NZ738016B2 - Amide-linked ep4 agonist-bisphosphonate compounds and uses thereof - Google Patents
Amide-linked ep4 agonist-bisphosphonate compounds and uses thereof Download PDFInfo
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- NZ738016B2 NZ738016B2 NZ738016A NZ73801616A NZ738016B2 NZ 738016 B2 NZ738016 B2 NZ 738016B2 NZ 738016 A NZ738016 A NZ 738016A NZ 73801616 A NZ73801616 A NZ 73801616A NZ 738016 B2 NZ738016 B2 NZ 738016B2
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- New Zealand
- Prior art keywords
- compound
- bone
- fracture
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- bis
- Prior art date
Links
- 229940122361 Bisphosphonate Drugs 0.000 title claims abstract 6
- 150000001408 amides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 38
- 210000000988 bone and bone Anatomy 0.000 claims abstract 19
- 239000000556 agonist Substances 0.000 claims abstract 9
- 150000004663 bisphosphonates Chemical group 0.000 claims abstract 6
- 238000000034 method Methods 0.000 claims 10
- 125000000217 alkyl group Chemical group 0.000 claims 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 7
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 claims 7
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 7
- 125000004432 carbon atom Chemical group C* 0.000 claims 7
- 239000011734 sodium Substances 0.000 claims 7
- 229910052708 sodium Inorganic materials 0.000 claims 7
- 230000002159 abnormal effect Effects 0.000 claims 6
- 125000003118 aryl group Chemical group 0.000 claims 6
- 229910052736 halogen Inorganic materials 0.000 claims 6
- 208000010392 Bone Fractures Diseases 0.000 claims 5
- 239000008194 pharmaceutical composition Substances 0.000 claims 5
- 206010017076 Fracture Diseases 0.000 claims 4
- 239000002253 acid Substances 0.000 claims 4
- 125000003277 amino group Chemical group 0.000 claims 4
- 150000002367 halogens Chemical class 0.000 claims 4
- 238000001727 in vivo Methods 0.000 claims 4
- 125000002843 carboxylic acid group Chemical group 0.000 claims 3
- 230000007062 hydrolysis Effects 0.000 claims 3
- 238000006460 hydrolysis reaction Methods 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical group NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims 2
- 208000006386 Bone Resorption Diseases 0.000 claims 2
- 206010065687 Bone loss Diseases 0.000 claims 2
- 206010010214 Compression fracture Diseases 0.000 claims 2
- 206010018720 Greenstick fracture Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 208000002565 Open Fractures Diseases 0.000 claims 2
- 208000005250 Spontaneous Fractures Diseases 0.000 claims 2
- 239000013543 active substance Substances 0.000 claims 2
- -1 amino bisphosphonate Chemical class 0.000 claims 2
- 230000024279 bone resorption Effects 0.000 claims 2
- 230000003913 calcium metabolism Effects 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 238000001356 surgical procedure Methods 0.000 claims 2
- 150000003536 tetrazoles Chemical class 0.000 claims 2
- UXMIHYCECZEABN-UHFFFAOYSA-N 3,5-bis(carboxymethyl)benzoic acid Chemical compound OC(=O)CC1=CC(CC(O)=O)=CC(C(O)=O)=C1 UXMIHYCECZEABN-UHFFFAOYSA-N 0.000 claims 1
- DMEDOWYXHVUPMO-UHFFFAOYSA-N 4-(carboxymethyl)benzoic acid Chemical group OC(=O)CC1=CC=C(C(O)=O)C=C1 DMEDOWYXHVUPMO-UHFFFAOYSA-N 0.000 claims 1
- 208000002679 Alveolar Bone Loss Diseases 0.000 claims 1
- 208000037848 Metastatic bone disease Diseases 0.000 claims 1
- 208000010191 Osteitis Deformans Diseases 0.000 claims 1
- 206010031243 Osteogenesis imperfecta Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 208000027868 Paget disease Diseases 0.000 claims 1
- 206010052306 Periprosthetic osteolysis Diseases 0.000 claims 1
- 208000008312 Tooth Loss Diseases 0.000 claims 1
- 229940062527 alendronate Drugs 0.000 claims 1
- 229960004343 alendronic acid Drugs 0.000 claims 1
- 150000007933 aliphatic carboxylic acids Chemical group 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 230000008416 bone turnover Effects 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 208000002551 irritable bowel syndrome Diseases 0.000 claims 1
- 125000005647 linker group Chemical group 0.000 claims 1
- 208000027202 mammary Paget disease Diseases 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 208000028169 periodontal disease Diseases 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 230000030991 negative regulation of bone resorption Effects 0.000 abstract 1
- 230000008685 targeting Effects 0.000 abstract 1
Classifications
-
- 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
- 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
- A61K47/54—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 compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Abstract
The present invention relates to EP4 agonist-bisphosphonate conjugates or related compounds and uses thereof. Said conjugates or related compounds may be used to provide delivery of an EP4 agonist or related compound to a desired site of action, such as a bone. Bisphosphonate moieties, linked to the EP4 agonists via amide linkers, have been implicated in the inhibition of bone resorption and bone targeting.
