Processable compositions and use for the same
AssigneeRipple Therapeutics Corporation
InventorsIan Charles PARRAG, Matthew Alexander John STATHAM, Kyle Giovanni BATTISTON, Wendy Alison NAIMARK, Jonathan DAY, Emily BALDWIN
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds having the formula D1-L-D2, wherein D1 is a processable group, L is a linker, and D2 is a drug. Also described herein are pharmaceutical compositions comprising said compounds and methods for the treatment of ocular diseases or disorders including glaucoma, ocular hypertension, ocular inflammation, diabetic macular edema, posterior inflammation, anterior inflammation, macular degeneration, post-cataract surgery and retinal vein occlusion.
Claims154
A compound comprising a first radical and a second radical, the first radical has a structure represented by Formula (I′):
- wherein:
- is a single bond or a double bond;
- each Ra, Rb, and Rc are independently selected the group consisting of oxo, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
- or any one of Ra, Rb, or Rc are taken together with another of Ra, Rb, or Rc to form a substituted or an unsubstituted cycloalkyl or heterocycloalkyl;
- X11, X12, X13, and X14 are each independently selected from the group consisting of a bond and Qy, wherein each Q is independently selected from the group consisting of —O—, —NR—, —S(R)x—, and —C(R)z—;
- each x is independently 0-5;
- each y is independently 1-3;
- each z is independently 1 or 2;
- each R is independently selected from the group consisting of H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, hydroxy, and thiol, or is taken together with another R to form an oxo;
- and
- each of m, n, and o are independently 0-6;
- the second radical being a therapeutically active agent (or drug) (e.g., in its free form) and the first radical (e.g., a radical of a carrier) being different than the second radical;
- the first radical and the second radical being attached to a linker (e.g., that links the first radical and the second radical);
- wherein, either the first radical, the second radical, or both the first radical and the second radical is not a steroid,
- or a pharmaceutically-acceptable salt or solvate thereof.
A compound having a structure represented by Formula (I):
- D1-L-D2 Formula (I);
- wherein:
- D1 is a radical of a carrier (e.g., a radical of an inactive agent (e.g., a non-medicinal agent (e.g., an agent that (in its free form) does not provide a (e.g., significant, measurable, and/or direct) therapeutic effect and/or benefit (e.g., to an individual (e.g., in need thereof)));
- D2 is a radical of an active agent (e.g., a therapeutically active agent) (or drug);
- L is -(Q1-M-Q2)-;
- Q1 and Q2 are each independently absent or (C═X1)X2;
- X1 is O or S;
- X2 is O, S, or NR1;
- R1 is hydrogen or C1-C6 alkyl;
- and
- M comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl),
- wherein, either the first radical, the second radical, or both the first radical and the second radical is not a steroid,
- or a pharmaceutically-acceptable salt or solvate thereof.
The compound of any one of the preceding claims, wherein the first radical or D1 is a radical of a natural compound (e.g., naturally occurring in nature or in the body).
The compound of any one of the preceding claims, wherein the first radical or D1 comprises a three-ring core structure (e.g., having a structure represented by Formula (I′)), wherein the three-ring core structure is a processable carrier group).
The compound of any one of the preceding claims, wherein the first radical or D1 and the second radical or D2 comprises a three-ring core structure (e.g., having a structure represented by Formula (I′))).
The compound of any one of the preceding claims, wherein the first radical or D1 is a radical of any compound provided in Table 1 or Table 2.
The compound of any one of the preceding claims, wherein the first radical or D1 is a radical of a steroid (e.g., an anti-inflammatory steroid (e.g., dexamethasone, hydrocortisone, or triamcinolone), an angiostatic steroid (e.g., anecortave), or a benign steroid (e.g., cholesterol, cholic acid, or deoxycholic acid)).
The compound of any one of the preceding claims, wherein the first radical or D1 is a radical of a compound selected from the group consisting of ursolic acid, amyrin, isoarborinol, boswellic acid, chamaecydin, cucurbalsaminol A, cycloartenol, lanosterol, dichapetalin, oleanolic acid, lepidolide, panaxatriol, riboflavin (vitamin B2), santonic acid, tetrahydrocannabiorcol, plicadin, annonamine, boldine, pukatiene, and (−)-stepholidine.
