US20080188545A1 - Synthesis of pyrrolidine compounds - Google Patents

Synthesis of pyrrolidine compounds Download PDF

Info

Publication number
US20080188545A1
US20080188545A1 US12/005,118 US511807A US2008188545A1 US 20080188545 A1 US20080188545 A1 US 20080188545A1 US 511807 A US511807 A US 511807A US 2008188545 A1 US2008188545 A1 US 2008188545A1
Authority
US
United States
Prior art keywords
compound
formula
optionally substituted
salt
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.)
Abandoned
Application number
US12/005,118
Other languages
English (en)
Inventor
Asaf R. Alimardanov
Lalitha Krishnan
Maotang Zhou
Ting-Zhong Wang
Jianxin Ren
John Leo Considine
Charles C. Wu
Jason Brazzillo
Panolil Raveendranath
Girija Raveendranath
Vijay Raveendranath
Sanjay Raveeendranath
Karen Sutherland
Mahmoud Mirmehrabi
Subodh S. Deshmukh
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.)
Zealand Pharma AS
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to US12/005,118 priority Critical patent/US20080188545A1/en
Assigned to WYETH reassignment WYETH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RAVEENDRANTH, VIJAY, ZHOU, MAOTANG, MIRMEHRABI, MAHMOUD, DESHMUKH, SUBODH S., CONSIDINE, JOHN LEO, WANG, TING-ZHONG, KRISHNAN, LALITHA, REN, JIANXIN, RAVEENDRANATH, GIRIJA, RAVEENDRANATH, SANJAY, WU, CHARLES C., SUTHERLAND, KAREN, ALIMARDANOV, ASAF R., BRAZZILLO, JASON
Assigned to WYETH reassignment WYETH CORRECTIVE COVER SHEET TO CORRECT THE INCORRECT SPELLING OF INVENTORS NAME PREVIOUSLY RECORDED ON REEL 020784 FRAME 0639. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: RAVEENDRANATH, VIJAY, ZHOU, MAOTANG, MIRMEHRABI, MAHMOUD, DESHMUKH, SUBODH S., CONSIDINE, JOHN LEO, WANG, TING-ZHONG, KRISHNAN, LALITHA, REN, JIANXIN, RAVEENDRANATH, GIRIJA, RAVEENDRANATH, SANJAY, SUTHERLAND, KAREN, WU, CHARLES C., ALIMARDANOV, ASAF R., BRAZZILLO, JASON
Assigned to WYETH reassignment WYETH CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT EXECUTION DATE FOR INVENTOR SUTHERLAND FROM 3/18/08 TO 3/13/08 PREVIOUSLY RECORDED ON REEL 020836 FRAME 0049. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: RAVEENDRANATH, VIJAY, ZHOU, MAOTANG, MIRMEHRABI, MAHMOUD, DESHMUKH, SUBODH S., CONSIDINE, JOHN LEO, WANG, TING-ZHONG, KRISHNAN, LALITHA, REN, JIANXIN, RAVEENDRANATH, GIRIJA, RAVEENDRANATH, SANJAY, WU, CHARLES C., SUTHERLAND, KAREN, ALIMARDANOV, ASAF R., BRAZZILLO, JASON
Publication of US20080188545A1 publication Critical patent/US20080188545A1/en
Priority to US12/690,043 priority patent/US20100249207A1/en
Assigned to ZEALAND PHARMA A/S reassignment ZEALAND PHARMA A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WYETH
Priority to US13/593,110 priority patent/US8927590B2/en
Priority to US14/572,262 priority patent/US9469609B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • gap junctions are specialized regions of the cell membrane that contain clusters of hundreds to thousands of densely packed channels that directly connect the cytoplasm of two adjacent cells.
  • the gap junction channels are composed of two hemichannels, or connexons, provided by each of two neighboring cells.
  • Each connexon is made up of six proteins called connexins.
  • gap junctional intercellular communication GJIC
  • antiarrhythmic peptides AAP, AAP10; and HP5.
  • those peptides exhibit undesirable characteristics, including low stability, short half-life, and a lack of oral bioavailability.
  • R 1 and R 2 are hydrogen or C 1 -C 6 alkyl, and the other is —C(O)R 5 ;
  • W is C 1-6 alkylene
  • R 3 and R 4 may be the same or different and are each independently chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, —C(O)OR 6 , and —C(O)R 9 ;
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl
  • R 7 in formula (III) is optionally substituted C 1 -C 6 alkyl
  • W, R 3 and R 4 are as defined herein or a reactive derivative thereof, for instance, a mixed anhydride thereof.
  • composition comprising
  • R 1 and R 2 are hydrogen or C 1 -C 6 alkyl, and the other is —C(O)R 5 ;
  • W is C 1-6 alkylene
  • R 3 and R 4 may be the same or different and are each independently chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, —C(O)OR 6 , and —C(O)R 9 ;
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl
  • Also provided is a method for preparing (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate comprising providing a solution of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride in a crystallization medium, wherein the crystallization medium comprises at least one water-miscible organic solvent and water, and maintaining the solution for a time and under conditions suitable for forming the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • Also provided is a pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers and a compound described herein.
  • FIG. 1 shows the X-ray powder diffraction patterns of preparations of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride as an amorphous solid and as a crystalline monohydrate.
  • FIG. 2 is the X-ray powder diffraction pattern of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • FIG. 3 is a differential scanning calorimetry (“DSC”) analysis of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • DSC differential scanning calorimetry
  • FIG. 4 is a DSC analysis of amorphous (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride.
  • FIG. 5 is a thermal gravimetric analysis (“TGA”) of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • FIG. 6 is a dynamic vapor sorption analysis of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • FIG. 7 is dynamic vapor sorption analysis of amorphous (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride.
  • alkyl refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C 1 -C 20 alkyl indicates that the group may be branched or unbranched, and may contain from 1 to 20 (inclusive) carbon atoms.
  • C 1 -C 6 alkyl indicates that the group may be branched or unbranched, and may contain from 1 to 6 (inclusive) carbon atoms. Any atom may optionally be substituted.
  • Non-limiting examples of alkyl groups include, for example, methyl, ethyl, and tert-butyl.
  • alkylene refers to a bivalent alkyl radical, i.e., an alkyl radical having two points of attachment.
  • a methylene group is a —CH 2 — group and an ethylene group is a —CH 2 CH 2 — group.
  • aralkyl refers to an alkyl moiety wherein an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety.
  • aralkyl also includes groups wherein more than one hydrogen atom on an alkyl moiety has been replaced by an aryl group. Any ring or chain atom may optionally be substituted by one or more substituents.
  • Non-limiting examples of “aralkyl” groups include benzyl, 2-phenylethyl (sometimes referred to as “phenethyl”), 3-phenylpropyl, benzhydryl (diphenylmethyl), and trityl (triphenylmethyl) groups.
  • aryl refers to a C 6 -C 14 (e.g., C 6 -C 10 , C 6 ) aromatic monocyclic (C 6 ), bicyclic (C 10 ), or tricyclic (C 14 ) hydrocarbon ring system. Any ring atom may optionally be substituted by one or more substituents.
  • Aryl groups may also contain fused rings. Fused rings are rings that share a common carbon atom.
  • Non-limiting examples of aryl moieties include phenyl, naphthyl, and anthracenyl.
  • the term “converting” refers to one or more chemical transformations, which can be performed in situ, or with isolation of intermediate compounds.
  • the transformations can include reacting the starting compounds or intermediates with additional reagents using techniques and protocols known in the art, including those described herein.
  • Intermediates can be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, chromatography).
  • cycloalkyl refers to saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any atom may optionally be substituted by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl groups may contain fused rings. Fused rings are rings that share a common carbon atom. Non-limiting examples of cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl).
  • cycloalkenyl refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups.
  • a ring carbon e.g., saturated or unsaturated is the point of attachment of the cycloalkenyl substituent. Any atom may optionally be substituted by one or more substituents.
  • Cycloalkenyl groups may contain fused rings. Fused rings are rings that share a common carbon atom.
  • Non-limiting examples of cycloalkenyl moieties include cyclohexenyl, cyclohexadienyl, or norbornenyl.
  • a “detectable amount” of a compound is intended to mean a sufficient amount to give positive identification but not necessarily quantitation of the compound by any suitable analytical technique, for example HPLC.
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group wherein at least one hydrogen atom is replaced by halo.
  • more than one hydrogen atom for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, etc. hydrogen atoms
  • more than one halogen e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, etc.
  • the hydrogen atoms may each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms may be replaced by a combination of different halogens (e.g., fluoro and chloro).
  • haloalkyl also include alkyl moieties wherein all hydrogens have been replaced by halo (e.g., perhaloalkyl, such as trifluoromethyl).
  • heteroarylkyl refers to an alkyl moiety wherein an alkyl hydrogen atom is replaced by a heteroaryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety.
  • heteroarylkyl also includes groups wherein more than one hydrogen atom on an alkyl moiety has been replaced by a heteroaryl group. Any ring or chain atom may optionally be substituted by one or more substituents.
  • Non-limiting examples of heteroaralkyl groups include 2-pyridylmethyl and 2-pyridylethyl.
  • heteroaryl refers to an aromatic monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups having 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, wherein said heteroatoms are independently selected from O, N, or S (and mono and dioxides thereof, e.g., N ⁇ O ⁇ , S(O), SO 2 ). Any atom may optionally be substituted by one or more substituents.
  • Heteroaryl groups may contain fused rings. Fused rings are rings that share a common carbon atom. Non-limiting examples of heteroaryl groups include pyridyl, thienyl, furyl (furanyl), imidazolyl, indolyl, isoquinolyl, quinolyl and pyrrolyl.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups having 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, wherein said heteroatoms are independently selected from O, N, or S (and mono and dioxides thereof, e.g., N ⁇ O ⁇ , S(O), SO 2 ). Any atom may optionally be substituted by one or more substituents.
  • Heteroaryl groups may contain fused rings. Fused rings are rings that share a common carbon atom.
  • Non-limiting examples of heteroaryl groups include morpholinyl, piperidinyl, piperazinyl and pyrrolidinyl.
  • nitrogen protecting group refers to a moiety which, when attached to a nitrogen atom of an acyclic or cyclic amino group (e.g., a pyrrolidine ring nitrogen atom), temporarily blocks that amino group so as to render it chemically inert.
  • a nitrogen protecting group may also be introduced and removed (i.e., “deprotected”) without complete destruction of the starting material and subsequent reaction product, respectively.
  • suitable protecting groups include those delineated herein.
  • Other non-limiting examples of suitable protecting groups may be found in, e.g., T. W. Greene et al., Protective Groups in Organic Synthesis , John Wiley and Sons (1991).
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • any substituent described herein e.g., C 1 -C 20 alkyl or C 1 -C 20 haloalkyl
  • polymorphism is defined as in the International Conference on Harmonization (ICH) Guideline Q6A Guideline: Specifications for New Drug Substances and Products: Chemical Substances, October 1999, and refers to the occurrence of different solid forms of the same drug substance.
  • Polymorphism includes solvation products and amorphous forms. Amorphous forms consist of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.
  • Solvation products are crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. If the incorporated solvent is water, the solvates are also commonly known as hydrates.
  • reacting or “contacting” refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system. Reacting or contacting can take place in the presence or absence of solvent.
  • salts is derived from the combination of a compound and an organic or inorganic acid or base.
  • the compounds described herein are useful in both free and salt form.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, Vol. 66, p. 1-19.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base function with a suitable organic acid.
  • salts of the compounds of the present teachings having an acidic moiety can be formed using organic and inorganic bases.
  • Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di- or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts
  • ammonia salts and organic amine salts such as those
  • salts can be formed using organic and inorganic acids.
  • salts can be formed from the following acids: acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.
  • Amino acid addition salts can also be formed with amino acids such as lysine, glycine, or phenylalanine.
  • Representative acid addition salts include hydrochloride salts.
  • Other acceptable salts may be found through compendia listing compounds previously approved by the Food & Drug Administration.
  • solution means a mixture of one or more solutes in one or more solvents.
  • Solution is intended to encompass homogeneous mixtures as well as heterogeneous mixtures, such as slurries or other mixtures having a suspension of insoluble (not dissolved) material.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like).
  • solvents used in the reactions described herein are inert organic solvents.
  • anti-solvent means a substance that reduces the solubility of a solute in a solvent.
  • an antisolvent is one or more chemical liquids or mixtures thereof in which the compound to be purified exhibits a lower solubility than the solvent in which it is partially or entirely dissolved.
  • C 1-6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
  • C 1-6 alkyl is also specifically intended to individually disclose methyl, ethyl, propyl, isoprop
  • the starting materials, intermediates, and products of the methods described herein may contain one, two, or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and enantiomeric or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present disclosure.
  • the compounds described herein may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers and rotational isomers are expressly included in the present disclosure.
  • the compounds described herein may also be represented in multiple tautomeric forms, in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds are expressly included in the present disclosure.
  • the starting materials, intermediates, and products of the methods described herein each include a pyrrolidine ring that is substituted at the 2- and the 4-positions of the ring.
  • each of the following absolute ring stereochemistries is contemplated for the starting materials, intermediates, and products of the methods described herein: 2S, 4R; 2R, 4S; 2S, 4S, and 2R, 4R.
  • any starting material, intermediate, or product of the methods described herein may occur as a stereoisomer mixture having at least about 60% (e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, greater than about 99%) of one of the four possible stereoisomers (e.g., 2S, 4R; 2R, 4S; 2S, 4S, or 2R, 4R).
  • the starting material, intermediate, or product may be substantially free of its enantiomer and the other two possible stereoisomers.
  • the starting material, intermediate, or product may be one of the four possible stereoisomers (e.g., 2S, 4R or 2S, 4S) in substantially pure form and be substantially free of its stereoisomers as well as other non-stereoisomer-related materials, e.g., solvents, reagents, reaction by-products and the like.
  • stereoisomers e.g., 2S, 4R or 2S, 4S
  • other non-stereoisomer-related materials e.g., solvents, reagents, reaction by-products and the like.
  • any starting material, intermediate, or product of the methods described herein may occur as a stereoisomer mixture having at least about 60% (e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, greater than about 99%) of two of the four possible stereoisomers (e.g., R,R and S,S; R,S and S,R; R,R and S,R; R,R and R,S; S,S and S,R; or S,S and R,S).
  • R,R and S,S e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, greater than about 99%
  • two of the four possible stereoisomers e.g., R,R and S,S; R,S and S,R; R,R and S,R; or S,S and R,
  • this invention encompasses all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography.
  • R 1 and R 2 are hydrogen or C 1 -C 6 alkyl, and the other is —C(O)R 5 ;
  • W is C 1-6 alkylene
  • R 3 and R 4 may be the same or different, and are each independently chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, —C(O)OR 6 , and —C(O)R 9 ;
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl; to a compound of formula (III) or a salt thereof:
  • R 7 in formula (III) is optionally substituted C 1 -C 6 alkyl
  • W in formula (I) is —CH 2 —.
  • each of R 3 and R 4 in formula (I) is hydrogen. In some embodiments, one of R 3 and R 4 is hydrogen, and the other is —C(O)OR 6 . In other embodiments, one of R 3 and R 4 in formula (I) is hydrogen, and the other is —C(O)R 9 .
  • W in formula (I) is —CH 2 —; and each of R 3 and R 4 in formula (I) is hydrogen.
  • W in formula (I) is —CH 2 —; and one of R 3 and R 4 in formula (I) is hydrogen, and the other is —C(O)OR 6 .
  • R 6 in formula (I) is C 1 -C 6 alkyl.
  • R 6 is tert-butyl.
  • R 6 is benzyl.
  • W in formula (I) is —CH 2 —; and one of R 3 and R 4 in formula (I) is hydrogen, and the other is —C(O)R 9 .
  • R 9 in formula (I) is hydrogen.
  • R 9 in formula (I) is C 1 -C 6 alkyl.
  • R 9 in formula (I) is methyl.
  • R 9 in formula (I) is optionally substituted phenyl.
  • R 5 in formula (I) is optionally substituted C 6 -C 10 aryl. In some embodiments, R 5 is phenyl.
  • R 7 is C 1 -C 6 alkyl. In some embodiments, R 7 in formula (II) is CH 3 .
  • the —NR 1 R 2 group and the —COOH group in formula (I) are trans with respect to one another.
  • the ring carbon attached to the —NR 1 —R 2 group has the R configuration
  • the ring carbon attached to the —COOH group has the S configuration.
  • the —NR 1 R 2 group and the —COOR 7 group in formula (II) are trans with respect to one another.
  • the ring carbon attached to the —NR 1 R 2 group has the R configuration
  • the ring carbon attached to the —COOR 7 group has the S configuration.
  • the compound of formula (II) can be in the form of a free base or a salt (e.g., an HCl salt).
  • the compound of formula (II) can be free-based separately or in situ by treatment with the appropriate organic or inorganic base, in an organic solvent or a mixture of organic solvent and water; for example, by treatment with NaOH in a mixture of THF and water.
  • the solvent is methylene chloride (CH 2 Cl 2 ), which can be exchanged with acetone for subsequent isolation.
  • triethylamine is used to neutralize the HCl salt of the compound of formula (II), which in some cases can minimize the likelihood of partial hydrolysis of the ester functionality (e.g., methyl ester) and generation of subsequent impurities.
  • the metal hydroxide is a Group IA metal hydroxide.
  • the Group IA metal hydroxide is chosen from NaOH, KOH, and LiOH.
  • the Group IA metal hydroxide is NaOH.
  • the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base is conducted in the presence of at least one solvent.
  • the at least one solvent is a mixture of two or more solvents.
  • the at least one solvent is a mixture of water and a C 1 -C 3 alcohol.
  • the C 1 -C 3 alcohol is methanol (CH 3 OH).
  • the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base is conducted at a temperature of at most about 5° C. In some embodiments, the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base is conducted at a temperature of from about ⁇ 10° C. to about 5° C. In some embodiments, the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base is conducted at a temperature of from about ⁇ 5° C. to about 5° C. In some embodiments, the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base is conducted at a temperature of from about ⁇ 5° C. to about 1° C.
  • the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base further comprises acidifying the reaction mixture.
  • the reaction mixture is acidified with dilute hydrochloric acid.
  • the product is extracted with ethyl acetate, and crystallized from acetone and heptane.
  • the crystallization can remove stereoisomeric impurities (e.g., a small amount of cis-isomer when the trans isomer is desired).
  • the chemical yield for the process is from about 80-90%.
  • R 1 and R 2 are hydrogen or C 1 -C 6 alkyl, and the other is —C(O)R 5 ;
  • W is C 1-6 alkylene
  • R 3 and R 4 may be the same or different, and are each independently chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, —C(O)OR 6 , and —C(O)R 9 ;
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl; with a metal hydroxide or other suitable base to provide a compound of formula (I) or a salt thereof.
  • the method further comprises converting the compound of formula (II) or a salt thereof to a compound of formula (III) or a salt thereof by contacting the compound of formula (II) or a salt thereof with a compound of formula (IV):
  • the compound of formula (IV) is glycine (e.g., R 3 and R 4 are H and W is —CH 2 —).
  • the compound of formula (IV) is Boc-Gly-OH (e.g., one of R 3 and R 4 is H and the other is tert-butyloxy carbonyl, and W is —CH 2 —).
  • the compound of formula (IV) is CHO-Gly-OH (e.g., one of R 3 and R 4 is H and the other is CHO (formyl), and W is —CH 2 —).
  • W in formula (IV) is —CH 2 —; and one of R 3 and R 4 in formula (IV) is hydrogen and the other is —C(O)OR 6 .
  • R 6 in formula (IV) is C 1 -C 6 alkyl (e.g., tert-butyl).
  • the compound of formula (II) or a salt thereof is contacted with the carboxylic acid of formula (IV) in the presence of a coupling agent.
  • a coupling agent refers to a compound used when coupling together an amine and a carboxylic acid.
  • the coupling agent is a carbodiimide.
  • the coupling agent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) or dicyclohexylcarbodiimide (DCC).
  • the compound of formula (II) or a salt thereof is contacted with the carboxylic acid of formula (IV) in the presence of a coupling agent and a hydroxylated moiety.
  • the hydroxylated moiety is N-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or pentafluorophenol.
  • the carboxylic acid of formula (IV) is converted to a mixed anhydride.
  • the compound of formula (IV) is Boc-Gly-OH and the mixed anhydride is formed by treatment of the compound of formula (IV) with ethyl chloroformate, optionally in the presence of triethylamine, followed by reaction with a compound of formula (II).
  • the compound of formula (III) or a salt thereof is isolated from acetone as an acetone solvate, which may eliminate the need for concentrating the reaction mixture to dryness.
  • the yield is greater than 70%, such as greater than 80%, for example, greater than 85%, such as about 86%.
  • R 3 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl when R 4 is —C(O)OR 6 .
  • the reaction of the compound of formula (III) or a salt thereof with a metal hydroxide or other suitable base may provide a compound of formula (I-A) or a salt thereof:
  • R 3 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl.
  • R 3 in formula (I-A) is hydrogen, and R 6 in formula (I-A) is tert-butyl. In some embodiments, R 3 in formula (I-A) is hydrogen, and R 6 in formula (I-A) is benzyl.
  • W in formula (I-A) is —CH 2 —.
  • R 5 in formula (I-A) is phenyl.
  • reaction of the compound of formula (II) with a metal hydroxide or other suitable base provides a compound of formula (I-A-1) or a salt thereof:
  • the methods further include removing the —C(O)OR 6 group of the compound of formula (I-A) (i.e., deprotecting the nitrogen atom to which R 3 and R 4 are attached) to provide a compound of formula (I-B) or a salt thereof:
  • the method further comprises converting the compound of formula (I-A) or a salt thereof to a compound of formula (I-B) or a salt thereof.
  • converting the compound of formula (I-A) or a salt thereof to a compound of formula (I-B) or a salt thereof comprises contacting the compound of formula (I-A) with at least one acid.
  • the at least one acid is HCl, e.g., anhydrous HCl or concentrated aqueous hydrochloric acid.
  • a solvent is used for the conversion.
  • the solvent is an organic solvent, such as dioxane or acetone.
  • the solvent is water.
  • R 3 in formula (I-A) is hydrogen, and R 6 in formula (I-A) is tert-butyl.
  • converting the compound of formula (I-B) or a salt thereof to a compound of formula (I-B) or a salt thereof comprises subjecting the compound of formula (I-A) to catalytic hydrogenation.
  • R 3 in formula (I-A) is hydrogen
  • R 6 in formula (I-A) is benzyl.
  • subjecting the compound of formula (I-A) to catalytic hydrogenation comprises contacting the compound of formula (I-A) with H 2 gas and a transition metal catalyst.
  • the transition metal catalyst is palladium.
  • subjecting the compound of formula (I-A) to transfer hydrogenation comprises contacting the compound of formula (I-A) with cyclohexene and a transition metal catalyst. In some embodiments, the transition metal catalyst is palladium.
