WO2019182015A1 - 非ステロイド性抗炎症性化合物結合アルギン酸誘導体 - Google Patents
非ステロイド性抗炎症性化合物結合アルギン酸誘導体 Download PDFInfo
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- WO2019182015A1 WO2019182015A1 PCT/JP2019/011715 JP2019011715W WO2019182015A1 WO 2019182015 A1 WO2019182015 A1 WO 2019182015A1 JP 2019011715 W JP2019011715 W JP 2019011715W WO 2019182015 A1 WO2019182015 A1 WO 2019182015A1
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- WIPO (PCT)
- Prior art keywords
- alginic acid
- compound
- group
- water
- acid derivative
- Prior art date
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- 229960001126 alginic acid Drugs 0.000 title claims abstract description 306
- 239000000783 alginic acid Substances 0.000 title claims abstract description 306
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- 150000004781 alginic acids Chemical class 0.000 title claims abstract description 269
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- 150000003839 salts Chemical class 0.000 claims abstract description 109
- IAJILQKETJEXLJ-SQOUGZDYSA-N L-guluronic acid Chemical compound O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O IAJILQKETJEXLJ-SQOUGZDYSA-N 0.000 claims abstract description 39
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 claims abstract description 38
- AEMOLEFTQBMNLQ-YBSDWZGDSA-N d-mannuronic acid Chemical compound O[C@@H]1O[C@@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-YBSDWZGDSA-N 0.000 claims abstract description 37
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- 239000003814 drug Substances 0.000 claims description 58
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 238000013268 sustained release Methods 0.000 claims description 42
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- 125000005843 halogen group Chemical group 0.000 claims description 41
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 16
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
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- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 claims description 10
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 10
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- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 9
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- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 7
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- 125000005647 linker group Chemical group 0.000 description 51
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
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- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 23
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61K47/6903—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
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Definitions
- the present invention relates to a water-soluble alginic acid derivative obtained by covalently binding alginic acid and a nonsteroidal anti-inflammatory compound via a linker, and a sustained-release pharmaceutical composition containing the same.
- Alginic acid is a high-molecular-weight polysaccharide composed of ⁇ -D-mannuronic acid and ⁇ -L-guluronic acid extracted from brown algae. It is not toxic and is not easily degraded due to the absence of a specific degrading enzyme in the body. Sexual and non-immunogenic. Furthermore, it has the characteristic of forming a gel by crosslinking with divalent metal ions such as calcium. Utilizing such properties of alginic acid, it is used for industrial use, food use, and further as a pharmaceutical additive. In recent years, as a main pharmaceutical agent, it has been further used as a wound covering (Japanese Patent Application Laid-Open No.
- Nonsteroidal anti-inflammatory agents (hereinafter also referred to as NSAIDs) are widely used as inhibitors and relievers of pain due to arthropathy. In general, when NSAIDs are used as an inhibitor and a relieving agent for these pains, they are used as oral dosage forms and transdermal preparations.
- the oral dosage form containing NSAIDs in order to reach the affected area with an effective amount of NSAIDs, a large amount of medication may be required, which may cause more adverse side effects on the digestive system. There was a problem. Further, in the percutaneous absorption type dosage form, the amount of NSAIDs absorbed from the start of contact with the affected part (joint) until the end of contact is not constant, so the effect may not be stable, and a high NSAIDs concentration is included. In the case of using a skin-absorbing preparation, there is a problem that side effects such as contact dermatitis more than expected can be caused.
- Non-Patent Document 5 a novel derivative in which NSAIDs or anti-rheumatic drugs (DMARDs) are chemically introduced into sodium hyaluronate, which is a therapeutic agent for arthropathy, is prepared and injected into the affected area.
- a drug that can greatly contribute to the relief and suppression of pain associated with the disease and the fundamental treatment of arthropathy, and the drug having a sustained effect by controlling the release of NSAIDs and DMARDs are disclosed.
- International Publication No. 2005/66214 Patent Document 5
- DMARDs anti-rheumatic drugs
- Patent Document 6 2015/5458 (Patent Document 6), it is possible to control the drug release rate without largely depending on the structure of the drug, and at an appropriate rate according to the disease to be applied, It is described to provide a glycosaminoglycan derivative into which a drug to be released is introduced and a method for producing the same.
- Patent Document 7 discloses hyaluronic acid derivatives having photoreactive groups introduced with drugs such as NSAIDs and DMARDs, and photocrosslinked hyaluronic acid derivative gels. And providing a preparation with enhanced drug sustained release.
- Non-Patent Document 1 Discloses a bead in which a mixture of alginic acid and diclofenac, which is confirmed to have a sustained release of diclofenac for several hours, is crosslinked with calcium ions.
- Patent Document 8 discloses that a therapeutically effective amount of a drug is released only at a lesion site where an enzyme is produced.
- JP-A-08-502053 discloses an alginate-bioactive agent combination connected via an acid-labile biodegradable spacer bond. This formulation is effective for delivering a bioactive agent to a target present in a low pH environment, to the target surface or into the target interior, and covalently attached to the bioactive agent (including drugs and prodrugs) It is described that the alginate produced can be used to control the rate of release of the substance.
- sustained-release preparations containing NSAIDs have not yet been put into wide use.
- a sustained-release preparation containing NSAIDs using hyaluronic acid as a base has been proposed, but hyaluronic acid is degraded by an enzyme (hyaluronidase) present in the living body, affecting the release of NSAIDs.
- hyaluronidase an enzyme present in the living body, affecting the release of NSAIDs.
- a sustained release preparation containing NSAIDs as a base material derived from plants and brown algae that can be used as a new base material option has not yet been achieved.
- the object of the present invention is to provide a sustained-release preparation capable of stably releasing a certain active ingredient in vivo using alginic acid as a base material that can be an option for a new base material. It is to provide a water-soluble compound that can be used.
- an alginic acid derivative having a structure in which alginic acid or a salt thereof and a non-steroidal anti-inflammatory compound are covalently bonded with a specific linker is water-soluble.
- the inventors have found that by using this as a sustained-release preparation, a non-steroidal anti-inflammatory compound can be delivered to the affected area stably for an unexpectedly long period of time, and the present invention has been completed. That is, the present invention is configured as follows:
- Another aspect of the present invention may be as described in the following [1] to [14].
- [1] A water-soluble alginic acid derivative having a structure in which alginic acid or a salt thereof and a nonsteroidal anti-inflammatory compound are covalently bonded via a linker.
- [1a] The water-soluble alginic acid derivative according to [1], wherein the linker is a divalent linker.
- Show (D) shows one residue of a non-steroidal anti-inflammatory compound
- X 1 and X 2 represent a hetero atom
- R 1 , R 2 , R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a C 1-10 alkyl group, a C 1-10 alkoxy group or a C 1-10 alkoxycarbonyl group, or R 1 and R 2 or R 3 and R 4 together represent ⁇ O
- Y represents a cycloalkane ring, an aromatic ring or a heterocyclic ring (the cycloalkane ring, aromatic ring or heterocyclic ring may be substituted with a halogen atom or a C 1-10 alkyl group)
- Z represents O or C ( ⁇ O) for forming an ester bond with (D)
- n1 represents any integer of 0 to 10
- n2 to n8 independently represent any integer of 0 to 3, but all of n1 to n8 are not 0).
- a group selected from carbonyl groups (R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 can be combined to form an oxo group ( ⁇ O));
- Y is a C 3-8 cycloalkyl ring, C 6-10 aryl ring, or heterocyclic ring (the C 3-8 cycloalkane ring, C 6-10 aryl ring, or heterocyclic ring is a halogen atom, or C 1- 6 is an alkyl group may be one to three substituents);
- Z is an oxygen atom or a carbonyl group;
- n1 or n8 is any integer from 0 to 10; n3, n5, or n6 is independently an integer of 0, 1, 2, 3; n2, n4, or n7 is independently an integer of 0 or 1;
- the non-steroidal anti-inflammatory compound is a salicylic acid-based, propionic acid-based or acetic acid-based non-steroidal anti-inflammatory drug (NSAIDs), and the carboxyl group of NSAIDs is bonded to a linker.
- NSAIDs non-steroidal anti-inflammatory drug
- the water-soluble alginic acid derivative according to any one of [4].
- the non-steroidal anti-inflammatory compound is a salicylic acid-based, propionic acid-based or phenylacetic acid-based non-steroidal anti-inflammatory drug (NSAIDs), and the carboxyl group of NSAIDs is represented by the formula (4a)
- the introduction rate (mol%) of the non-steroidal anti-inflammatory compound is at least 1.0 mol% or more, [1a], [2], [3a], [4a], [5a], The alginic acid derivative according to any one of [6a], [6a-1], [7a] and [7a-1].
- [9] An alginic acid derivative gel obtained by crosslinking the water-soluble alginic acid derivative according to any one of [1] to [8]. [9a] Any of [1a], [2], [3a], [4a], [5a], [6a], [6a-1], [7a], [7a-1] and [8a] An alginic acid derivative gel obtained by crosslinking the alginic acid derivative according to item 1. [10] A sustained-release pharmaceutical composition comprising the water-soluble alginic acid derivative according to any one of [1] to [8] or the alginic acid derivative gel according to [9].
- a sustained-release pharmaceutical composition comprising the alginic acid derivative according to Item 1 or the alginic acid derivative gel according to [9a].
- the sustained-release pharmaceutical composition according to [10] which is used as a therapeutic agent for arthritis.
- the sustained-release pharmaceutical composition according to [10a] as a therapeutic agent for arthritis.
- [12] The water-soluble alginic acid derivative according to any one of the above [1] to [8] or the alginic acid derivative gel according to the above [9] for sustained release of a nonsteroidal anti-inflammatory compound Use of.
- [12a] The above-mentioned [1a], [2], [3a], [4a], [5a], [6a], [6a-1], [7a] for sustained release of a nonsteroidal anti-inflammatory compound ] Use of the alginic acid derivative according to any one of [7a-1] and [8a] or the alginic acid derivative gel according to [9a].
- alginic acid derivative of the formula (2) of the above [3a] a preferable one is selected from the alginic acid derivatives listed below.
- (A) is one residue derived from alginic acid or a salt thereof, and C ( ⁇ O) — of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid. 1 residue having a group)
- the present invention can provide a water-soluble compound that can be used in a sustained-release preparation that can release a non-steroidal anti-inflammatory compound at a stable rate. Moreover, the water-soluble compound which can further improve the sustained release of the compound can be provided by making it gelatinize.
- the present invention relates to a water-soluble alginic acid derivative having a structure in which alginic acid or a salt thereof and a nonsteroidal anti-inflammatory compound are covalently bonded via a linker.
- the linker is preferably covalently bonded to the carboxyl group of alginic acid or a salt thereof and the carboxyl group or hydroxyl group of the nonsteroidal anti-inflammatory compound.
- the binding mode is not particularly limited as long as the object of the present invention is achieved. It is preferably an ester bond.
- binding site functional group of alginic acid or a salt thereof
- alginic acid or a salt thereof examples include a hydroxyl group or a carboxyl group, but a carboxyl group capable of forming an amide bond is more preferable.
- the water-soluble alginic acid derivative has a structure represented by the following formula (1): (A) -L- (D) (1)
- (A) is a residue derived from alginic acid or a salt thereof, and is a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- L is a linker having a functional group that can be bonded to (A) by an amide bond and a functional group that can be bonded to (D) by an ester bond.
- (D) represents one residue of a non-steroidal anti-inflammatory compound, and one residue of (D) may be a hydroxyl group or a carboxyl group. A carboxyl group is preferable.
- the water-soluble alginic acid derivative is represented by the following formula (1): (In the formula (1), (A) is a residue derived from alginic acid or a salt thereof, and C ( ⁇ O) — of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- (D) represents one residue of a non-steroidal anti-inflammatory compound, and one residue of (D) is a hydroxyl group or a carboxyl group, preferably a carboxyl group;
- ethyl group, n- propyl group, iso- propyl group and is selected from such
- C 1-6 alkoxy group e.g., methoxy group, ethoxy group, propoxy Shi group, selected from such
- C 1-6 alkoxycarbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, are selected from such
- C 7-16 aralkyl group e.g., benzyl group
- 1-10, preferably 1-5) may be substituted
- Z is an oxygen atom or a carbonyl group, preferably an oxygen atom).
- the water-soluble alginic acid derivative has a structure represented by the following formula (2): (A) —NH— (CH 2 ) n1 — [X 1 ] n2 — (CR 1 R 2 ) n3 — [Y] n4 — (CH 2 ) n5 — (CR 3 R 4 ) n6 — [X 2 ] n7 -(CH 2 ) n8- [Z]-(D) (2)
- (A) is a residue derived from alginic acid or a salt thereof, and C ( ⁇ O) — of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- X 1 represents a residue having a group
- (D) represents one residue of a non-steroidal anti-inflammatory compound
- X 1 and X 2 represent heteroatoms
- R 1 , R 2 , R 3 and R 4 Each independently represents a hydrogen atom, a halogen atom, a C 1-10 alkyl group, a C 1-10 alkoxy group or a C 1-10 alkoxycarbonyl group, or R 1 and R 2 or R 3 and R 4. Together represent ⁇ O
- Y represents a cycloalkane ring, aromatic ring or heterocyclic ring (the cycloalkane ring, aromatic ring or heterocyclic ring is substituted with a halogen atom or a C 1-10 alkyl group).
- Z may be O or C to form an ester bond with (D).
- N1 represents an integer of 0 to 10
- n2 to n8 independently represent an integer of 0 to 3, but all of n1 to n8 are not 0.
- n2, n4 and n7 are independently 0-2, more preferably independently 0-1.
- n3, n5, n6 and n8 in total are preferably 1 to 12, more preferably 2 to 10.
- the water-soluble alginic acid derivative is The following formula (2a): (Where (A) is one residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- a group; (D) is a residue of a non-steroidal anti-inflammatory compound;
- X 1 and X 2 are an oxygen atom or an imino group (NH);
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkoxycarbonyl.
- a group selected from the group (R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 together can form an oxo group ( ⁇ O)), preferably hydrogen
- a group selected from an atom, a halogen atom, a C 1-3 alkyl group, a C 1-3 alkoxy group, and a C 1-3 alkoxycarbonyl group (R 1 and R 2 , R 3 and R 4 , or R 5 And R 6 together can form an oxo group ( ⁇ O));
- Y is a C 6-10 aryl ring or a heterocyclic ring;
- Z is an oxygen atom or a carbonyl group;
- n1 is an integer from 0 to 5;
- n8 is any integer from 0 to 10;
- n3, n5, or n6 is independently an integer of 0, 1, 2, 3; n2, n4, or
- n7 is independently an integer of 0 or 1; n1 to n8 are not all 0
- the water-soluble alginic acid derivative is represented by the following formula (2a): (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid Is; (D) is a residue of a non-steroidal anti-inflammatory compound selected from diclofenac, ketoprofen, naproxen, and felbinac; X 1 and X 2 are an oxygen atom or an imino group (NH); R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently a group selected from a hydrogen atom, a fluorine atom, a methyl group and an ethoxycarbonyl group (said R 1 and R 2 Or R 3 and R 4 together can form an oxo group ( ⁇ O)); Y is a benzyl group (where (A) is
- preferred water-soluble alginic acid derivatives have structures represented by the following formulas (3) to (6): (A) -NH- (CH 2 ) n1- (CR 1 R 2 ) n3- (CH 2 ) n5- [Z]-(D) (3) (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- Show (D) shows one residue of a non-steroidal anti-inflammatory compound
- R 1 and R 2 are either R 1 represents hydrogen or a halogen atom
- R 2 represents hydrogen, a halogen atom, a methyl group or an ethyl group, or R 1 and R 2 together represent ⁇ O.
- Show Z represents O for forming an ester bond with (D), n1, n3, and n5 represent any integer of 1 to 4 in total).
- (A) —NH— (CH 2 ) n1 — [X 1 ] — (CR 1 R 2 ) n3 — (CR 3 R 4 ) n6 — (CH 2 ) n8 — [Z] — (D) (4) (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- Show (D) shows one residue of a non-steroidal anti-inflammatory compound
- X 1 represents O or NH
- R 1 and R 2 are those in which R 1 represents hydrogen and R 2 represents hydrogen, a halogen atom, a methyl group or an ethyl group, or R 1 and R 2 together represent ⁇ O
- R 1 is preferably hydrogen
- R 2 is preferably hydrogen, methyl group or ethyl group
- R 3 and R 4 are those in which R 3 represents hydrogen and R 4 represents hydrogen, a halogen atom, a methyl group or an ethyl group, or R 3 and R 4 together represent ⁇ O
- Z represents O for forming an ester bond with (D)
- n1 represents any integer of 1 to 3
- n3, n6 and n8 represent any integer of
- (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- Show (D) shows one residue of a non-steroidal anti-inflammatory compound; Y represents an aromatic ring; Z represents O for forming an ester bond with (D), n1 and n5 represent any integer of 1 to 4 in total).
- (A) —NH— (CH 2 ) n1 — (CR 1 R 2 ) n3 — (CH 2 ) n5 — (CR 3 R 4 ) n6 — (CH 2 ) n8 — [Z] — (D) (6)
- (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid.
- Show (D) shows one residue of a non-steroidal anti-inflammatory compound
- R 1 and R 2 are those in which R 1 represents hydrogen and R 2 represents hydrogen, methoxy group, ethoxy group, methoxycarbonyl group or ethoxycarbonyl group, or R 1 and R 2 together represent O
- R 3 and R 4 are those in which R 3 represents hydrogen and R 4 represents hydrogen, a methyl group or an ethyl group, or R 3 and R 4 together represent ⁇ O
- Z represents O for forming an ester bond with (D), n1, n3, n5, n6 and n8 in total represent any integer of 1 to 4.
- preferred water-soluble alginic acid derivatives include the following formula (3a): (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid Is; (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; R 1 and R 2 are each independently a group selected from a hydrogen atom, a halogen atom, a methyl group, and an ethoxycarbonyl group (the R 1 and R 2 together represent an oxo group ( ⁇ O ) Can be formed); Z is an oxygen atom; n1, n3, and n5 are a water-soluble alginic acid derivative having a structure represented by:
- formula (3a) include, for example, the following formula: A water-soluble alginic acid derivative selected from (wherein (A) is a residue derived from alginic acid or a salt thereof, and is a single residue of either L-guluronic acid or D-mannuronic acid constituting alginic acid.) 1 residue having a C ( ⁇ O) — group of sugar.
- preferred water-soluble alginic acid derivatives include the following formula (4a): (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid Is; (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; X 1 is an oxygen atom or an imino group (NH); R 1, R 2, R 3, R 4, R 5 and R 6 are each independently hydrogen atom, a halogen atom, a group selected from methyl group, an ethyl group, and ethoxycarbonyl group (wherein R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 can be combined to form an oxo group ( ⁇ O).
- R 1 is a hydrogen atom.
- R 2 is preferably a hydrogen atom, methyl group or ethyl group
- R 3 is preferably a hydrogen atom
- R 4 is preferably a hydrogen atom, methyl group or ethyl group
- R 5 is preferably a hydrogen atom
- R 6 is preferably a hydrogen atom, a methyl group or an ethyl group; more preferably, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are a hydrogen atom
- R 3 is hydrogen are preferred
- R 4 is a hydrogen atom, a methyl group, or ethyl group is preferred
- R 5 is preferably hydrogen
- R 6 is a hydrogen atom , Methyl group,
- preferred water-soluble alginic acid derivatives include the following formula (5a): (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid Is; (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; Y is a C 6-10 aryl ring, preferably a benzene ring; Z is an oxygen atom; n1 and n5 are each a water-soluble alginic acid derivative having a structure represented by the following formula:
- formula (5a) include, for example, the following formula: A water-soluble alginic acid derivative selected from (wherein (A) is one residue derived from alginic acid or a salt thereof, and is a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid) A C ( ⁇ O) — group of 1 residue).
- formula (6a) include, for example, the following formula: A water-soluble alginic acid derivative selected from (wherein (A) is one residue derived from alginic acid or a salt thereof, and is a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid) A C ( ⁇ O) — group of 1 residue).
- (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid Is;
- (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of a non-steroidal anti-inflammatory compound selected from diclofenac, ketoprofen, naproxen, and felbinac;
- R 1 and R 2 are each independently a group selected from a hydrogen atom, a halogen atom, a methyl group, and an ethyl group (the R 1 and R 2 together represent an oxo group ( ⁇ O)
- R 1 and R 2 together form an oxo group ( ⁇ O)
- R 5 and R 6 are each independently a group selected from a hydrogen atom,
- formula (7a) include, for example, the following formula: A water-soluble alginic acid derivative selected from (wherein (A) is one residue derived from alginic acid or a salt thereof, and is a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid) A C ( ⁇ O) — group of 1 residue).
- the following formula (8a) (Where (A) is a residue derived from alginic acid or a salt thereof, and one residue having a C ( ⁇ O) — group of a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid Is; (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; R 1 and R 2 are each independently a group selected from a hydrogen atom, a halogen atom, a methyl group, and an ethyl group (the R 1 and R 2 together represent an oxo group ( ⁇ O) Preferably R 1 and R 2 together form an oxo group ( ⁇ O); R 5 and R 6 are each independently a group selected from a hydrogen atom, a halogen atom, a methyl group, and an ethyl group (the R 5 and
- formula (8a) include, for example, the following formula: A water-soluble alginic acid derivative selected from (wherein (A) is one residue derived from alginic acid or a salt thereof, and is a monosaccharide of either L-guluronic acid or D-mannuronic acid constituting alginic acid) A C ( ⁇ O) — group of 1 residue).
- a linker structure of the water-soluble alginic acid derivative of the present invention will be described later in the section of ⁇ Linker >>.
- non-steroidal anti-inflammation that is less likely to cause side effects in the body and can continue to release a non-steroidal anti-inflammatory compound at a concentration that can moderate or relieve arthritis, for example.
- the introduction rate of the functional compound is preferably 1.0 mol% or more. More preferably, it is 2.0 mol% or more, More preferably, it is 4.0% or more.
- the introduction rate (mol%) in the present invention refers to, for example, when a nonsteroidal anti-inflammatory compound is introduced into the carboxyl group of L-guluronic acid or D-mannuronic acid constituting alginic acid via a linker.
- the introduction rate of 10 mol% is a ratio of L-guluronic acid or D-mannuronic acid monosaccharide constituting alginic acid as 1 unit (unit), and 10 non-steroidal anti-inflammatory compounds per 100 monosaccharides. It has been introduced in. Therefore, a non-steroidal anti-inflammatory compound may be introduced to each carboxyl group of adjacent monosaccharides via a linker.