The compound of any one of the preceding claims, wherein the second radical or D2 is a radical of:
- an angiotensin-converting-enzyme (ACE) inhibitor (e.g., enalapril, captopril, cilazapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, zofenopril, or the like), an immunosuppressant (e.g., everolimus, tacrolimus, or the like), an angiotensin II receptor blocker (e.g., candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, azilsartan, or the like), an atypical antipsychotic (e.g., paliperidone or the like), a human immunodeficiency virus (HIV) integrase inhibitor (e.g., dolutegravir or the like), a tyrosine kinase inhibitor (e.g., axitinib or the like), a beta-3-adrenergic agonist (e.g., mirabegron or the like), a 1,3-benzoxazole (e.g., tafamidis or the like), a statin (rosuvastatin, simvastatin, or the like), a vasopressin receptor antagonist (e.g., tolvaptan or the like), an antineoplastic (e.g., belzutifan, dichapetalin, or the like), a dopamine agonist (e.g., rotigotine or the like), an acetyl cholinesterase inhibitor (e.g., donepezil, galantamine, or the like), an anti-epileptic (e.g., valproic acid or the like), an opioid agonist (e.g., oxycodone, hydrocodone, or the like), an opioid antagonist (e.g., naltrexone, naloxone, nalmefene, or the like), an antimuscarinic (e.g., fesoterodine, tolterodine, or the like), an anticholinergic (e.g., darifenacin or the like), a vasodilator (e.g., treprostinil or the like), an anti-arrhythmic (e.g., propafenone or the like), an nonsteroidal anti-inflammatory drug (NSAID) (e.g., naproxen, bromfenac, celecoxib, indomethacin, or the like), an antidepressant (e.g., paroxetine, bupropion, noritriptyline, or the like), a vitamin (e.g., a vitamin D3 (e.g., calcifediol or the like)), an antihistamine (e.g., cetirizine, desloratadine, or the like), a triterpenoid topoisomerase inhibitor (e.g., betulinic acid or the like), a triterpenoid (e.g., acetoxolone or the like), a mineralocorticoid (e.g., fludrocortisone or the like), nicotinic acetylcholine receptor agonist (e.g., varenicline or the like), a fatty acid synthase (FAS) inhibitor (e.g., bicycol or the like), a carbonic anhydrase inhibitor (e.g., dorzolamide or the like), an alpha-adrenergic agonist (e.g., brimonidine), a sympathomimetic (e.g., epinephrine), a Rho-associated kinase (ROCK) inhibitor (e.g., fasudil, hydroxyfasudil, ripasudil, netarsudil, belumosudil, verosudil, or thiazovivin), a prostaglandin (e.g., latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, or bimatoprost acid), or any combination thereof.
The compound of any one of the preceding claims, wherein the second radical or D2 is a radical of:
- a nonsteroidal anti-inflammatory drug (NSAID) (e.g., naproxen, bromfenac, celecoxib, indomethacin, or the like), a tyrosine kinase inhibitor (e.g., axitinib or the like), a statin (e.g., rosuvastatin, simvastatin, or the like), an antineoplastic (e.g., belzutifan, dichapetalin, fluorouracil, or the like), or any combination thereof.
The compound of any one of the preceding claims, wherein the second radical or D2 is a radical of a steroid (e.g., an anti-inflammatory steroid (e.g., dexamethasone, hydrocortisone, or triamcinolone) or an angiostatic steroid (e.g., anecortave)).
The compound of any one of the preceding claims, wherein the second radical or D2 is a radical of a prostaglandin (e.g., latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, or bimatoprost acid).
The compound of any one of the preceding claims, wherein the second radical or D2 is a radical of any therapeutic agent (or drug) provided herein (e.g., any therapeutic agent (or drug) provided in Table 2).