  • the compound of formula (I-B) is obtained as the free acid. In some embodiments, the compound of formula (I-B) is obtained as a salt (e.g., as an HCl salt).
  • the method further comprises converting the compound of formula (I-A-1) or a salt thereof to a compound of formula (I-B-1) or a salt thereof:
  • subsequent deprotection of (2S,4R)-4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid to (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid, hydrochloride is accomplished by treating the former compound with concentrated hydrochloric acid in acetone. The precipitated product is dissolved by addition of water to form a clear solution, which is filtered to remove particulates. The desired product is then crystallized by the addition of acetone. In some embodiments, the crystalline hydrochloride is isolated as a monohydrate. The chemical yield for the process can be about 80-95%.
  • the base used to convert compound Iv into compound v can be a metal hydroxide (e.g., LiOH, NaOH, KOH).
  • the base can be a metal carbonate (e.g., Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 ) or metal hydrogencarbonate (e.g., NaHCO 3 , KHCO 3 ) in combination with water.
  • the compound of formula (II) is prepared from a compound of formula (V). In some embodiments, the compound of formula (V) is prepared from a compound of formula (VIII) or a compound of formula (X).
  • the method for preparing a compound of formula (I) from a compound of formula (II) can further include one or both of those methods.
  • the compound of formula (II) is prepared by a method comprising:
  • R 2 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl
  • R 8 is a nitrogen protecting group
  • R 2 in formulae (V) and (VII) is hydrogen.
  • R 8 in formulae (V) and (VII) is —C(O)OR a , in which R a is chosen from:
  • R 8 in formulae (V) and (VII) is —C(O)O(tert-butyl) or —C(O)O(benzyl).
  • R 5 in formula (VII) is optionally substituted C 6 -C 10 aryl or optionally substituted heteroaryl including 5-10 atoms. In some embodiments, R 5 is optionally substituted C 6 -C 10 aryl. In some embodiments, R 5 is phenyl.
  • R 8 in formulae (V) and (VII) is an acid labile nitrogen protecting group and removing the protecting group from the compound of formula (VII) comprises contacting the compound of formula (VII) with at least one acid.
  • the at least one acid is HCl or trifluoroacetic acid.
  • the nitrogen protecting group is —C(O)O(tert-butyl).
  • R 8 in formulae (V) and (VII) is a nitrogen protecting group that is susceptible to cleavage by hydrogenolysis and removing the protecting group from the compound of formula (VII) comprises subjecting the compound of formula (VII) to catalytic hydrogenation.
  • the nitrogen protecting group is —C(O)O(benzyl).
  • subjecting the compound of formula (VII) to catalytic hydrogenation comprises contacting the compound of formula (VII) with H 2 gas and a transition metal catalyst.
  • the transition metal catalyst is palladium.
  • R 8 in formulae (V) and (VII) is a nitrogen protecting group that is susceptible to cleavage by hydrogenolysis and removing the protecting group from the compound of formula (VII) comprises subjecting the compound of formula (VII) to transfer hydrogenation.
  • subjecting the compound of formula (VII) to transfer hydrogenation comprises contacting the compound of formula (VII) with cyclohexene and a transition metal catalyst.
  • the transition metal catalyst is palladium.
  • the activated carboxylic acid is a compound of formula (VI):
  • removing the protecting group from the compound of formula (VII) provides the compound of formula (II) as an HCl salt.
  • benzoylation of commercially available N-Boc-trans-4-amino-L-proline methyl ester is accomplished using conventional amide bond forming methods, including reacting with benzoic acid in the presence of a coupling agent, reacting with corresponding anhydride of benzoic acid (or mixed anhydride), or with benzoyl halide.
  • N-Boc-trans-4-amino-L-proline methyl ester (either as a HCl salt or free base) is treated with benzoyl chloride under Schotten-Bauman conditions, i.e., in a biphasic mixture of organic solvent (e.g., ethyl acetate (EtOAc), toluene, methyl tert-butyl ether (MTBE), etc.) and water in the presence of a base (e.g., NaHCO 3 ).
  • organic solvent e.g., ethyl acetate (EtOAc), toluene, methyl tert-butyl ether (MTBE), etc.
  • a base e.g., NaHCO 3
  • Schotten-Bauman conditions can include EtOAc, water, and NaHCO 3 .
  • azeotropic distillation can be used to dry the reaction mixture when toluene is employed as the organic solvent (the use of toluene can also facilitate the isolation of the formula (II) compound as a crystalline solid after deprotection).
  • benzoylation is performed by treatment with benzoyl halide (e.g., benzoyl chloride) in an organic solvent (e.g., CH 2 Cl 2 ) in the presence of organic (e.g., pyridine) or inorganic base.
  • benzoyl halide e.g., benzoyl chloride
  • organic solvent e.g., CH 2 Cl 2
  • organic e.g., pyridine
  • deprotection of the formula (VII) compound is carried out using an acid (e.g., HCl, CF 3 COOH, etc.) in an ethereal solvent (Et 2 O, dioxane, etc.).
  • deprotection of the formula (VII) compound is carried out using anhydrous HCl in MeOH.
  • the use of anhydrous HCl in MeOH can minimize the likelihood of unwanted hydrolysis side reactions.
  • the compound of formula (VII) is not isolated prior to deprotection.
  • the compound of formula (II) is prepared by a method comprising:
  • a compound of formula (V), in which R 2 is hydrogen is prepared by a method comprising
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl, with a compound of the formula (R b )(R c )NH, wherein R b and/or R c are other than hydrogen to provide a compound of formula (IX):
  • the compound of the formula (R b )(R c )NH is chosen such that when it is incorporated into a substrate it can be transformed in one or more chemical steps into an amino group (i.e., —NH 2 ).
  • the compound of the formula (R b )(R c )NH is chosen from phthalimide, O-tert-butyl carbamate, N-Boc ethyl oxamate, benzhydryl amine, trityl amine, lithium hexamethyldisilazane, triphenylsilyl amine, LiNH 2 , allylamine, and bis(allyl)amine.
  • the methods of preparing compounds of Formula (V) involve the conversion of a trans-4-hydroxy-L-proline (or derivative thereof) to a trans-4-amino-L-proline (or derivative thereof).
  • An exemplary, but non-limiting example is discussed below and outlined in Scheme 2.
  • trans-4-hydroxy-L-proline 1 can be converted to 1-benzyl 2-methyl (2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylate 3 based on literature references (Bridges et al. J. Med. Chem. 1991, 34, 717; Gregson et al. J. Med. Chem. 2004, 47, 1161).
  • Compound 3 can be treated with a water soluble organic acid such as chloroacetic acid (Hughes and Reamer, J. Org. Chem., 1996, 61, 2967) in presence of triphenylphosphine and an azodicarboxylate such as diisopropyl azodicarboxylate (DIAD) in a solvent such as toluene to afford compound 4.
  • a water soluble organic acid such as chloroacetic acid (Hughes and Reamer, J. Org. Chem., 1996, 61, 2967) in presence of triphenylphosphine and an azodicarboxylate such as diisopropyl azodicarboxylate (DIAD) in a solvent such as toluene to afford compound 4.
  • a water soluble organic acid such as chloroacetic acid (Hughes and Reamer, J. Org. Chem., 1996, 61, 2967)
  • the by-products from the Mitsunobu reaction i.e., triphenylphosphine oxide and the hydrazide byproduct
  • a solvent such as toluene
  • Neutralization and back-extraction with an organic solvent such as dichloromethane affords acid 5.
  • the resulting acid 5 can be esterified under conventional acid catalyzed esterification conditions with acid such as sulfuric acid in an alkyl alcohol such as MeOH to furnish cis-4-hydroxy-L-proline methyl ester 6.
  • the cis-4-hydroxy-proline derivative 6 can be coupled with N-Boc-ethyl oxamate (7) (see Berree et al. Tetrahedron Lett., 1998, 39, 8275) under conventional Mitsunobu reaction conditions using triphenyl phosphine and DIAD to provide the protected trans-4-aminoproline derivative 8.
  • Oxamate 8 can be selectively hydrolyzed with aqueous lithium hydroxide, and the Boc protecting group can be subsequently cleaved with hydrochloric acid in methanol. At this point, the desired product 10 remains in the acidic aqueous phase.
  • the byproducts from the Mitsunobu reaction can be removed by extraction with an organic solvent such as toluene.
  • the acidic aqueous phase is then neutralized and extracted with another organic solvent such as ethyl acetate to give N-Cbz protected trans-4-amino-L-proline methyl ester 10, therefore, chromatographic separation can again be avoided in this portion of the process.
  • the methods involve the conversion of a cis-4-hydroxy-L-proline (or derivative thereof) to a trans-4-amino-L-proline (or derivative thereof).
  • a cis-4-hydroxy-L-proline or derivative thereof
  • a trans-4-amino-L-proline or derivative thereof
  • the alcohol 6 can be reacted with phthalimide in the presence of triphenylphosphine and diisopropyl azodicarboxylate in solvents such as tetrahydrofuran and toluene to give compound 11, which can be isolated as a crude toluene solution.
  • the crude phthalimide 11 can then be converted to amine 10 by the treatment with hydrazine hydrate in methanol.
  • the amine can be isolated in high purity through an extractive work-up under acidic conditions.
  • the extractive workup under acidic conditions in this case allows of the by-products of the Mitsunobu reaction such as triphenylphosphine oxide, to be removed without the use of chromatography.
  • the overall yield for this process can be about 66%.
  • the amine 10 can be used to prepare compounds of formula (II), such as compound 13 via a compound of formula (VII), such as compound 12. See Scheme 4.
  • a stereoisomer or an enriched stereoisomeric mixture of a compound of formula (V) is used, wherein said stereoisomer or enriched stereoisomeric mixture of a compound of formula (V) is prepared by a method comprising:
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl
  • R 8 is hydrogen or a nitrogen protecting group
  • stereochemistry depicted in formula (X) and in each of the formulas is intended to show relative stereochemistry.
  • the aforementioned stereoselective or stereospecific methods described herein can be used to prepare any one of the four possible stereoisomeric products (i.e., 2S, 4R; 2R, 4S; 2S, 4S, and 2R, 4R).
  • R 8 is C(O)OR a wherein R a is chosen from optionally substituted C 6 -C 10 aryl; optionally substituted heteroaryl including 5-10 atoms; optionally substituted C 1 -C 20 alkyl; optionally substituted C 1 -C 20 haloalkyl; optionally substituted C 7 -C 12 aralkyl; optionally substituted heteroaralkyl including 6-12 atoms; optionally substituted C 3 -C 10 cycloalkyl; and optionally substituted C 3 -C 10 cycloalkenyl.
  • R 8 is —C(O)O(tert-butyl) or —C(O)O(benzyl). In some embodiments, R 8 is —C(O)O(benzyl).
  • the compound of formula P(R d ) 3 is triphenylphosphine.
  • the di(C 1 -C 6 alkyl)azodicarboxylate is diisopropyl azodicarboxylate.
  • phosphines and di(C 1 -C 6 alkyl)azodicarboxylates that are suitable for use in a Mitsunobu reaction are employed.
  • the method can be carried out and scaled up without the use of purification by chromatography.
  • the post-Mitsunobu reaction products can be purified by non-chromatographic methods, e.g., extraction, and be substantially free of Mitsunobu reaction by-products.
  • the compound of formula (I) or a salt thereof is:
  • the compound of formula (II) or a salt thereof is:
  • the compound of formula (III) or a salt thereof is:
  • the compound of formula (IV) or a salt thereof is Boc-Gly-OH.
  • composition comprising
  • R 1 and R 2 are hydrogen or C 1 -C 6 alkyl, and the other is —C(O)R 5 ;
  • W is C 1-6 alkylene
  • R 3 and R 4 may be the same or different and are each independently chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, —C(O)OR 6 , and —C(O)R 9 ;
  • R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl
  • the composition comprises greater than about 95%, such as greater than about 98%, for example, greater than about 99% of a compound of formula (I). In some embodiments, the composition comprises greater than about 99.9% of a compound of formula (I).
  • the compound of formula (I) is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid or a salt thereof. In some embodiments, the compound of formula (I) is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride. In some embodiments, the compound of formula (I) is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • the compound of formula (I) is (2S,4R)-4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid.
  • the compound of formula (III) is (2S,4R)-methyl 1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylate.
  • the compound of formula (III) is (2S,4R)-methyl 4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylate.
