Chemically modified small molecules

• US 20050136031A1
• Filed: 12/16/2004
• Published: 06/23/2005
• Est. Priority Date: 12/16/2003
• Status: Active Grant

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Zhao, Xuan, Bentley, Michael D., Cheng, Lin, Goodin, Richard R., Viegas, Tacey X.
• Granted Patent: US 7,786,133 B2
• Time in Patent Office: Days
• US Class Current: 424/78.270
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/36 Opioid-abuse
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08G 65/332 containing carboxyl groups, or halides, or esters thereof
• CPC Class Codes: C08G 65/33317 heterocyclic
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08G 65/337 containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

The invention provides small molecule drugs that are chemically modified by covalent attachment of a water-soluble oligomer obtained from a monodisperse or bimodal water-soluble oligomer composition. A conjugate of the invention, when administered by any of a number of administration routes, exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer.

Claims

1. A composition comprising monodisperse or bimodal conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer, wherein said conjugate exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer.

2. The composition of claim 1, wherein the conjugate comprises the structure O-X-D, wherein O corresponds to the water-soluble oligomer, X corresponds to the stable linkage, and D corresponds to the moiety derived from the small molecule drug.

3. The composition of claim 2, wherein the biological membrane is associated with barriers selected from the group consisting of the blood-brain barrier, the blood-cerebrospinal fluid barrier, the blood-placental barrier, and the blood-milk barrier.

4. The composition of claim 3, wherein the biological membrane is associated with the blood-brain barrier.

5. The composition of claim 3 or claim 4, wherein the conjugate exhibits a biological membrane crossing rate that is reduced by at least 20% as compared to the biological membrane crossing rate of the small molecule drug.

6. The composition of claim 3 or claim 4, wherein the conjugate exhibits a biological membrane crossing rate that is reduced by at least 70% as compared to the biological membrane crossing rate of the small molecule drug.

7. The composition of claim 1, wherein the small molecule drug is orally bioavailable.

8. The composition of claim 1 or claim 7, wherein the conjugate possesses an oral bioavailability that is at least 10% of the oral bioavailability of the small molecule drug.

9. The composition of claim 1 or claim 7, wherein the conjugate possess an oral bioavailability that is at least 50% of the oral bioavailability of the small molecule drug.

10. The composition of claim 1 or claim 7, wherein the conjugate, when administered orally, exhibits a reduction in first-pass metabolism when compared to the small molecule drug.

11. The composition of claim 1, wherein the conjugate possesses a molecular weight between about 300 and 1800 Daltons.

12. The composition of claim 1, wherein the small molecule drug possesses a molecular weight of less than about 750 Daltons.

13. The composition of claim 1, wherein the small molecule drug is a non-opioid antagonist.

14. The composition of claim 1, wherein the water-soluble oligomer is composed of monomers selected from the group consisting of alkylene oxide, olefinic alcohol, vinylpyrrolidone, hydroxyalkylmethacrylamide, hydroxyalkylmethacrylate, saccharide, α

-hydroxy acid, phosphazene, oxazoline, amino acids, and N-acryloylmorpholine.

15. The composition of claim 1, wherein the water-soluble oligomer is composed of ethylene oxide monomer subunits.

16. The composition of any one of claims 14 and 15, wherein the oligomer has a number of monomers of between 3 and 15.

17. The composition of claim 1, wherein the conjugates are monodisperse.

18. The composition of claim 1, wherein the conjuguates are bimodal.

19. The composition of any one of claims 1, 2, 3, 4, 7, 11, 12, 13, 14, 15, 17 and 18, wherein the conjugate has a single water-soluble oligomer covalently attached to the moiety derived from a small molecule drug.

20. The composition of any one of claims 1, 2, 3, 4, 7, 11, 12, 13, 14, 15, 17 and 18, wherein the stable linkage is selected from the group consisting of ether, amide, urethane, amine, thioether, ether, urea, and a carbon-carbon bond.

21. The composition of any one of claims 1, 2, 3, 4, 7, 11, 12, 13, 14, 15, 17 and 18, wherein the conjugates comprise a mixture of stereoisomers.

22. The composition of any one of claims 1, 2, 3, 4, 7, 11, 12, 13, 14, 15, 17 and 18, wherein the conjugates are a single stereoisomer.

23. A pharmaceutical composition comprising:

(i) monodisperse or bimodal conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer, wherein said conjugate exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer; and

(ii) a pharmaceutically acceptable excipient.

24. The pharmaceutical composition of claim 23, in an oral dosage form.

25. A method comprising the step of administering a composition comprised of monodisperse or bimodal conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer, wherein said conjugate exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer.

26. The method of claim 25, wherein the administering step is selected from the group consisting of oral administration, transdermal administration, buccal administration, transmucosal administration, vaginal administration, rectal administration, parenteral administration, and pulmonary administration.

27. A method for optimizing the selective biological membrane crossing of a small molecule drug, said method comprising the step of conjugating a water-soluble oligomer from a monodisperse or bimodal composition of the oligomer to a small molecule drug via a stable covalent linkage, to thereby form a conjugate that exhibits a biological membrane crossing rate that is reduced when compared to the biological membrane crossing rate of the small molecule drug prior to said conjugating.