The compound of any one of the preceding claims, wherein the linker (e.g., L) is or comprises (e.g., a diradical (e.g., a molecular species (e.g., an organic compound) with two electrons occupying degenerate molecular orbitals) of) one or more linker groups, each linker group being independently selected from any linker or linker group provided herein (e.g., any linker or linker group provided in Table 3).
The compound of any one of the preceding claims, wherein the first radical or D1 is a radical of any carrier provided herein (e.g., any carrier provided in Table 1 or Table 2), the second radical or D2 is a radical of any therapeutic agent (or drug) provided herein (e.g., any therapeutic agent (or drug) provided in Table 2), and the linker (e.g., L) is or comprises (e.g., a diradical (e.g., a molecular species (e.g., an organic compound) with two electrons occupying degenerate molecular orbitals) of) one or more linker groups, each linker group being independently selected from any linker or linker group provided herein (e.g., any linker or linker group provided in Table 3).
A compound comprising a structure of Formula (IE):
- wherein:
- is a single bond or a double bond;
- R7 is hydrogen or halogen;
- R8 is hydrogen or C1-C4 alkyl;
- R9 is absent, hydrogen, or hydroxyl;
- R15 is absent, hydrogen, or halogen;
- R16 is hydrogen or hydroxyl;
- D2 is a radical of an active agent (e.g., a therapeutically active agent) (or drug);
- L is -(Q1-M-Q2)-;
- Q1 and Q2 are each independently absent or (C═X1)X2;
- X1 is O or S;
- X2 is O, S, or NR1;
- R1 is hydrogen or C1-C6 alkyl;
- and
- M comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl);
- wherein D2 is not a steroid;
- or a pharmaceutically acceptable salt or solvate thereof.
The compound of any one of the preceding claims, wherein R7 is hydrogen.
The compound of any one of the preceding claims, wherein R8 is methyl.
The compound of any one of the preceding claims, wherein R9 is hydroxyl.
The compound of any one of the preceding claims, wherein R15 is fluoro.
The compound of any one of the preceding claims, wherein R16 is hydroxyl.
A compound comprising a first radical and a second radical, the first radical comprising a structure of Formula (IF):
- wherein:
- is a single bond or a double bond;
- each Ra is independently selected the group consisting of hydrogen, halogen, —CN, —NO2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
- or a first Ra is taken together with another Ra to form oxo, a substituted or an unsubstituted cycloalkyl or heterocycloalkyl;
- each R1 is independently H, alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted;
- R17 is H or —OH;
- p is 0-8;
- and
- q is 1 or 2;
- D2 is a radical of an active agent (e.g., a therapeutically active agent) (or drug);
- L is -(Q1-M-Q2)-;
- Q1 and Q2 are each independently absent or (C═X1)X2;
- X1 is O or S;
- X2 is O, S, or NR1;
- R1 is hydrogen or C1-C6 alkyl;
- and
- M comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl);
- wherein D2 is not an opioid;
- or a pharmaceutically acceptable salt or solvate thereof.
The compound of any one of the preceding claims, wherein Q1 and Q2 are each independently absent, C═O, C=S, (C═O)O, (C═O)S, (C═O)N, or (C═S)S.
The compound of any one of the preceding claims, wherein Q1 and Q2 are each independently absent, C═O, or (C═O)O.
The compound of any one of the preceding claims, wherein M is substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl), or substituted or unsubstituted aryl.
The compound of any one of the preceding claims, wherein M is substituted or unsubstituted alkyl (e.g., C1-C6 alkyl (e.g., alkyl-carbocyclyl-alkyl)) or substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl).
The compound of any one of the preceding claims, wherein L is —(CH2CH2O)—, —(CH2CH2O)2—(CH2CH2O)3—, -methyl-cyclohexyl-methyl-, —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, or —CH2CH2CH2CH2CH2CH2—.
The compound of any one of the preceding claims, wherein the compound does not have the structure:
A compound having a structure represented by Formula (ID):
- D1-L-D2 Formula (ID);
- wherein:
- D1 is a steroid radical;
- D2 is a prostaglandin radical;
- L is -(Q1-M-Q2)-;
- Q1 and Q2 are each independently absent or (C═X1)X2;
- X1 is O or S;
- X2 is O, S, or NR1;
- R1 is hydrogen or C1-C6 alkyl;
- and
- M comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl),
- or a pharmaceutically-acceptable salt or solvate thereof.