  • (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is also provided.
  • the compound (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid may be prepared according to methods known in the art (e.g., as described in U.S. patent application Ser. No. 11/643,192, which is incorporated herein by reference in its entirety) and as described herein.
  • Such preparation method includes the steps of providing a solution of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride in a crystallization medium wherein the crystallization medium comprises water and one or more water-miscible organic solvents.
  • Such preparation method further includes maintaining the solution for a time and under conditions suitable for forming (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride is added, e.g., portionwise, as a solid to the crystallization medium.
  • the crystallization medium is heated to an elevated temperature, e.g., at reflux.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride is added, e.g., portionwise, as a solid to one or more water-miscible organic solvents.
  • the one or more water-miscible organic solvents is heated to an elevated temperature, e.g., at reflux.
  • the solution of the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride in the one or more water-miscible organic solvents is then combined with water and any other water-miscible organic solvents which are found in the crystallization medium.
  • the solution provided is a fully dissolved solution of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride. In some embodiments, the solution provided is a partially dissolved suspension or slurry of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride.
  • the solubility of the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride will vary depending on the composition of the medium, as is well-appreciated in the art, but, in some embodiments, is at least about 1 mg/mL, such as from about 1 to about 500 mg/mL, for example, from about 5 to about 100 mg/mL.
  • the water-miscible organic solvent is selected from alcohols, ketones, ethers, or a combination of such solvents. In some embodiments, the water-miscible organic solvent is selected from C 1-4 alcohols, C 1-6 ketones, and C 1-6 ethers. Where more than one water-miscible organic solvent is used, a solvent of the same type or different type may be combined. For example, if an alcohol is selected, another alcohol may also be selected for use in the solvent mixture.
  • Suitable alcohols include methanol, ethanol, n-propanol, isopropanol, t-butanol, and the like.
  • Suitable ketones include acetone, diethyl ketone, and the like.
  • Suitable ethers include t-butyl methyl ether, diethyl ether, 1,3-dioxane, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and the like.
  • the alcohol is isopropanol
  • the ketone is acetone
  • the ether is t-butyl methyl ether.
  • water-miscible organic solvent or combination of water-miscible organic solvents is well within the ability of one skilled in the art, and will depend on factors such the desired scale, yield, operating temperature, time of operation, and the like.
  • the ratio of the components may be varied.
  • the ratio of alcohol to ketone may range from a ratio of about 1:9 to about 9:1. Ratios outside this range are also contemplated.
  • Ternary combinations of an alcohol, ketone, and ether are also provided.
  • the ratio of three components may vary without limit. In one embodiment, a combination comprising up to about 10% of an alcohol, up to about 5% of an ether, and at least about 85% of a ketone is used.
  • Water is included in the crystallization medium. Water may be adventitiously present, but in some embodiments water is combined with the water-miscible organic solvent.
  • the amount of water in the solvent mixture is generally no more than 25% by volume.
  • the solution can comprise less than 10% water by volume, and in some embodiments the water is less than 5% by volume.
  • the water-miscible organic solvent portion is about 97.5% by volume and water is about 2.5% by volume.
  • any method known in the art may be used, such as cooling the solution, adding seeding crystals, reducing the volume of the solvent under ambient or reduced pressure, adding an anti-solvent, using diffusion techniques, and/or by combination of these techniques.
  • the solution may left undisturbed, or stirred during the crystallization process.
  • the solution is maintained at room temperature and stirred until the crystallization is sufficiently complete.
  • the solution is maintained at room temperature and at least some of the crystallization medium is permitted to evaporate, whereupon crystals form.
  • the evaporation process may be carried out at ambient pressure or under reduced pressure, and may be with or without control of the temperature of the medium.
  • the method further includes the step of recovering the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate, which may be accomplished by means known by those of skill in the art, such as filtration, centrifugation, decanting, and the like.
  • the method further comprises washing the recovered (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate with a suitable solvent upon recovery of the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.
  • the method further comprises drying the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate. Drying may be performed at ambient or reduced pressure, and at ambient or elevated temperature. For example, a vacuum drying oven may be used. In some embodiments, the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is dried at about 45° C. under vacuum.
  • the crystalline (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by X-ray powder diffraction.
  • X-ray powder diffraction is a suitable technique for differentiating amorphous solid forms from crystalline solid forms and for characterizing and identifying crystalline solid forms of a compound.
  • X-ray powder diffraction is also suitable for quantifying the amount of a crystalline solid form (or forms) in a mixture.
  • characterize means to select an appropriate set of data capable of distinguishing one solid form from another. That set of data in X-ray powder diffraction is the position of one or more peaks. Selecting which X-ray powder diffraction peaks define a particular form is said to characterize that form.
  • peak values Due to differences in instruments, samples, and sample preparation, peak values are reported with the modifier “about” in front of the peak values. This is common practice in the solid-state chemical arts because of the variation inherent in peak values.
  • a typical precision of the 2 ⁇ x-axis value of a peak in a powder pattern is on the order of plus or minus 0.3° 2 ⁇ .
  • a powder diffraction peak that appears at “about 19.0° 2 ⁇ ” means that the peak could be between 18.7° 2 ⁇ and 19.3° 2 ⁇ when measured on most X-ray diffractometers under most conditions.
  • Variability in peak intensity is a result of how individual crystals are oriented in the sample container with respect to the external X-ray source, the size of the crystallites, instrumental factors, and the temperature during the measurement.
  • X-Ray diffraction data presented herein was collected using a Bruker-AXS Model D8 Advance instrument.
  • the powdered sample was prepared and mounted according to the manufacturer's recommendation.
  • a Bruker-axs model D8 advance X-ray powder diffractometer was operated at 40 kV and 40.0 mA, and a VANTEC detector was used with a 1 mm antiscattering slit.
  • the samples were scanned from a scattering angle of 3.7° 2 ⁇ to 30° 2 ⁇ , at a step size of 0.01° 2 ⁇ over a total scan time of 33 minutes.
  • FIG. 1 shows the X-ray powder diffraction patterns for three preparations of crystalline forms of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride (traces 1-3), and one amorphous preparation of the compound (trace 4).
  • the diffractogram of the amorphous material reveals no diffraction peaks, indicating that material is in fact amorphous and lacks crystallinity. Converting the amorphous material to a crystalline form yielded the material used to obtain the data shown in traces 1-3.
  • the overlaid diffractograms reveal a consistent pattern of peaks and relative intensities for the crystalline hydrochloride monohydrate for a series of batches crystallized from acetone/water.
  • FIG. 2 illustrates the diffractogram of the crystalline hydrochloride monohydrate from 50 20 to 300 20.
  • the entire diffractogram and the peaks found therein is used to characterize the crystalline solid forms described herein.
  • the crystalline solid forms are characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 2 .
  • a subset of the peaks in the pattern is used to characterize the crystalline form. Where another substance is suspected of being present, peaks common to the substances are ordinarily not useful to confirm the presence of either. In some embodiments, the subset of peaks having the greatest relative intensity are of interest. Any subset based on relative peak intensity may of course be modified to exclude certain peaks that overlap with those of other crystalline components suspected to be present.
  • the crystalline hydrochloride monohydrate compound is characterized by a pattern having peaks at about the scattering angles, and with about the relative intensities described in Table 1.
  • the relative intensities of the peaks can vary depending on, for example, the sample preparation method, crystallite size, distribution of sizes, filters, instrument type, X-ray source, temperature, and the like. As mentioned above, these and other factors can also effect the scattering angle value. Furthermore, other peaks may be observed, or certain peaks listed in Table 1 may not be observed, depending on the instrumentation and the parameters used to record a diffractogram.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate has X-ray powder diffraction peaks at about 12.5° 2 ⁇ and 19.0° 2 ⁇ . In some embodiments, the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate has powder x-ray diffraction peaks at about 17.1° 2 ⁇ , 19.7° 2 ⁇ , 20.5° 2 ⁇ , 21.8° 2 ⁇ , 23.3° 2 ⁇ , and 23.4° 2 ⁇ .
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate has powder x-ray diffraction peaks at about 5.4° 2 ⁇ , 20.7° 2 ⁇ , 21.2° 2 ⁇ , 23.1° 2 ⁇ , 26.4° 2 ⁇ , and 27.4° 2 ⁇ .
  • X-ray powder diffraction is just one of several analytical techniques available for characterizing and/or identifying crystalline solid forms.
  • Spectroscopic techniques such as Raman (including microscopic Raman), infrared, and solid-state NMR spectroscopies may be used to characterize and/or identify crystalline solid forms. These techniques may also be used to quantify the amount of one or more crystalline solid forms in a mixture.
  • Other methods for characterizing and/or identifying different crystalline solid forms of a compound include thermal techniques such as melting point or differential scanning calorimetry, thermal gravimetric analysis and dynamic vapor sorption.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by differential scanning calorimetry (“DSC”).
  • DSC differential scanning calorimetry
  • a DSC trace is shown in FIG. 3 .
  • DSC data were collected using a model Q1000 DSC from TA Instruments. Samples were analyzed by scanning the temperature from 400 to 200° C. at a scan rate of 10° C./min while under a dinitrogen gas purge of 50 mL/min.
  • the calorimetric events observed in the DSC trace may vary in temperature or magnitude depending on, for example, the sample preparation method, crystallite size, impurities, type of instrument, calibration, heating rate, and the like, with variations in the temperature of about 5° C. possible.
  • the DSC thermogram of the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by two peaks.
  • the first peak is observed at about 135° C., with an onset temperature of about 104° C., and is believed to correspond to loss of the water of hydration.
  • the second peak is observed at about 180° C., with an onset temperature of about 168° C., and is believed to represent a melting event.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by a DSC trace substantially as depicted in FIG. 3 .
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by having two endothermic transitions with onset temperatures of about 104° C. and about 168° C.
  • the DSC thermogram of amorphous (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride is characterized by a broad endothermic transition between about 185° C. and 230° C.
  • the response of the material to DSC analysis is representative of the behavior typically observed for amorphous materials.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by thermal gravimetric analysis (“TGA”).