- the type of linker and the introduction rate of the non-steroidal anti-inflammatory compound are determined according to the final dosage form (gel, sol, microbead, etc.) of the pharmaceutical composition containing the compound described later, or when administered to a living body. It may be appropriately adjusted in consideration of the necessary amount of steroidal anti-inflammatory compound in the affected area or the sustained release efficiency.
- the water-soluble alginic acid derivative of the present invention is a polymer compound containing a non-steroidal anti-inflammatory compound, but is characterized by being water-soluble. That is, even when the introduction rate of the non-steroidal anti-inflammatory compound, which is generally known to be hydrophobic, in the water-soluble alginic acid derivative is high, for example, 10 mol% or more, it can be dissolved in water. is there. For example, when 0.1 part by mass of a water-soluble alginic acid derivative is added to 100 parts by mass of water and shaken or stirred at room temperature (for example, 20 ° C.), it may dissolve without being gelled within 24 hours. Indicated.
- the water-soluble alginic acid derivative of the present invention is soluble in an aqueous solvent at a concentration of 0.1% or more.
- room temperature usually indicates a temperature of about 0 ° C. to about 35 ° C.
- the water solubility of the water-soluble alginic acid derivative in the present invention is equivalent to, for example, the water solubility of sodium alginate, and there is an advantage that it is easy to handle gelation or solification according to the use described later. Therefore, the solution of the water-soluble alginic acid derivative of the present invention can be filtered, and dust removal, sterilization, and sterilization can be performed by filter filtration.
- dust removal and sterilization can be performed by passing through a 5 ⁇ m to 0.45 ⁇ m filter, and more preferably, sterilization can be performed by passing through a 0.22 ⁇ m filter.
- the water-soluble alginic acid derivative of the present invention can be dissolved in water, an aqueous solution containing a pharmaceutically acceptable metal salt or a pH adjuster, or an aqueous solvent such as a buffer solution. Specifically, it can be dissolved in water for injection, phosphate buffered saline, physiological saline and the like.
- the water-soluble alginic acid derivative in the present invention alone does not bring about the anti-inflammatory effect of the non-steroidal anti-inflammatory compound, but when it is administered in vivo, for example, it is removed from the linker depending on the situation in the living body.
- the non-steroidal anti-inflammatory compound By appropriately cleaving the non-steroidal anti-inflammatory compound, the non-steroidal anti-inflammatory compound is released and exerts an effect.
- nonsteroidal anti-inflammatory compounds suppress the inflammation of the affected area and only release the amount necessary for analgesia, the result is to concentrate on the affected area stably for a certain period of time, resulting in anti-inflammatory and analgesic effects Can do.
- the water-soluble alginic acid derivative can adjust the sustained release rate of the non-steroidal anti-inflammatory compound to a desired mode according to the structure of the linker that is a constituent component thereof.
- the rate of introduction of the active compound and the type of linker By optimizing the combination of the rate of introduction of the active compound and the type of linker, long-term sustainable analgesic effects and the like can be achieved when injected into a living body, for example, when injected intra-articularly, particularly when injected into the knee joint. May have anti-inflammatory effects.
- the water-soluble alginic acid derivative in the present invention is not easily affected by the release rate of the non-steroidal anti-inflammatory compound due to factors other than the cleavage of the linker site. Certain active ingredients can be released.
- the degradability and degradation sequence in vivo can be changed by changing the binding mode of alginic acid or a salt thereof and the linker and the binding mode of the non-steroidal anti-inflammatory compound and the linker.
- the release rate and release rate of the non-steroidal anti-inflammatory compound can be controlled.
- ester bonds are more susceptible to hydrolysis than amide bonds in vivo.
- the water-soluble alginic acid derivative of the present invention can be decomposed in any order as long as the non-steroidal anti-inflammatory compound is finally released, but the non-steroidal anti-inflammatory compound and the linker are first hydrolyzed.
- the non-steroidal anti-inflammatory compound is released.
- alginic acid or a salt thereof and a linker are bonded by an amide bond, and a nonsteroidal anti-inflammatory compound and a linker are bonded by an ester bond, so that the ester bond is first hydrolyzed, and the nonsteroidal anti-inflammatory compound is bonded.
- Inflammatory compounds are released first from the linker.
- alginic acid does not adversely affect the applied organism, and since no specific receptor that binds to alginic acid in vivo has been identified, alginic acid or its salt after releasing a non-steroidal anti-inflammatory compound is Decomposes without causing toxicity in the body.
- the water-soluble alginic acid derivative of the present invention is preferably released very slowly in a situation where sustained release is expected over a long period under weakly acidic conditions.
- the nonsteroidal anti-inflammatory compound has a release rate of 1.0% at pH 5.3. It is preferable to show the release behavior below.
- the release rate is greater than 0% and 50% or less under the above conditions (pH 7.0), and the release rate is 0.04 to 45%.
- each water-soluble alginic acid derivative of the present invention can be properly used depending on the release rate at each pH.
- the sustained release effect can be further enhanced by gelling the water-soluble alginic acid derivative of the present invention with a crosslinking agent.
- the water-soluble alginic acid derivative of the present invention is used as a therapeutic agent for arthritis for intra-knee joint administration, it is administered to the affected area by injection, etc.
- the sustained release of the non-steroidal anti-inflammatory compound is stably continued for 7 days or more, preferably 15 days or more, more preferably 30 days or more.
- the release rate indicates the ratio of the amount of released non-steroidal anti-inflammatory compound to the total amount of non-steroidal anti-inflammatory compound contained in the water-soluble alginic acid derivative.
- alginic acid or a salt thereof is a monovalent metal such as Na + or K + , which is a “monovalent metal salt of alginic acid” and a hydrogen atom of carboxylic acid of D-mannuronic acid or L-guluronic acid of alginic acid.
- Water-soluble salts produced by ion exchange with ions are preferred.
- Specific examples of the monovalent metal salt of alginic acid include sodium alginate and potassium alginate, and sodium alginate is particularly preferable.
- the form of the water-soluble alginic acid derivative of the present invention can be adjusted by utilizing the property that a solution of a monovalent metal salt of alginic acid forms a gel when mixed with a crosslinking agent.
- Alginic acid is a kind of natural polysaccharide that is produced by extracting and purifying from brown seaweed seaweed. Further, it is a polymer obtained by polymerizing D-mannuronic acid (M) and L-guluronic acid (G).
- M D-mannuronic acid
- G L-guluronic acid
- the composition ratio (M / G ratio) of D-mannuronic acid and L-guluronic acid of alginic acid varies depending on the type of organism mainly derived from seaweed, etc.
- alginic acid It ranges from a high G type with an M / G ratio of about 0.4 to a high M type with an M / G ratio of about 5.
- Industrial methods for producing alginic acid include an acid method and a calcium method. In the present invention, those produced by any method can be used. What is contained in the range of 80 to 120% by mass of the quantitative value by HPLC method by purification is preferred, more preferably in the range of 90 to 110% by mass, and in the range of 95 to 105% by mass. Further preferred.
- a substance whose quantitative value by the HPLC method is included in the above range is referred to as high purity alginic acid.
- the alginic acid or a salt thereof used in the present invention is preferably high-purity alginic acid.
- a commercially available product for example, a product sold by Kimika Co., Ltd., preferably a high-purity food / pharmaceutical grade product can be purchased and used as the Kimika Argin series.
- Commercially available products can be used after further appropriate purification.
- a low endotoxin treatment is preferable.
- the purification method and the low endotoxin treatment method for example, the method described in JP-A-2007-75425 (Patent Document 1) can be employed.
- alginic acid or a salt thereof used in the present invention one having an appropriate weight average molecular weight may be used according to the end use application.
- those having a weight average molecular weight of 10,000 to 10 million are preferably used, more preferably 100,000 to 5,000,000, and still more preferably 20 It is 10,000 to 3,000,000. More specifically, for example, it is preferable to use alginic acid having physical properties shown in Table 1 below or any one of A1 to A4 thereof.
- alginate commercially available sodium alginate (release source: Mochida Pharmaceutical Co., Ltd.) shown below can also be used.
- sodium alginate of A-1, A-2, A-3 and B-2 shown in the table below was used as the sodium alginate.
- Table 2 shows the viscosity, weight average molecular weight, and M / G ratio of a 1 w / w% aqueous solution of each sodium alginate.
- the physical properties of the sodium alginate A-1, A-2, A-3, B-1, B-2, and B-3 were measured by the methods described later.
- the measurement method is not limited to this method, but each physical property value may differ from the above depending on the measurement method.
- Viscosity measurement of sodium alginate According to the Japanese Pharmacopoeia (16th edition) viscosity measurement method, it was measured using a rotational viscometer method (cone plate type rotational viscometer). Specific measurement conditions are as follows. The sample solution was prepared using MilliQ water. As a measuring instrument, a cone plate type rotational viscometer (visco-viscoelasticity measuring device Rheostress RS600 (Thermo Haake GmbH) sensor: 35/1) was used. The number of revolutions was 1 rpm when measuring a 1 w / w% sodium alginate solution. The reading time was measured for 2 minutes, and an average value from 1 minute to 2 minutes from the start. The average value of three measurements was taken as the measurement value. The measurement temperature was 20 ° C.
- Da (Dalton) may be added as a unit in the molecular weights of alginic acid, alginic acid derivatives, crosslinked alginic acid, and crosslinked alginic acid.
- the composition ratio (M / G ratio) of D-mannuronic acid and L-guluronic acid of alginic acids varies depending on the type of organisms that are mainly derived from seaweeds, etc., and is also affected by the location and season of the organism. , Ranging from a high G type with an M / G ratio of about 0.2 to a high M type with an M / G ratio of about 5. It is known that the gelation ability of alginic acids and the properties of the generated gel are affected by the M / G ratio, and generally the gel strength increases when the G ratio is high. In addition, the M / G ratio affects the hardness, brittleness, water absorption, flexibility, and the like of the gel.
- the M / G ratio of the alginic acids and / or salts thereof used is usually 0.2 to 4.0, more preferably 0.4 to 3.0, still more preferably 0.5 to 3.0. is there.
- a high molecular substance derived from a natural product is not a single molecular weight but an aggregate of molecules having various molecular weights, and thus is measured as a molecular weight distribution having a certain width.
- a typical measurement technique is gel filtration chromatography.
- Representative information on the molecular weight distribution obtained by gel filtration chromatography includes weight average molecular weight (Mw), number average molecular weight (Mn), and dispersion ratio (Mw / Mn).
- Mw weight average molecular weight
- Mn number average molecular weight
- Mn dispersion ratio
- the weight average molecular weight places importance on the contribution to the average molecular weight of a polymer having a large molecular weight and is represented by the following formula.
- the number average molecular weight is calculated by dividing the total weight of the polymer by the total number of polymers.
- W is the total weight of the polymer
- Wi is the weight of the i-th polymer
- Mi the molecular weight at the i-th elution time
- Ni is the number of molecular weights Mi
- Hi is the height at the i-th elution time.
- the molecular weight of a high molecular weight substance derived from a natural product may vary depending on the measurement method (example of hyaluronic acid: Chikako YOMOTA et. Al. Bull. Natl. Health Sci., Vol. 117). , Pp135-139 (1999), Chikako YOMOTA et.al.Bull.Natl.Inst.Health Sci., Vol.121, pp30-33 (2003)).
- the molecular weight by SEC-MALLS is used as a standard value on a catalog of alginic acid (FMC Biopolymer, PRONOVATM sodium alloys catalog).
- FMC Biopolymer, PRONOVATM sodium alloys catalog a catalog of alginic acid
- a measurement error of 10 to 20% can occur. For example, if it is 400,000, it is 32 to 480,000, and if it is 1 million, 80 to Value fluctuations can occur in the range of about 1.2 million.
- the molecular weight of sodium alginate used is, for example, preferably in the range of 300,000 to 2.5 million, more preferably in the range of 300,000 to 900,000 in terms of weight average molecular weight (GPC), or More preferably, it is in the range of 700,000 to 1.7 million, or more preferably in the range of 1.4 to 2 million.
- GPC weight average molecular weight
- the molecular weight of alginic acid or a salt thereof is specified, it is a weight average molecular weight calculated by gel filtration chromatography unless otherwise specified.
- the gel filtration chromatography for example, the conditions of this example described later can be adopted.
- alginic acid or a salt thereof used in the present invention it is preferable to use one having an appropriate viscosity and an appropriate M / G ratio according to the end use application. Also, it is preferable to use alginic acid or a salt thereof used in the present invention with a lowered endotoxin level.
- the endotoxin value measured by the JP endotoxin test is preferably less than 100 EU / g, more preferably less than 75 EU / g, and even more preferably less than 50 EU / g.
- “substantially free of endotoxin” means that the endotoxin value measured by the JP endotoxin test is in the above numerical range.
- the linker of the water-soluble alginic acid derivative of the present invention has a functional group that can be bonded to one residue derived from alginic acid or a salt thereof by an amide bond, and is one residue of a nonsteroidal anti-inflammatory compound.
- the linker of the water-soluble alginic acid derivative of the present invention has a functional group that can be bonded to one residue derived from alginic acid or a salt thereof by an amide bond, and is one residue of a nonsteroidal anti-inflammatory compound.
- it is not particularly limited as long as it has a functional group that can be bonded to the group by an ester bond and has a structure capable of forming a water-soluble alginic acid derivative, for example, it has a structure represented by the following formula (7) It is preferable.
- —NH represents a terminal that forms an amide bond with a residue of alginic acid or a salt 1 thereof, and [Z] — forms an ester bond with one residue of a nonsteroidal anti-inflammatory compound. The end to be shown.
- X 1 and X 2 each represent a hetero atom, preferably any atom selected from O, S, and N (in the case of N, strictly speaking, N (H) More preferably O or N.
- R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen atom, C 1-10 alkyl group, C 1-10 alkoxy group or C 1-10 alkoxycarbonyl group.
- Y represents a cycloalkane ring, an aromatic ring or a heterocyclic ring (the cycloalkane ring, aromatic ring or heterocyclic ring may be substituted with a halogen atom or a C 1-10 alkyl group), preferably cyclo An alkane ring, an aromatic ring or a heterocyclic ring, more preferably an aromatic ring.
- n1 represents any integer of 0 to 10
- n2 to n8 independently represent any integer of 0 to 3.
- n1 to n8 do not become zero.
- n2, n4 and n7 are independently 0-2, more preferably independently 0-1.
- n3, n5, n6 and n8 in total are preferably 1 to 12, more preferably 2 to 10.
- the linker of the water-soluble alginic acid derivative of the present invention preferably has, for example, a structure represented by the following formula (LK) [wherein both sides of the broken line are not included].
- —NH is a terminal which forms an amide bond with one residue of alginic acid or a salt thereof
- Z- is a terminal that forms an ester bond with one residue of a non-steroidal anti-inflammatory compound; depending on the structure of the binding moiety of the non-steroidal anti-inflammatory compound, Z is an oxygen atom or a carbonyl group , Preferably an oxygen atom
- X 1 and X 2 represent a hetero atom, preferably an oxygen atom or an imino group (NH);
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkoxycarbonyl
- examples of the “heteroatom” include O, S, and N or P.
- examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the “C 1-10 alkyl (group)” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2 , 2-Trimethylpropyl, 1-ethyl-1-methyl
- examples of the “C 1-6 alkyl (group)” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Examples include groups such as n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, and 3-methylpentyl.
- examples of the “C 1-3 alkyl (group)” include groups such as methyl, ethyl, n-propyl, and isopropyl.
- examples of the “C 1-10 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyl.
- examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyl.
- examples of the “C 1-3 alkoxy group” include groups such as methoxy, ethoxy, propoxy, and isopropoxy.
- C 1-10 alkoxycarbonyl group means —C ( ⁇ O) —R (R is a C 1-10 alkoxy group).
- C 1-6 alkoxycarbonyl group means —C ( ⁇ O) —R (R is a C 1-6 alkoxy group), for example, a methoxycarbonyl group, Examples include ethoxycarbonyl group, tert-butoxycarbonyl group and the like.
- C 1-3 alkoxycarbonyl group means —C ( ⁇ O) —R (R is a C 1-3 alkoxy group), for example, a methoxycarbonyl group, Examples include ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, and the like.
- examples of the “cycloalkane ring” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.
- examples of the “aromatic ring” include a benzene ring, 1-naphthalene ring, 2-naphthalene ring, 2-, 3-, 4-biphenylanthrone ring, phenanthrene ring, and acenaphthene ring. Is mentioned.
- examples of the “C 3-8 cycloalkyl ring” include cycloalkyl rings such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
- examples of the “C 6-10 aryl ring” include a benzene ring, 1-naphthalene ring, 2-naphthalene ring, 2-, 3-, 4-biphenylanthrone ring, phenanthrene. And a ring such as a ring or an acenaphthene ring.
- heterocycle means a 3 to 14-membered monocyclic or condensed ring containing 1 to 5 heteroatoms of nitrogen, sulfur or oxygen. Means a ring.
- heterocycle includes “aromatic heterocycle”, “partially hydrogenated condensed heterocycle”, and “non-aromatic heterocycle”. .
- the “aromatic heterocycle” includes a monocyclic aromatic heterocycle having 5 to 7 ring members, preferably, for example, pyrrole, furan, thiophene, imidazole, Pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3 , 4-oxadiazole, frazal, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine 1,2,4-triazine, 1,3,5-triazine, 2H-1,2,3-thiadiazine, 4H-1,2,4-thiadiazine, 6H 1,3,4-thiadiazin
- the “aromatic heterocycle” includes a condensed aromatic heterocycle having 8 to 12 ring members (condensed heterocycle), preferably, for example, indole , Isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, 1,2-benzisoxazole, benzothiazole, 1,2-benzisothiazole, 1H-benzimidazole, 1H-indazole, 1H- Benzotriazole, 2,1,3-benzothiadiazine, chromene, isochromene, 4H-1,4-benzoxazine, 4H-1,4-benzothiazine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, benzoxase Pin, benzoazepine, benzodiazepine, naphthyridine, P
- the “partially hydrogenated condensed heterocyclic ring” means “heterocycle” and “C 6-10 aryl ring”, or “heterocycle” and “ In a condensed ring formed by condensing an “aromatic heterocycle”, it means a condensed ring in which any ring is partially hydrogenated.
- the “partially hydrogenated condensed heterocyclic ring” preferably has 8 to 12 ring members, such as indoline, 4,5,6,7- Tetrahydro-1H-indoline, 2,3-dihydrobenzofuran, 4,5,6,7-tetrahydro-benzofuran, 2,3-dihydrobenzo [d] oxazoline, 2,3-dihydrobenzo [d] thiazoline, chroman, 2H -Chromene, 4H-chromene, isochroman, 1H-isochromene, 3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,4-benzothiazine, 5,6,7,8- Tetrahydroquinoline, 1,2,3,4-tetrahydroquinoline, 1,2-dihydroquinoline, 1,2,3,4-tetrahydroquinazoline, 1,2-dihydride
- non-aromatic heterocycle those having 3 to 14 ring members are preferable.
- the ester bond between the linker and the non-steroidal anti-inflammatory compound is hydrolyzed to release the non-steroidal anti-inflammatory compound.
- the rate of hydrolysis of ester bonds varies depending on the surrounding environment. Therefore, there are some which can obtain a longer-term sustained release effect in the form of an ester bond.
- introduction of an electron donating group or bulky group in the vicinity of Z of the linker or introduction as a substituent may slow the hydrolysis rate.
- the hydrolysis rate may be increased, and examples thereof include a haloalkyl group and a halogen atom.
- the target hydrolysis rate that is, the sustained release effect.
- alginic acid or a salt thereof and a non-steroidal anti-inflammatory compound are combined with any of a group of linkers shown below.
- linkers —NH represents a terminal that forms an amide bond with one residue of alginic acid or a salt thereof, and —O represents a terminal that forms an ester bond with a carboxyl group of a nonsteroidal anti-inflammatory compound. Show.
- alginic acid or a salt thereof via any one selected from the group consisting of linkers represented by the following formulas (LK-1) to (LK-17) (not including those outside the broken line) And a non-steroidal anti-inflammatory compound is preferably bound.
- the imino group (—NH) side represents a terminal that forms an amide bond with one residue of alginic acid or a salt thereof
- the —O side represents a carboxyl group and an ester bond of a nonsteroidal anti-inflammatory compound. The end to be formed is indicated.
- Non-steroidal anti-inflammatory compounds having residues derived from non-steroidal anti-inflammatory drugs (NSAIDs) and having functional groups such as carboxyl, hydroxyl and amino groups in their chemical structure Is used.
- the non-steroidal anti-inflammatory compound may be in the form of a salt.
- the NSAIDs in the present invention include all compounds generally called non-steroidal anti-inflammatory drugs, and thus are not particularly limited. Among them, those particularly applicable to arthritis are desirable. From the viewpoint of binding with a linker, carboxyls NSAIDs having at least groups are particularly preferred. It is preferable that the non-steroidal anti-inflammatory compound has a carboxyl group, and the carboxyl group is bonded to a linker.
- NSAIDs having a carboxyl group examples include (1) salicylic acid type, (2) propionic acid type or (3) acetic acid type (phenylacetic acid type), (4) phenamic acid type, (5) oxicam type, and (6) pyrrolo. -Pyrrole derivatives, and (7) non-steroidal anti-inflammatory drugs such as coxib (COX-2 inhibitors), and acetic acid (phenylacetic acid) non-steroidal anti-inflammatory drugs (NSAIDs)
- the non-steroidal anti-inflammatory compound is most preferably diclofenac.
- salicylic acid-based non-steroidal anti-inflammatory drugs include salicylic acid, sazapyrine, aspirin, diflunisal, salicylamide, etc.
- propionic acid-based non-steroidal Anti-inflammatory drugs include ibuprofen, flurbiprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, thiaprofenic acid, oxaprozin, loxoprofen sodium, aluminoprofen, zaltoprofen, thiaprofenic acid, etc.
- Aryl acetic acid (phenylacetic acid) non-steroidal anti-inflammatory drugs include felbinac, diclofenac, tolmetin sodium, sulindac, fenbufen, indomethacin, indomethacin farnesyl, acemetacin, ma Ynoic acid proglumetacin, amfenac sodium, nabumetone, mofezolac, etodolac, alclofenac, and the like.
- ketoprofen or naproxen which is a propionic non-steroidal anti-inflammatory drug
- an arylacetic acid (phenylacetic acid) non-steroidal anti-inflammatory drug Felbinac or diclofenac is more preferred, and diclofenac is particularly preferred.
- DCC N, N′-dicyclohexylcarbodiimide
- EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
- DMT-MM 4- (4,6 A method using a condensing agent such as -dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride
- HOSu N-hydroxysuccinimide
- HOBt 1-hydroxybenzotriazole
- the linker is interpreted as “(O) -Linker-NH”
- AL is a residue derived from alginic acid or a salt thereof
- L-guluronic acid and D-mannuron constituting alginic acid.