The compound of any one of the preceding claims, wherein D1 is anecortave (e.g., anecortave desacetate).
A compound having a structure represented by Formula (II):
- or a pharmaceutically acceptable salt or solvate thereof,
- wherein,
- D2 is a prostaglandin radical;
- L1 is -(Q1-M-Q2)-;
- Q1 and Q2 are each independently absent or (C═X1)X2;
- X1 is O or S;
- X2 is O, S, or NR1;
- R1 is hydrogen or C1-C6 alkyl;
- and
- M comprises one or more linker group, each linker group being independently selected from the group consisting of substituted or unsubstituted alkyl (e.g., C1—C6 alkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl).
The compound of any one of the preceding claims, wherein D2 is selected from the group consisting of latanoprost, latanoprost acid, travoprost, travoprost acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, sepetaprost acid, 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl ester, 5Z-heptenoic acid, latanoprostene bunod, and (S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-en-1-yl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate, or a fragment or radical of any of the foregoing.
The compound of any one of the preceding claims, wherein D2 is a radical represented by a structure of Formula (III):
- wherein:
- each is independently a single bond or a double bond;
- G is OH;
- Y1 is hydrogen;
- or G is taken together with Y1 to form —O—CH2—;
- Y2 is a bond or alkylene (e.g., —CH2—);
- g is 1 or 2;
- Z is —O— or alkylene (e.g., —CH2—);
- R6 and R6′ are each independently hydrogen, halogen, alkyl, —OR14, or R6 and R6′ are taken together to form an oxo (e.g., R6 and R6′ are each independently hydrogen, halogen, or OH);
- R14 is hydrogen, unsubstituted or substituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl (e.g., alkyl substituted with NO2 or alkyl substituted with oxo and ONO2)), or a point of attachment to the linker (e.g., L1);
- R11 is —OR13 or —NR13R13b;
- R13, R13a, and R13b are each independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl (e.g., alkyl substituted with NO2 or alkyl substituted with oxo and ONO2)), substituted or unsubstituted aryl (e.g., aryl substituted with (cyclic) heteroalkyl (e.g., aryl substituted with 3H-1,2-dithiole-3-thione)), or a point of attachment to the linker (e.g., L1);
- each R12 is independently halogen (e.g., fluoro or chloro) or alkyl (e.g., haloalkyl (e.g., CF3));
- and
- u is 0-5.
The compound of any one of the preceding claims, wherein D2 is a radical represented by a structure of Formula (III-A):
- wherein:
- a single bond or a double bond;
- Z is —O— or —CH2—;
- R6 and R6′ are each independently hydrogen, halogen, or —OR14;
- R14 is hydrogen or a point of attachment to the linker (e.g., L1);
- R11 is —OR13 or —NR13aR13b;
- R13, R13a, and R13b are each independently hydrogen, C1-C3 alkyl, or a point of attachment to the linker (e.g., L1);
- each R12 is independently halogen (e.g., fluoro or chloro) or alkyl (e.g., haloalkyl (e.g., CF3));
- and
- u is 0-5.
The compound of any one of the preceding claims, wherein D2 is latanoprost, bimatoprost, travoprost, or an acid or radical thereof.
The compound of any one of the preceding claims, wherein D2 is C1-latanoprost (radical), C15-latanoprost (radical), C1-bimatoprost (radical), C15-bimatoprost (radical), C1-travoprost (radical), or C15-travoprost (radical) (e.g., the carbon atom (e.g., C1 or C15) indicating which carbon atom the hydroxy radical (e.g., R6, R6′, or R11) is attached)).
The compound of any one of the preceding claims, wherein Q1 and Q2 are each independently absent, C═O, C=S, (C═O)O, (C═O)S, (C═O)N, or (C═S)S.
The compound of any one of the preceding claims, wherein Q1 and Q2 are each independently C═O or (C═O)O.
The compound of any one of the preceding claims, wherein Q1 and Q2 are each independently is C═O.