  • TGA trace is shown in FIG. 4 .
  • TGA data were collected using a model TGA/SDTA 851e from Mettler Toledo. Samples were analyzed by scanning the temperature from 300 to 250° C. at a scan rate of 1° C./min while under a dinitrogen gas purge of 40 mL/min.
  • thermogravimetric events observed in the TGA trace may vary in temperature or magnitude depending on, for example, the sample preparation method, crystallite size, impurities, type of instrument, calibration, heating rate, and the like, with variations in the temperature of about 5° C., or in the magnitude of a few percent possible.
  • the TGA thermogram of the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized primarily by a weight loss of about 4.7% in one step. The step is roughly complete when the temperature ramp reaches about 90° C. The weight loss is believed to correspond to a loss of the water of the monohydrate crystal form. The theoretical water content of a monohydrate form is 5.2%. It is recognized by those of skill in the art that the amount of water in a hydrate can vary depending on the methods and conditions of crystallization, and the handling of the crystals thereafter.
  • the molar ratio of the hydrate present in the crystalline form is about 0.5 to about 1.2, from about 0.7 to about 1.0, or about 1.0.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by a TGA trace substantially as depicted in FIG. 5 .
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by having a weight loss of about 5.0% upon an increase in temperature to about 100° C.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by having a weight loss of about 4.7% upon an increase in temperature to about 90° C.
  • the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by dynamic vapor sorption (“DVS”).
  • DVS trace in shown in FIG. 6 .
  • DVS data were collected using Dynamix Vapor Sorption Apparatus (DVS-1) made by Surface Measurement System Ltd. Samples were analyzed by subjecting them to a series of relative humidity (RH) conditions at 25° C. The relative humidity was scanned from about 0% to about 90%.
  • RVS dynamic vapor sorption
  • the DVS trace of the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate is characterized by reversible change of mass of about 1.5% between 0% RH and 10% RH, followed by a relatively stable mass between 10% RH and about 70% RH, followed by about a 2.5% reversible mass change between about 70% RH and 90% RH.
  • the DVS trace indicates that although the crystalline forms described herein may be prone to gain water at high humidity, the sorbed water is reversibly lost and does not appear to adversely affect the integrity of the crystalline form.
  • the DVS trace of the amorphous form of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride is characterized by a large increase in weight when first exposed to high humidity and that these changes are not reversible upon cycling of the relative humidity.
  • the amorphous form increased in mass by 21.7% when the relative humidity increased from 0% RH to 90% RH in the first cycle, from 0 to about 1200 min.
  • compositions can serve as medicaments in their pure form or as pharmaceutical formulations, which can be administered via any acceptable method known in the art, either singly or in combination.
  • Pharmaceutical formulations generally comprise a compound described herein in admixture with one or more pharmaceutically acceptable carriers.
  • Such compositions can be formulated to oral administration (including buccal cavity or sublingually) or by parenteral administration (including intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.)) administration.
  • parenteral administration including intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.), intraperitoneal (i.p.)) administration.
  • Other administration routes include epidural, rectal, intranasal or dermal administration or by pulmonary inhalation.
  • sustained release of the compounds described herein are used.
  • compositions are in the form of solid or liquid formulations and methods for their preparation are generally described in “Remington's Pharmaceutical Sciences”, 17th Ed., Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985.
  • the carrier is in the form of one or more substances chosen from vehicles, diluents, buffering agents, tonicity adjusting agents, preservatives and stabilizers.
  • the excipients constituting the carrier should be compatible with the active pharmaceutical ingredient(s) and are capable of stabilizing the compounds without being deleterious to the subject being treated.
  • a form of repository or sustained-release formulation can be used so that therapeutically effective amounts of the preparation are delivered into the bloodstream over many hours or days following administration of the compound or composition, e.g., by transdermal injection or deposition.
  • Formulations suitable for sustained release include biodegradable polymers, such as L-lactic acid, D-lactic acid, DL-lactic acid, glycolide, glycolic acid, and isomers thereof.
  • the carrier can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release formulations can include, but are not limited to, formulations that include at least one of the compounds disclosed herein combined with liposomes, microspheres, emulsions or micelles and liquid stabilizers.
  • a therapeutically effective amount refers to an amount that reduces symptoms of a given condition or pathology, and in some embodiments, which normalizes physiological responses in a subject with the condition or pathology. Reduction of symptoms or normalization of physiological responses can be determined using methods routine in the art and can vary with a given condition or pathology.
  • a therapeutically effective amount of one or more compounds or pharmaceutical formulations is an amount which restores a measurable physiological parameter to substantially the same value (preferably to within ⁇ 30%, more preferably to within ⁇ 20%, and still more preferably, to within ⁇ 10% of the value) of the parameter in a subject without the condition or pathology.
  • the therapeutically effective amount will be determined by the skilled person taking into account such factors as potency of the drug, age and constitution of the patient, body weight, pharmacokinetic profile of the drug, and in general the drug will be prescribed for each patient or group of patients.
  • the therapeutically effective amount of the compound is at least about 10 ⁇ g/kg body weight/day, such as at least about 100 ⁇ g/kg body weight/day, at least about 300 ⁇ g/kg body weight/day, and at least about 1000 ⁇ g/kg body weight/day.
  • the therapeutically effective amount of the compound is at most about 100 mg/kg body weight/day, such as at most about 50 mg/kg body weight/day and at most about 10 mg/kg body weight/day.
  • the therapeutically effective amount of the compound will be about 100 ⁇ g/kg body weight/day, about 300 ⁇ g/kg body weight/day or about 1000 ⁇ g/kg body weight.
  • the compounds are administrated in the range of about 0.001 g to 10 g per patient per day.
  • the compounds are administered in the range from about 1 mg to about 1000 mg per patient per day, from about 10 mg to about 100 mg per patient per day, or about 50 mg per patient per day.
  • the most suitable dosing regimen can best be determined by a medical practitioner for each patient individually.
  • the optimal dosing regimen with the compounds and pharmaceutical formulations described herein depends on factors such as the particular disease or disorder being treated, the desired effect, and the age, weight or body mass index, and general physical conditions of the patient.
  • the administration can be conducted in a single unit dosage form to alleviate acute symptoms or as a continuous therapy in the form of multiple doses over time. Alternatively, continuous infusion systems or slow release depot formulations can be employed. Two or more compounds or pharmaceutical formulations described herein can be co-administered simultaneously or sequentially in any order.
  • the compounds and compositions can be administered in a similar manner for prophylactic purposes. Ultimately, the best dosing regimen will be decided by the attending physician for each patient individually.
  • Also provided are methods of preventing or treating a condition comprising administering to a subject in need thereof (e.g., a human being) a therapeutically effective amount of a compound or pharmaceutical formulation as described herein.
  • a subject in need thereof e.g., a human being
  • a therapeutically effective amount of a compound or pharmaceutical formulation as described herein include, but are not limited to, cardiovascular disease (e.g., atrial fibrillation, atrial flutter, ventricular tachycardia or ventricular fibrillation); osteoporosis; inflammation of airway epithelium; disorders of alveolar tissue; bladder incontinence; impaired hearing, such as due to diseases of the cochlea; endothelial lesions; diabetes including diabetic retinopathy and diabetic neuropathy; CNS related conditions; ischemia (e.g.
  • ischemia of the central nervous system, spinal cord, brain or brain stem dental tissue disorders including periodontal disease; kidney diseases; haematologic manifestations (e.g., anaemia, leukopenia, thrombocytopenia, and pancytopenia) especially following treatment with cytostatic compounds or irradiation therapy; wounds such as superficial wounds and deep wounds resulting from trauma; erectile dysfunction; urinary bladder incontinence; neuropathic pain; subchronic and chronic inflammation; cancer; failure of bone marrow and stem cell transplantation; conditions which arise during transplantation of cells and tissues or during medical procedures such as surgery; conditions caused by an excess of reactive oxygen species, free radicals or nitric oxide; diseases or disorders of pregnancy (e.g., preeclampsia and preterm labor); and stroke.
  • haematologic manifestations e.g., anaemia, leukopenia, thrombocytopenia, and pancytopenia
  • wounds such as superficial wounds and deep wounds resulting from trauma;
  • the compounds or pharmaceutical formulations described herein can be used to maintain normal sinus rhythm (NSR) following cardioversion of atrial fibrilation (AF), to prevent post-operative AF following cardiac surgery, and to pharmacologically cause cardioversion of AF.
  • NSR normal sinus rhythm
  • AF atrial fibrilation
  • the compounds and pharmaceutical formulations described herein can facilitate and/or maintain the intercellular communication mediated by gap junctions.
  • the compounds and pharmaceutical formulations described herein target the same cells targeted by AAP, AAP10, HP5, and/or functional analogues thereof, i.e. the compounds are able to modulate the function of these cells by agonizing or antagonizing the function of AAP, AAP10, HP5, and/or functional analogues thereof.
  • the embodiments are, however, not limited to compounds having specific AAP agonistic or antagonistic properties.
  • Some embodiments also relate to the preparation and use of pharmaceutical formulations for the treatment of pathologies which can be associated with impaired intercellular gap junction communication and methods for using these compositions, e.g., as disclosed in WO 02/077017 “New Medical Uses of Intercellular Communication Facilitating Compounds.”
  • Some embodiments also provide methods of treating a subject having, or preventing a subject at risk from developing, a condition associated with impaired GJIC (e.g., cardiac arrhythmia or osteoporosis) comprising administering a therapeutically effective amount of any of the compounds or pharmaceutical formulations described herein.
  • a condition associated with impaired GJIC e.g., cardiac arrhythmia or osteoporosis
  • Individuals who can be treated using compounds described herein include, but are not limited to, animals, preferably mammals, e.g., rodents (including mice, rats, hamsters, and lagomorphs, such as rabbits), dogs, pigs, goats (generally any domestic animal), and primates.
  • the subject is a human being.
  • conditions which can be treated or prevented using compounds and pharmaceutical formulations described herein include, but are not limited to, cardiovascular disease; osteoporosis; inflammation of airway epithelium; disorders of alveolar tissue; bladder incontinence; impaired hearing (e.g. due to diseases of the cochlea); endothelial lesions; diabetes (Type I or Type II) and diabetic complications (including diabetic retinopathy and diabetic neuropathy); atherosclerosis; CNS related conditions; seizures; ischemia (e.g.