- DF shows the abbreviation of diclofenac, this is an illustration and does not mean that NSAIDs is limited to diclofenac in the present invention.
- the introduction rate of the non-steroidal anti-inflammatory compound in the water-soluble alginic acid derivative in the present invention is the same as in the synthesis step of the water-soluble alginic acid derivative of the present invention. It can be adjusted by changing the input amount of.
- the introduction rate can be measured by a method using absorbance measurement, HPLC, NMR, or the like.
- the water solubility of the water-soluble alginic acid derivative can be appropriately adjusted depending on the structure and introduction rate of the linker.
- an amino compound represented by the following formula (AM) is used as an amino compound used when binding a linker and a nonsteroidal anti-inflammatory compound and then binding to alginic acid or a salt thereof.
- a group selected from carbonyl groups (R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 can be combined to form an oxo group ( ⁇ O)), preferably A group selected from a hydrogen atom, a halogen atom, a C 1-6 alkyl group, and a C 1-6 alkoxycarbonyl group (R 1 and R 2 together form an oxo group ( ⁇ O)).
- Y is a heterocycle (the heterocycle may be substituted with 1 to 3 halogen atoms or C 1-6 alkyl groups, preferably 1 to 3 halogen atoms or C 1-3 alkyl groups are substituted)
- Z is an oxygen atom;
- n1 or n8 is any integer from 0 to 10; n3, n5, or n6 is independently an integer of 0, 1, 2, 3; n2, n4, or n7 is independently an integer of 0 or 1; Provided that all of n1 to n8 are not 0), a salt thereof, or
- AM-1 (Where (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; Y is a C 6-10 aryl ring, a C 3-8 alkyl ring, or a heterocyclic ring; preferably a benzene ring; n1a and n5a are each independently an integer of 1 to 4), a salt thereof, or a solvate thereof.
- formula (AM-1) include, for example, the following formula: An amino compound selected from: a salt thereof, or a solvate thereof.
- AM-2 is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; R 1 and R 2 are each independently a group selected from a hydrogen atom and a halogen atom; n1a, n3a and n5a are each independently an integer of 1 to 4), a salt thereof, or a solvate thereof (provided that ( ⁇ R) -3-benzoyl- ⁇ - Methyl-phenylacetic acid 3-amino-2-fluoropropyl ester [CAS No.
- formula (AM-2) include, for example, the following formula: An amino compound thereof, a salt thereof, or a solvate thereof.
- amino compounds represented by the formula (AM) preferred are the following formulas (AM-3): (Where (D) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac; R 3 , R 4 , R 5 and R 6 are each independently a group selected from a hydrogen atom, a halogen atom, and a methyl group; n1a, n6a and n8a are each independently an integer of 1 to 4), a salt thereof, or a solvate thereof.
- D is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of diclofenac
- R 3 , R 4 , R 5 and R 6 are each independently a group selected from a hydrogen atom, a halogen atom, and a methyl group
- n1a, n6a and n8a are each independently an integer of 1 to 4
- a salt thereof or a solvate thereof.
- formula (AM-3) include, for example, the following formula: An amino compound thereof, a salt thereof, or a solvate thereof.
- (AM) is one residue of a non-steroidal anti-inflammatory compound; preferably one residue of a non-steroidal anti-inflammatory compound selected from diclofenac, ketoprofen, naproxen, and felbinac;
- R 5 and R 6 are each independently a hydrogen atom, a halogen atom or a methyl group; preferably, R 5 is a hydrogen atom and R 6 is a hydrogen atom or a methyl group;
- X 3 is an imino group (NH), a C 3-8 cycloalkyl ring, a C 6-10 aryl ring or a heterocyclic ring (the C 3-8 cycloalkyl ring, C 6-10 aryl ring or heterocyclic ring is 1 to 3 halogen atoms or C 1-6 alkyl groups may be substituted), preferably an imino group (NH) or a heterocyclic ring, more preferably an imino group (NH) or a heterocyclic ring, more preferably an im
- formula (AM-4) include, for example, the following formula: An amino compound thereof, a salt thereof, or a solvate thereof.
- Non-steroidal anti-inflammatory compounds that may form pharmaceutically acceptable salts (eg, acid addition salts).
- a salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include a salt with an inorganic acid, a salt with an organic acid, and a salt with an acidic amino acid.
- the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc.
- Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
- Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Of these, pharmaceutically acceptable salts are preferred.
- the salt is formed by mixing a solution containing the compound of the present invention and an appropriate amount of acid to form a target salt and then fractionally filtered, or the mixed solvent is distilled off.
- Obtainable. Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) are published as detailed reviews on salt, and are described in detail in this document.
- the water-soluble alginic acid derivative of the present invention can form an alginic acid derivative gel by mixing with a substance generally used as a crosslinking agent for alginic acid.
- a crosslinking agent is not particularly limited as long as it can fix the surface of the monovalent metal salt of alginic acid by crosslinking, but is not limited to Ca 2+ , Mg 2+ , Ba.
- Examples thereof include divalent or higher-valent metal ion compounds such as 2+ and Sr 2+, and crosslinkable reagents having 2 to 4 amino groups in the molecule. More specifically, CaCl 2 , MgCl 2 , CaSO 4 , BaCl 2, etc.
- a diaminoalkane that may have a lysyl group (—COCH (NH 2 ) — (CH 2 ) 4 —NH 2 ), that is, a diaminoalkane and its amino group are substituted with a lysyl group to form a lysylamino group.
- specific examples include diaminoethane, diaminopropane, N- (lysyl) -diaminoethane, etc., but CaCl 2 solution is particularly preferred because of its availability and gel strength. Is preferable.
- the crosslinking agent contains calcium
- the higher the calcium concentration the faster the gelation and the formation of a harder gel.
- calcium is cytotoxic, if the concentration is too high, there is a risk of adverse effects on the body (trunk) when it is administered to the body, and an appropriate amount may be used depending on the amount of alginic acid. Good.
- the sustained-release pharmaceutical composition of the present invention uses alginic acid or a salt thereof as the sustained-release base.
- Alginic acid or a salt thereof has an effect on wound dressing, cartilage disease treatment and rheumatoid arthritis treatment. For example, the effect of cartilage regeneration is exhibited in knee joint deformity, and the effect of cartilage regeneration and the therapeutic effect of rheumatoid arthritis itself is expected in rheumatoid arthritis.
- the sustained-release pharmaceutical composition of the present invention is expected in combination with the analgesic and anti-inflammatory therapeutic effects of sustained-release NSAIDs and the therapeutic effects of alginic acid.
- the target disease and administration route of the sustained-release pharmaceutical composition of the present invention are not particularly limited, but it may be intended for the treatment of arthropathy, suppression of inflammation or pain, prevention or alleviation of symptoms, etc.
- it is preferably administered by a route of administration that is directly injected into the joint cavity.
- the sustained-release pharmaceutical composition of the present invention is used as a therapeutic agent for arthritis for intra-knee joint administration, when the pH of the affected area causing inflammation is weakly acidic, the affected area may be injected by injection or the like.
- the sustained release of the nonsteroidal anti-inflammatory compound stably will be continued for 7 days or longer, preferably 15 days or longer, more preferably 30 days or longer, and even more preferably 100 days or longer.
- the dosage of the sustained-release pharmaceutical composition of the present invention includes the amount of the nonsteroidal anti-inflammatory compound contained, the administration route, the dosage form, the purpose of use, the specific symptoms of the animal to be administered, the age, the body weight According to the above, it is determined individually so that the therapeutic effect is most appropriately exhibited, and is not particularly limited. For example, an amount that maintains a concentration of 1/100 to 10 times the working concentration showing the effect of NSAIDs is preferable.
- the application site of the sustained-release pharmaceutical composition of the present invention is not particularly limited as long as it can be administered by parenteral administration.
- a joint is preferable, and a knee joint, a shoulder joint, a hip joint, a temporomandibular joint, and the like are particularly preferable.
- arthritis such as osteoarthritis (OA) and rheumatoid arthritis (RA)
- RA rheumatoid arthritis
- osteoarthritis of the knee and rheumatoid knee arthritis is desirable.
- a water-soluble alginic acid derivative may be applied to the affected knee joint cavity.
- a crosslinking agent may be applied to the surface of the derivative by application. Leakage from the knee joint cavity can be effectively prevented by gelling the derivative surface and solidifying the surface.
- the crosslinking agent When the water-soluble alginic acid derivative is first administered to the affected area and the crosslinking agent is added later, it is desirable that the crosslinking agent gradually penetrates into the interior of the applied composition to promote crosslinking. In order not to exert a strong influence of the crosslinking agent on the contact part with the affected part, the application amount of the crosslinking agent is adjusted so as not to be excessive.
- the application amount of the divalent or higher metal ion is not particularly limited as long as it can solidify the surface of the composition containing the monovalent metal salt of alginic acid.
- the water-soluble alginic acid derivative of the present invention When applying the water-soluble alginic acid derivative of the present invention to the affected area, if the surface is gelled with a crosslinking agent or mixed in advance with a crosslinking agent so that the whole is gelled, the water-soluble alginic acid derivative of the present invention is applied to the affected area. It is possible to localize in a state of being hardened and adhered to the affected area. Thereby, when cells or the like are embedded, components such as cells can be localized in the affected area.
- the concentration of the cross-linking agent that promotes gelation is adjusted by changes in the environment such as time differences, temperature differences, or contact with calcium ions in vivo.
- a composition that maintains a liquid state before administration and self-gelates after administration into a living body can be used.
- examples of such a crosslinking agent include calcium gluconate, CaSO 4 , calcium alginate, and the like.
- the method for adding a divalent or higher metal ion to a pharmaceutical composition containing a water-soluble alginic acid derivative is not particularly limited.
- a solution of a divalent or higher metal ion can be prepared using a syringe or a sprayer. Examples thereof include a method applied to the surface of the composition.
- the timing of applying the cross-linking agent to the surface of the composition of the present invention may be after applying the composition of the present invention to the affected area, or at the same time.
- the sustained-release pharmaceutical composition containing the alginic acid derivative gel of the present invention may contain microbeads having an average particle size of less than 500 ⁇ m, for example.
- JEOL JNM-ECX400 FT-NMR was used for measurement of nuclear magnetic resonance spectrum (NMR).
- NMR nuclear magnetic resonance spectrum
- 1 H-NMR data NMR signal pattern
- s is singlet
- d is doublet
- t is triplet
- q is quartet
- m multiplet
- br is broad
- J coupling constant
- Hz Hertz
- CDCl 3 Means deuterated chloroform
- DMSO-d 6 means deuterated dimethyl sulfoxide.
- the introduction rate (mol%) of the drug (non-steroidal anti-inflammatory compound) in the examples is 1 unit of monosaccharide of D-mannuronic acid or L-guluronic acid constituting alginic acid calculated from 1 H-NMR ( Mol) and the ratio of the number of moles of the introduced drug to 100 units (mol) of monosaccharides constituting alginic acid.
- the molecular weight was measured by the following method.
- the water-soluble alginic acid derivative solid according to the present invention obtained in the examples was weighed, 10 mmol / L phosphate buffer (pH 7.7) was added, stirred and dissolved at room temperature for 1 hour or more, diluted, and 0.05 % Solution was prepared.
- This solution was passed through a hydrophilic PVDF filtration filter (Mylex GV33 filter, Merck Millipore) having a pore size of 0.22 ⁇ m to remove insoluble matters, and then 200 ⁇ L of the solution was applied to a Superose 6 Increase 10/300 GL column (GE Healthcare Science). Gel filtration was performed.
- the molecular weight (Mi) at the elution time i in the chromatogram of the previously obtained sample was calculated.
- the absorbance at the elution time i was read and taken as Hi. From these data, the weight average molecular weight (Mw) was determined from the following equation.
- the molecular weight of the raw material alginic acid or a salt thereof was determined by the following method. Each alginic acid was weighed in consideration of loss on drying, and ultrapure water was added to prepare a 1% aqueous solution. Subsequently, it diluted with 100 mmol / L phosphate buffer and ultrapure water so that it might become final concentration 10 mmol / L phosphate buffer (pH 7.7), and prepared 0.05% solution. Insoluble matter was removed by a hydrophilic PVDF filter with a pore size of 0.22 ⁇ m (Mylex GV33 filter, Merck Millipore), and then 200 ⁇ L was subjected to gel filtration. Carried out.
- Detection was carried out using a differential refractometer, and the weight average molecular weight (Mw) was determined in the same manner as the water-soluble alginic acid derivative according to the present invention.
- Mw weight average molecular weight
- Step 3-1 Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (compound 5a) 200 mg of sodium alginate (Kimika Co., Ltd., A1) was dissolved in water (20 mL) and 4- (4,6- Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (102 mg) and 1M aqueous sodium hydrogen carbonate solution (0.28 mL) were added, and a solution of compound 4 (70 mg) in ethanol (5 mL) was added. Was added dropwise and stirred at room temperature for 20 hours.
- compound 5a 200 mg of sodium alginate (Kimika Co., Ltd., A1) was dissolved in water (20 mL) and 4- (4,6- Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (102 mg) and 1M aqueous sodium hydrogen carbonate solution (0.28 mL) were added, and a solution of compound
- ⁇ Step 3-2> Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (Compound 5b) Using 200 mg of sodium alginate (Akima Corporation, A2) (Example 1) Same as ⁇ Step 3-1> The title compound (194 mg) was obtained as a white solid. The drug introduction rate was 13.5 mol%.
- Step 3-3> Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (Compound 5c) Using 200 mg of sodium alginate (A3, manufactured by Kimika Co., Ltd.), as in Example 1 ⁇ Step 3-1> The title compound (245 mg) was obtained as a white solid. The drug introduction rate was 13.9 mol%.
- Step 3-4> Synthesis of diclofenac- (2-aminoethanol) -alginic acid derivative (Compound 5d) Using 200 mg of sodium alginate (A4, manufactured by Kimika Co., Ltd.), as in (Example 1) ⁇ Step 3-1> The title compound (239 mg) was obtained as a white solid. The drug introduction rate was 9.6 mol%.
- reaction solution is cooled to room temperature, ethyl acetate (40 mL) and heptane (20 mL) are added, washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Distilled off. The residue was purified by silica gel column chromatography (10-15% ethyl acetate / heptane) to give compound 7 (343 mg) as a colorless gum.
- Step 3> Synthesis of diclofenac- (1-amino-2-propanol) -alginate derivative (Compound 9) 1% (w / w) sodium alginate (A2) manufactured by Kimika Co., Ltd. (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (49 mg) and 1M aqueous sodium hydrogen carbonate solution (0.13 mL) were added, and compound 8 (52 mg) was added. Ethanol (5 mL) solution was added dropwise and stirred at room temperature for 16 hours.
- reaction mixture was filtered using ethyl acetate (60 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (10-50% ethyl acetate / heptane) to give compound 12 (2.44 g) as a colorless gum.
- reaction solution was dissolved in ethyl acetate (100 mL), and the solution was successively added with 5% aqueous citric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and saturated aqueous sodium chloride solution (50 mL). After washing and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product of compound 16 (1.08 g).
- the extract was washed with water (20 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
- the residue was purified by silica gel column chromatography (20% ethyl acetate / heptane) to obtain a fraction containing compound 17 (1.09 g).
- a mixture of the fraction containing compound 17 (1.09 g) and 4N hydrochloric acid-ethyl acetate solution (10 mL) was stirred at room temperature for 1 hour.
- the solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by crystallization from ethyl acetate to obtain Compound 18 (91 mg) as a white solid.
- Step 2 Synthesis of diclofenac- (serine ethyl ester) -alginate derivative (Compound 19) 1% (w / w) sodium alginate (A2) manufactured by Kimika Co., Ltd. 84 ⁇ L), a solution of compound 18 (30 mg) in ethanol (5 mL), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (37 mg), Stir at room temperature for 3 days. A 0.1 g / mL sodium chloride aqueous solution (1 mL) and ethanol (15 mL) were added, followed by stirring for 30 minutes. The resulting precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to give the title compound (61.9 mg) as a white solid. The drug introduction rate was 13.1 mol%.
- reaction mixture was filtered using ethyl acetate (60 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (15% ethyl acetate / heptane) to give compound 22 (0.96 g) as a colorless oil.
- Step 3> Synthesis of diclofenac-((4- (aminomethyl) phenyl) methanol) -alginic acid derivative (Compound 28) 1% (w / w) of an aqueous solution (10 g) of sodium alginate (A2) manufactured by Kimika Co., Ltd. 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (49 mg), 1M aqueous sodium hydrogen carbonate solution (0.16 mL), compound 27 (60 mg) Of ethanol (5 mL) was added and stirred at room temperature overnight.
- reaction mixture was filtered using ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (15 mL) and water (15 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by crystallization from ethyl acetate to give compound 30 (0.64 g) as a white solid.
- Step 3 Synthesis of diclofenac- (tyramine) -alginic acid derivative (Compound 32)
- aqueous solution 10 g
- 1% (w / w) sodium alginate manufactured by Kimika Co., Ltd., A2
- 4- (4,6-dimethoxy -1,3,5-triazin-2-yl) -4-methylmorpholinium chloride 37 mg
- 1M aqueous sodium hydrogen carbonate solution (0.11 mL)
- compound 31 40 mg
- ethanol 5 mL
- reaction mixture was filtered using ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (15 mL) and water (15 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (5-30% ethyl acetate / heptane) to give compound 34 (1.02 g) as a colorless gum.
- Step 3> Synthesis of diclofenac- (3-amino-2,2-difluoropropan-1-ol) -alginate derivative (compound 36) 1% (w / w) aqueous solution of sodium alginate (A2) manufactured by Kimika Co., Ltd. (10 g) was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (37 mg), 1M aqueous sodium hydrogen carbonate solution (0.11 mL), compound A solution of 35 (38 mg) in ethanol (5 mL) was added and stirred overnight at room temperature.
- Step 4 Synthesis of diclofenac- (N- (aminoethyl) -2-hydroxyacetamide) -alginic acid derivative (Compound 42) 1% (w / w) aqueous solution of sodium alginate (A2 manufactured by Kimika Co., Ltd.) (10 g) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (37 mg), 1M aqueous sodium hydrogen carbonate solution (0.11 mL), compound 41 (38 mg ) In ethanol (5 mL) was added and stirred overnight at room temperature.
- reaction solution was extracted twice with ethyl acetate (80 mL), the combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with heptane-ethyl acetate (3: 2, 20 mL) to obtain a crude product of compound 44 (0.39 g).
- a mixture of the crude product of Compound 44 (0.39 g), commercially available diclofenac sodium (Compound 1, 0.84 g) and N-methylpyrrolidone (2.6 mL) was stirred at 50 ° C. for 1 hour and at 60 ° C. for 3 hours. .
- reaction solution is cooled to room temperature, ethyl acetate (40 mL) and heptane (20 mL) are added, washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Distilled off. The residue was purified by silica gel column chromatography (30-100% ethyl acetate / heptane) to give compound 45 (0.34 g) as a white solid.
- Step 3> Synthesis of diclofenac- (N- (aminoethyl) -2-hydroxypropanamide) -alginate derivative (Compound 47) 1% (w / w) aqueous solution of sodium alginate (A2 manufactured by Kimika Co., Ltd.) (10 g ) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (37 mg), 1M aqueous sodium hydrogen carbonate solution (0.11 mL), compound 46 ( 40 mg) in ethanol (5 mL) was added and stirred at room temperature overnight.
- diclofenac- (N- (aminoethyl) -2-hydroxypropanamide) -alginate derivative Compound 47) 1% (w / w) aqueous solution of sodium alginate (A2 manufactured by Kimika Co., Ltd.) (10 g ) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)
- Example 11 Release test of compounds prepared in Examples 1 to 10
- concentration of each conjugate was 0.1% w / w. 20 mM sodium phosphate buffer (pH 5.3 or 7.0) or 1N aqueous sodium hydroxide solution was added, and a magnetic stirrer (ASONE REMIX RS-6A, 750 r.p. m.) and stirred for 6 hours. After confirming that the gel was not formed, this solution was dispensed. Immediately after dissolution, the amount of free diclofenac present in each solution as an initial state (0 days of storage) was measured by LC-MS / MS. In addition, after the other dispensing solutions were incubated at 37 ° C. for 1, 3 and 7 days, the amount of free diclofenac was measured. At each time point, the release rate (%) was calculated using the ratio to the amount of free diclofenac by forced decomposition in 1N aqueous sodium hydroxide solution.
- MS conditions are as follows: Ionization mode: ESI-negative Ion source temperature: 300 degrees Capillary voltage: -4000 V
- Step 1-1 Synthesis of diclofenac- (2-aminoethoxyethanol) -alginic acid derivative (Compound 14a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was dissolved in water (100 mL) and ethanol (30 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (456 mg) was added to the solution to which was added at room temperature.
- Step 1-2 Synthesis of diclofenac- (2-aminoethoxyethanol) -alginate derivative (Compound 14b) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) was used (Example 12) ⁇ Step 1-1 The same operation as above was performed to obtain the title compound (1.11 g) as a white solid. The drug introduction rate was 16.4 mol%.
- reaction mixture was filtered using ethyl acetate (60 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give compound 51 (2.7 g) as a white amorphous.
- Step 4-1 Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 53a) 2 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-1) in water (200 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (1.3 g) was added to a solution obtained by dissolving in ethanol and adding ethanol (60 mL) to room temperature. Added in.
- Step 4-2 Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 53b) 2 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) in water (200 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (611 mg) was added at room temperature to a solution in which ethanol (60 mL) was added. It was.
- ⁇ Step 4-3> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 53c) Using 2 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) Example 13) The same operation as in ⁇ Step 4-2> was performed to obtain the title compound (1.99 g) as a white solid. The drug introduction rate was 17.0 mol%.
- Step 4-4> Synthesis of diclofenac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 53d) 100 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., B-2) in water (10 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46 mg) was added at room temperature to a solution in which ethanol (3 mL) was added. It was.
- reaction mixture was filtered using ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (5-50% ethyl acetate / heptane) to give compound 56 (1.4 g) as a white amorphous.
- Step 4 Synthesis of Diclofenac- (2-amino-1- (4- (hydroxymethyl) piperidin-1-yl) ethane-1-one) -alginic acid derivative (Compound 58) Sodium alginate (Mochida Pharmaceutical Co., Ltd., B -2) 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium was added to a solution obtained by dissolving 100 mg in water (20 mL) and adding ethanol (5 mL). Chloride (39 mg) was added at room temperature.