The compound of any one of the preceding claims, wherein Q1 and Q2 are C═O.
The compound of any one of the preceding claims, wherein Q1 is C═O and Q2 is absent.
The compound of any one of the preceding claims, wherein Q1 is absent and Q2 is C═O.
The compound of any one of the preceding claims, wherein Q1 and Q2 are (C═O)O.
The compound of any one of the preceding claims, wherein Q1 is (C═O)O and Q2 is absent.
The compound of any one of the preceding claims, wherein Q1 is absent and Q2 is (C═O)O.
The compound of any one of the preceding claims, wherein Q1 is C═O and Q2 is (C═O)S.
The compound of any one of the preceding claims, wherein Q1 is (C═O)S and Q2 is C═O.
The compound of any one of the preceding claims, wherein Q1 is C═O and Q2 is (C═S)S.
The compound of any one of the preceding claims, wherein Q1 is (C═S)S and Q2 is C═O.
The compound of any one of the preceding claims, wherein Q1 is C═O and Q2 is (C═O)N.
The compound of any one of the preceding claims, wherein Q1 is (C═O)N and Q2 is C═O.
The compound of any one of the preceding claims, wherein M is substituted or unsubstituted alkyl (e.g., C1-C6 alkyl), substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl), or substituted or unsubstituted aryl.
The compound of any one of the preceding claims, wherein M is substituted or unsubstituted alkyl (e.g., C1-C6 alkyl).
The compound of any one of the preceding claims, wherein M is substituted alkyl (e.g., C1-C6 alkyl), the alkyl being substituted with one or more substituent, each substituent being independently selected from the group consisting of oxo, halo, alkyl, and heteroalkyl (e.g., —NHCOCH3).
The compound of any one of the preceding claims, wherein M is alkyl (e.g., C1-C6 alkyl) substituted with oxo.
The compound of any one of the preceding claims, wherein M is alkyl (e.g., C1-C6 alkyl) substituted with one or more —NHCOCH3.
The compound of any one of the preceding claims, wherein M is —CH(NHCOCH3)CH2—.
The compound of any one of the preceding claims, wherein M is unsubstituted alkyl (e.g., C1-C6 alkyl).
The compound of any one of the preceding claims, wherein M is —(CH2)m—, m being 1-10.
The compound of any one of the preceding claims, wherein M is —CH2—, —CH2CH2—, or —CH2CH2CH2—.
The compound of any one of the preceding claims, wherein M is substituted or unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl).
The compound of any one of the preceding claims, wherein M is unsubstituted heteroalkyl (e.g., C1-C6 heteroalkyl).
The compound of any one of the preceding claims, wherein M is —SCH2CH2—.
The compound of any one of the preceding claims, wherein M is substituted or unsubstituted aryl.
The compound of any one of the preceding claims, wherein M is unsubstituted aryl (e.g., unsubstituted phenyl).
The compound of any one of the preceding claims, wherein M is alkyl (e.g., methyl) substituted with oxo and Q1 and Q2 are absent.
The compound of any one of the preceding claims, wherein:
- Q1 and Q2 are (C═O)O;
- and
- M is —CH2CH2CH2—.
The compound of any one of the preceding claims, wherein:
- Q1 and Q2 are C═O;
- and
- M is —CH2CH2— or phenyl.
The compound of any one of the preceding claims, wherein:
- Q1 is C═O and Q2 is absent;
- and
- M is —CH2—, —CH2CH2—, —CHCH3—, or —CH(NHCOCH3)CH2—.
The compound of any one of the preceding claims, wherein:
- Q1 is C═O and Q2 is absent;
- and
- M is —SCH2CH2—.
The compound of any one of the preceding claims, wherein:
- Q1 is C═O and Q2 is S(C═O);
- and
- M is —CH2CH2—.
The compound of any one of the preceding claims, wherein:
- Q1 is C═O and Q2 is S(C═S);
- and
- M is —CH2CH2—.
The compound of any one of the preceding claims, wherein:
- Q1 is C═O and Q2 is N(C═O);
- and
- M is —CH2CH2—.