  • ischemia of the central nervous system, spinal cord, brain or brain stem dental tissue disorders (including periodontal disease); kidney diseases; haematologic manifestations (e.g., anaemia, leukopenia, thrombocytopenia, and pancytopenia, especially following treatment with cytostatic compounds or irradiation therapy); wounds (e.g., superficial wounds and deep wounds resulting trauma); bone fracture; erectile dysfunction; urinary bladder incontinence; neuropathic pain; subchronic and chronic inflammation; cancer; failure of bone marrow and stem cell transplantation; conditions which arise during transplantation of cells and tissues or during medical procedures such as surgery; conditions caused by an excess of reactive oxygen species and/or free radicals and/or nitric oxide; diseases or disorders of pregnancy (e.g., preeclampsia and preterm labor); female infertility; and stroke.
  • Compounds and pharmaceutical formulations described herein can also be used to induce labor (e.g., by facilitating the effect of oxytocin on
  • Some embodiments provide a pharmacologically active antiarrhythmic compound for treatment or prevention of arrhythmias and thrombotic complications arising during cardiovascular disorders, such as acute ischemic heart disease (e.g., stable angina pectoris, unstable angina pectoris, acute myocardial infarction), congestive heart failure (e.g., systolic, diastolic, high-output, low-output, right or left sided heart failure), congenital heart diseases, cor pulmonale, cardiomyopathies, myocarditis, hypertensive heart disease, during coronary revascularization, and the like.
  • acute ischemic heart disease e.g., stable angina pectoris, unstable angina pectoris, acute myocardial infarction
  • congestive heart failure e.g., systolic, diastolic, high-output, low-output, right or left sided heart failure
  • congenital heart diseases cor pulmonale,
  • compounds described herein can be used to treat and/or prevent bradyarrhythmias (e.g., due to disease in sinus node, AV node, bundle of His, right or left bundle branch), and tachyarrhythmias associated with reentry (e.g., atrial premature complexes, AV junctional complexes, ventricular premature complexes, atrial fibrillation, atrial flutter, paroxymal supraventricular tachycardia, sinus node reentrant tachycardia, AV nodal reentrant tachycardia, and non-sustained ventricular tachycardia).
  • bradyarrhythmias e.g., due to disease in sinus node, AV node, bundle of His, right or left bundle branch
  • tachyarrhythmias associated with reentry e.g., atrial premature complexes, AV junctional complexes, ventricular premature complexes, atrial fibrillation, atrial
  • compounds and pharmaceutical formulations described herein can be useful for alleviating conditions wherein slowing of conduction velocity is an important factor, e.g. ventricular tachycardia, ventricular fibrillation, and atrial fibrillation.
  • Compounds and pharmaceutical formulations described herein can be administered either alone or in combination with other antiarrhythmic compounds, such as class I agents (e.g., lidocaine), class II agents (e.g., metoprolol or propranolol), class III agents (e.g., amiodarone or sotalol) or class IV agents (e.g., verapamil).
  • class I agents e.g., lidocaine
  • class II agents e.g., metoprolol or propranolol
  • class III agents e.g., amiodarone or sotalol
  • class IV agents e.g., verapamil
  • Compounds and pharmaceutical formulations described herein can also be used to treat or prevent one or more of reentry arrhythmia, ventricular reentry (e.g., arising during acute myocardial infarction, chronic myocardial infarction, stable angina pectoris and unstable angina pectoris), infectious or autonomic cardiomyopathy, atrial fibrillation, repolarization alternans, monomorphic ventricular tachycardia, T-wave alternans, bradyarrhythmias, reduced contractility of cardiac tissue, thrombosis, and the like.
  • reentry arrhythmia e.g., arising during acute myocardial infarction, chronic myocardial infarction, stable angina pectoris and unstable angina pectoris
  • infectious or autonomic cardiomyopathy e.g., atrial fibrillation, repolarization alternans, monomorphic ventricular tachycardia, T-wave alternans, bradyarrhythmias, reduced contractility of
  • Cytoprotecting refers to reducing, preventing or alleviating symptoms associated with unwanted cell swelling.
  • Particular tissues and organs that will benefit from the method include those confined or otherwise impacted by a fiborous capsule such as heart or kidney. Also included are tissues associated with bone such as brain, spinal cord and bone marrow.
  • Compounds and pharmaceutical formulations described herein can be used to prevent or treat ischemic injury in the organs of a mammal in need of such treatment, including, for example, the heart, central nervous system, kidney, gastrointestinal tract, liver, lungs, and limbs.
  • Some embodiments provide the use of the compounds and pharmaceutical formulations described herein to treat or prevent haematologic manifestations following treatment with cytostatic compounds or irradiation therapy. Impaired haematopoiesis recovery is observed in patients after 5-fluorouracil (5-FU) cytostatic treatment. This includes absence of recovery of peripheral blood counts, including severe neutropenia, severe anemia with reticulocytopenia and presence of abnormal peripheral erythrocytes and severe thrombocytopenia.
  • 5-fluorouracil 5-fluorouracil
  • CFU-GM granulomacrophagic colony-forming-units
  • BFU-E erythroid burst forming units
  • CFU-mix mixed colony forming units
  • CFU-C overall colony forming units
  • Compounds and pharmaceutical formulations described herein can be use to treat or prevent osteoporosis. It is known that that GJIC is important in bone formation.
  • the efficacy of the compounds can be assessed, for example, by an increase in osteoblast activity in a standard osteoblast activity assay which measures either calcium wave formation and/or alkaline phosphatase activity of osteoblast cells in the presence of the compounds. Alkaline phosphatase activity also can be used to provide a measure of osteoblast activity using standard calorimetric assays.
  • N-Boc-trans-4-amino-L-proline methyl ester hydrochloride 50 g, 0.1745 mol, CNH Technologies, 98%) was added in portions, followed by EtOAc (500 mL). The mixture was cooled to 0° C. A solution of benzoyl chloride (20.26 mL, 0.1745 mol) in EtOAc (100 mL) was added over 25 min at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Phases were separated. Aqueous phase was extracted 2 ⁇ 200 mL of EtOAc.
  • (2S,4R)-1-tert-Butyl-2-methyl-4-benzamidopyrrolidine-1,2-dicarboxylate (60.19 g, contains 5.6% EtOAc; 0.1631 mol) was dissolved in Et 2 O (100 mL), and the solvent was evaporated in vacuum to remove residual EtOAc. The residual oil was dissolved in Et 2 O (100 mL). 2N HCl solution in Et 2 O (700 mL) was added (mild exotherm; precipitation commenced after ca. 5 min). The mixture was stirred at ambient temperature for 21 h. At that point, 200 mL of 2N HCl solution in Et 2 O were added, and the mixture was stirred for additional 24 h.
  • Step 3 Synthesis of (2S,4R)-Methyl 4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylate
  • the THF solution was demayted from the heavy oil, and added to the mixture in Flask B.
  • the reaction mixture was stirred at ambient temperature for 40 min. Water (500 mL) was added, and the mixture was concentrated in vacuum to remove THF ( ⁇ 550 mL residual volume).
  • EtOAc 500 mL was added, followed by brine (300 mL). Phases were separated. Aqueous phase was extracted with 2 ⁇ 300 mL of EtOAc. Combined organic fraction was washed 2 ⁇ 250 mL of 1N HCl, 2 ⁇ 250 mL of sat. NaHCO 3 solution, 150 mL of brine, dried over MgSO 4 , and concentrated to afford 48.31 g of the title product as a foamy solid (74% yield).
  • Step 4 Synthesis of (2S,4R)-4-Benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid
  • (2S,4R)-4-Benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid (21.97 g; contains 6.6 wt % EtOAc; 0.0524 mol, adjusted to residual EtOAc) was dissolved in dioxane (100 mL). The solvent was evaporated in vacuum to remove residual EtOAc. The residue was dissolved in anhydrous dioxane (200 mL). HCl (100 mL of freshly prepared ⁇ 3.6 N solution in dioxane) was added at 10-12° C. The solution was allowed to warm up to ambient temperature (precipitation commenced after about 2 min).
  • reaction mixture was stirred at ambient temperature for 21 h, at which time 30 mL of ⁇ 3.6N HCl solution were added, and the mixture was stirred for additional 5.5 h.
  • Precipitated solids were filtered using N 2 pressure, washed with 4 ⁇ 25 mL of dioxane, and dried in vacuum at room temperature for 24 h to afford 18.7 g of crude product as white solid.
  • the mixture was stirred at 0-10° C. for 3 h and monitored by LC (forms two clear phases). After 3 h, LC showed less than 3% by area of benzoyl chloride.
  • the temperature was adjusted to 20-25° C. The stirring was stopped and the phases were separated.
  • the organic phase was successively extracted with ⁇ 1N HCl (1.3 kg), saturated NaHCO 3 aqueous solution (3.25 kg), and water (1.3 L mL).
  • the toluene solution was concentrated to 1.5-2.5 L and then chased 2 ⁇ 3.0 kg of toluene.
  • the solution was concentrated to a volume of 2 L at 40-50° C. and 26 in Hg.
  • the concentrate was transferred to a 30-L jacketed reactor with mechanical stirring, under N 2 and diluted with 1.8 kg of additional toluene.
  • Step 2 Synthesis of (2S,4R)-Methyl 4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylate
  • Benzoyl chloride (2.0 g, 14.2 mmol) in 8 mL EtOAc was charged dropwise over 10 min maintaining temperature between 5-10° C. The mixture was stirred at 5-10° C. for 1 h and monitored by LC, which showed less than 0.5% by area of benzoyl chloride. The stirring was stopped and the phases were separated. The lower aqueous phase was extracted with EtOAc (2 ⁇ 20 mL). The combined EtOAc layer was washed with 1N HCl (20 mL), saturated NaHCO 3 aqueous solution (20 mL), brine (20 mL) and dried with Na 2 SO 4 .
  • Step 3 Synthesis of (2S,4S)-Methyl 4-benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylate hydrochloride
  • Step 4 Synthesis of (2S,4S)-4-Benzamido-1-(2-(tert-butoxycarbonylamino)acetyl)pyrrolidine-2-carboxylic acid
  • the stirred the reaction mixture was cooled to 0-10° C. and was charged with methanol (40 mL). To the stirred reaction mixture was charged 5 N NaOH (40 mL) while maintaining the reaction temperature 0-10° C. The reaction mixture is stirred at 0-10° C. for 2 h. Phases were separated. The aqueous phase was extracted with toluene (4 ⁇ 30 mL). The aqueous phase was cooled to 0-10° C. and was acidified with concentrated HCl (18 mL) to pH 2. The acidified aqueous solution was extracted with ethyl acetate (3 ⁇ 40 mL). The combined ethyl acetate solution was concentrated under vacuum to give 23 g of an oil.
  • reaction may be run at a range from about ⁇ 5 to 35° C. with little effect on results.
  • the acidic mixture was concentrated under vacuum to a residual volume of about 200 mL, and further acidified with hydrochloric acid to pH ⁇ 1.
  • Dichloromethane (170 mL) and water (65 mL) were added to the above concentrate with efficient stirring.
  • the organic phase was separated, extracted with water (50 mL) and discarded.
  • the combined aqueous phases were washed with dichloromethane (170 mL), and then diluted with more dichloromethane (150 mL).
  • the biphasic mixture was neutralized with 5 N aqueous sodium hydroxide solution to pH ⁇ 12.
  • the aqueous phase was separated, and extracted with dichloromethane (150 mL).
  • reaction is generally most effective in alcoholic solvents such as methanol, ethanol or propanol, but other solvents such as tetrahydrofuran, acetonitrile also give satisfactory results.
  • Reaction temperatures may vary up to boiling points of solvents used.
  • Step 3 Synthesis of (2S,4R)-Methyl 4-benzamidopyrrolidine-2-carboxylate hydrochloride (Methyl (4R)-4-(benzoylamino)-L-prolinate hydrochloride)
  • solvents such as toluene, ethyl acetate, or tetrahydrofuran may substituted for dichloromethane.
  • This transformation may also be performed under non-aqueous conditions using bases such as triethylamine, N,N-diisopropylethylamine.
  • Cyclohexene may be replaced by other hydrogen transfer agents such as 2-methyl-cyclohexene, cyclohexadiene, ammonium formate.
  • the benzyloxycarbonyl group may also be removed by catalytic hydrogenation.
US12/005,118 2006-12-21 2007-12-20 Synthesis of pyrrolidine compounds Abandoned US20080188545A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US12/005,118 US20080188545A1 (en) 2006-12-21 2007-12-20 Synthesis of pyrrolidine compounds
US12/690,043 US20100249207A1 (en) 2006-12-21 2010-01-19 Synthesis of pyrrolidine compounds
US13/593,110 US8927590B2 (en) 2006-12-21 2012-08-23 Synthesis of pyrrolidine compounds
US14/572,262 US9469609B2 (en) 2006-12-21 2014-12-16 Synthesis of pyrrolidine compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87629006P 2006-12-21 2006-12-21
US12/005,118 US20080188545A1 (en) 2006-12-21 2007-12-20 Synthesis of pyrrolidine compounds

