CONTROL RELEASE OF BIOLOGICALLY ACTIVE COMPOUNDS FROM MULTI-ARMED OLIGOMERS

• US 20090076174A1
• Filed: 09/03/2008
• Published: 03/19/2009
• Est. Priority Date: 09/04/2007
• Status: Active Grant

• Current Assignee: Bezwada Biomedical, LLC
• Original Assignee: Bezwada Biomedical, LLC
• Inventors: Bezwada, Rao S.
• Granted Patent: US 8,026,285 B2
• Time in Patent Office: Days
• US Class Current: 514/772.300
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/552 one of the codrug's components being an antibiotic
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 39/02 Antidotes

Abstract

The present invention relates to the discovery of biodegradable multi-armed oligomers wherein the end groups of these oligomers have been functionalized with biologically active molecules. The resultant multi-armed oligomers end-functionalized with biologically active molecules have a controllable degradation profile. The hydrolytic degradation of oligomers of the present invention releases the biologically active compound as such with no change in native chemical structure.

Claims

1. An oligomer or pharmaceutically acceptable salt thereof of formula I or II:

[R¹—

O—

(Y)_b—

C(O)CH₂—

(X)_a—

OC(O)]_w—

R 

 

I

[R²—

C(O)O—

(X¹)_a—

CH₂C(O)—

(Y¹)_b—

O]_w—

R 

 

II

wherein;

R¹—

O—

is a biologically active compound residue;

R²—

C(═

O)O—

is a biologically active compound residue;

X is selected from;

—

OC(═

O)CH₂—

(inverse glycolic acid moiety), —

OC(═

O)CH(CH₃)—

(inverse lactic acid moiety), —

OC(═

O)CH₂OCH₂CH₂—

(inverse dioxanone acid moiety), —

OC(═

O)CH₂CH₂CH₂CH₂CH₂—

(inverse caprolactone acid moiety), —

OC(═

O)(CH₂)_y—

, or —

OC(═

O)CH₂(OCH₂CH₂)_z—

.

X¹ is selected from;

—

CH₂C(═

O)O—

(glycolic acid moiety), —

CH(CH₃)C(═

O)O—

(lactic acid moiety), —

CH₂CH₂OCH₂C(═

O)O—

(dioxanone acid moiety), —

CH₂CH₂CH₂CH₂CH₂C(═

O)O—

(caprolactone acid moiety), —

(CH₂)_yC(═

O)O—

, or —

(CH₂CH₂O)_nCH₂C(═

O)O—

;

Y is selected from;

—

C(═

O)CH₂O—

(glycolic ester moiety), —

C(═

O)CH(CH₃)O—

(lactic ester moiety), —

C(═

O)CH₂OCH₂CH₂O—

(dioxanone ester moiety), —

C(═

O)CH₂CH₂CH₂CH₂CH₂O—

(caprolactone ester moiety), —

C(═

O)(CH₂)_mO—

, or —

C(═

O)CH₂—

O—

(CH₂CH₂O)_n—

;

Y¹ is selected from;

—

OCH₂C(═

O)—

(inverse glycolic ester moiety), —

OCH(CH₃)C(═

O)—

(inverse lactic ester moiety), —

OCH₂CH₂OCH₂C(═

O)—

(inverse dioxanone ester moiety), —

OCH₂CH₂CH₂CH₂CH₂C(═

O)—

(inverse caprolactone ester moiety), —

O(CH₂)_mC(═

O)—

, or —

O(CH₂CH₂O)_nOCH₂C(═

O)—

;

R is a di-, tri, tetra-, penta- or hexaradical derived from C_2-25 alkyl, aryl, or aryl-(C_1-6alkyl)_1-3-, wherein from 1-3 of the CH₂ groups within the alkyl chain are optionally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH₂ groups within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom;

or R is the backbone of a polymer or copolymer bearing carboxylic acid and/or hydroxyl functional groups, where the average molecular weight of the polymer or copolymer is between 500 to 5000 and wherein w is an integer from about 6 to about 50;

each a and b is independently an integer from about 1 to about 10;

each m, n, y, and z is independently an integer from about 2 to about 24; and

w is an integer from about 2 to about 6.

2. An oligomer of claim 1, wherein:

R is a di-, tri, tetra-, penta- or hexaradical derived from C_2-12alkyl, phenyl, or phenyl-(C_1-6alkyl)_1-3-, wherein from 1-3 of the CH₂ groups within the alkyl chain are optionally independently replaced by O atoms, such that each of said O atom is attached only to carbon atoms in the alkyl chain, with the proviso that multiple O atoms that replace CH₂ groups within the alkyl chain must be separated from each other by at least two carbon atoms and from the di-, tri, tetra-, penta- or hexaradical chain ends by at least one carbon atom;

each a and b is independently an integer from about 1 to about 5; and

w is an integer from about 2 to about 4.