- reaction mixture was filtered using ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (5-50% ethyl acetate / heptane) to give compound 61 (1.0 g) as a white amorphous.
- Step 4-1 Synthesis of Diclofenac- (2-amino-1- (4- (hydroxymethyl) piperidin-1-yl) ethane-1-one) -alginic acid derivative (Compound 63a) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-2) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmol was dissolved in 1 g of water (100 mL) and ethanol (30 mL) was added. Holinium chloride (370 mg) was added at room temperature.
- Step 4-2> Synthesis of Diclofenac- (2-amino-1- (4- (hydroxymethyl) piperidin-1-yl) ethane-1-one) -alginic acid derivative (Compound 63b) Sodium alginate (Mochida Pharmaceutical Co., Ltd.) , A-3) 1 g was used, and the same operation as in Example 15 ⁇ Step 4-1> was performed to obtain the title compound (1.09 g) as a white solid. The drug introduction rate was 12.6 mol%.
- reaction mixture was filtered using ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (10-100% ethyl acetate / heptane) to give compound 66 (1.5 g) as a white amorphous.
- Step 4 Synthesis of diclofenac- (2-amino-N- (6-hydroxyhexyl) acetamide) -alginic acid derivative (Compound 68) 100 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., B-2) was dissolved in water (20 mL). Then, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (39 mg) was added to the solution to which ethanol (5 mL) was added at room temperature.
- Step 1 Synthesis of Compound 70 1-amino-2-propanol (0.38 g), (tert-butoxycarbonyl) glycine (0.88 g), N, N-dimethyl-4-aminopyridine (0.12 g), To a mixture of dichloromethane (20 mL), a solution of N, N′-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise under ice cooling. The reaction was stirred at room temperature overnight.
- Step 3-1 Synthesis of diclofenac- (2-amino-N- (2-hydroxypropyl) acetamide) -alginic acid derivative (Compound 72a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) in water (100 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (305 mg) was added at room temperature to a solution in which ethanol (30 mL) was added. .
- Step 3-2> Synthesis of Diclofenac- (2-amino-N- (2-hydroxypropyl) acetamide) -alginic acid derivative (Compound 72b) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) in water (20 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (62 mg) was added at room temperature to a solution in which ethanol (6 mL) was added. .
- Step 1 Synthesis of Compound 74 3-amino-1-propanol (0.38 g), (tert-butoxycarbonyl) glycine (0.88 g), N, N-dimethyl-4-aminopyridine (0.12 g), To a mixture of dichloromethane (20 mL), a solution of N, N′-dicyclohexylcarbodiimide (1.03 g) in dichloromethane (5 mL) was added dropwise under ice cooling. The reaction was stirred at room temperature overnight.
- Step 3-1 Synthesis of diclofenac- (2-amino-N- (3-hydroxypropyl) acetamide) -alginic acid derivative (Compound 76a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) in water (100 mL) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (305 mg) was added at room temperature to a solution in which ethanol (30 mL) was added. .
- ⁇ Step 3-2> Synthesis of diclofenac- (2-amino-N- (3-hydroxypropyl) acetamide) -alginic acid derivative (Compound 76b) Using 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) Example 18) The same operation as in ⁇ Step 3-1> was performed to give the title compound (0.99 g) as a white solid. The drug introduction rate was 14.4 mol%.
- Step 3-1 Synthesis of diclofenac- (2-amino-N- (1-hydroxypropan-2-yl) acetamide) -alginic acid derivative (Compound 80a) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (305 mg) was dissolved in water (100 mL) and ethanol (30 mL) was added. Added at room temperature.
- Step 3-2> Synthesis of diclofenac- (2-amino-N- (1-hydroxypropan-2-yl) acetamide) -alginic acid derivative (Compound 80b) 1 g of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-3) And the same operation as in (Example 19) ⁇ Step 3-1> was performed to give the title compound (0.99 g) as a white solid.
- the drug introduction rate was 14.4 mol%.
- reaction mixture was filtered using ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with ethanol to give compound 82 (0.80 g) as a white solid.
- ferbinac- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 84) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) dissolved in water (20 mL) Then, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46 mg) was added to the solution to which ethanol (8 mL) was added at room temperature.
- reaction mixture was diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound 86 (1.38 g) as a colorless gum.
- Step 3 Synthesis of ketoprofen- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 88) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) dissolved in water (20 mL) Then, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46 mg) was added to the solution to which ethanol (6 mL) was added at room temperature.
- reaction mixture was diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
- the residue was purified by silica gel column chromatography (5-100% ethyl acetate / heptane) to give compound 90 (1.39 g) as a colorless gum.
- Step 3 Synthesis of ketoprofen- (2-amino-N- (2-hydroxyethyl) acetamide) -alginic acid derivative (Compound 92) 200 mg of sodium alginate (Mochida Pharmaceutical Co., Ltd., A-2) was dissolved in water (20 mL). Then, 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (46 mg) was added to the solution to which ethanol (6 mL) was added at room temperature.
- the release rate was calculated by measuring the free drug amounts of felbinac, ketoprofen and naproxen.
- MS conditions are as follows: Ionization mode: ESI-negative Ion source temperature: 300 degrees Capillary voltage: -4000 V
- Example 24 Effects of intraarticular administration of compound 53b obtained in Example 13 on rat 1% silver nitrate-induced pain model
- the DF-ALG (Compound 53b) administration group showed a faster degree of pain reduction (degree of recovery from pain) than the diclofenac administration group, the alginic acid administration group, the diclofenac + alginic acid administration group, and the like.
- Test substance administration method The following test substances were prepared. A 0.9% solution of compound 53b obtained in Example 13 (solvent: 10 mM phosphate buffer containing 5% glucose) (DF-ALG-53b) 0.9% solution of compound 63a obtained in Example 15 (solvent: 5% glucose, 3 mM HP- ⁇ -CD containing 10 mM phosphate buffer) (DF-ALG-63a)
- test substance For each test substance, 4 rabbits were used, the whole body was fixed with a towel under no anesthesia, the area around the left knee joint was wiped with alcohol, and a Terumo 1 mL syringe equipped with a 26G injection needle (manufactured by Terumo) The test substance was administered at 0.1 mL / kg into the joint cavity from the outside of the rabbit knee. Necropsy was performed 3 days, 7 days, 14 days, 28 days, 56 days, and 84 days after administration of the test substance.
- 1N HCl (0.02 mL) was added to the joint fluid (0.05 mL), and after sufficient stirring, the mixture was incubated at room temperature for 30 minutes or more. Further, 0.12 mL of a 0.1% formic acid aqueous solution and 0.01 mL of an internal standard solution (a methanol solution having a Celecoxib concentration of 0.1 ⁇ g / mL) were added and stirred sufficiently, followed by centrifugation at 450 G for 5 minutes.
- an internal standard solution a methanol solution having a Celecoxib concentration of 0.1 ⁇ g / mL
- the concentration of diclofenac in the synovium at the time of administration of DF-ALG is also high at 84 days after administration, and is long-term (for example, 2 to 3 months) The pain-suppressing effect is expected to last.
- the sustained release rate can be adjusted by the linker structure, and the derivative of the present invention can be adjusted by adjusting the linker type and the drug introduction rate. It was found that long-term sustainable analgesic and anti-inflammatory effects can be expected.
- Example 1 Compound 5a obtained in Example 1 was confirmed to have a release rate of 2.3% on the third day and 4.1% on the seventh day. Similarly, compound 5b, compound 5c, compound 5d, compound 42 and compound 47 were also released stably. Furthermore, the compound 53b obtained in Example 13 was confirmed to have a release rate of 3.7% on the third day and 10.0% on the seventh day in the release test at pH 7.0. In addition, in the release test at pH 7.0, the compound 63a obtained in Example 15 was confirmed to have a release rate of 0.8% on the third day and 2.2% on the seventh day. In any compound, the number of days and the release rate are almost proportional, and from this, stable and sustained release can be expected.
- the pH may vary between neutral and weakly acidic, and the sustained release rate may vary accordingly, but the linker structure should be adjusted.
- an analgesic / anti-inflammatory agent having a stable sustained release action even when the pH varies.
- results were obtained that could be maintained in excess of the amount (5 ng / g), so that the non-steroidal anti-inflammatory compound-bound alginic acid derivatives of the present invention, especially diclofenac-bound alginic acid derivatives, can be used for extended periods of time (eg 2-3 months). It is expected that pain suppression during
- the release rate on the 7th day in the release test is preferably about 2%, it is a nonsteroidal anti-inflammatory compound.
- the bound alginic acid derivative can be expected to suppress pain continuously for 2 to 3 months.
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Abstract
Description
一方、関節症による痛みの抑制剤及び緩和剤として非ステロイド性抗炎症剤(以下、NSAIDsとも呼ぶ)が広く使用されている。一般に、これらの痛みの抑制剤及び緩和剤としてNSAIDsを使用する場合には、経口投与剤形や経皮吸収型製剤として使用されている。しかしながら、NSAIDsを含む経口投与剤形では、有効量のNSAIDsを患部に行き届かせるために、多量の服用が必要となる場合があり、想定以上の消化器系などへの副作用を引き起こしうるとの問題点があった。また、経皮吸収型剤形では、患部(関節)との接触開始から接触終了までにおける吸収されるNSAIDsの量が一定ではないため、効果が安定しない場合があり、また高いNSAIDs濃度を含む経皮吸収型製剤を使用する場合には、想定以上の接触皮膚炎などの副作用を引き起こしうるとの問題点があった。
このような課題を踏まえて、本発明の目的は、新たな基材の選択肢となりうる基材としてアルギン酸を用いて、生体内において安定して一定の有効成分を放出しうる、徐放性製剤に使用し得る水溶性化合物を提供することである。
すなわち、本発明は以下のように構成される:
〔1〕アルギン酸又はその塩と非ステロイド性抗炎症性化合物とがリンカーを介して共有結合されてなる構造を有する、水溶性アルギン酸誘導体。
〔1a〕リンカーが2価のリンカーである、前記〔1〕の水溶性アルギン酸誘導体。
〔2〕下記式(1)で表される構造を有する、前記〔1〕に記載の水溶性アルギン酸誘導体:
(A)-L-(D) (1)
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
Lは、(A)とアミド結合で結合しうる官能基を有し、かつ(D)とエステル結合で結合しうる官能基を有するリンカーである)。
(A)-NH-(CH2)n1-[X1]n2-(CR1R2)n3-[Y]n4-(CH2)n5-(CR3R4)n6-[X2]n7-(CH2)n8-[Z]-(D) (2)
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
X1及びX2は、ヘテロ原子を示し、
R1、R2、R3及びR4はそれぞれ独立して、水素、ハロゲン原子、C1-10アルキル基、C1-10のアルコキシ基又はC1-10アルコキシカルボニル基を示すか、又は、R1及びR2若しくはR3及びR4が一緒になって=Oを示し、
Yは、シクロアルカン環、芳香族環又は複素環(前記シクロアルカン環、芳香族環又は複素環は、ハロゲン原子又はC1-10アルキル基で置換されていてもよい)を示し、
Zは、(D)とエステル結合を形成するための、O又はC(=O)を示し、
n1は0~10のいずれかの整数を示し、n2~n8は独立して0~3のいずれかの整数を示すが、n1~n8の全てが0になることはない)。
(A)は、アルギン酸又はその塩由来の1残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;
X1及びX2は、ヘテロ原子であり;
R1、R2、R3、R4、R5及びR6は、それぞれ独立して、水素原子、ハロゲン原子、C1-6アルキル基、C1-6アルコキシ基、及びC1-6アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、又はR5及びR6は一緒になってオキソ基(=O)を形成することができ);
Yは、C3-8シクロアルキル環、C6-10アリール環、又は複素環(前記C3-8シクロアルカン環、C6-10アリール環、又は複素環は、ハロゲン原子、又はC1-6アルキル基が1~3個置換されていても良い)であり;
Zは、酸素原子又はカルボニル基であり;
n1又はn8は、0~10のいずれかの整数であり;
n3、n5、又はn6は、独立して0、1、2、3のいずれかの整数であり;
n2、n4、又はn7は、独立して0又は1の整数であり;
但し、n1~n8の全てが0になることはない)で表される、前記〔1〕に記載の水溶性アルギン酸誘導体。
〔4a〕非ステロイド性抗炎症性化合物がカルボキシル基を有し、当該カルボキシル基が、下記式(LKA-1)[式中破線左側は除く]:
又は、式(LKA-2)[式中破線左側は除く]:
〔5a〕非ステロイド性抗炎症性化合物がサリチル酸系、プロピオン酸系、又はフェニル酢酸系の非ステロイド性抗炎症薬(NSAIDs)であり、NSAIDsのカルボキシル基が、前記〔4a〕に記載の式(LKA-1)又は式(LKA-2)で表わされるリンカーと結合されてなる、前記〔1a〕、〔2〕、〔3a〕及び〔4a〕のいずれか1項に記載のアルギン酸誘導体。
〔6〕非ステロイド性抗炎症性化合物が酢酸系の非ステロイド性抗炎症薬(NSAIDs)である、前記〔5〕に記載の水溶性アルギン酸誘導体。
〔6a〕非ステロイド性抗炎症性化合物が、フェニル酢酸系の非ステロイド性抗炎症薬(NSAIDs)である、前記〔5a〕に記載のアルギン酸誘導体。
〔6a-1〕非ステロイド性抗炎症性化合物が、プロピオン酸系の非ステロイド性抗炎症薬(NSAIDs)である、前記〔5a〕に記載のアルギン酸誘導体。
〔7a〕非ステロイド性抗炎症性化合物が、ジクロフェナク又はフェルビナクである、前記〔6a〕に記載の水溶性アルギン酸誘導体。
〔7a-1〕非ステロイド性抗炎症性化合物が、ケトプロフェン又はナプロキセンである、前記〔6a-1〕に記載の水溶性アルギン酸誘導体。
〔8〕非ステロイド性抗炎症性化合物の導入率(モル%)が、少なくとも1.0モル%以上である、前記〔1〕~〔7〕のいずれか1項に記載の水溶性アルギン酸誘導体。
〔8a〕非ステロイド性抗炎症性化合物の導入率(モル%)が、少なくとも1.0モル%以上である、前記〔1a〕、〔2〕、〔3a〕、〔4a〕、〔5a〕、〔6a〕、〔6a-1〕、〔7a〕及び〔7a-1〕のいずれか1項に記載のアルギン酸誘導体。
〔9a〕前記〔1a〕、〔2〕、〔3a〕、〔4a〕、〔5a〕、〔6a〕、〔6a-1〕、〔7a〕、〔7a-1〕及び〔8a〕のいずれか1項に記載のアルギン酸誘導体を架橋してなる、アルギン酸誘導体ゲル。
〔10〕前記〔1〕~〔8〕のいずれか1項に記載の水溶性アルギン酸誘導体、又は、前記〔9〕に記載のアルギン酸誘導体ゲルを含む、徐放性医薬組成物。
〔10a〕前記〔1a〕、〔2〕、〔3a〕、〔4a〕、〔5a〕、〔6a〕、〔6a-1〕、〔7a〕、〔7a-1〕及び〔8a〕のいずれか1項に記載のアルギン酸誘導体、又は、前記〔9a〕に記載のアルギン酸誘導体ゲルを含む、徐放性医薬組成物。
〔11〕関節炎治療剤としての、前記〔10〕に記載の徐放性医薬組成物。
〔11a〕関節炎治療剤としての、前記〔10a〕に記載の徐放性医薬組成物。