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/690,043 Continuation US20100249207A1 (en) 2006-12-21 2010-01-19 Synthesis of pyrrolidine compounds

Publications (1)

Publication Number Publication Date
US20080188545A1 true US20080188545A1 (en) 2008-08-07

Family

ID=39470360

Family Applications (4)

Application Number Title Priority Date Filing Date
US12/005,118 Abandoned US20080188545A1 (en) 2006-12-21 2007-12-20 Synthesis of pyrrolidine compounds
US12/690,043 Abandoned US20100249207A1 (en) 2006-12-21 2010-01-19 Synthesis of pyrrolidine compounds
US13/593,110 Active US8927590B2 (en) 2006-12-21 2012-08-23 Synthesis of pyrrolidine compounds
US14/572,262 Active US9469609B2 (en) 2006-12-21 2014-12-16 Synthesis of pyrrolidine compounds

Family Applications After (3)

Application Number Title Priority Date Filing Date
US12/690,043 Abandoned US20100249207A1 (en) 2006-12-21 2010-01-19 Synthesis of pyrrolidine compounds
US13/593,110 Active US8927590B2 (en) 2006-12-21 2012-08-23 Synthesis of pyrrolidine compounds
US14/572,262 Active US9469609B2 (en) 2006-12-21 2014-12-16 Synthesis of pyrrolidine compounds

Country Status (9)

Country Link
US (4) US20080188545A1 (es)
EP (2) EP2074087A2 (es)
AR (1) AR064626A1 (es)
DK (1) DK2468724T3 (es)
ES (1) ES2558856T3 (es)
PE (1) PE20081400A1 (es)
PL (1) PL2468724T3 (es)
TW (1) TW200833660A (es)
WO (1) WO2008079266A2 (es)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101863817A (zh) * 2009-06-09 2010-10-20 大连凯飞精细化工有限公司 (2s,4r)-4-氨基吡咯啉-1,2-二羧酸-1-叔丁酯-2-甲酯盐酸盐的制法
US8431540B2 (en) 2005-12-23 2013-04-30 Zealand Pharma A/S Modified lysine-mimetic compounds
US9469609B2 (en) 2006-12-21 2016-10-18 Zealand Pharma A/S Synthesis of pyrrolidine compounds
US11324799B2 (en) 2017-05-05 2022-05-10 Zealand Pharma A/S Gap junction intercellular communication modulators and their use for the treatment of diabetic eye disease

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103333094B (zh) * 2013-06-19 2015-05-13 广东肇庆星湖生物科技股份有限公司 一种脯氨酸结晶精制的工艺方法
CN112142823B (zh) * 2019-06-28 2022-08-05 深圳翰宇药业股份有限公司 一种zp-1609的合成方法
EP3904339A1 (en) * 2020-04-28 2021-11-03 Esteve Pharmaceuticals, S.A. Alkylaminoproline derivatives as alfa-2-delta-1 blockers
WO2022171525A1 (en) 2021-02-10 2022-08-18 Ciana Therapeutics Aps Danegaptide for use in the treatment or prevention of a kidney disease
WO2023118366A1 (en) 2021-12-22 2023-06-29 Breye Therapeutics Aps Gap junction modulators and their use for the treatment of age-related macular degeneration

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4780528A (en) * 1984-12-22 1988-10-25 Ajinomoto Co., Inc. Tripeptides and sweetening agents containing the same
US4849525A (en) * 1987-09-21 1989-07-18 E. R. Squibb & Sons, Inc. Phosphinylcycloalkylcarbonyl and phosphinylcycloalkenylcarbonyl dipeptides
US5120859A (en) * 1989-09-22 1992-06-09 Genentech, Inc. Chimeric amino acid analogues
US5707991A (en) * 1993-01-07 1998-01-13 Rhone-Poulenc Rorer S.A. N-acylpyrrolidines and medicaments for the treatment or prevention of disorders linked to CKK and to gastrin
US20050203143A1 (en) * 2004-03-15 2005-09-15 Breslin Henry J. Novel compounds as opioid receptor modulators
US20070149460A1 (en) * 2005-12-23 2007-06-28 Larsen Bjarne D Modified lysine-mimetic compounds
US20070232574A1 (en) * 2000-11-17 2007-10-04 Societe L'oreal, S.A. 2-Oxothiazolidine 4-Carboxylic acid compounds for promoting desquamation of the skin