3. An oligomer of claim 1, wherein:

R—

[O]_w is O(CH₂)₂O, O(CH₂)₃O, CH(CH₂O)₃, C(CH₂O)₄, or C(CH₂CH₃)(CH₂OH)₃.

4. An oligomer of claim 1, wherein:

each X is independently —

OC(═

O)CH₂—

, —

OC(═

O)CH(CH₃)—

, —

OC(═

O)CH₂OCH₂CH₂—

, or —

OC(═

O)CH₂CH₂CH₂CH₂CH₂—

.

each X¹ is independently —

CH₂COO—

;

—

CH(CH₃)COO—

;

—

CH₂CH₂OCH₂COO—

;

or —

CH₂CH₂CH₂CH₂CH₂COO—

.

each Y is independently —

COCH₂O—

;

—

COCH(CH₃)O—

;

—

COCH₂OCH₂CH₂O—

;

or —

COCH₂CH₂CH₂CH₂CH₂O—

. and

each Y¹ is independently —

OCH₂CO—

;

—

OCH(CH₃)CO—

;

—

OCH₂CH₂OCH₂CO—

;

or —

OCH₂CH₂CH₂CH₂CH₂CO—

.

5. An oligomer of claim 4, wherein:

X is independently —

OCOCH₂— and

—

OCOCH(CH₃)—

;

each X¹ is independently —

CH₂COO— and

—

CH(CH₃)COO—

;

each Y is independently —

COCH₂O— and

—

COCH(CH₃)O—

; and

,

each Y¹ is independently —

OCH₂CO— and

—

OCH(CH₃)CO—

.

6. An oligomer of claim 1, wherein R¹—

O—

is selected from acenocoumarol, acetarsol, actinoquinol, adrenalone, alibendol, amodiaquine, anethole, balsalazide, bamethan, benserazide, bentiromide, benzarone, benzquinamide, bevantolol, bifluranol, buclosamide, bupheniode, chlorotrianisene, chloroxylenol, cianidanol, cinepazide, cinitapride, cinepazide, cinmetacin, clebopride, clemastine, clioquinol, cyclovalone, cynarine, denopamine, dextroythyroxine, diacerein, dichlorophen, dienestrol, diethylstilbestrol, diflunisal, diiodohydroxyquinoline, dilazep, dilevalol, dimestrol, dimoxyline, diosmin, dithranol, dobutamine, donepezil, dopamine, dopexamine, doxazosin, entacapone, epanolol, epimestrol, epinephrine, estradiol valerate, estriol, estriol succinate, estrone, etamivan, etamsylate, ethaverine, ethoxzolamide, ethyl biscoum-acetate, etilefrine, etiroxate, exalamide, exifone, fendosal, fenoldopam mesilate, fenoterol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, folescutol, formo-terol, gallopamil, gentistic acid, glaziovine, glibenclamide, glucametacin, guajacol, halquinol, hexachlorophene, hexestrol, hexobendine, hexoprenaline, hexylresorcinol, hydroxyethyl salicylate, hydroxystilbamidine isethionate, hymecromone, ifenprodil, indomethacin, ipriflavone, isoetarine, isoprenaline, isoxsuprine, itopride hydrochlor-ide, ketobemidone, khellin, labetalol, lactylphenetidin, levodopa. levomepromazine, levorphanol, levothyroxine, mebeverine, medrylamine, mefexamide, mepacrine, mesalazine, mestranol, metaraminol, methocarbamol, methoxamine, methoxsalen, methyldopa, midodrine, mitoxantrone, morclofone, nabumetone, naproxen, nitroxo-line, norfenefrine, normolaxol, octopamine, omeprazole, orciprenaline, oxilofrine, oxitriptan, oxyfedrine, oxypertine, oxyphenbutazone, oxyphenisatin acetate, oxyquin-oline, papaverine, paracetanol, parethoxycaine, phenacaine, phenacetin, phenazocine, phenolphthalein, phenprocoumon, phentolamine, phloedrine, picotamide, pimoben-dan, prenalterol, primaquine, progabide, propanidid, protokylol, proxymetacaine, raloxifene hydrochloride, repaglinide, reproterol, rimiterol, ritodrine, salacetamide, salazosulfapyridine, salbutamol, salicylamide, salicylic acid, salmeterol, salsalate, sildenafil, silibinin, sulmetozin, tamsulosin, terazosin, terbutaline, tetroxoprim, theo-drenaline, tioclomarol, tioxolone, α

-tocopherol (vitamin E), tofisopam, tolcapone, tolterodine, tranilast, tretoquinol, triclosan, trimazosin, trimetazidine, trimethobenz-amide, trimethoprim, trimetozine, trimetrexate glucuronate, troxipide, verapamil, vesnarinone, vetrabutine, viloxazine, warfarin, and xamoterol.