Claims (29)
1. A compound, or a pharmaceutically acceptable salt thereof, the compound comprising at least one EP4 agonist or related moiety linked to an amide linker through an ester bond and an amino bisphosphonate moiety linked to the amide linker through an amide bond, wherein the EP4 agonist or related compound is selected from the group consisting of: i) a compound according to the chemical structure wherein: X is -CH -, -S-, -O-, or -NH-; Y is COOR', tetrazole, or C(O)NHSO R; R is alkyl with one to ten carbon atoms or aryl; n is 1, 2, or 3; R is independently H or halogen; Ar is aryl, aryl substituted with halogen or alkyl with one to ten carbon atoms, or heteroaryl; R' is H or alkyl with one to ten carbon atoms, and is a double or single bond; or ii) a compound selected from Compound B, wherein, in Compound B, a dashed line indicates the presence or absence of a bond; A is 1 1 2 1 2 phenyl; X is CH , O or S; Y is OR or NR R and R and R are independently H or C 2 1-6 alkyl; wherein the amide linker has a structure selected from the group consisting of , and wherein R is each independently H, OR', halogen, CN, or C(O)R', R' is each independently H or alkyl with one to ten carbon atoms, or the two R's form a ring of up to 6 carbons, NHR'', if present, is the amino group of the amino bisphosphonate, q, if present, is 1 or 2, and n, if present, is 1, 2 or 3, wherein one or more of the aliphatic carboxylic acid groups of the amide linker can react with the C-15 or equivalent hydroxyl group of the EP4 agonist or related compound, to form the ester bond, and the remaining carboxylic acid group can react with the amino group of the amino bisphosphonate to form the amide bond, and wherein the amino bisphosphonate moiety has the following formula wherein m is 1, 2, 3, 4, 5 or 6.
2. The compound of claim 1 wherein the amide linker is 4-(carboxymethyl) benzoic acid or 3,5-bis-(carboxymethyl)benzoic acid.
3. The compound of claim 1 or claim 2 wherein the bisphosphonate is alendronic acid, 4-aminohydroxybutylidene-1,1-bisphosphonic acid, alendronate, 4-amino hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, 6-amino hydroxyhexylidene-1,1-bisphosphonic acid, or 3-aminohydroxypropylidene-1,1- bisphosphonic acid.
4. A compound according to Formula I, or a pharmaceutically acceptable salt thereof: Formula I wherein: X is -CH -, -S-, -O-, or -NH-; Y is COOR', tetrazole, or C(O)NHSO R; Z is OH or H; R is alkyl with one to ten carbon atoms or aryl; n is 1, 2, or 3; m is 0, 1, 2, 3, 4, 5, or 6; q is 1 or 2; R is independently H or halogen; Ar is aryl, aryl substituted with halogen or alkyl with one to ten carbon atoms, or heteroaryl; R is each independently H, OR', halogen, CN, or C(O)R'; R' is each independently H or alkyl with one to ten carbon atoms, or two R's may form a ring of up to 6 carbons; and is a double or single bond.
5. The compound of claim 1 or 4 selected from the group consisting of: Sodium (4-(4-(2-(((R,E)((R)(7-ethoxyoxoheptyl)oxopyrrolidinyl)-1,1-difluoro- 1-phenylbutenyl)oxy)oxoethyl)benzamido)hydroxybutane-1,1-diyl)bis(hydrogen phosphonate); Sodium (3-(4-(2-(((R,E)((R)(7-ethoxyoxoheptyl)oxopyrrolidinyl)-1,1-difluoro- 1-phenylbutenyl)oxy)oxoethyl)benzamido)hydroxypropane-1,1- diyl)bis(hydrogen phosphonate); Sodium (6-(4-(2-(((R,E)((R)(7-ethoxyoxoheptyl)oxopyrrolidinyl)-1,1-difluoro- 1-phenylbutenyl)oxy)oxoethyl)benzamido)hydroxyhexane-1,1- diyl)bis(hydrogen phosphonate); Sodium (4-(4-(2-(((R,E)((R)(6-carboxyhexyl)oxopyrrolidinyl)-1,1-difluoro phenylbutenyl)oxy)oxoethyl)benzamido)hydroxybutane-1,1-diyl)bis(hydrogen phosphonate); Sodium (3-(4-(2-(((R,E)((R)(6-carboxyhexyl)oxopyrrolidinyl)-1,1-difluoro phenylbutenyl)oxy)oxoethyl)benzamido)hydroxypropane-1,1-diyl)bis(hydrogen phosphonate); Sodium (6-(4-(2-(((R,E)((R)(6-carboxyhexyl)oxopyrrolidinyl)-1,1-difluoro phenylbutenyl)oxy)oxoethyl)benzamido)hydroxyhexane-1,1-diyl)bis(hydrogen phosphonate); and Sodium (4-(3,5-bis(2-(((R,E)((R)(6-carboxyhexyl)oxopyrrolidinyl)-1,1-difluoro phenylbutenyl)oxy)oxoethyl)benzamido)hydroxybutane-1,1-diyl)bis(hydrogen phosphonate).