The compound of any one of the preceding claims, wherein the linker (e.g., L or L1) is C═O, —C═OCH2CH2C═O—, —C═OphenylC═O—, —C═OCH2CH2—, —(C═O)OCH2CH2CH2O(C═O)—, —C═OCH(NHCOCH3)CH2—, —C═OCH2O(C═O)—, —(C═O)OCH2C═O—, —C═OCH(CH3)O(C═O)—, —(C═O)OCH(CH3)C═O—, —C═OCH2CH2S—, —C═OCH2CH2SC═O—, —C═OCH2CH2SC═S—, or —C═OCH2CH2NHC═O—.
The compound of any one of the preceding claims, wherein the linker (e.g., L or L1) is —C═OCH2CH2C═O—, —C═OphenylC═O—, —C═OCH2CH2—, —(C═O)OCH2CH2CH2O(C═O)—, —C═OCH(NHCOCH3)CH2—, —C═OCH2O(C═O)—, —(C═O)OCH2C═O—, —C═OCH(CH3)O(C═O)—, —(C═O)OCH(CH3)C═O—, —C═OCH2CH2S—, —C═OCH2CH2SC═O—, —C═OCH2CH2SC═S—, or —C═OCH2CH2NHC═O—.
The compound of any one of the preceding claims, wherein the compound does not have the structure:
The compound of any one of the preceding claims, wherein the compound is represented by the structure:
- or a pharmaceutically acceptable salt or solvate thereof.
A compound having a structure represented by Formula (IV):
- D1-L2-D2 Formula (IV);
- wherein:
- D1 is a steroid radical;
- D2 is a substituted prostaglandin radical;
- and
- L2 is a linker,
- or a pharmaceutically-acceptable salt or solvate thereof.
The compound of any one of the preceding claims, wherein D1 is anecortave (e.g., anecortave desacetate).
The compound of any one of the preceding claims, wherein D1 is a corticosteroid (e.g., glucocorticoid or mineralcorticoid), a sex steroid, a neurosteroid, an aminosteroid, or a secosteroid.
The compound of any one of the preceding claims, wherein D2 is selected from the group consisting of substituted latanoprost, substituted latanoprost acid, substituted travoprost, substituted travoprost acid, substituted tafluprost, substituted tafluprost acid, substituted bimatoprost, substituted bimatoprost acid, substituted sepetaprost, substituted sepetaprost acid, substituted 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl ester, 5Z-heptenoic acid, substituted latanoprostene bunod, and substituted (S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-en-1-yl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate, or a fragment or radical of any of the foregoing.
The compound of any one of the preceding claims, wherein D2 is substituted latanoprost (e.g., latanoprost substituted with substituted alkyl (e.g., alkyl substituted with one or more alkyl substituent, each alkyl substituent being independently selected from the group consisting of oxo and aryl)), substituted bimatoprost (e.g., bimatoprost substituted with substituted alkyl (e.g., alkyl substituted with one or more alkyl substituent, each alkyl substituent being independently selected from the group consisting of oxo and aryl)), substituted travoprost (e.g., travoprost substituted with substituted alkyl (e.g., alkyl substituted with one or more alkyl substituent, each alkyl substituent being independently selected from the group consisting of oxo and aryl)), or an acid or radical thereof.
The compound of any one of the preceding claims, wherein D2 is substituted C1-latanoprost (radical), substituted C15-latanoprost (radical), substituted C1-bimatoprost (radical), substituted C15-bimatoprost (radical), substituted C1-travoprost (radical), or substituted C15-travoprost (radical) (e.g., the carbon atom (e.g., C1 or C15) indicating which carbon atom the hydroxy radical (e.g., R6, R6′, or R11) is attached)).
The compound of any one of the preceding claims, wherein D2 is C1-bimatoprost (radical) substituted at C15 with substituted alkyl (e.g., alkyl substituted with one or more alkyl substituent, each alkyl substituent being independently selected from the group consisting of oxo and aryl).
The compound of any one of the preceding claims, wherein D2 is C1-bimatoprost (radical) substituted at C15 with alkyl substituted with oxo.
