JP-2022511030-A5 -

Dates

Publication Date

20221212

Application Date

20191205

Description

While various specific embodiments are illustrated and described, it should be understood that various modifications can be made without departing from the spirit and scope of the invention. In one embodiment, for example, the following items are provided. (Item 1) Compound of formula I: or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, wherein, W, X, Y, or Z are each independently selected from N, O, S, CU, CH, and C-NH2 , and one of W, X, Y, or Z is C- NH2 . Ra is a C1-4 aliphatic element which is optionally substituted with one, two, or three deuterium or halogen atoms . R b is a C1-4 aliphatic atom optionally substituted with one, two, or three deuterium or halogen atoms ; or R a and R b together with the carbon atoms to which they are bonded form a 3-8 membered cycloalkyl or heterocyclyl ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur. k is 0, 1, 2, 3, or 4. U is independently selected from halogen, cyano, -R, -OR, -SR, -N(R) ² , -N(R)C(O)R, -C(O)N(R) ² , -N(R)C(O)N(R) ² , -N(R)C(O)OR, -OC(O)N(R) ² , -N(R)S (O) ²R , -SO₂N ( R) ² , -C(O)R, -C(O)OR, -OC(O)R, -S(O)R and -S(O) ²R . The two U atoms present on adjacent carbon atoms can form optionally substituted condensed rings, selected from: condensed phenyl rings; 5-6 member saturated or partially unsaturated condensed heterocyclic rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 member condensed heteroaryl rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. R is independently selected from hydrogen, deuterium, and optionally substituted groups selected from C1-6 aliphatic; 3-8 member saturated or partially unsaturated monocyclic carbocyclic rings; phenyl; 8-10 member bicyclic aryl rings; 3-8 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-10 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 7-10 member bicyclic heteroaryl rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The aforementioned pharmaceutical composition is an injectable composition. Pharmaceutical composition. (Item 2) The injectable composition (a) Viscosity enhancers (b) Liposomes (c) Microparticles or nanoparticles of biodegradable polymers (d) Calcium phosphate particles (e) Cyclodextrins, wherein the composition is suitable for parenteral administration, or (f) Hydrogel A pharmaceutical composition containing the information described in item 1. (Item 3) A pharmaceutical composition according to item 2, comprising a viscosity enhancer. (Item 4) The pharmaceutical composition according to item 3, wherein the viscosity enhancer is selected from the group consisting of hyaluronate, hyaluronic acid, cross-linked hyaluronic acid, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, glycerol, or mixtures thereof. (Item 5) The pharmaceutical composition according to any one of item 3 or 4, wherein the pharmaceutical composition has a viscosity between 1 kcP and 200 kcP. (Item 6) The pharmaceutical composition according to any one of items 3 to 5, wherein the viscosity enhancer is hyaluronate, hyaluronic acid, or a pharmaceutically acceptable salt thereof. (Item 7) The pharmaceutical composition according to item 6, wherein the hyaluronate or hyaluronic acid or a pharmaceutically acceptable salt thereof has a molecular weight of about 500,000 to about 5 × 10⁶ daltons . (Item 8) A pharmaceutical composition according to any one of items 3 to 7, further comprising one or more excipients selected from isotonic agents, buffering agents, chelating agents, surfactants, preservatives, and antioxidants. (Item 9) A pharmaceutical composition as described in item 2, comprising liposomes. (Item 10) The pharmaceutical composition according to item 9, wherein the liposomes are submicron-sized liposomes. (Item 11) The pharmaceutical composition according to any one of items 9 to 10, wherein the liposomes have an average diameter of about 20 nm to about 1 μm. (Item 12) The pharmaceutical composition according to any one of items 9 to 11, wherein the liposome comprises 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). (Item 13) The pharmaceutical composition according to any one of items 9 to 11, wherein the liposome comprises egg phosphatidylcholine (EPC) and l-α-distearoylphosphatidylcholine (DSPC). (Item 14) The pharmaceutical composition according to any one of items 9 to 11, wherein the liposome comprises egg phosphatidylcholine (EPC) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and cholesterol or a derivative thereof. (