6. The compound of any one of claims 1 to 5 wherein the compound is hydrolyzable in vivo.
7. The compound of claim 6 wherein the compound is inactive prior to hydrolyzation.
8. The compound of any one of claims 1 to 7 wherein the amide bond is resistant to hydrolysis in vivo.
9. A composition comprising the compound of any one of claims 1 to 8 in combination with a carrier.
10. A pharmaceutical composition comprising the compound of any one of claims 1 to 8, in combination with a pharmaceutically acceptable carrier.
11. Use of the compound of any one of claims 1 to 8, or the pharmaceutical composition of claim 10, in the manufacture of a medicament for treating or preventing a condition associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism, or that would be benefited by administration of an EP4 agonist or related compound, in a subject in need thereof.
12. The use of claim 11, wherein the condition is selected from the group consisting of osteoporosis, Paget's disease, abnormally increased bone turnover, bone graft, periodontal disease, alveolar bone loss, tooth loss, bone fracture, periprostheticosteolysis, osteogenesis imperfecta, metastatic bone disease, and irritable bowel syndrome.
13. Use of the compound of any one of claims 1 to 8, or the pharmaceutical composition of claim 10, in the manufacture of a medicament for selectively delivering a compound to bone, in a subject in need thereof.
14. The use of claim 13 wherein the bone is a bone in need of treatment.
15. The use of claim 14 wherein the bone in need of treatment is selected from the group consisting of a green stick fracture, compound fracture, lateral fracture, pathologic fracture resulting from an invasive tumor, compression fracture, and fracture requiring a surgical procedure for realignment of a bone.
16. The use of any one of claims 11 to 15 wherein the compound binds to bone.
17. The use of any one of claims 11 to 16 wherein the compound is hydrolyzed after binding to bone, is inactive prior to hydrolyzation or releases an active agent after hydrolyzation.
18. The use of any one of claims 11 to 17 wherein the amide bond of the compound is resistant to hydrolysis in vivo.
19. The use of any one of claims 16 to 18 wherein the bisphosphonate moiety remains attached to the bone.
20. A method of preparing a compound in accordance with any one of claims 1 to 8, comprising: i) providing at least one EP4 agonist or related moiety comprising a hydroxyl group, an amide linker comprising at least two carboxylic acid groups, and a bisphosphonate moiety comprising an amino group; ii) reacting one of the carboxylic acid groups of the amide linker with the hydroxyl group of the EP4 agonist or related moiety, to form an ester bond, and iii) reacting the other carboxylic acid of the amide linker group with the amino group of the bisphosphonate to form an amide bond.
21. A method of selectively delivering a compound to bone, the method comprising administering an effective amount of the compound of any one of claims 1 to 8 or the pharmaceutical composition of claim 10 to a non-human subject in need thereof.
22. The method of claim 21 wherein the bone is a bone in need of treatment.
23. The method of claim 22 wherein the bone in need of treatment is selected from the group consisting of a green stick fracture, compound fracture, lateral fracture, pathologic fracture resulting from an invasive tumor, compression fracture, and fracture requiring a surgical procedure for realignment of a bone.
24. A method of treating or preventing a condition associated with abnormal or excessive bone loss, or with abnormal or reduced bone resorption, or with abnormal calcium metabolism, or that would be benefited by administration of an EP4 agonist or related compound, comprising administering an effective amount of the compound of any one of claims 1 to 8, or the pharmaceutical composition of claim 10, to a non-human subject in need thereof.
25. The method of any one of claims 21 to 24 wherein the compound binds to bone.
26. The method of any one of claims 21 to 25 wherein the compound is hydrolyzed after binding to bone, is inactive prior to hydrolyzation or releases an active agent after hydrolyzation.
27. The method of any one of claims 21 to 26 wherein the amide bond of the compound is resistant to hydrolysis in vivo.
28. The method of any one of claims 25 to 27 wherein the bisphosphonate moiety remains attached to the bone.
29. The compound of claim 1 or 4, substantially as herein described with reference to any one of the Examples and/or
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562175118P | 2015-06-12 | 2015-06-12 | |
| PCT/IB2016/053482 WO2016199111A1 (en) | 2015-06-12 | 2016-06-13 | Amide-linked ep4 agonist-bisphosphonate compounds and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ738016A NZ738016A (en) | 2024-10-25 |
| NZ738016B2 true NZ738016B2 (en) | 2025-01-28 |
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