The compound of any one of the preceding claims, wherein D2 is C1-bimatoprost (radical) substituted at C15 with alkyl substituted with oxo and aryl.
The compound of any one of the preceding claims, wherein D2 is C1-bimatoprost (radical) substituted at C9 and C11 with substituted alkyl (e.g., alkyl substituted with oxo), the C9 and C11 being taken together with the substituted alkyl (e.g., to form a substituted heterocyclyl).
The compound of any one of the preceding claims, wherein D2 is C1-bimatoprost (radical) substituted at C9 and C11 with alkyl substituted with oxo, the C9 and C11 being taken together with the alkyl substituted with oxo (e.g., to form a substituted heterocyclyl).
The compound of any one of the preceding claims, wherein D2 is C1-latanoprost (radical) substituted at C15 with substituted alkyl (e.g., alkyl substituted with one or more alkyl substituent, each alkyl substituent being independently selected from the group consisting of oxo and aryl).
The compound of any one of the preceding claims, wherein D2 is C1-latanoprost (radical) substituted at C15 with alkyl substituted with oxo.
The compound of any one of the preceding claims, wherein D2 is C1-latanoprost (radical) substituted at C15 with alkyl substituted with oxo and aryl.
The compound of any one of the preceding claims, wherein D2 is C1-latanoprost (radical) substituted at C9 and C11 with substituted alkyl (e.g., alkyl substituted with oxo), the C9 and C11 being taken together with the substituted alkyl (e.g., to form a substituted heterocyclyl).
The compound of any one of the preceding claims, wherein D2 is C1-latanoprost (radical) substituted at C9 and C11 with alkyl substituted with oxo, the C9 and C11 being taken together with the alkyl substituted with oxo (e.g., to form a substituted heterocyclyl).
A compound represented by the structure:
- or a pharmaceutically acceptable salt or solvate thereof.
A pharmaceutical implant or article comprising a compound of any one of the preceding claims, or a pharmaceutically-acceptable salt thereof.
The pharmaceutical implant or article of any one of the preceding claims, wherein the implant or article comprises at least 50 wt. % (at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, or the like) of the compound or pharmaceutically acceptable salt thereof.
The pharmaceutical implant or article of any one of the preceding claims, wherein the implant or article undergoes surface erosion to release the compound, the first radical (e.g., a steroid radical) (in its free form), D1 (in its free form), D2 (in its free form), and/or the second radical (e.g., a prostaglandin radical) (in its free form).
The pharmaceutical implant or article of any one of the preceding claims, wherein the first radical (D1) (e.g., a steroid radical) and the second radical (D2) (e.g., a prostaglandin radical) are released (in their free form) from the pharmaceutical implant or article at near zero-order in a buffered solution or in vivo.
The pharmaceutical implant or article of any one of the preceding claims, wherein the first radical (D1) (e.g., a steroid radical) and the second radical (D2) (e.g., a prostaglandin radical) are released from the pharmaceutical implant or article (in their free form) at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t10 is greater than or equal to 1/10 of t50.
The pharmaceutical implant or article of any one of the preceding claims, wherein the first radical (D1) (e.g., a steroid radical) and the second radical (D2) (e.g., a prostaglandin radical) are released from the pharmaceutical implant or article (in their free form) at 37° C. in 1% fetal bovine serum (FBS) in phosphate buffered saline (PBS) at a rate such that t10 is greater than or equal to 1/10 of t50.
The implant, article, or composition of any one of the preceding claims, wherein the pharmaceutical composition is suitable for ophthalmic administration, subcutaneous administration, intramuscular, or intraspinal administration.
The implant, article, coatings, or composition of any one of the preceding claims, in a form suitable for ophthalmic administration.
A method of treating a medical indication orabnormality in an individual in need thereof, the method comprising administering to the individual a compound, pharmaceutically acceptable salt, implant, article, coating, or composition of any one of the preceding claims.
A method of treating an ophthalmic disease or disorder in an individual in need thereof, the method comprising administering to the individual a compound, pharmaceutically acceptable salt, implant, article, or composition of any one of the preceding claims.
Dependencies are inferred from the claim text.