〔12a〕非ステロイド性抗炎症性化合物を徐放するための、前記〔1a〕、〔2〕、〔3a〕、〔4a〕、〔5a〕、〔6a〕、〔6a-1〕、〔7a〕、〔7a-1〕及び〔8a〕のいずれか1項に記載のアルギン酸誘導体、又は、前記〔9a〕に記載のアルギン酸誘導体ゲルの使用。
〔13〕前記〔3a〕の式(2)のアルギン酸誘導体において、好ましいものとしては、以下に列挙されるアルギン酸誘導体から選ばれる。(各式中、(A)は、アルギン酸又はその塩由来の1残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基である)
本発明は、アルギン酸又はその塩と非ステロイド性抗炎症性化合物とがリンカーを介して共有結合されてなる構造を有する、水溶性アルギン酸誘導体に関する。リンカーは、アルギン酸又はその塩のカルボキシル基、及び、非ステロイド性抗炎症性化合物のカルボキシル基または水酸基と、共有結合により結合されることが好ましい。結合様式は本発明の目的が達成される限り特に限定されないが、水溶性アルギン酸誘導体において、アルギン酸とリンカーとの結合は、アミド結合であり、非ステロイド性抗炎症性化合物とリンカーとの結合は、エステル結合であることが好ましい。アルギン酸又はその塩における、リンカーとの結合部位(アルギン酸又はその塩の官能基)は、水酸基又はカルボキシル基が挙げられるが、アミド結合を形成しうるカルボキシル基がより好ましい。
(A)-L-(D) (1)
式(1)中、(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示す。また、式(1)中、Lは、(A)とアミド結合で結合しうる官能基を有し、かつ(D)とエステル結合で結合しうる官能基を有するリンカーである。また、式(1)中、(D)は、非ステロイド性抗炎症性化合物の1残基を示すが、当該(D)の1残基は、水酸基であってもよいし、カルボキシル基であってもよく、好ましくは、カルボキシル基である。
(D)は、非ステロイド性抗炎症性化合物の1残基を表わし、当該(D)の1残基は、水酸基又はカルボキシル基であり、好ましくは、カルボキシル基であり;
-L-は、下記部分構造式(LS-1)[式中破線外側は除く]:
Zは、酸素原子又はカルボニル基であり、好ましくは酸素原子である)で表される構造を有する、アルギン酸誘導体である。)
(A)-NH-(CH2)n1-[X1]n2-(CR1R2)n3-[Y]n4-(CH2)n5-(CR3R4)n6-[X2]n7-(CH2)n8-[Z]-(D) (2)
式(2)中では、(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、(D)は非ステロイド性抗炎症性化合物の1残基を示し、X1及びX2は、ヘテロ原子を示し、R1、R2、R3及びR4はそれぞれ独立して、水素、ハロゲン原子、C1-10アルキル基、C1-10のアルコキシ基又はC1-10アルコキシカルボニル基を示すか、又は、R1及びR2若しくはR3及びR4が一緒になって=Oを示し、Yは、シクロアルカン環、芳香族環又は複素環(前記シクロアルカン環、芳香族環又は複素環は、ハロゲン原子又はC1-10アルキル基で置換されていてもよい)を示し、Zは、(D)とエステル結合を形成するための、O又はC(=O)を示し、n1は0~10のいずれかの整数を示し、n2~n8は独立して0~3のいずれかの整数を示すが、n1~n8の全てが0になることはない。好ましくは、n2、n4及びn7は独立して0~2であり、より好ましくは独立して0~1である。また、n3、n5、n6及びn8は合計して1~12が好ましく、2~10がより好ましい。
下記式(2a):
(A)は、アルギン酸又はその塩由来の1残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;
X1及びX2は、酸素原子又はイミノ基(NH)であり;
R1、R2、R3、R4、R5及びR6はそれぞれ独立して、水素原子、ハロゲン原子、C1-6アルキル基、C1-6アルコキシ基、及びC1-6アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、又はR5及びR6は一緒になってオキソ基(=O)を形成することができ)、 好ましくは、水素原子、ハロゲン原子、C1-3アルキル基、C1-3アルコキシ基、及びC1-3アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、又はR5及びR6は一緒になってオキソ基(=O)を形成することができ);
Yは、C6-10アリール環、又は複素環であり;
Zは、酸素原子又はカルボニル基であり;
n1は、0~5のいずれかの整数であり;
n8は、0~10のいずれかの整数であり;
n3、n5、又はn6は、独立して0、1、2、3のいずれかの整数であり;
n2、n4、又はn7は、独立して0又は1の整数であり;
n1~n8の全てが0になることはない;n3、n5、n6及びn8は合計して1~12が好ましく、2~10がより好ましい)で表される構造を有する、水溶性アルギン酸誘導体である。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、ジクロフェナク、ケトプロフェン、ナプロキセン、及びフェルビナクから選択される、非ステロイド性抗炎症性化合物の1残基であり;
X1及びX2は、酸素原子又はイミノ基(NH)であり;
R1、R2、R3、R4、R5及びR6はそれぞれ独立して、水素原子、フッ素原子、メチル基、及びエトキシカルボニル基から選択される基であり(前記R1及びR2、又はR3及びR4は、一緒になってオキソ基(=O)を形成することができる);
Yは、ベンゼン環又はピペリジン環であり;、
Zは、酸素原子であり;
n1は、0~2のいずれかの整数であり;
n8は、0~6のいずれかの整数であり;
n3、n5、又はn6は、独立して0又は1の整数であり;
n2、n4、又はn7は、独立して0又は1の整数であり;
n1~n8の全てが0になることはない;n3、n5、n6及びn8は合計して1~12が好ましく、2~10がより好ましい)で表される構造を有する、水溶性アルギン酸誘導体である。
(A)-NH-(CH2)n1-(CR1R2)n3-(CH2)n5-[Z]-(D) (3)
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
R1及びR2は、R1が水素若しくはハロゲン原子を示し、R2が、水素、ハロゲン原子、メチル基若しくはエチル基を示すか、或いは、R1及びR2が一緒になって=Oを示し、
Zは、(D)とエステル結合を形成するための、Oを示し、
n1、n3及びn5は合計して1~4のいずれかの整数を示す)。
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
X1は、OまたはNHを示し、
R1及びR2は、R1が水素を示し、R2が、水素、ハロゲン原子、メチル基若しくはエチル基を示すか、或いは、R1及びR2が一緒になって=Oを示し、
X1がOの場合は、R1は水素が好ましく、R2は水素、メチル基又はエチル基が好ましく、
X1がNHの場合は、R1は水素が好ましく、R2は水素、メチル基又はエチル基が好ましく、または、R1及びR2が一緒になって=Oを示すのが好ましく、
R3及びR4は、R3が水素を示し、R4が、水素、ハロゲン原子、メチル基若しくはエチル基を示すか、或いは、R3及びR4が一緒になって=Oを示し、
Zは、(D)とエステル結合を形成するための、Oを示し、
n1は1~3のいずれかの整数を示し、n3、n6及びn8は合計して1~3のいずれかの整数を示す)。
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
Yは、芳香族環を示し、
Zは、(D)とエステル結合を形成するための、Oを示し、
n1及びn5は合計して1~4のいずれかの整数を示す)。
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
R1及びR2は、R1が水素を示し、R2が、水素、メトキシ基、エトキシ基、メトキシカルボニル基またはエトキシカルボニル基を示すか、或いは、R1及びR2が一緒になって=Oを示し、
R3及びR4は、R3が水素を示し、R4が、水素、メチル基若しくはエチル基を示すか、或いは、R3及びR4が一緒になって=Oを示し、
Zは、(D)とエステル結合を形成するための、Oを示し、
n1、n3、n5、n6及びn8は合計して1~4のいずれかの整数を示す)。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
R1及びR2は、各々独立して、水素原子、ハロゲン原子、メチル基、及びエトキシカルボニル基から選択される基であり(前記R1及びR2は、一緒になってオキソ基(=O)を形成することができる);
Zは、酸素原子であり;
n1、n3及びn5は合計して1~4のいずれかの整数である)で表される構造を有する、水溶性アルギン酸誘導体である。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
X1は、酸素原子又はイミノ基(NH)であり;
R1、R2、R3、R4、R5及びR6は、各々独立して、水素原子、ハロゲン原子、メチル基、エチル基、及びエトキシカルボニル基から選択される基であり(前記R1及びR2、R3及びR4、又はR5及びR6は、一緒になってオキソ基(=O)を形成することができる)(X1がOの場合は、R1は水素原子が好ましく、R2は水素原子、メチル基、又はエチル基が好ましく、R3は水素原子が好ましく、R4は水素原子、メチル基、又はエチル基が好ましく、R5は水素原子が好ましく、R6は水素原子、メチル基、又はエチル基が好ましく;より好ましくは、R1、R2、R3、R4、R5及びR6は、水素原子であり;X1がイミノ基(NH)の場合は、R1は水素が好ましく、R2は水素、メチル基又はエチル基が好ましく、又は、R1及びR2が一緒になって=Oとなるのが好ましく、R3は水素が好ましく、R4は水素原子、メチル基、又はエチル基が好ましく、R5は水素が好ましく、R6は水素原子、メチル基、又はエチル基が好ましく;より好ましくは、R1及びR2が一緒になって=Oとなり、R3は水素原子、R4は水素原子又はメチル基、R5は水素原子、R6は水素原子又はメチル基であり);
Zは、酸素原子を表わし
n1は、1~3のいずれかの整数を示し、n3、n6及びn8は、合計して1~3のいずれかの整数である)で表される構造を有する、水溶性アルギン酸誘導体である。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
Yは、C6-10アリール環であり、好ましくはベンゼン環であり;
Zは、酸素原子であり;
n1及びn5は、合計して1~4のいずれかの整数である)で表される構造を有する、水溶性アルギン酸誘導体である。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
R1及びR2は、各々独立して、水素原子、ハロゲン原子、メチル基、エチル基及びエトキシカルボニル基から選択される基であり(前記R1及びR2は、一緒になってオキソ基(=O)を形成することができる);
R3及びR4は、各々独立して、水素原子、ハロゲン原子、メチル基、エチル基及びエトキシカルボニル基から選択される基であり(前記R3及びR4は、一緒になってオキソ基(=O)を形成することができる);
R5及びR6は、各々独立して、水素原子、ハロゲン原子、メチル基、エチル基及びエトキシカルボニル基から選択される基であり(前記R5及びR6は、一緒になってオキソ基(=O)を形成することができる);
Zは、酸素原子であり;
n1、n3、n5、n6及びn8は合計して1~4のいずれかの整数である)で表される構造を有する、水溶性アルギン酸誘導体である。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナク、ケトプロフェン、ナプロキセン、及びフェルビナクから選択される、非ステロイド性抗炎症性化合物の1残基であり;
R1及びR2は、各々独立して、水素原子、ハロゲン原子、メチル基、及びエチル基から選択される基であり(前記R1及びR2は、一緒になってオキソ基(=O)を形成することができる);好ましくは、R1及びR2は、一緒になってオキソ基(=O)を形成する;
R5及びR6は、各々独立して、水素原子、ハロゲン原子、メチル基、及びエチル基から選択される基であり(前記R5及びR6は、一緒になってオキソ基(=O)を形成することができる);好ましくは、R5は水素原子、R6は水素原子又はメチル基であり;
X2は、イミノ基(NH)であり;
Zは、酸素原子であり;、
n1、n3、及びn8は、合計して1~10のいずれかの整数である)で表される構造を有する、アルギン酸誘導体である。
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
R1及びR2は、各々独立して、水素原子、ハロゲン原子、メチル基、及びエチル基から選択される基であり(前記R1及びR2は、一緒になってオキソ基(=O)を形成することができる);好ましくは、R1及びR2は、一緒になってオキソ基(=O)を形成する;
R5及びR6は、各々独立して、水素原子、ハロゲン原子、メチル基、及びエチル基から選択される基であり(前記R5及びR6は、一緒になってオキソ基(=O)を形成することができる);好ましくは、R5は水素原子、R6は水素原子であり;
Yは、複素環であり;好ましくは、ピペリジン環であり;
Zは、酸素原子であり;、
n1、n3、及びn8は、合計して1~5のいずれかの整数である)で表される構造を有する、アルギン酸誘導体である。
リンカーの種類および非ステロイド性抗炎症性化合物の導入率は、後述する当該化合物を含む医薬組成物の最終投与形態(ゲル状、ゾル状、マイクロビーズ状など)、あるいは生体に投与するときの非ステロイド性抗炎症性化合物の患部における必要量あるいは徐放効率などを考慮して適宜調整されうる。
また、本発明における水溶性アルギン酸誘導体の水溶性は、例えばアルギン酸ナトリウム塩の水溶性と同等であり、後述する用途に応じたゲル化又はゾル化のハンドリングが容易であるとの利点がある。よって、本発明の水溶性アルギン酸誘導体の溶液はフィルター濾過が可能であり、フィルター濾過による除塵、除菌、滅菌が可能となる。すなわち、5μm~0.45μmのフィルターを通過させることにより除塵、除菌が可能となり、更に望ましくは0.22μmのフィルターを通過させることにより滅菌することも可能となる。
なお、本発明の水溶性アルギン酸誘導体は、水、薬学的に許容される金属塩若しくはpH調整剤等を含む水溶液、緩衝液等の水性溶媒に溶解可能である。具体的には注射用水、リン酸緩衝生理食塩水、生理食塩水等に溶解可能である。
また、アルギン酸は生体内の酵素によって分解されないため、本発明における水溶性アルギン酸誘導体は、リンカー部位の切断以外の要因では、非ステロイド性抗炎症性化合物の放出速度に影響を受けにくく、安定して一定の有効成分を放出しうる。
また、アルギン酸は、適用した生体に悪影響を及ぼさず、生体内においてアルギン酸と結合する特定の受容体は同定されていないことから、非ステロイド性抗炎症性化合物を放出した後のアルギン酸又はその塩は体内において毒性をもたらさずに分解される。
このように使用する環境に対応して、本発明の各水溶性アルギン酸誘導体を各pHでの遊離率により、使い分けることができる。また、本発明の水溶性アルギン酸誘導体を架橋剤によってゲル化させることにより、徐放効果をさらに強めることも可能である。
例えば、本発明の水溶性アルギン酸誘導体を膝関節腔内投与用の関節炎治療剤として使用したときに、炎症を起こしている患部のpHが弱酸性の挙動を示す場合、患部に注射等により投与した際に、7日間以上、好ましくは15日間以上、より好ましくは30日間以上、安定して非ステロイド性抗炎症性化合物を徐放し続けることが期待される。ここで、遊離率とは、水溶性アルギン酸誘導体に含まれる非ステロイド性抗炎症性化合物総量に対する、放出された非ステロイド性抗炎症性化合物量の比率を示す。
本発明の水溶性アルギン酸誘導体を用いることにより、薬剤の単独投与よりも、膝関節腔内等の患部又はその近縁部位に投与した場合において、患部に有効な薬剤量が効率的に保持され、経口投与の場合よりも少ない薬剤の量であっても強力な治療効果が期待できる。また、徐放性および持続性の調整により、臨床において投与回数の減少等につなげることもできる。
以下、本発明の水溶性アルギン酸誘導体の構成を説明するために、各構成成分である、アルギン酸、リンカー及び非ステロイド性抗炎症性化合物について説明した後、水溶性アルギン酸誘導体ゲルやこれらの用途等について詳述する。
本発明において、アルギン酸又はその塩としては、「アルギン酸の1価金属塩」であるアルギン酸のD-マンヌロン酸またはL-グルロン酸のカルボン酸の水素原子を、Na+やK+などの1価金属イオンとイオン交換することでつくられる水溶性の塩が好ましい。アルギン酸の1価金属塩としては、具体的には、アルギン酸ナトリウム、アルギン酸カリウムなどを挙げることができるが、特には、アルギン酸ナトリウムが好ましい。後述するようにアルギン酸の1価金属塩の溶液は、架橋剤と混合したときにゲルを形成する性質を利用して、本発明の水溶性アルギン酸誘導体の形態を調整することもできる。
アルギン酸は、褐藻類の海藻から抽出し、精製して製造される天然多糖類の一種である。又、D-マンヌロン酸(M)とL-グルロン酸(G)が重合したポリマーである。アルギン酸のD-マンヌロン酸とL-グルロン酸の構成比(M/G比)は、主に海藻等の由来となる生物の種類によって異なり、また、その生物の生育場所や季節による影響を受け、M/G比が約0.4の高G型からM/G比が約5の高M型まで高範囲にわたる。アルギン酸のM/G比、MとGの配列の仕方等によってアルギン酸の物理化学的性質が異なり、また好ましい用途が異なる場合がある。アルギン酸の工業的な製造方法には、酸法とカルシウム法などがあるが、本発明ではいずれの製法で製造されたものも使用することができる。精製により、HPLC法による定量値が80~120質量%の範囲に含まれるものが好ましく、90~110質量%の範囲に含まれるものがより好ましく、95~105質量%の範囲に含まれるものがさらに好ましい。本発明においては、HPLC法による定量値が前記の範囲に含まれるものを高純度のアルギン酸と称する。本発明で使用するアルギン酸又はその塩は、高純度アルギン酸であることが好ましい。市販品としては、例えば、キミカアルギンシリーズとして、(株)キミカより販売されているもの、好ましくは、高純度食品・医薬品用グレードのものを購入して使用することができる。市販品を、さらに適宜精製して使用することも可能である。例えば、低エンドトキシン処理することが好ましい。精製法や低エンドトキシン処理方法は、例えば特開2007-75425(特許文献1)に記載されている方法を採用することができる。
日本薬局方(第16版)の粘度測定法に従い、回転粘度計法(コーンプレート型回転粘度計)を用いて測定した。具体的な測定条件は以下のとおりである。試料溶液の調製は、MilliQ水を用いて行った。測定機器は、コーンプレート型回転粘度計(粘度粘弾性測定装置レオストレスRS600(Thermo Haake GmbH)センサー:35/1)を用いた。回転数は、1w/w%アルギン酸ナトリウム溶液測定時は1rpmとした。読み取り時間は、2分間測定し、開始1分から2分までの平均値とした。3回の測定の平均値を測定値とした。測定温度は20℃とした。
(1)ゲル浸透クロマトグラフィー(GPC)と、(2)GPC-MALSの2種類の測定法で測定した。測定条件は以下のとおりである。
試料に溶離液を加え溶解後、0.45μmメンブランフィルターろ過したものを測定溶液とした。
(1)ゲル浸透クロマトグラフィー(GPC)測定
[測定条件(相対分子量分布測定)]
カラム:TSKgel GMPW-XL×2+G2500PW-XL(7.8mm I.D.×300mm×3本)
溶離液:200mM硝酸ナトリウム水溶液
流量:1.0mL/min
濃度:0.05%
検出器:RI検出器
カラム温度:40℃
注入量:200μL
分子量標準:標準プルラン、グルコース
[屈折率増分(dn/dc)測定(測定条件)]
示差屈折率計:Optilab T-rEX
測定波長:658nm
測定温度:40℃
溶媒:200mM硝酸ナトリウム水溶液
試料濃度:0.5~2.5mg/mL(5濃度)
カラム:TSKgel GMPW-XL×2+G2500PW-XL(7.8mm I.D.×300mm×3本)
溶離液:200mM硝酸ナトリウム水溶液
流量:1.0mL/min
濃度:0.05%
検出器:RI検出器、光散乱検出器(MALS)
カラム温度:40℃
注入量:200μL
分子量の大きい高分子の平均分子量への寄与を重視したのが重量平均分子量であり、下記式で表される。
Mw=Σ(WiMi)/W=Σ(HiMi)/Σ(Hi)
数平均分子量は、高分子の総重量を高分子の総数で除して算出される。
Mn=W/ΣNi=Σ(MiNi)/ΣNi=Σ(Hi)/Σ(Hi/Mi)
ここで、Wは高分子の総重量、Wiはi番目の高分子の重量、Miはi番目の溶出時間における分子量、Niは分子量Miの個数、Hiはi番目の溶出時間における高さである。
なお、通常高分子多糖類の分子量を上記のような手法で算出する場合、10~20%の測定誤差を生じうる、例えば、40万であれば32~48万、100万であれば80~120万程度の範囲で値の変動が生じうる。
本明細書において、用いるアルギン酸ナトリウムの分子量は、重量平均分子量(GPC)にて、例えば、好ましくは30万~250万の範囲であり、より好ましくは、30万~90万の範囲であり、又はより好ましくは、70万~170万の範囲であり、又はより好ましくは、140万~200万の範囲である。
本発明の水溶性アルギン酸誘導体のリンカーは、上述したように、アルギン酸又はその塩由来の1残基とアミド結合で結合しうる官能基を有し、かつ、非ステロイド性抗炎症性化合物の1残基とエステル結合で結合しうる官能基を有し、水溶性アルギン酸誘導体を形成しうる構造を有するものであれば、特に限定はされないが、例えば、以下の式(7)に示される構造を有することが好ましい。
-NH-(CH2)n1-[X1]n2-(CR1R2)n3-[Y]n4-(CH2)n5-(CR3R4)n6-[X2]n7-(CH2)n8-[Z]- (7)
式(7)中、-NHは、アルギン酸又はその塩1の残基とアミド結合を形成する末端を示し、[Z]-は、非ステロイド性抗炎症性化合物の1残基とエステル結合を形成する末端を示す。非ステロイド性抗炎症性化合物の結合部分の構造に応じて、ZはOであってもよいし、C(=O)であってもよいが、好ましくはOである。式(7)中、X1及びX2は、ヘテロ原子を示し、好ましくはO、S、及びNから選択されるいずれかの原子を示し(Nの場合には、厳密にはN(H)を示し)、より好ましくは、O又はNを示す。式(7)中、R1、R2、R3及びR4はそれぞれ独立して、水素、ハロゲン原子、C1-10アルキル基、C1-10のアルコキシ基又はC1-10アルコキシカルボニル基を示し、好ましくは、水素、フッ素、C1-6アルキル基、C1-6のアルコキシ基又はC1-6アルコキシカルボニル基を示すか、又は、R1及びR2若しくはR3及びR4が一緒になって=Oを示す。
Yは、シクロアルカン環、芳香族環又は複素環(前記シクロアルカン環、芳香族環又は複素環は、ハロゲン原子又はC1-10アルキル基で置換されていてもよい)を示し、好ましくはシクロアルカン環、芳香族環又は複素環、より好ましくは芳香族環を示す。
n1は0~10のいずれかの整数を示し、n2~n8は独立して0~3のいずれかの整数を示す。ただし、n1~n8の全てが0になることはない。好ましくは、n2、n4及びn7は独立して0~2であり、より好ましくは独立して0~1である。また、n3、n5、n6及びn8は合計して1~12が好ましく、2~10がより好ましい。
Z-は、非ステロイド性抗炎症性化合物の1残基とエステル結合を形成する末端であり;非ステロイド性抗炎症性化合物の結合部分の構造に応じて、Zは酸素原子又はカルボニル基であり、好ましくは酸素原子であり;
X1及びX2は、ヘテロ原子を表わし、好ましくは酸素原子又はイミノ基(NH)であり;
R1、R2、R3、R4、R5、及びR6は各々独立して、水素原子、ハロゲン原子、C1-6アルキル基、C1-6アルコキシ基及びC1-6アルコキシカルボニル基から選択される基であり、好ましくは、水素原子、フッ素原子、C1-6アルキル基、C1-6アルコキシ基及びC1-6アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、又はR5及びR6が一緒になって=Oを形成することができる)、より好ましくは、水素原子、フッ素原子、C1-3アルキル基、C1-3アルコキシ基及びC1-3アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、又はR5及びR6が一緒になって=Oを形成することができる);
Yは、C3-8シクロアルキル環、C6-10アリール環又は複素環(前記C3-8シクロアルキル環、C6-10アリール環又は複素環は、ハロゲン原子又はC1-6アルキル基で置換されていてもよい)であり、好ましくはC6-10アリール環又は複素環であり、より好ましくはベンゼン環又はピペリジン環であり;
n1又はn8は、各々独立して0~10のいずれかの整数であり;
n3、n5、又はn6は、各々独立して0、1、2、3のいずれかの整数であり;n2、n4、又はn7は、各々独立して0又は1の整数であり;
但し、n1~n8の全てが0になることはなく;
好ましくは、n2、n4及びn7は、各々独立して0~2であり、より好ましくは独立して0~1であり;
又、n3、n5、及びn6は、合計して1~12が好ましく、2~10がより好ましい、である。
本明細書中、特に断りのない限り、「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子及びヨウ素原子等が挙げられる。
本明細書中、特に断りのない限り、「C1-10アルキル(基)」としては、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、tert-ペンチル3-メチルブチル、1,2-ジメチルプロピル、1-エチルプロピル、ヘキシル、イソヘキシル、1-メチルペンチル、2-メチルペンチル、3-メチルペンチル、1,1-ジメチルブチル、1,2-ジメチルブチル、2,2-ジメチルブチル、1,3-ジメチルブチル、2,3-ジメチルブチル、3,3-ジメチルブチル、1-エチルブチル、2-エチルブチル、1,1,2-トリメチルプロピル、1,2,2-トリメチルプロピル、1-エチル-1-メチルプロピル、1-エチル-2-メチルプロピル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、1-シクロプロピルエチル、2-シクロプロピルエチル、2-シクロブチルエチル、および2-メチルシクロプロピル、ヘプチル、1-メチルヘキシル、オクチル、2-エチルヘキシル、1,1-ジメチルヘキシル、ノニル、デシル、シクロヘプチル、シクロヘキシルメチル、2-シクロヘキシルエチル、4-メチルシクロヘキシル、4,4-ジメチルシクロヘキシル及び3,3,5,5-テトラメチルシクロヘキシル等が挙げられる。
なお、上記C1-10アルキル基、C1-10のアルコキシ基及びC1-10アルコキシカルボニル基におけるC1-10は、C1-6であることが好ましく、C1-3であることがより好ましい。
本明細書中、特に断りのない限り、「芳香族環」としては、ベンゼン環、1-ナフタレン環、2-ナフタレン環、2-、3-、4-ビフェニルアントロン環、フェナントレン環及びアセナフテン環等が挙げられる。
本明細書中、特に断りのない限り、「複素環」には、「芳香族複素環」、「部分的に水素化された縮環式複素環」、「非芳香族複素環」が挙げられる。
本明細書中、特に断りのない限り、「芳香族複素環」には、環員数5~7の単環式芳香族複素環が含まれ、好ましくは、例えば、ピロール、フラン、チオフェン、イミダゾール、ピラゾール、オキサゾール、イソキサゾール、チアゾール、イソチアゾール、1,2,3-トリアゾール、1,2,4-トリアゾール、1,2,3-オキサジアゾール、1,2,4-オキサジアゾール、1,3,4-オキサジアゾール、フラザール、1,2,3-チアジアゾール、1,2,4-チアジアゾール、1,3,4-チアジアゾール、テトラゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、1,2,3-トリアジン、1,2,4-トリアジン、1,3,5-トリアジン、2H-1,2,3-チアジアジン、4H-1,2,4-チアジアジン、6H-1,3,4-チアジアジン、1,4-ジアゼピン、1,4-オキサゼピン等が挙げられる。
