention de troubles oculaires
US7718767B2 (en) 2004-10-01 2010-05-18 Scynexis, Inc. 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection
US7754685B2 (en) 2005-09-30 2010-07-13 Scynexis, Inc. Methods and pharmaceutical compositions for the treatment and prevention of hepatitis C infection
US8329658B2 (en) 2005-09-30 2012-12-11 Scynexis, Inc. Arylalkyl and heteroarylalkyl derivatives of cyclosporine A for the treatment and prevention of viral infection
US20130183267A1 (en) * 2009-01-30 2013-07-18 Enanta Pharmaceuticals, Inc. Cyclosporin analogues for preventing or treating hepatitis c infection
US8536114B2 (en) 2008-12-31 2013-09-17 Scynexis, Inc. Macrocycles
US20140005100A1 (en) * 2010-08-12 2014-01-02 Zhuang Su Novel cyclosporin derivatives for the treatment and prevention of a viral infection
US9090671B2 (en) 2008-06-06 2015-07-28 Scynexis, Inc. Macrocyclic peptides
US9217015B2 (en) 2010-07-16 2015-12-22 S&T Global Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US9266927B2 (en) 2012-06-01 2016-02-23 Allergan, Inc. Cyclosporin A analogs
US9890198B2 (en) 2010-12-03 2018-02-13 S&T Global Inc. Cyclosporin derivatives and uses thereof
US9914755B2 (en) 2015-01-08 2018-03-13 Allergan, Inc. Cyclosporin derivatives wherein the MeBmt sidechain has been cyclized
WO2019016572A1 (fr) * 2017-07-21 2019-01-24 Cypralis Ltd Analogues de la ciclosporine et leurs utilisations
WO2021190604A1 (fr) * 2020-03-26 2021-09-30 Farsight Medical Technology (Shanghai) Co., Ltd. Préparation de dérivés de cyclosporine
WO2024245384A1 (fr) * 2023-06-02 2024-12-05 Farsight Medical Technology (Shanghai) Co., Ltd. Inhibiteurs de cyclophiline et leurs utilisations
US12350310B2 (en) 2019-10-12 2025-07-08 Farsight Medical Technology (Shanghai) Co., Ltd. Treatment and prevention of nephrotoxin-induced kidney injuries
US12465629B2 (en) 2020-04-15 2025-11-11 Farsight Medical Technology (Shanghai) Co., Ltd. Prevention and treatment of organ injuries

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040235716A1 (en) * 2003-03-17 2004-11-25 Molino Bruce F. Novel cyclosporins
WO2006041631A2 (fr) * 2004-10-06 2006-04-20 Amr Technology, Inc. Alcynes de cyclosporine, et leur utilite comme agents pharmaceutiques
US7196161B2 (en) * 2004-10-01 2007-03-27 Scynexis Inc. 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040235716A1 (en) * 2003-03-17 2004-11-25 Molino Bruce F. Novel cyclosporins
US7196161B2 (en) * 2004-10-01 2007-03-27 Scynexis Inc. 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection
WO2006041631A2 (fr) * 2004-10-06 2006-04-20 Amr Technology, Inc. Alcynes de cyclosporine, et leur utilite comme agents pharmaceutiques

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7718767B2 (en) 2004-10-01 2010-05-18 Scynexis, Inc. 3-ether and 3-thioether substituted cyclosporin derivatives for the treatment and prevention of hepatitis C infection
US7754685B2 (en) 2005-09-30 2010-07-13 Scynexis, Inc. Methods and pharmaceutical compositions for the treatment and prevention of hepatitis C infection
US8329658B2 (en) 2005-09-30 2012-12-11 Scynexis, Inc. Arylalkyl and heteroarylalkyl derivatives of cyclosporine A for the treatment and prevention of viral infection
US8551952B2 (en) 2006-05-19 2013-10-08 Scynexis, Inc. Methods for the treatment and prevention of ocular disorders
US8188052B2 (en) 2006-05-19 2012-05-29 Scynexis, Inc. Method for the treatment and prevention of ocular disorders
WO2007136759A3 (fr) * 2006-05-19 2009-04-16 Scynexis Inc Procédé de traitement et de prévention de troubles oculaires
US9090671B2 (en) 2008-06-06 2015-07-28 Scynexis, Inc. Macrocyclic peptides
US8536114B2 (en) 2008-12-31 2013-09-17 Scynexis, Inc. Macrocycles
US9156886B2 (en) * 2009-01-30 2015-10-13 Enanta Pharmaceuticals, Inc. Cyclosporin analogues for preventing or treating hepatitis C infection
US20130183267A1 (en) * 2009-01-30 2013-07-18 Enanta Pharmaceuticals, Inc. Cyclosporin analogues for preventing or treating hepatitis c infection
US9217015B2 (en) 2010-07-16 2015-12-22 S&T Global Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US20140005100A1 (en) * 2010-08-12 2014-01-02 Zhuang Su Novel cyclosporin derivatives for the treatment and prevention of a viral infection
US9573978B2 (en) * 2010-08-12 2017-02-21 S&T Global, Inc. Cyclosporin derivatives for the treatment and prevention of a viral infection
US10647747B2 (en) 2010-12-03 2020-05-12 S&T Global Inc. Cyclosporin derivatives and uses thereof
US9890198B2 (en) 2010-12-03 2018-02-13 S&T Global Inc. Cyclosporin derivatives and uses thereof
US9266927B2 (en) 2012-06-01 2016-02-23 Allergan, Inc. Cyclosporin A analogs
US9914755B2 (en) 2015-01-08 2018-03-13 Allergan, Inc. Cyclosporin derivatives wherein the MeBmt sidechain has been cyclized
WO2019016572A1 (fr) * 2017-07-21 2019-01-24 Cypralis Ltd Analogues de la ciclosporine et leurs utilisations
CN115299430A (zh) * 2017-07-21 2022-11-08 西普拉里斯有限公司 环孢菌素类似物及其用途
US12350310B2 (en) 2019-10-12 2025-07-08 Farsight Medical Technology (Shanghai) Co., Ltd. Treatment and prevention of nephrotoxin-induced kidney injuries
WO2021190604A1 (fr) * 2020-03-26 2021-09-30 Farsight Medical Technology (Shanghai) Co., Ltd. Préparation de dérivés de cyclosporine
WO2021190601A1 (fr) * 2020-03-26 2021-09-30 Farsight Medical Technology (Shanghai) Co., Ltd. Inhibiteurs de cyclophiline et leurs utilisations
US12060440B2 (en) 2020-03-26 2024-08-13 Farsight Medical Technology (Shanghai) Co., Ltd. Cyclophilin inhibitors and uses thereof
US12465629B2 (en) 2020-04-15 2025-11-11 Farsight Medical Technology (Shanghai) Co., Ltd. Prevention and treatment of organ injuries
WO2024245384A1 (fr) * 2023-06-02 2024-12-05 Farsight Medical Technology (Shanghai) Co., Ltd. Inhibiteurs de cyclophiline et leurs utilisations

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