28. A method for optimizing the biological membrane crossing of a small molecule drug, said method comprising the steps of:

(a) preparing a series of monodisperse or biomodal conjugates, each conjugate in the series comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer, wherein each conjugate in the series differs only in size of the oligomer as based on the number of monomers in the oligomer;

(b) characterizing, for each conjugate in the series prepared in step (a), the extent to which the conjugate does not cross the biological membrane; and

(c) based upon the results from (b), identifying the conjugate from the series of conjugates prepared in step (a) that possesses the optimal reduction in biological membrane crossing.

29. The method of claim 28, further comprising the steps of

characterizing for each conjugate in the series prepared in step (a), the extent of oral bioavailability and identifying the conjugate that possesses the optimal balance between reduction in biological membrane crossing and bioavailability.

30. The method of claim 28, further comprising the steps of

characterizing for each conjugate in the series prepared in step (a), the extent of bioactivity and identifying the conjugate that possesses the optimal balance between reduction in biological membrane crossing and bioactivity.

31. A method for preparing a conjugate, said method comprising the step of covalently attaching a water-soluble oligomer obtained from a monodisperse or bimodal water-soluble oligomer composition to a small molecule drug to provide a conjugate comprised of a stable linkage connecting the oligomer to the moiety derived from the small molecule drug.

32. The method of claim 31, wherein the stable linkage is hydrolytically stable.

33. The method of claim 31, wherein said linkage is enzymatically stable.

34. The method of any one of claims 31, 32 and 33, wherein the attaching step comprises reacting, in one or more synthetic steps, the oligomer having a reactive group, A, with a small molecule comprising a reactive group, B, suitable for reaction with A, under conditions effective to form a stable linkage resulting from reaction of A with B.

35. The method of claim 34, wherein the conjugate comprises a mixture of isomers.

36. The method of claim 35, further comprising the step of separating the mixture of isomers to obtain a substantially pure composition of a single conjugate isomer.

37. A method of preparing a monodisperse oligo(ethylene glycol) reagent composition, said method comprising the step of reacting a halo-terminated oligo(ethylene glycol) having (m) monomer subunits with a hydroxyl-terminated oligo(ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo(ethylene glycol) having (m)+(n) monomer subunits (OEG_m+n), where (m) and (n) each independently range from 1-10.

38. The method of claim 37, wherein (m) ranges from 1-3 and (n) ranges from 2-6.

39. The method of claim 37, wherein the reacting step is carried out in the presence of a strong base.

40. The method of any one of claims 37, 38 and 39, wherein the halo-terminated oligo(ethylene glycol) comprises an end-capping group.

41. The method of claim 37, wherein the hydroxyl-terminated oligo(ethylene glycol) corresponds to the structure:

HO—

(CH₂CH₂O)_n—

H.

42. The method of claim 41, further comprising the step of converting the terminal hydroxyl group of OEG_m+n into a halo group, —

X, to form OEG_m+n-X.

43. The method of claim 42, further comprising the step of reacting OEG_m+n-X with a second hydroxyl-terminated oligo(ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo(ethylene glycol) having (m)+2(n) monomer subunits (OEG_m+2n), where (m) and (n) each independently range from 1-10.

44. The method of claim 43, wherein said second hydroxyl-terminated oligo(ethylene glycol) corresponds to the structure HO—

(CH₂CH₂O)_n—

H.

45. The method of claim 44, wherein (OEG_m+2n) corresponds to the structure CH₃O(CH₂CH₂O)_m+2nH, and is present as part of a monodisperse composition of CH₃O(CH₂CH₂O)_m+2nH.

46. The method of claim 43, wherein OEG_m+2n possesses a primary or secondary hydroxyl group.

47. The method of claim 46, further comprising the step of converting said primary or secondary hydroxyl group into a halo group, —

X, to form OEG_m+2n-X.

48. The method of claim 47, further comprising the step of reacting OEG_m+2n-X with a third hydroxyl-terminated oligo(ethylene glycol) having (n) monomer subunits under conditions effective to displace said halo group to thereby form an oligo(ethylene glycol) having m+3n monomer subunits (OEG_m+3n), where (m) and (n) each independently range from 1-10.

49. The method of claim 48, wherein (OEG_m+3n) corresponds to the structure CH₃O(CH₂CH₂O)_m+3nH, and is present as a monodisperse composition of CH₃O(CH₂CH₂O)_m+3nH.

50. A method for reducing the metabolism of an active agent, the method comprising the steps of:

providing monodisperse or bimodal conjugates, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble oligomer, wherein said conjugate exhibits a reduced rate of metabolism as compared to the rate of metabolism of the small molecule drug not attached to the water-soluble oligomer; and

administering said conjugate to a patient.

51. The method of claim 50, wherein said administering step is carried out via one type of administration selected from the group consisting of oral administration, transdermal administration, buccal administration, transmucosal administration, vaginal administration, rectal administration, parenteral administration, and pulmonary administration.

52. The method of claim 51, wherein the small molecule drug is metabolized by a hepatic enzyme.

53. The method of claim 52, wherein the hepatic enzymes comprise one or more cytochrome P450 isoforms.

54. The method of claim 51, wherein the administering step is carried out via oral administration.

55. The method of claim 54, wherein the small molecule drug is metabolized by one or more intestinal enzymes.