非ステロイド性抗炎症性化合物としては、非ステロイド性抗炎症薬(NSAIDs)に由来する残基を有し、その化学構造中にカルボキシル基、水酸基、アミノ基等の官能基を有しているものを使用する。また、非ステロイド性抗炎症性化合物は塩の形態であっても構わない。本発明における上記NSAIDsとしては、通常、非ステロイド性抗炎症薬と呼ばれる化合物全般を含むため、特に限定されないが、中でも特に関節炎への適用があるものが望ましく、リンカーとの結合の観点から、カルボキシル基を少なくとも有しているNSAIDsが特に好ましい。非ステロイド性抗炎症性化合物がカルボキシル基を有し、前記カルボキシル基がリンカーと結合されてなることが好ましい。カルボキシル基を有するNSAIDsとしては、例えば(1)サリチル酸系、(2)プロピオン酸系または(3)酢酸系(フェニル酢酸系)、(4)フェナム酸系、(5)オキシカム系、(6)ピロロ-ピロール誘導体、及び(7)コキシブ系(COX-2阻害剤)等の非ステロイド性抗炎症薬が挙げられ、酢酸系(フェニル酢酸系)の非ステロイド性抗炎症薬(NSAIDs)であることが好ましく、非ステロイド性抗炎症性化合物がジクロフェナクであることが最も好ましい。前記、非ステロイド性抗炎症性薬において、(1)サリチル酸系非ステロイド性抗炎症薬としては、サリチル酸、サザピリン、アスピリン、ジフルニサル、サリチルアミド、等が挙げられ、(2)プロピオン酸系非ステロイド性抗炎症薬としては、イブプロフェン、フルルビプロフェン、ケトプロフェン、ナプロキセン、プラノプロフェン、フェノプロフェン、チアプロフェン酸、オキサプロジン、ロキソプロフェンナトリウム、アルミノプロフェン、ザルトプロフェン、チアプロフェン酸、等が挙げられ、(3)アリール酢酸系(フェニル酢酸系)非ステロイド性抗炎症薬としては、フェルビナク、ジクロフェナク、トルメチンナトリウム、スリンダク、フェンブフェン、インドメタシン、インドメタシンファルネシル、アセメタシン、マレイン酸プログルメタシン、アンフェナクナトリウム、ナブメトン、モフェゾラク、エトドラク、アルクロフェナク、等が挙げられる。
本発明の例示的な実施態様の実施において、(2)プロピオン酸系非ステロイド性抗炎症薬であるケトプロフェン又はナプロキセン、又は(3)アリール酢酸系(フェニル酢酸系)非ステロイド性抗炎症薬であるフェルビナク又はジクロフェナクがより好ましく、ジクロフェナクが特に好ましい。
水溶性アルギン酸誘導体の合成において、リンカーへの非ステロイド性抗炎症性化合物の結合、及び、リンカーへのアルギン酸又はその塩の結合は、どちらが先でも構わないが、水溶媒中でエステル化を行うことは難しいなどのような理由から、リンカーへの非ステロイド性抗炎症性化合物の結合を先にするほうが好ましい。このような結合を達成する方法としては、DCC(N,N’-ジシクロヘキシルカルボジイミド)、EDCI(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド)、DMT-MM(4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド)などの縮合剤を使用する方法、HOSu(N-ヒドロキシスクシンイミド)、HOBt(1-ヒドロキシベンゾトリアゾール)などの縮合補助剤と前記縮合剤とを使用する縮合反応、求核置換反応、活性エステル法、酸無水物法等が挙げられ、縮合反応、及び、求核置換反応を用いて結合させるのが副反応を抑えるなどの理由で好ましい。
より具体的には、例えば以下のような概念を示すスキームのように、縮合反応(エステル化反応)を利用する方法又は求核置換反応を利用する方法で合成することができる。下記の反応スキームにおいては、便宜上、リンカーを「(O)-Linker-NH」として解釈し、ALをアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基として解釈し、Bocをブトキシカルボニル基(保護基)として解釈すると、反応の概略を理解し得る。なお、DFはジクロフェナクの略を示すが、これは例示であって、本発明においてNSAIDsがジクロフェナクに限定されることを意味するわけではない。
アルギン酸誘導体の合成において、リンカーと非ステロイド性抗炎症性化合物とのを結合させた後、アルギン酸又はその塩と結合させる際に用いるアミノ化合物としては、下記式(AM)で表わされるアミノ化合物挙げられる。
式(AM):
(D)は、非ステロイド性抗炎症性化合物由来の1残基であり;
X1及びX2は、酸素原子又はNH(イミノ基)であり;
R1、R2、R3、R4、R5、及びR6はそれぞれ独立して、水素原子、ハロゲン原子、C1-6アルキル基、C1-6アルコキシ基、及びC1-6アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、若しくはR5及びR6は一緒になってオキソ基(=O)を形成することができ)、好ましくは、水素原子、ハロゲン原子、C1-6アルキル基、及びC1-6アルコキシカルボニル基から選択される基であり(R1及びR2は一緒になってオキソ基(=O)を形成することができ)、より好ましくは、水素原子、ハロゲン原子、C1-3アルキル基、及びC1-3アルコキシカルボニル基から選択される基であり(R1及びR2は一緒になってオキソ基(=O)を形成することができ)更に、好ましくは、水素原子、フッ素、又はメチル基であり(R1及びR2は一緒になってオキソ基(=O)を形成することができ);
Yは、複素環(前記複素環は、ハロゲン原子又はC1-6アルキル基が1~3個置換されていてもよく、好ましくは、ハロゲン原子又はC1-3アルキル基が1~3個置換されていてもよい)であり、好ましくはピペリジンであり;
Zは、酸素原子であり;
n1又はn8は、0~10のいずれかの整数であり;
n3、n5、又はn6は、独立して0、1、2、3のいずれかの整数であり;
n2、n4、又はn7は、独立して0又は1の整数であり;
但し、n1~n8の全てが0になることはない)で表わされるアミノ化合物、その塩、又はそれらの溶媒物。
下記式(AM-1):
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
Yは、C6-10アリール環、C3-8アルキル環、又は複素環であり;好ましくはベンゼン環であり;
n1a及びn5aは、各々独立して1~4の整数である)で表されるアミノ化合物、その塩、又はそれらの溶媒和物である。
下記式(AM-2):
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
R1及びR2は、各々独立して、水素原子、及びハロゲン原子から選択される基であり;
n1a、n3a及びn5aは、各々独立して1~4の整数である)で表されるアミノ化合物、その塩、又はそれらの溶媒和物である
(但し、(αR)-3-ベンゾイル-α-メチル-フェニル酢酸 3-アミノ-2-フルオロプロピルエステル[CAS No.1644429-26-4]、(αR)-3-ベンゾイル-α-メチル-フェニル酢酸 3-アミノ-プロピルエステル[CAS No.1644429-25-3]、2-フルオロ-α-メチル- [1,1’-ビフェニル]-4-酢酸 3-アミノ-2,2-ジフルオロプロピルエステル[CAS No.1644429-24-2]、(αR)-3-ベンゾイル-α-メチル-フェニル酢酸 3-アミノ-2,2-ジフルオロプロピルエステル[CAS No.1644429-23-1]、[1,1’-ビフェニル]-4-酢酸 3-アミノ-2,2-ジフルオロプロピルエステル[CAS No.1644429-21-9]、(αS)-α-メチル-4-(2-メチルプロピル)- フェニル酢酸 3-アミノ-プロピルエステル [CAS No.1384127-03-0]、2-[(2,6-ジクロロフェニル)アミノ]-フェニル酢酸 3-アミノ-プロピルエステル[CAS No.918636-69-8]、 [1,1’-ビフェニル]-4-酢酸 3-アミノ-プロピルエステル[CAS No.918636-66-5]、2-フルオロ-α-メチル- [1,1’-ビフェニル]-4-酢酸 3-アミノ-プロピルエステル[CAS No.918636-63-2]、α-メチル-4-(2-メチルプロピル)- フェニル酢酸 3-アミノ-プロピルエステル[CAS No.918636-60-9]、及び(αS)-6-メトキシ-α-メチル-2-ナフタレン酢酸 3-アミノ-プロピルエステル [CAS No.918636-57-4]、その塩、又はそれらの溶媒和物を除く)で表されるアミノ化合物、その塩、又はそれらの溶媒和物である。
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナクの1残基であり;
R3、R4、R5及びR6は、各々独立して、水素原子、ハロゲン原子、及びメチル基から選択される基であり;
n1a、n6a及びn8aは、各々独立して1~4の整数である)で表されるアミノ化合物、その塩、又はそれらの溶媒和物である。
下記式(AM-4):
(D)は、非ステロイド性抗炎症性化合物の1残基であり;好ましくは、ジクロフェナク、ケトプロフェン、ナプロキセン、及びフェルビナクから選択される、非ステロイド性抗炎症性化合物の1残基であり;
R5及びR6は、各々独立して、水素原子、ハロゲン原子、又はメチル基であり;好ましくは、R5は水素原子、R6は水素原子又はメチル基であり;
X3は、イミノ基(NH)、C3-8シクロアルキル環、C6-10アリール環又は複素環であり(前記C3-8シクロアルキル環、C6-10アリール環又は複素環は、ハロゲン原子又はC1-6アルキル基が1~3個置換しても良く)、好ましくは、イミノ基(NH)、又は複素環であり、より好ましくは、イミノ基(NH)、又はピペリジンであり;
n1aは、1~4のいずれかの整数であり;
n8aは、0~8のいずれかの整数である)で表されるアミノ化合物、その塩、又はそれらの溶媒和物である。
本発明の水溶性アルギン酸誘導体は、一般的にアルギン酸の架橋剤として使用される物質と混合することによってアルギン酸誘導体ゲルを形成することができる。そのような架橋剤としては、アルギン酸の1価金属塩の溶液を架橋することにより、その表面を固定化することができるものであれば、特に限定されないが、Ca2+、Mg2+、Ba2+、Sr2+などの2価以上の金属イオン化合物、分子内に2~4個のアミノ基を有する架橋性試薬などが挙げられる。より具体的には、2価以上の金属イオン化合物として、CaCl2、MgCl2、CaSO4、BaCl2等を、分子内に2~4個のアミノ基を有する架橋性試薬として、窒素原子上にリジル(lysyl)基(-COCH(NH2)-(CH2)4-NH2)を有することもあるジアミノアルカン、すなわちジアミノアルカンおよびそのアミノ基がリジル基で置換されてリジルアミノ基を形成している誘導体が包含され、具体的にはジアミノエタン、ジアミノプロパン、N-(リジル)-ジアミノエタン等を挙げることができるが、入手しやすいこと、ゲルの強度等の理由から、特に、CaCl2溶液とするのが好ましい。
ここで、架橋剤にカルシウムが含まれる場合、カルシウムの濃度が高い方が、ゲル化が早く、また、より硬いゲルを形成することができることが知られている。しかし、カルシウムには細胞毒性があるため、濃度が高すぎると、これを体内に投与した場合に体内(幹部)に悪影響を及ぼすおそれもあり、アルギン酸の量に応じて、適量を使用することがよい。
本発明の水溶性アルギン酸誘導体又はアルギン酸誘導体ゲルは、生体内において非ステロイド性抗炎症性化合物を徐放する挙動を示すため、徐放性医薬組成物として使用することができる。さらに、本発明の徐放性医薬組成物は、その徐放基材としてアルギン酸又はその塩が用いられている。アルギン酸又はその塩は、創傷被覆、軟骨疾患治療及び関節リウマチ治療に対する効果を持ち合わせている。例えば膝関節変形症では軟骨再生の効果の発揮し、関節リウマチでは軟骨再生や関節リウマチ自体の治療効果の発揮が期待される。すなわち、本発明の徐放性医薬組成物は、徐放されるNSAIDsの鎮痛及び抗炎症の治療効果とアルギン酸の治療効果が合わせて、期待されるものである。本発明の徐放性医薬組成物の対象疾患、投与ルートは特に限定されるものでは無いが、関節症の処置、炎症の抑制や疼痛の抑制、症状の予防や緩和などを目的とすることが好ましく、関節腔内へ直接注入する投与ルートで投与されることが好ましい。
例えば、本発明の徐放性医薬組成物を膝関節腔内投与用の関節炎治療剤として使用したときに、炎症を起こしている患部のpHが弱酸性の挙動を示す場合、患部に注射等により投与した際に、7日間以上、好ましくは15日間以上、より好ましくは30日間以上、更に好ましくは100日間以上、安定して非ステロイド性抗炎症性化合物を徐放し続けることが期待される。
先に水溶性アルギン酸誘導体を患部に投与し、あとから架橋剤を添加する場合、架橋剤は、適用した組成物の表面から徐々に内部に浸透し、架橋をすすめるのが望ましい。患部との接触部分に、架橋剤の影響を強く及ぼさないためには、架橋剤の適用量を過剰にならないよう調節する。2価以上の金属イオンの適用量としては、アルギン酸の1価金属塩を含有する組成物の表面を固めることができる量であれば、特に限定されない。
本発明の水溶性アルギン酸誘導体を患部に適用する際に、架橋剤により表面をゲル化させ、あるいは全体がゲル化するようあらかじめ架橋剤と混合して適用すると、本発明の水溶性アルギン酸誘導体は患部で硬化し、適用した患部に密着した状態で局在させることができる。これにより、細胞等を包埋した際に、細胞等の成分を患部に局在させることができる。
核磁気共鳴スペクトル(NMR)の測定には、JEOL JNM-ECX400 FT-NMR(日本電子)を用いた。
1H-NMRデータ中、NMRシグナルのパターンで、sはシングレット、dはダブレット、tはトリプレット、qはカルテット、mはマルチプレット、brはブロード、Jはカップリング定数、Hzはヘルツ、CDCl3は重クロロホルム、DMSO-d6は重ジメチルスルホキシドを意味する。1H-NMRデータ中、水酸基(OH)、アミノ基(NH2)、カルボキシル基(COOH)のプロトン等、ブロードバンドであるため確認ができないシグナルについては、データに記載していない。
実施例中の薬剤(非ステロイド性抗炎症性化合物)導入率(モル%)は、1H-NMRから算出されたアルギン酸を構成するD-マンヌロン酸又はL-グルロン酸の単糖を1単位(モル)とし、アルギン酸を構成する単糖100単位(モル)に対する導入された薬剤のモル数の割合を示すものとする。
本発明に係る水溶性アルギン酸誘導体の分子量は、以下の方法にて求めた。ブルーデキストラン(分子量200万Da、SIGMA社)、チログロブリン(分子量66.9万Da、GEヘルスケアサイエンス社)、フェリチン(分子量44万Da、GEヘルスケアサイエンス社)、コンアルブミン(分子量7.5万Da、GEヘルスケアサイエンス社)、及びリボヌクレアーゼA(分子量1.37万Da、GEヘルスケアサイエンス社)を標準品として用い、試料と同じ条件でゲルろ過を行い、各成分の溶出液量を決定した。各成分の溶出液量を横軸に、分子量の対数値を縦軸にそれぞれプロットし、2次回帰し、検量線を作成した。この検量線を用いて、先に得られた試料のクロマトグラムの溶出時間iにおける分子量(Mi)を計算した。次いで、溶出時間iにおける吸光度を読み取り、Hiとした。これらのデータから重量平均分子量(Mw)を以下の式から求めた。
なお、本実施例のスキームにおける「AL」とは、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖の-C(=O)基を有する残基を意味する。
市販のジクロフェナクナトリウム(化合物1、1.59g)、市販のtert-ブチル(2-ブロモエチル)カルバメート(化合物2、1.12g)、N-メチルピロリドン(5.0mL)の混合物を60℃で18時間撹拌した。反応溶液を室温に冷却後、酢酸エチル(40mL)とヘプタン(20mL)を加え、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物を酢酸エチルによる結晶化によって精製し、化合物3を1.19g得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.22(1H,dd,J=2,7Hz),7.13(1H,dt,J=2,8Hz),7.01-6.92(2H,m),6.85(1H,s),6.55(1H,d,8Hz)4.72(1H,br),4.21(2H,t,J=5Hz),3.83(2H,s),3.45-3.36(2H,m),1.43(9H,s)ppm.
化合物3(1.1g)と4N塩酸-酢酸エチル溶液(11mL)の混合物を室温で30分間撹拌した。反応液を減圧下溶媒を留去し、化合物4を1.0g得た。
1H-NMR(400MHz,DMSO-d6) δ 8.15(3H,br),7.53(2H,d,J=8Hz),7.25-7.16(2H,m),7.07-7.01(2H,m),6.85-6.79(1H,m),6.20(1H,d,J=8Hz),4.27(2H,t,J=5Hz),3.85(2H,s),3.09(2H,t,J=5Hz)ppm.
アルギン酸ナトリウム(株式会社キミカ製、A1)200mgを水(20mL)に溶解し、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(102mg)と1M炭酸水素ナトリウム水溶液(0.28mL)を加え、化合物4(70mg)のエタノール(5mL)溶液を滴下し、室温で20時間攪拌した。エタノール(40mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(2mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(227mg)を白色固体として得た。薬剤導入率は10.2モル%であった。
アルギン酸ナトリウム(株式会社キミカ製、A2)200mgを用い、(実施例1)<工程3-1>と同様の操作を行い、標記化合物(194mg)を白色固体として得た。薬剤導入率は13.5モル%であった。
アルギン酸ナトリウム(株式会社キミカ製、A3)200mgを用い、(実施例1)<工程3-1>と同様の操作を行い、標記化合物(245mg)を白色固体として得た。薬剤導入率は13.9モル%であった。
アルギン酸ナトリウム(株式会社キミカ製、A4)200mgを用い、(実施例1)<工程3-1>と同様の操作を行い、標記化合物(239mg)を白色固体として得た。薬剤導入率は9.6モル%であった。
市販のジクロフェナクナトリウム(化合物1、668mg)、市販のtert-ブチル(2-ブロモプロピル)カルバメート(化合物6、500mg)、N-メチルピロリドン(5.0mL)の混合物を60℃で2日間撹拌した。さらに化合物2(500mg)を加えて、60℃で1日間撹拌した。反応溶液を室温に冷却後、酢酸エチル(40mL)とヘプタン(20mL)を加え、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(10-15%酢酸エチル/ヘプタン)によって精製し、化合物7(343mg)を無色ガム状物質として得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.22(1H,dd,J=1,8Hz),7.12(1H,dt,J=1,8Hz),7.01-6.92(2H,m),6.84(1H,br),6.55(1H,d,J=8Hz),5.06-4.92(1H,m),4.66-4.57(1H,m),3.82(1H,d,J=15Hz),3.78(1H,d,J=15Hz),3.42-3.16(2H,m),1.40(9H,s),1.25(3H,d,J=6Hz)ppm.
化合物7(334mg)と4N塩酸-酢酸エチル溶液(3mL)の混合物を室温で1時間撹拌した。反応液を減圧下溶媒を留去し、残留物を酢酸エチルから結晶化により精製し、化合物8(190mg)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.06(3H,s),7.55(2H,d,J=8Hz),7.26-7.18(2H,m),7.06(1H,dt,J=2,7Hz),6.99(1H,s),6.84(1H,dt,J=1,7Hz),6.23(1H,d,J=8Hz),5.09-4.98(1H,m),3.86(1H,d,J=16Hz),3.82(1H,d,J=16Hz),3.11-2.95(2H,m),1.22(3H,d,J=6Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(49mg)と1M炭酸水素ナトリウム水溶液(0.13mL)を加え、化合物8(52mg)のエタノール(5mL)溶液を滴下し、室温で16時間攪拌した。エタノール(15mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、30分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(111mg)を白色固体として得た。薬剤導入率は9.9モル%であった。
市販のジクロフェナク(化合物10、2.0g)、市販のtert-ブチル(2-(2-ヒドロキシエトキシ)エチル)カルバメート(化合物11、1.39g)、N,N-ジメチル-4-アミノピリジン(0.17g)、ジクロロメタン(7mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(1.39g)のジクロロメタン(7mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(60mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(10-50%酢酸エチル/ヘプタン)によって精製し、化合物12(2.44g)を無色ガム状物質として得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.24(1H,dd,J=1,8Hz),7.12(1H,dt,J=1,8Hz),7.01-6.93(2H,m),6.89(1H,s),6.55(1H,d,J=8Hz),4.86(1H,br),4.32-4.27(2H,m),3.85(2H,s),3.69-3.64(2H,m),3.48(2H,t,J=5Hz),3.31-3.21(2H,m),1.44(9H,s)ppm.
化合物12(2.4g)と4N塩酸-酢酸エチル溶液(24mL)の混合物を室温で1時間撹拌した。反応液を減圧下溶媒を留去し、残留物を酢酸エチルから結晶化により精製し、化合物13(1.9g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 7.97(3H,br),7.53(2H,d,J=8Hz),7.24-7.18(2H,m),7.10-7.03(2H,m),6.87-6.83(1H,dt,J=1,7Hz),6.26(1H,d,J=8Hz),4.26-4.20(2H,m),3.83(2H,s),3.70-3.65(2H,m),3.60(2H,t,J=5Hz),2.93(2H,t,J=5Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、1M炭酸水素ナトリウム水溶液(0.13mL)、化合物13(56mg)、エタノール(5mL)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)を加え、室温で一晩攪拌した。エタノール(15mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(91.3mg)を白色固体として得た。薬剤導入率は7.0モル%であった。
市販の(tert-ブトキシカルボニル)-L-セリン(化合物15、2.0g)のエタノール(100mL)溶液に、室温で1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(3.74g)、N,N-ジメチル-4-アミノピリジン(0.12g)を加えた。反応液を室温で3日間撹拌した。反応液を減圧下溶媒を留去した後、酢酸エチル(100mL)に溶かし、その溶液を5%クエン酸水溶液(50mL)、飽和炭酸水素ナトリウム水溶液(50mL)、飽和塩化ナトリウム水溶液(50mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、化合物16の粗生成物(1.08g)を得た。
化合物16の粗生成物(1.08g)と市販のジクロフェナクナトリウム(化合物1、2.95g)のN-メチルピロリドン(9mL)溶液に、室温で1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(2.66g)、N,N-ジメチル-4-アミノピリジン(0.11g)を加えた。反応液を室温で2日間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)を加え、酢酸エチル(100mL)で抽出した。抽出液を水(20mL)で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(20%酢酸エチル/ヘプタン)で精製し、化合物17を含む画分(1.09g)を得た。
化合物17を含む画分(1.09g)と4N塩酸-酢酸エチル溶液(10mL)の混合物を室温で1時間撹拌した。反応液を減圧下溶媒を留去し、残留物を酢酸エチルから結晶化により精製し、化合物18(91mg)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.61(3H,br),7.54(2H,d,J=8Hz),7.25-7.15(2H,m),7.06(1H,dt,J=1,8Hz),6.96(1H,s),6.84(1H,dt,J=1,7Hz),6.23(1H,d,J=8Hz),4.55-4.22(3H,m),4.23-4.14(2H,m),3.87(1H,d,H=16Hz),3.82(2H,d,J=16Hz),1.20(3H,t,J=7Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、1M炭酸水素ナトリウム水溶液(84μL)、化合物18(30mg)のエタノール(5mL)溶液、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)を加え、室温で3日間撹拌した。0.1g/mLの塩化ナトリウム水溶液(1mL)とエタノール(15mL)を加えた後、30分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(61.9mg)を白色固体として得た。薬剤導入率は13.1モル%であった。
市販の(tert-ブトキシカルボニル)-L-トレオニン(化合物20、2.14g)のエタノール(100mL)溶液に、室温で1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(3.74g)、N,N-ジメチル-4-アミノピリジン(0.12g)を加えた。反応液を一晩撹拌した。反応液を減圧下溶媒を留去した後、酢酸エチル(100mL)に溶かし、その溶液を5%クエン酸水溶液(50mL)、飽和炭酸水素ナトリウム水溶液(50mL)、飽和塩化ナトリウム水溶液(50mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、化合物21の粗生成物(0.96g)を得た。
化合物21の粗生成物(0.96g)、市販のジクロフェナク(化合物10、1.15g)、N,N-ジメチル-4-アミノピリジン(0.09g)のジクロロメタン(4mL)溶液に、N,N´-ジシクロヘキシルカルボジイミド(0.8g)のジクロロメタン(4mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(60mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(15%酢酸エチル/ヘプタン)によって精製し、化合物22(0.96g)を無色オイル状物質として得た。
1H-NMR(400MHz,CDCl3) δ 7.33(2H,d,J=8Hz),7.17(1H,dd,J=1,7Hz),7.11(1H,dt,J=1,8Hz),7.00-6.92(2H,m),6.82(1H,s),6.54(1H,d,J=8Hz),5.41-5.43(1H,m),5.23(1H,d,J=10Hz),4.43(1H,dd,J=3,10Hz),4.07-3.91(2H,m),3.78(1H,d,J=14Hz),3.72(1H,d,J=14Hz),1.47(9H,s),1.33(3H,d,J=6Hz),1.11(3H,t,J=7Hz)ppm.