7. An oligomer of claim 6, wherein R¹—

O—

is;

8. An oligomer of claim 1, wherein R²—

C(═

O)O—

is selected from Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, Alminoprofen, Amlexanox, Anileridine, Baccofen, Balsalazide sodium, Bentiromide, Benzocaine, Bumetanide, Carprofen, Carzenide, Cinmetacin, Clometacin, Cromoglicic acid, Diclofenac, Diflunisal, Eprosartan, Fendosal, Flufenamic acid, Furosemide, Indometacin, lobenzamic acid, locarmic acid, locetamic acid, Iodoxamic acid, loglycamic acid, lophenoic acid, lotroxic cid, Mefenamic acid, Naproxen, Nedocromil, Repaglinide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Sarpogrelate.

9. An oligomer of claim 1, wherein R²—

C(═

O)O—

is;

10. An oligomer of claim 1, wherein R¹—

O—

is selected from capsaicin, coumarins, furanocoumarins, alkaloids, catechins, chromones, chalcones, flavonoids or bioflavonoids, isoflavones, resveratrol, and sinapic acid.

11. An oligomer of claim 1, wherein R¹—

O—

is selected from 4-hydroxycinnamic acid, caffeic acid, chlorogenic acid, ferulic acid, capsaicin, 4-hydroxycoumarin, psoralen, bergapten, bergaptol, xanthotoxin, isopimpinellin.

12. An oligomer of claim 1, wherein —

OC(═

O)]_w—

R is;

wherein each carboxylic acid proton (H) present in the di- or poly-acid shown is absent in the moiety —

OC(═

O)]_w—

R.

13. An oligomer of claim 1, wherein —

(Y¹)_b—

O]_wR is;

wherein each Q is a bond.

14. An oligomer of claim 1, wherein —

(X)_a—

OC(═

O)]_w—

R is;

wherein each carboxylic acid proton (H) present in the di-acid shown is absent in the moiety. —

(X)_a—

OC(═

O)]_w—

R.

15. An oligomer of claim 1, wherein —

CH₂C(═

O)—

(Y¹)_b—

O]_wR) is;

wherein Q is a bond.

16. An oligomer of claim 1, wherein R¹—

O—

is selected from chalcones, hydroxy-benzoic acid, dihydroxy-benzoic acid, indoles, acetophenones, benzophenones, catechins, flavonoids, coumarins, hydroquinone, naproxen, acetaminophen, and acetylsalicylic acid.

17. A cosmetic composition, comprising at least one compound of claim 1 and a cosmetic ingredient.

18. A pharmaceutical composition, comprising at least one compound of claim 1 and a pharmaceutically acceptable excipient.

19. A pharmaceutical composition of claim 18, wherein the composition is suitable for administration via a route selected from oral, enteral, parenteral, topical, transdermal, ocular, vitreal, rectal, nasal, pulmonary, and vaginal.

20. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a cancer preventing phenolic.

21. A pharmaceutical composition of claim 20, further comprising:

an anti-cancer agent.

22. A pharmaceutical composition of claim 18, wherein the phenolic residue of formula I or II is derived from a phenolic compound with antimicrobial properties.

23. A pharmaceutical composition of claim 22, further comprising:

an antimicrobial agent.

24. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with anti-inflammatory properties.

25. A pharmaceutical composition of claim 24, further comprising:

anti-inflammatory agent.

26. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with pain-reducing properties.

27. A pharmaceutical composition of claim 26, further comprising:

a pain reducing agent.

28. A pharmaceutical composition of claim 18, wherein the phenolic residue in the compound of formula I was derived from a phenolic with antioxidant properties.

29. A pharmaceutical composition of claim 28, further comprising:

an antioxidant agent.

30. A suture coating, comprising:

at least one oligomer of claim 1.

31. An antimicrobial agent, comprising:

at least one oligomer of claim 1.

32. A therapeutic method for treating a disease in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

33. A therapeutic method for producing an analgesic effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

34. A therapeutic method for treating cancer in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

35. A therapeutic method for producing an anti-inflammatory effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

36. A therapeutic method for producing an anti-bacterial effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

37. A therapeutic method for producing an anti-fungal effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

38. A therapeutic method for producing an immunosuppressive effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

39. A therapeutic method for producing an anti-thrombotic effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

40. A therapeutic method for treating psoriasis, inflammatory bowel disease, skin cancer, or a brain tumor in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

41. A therapeutic method for producing an anti-infective effect in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.

43. A therapeutic method for treating pain in a patient, comprising:

administering to a patient in need of such therapy, an effective amount of at least one oligomer of claim 1.