Family Cites Families (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5784223A (en) 1980-11-13 1982-05-26 Nissan Motor Co Ltd Vibration absorber of vehicle
US4462943A (en) 1980-11-24 1984-07-31 E. R. Squibb & Sons, Inc. Carboxyalkyl amino acid derivatives of various substituted prolines
EP0071544B1 (en) 1981-08-03 1986-10-08 E.R. Squibb & Sons, Inc. Phosphonamidate compounds
US4514391A (en) 1983-07-21 1985-04-30 E. R. Squibb & Sons, Inc. Hydroxy substituted peptide compounds
US4560506A (en) 1984-05-25 1985-12-24 E. R. Squibb & Sons, Inc. Mercaptocycloalkylcarbonyl and mercaptoarylcarbonyl dipeptides
DE3588094T2 (de) * 1984-09-12 1996-08-22 Rhone Poulenc Rorer Pharma Antihypertensive Derivate
EP0566157A1 (en) 1986-06-20 1993-10-20 Schering Corporation Neutral metalloendopeptidase inhibitors in the treatment of hypertension
EP0254032A3 (en) 1986-06-20 1990-09-05 Schering Corporation Neutral metalloendopeptidase inhibitors in the treatment of hypertension
PL322706A1 (en) 1993-11-09 1998-02-16 Merck & Co Inc Piperidines, pyrolidines and hexahydro-1h-azepins enhancing growth hormone liberation
DE4408531A1 (de) 1994-03-14 1995-09-28 Hoechst Ag PNA-Synthese unter Verwendung einer gegen schwache Säuren labilen Amino-Schutzgruppe
US5491164A (en) 1994-09-29 1996-02-13 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036873A1 (en) 1996-04-03 1997-10-09 Merck & Co., Inc. Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
AU4342097A (en) 1996-09-13 1998-04-02 Merck & Co., Inc. Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
PL192280B1 (pl) 1996-10-18 2006-09-29 Vertex Pharma Inhibitory proteaz serynowych, a zwłaszcza proteazy wirusa NS3 zapalenia wątroby C, kompozycja farmaceutyczna i zastosowania
WO1998025897A1 (en) 1996-12-12 1998-06-18 Merck & Co., Inc. Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
ES2275313T3 (es) 1997-08-22 2007-06-01 Kaken Pharmaceutical Co., Ltd. Derivados de amida como promotores de la liberacion de la hormona del crecimiento.
US6242422B1 (en) 1998-10-22 2001-06-05 Idun Pharmacueticals, Inc. (Substituted)Acyl dipeptidyl inhibitors of the ice/ced-3 family of cysteine proteases
CN1420882A (zh) 1999-07-28 2003-05-28 阿温蒂斯药物公司 取代的氧代氮杂杂环基化合物
US6552016B1 (en) 1999-10-14 2003-04-22 Curis, Inc. Mediators of hedgehog signaling pathways, compositions and uses related thereto
WO2001026644A2 (en) 1999-10-14 2001-04-19 Curis, Inc. Mediators of hedgehog signaling pathways, compositions and uses related thereto
AU1916401A (en) 1999-11-12 2001-06-06 Guilford Pharmaceuticals Inc. Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
AU781674B2 (en) 2000-02-23 2005-06-02 Zealand Pharma A/S Novel antiarrhythmic peptides
CA2404314A1 (en) 2000-03-31 2001-10-11 Lorin Andrew Thompson Succinoylamino heterocycles as inhibitors of a.beta. protein production
CA2406247A1 (en) 2000-04-17 2001-10-25 Robert J. Ternansky Inhibitors of the ice/ced-3 family of cysteine proteases
WO2001083517A1 (en) 2000-05-03 2001-11-08 Tularik Inc. Stat4 and stat6 binding dipeptide derivatives
JP4298289B2 (ja) 2000-07-21 2009-07-15 シェーリング コーポレイション Ｃ型肝炎ウイルスのｎｓ３−セリンプロテアーゼ阻害剤としての新規ペプチド
AR029851A1 (es) 2000-07-21 2003-07-16 Dendreon Corp Nuevos peptidos como inhibidores de ns3-serina proteasa del virus de hepatitis c
US7244721B2 (en) 2000-07-21 2007-07-17 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
AU2001277967A1 (en) 2000-07-21 2002-02-05 Corvas International, Inc. Peptides as ns3-serine protease inhibitors of hepatitis c virus
AU9684401A (en) 2000-10-13 2002-04-22 Curis Inc Hedgehog antagonists, methods and uses related thereto
JP2005506295A (ja) 2001-02-22 2005-03-03 ジーランド ファーマ アクティーゼルスカブ 細胞間連絡促進化合物の新規医薬使用
WO2002089738A2 (en) 2001-05-08 2002-11-14 Yale University Proteomimetic compounds and methods
US6894072B2 (en) 2002-01-23 2005-05-17 Schering Corporation Compounds as NS3-serine protease inhibitors of hepatitis C virus
US20030232788A1 (en) 2002-02-08 2003-12-18 Idun Pharmaceuticals, Inc. (Substituted)acyl dipeptidyl inhibitors of the ICE/ced-3 family of cysteine proteases
WO2004005248A1 (en) 2002-07-02 2004-01-15 Novartis Ag Peptide inhibitors of smac protein binding to inhibitor of apoptosis proteins (iap)
CA2492830A1 (en) * 2002-07-26 2004-02-12 Altana Pharma Ag Pyrrolidine derivatives as tryptase inhibitors
WO2004020599A2 (en) 2002-08-29 2004-03-11 Curis, Inc. Hedgehog antagonists, methods and uses related thereto
AU2003302084A1 (en) 2002-11-15 2004-06-15 Bristol-Myers Squibb Company Open chain prolyl urea-related modulators of androgen receptor function
AU2004226278B2 (en) 2003-04-03 2010-07-29 Merck Patent Gmbh Pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxo-morpholino-4-yl)-phenylamide) derivatives and related compounds for use as inhibitors of coagulation factor Xa in the treatment of thrombo-embolic diseases
EP1622870A2 (en) 2003-05-05 2006-02-08 Prosidion Ltd. Glutaminyl based dp iv-inhibitors
SI21507A (sl) * 2003-05-16 2004-12-31 LEK farmacevtska dru�ba d.d. Postopek za pripravo spojin z ace inhibitornim delovanjem
ES2398912T3 (es) 2003-10-14 2013-03-22 F. Hoffmann-La Roche Ltd. Ácido carboxílico macrocíclico y compuesto de acilsulfonamida como inhibidor de la replicación del virus de la hepatitis C
CN1528745A (zh) 2003-10-21 2004-09-15 山东大学 吡咯烷类基质金属蛋白酶抑制剂及其制备方法
CA2557301A1 (en) 2004-02-27 2005-09-15 Schering Corporation Cyclobutenedione groups-containing compounds as inhibitors of hepatitis c virus ns3 serine protease
JP4950026B2 (ja) 2004-03-30 2012-06-13 インターミューン・インコーポレーテッド ウイルス複製阻害剤としての大環状化合物
EP1604977A1 (en) 2004-06-02 2005-12-14 Faust Pharmaceuticals CIS pyrrolidinyl derivatives and their uses
CA2571984C (en) 2004-07-16 2012-04-10 Gilead Sciences, Inc. Antiviral compounds
US7820699B2 (en) 2005-04-27 2010-10-26 Hoffmann-La Roche Inc. Cyclic amines
PL2468724T3 (pl) 2006-12-21 2016-05-31 Zealand Pharma As Synteza związków pirolidynowych

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4780528A (en) * 1984-12-22 1988-10-25 Ajinomoto Co., Inc. Tripeptides and sweetening agents containing the same
US4849525A (en) * 1987-09-21 1989-07-18 E. R. Squibb & Sons, Inc. Phosphinylcycloalkylcarbonyl and phosphinylcycloalkenylcarbonyl dipeptides
US5120859A (en) * 1989-09-22 1992-06-09 Genentech, Inc. Chimeric amino acid analogues
US5707991A (en) * 1993-01-07 1998-01-13 Rhone-Poulenc Rorer S.A. N-acylpyrrolidines and medicaments for the treatment or prevention of disorders linked to CKK and to gastrin
US20070232574A1 (en) * 2000-11-17 2007-10-04 Societe L'oreal, S.A. 2-Oxothiazolidine 4-Carboxylic acid compounds for promoting desquamation of the skin
US20050203143A1 (en) * 2004-03-15 2005-09-15 Breslin Henry J. Novel compounds as opioid receptor modulators
US20070149460A1 (en) * 2005-12-23 2007-06-28 Larsen Bjarne D Modified lysine-mimetic compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8431540B2 (en) 2005-12-23 2013-04-30 Zealand Pharma A/S Modified lysine-mimetic compounds
US9469609B2 (en) 2006-12-21 2016-10-18 Zealand Pharma A/S Synthesis of pyrrolidine compounds
CN101863817A (zh) * 2009-06-09 2010-10-20 大连凯飞精细化工有限公司 (2s,4r)-4-氨基吡咯啉-1,2-二羧酸-1-叔丁酯-2-甲酯盐酸盐的制法
US11324799B2 (en) 2017-05-05 2022-05-10 Zealand Pharma A/S Gap junction intercellular communication modulators and their use for the treatment of diabetic eye disease

Also Published As

Publication number Publication date
WO2008079266A2 (en) 2008-07-03
US8927590B2 (en) 2015-01-06
US20130053344A1 (en) 2013-02-28
EP2074087A2 (en) 2009-07-01
US20100249207A1 (en) 2010-09-30
DK2468724T3 (en) 2016-02-22
PL2468724T3 (pl) 2016-05-31
US20150322007A1 (en) 2015-11-12
EP2468724A1 (en) 2012-06-27
AR064626A1 (es) 2009-04-15
TW200833660A (en) 2008-08-16
EP2468724B1 (en) 2015-11-18
US9469609B2 (en) 2016-10-18
ES2558856T3 (es) 2016-02-09
WO2008079266A3 (en) 2008-11-06
PE20081400A1 (es) 2008-10-24

Similar Documents

Publication Publication Date Title
US9469609B2 (en) Synthesis of pyrrolidine compounds
JP3987890B2 (ja) シアノピロリジン誘導体
AU2005210285B2 (en) Bicycloester derivative
US8232293B2 (en) Crystalline forms of a potent HCV inhibitor
RU2201937C2 (ru) Производные d-пролина
KR20060037391A (ko) (2Ｓ,4Ｓ)-4-플루오로-1-[4-플루오로-베타-(4-플루오로페닐)-Ｌ-페닐알라닐]-2-피롤리딘카르보니트릴 ｐ-톨루엔설폰산염 및 이의 무수 결정 형태
US20020115863A1 (en) Novel succinate compounds, compositions and methods of use and preparation
WO2005115975A1 (ja) アリールアルキルアミン化合物及びその製法
WO2005058849A1 (en) New dipeptidyl peptidase in inhibitors; process for their preparation and compositions containing them
EP1237862A1 (en) Succinate compounds, compositions and methods of use and preparation
AU2013318779B2 (en) Dolastatin-10 derivative, method of producing the same and anticancer drug composition containing the same
JP2001513767A (ja) メタロプロテアーゼ阻害剤としての逆ヒドロキサメート誘導体
JPWO2003095425A1 (ja) シアノピロリジン誘導体
US20040254221A1 (en) Novel Nitrogenous Compound and use thereof
JP6827942B2 (ja) トリプトリドのｃ１４ヒドロキシルエステル化アミノ酸誘導体、ならびにその製造方法および使用
US5859026A (en) Quinoline carboxylic acid
US6222043B1 (en) Methods of preparing novel dipeptide compounds or pharmaceutically acceptable salts thereof
US5420283A (en) Resolution of (R)-2-benzylsuccinic acid 4-[4-(N-t-butoxycarbonylmethylamino)-piperidine] amide
SK3242000A3 (en) Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase
JPH02502012A (ja) アミノ酸エステル、その調製方法およびこれを含有する薬学的製剤
EP0812838A1 (en) Pyridonecarboxylic acid derivative substituted by bicyclic amino group, ester thereof, salt thereof, and bicyclic amine as intermediate therefor
JP7279134B2 (ja) プロリンアミド化合物の製造方法
JP3233276B2 (ja) カッパアゴニストとしてのヒドラジド化合物
TWI449711B (zh) Ｃ型肝炎病毒（ｈｃｖ）抑制劑
US20110281928A1 (en) Process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: WYETH, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ALIMARDANOV, ASAF R.;KRISHNAN, LALITHA;ZHOU, MAOTANG;AND OTHERS;REEL/FRAME:020784/0639;SIGNING DATES FROM 20080311 TO 20080407

AS Assignment

Owner name: WYETH, NEW JERSEY

Free format text: CORRECTIVE COVER SHEET TO CORRECT THE INCORRECT SPELLING OF INVENTORS NAME PREVIOUSLY RECORDED ON REEL 020784 FRAME 0639. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT.;ASSIGNORS:ALIMARDANOV, ASAF R.;KRISHNAN, LALITHA;ZHOU, MAOTANG;AND OTHERS;REEL/FRAME:020836/0049;SIGNING DATES FROM 20080311 TO 20080407

AS Assignment

Owner name: WYETH, NEW JERSEY

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT EXECUTION DATE FOR INVENTOR SUTHERLAND FROM 3/18/08 TO 3/13/08 PREVIOUSLY RECORDED ON REEL 020836 FRAME 0049. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT.;ASSIGNORS:ALIMARDANOV, ASAF R.;KRISHNAN, LALITHA;ZHOU, MAOTANG;AND OTHERS;REEL/FRAME:020872/0773;SIGNING DATES FROM 20080311 TO 20080407

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: ZEALAND PHARMA A/S, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:WYETH;REEL/FRAME:026721/0174

Effective date: 20110513