化合物22(0.96g)と4N塩酸-酢酸エチル溶液(5mL)の混合物を室温で1時間撹拌した。反応液を減圧下溶媒を留去し、残留物を酢酸エチルから結晶化により精製し、化合物23(0.41g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.77(3H,br),7.54(2H,d,J=8Hz),7.22(1H,t,J=8Hz),7.17(1H,dd,J=1,7Hz),7.07(1H,dt,J=1,8Hz),6.94(1H,s),6.85(1H,dt,J=1,7Hz),6.24(1H,d,J=8Hz),5.35-5.27(1H,m),4.35(1H,d,J=4Hz), 4.12(2H,q,J=7Hz),3.86(1H,d,J=16Hz),3.78(1H,d,J=16Hz),1.36(3H,d,J=7Hz),1.15(3H,t,J=7Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)と2-モルホリノエタンスルホン酸一水和物(213mg)、化合物23(31mg)のエタノール(5mL)溶液を加えた。2時間後に0.1M水酸化ナトリウム水溶液(0.2mL)を追加、3時間後に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(16mg)を追加、4時間後と5時間後にそれぞれ0.1M水酸化ナトリウム水溶液(0.1mL)を追加、6時間後に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(23mg)と0.1M水酸化ナトリウム水溶液(0.2mL)を加えた。24時間後にエタノール(15mL)と0.1g/mLの塩化ナトリウム水溶液(1mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(111.2mg)を白色固体として得た。薬剤導入率は5.6モル%であった。
市販のジクロフェナクナトリウム(化合物1、0.48g)、市販のtert-ブチル(4-(ブロモメチル)ベンジル)カルバメート(化合物25、0.45g)、N-メチルピロリドン(3.0mL)の混合物を40℃で2時間撹拌した。反応溶液を室温に冷却後、酢酸エチル(40mL)とヘプタン(20mL)を加え、水(20mL)で2回洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(15%酢酸エチル/ヘプタン)によって精製し、化合物26(0.75g)を白色固体として得た。
1H-NMR(400MHz,CDCl3) δ 7.33-7.21(7H,m),7.12(1H,dt,J=1,8Hz),7.00-6.92(2H,m),6.86(1H,s),6.55(1H,d,J=8Hz),5.15(2H,s),4.81(1H,br),4.30(2H,d,J=6Hz),3.85(2H,s),1.46(9H,s)ppm.
化合物26(0.75g)と4N塩酸-酢酸エチル溶液(20mL)の混合物を室温で1時間撹拌した。反応懸濁液をろ過し、ろ取した固体を酢酸エチルで洗い、化合物27(0.36g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 7.53(2H,d,J=8Hz),7.45-7.36(4H,m),7.23-7.18(2H,m),7.10-7.03(2H,m),6.84(1H,dt,J=1,7Hz),6.25(1H,d,J=8Hz),5.16(2H,s),4.00(2H,s),3.88(2H,s)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(49mg)、1M炭酸水素ナトリウム水溶液(0.16mL)、化合物27(60mg)のエタノール(5mL)溶液を加え、室温で一晩攪拌した。エタノール(20mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(88.8mg)を白色固体として得た。薬剤導入率は5.3モル%であった。
市販のジクロフェナク(化合物10、0.7g)、市販のN-(tert-ブトキシカルボニル)チラミン(化合物29、0.56g)、N,N-ジメチル-4-アミノピリジン(0.06g)、ジクロロメタン(2.5mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(0.49g)のジクロロメタン(2.5mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(50mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(15mL)と水(15mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物を酢酸エチルからの結晶化により精製し、化合物30(0.64g)を白色固体として得た。
1H-NMR(400MHz,CDCl3) δ 7.36-7.30(3H,m),7.20-7.13(3H,m),7.05-6.95(4H,m),6.77(1H,s),6.58(1H,d,J=8Hz),4.60-4.46(1H,m),4.04(2H,s),3.40-3.30(2H,m), 2.78(2H,t,J=7Hz),1.43(9H,s)ppm.
化合物30(0.64g)と4N塩酸-酢酸エチル溶液(7mL)の混合物を室温で1時間撹拌した。反応液を減圧下溶媒を留去し、残留物を酢酸エチル-ヘプタン(2:1)で洗い、化合物31(0.56g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 7.91(3H,br),7.54(2H,d,J=8Hz),7.33-7.27(3H,m),7.25-7.21(1H,m),7.15-7.05(4H,m),6.86(1H,dt,J=1,7Hz),6.24(1H,d,J=8Hz),4.09(2H,s),3.08-3.00(2H,m),2.91-2.83(2H,m)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)、1M炭酸水素ナトリウム水溶液(0.11mL)、化合物31(40mg)のエタノール(5mL)溶液を加え、室温で一晩攪拌した。エタノール(20mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(81.0mg)を白色固体として得た。薬剤導入率は5.0モル%であった。
市販のジクロフェナク(化合物10、0.7g)、市販のtert-ブチル(2,2-ジフルオロ-3-ヒドロキシプロピル)カルバメート(化合物33、0.5g)、N,N-ジメチル-4-アミノピリジン(0.06g)、ジクロロメタン(2.5mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(0.49g)のジクロロメタン(2.5mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(50mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(15mL)と水(15mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-30%酢酸エチル/ヘプタン)より精製し、化合物34(1.02g)を無色ガム状物質として得た。
1H-NMR(400MHz,CDCl3) δ 7.33(2H,d,J=8Hz),7.27-7.22(1H,m),7.13(1H,dt,J=1,8Hz),7.01-6.94(2H,m),6.72(1H,s),6.56(1H,d,J=8Hz),4.86-4.76(1H,m),4.37(2H,t,J=13Hz),3.91(2H,s),3.60(2H,dt,J=7,13Hz),1.42(9H,s)ppm.
化合物34(1.0g)と4N塩酸-酢酸エチル溶液(10mL)の混合物を室温で1時間撹拌した。反応液を減圧下溶媒を留去し、残留物を酢酸エチル-ヘプタン(2:1)で洗い、化合物35(0.48g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.54(3H,br),7.53(2H,d,J=8Hz),7.25-7.18(2H,m),7.09-7.02(2H,m),6.84(1H,dt,J=1,7Hz),6.23(1H,d,J=8Hz),4.56(2H,t,J=14Hz),3.94(2H,s),3.50(2H,t,J=16Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)、1M炭酸水素ナトリウム水溶液(0.11mL)、化合物35(38mg)のエタノール(5mL)溶液を加え、室温で一晩攪拌した。エタノール(20mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(93.6mg)を白色固体として得た。薬剤導入率は14.9モル%であった。
氷冷した市販のtert-ブチル(2-アミノエチル)カルバメート(化合物37、1.6g)、飽和炭酸水素ナトリウム水溶液(5mL)、水(20mL)、1,2-ジメトキシエタン(20mL)の混合液に、市販の2-ブロモアセチルクロリド(化合物38、1.66mL)を滴下し、さらに飽和炭酸水素ナトリウム水溶液(25mL)を加え、10分間撹拌した。反応溶液を酢酸エチル(80mL)で2回抽出し、合わせた抽出液を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をヘプタン-酢酸エチル(1:1、10mL)で洗浄し、化合物39(0.62g)を白色固体として得た。
1H-NMR(400MHz,CDCl3) δ 7.09(1H,br),4.86(1H,br), 3.87(2H,s),3.43-3.37(2H,m),3.36-3.28(2H,m),1.45(9H,s)ppm.
市販のジクロフェナクナトリウム(化合物1、1.4g)、化合物39(0.62g)、N-メチルピロリドン(4.4mL)の混合物を50℃で1時間撹拌した。反応溶液を室温に冷却後、酢酸エチル(40mL)とヘプタン(20mL)を加え、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(50-100%酢酸エチル/ヘプタン)によって精製し、化合物40(0.87g)を白色固体として得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.29(1H,dd,J=1,7Hz),7.15(1H,dt,J=1,8Hz),7.03-6.91(3H,m),6.69(1H,br),6.55(1H,d,J=8Hz),4.92-4.79(1H,m),4.63(2H,s),3.96(2H,s),3.36-3.27(2H,m),3.25-3.16(2H,m),1.44(9H,s)ppm.
化合物40(0.87g)と4N塩酸-酢酸エチル溶液(10mL)の混合物を室温で1時間撹拌した。反応懸濁液をろ過し、ろ取した固体を酢酸エチル-ヘプタン(2:1)で洗い、化合物41(0.62g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.42(1H,t,J=5Hz),7.99(3H,br),7.53(2H,d,J=8Hz),7.26-7.19(2H,m),7.09-7.02(2H,m),6.85(1H,dt,J=1,7Hz),6.23(1H,d,J=8Hz),4.56(2H,s),3.94(2H,s),3.39-3.30(5H,m),2.85(2H,t,J=6Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)、1M炭酸水素ナトリウム水溶液(0.11mL)、化合物41(38mg)のエタノール(5mL)溶液を加え、室温で一晩攪拌した。エタノール(20mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(87.1mg)を白色固体として得た。薬剤導入率は12.3モル%であった。
氷冷した市販のtert-ブチル(2-アミノエチル)カルバメート(化合物37、1.6g)、飽和炭酸水素ナトリウム水溶液(10mL)、水(20mL)、1,2-ジメトキシエタン(30mL)の混合液に、市販の2-ブロモプロパノイルブロミド(化合物43、2.12mL)を滴下し、さらに飽和炭酸水素ナトリウム水溶液(25mL)を加え、10分間撹拌した。反応溶液を酢酸エチル(80mL)で2回抽出し、合わせた抽出液を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をヘプタン-酢酸エチル(3:2、20mL)で洗浄し、化合物44の粗生成物(0.39g)を得た。
化合物44の粗生成物(0.39g)、市販のジクロフェナクナトリウム(化合物1、0.84g)、N-メチルピロリドン(2.6mL)の混合物を50℃で1時間と60℃で3時間撹拌した。反応溶液を室温に冷却後、酢酸エチル(40mL)とヘプタン(20mL)を加え、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(30-100%酢酸エチル/ヘプタン)によって精製し、化合物45(0.34g)を白色固体として得た。
1H-NMR(400MHz,CDCl3) δ 7.36(2H,d,J=8Hz),7.31(1H,dd,J=1,7Hz),7.16(1H,dt,J=1,8Hz),7.04-6.97(2H,m),6.80(1H,br),6.68(1H,br),6.57(1H,d,J=8Hz),5.27(1H,q,J=7Hz),4.81(1H,br),4.02-3.88(2H,m),3.36-3.09(4H,m),1.50(3H,d,J=7Hz),1.44(9H,d,J=9Hz)ppm.
化合物45(0.34g)と4N塩酸-酢酸エチル溶液(4mL)の混合物を室温で1時間撹拌した。反応懸濁液をろ過し、ろ取した固体を酢酸エチル-ヘプタン(2:1)とtert-ブチルメチルエーテルで洗い、化合物46(0.24g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.36(1H,t,J=5Hz),7.89(3H,br),7.53(2H,d,J=8Hz),7.25-7.18(2H,m),7.06(1H,dt,J=1,8Hz),6.99(1H,s),6.84(1H,dt,J=1,7Hz),6.23(1H,d,J=8Hz),5.02(1H,q,J=7Hz),3.91(2H,s),3.40-3.22(2H,m),2.83(2H,t,J=6Hz),1.37(3H,d,J=7Hz)ppm.
1%(w/w)アルギン酸ナトリウム(株式会社キミカ製、A2)の水溶液(10g)に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(37mg)、1M炭酸水素ナトリウム水溶液(0.11mL)、化合物46(40mg)のエタノール(5mL)溶液を加え、室温で一晩攪拌した。エタノール(20mL)を加えた後、0.1g/mLの塩化ナトリウム水溶液(1mL)を加え、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(87.0mg)を白色固体として得た。薬剤導入率は12.5モル%であった。
実施例1から10で作製した各コンジュゲート1mgに、各コンジュゲートの濃度がそれぞれ0.1%w/w濃度となるように20mMリン酸ナトリウム緩衝液(pH5.3若しくは7.0)または1N水酸化ナトリウム水溶液を加え、20℃の室内環境下(空調設定温度)で、マグネティックスターラー(ASONE REMIX RS-6A、750r.p.m.)を用いて、6時間撹拌した。ゲル状になっていないことを確認し、この溶液を分注した。溶解直後に初期状態(保存0日)として各溶液に存在した遊離ジクロフェナク量をLC-MS/MSにて測定した。また、それ以外の分注液は37℃で1,3,7日間インキュベートしたのちに遊離ジクロフェナク量を測定した。各時点において、1N水酸化ナトリウム水溶液中の強制分解による遊離ジクロフェナク量との比を用いて遊離率(%)を算出した。
イオン化モード:ESI-negative
イオン源温度:300度
キャピラリー電圧:-4000 V
アルギン酸ナトリウム(持田製薬株式会社、A-2)1gを水(100mL)に溶解し、エタノール(30mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(456mg)を室温で加えた。30分間撹拌後、化合物13(346mg)のエタノール(10mL)-水(5mL)溶液と1M炭酸水素ナトリウム水溶液(0.82mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(5mL)とエタノール(100mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(1.06g)を白色固体として得た。薬剤導入率は14.0モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-3)1gを用い、(実施例12)<工程1-1>と同様の操作を行い、標記化合物(1.11g)を白色固体として得た。薬剤導入率は16.4モル%であった。
2-アミノエタノール(2.09g)と(tert-ブトキシカルボニル)グリシン(5.0g)のエタノール(30mL)混合液に室温で4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(11.4g)を加え、5時間撹拌した。反応懸濁液をエタノールを用いてろ過し、ろ液を減圧下濃縮した。残留物に酢酸エチルを加え、懸濁液をろ過し、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー(0-20%メタノール/酢酸エチル)によって精製し、化合物50(7.3g)を得た。
1H-NMR(400MHz,CDCl3) δ 6.92(1H,br),5.50(1H,br),4.03(1H,s),3.80(2H,d,J=6Hz),3.73-3.68(2H,m),3.46-3.40(2H,m),1.45(9H,s)ppm.
市販のジクロフェナク(化合物10、2.0g)、化合物50(2.2g)、N,N-ジメチル-4-アミノピリジン(0.17g)、ジクロロメタン(7mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(1.39g)のジクロロメタン(7mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(60mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(10-100%酢酸エチル/ヘプタン)によって精製し、化合物51(2.7g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.35(2H,d,J=8Hz),7.23(1H,dd,J=7,1Hz),7.14(1H,td,J=8,1Hz),7.02-6.94(2H,m),6.83(1H,s),6.55(1H,d,J=8Hz),6.23(1H,br),4.96(1H,br),4.25(2H,t,J=5Hz),3.83(2H,s),3.69(2H,d,J=6Hz),3.59-3.53(2H,m),1.44(9H,s)ppm.
化合物51(2.7g)と4N塩酸-1,4-ジオキサン溶液(27.2mL)の混合物を室温で30分間撹拌した。反応懸濁液をろ過し、ろ取した固体をジメトキシエタン-エタノール(1:1)とジメトキシエタンで洗い、化合物52(1.73g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.66(1H,t,J=5Hz),8.11(3H,br),7.54(2H,d,J=8Hz),7.24-7.17(2H,m),7.09-7.03(2H,m),6.85(1H,td,J=7,1Hz),6.24(1H,d,J=8Hz),4.12(2H,t,J=6Hz),3.83(2H,s),3.52(2H,s),3.45-3.38(2H,m)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-1)2gを水(200mL)に溶解し、エタノール(60mL)を加えた溶液に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(1.3g)を室温で加えた。30分間撹拌後、化合物52(0.85g)のエタノール(20mL)-水(10mL)溶液と1M炭酸水素ナトリウム水溶液(1.97mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(10mL)とエタノール(200mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(1.80g)を白色固体として得た。薬剤導入率は19.7モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-2)2gを水(200mL)に溶解し、エタノール(60mL)を加えた溶液に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(611mg)を室温で加えた。30分間撹拌後、化合物52(396mg)のエタノール(20mL)-水(10mL)溶液と1M炭酸水素ナトリウム水溶液(0.92mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(10mL)とエタノール(200mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(2.04g)を白色固体として得た。薬剤導入率は14.6モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-3)2gを用い、(実施例13)<工程4-2>と同様の操作を行い、標記化合物(1.99g)を白色固体として得た。薬剤導入率は17.0モル%であった。
<工程4-4>ジクロフェナク-(2-アミノ-N-(2-ヒドロキシエチル)アセトアミド)-アルギン酸誘導体(化合物53d)の合成
アルギン酸ナトリウム(持田製薬株式会社、B-2)100mgを水(10mL)に溶解し、エタノール(3mL)を加えた溶液に、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(46mg)を室温で加えた。10分間撹拌後、化合物52(40mg)のエタノール(2mL)-水(1mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(1mL)とエタノール(20mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(108mg)を白色固体として得た。薬剤導入率は23.1モル%であった。
4-ピペリジンメタノール(0.79g)と(tert-ブトキシカルボニル)グリシン(1g)のエタノール(10mL)混合液に室温で4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(1.9g)を加え、4時間撹拌した。反応懸濁液に酢酸エチルを加え、懸濁液をろ過し、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー(0-20%メタノール/酢酸エチル)によって精製し、化合物55(1.2g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 5.57(1H,br),4.64-4.56(1H,m),4.02-3.89(2H,m),3.77-3.68(1H,m),3.56-3.46(2H,m),3.01(1H,td,J=13,3Hz),2.63(1H,td,J=13,3Hz),1.89-1.67(3H,m),1.46(9H,s),1.24-1.09(2H,m)ppm.
市販のジクロフェナク(化合物10、0.87g)、化合物55(1.2g)、N,N-ジメチル-4-アミノピリジン(0.07g)、ジクロロメタン(5mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(0.61g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(50mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-50%酢酸エチル/ヘプタン)によって精製し、化合物56(1.4g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.22(1H,dd,J=7,2Hz),7.12(1H,td,J=8,2Hz),7.01-6.93(2H,m),6.86(1H,s),6.55(1H,d,J=8Hz),5.53(1H,br),4.61-4.54(1H,m),4.06-3.96(2H,m),3.95-3.91(2H,m),3.81(2H,s),3.71-3.63(1H,m),3.02-2.90(1H,m),2.64-2.53(1H,d,J=2.7Hz),2.00-1.86(1H,m),1.80-1.67(2H,m),1.45(9H,m),1.30-1.04(2H,m)ppm.
化合物56(1.4g)と4N塩酸-1,4-ジオキサン溶液(12.7mL)の混合物を室温で30分間撹拌した。反応液を減圧下ろ過し、化合物57(1.3g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.09(3H,br),7.53(2H,d,J=8Hz),7.23-7.17(2H,m),7.08-7.03(2H,m),6.85(1H,td,J=7,1Hz),6.26(1H,d,J=8Hz),4.36-4.28(1H,m),4.01-3.92(2H,m),3.89-3.76(2H,m),3.70-3.61(1H,m),3.48-3.40(1H,m),3.03-2.92(1H,m),2.67-2.57(1H,m),1.98-1.85(1H,m),1.73-1.63(2H,m),1.27-0.95(3H,m)ppm.
アルギン酸ナトリウム(持田製薬株式会社、B-2)100mgを水(20mL)に溶解し、エタノール(5mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(39mg)を室温で加えた。10分間撹拌後、化合物57(45mg)のエタノール(3mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(1mL)とエタノール(20mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(108mg)を白色固体として得た。薬剤導入率は18.4モル%であった。
4-ヒドロキシピペリジン(0.69g)と(tert-ブトキシカルボニル)グリシン(1.0g)のエタノール(10mL)混合液に室温で4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(1.9g)を加え、4時間撹拌した。反応懸濁液に酢酸エチルを加え、懸濁液をろ過し、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー(0-20%メタノール/酢酸エチル)によって精製し、化合物60(1.0g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 5.56(1H,br),4.06-3.92(5H,m),3.67-3.57(1H,m),3.34-3.25(1H,m),3.22-3.13(1H,m),1.99-1.84(2H,m),1.62-1.47(2H,m),1.45(9H,s)ppm.
市販のジクロフェナク(化合物10、0.76g)、化合物60(0.99g)、N,N-ジメチル-4-アミノピリジン(0.06g)、ジクロロメタン(5mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(0.53g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(50mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-50%酢酸エチル/ヘプタン)によって精製し、化合物61(1.0g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz), 7.21(1H,dd,J=8,2Hz),7.13(1H,td,J=8,2Hz),7.01-6.92(2H,m),6.81(1H,s),6.55(1H,d,J=8Hz),5.50(1H,br),5.08-5.01(1H,m),3.95(2H,d,J=4Hz),3.88-3.79(3H,m),3.56-3.42(2H,m),3.31-3.21(1H,m),1.97-1.84(2H,m),1.75-1.64(2H,m),1.45(9H,s)ppm.
化合物61(1.0g)と4N塩酸-1,4-ジオキサン溶液(9.3mL)の混合物を室温で30分間撹拌した。反応液を減圧下ろ過し、化合物62(0.91g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.14(3H,br),7.53(2H,d,J=8Hz),7.24-7.17(2H,m),7.08-7.02(2H,m),6.84(1H,td,J=7,1Hz),6.24(1H,d,J=8Hz),5.03-4.94(1H,m),3.93-3.79(4H,m),3.77-3.63(1H,m),3.54-3.24(3H,m),1.94-1.45(4H,m)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)1gを水(100mL)に溶解し、エタノール(30mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(370mg)を室温で加えた。10分間撹拌後、化合物62(350mg)のエタノール(10mL)溶液と1M炭酸水素ナトリウム水溶液(0.74mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(10mL)とエタノール(100mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(1.07g)を白色固体として得た。薬剤導入率は11.5モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-3)1gを用い、(実施例15)<工程4-1>と同様の操作を行い、標記化合物(1.09g)を白色固体として得た。薬剤導入率は12.6モル%であった。
6-アミノ-1-ヘキサノール(0.8g)と(tert-ブトキシカルボニル)グリシン(1g)のエタノール(10mL)混合液に室温で4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(1.9g)を加え、4時間撹拌した。反応懸濁液に酢酸エチルを加え、懸濁液をろ過し、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー(0-20%メタノール/酢酸エチル)によって精製し、化合物65(1.6g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 6.42(1H,br),5.38(1H,br),3.77(2H,d,J=6Hz),3.63(2H,t,J=6Hz),3.31-3.22(2H,m),1.62-1.47(4H,m),1.45(9H,s),1.43-1.28(4H,m)ppm.
市販のジクロフェナク(化合物10、1.0g)、化合物65(1.39g)、N,N-ジメチル-4-アミノピリジン(0.08g)、ジクロロメタン(5mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(0.7g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(50mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(10-100%酢酸エチル/ヘプタン)によって精製し、化合物66(1.5g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.22(1H,dd,J=8,2Hz),7.12(1H,td,J=8,2Hz),7.00-6.90(3H,m),6.54(1H,d,J=8Hz),6.12(1H,br),5.16(1H,br),4.13(2H,t,J=7Hz),3.80(2H,s),3.76(2H,d,J=6Hz),3.27-3.19(2H,m),1.69-1.59(2H,m),1.52-1.40(11H,m),1.38-1.25(4H,m)ppm.
化合物66(1.5g)と4N塩酸-1,4-ジオキサン溶液(13.6mL)の混合物を室温で30分間撹拌した。反応液を減圧下ろ過し、化合物67(1.3g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.34(1H,br),8.03(3H,br),7.53(2H,d,J=8Hz),7.23-7.16(2H,m),7.08-7.03(2H,m),6.85(1H,td,J=8,1Hz),6.26(1H,d,J=8Hz),4.07(2H,t,J=7Hz),3.79(2H,s),3.49(2H,s),3.12-3.04(2H,m),1.63-1.51(2H,m),1.41-1.33(2H,m),1.32-1.21(4H,m)ppm.
アルギン酸ナトリウム(持田製薬株式会社、B-2)100mgを水(20mL)に溶解し、エタノール(5mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(39mg)を室温で加えた。10分間撹拌後、化合物67(45mg)のエタノール(3mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(1mL)とエタノール(20mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(106mg)を白色固体として得た。薬剤導入率は18.0モル%であった。
1-アミノ-2-プロパノール(0.38g)、(tert-ブトキシカルボニル)グリシン(0.88g)、N,N-ジメチル-4-アミノピリジン(0.12g)、ジクロロメタン(20mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(1.03g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で終夜撹拌した。その反応液に市販のジクロフェナク(化合物10、1.48g)とN,N´-ジシクロヘキシルカルボジイミド(1.03g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で終夜撹拌した。反応液をろ過した後、ろ液を減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-100%酢酸エチル/ヘプタン)によって精製し、化合物70(0.74g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.24(1H,dd,J=8,1Hz),7.14(1H,td,J=8,1Hz),7.02-6.95(2H,m),6.87(1H,s),6.56(1H,d,J=8Hz),6.08(1H,br),5.12-5.02(1H,m),4.84(1H,br),3.84-3.76(2H,m),3.67-3.34(4H,m),1.43 (9H,s),1.27(3H,d,J=6Hz)ppm.
化合物70(0.74g)と4N塩酸-1,4-ジオキサン溶液(8mL)の混合物を室温で30分間撹拌した。反応液を減圧下ろ過し、化合物71(0.7g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.62(1H,t,J=6Hz),8.12(3H,br),7.53(2H,d,J=8Hz),7.24-7.17(2H,m),7.09-7.02(2H,m),6.85(1H,td,J=7,1Hz),6.25(1H,d,J=8Hz),4.95-4.84(1H,m),3.80(2H,s),3.59-3.21(4H,m),1.18(3H,d,J=6Hz)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)1gを水(100mL)に溶解し、エタノール(30mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(305mg)を室温で加えた。30分間撹拌後、化合物71(205mg)のエタノール(10mL)溶液と1M炭酸水素ナトリウム水溶液(0.46mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(5mL)とエタノール(100mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(1.04g)を白色固体として得た。薬剤導入率は13.1モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-3)200mgを水(20mL)に溶解し、エタノール(6mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(62mg)を室温で加えた。10分間撹拌後、化合物71(41mg)のエタノール(2mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(1mL)とエタノール(40mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(199mg)を白色固体として得た。薬剤導入率は14.5モル%であった。
3-アミノ-1-プロパノール(0.38g)、(tert-ブトキシカルボニル)グリシン(0.88g)、N,N-ジメチル-4-アミノピリジン(0.12g)、ジクロロメタン(20mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(1.03g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で終夜撹拌した。その反応液に市販のジクロフェナク(化合物10、1.48g)とN,N´-ジシクロヘキシルカルボジイミド(1.03g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で終夜撹拌した。反応液をろ過し、ろ液を減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-100%酢酸エチル/ヘプタン)によって精製し、化合物74(1.4g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.22(1H,dd,J=8,1Hz),7.12(1H,td,J=8,1Hz),7.02-6.92(2H,m),6.86(1H,s),6.54(1H,d,J=8Hz),6.40(1H,br),5.14(1H,br),4.21(2H,t,J=6Hz),3.82(2H,s),3.74(2H,d,J=6Hz),3.30(2H,q,J=6Hz),1.91-1.82(2H,m),1.44(9H,s)ppm.
化合物74(1.4g)と4N塩酸-1,4-ジオキサン溶液(14mL)の混合物を室温で30分間撹拌した。反応液を減圧下ろ過し、化合物75(1.3g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.46(1H,t,J=5Hz),8.07(3H,br),7.53(2H,d,J=8Hz),7.23-7.17(2H,m),7.10-7.03(2H,m),6.85(1H,td,J=7,1Hz),6.25(1H,d,J=8Hz),4.10(2H,t,J=6Hz),3.81(2H,s),3.51(2H,s),3.22-3.15(2H,m),1.82-1.72(2H,m)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)1gを水(100mL)に溶解し、エタノール(30mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(305mg)を室温で加えた。30分間撹拌後、化合物75(205mg)のエタノール(10mL)溶液と1M炭酸水素ナトリウム水溶液(0.46mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(5mL)とエタノール(100mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(1.03g)を白色固体として得た。薬剤導入率は13.7モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-3)1gを用い、(実施例18)<工程3-1>と同様の操作を行い、標記化合物(0.99g)を白色固体として得た。薬剤導入率は14.4モル%であった。
3-アミノ-1-プロパノール(0.38g)、(tert-ブトキシカルボニル)グリシン(0.88g)、N,N-ジメチル-4-アミノピリジン(0.12g)、ジクロロメタン(20mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(1.03g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で終夜撹拌した。その反応液に市販のジクロフェナク(化合物10、1.48g)とN,N´-ジシクロヘキシルカルボジイミド(1.03g)のジクロロメタン(5mL)溶液を滴下した。反応液を室温で終夜撹拌した。反応液をろ過し、ろ液を減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-100%酢酸エチル/ヘプタン)によって精製し、化合物78(1.4g)を白色アモルファスとして得た。
1H-NMR(400MHz,CDCl3) δ 7.34(2H,d,J=8Hz),7.23(1H,dd,J=8,1Hz),7.13(1H,td,J=8,1Hz),7.02-6.93(2H,m),6.86(1H,s),6.55(1H,d,J=8Hz),6.03(1H,d,J=8Hz),4.94(1H,br),4.37-4.25(1H,m),4.22-4.07(2H,m),3.89-3.77(2H,m),3.72-3.52(2H,m),1.44(9H,s),1.16(3H,d,J=7Hz)ppm.
化合物78(1.4g)と4N塩酸-1,4-ジオキサン溶液(14mL)の混合物を室温で30分間撹拌した。反応液を減圧下ろ過し、化合物79(1.3g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.53(1H,d,J=8Hz),8.13(3H,br),7.53(2H,d,J=8Hz),7.21(2H,t,J=8Hz),7.09-7.03(2H,m),6.85(1H,td,J=7,1Hz),6.25(1H,d,J=8Hz),4.14-3.99(3H,m),3.83(2H,s),3.56-3.44(2H,m),1.09(3H,d,J=7Hz)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)1gを水(100mL)に溶解し、エタノール(30mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(305mg)を室温で加えた。30分間撹拌後、化合物79(205mg)のエタノール(10mL)溶液と1M炭酸水素ナトリウム水溶液(0.46mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(5mL)とエタノール(100mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(0.97g)を白色固体として得た。薬剤導入率は12.2モル%であった。
アルギン酸ナトリウム(持田製薬株式会社、A-3)1gを用い、(実施例19)<工程3-1>と同様の操作を行い、標記化合物(0.99g)を白色固体として得た。薬剤導入率は14.4モル%であった。
市販のフェルビナク(化合物81、1.0g)、化合物50(1.13g)、N,N-ジメチル-4-アミノピリジン(0.12g)、ジクロロメタン(6mL)の混合物に氷冷下、N,N´-ジシクロヘキシルカルボジイミド(1.07g)のジクロロメタン(4mL)溶液を滴下した。反応液を室温で2時間撹拌した。反応液を酢酸エチル(50mL)を用いてろ過した後、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をエタノールでトリチュレートし、化合物82(0.80g)を白色固体として得た。
1H-NMR(400MHz,CDCl3) δ 7.60-7.54(4H,m),7.46-7.40(2H,m),7.38-7.31(3H,m),6.27(1H,br),4.97(1H,br),4.21(2H,t,J=5Hz),3.72(2H, d,J=6Hz),3.68(2H,s),3.58-3.52(2H,m),1.45(9H,s)ppm.
化合物82(0.80g)と4N塩酸-1,4-ジオキサン溶液(10mL)の混合物を室温で30分間撹拌した。反応懸濁液をろ過し、ろ取した固体をジメトキシエタンでトリチュレートし、化合物83(0.56g)を白色固体として得た。
1H-NMR(400MHz,DMSO-d6) δ 8.68(1H,br),8.14(3H,br),7.67-7.60(4H,m),7.49-7.43(2H,m),7.39-7.33(3H,m),4.10(2H,t,J=6Hz),3.74(2H,s),3.55(2H,s),3.46-3.37(2H,m)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)200mgを水(20mL)に溶解し、エタノール(8mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(46mg)を室温で加えた。10分間撹拌後、化合物83(32mg)のエタノール(2mL)-水(1mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(2mL)とエタノール(40mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(193mg)を白色固体として得た。薬剤導入率は10.8モル%であった。
市販のケトプロフェン(化合物85、1.0g)、化合物50(0.94g)、N,N-ジメチル-4-アミノピリジン(0.1g)、ジクロロメタン(10mL)の混合物に、室温で1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(0.83g)を加えた。反応液を室温で3時間撹拌した。反応液を酢酸エチル(50mL)で希釈し、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-100%酢酸エチル/ヘプタン)によって精製し、化合物86(1.38g)を無色ガム状物質として得た。
1H-NMR(400MHz,CDCl3) δ 7.84-7.77(3H,m),7.65-7.58(2H,m),7.55-7.42(4H,m),6.50(1H,br),5.28(1H,br),4.27-4.13(2H,m),3.74(2H,d,J=6Hz),3.58-3.41(3H,m),1.56(3H,d,J=7Hz),1.43(9H,s)ppm.
化合物86(1.38g)と4N塩酸-1,4-ジオキサン溶液(15mL)の混合物を室温で30分間撹拌した。反応液を減圧下溶媒を留去し、化合物87(1.27g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.67(1H,t,J=6Hz),8.19(3H,br),7.76-7.51(9H,m),4.17-4.10(1H,m),4.04-3.92(2H,m),3.51(2H,s),3.44-3.27(2H,m),1.45(3H,d,J=7Hz)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)200mgを水(20mL)に溶解し、エタノール(6mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(46mg)を室温で加えた。10分間撹拌後、化合物87(36mg)のエタノール(2mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(2mL)とエタノール(40mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(201mg)を白色固体として得た。薬剤導入率は11.9モル%であった。
市販のナプロキセン(化合物89、1.0g)、化合物50(1.04g)、N,N-ジメチル-4-アミノピリジン(0.11g)、ジクロロメタン(10mL)の混合物に、室温で1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(0.92g)を加えた。反応液を室温で3時間撹拌した。反応液を酢酸エチル(50mL)で希釈し、飽和炭酸水素ナトリウム水溶液(20mL)と水(20mL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(5-100%酢酸エチル/ヘプタン)によって精製し、化合物90(1.39g)を無色ガム状物質として得た。
1H-NMR(400MHz,CDCl3) δ 7.72(2H,dd,J=8,4Hz),7.66(1H,d,J=1Hz),7.39(1H,dd,J=8,2Hz),7.17-7.10(2H,m),5.97(1H,br),4.79(1H,br),4.23-4.08(2H,m),3.92(3H,s),3.86(1H,q,J=7Hz),3.56-3.37(4H,m),1.58(3H,d,J=7Hz),1.45(9H,s)ppm.
化合物90(1.39g)と4N塩酸-1,4-ジオキサン溶液(15mL)の混合物を室温で30分間撹拌した。反応液を減圧下溶媒を留去し、化合物91(1.28g)を白色アモルファスとして得た。
1H-NMR(400MHz,DMSO-d6) δ 8.61(1H,t,J=5Hz),8.13(3H,br),7.79(2H,t,J=9Hz),7.72(1H,d,J=2Hz),7.40(1H,dd,J=9,2Hz),7.29(1H,d,J=2Hz),7.15(1H,dd,J=8,2Hz),4.17-4.09(1H,m),4.02-3.88(2H,m),3.86(3H,s),3.50(2H,s),3.43-3.26(2H,m),1.49(3H,d,J=7Hz)ppm.
アルギン酸ナトリウム(持田製薬株式会社、A-2)200mgを水(20mL)に溶解し、エタノール(6mL)を加えた溶液に4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(46mg)を室温で加えた。10分間撹拌後、化合物91(34mg)のエタノール(2mL)溶液と1M炭酸水素ナトリウム水溶液(0.09mL)を滴下し、室温で4時間攪拌した。反応液に0.1g/mLの塩化ナトリウム水溶液(2mL)とエタノール(40mL)を加えた後、10分間攪拌した。得られた沈殿をろ取し、エタノールで洗浄後、減圧乾燥して、標記化合物(196mg)を白色固体として得た。薬剤導入率は12.9モル%であった。
(実施例10)の方法と同様にして、pH=5.3又はpH=7.0のリン酸ナトリウム緩衝液中におけるジクロフェナクフェルビナク、ケトプロフェン、及びナプロキセンの遊離薬物量を測定し、リリース率を算出した。
イオン化モード:ESI-negative
イオン源温度:300度
キャピラリー電圧:-4000 V
ラット1% 硝酸銀惹起疼痛モデルに対する(実施例13)で得られた化合物53bの関節腔内投与による効果
全身麻酔剤としてイソフルランの吸入麻酔を用いた。
ラット(Crj:SD系(SPF)、雄性、6週齢)に麻酔下、1%硝酸銀溶液を50μL/jointの用量で左後肢膝関節腔内に投与した。
下記の被験物質を準備した。
・Vehicle(VH):10mMリン酸緩衝液(PB)を溶媒とする5%グルコース溶液
・0.9mg/mL ジクロフェナクNa in Vehicle(DF)
・0.9%アルギン酸Na(持田製薬株式会社、A-2)in Vehicle(ALG)
・0.9mg/mL ジクロフェナクNa+0.9%アルギン酸Na(持田製薬株式会社、A-2)in Vehicle(DF&ALG)
・実施例13で得た化合物53bの0.9%溶液(DF-ALG)(結合体)
歩行スコアを被験物質投与日より1日1回5日間スコアを付ける。ただし、1日目のスコアについては、投与前(群分け)のスコアを用いる。歩行状態をブラインド下でスコア化した下記疼痛スコア表を用いて、各群の歩行状態を肉眼観察した。結果は表16に示す。
0:ノーマル
1:足を持ち上げて軽度の跛行
2:つま先を完全に閉塞した重度の跛行
3:3足歩行
下記の被験物質を準備した。
・実施例13で得た化合物53bの0.9%溶液(溶媒:5%グルコース含有10mMリン酸緩衝液)(DF-ALG-53b)
・実施例15で得た化合物63aの0.9%溶液(溶媒:5%グルコース、3%HP-β-CD含有10mMリン酸緩衝液)(DF-ALG-63a)
ウサギを塩酸ケタミン及びキシラジンの筋肉内投与による併用麻酔下で放血屠殺した。関節包を膝蓋骨直下で切開して膝関節腔を露呈し、サーフロー留置針20Gのカテーテルを用いて2mLの生理的食塩液で関節腔内を洗浄し、生理食塩液に混じた関節液を採取した。回収した関節液中のDF量を下記手順にて測定する。
上記(2)の関節液を回収した後の膝関節から滑膜組織を分離、採取した。採取した滑膜組織は生理的食塩液で洗浄し、付着する関節液を除去した。滑膜組織は膝蓋骨を取り除いた後、チューブに入れ、鋏で組織を細切れにした。ステンレスビーズ入りチューブに滑膜組織50mg程度を取り、19倍の精製水を添加し、ビーズ式ホモジナイザーを用いてホモジネートした。ホモジネート(0.1mL)に1NHCl(0.02mL)を加え十分に撹拌した後に室温で30分間以上インキュベートした。さらに、0.1%ギ酸水溶液0.07mL及び内部標準溶液(Celecoxib濃度0.1μg/mLのメタノール溶液)0.01mLを添加して十分に撹拌した後、450Gで5分間遠心をした。この上清全量をメタノール0.2mL及び精製水0.2mLで平衡化したOasis(登録商標)PRiME HLB μ-Elution Plate(抽出カラム)に添加し、エアーポンプで添加サンプルを吸引した。上記(2)と同様の抽出操作を行い、LC-MS/MSを用いて、遊離ジクロフェナク量を測定した。結果は表17に示す。
特に、先行技術(BMC Musculoskeletal Disorders (2018) 19:P157~)に記載のDF-HA(結合体)投与時の滑膜中DF濃度(約10ng/g(day28)、<5ng/g(day35))(文献中Fig.7aを参照)に比べて、DF-ALG(結合体)投与時の滑膜中ジクロフェナク濃度は投与後84日においても高く、長期間(例えば、2~3カ月間)の疼痛抑制効果が持続すると期待される。
疼痛抑制効果は、滑膜中でのジクロフェナク量に依存することが知られており、28日目、56日目、84日目において、化合物53b及び63aの両化合物とも疼痛抑制効果が発現する最低量(5ng/g)を上回って維持できる結果が得られたことから、本発明の非ステロイド性抗炎症性化合物結合アルギン酸誘導体、とりわけジクロフェナク結合アルギン酸誘導体には、長期間(例えば、2~3カ月間)の疼痛抑制が持続的することが期待できる。
Claims (16)
- アルギン酸又はその塩と非ステロイド性抗炎症性化合物とがリンカーを介して共有結合されてなる構造を有する、水溶性アルギン酸誘導体。
- 下記式(2)で表される構造を有する、請求項1に記載の水溶性アルギン酸誘導体:
(A)-NH-(CH2)n1-[X1]n2-(CR1R2)n3-[Y]n4-(CH2)n5-(CR3R4)n6-[X2]n7-(CH2)n8-[Z]-(D) (2)
(式中、
(A)はアルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基を示し、
(D)は非ステロイド性抗炎症性化合物の1残基を示し、
X1及びX2は、ヘテロ原子を示し、
R1、R2、R3及びR4はそれぞれ独立して、水素、ハロゲン原子、C1-10アルキル基、C1-10のアルコキシ基又はC1-10アルコキシカルボニル基を示すか、又は、R1及びR2若しくはR3及びR4が一緒になって=Oを示し、
Yは、シクロアルカン環、芳香族環又は複素環(前記シクロアルカン環、芳香族環又は複素環は、ハロゲン原子又はC1-10アルキル基で置換されていてもよい)を示し、
Zは、(D)とエステル結合を形成するための、O又はC(=O)を示し、
n1は0~10のいずれかの整数を示し、n2~n8は独立して0~3のいずれかの整数を示すが、n1~n8の全てが0になることはない)。 - 下記式(2a):
(A)は、アルギン酸又はその塩由来の残基であって、アルギン酸を構成するL-グルロン酸及びD-マンヌロン酸のいずれか一方の単糖のC(=O)-基を有する1残基であり;
(D)は、非ステロイド性抗炎症性化合物の1残基であり;
X1及びX2は、ヘテロ原子であり;
R1、R2、R3、R4、R5、及びR6は、それぞれ独立して、水素原子、ハロゲン原子、C1-6アルキル基、C1-6のアルコキシ基、又はC1-6アルコキシカルボニル基から選択される基であり(R1及びR2、R3及びR4、又はR5及びR6は一緒になってオキソ基(=O)を形成することができ);
Yは、C3-8シクロアルキル環、C6-10アリール環、又は複素環(前記C3-8シクロアルカン環、C6-10アリール環、又は複素環は、ハロゲン原子、又はC1-6アルキル基が1~3個置換されていても良い)であり;
Zは、酸素原子又はカルボニル基であり;
n1又はn8は、0~10のいずれかの整数であり;
n3、n5、又はn6は、独立して0、1、2、3のいずれかの整数であり;
n2、n4、又はn7は、独立して0又は1の整数であり;
但し、n1~n8の全てが0になることはない)で表される、請求項1に記載の水溶性アルギン酸誘導体。 - 非ステロイド性抗炎症性化合物がカルボキシル基を有し、前記カルボキシル基がリンカーと結合されてなる、請求項1~3のいずれか1項に記載の水溶性アルギン酸誘導体。
- 非ステロイド性抗炎症性化合物がサリチル酸系、プロピオン酸系、又はフェニル酢酸系の非ステロイド性抗炎症薬(NSAIDs)であり、NSAIDsのカルボキシル基が、請求項4に記載の式(LKA-1)又は式(LKA-2)で表わされるリンカーと結合されてなる、請求項1~6のいずれか1項に記載の水溶性アルギン酸誘導体。
- 非ステロイド性抗炎症性化合物が、フェニル酢酸系の非ステロイド性抗炎症薬(NSAIDs)、又はプロピオン酸系の非ステロイド性抗炎症薬(NSAIDs)である、請求項7に記載の水溶性アルギン酸誘導体。
- 非ステロイド性抗炎症性化合物が、ジクロフェナク、フェルビナク、ケトプロフェン、又はナプロキセンから選択される、請求項8に記載の水溶性アルギン酸誘導体。
- 非ステロイド性抗炎症性化合物の導入率(モル%)が、少なくとも1.0モル%以上である、請求項1~9のいずれか1項に記載の水溶性アルギン酸誘導体。
- 請求項1~10のいずれか1項に記載の水溶性アルギン酸誘導体を架橋してなる、水溶性アルギン酸誘導体ゲル。
- 請求項1~10のいずれか1項に記載の水溶性アルギン酸誘導体、又は、請求項11に記載の水溶性アルギン酸誘導体ゲルを含む、徐放性医薬組成物。
- 関節炎治療剤としての、請求項12に記載の徐放性医薬組成物。
- 非ステロイド性抗炎症性化合物を徐放するための、請求項1~10のいずれか1項に記載の水溶性アルギン酸誘導体、又は、請求項11に記載の水溶性アルギン酸誘導体ゲルの使用。
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JP7404228B2 (ja) | 2023-12-25 |
US20230190943A1 (en) | 2023-06-22 |
EP3770180A4 (en) | 2021-12-22 |
US20210000968A1 (en) | 2021-01-07 |
JPWO2019182015A1 (ja) | 2021-03-11 |
CN116891540A (zh) | 2023-10-17 |
CN112154158A (zh) | 2020-12-29 |
EP3770180A1 (en) | 2021-01-27 |
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