Carbinols for the treatment of neuropathic dysfunction

• US 6,825,217 B2
• Filed: 10/16/2002
• Issued: 11/30/2004
• Est. Priority Date: 10/16/2001
• Status: Expired due to Fees

• Current Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Original Assignee: Endo Pharmaceuticals Incorporated (Endo International PLC)
• Inventors: Carliss, Richard, Lee, David A. H.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US10/272,375
• Publication Number:
  US 20030162811A1
• Time in Patent Office: 776 Days
• Field of Search: 514/212, 514/318, 514/326, 514/422, 540/596, 540/597, 540/602, 540/609, 645/193, 645/212, 645/240, 548/517, 548/518, 548/527, 548/574
• US Class Current: 514/326
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/451 having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 29/02 without antiinflammatory effect
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 211/22 : by oxygen atoms
• CPC Class Codes: C07D 223/04 : with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond

Abstract

Compositions and methods are provided for treating neuropathic pain or neuropathic dysfunction that include the administration of an effective amount of a defined carbinol or a pharmaceutically acceptable salt or prodrug thereof.

Claims

1. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

2. The method of claim 1, wherein the compound is in the form of a dosage unit.

3. The method of claim 2, wherein the patient is a human.

4. The method of claim 2, wherein the dosage is 50-1000 mg.

5. The method of claim 2, wherein the dosage unit is an immediate release tablet, controlled release tablet, capsule, oral solution, oral suspension, pill, gel, or cream.

6. The method of claim 1, wherein the compound is suitable for oral delivery.

7. The method of claim 1, wherein the compound is suitable for parental delivery.

8. The method of claim 1, wherein the compound is suitable for intravenous delivery or intranasal delivery.

9. The method of claim 1, wherein the compound is suitable for transdermal delivery.

10. The method of claim 1, wherein the peak is suitable for rectal suppository delivery or transmucosal delivery.

11. The method of claim 1, wherein the neuropathic pain is caused by a disorder selected from carpal tunnel syndrome, cervical or lumbar radiculopathy, complex regional pain syndrome, spinal cord injury, or stump pain.

12. The method of claim 1, wherein the neuropathic pain is caused by a disorder selected from metabolic or toxic diseases.

13. The method of claim 1, wherein the neuropathic pain is caused by endocrinologic disorders.

14. The method as in claim 13, wherein the endocrinologic disorder is selected from diabetes mellitus, diabetic neuropathy, amyloidosis, or amyloid polyneuropathy.

15. The method as in claim 1, wherein the neuropathic pain is caused by a malignant tumor, Eosinophilia-myalgia syndrome, monoclonal gammopathy, mulitiple sclerosis, stoke, postherpetic neuralgia, neuropathy with monoclonal protein, vasculitic neuropathy, neuropathy associated with Guillain-Barré

syndrome, neuropathy associated with Fabry'"'"'s disease, entrapment due to anatomic abnormality, trigeminal, CNS neuralgia, malignancy, inflammatory condition, autoimmune disorder, idiopathic distal small-fiber neuropathy, toxin, drug, dietary or absorption abnormality, immuno-globulinemia, hereditary abnormality, mastectomy, or amputation.

16. The method of claim 1, wherein the neuropathic pain is caused by a viral infection.

17. The method of claim 16, wherein the viral infection is HIV infection or herpes.

18. The method as in claim 15, wherein said autoimmune disorder is selected from the group consisting of demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, or Sjö

gren'"'"'s syndrome.

19. The method as in claim 15, wherein toxin or drug is selected from the group consisting of arsenic, lead, mercury, thallium, alcohol, vincrisitne, cisplatinum, or dideoxynucleoside.

20. The method of claim 1, wherein the compound inhibits uptake of serotonin, norepinephrine, or dopamine.

21. The method of claim 1, wherein the compound inhibits ectopic activity.

22. The method of claim 1, wherein the compound inhibits ectopic discharge in the peripheral nervous system pathways.

23. The method of claim 1, wherein the compound inhibits ectopic discharge in the dorsal-root-ganglion cells of damaged afferent axons.

24. The method of claim 1, wherein the treatment is a maintenance treatment to prevent the reoccurrence of neuropathic pain.

25. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, in combination or alternation with one or more other agents that are useful for the treatment of conventional or neuropathic pain.

42. The method of claim 25, wherein the treatment is a maintenance treatment to prevent the reoccurrence of neuropathic pain.

26. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or its pharmaceutically acceptable salt or prodrug thereof, wherein;

m is 1, 2 or 3;

R¹ is CH₃, C₂H₅, n—

C₃H₇ or allyl;

R² and R³ independently are H or alkyl of 1-4 carbon atoms;

or R¹ and R² taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;

or R² and R³ taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;

R⁴ is;

(a) phenyl or

 

wherein X is independently one or two substituents, selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;

(b) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy, arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;

(c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;

(d) 2-, 3-, or 4-pyridyl, or 2- or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;

(e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;

or

(f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF₃;

R⁵ is alkyl of 1-4 carbon atoms, or is taken together with R⁶ to form a branched or unbranched alkylene bridge of 3-11 carbon atoms;

R⁶ is H, alkyl of 1-4 carbon atoms, or is taken together with R⁵ to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; and

R⁷ is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4 carbon atoms, or —

CH₂phenyl;

or a pharmaceutically salt or N-oxide thereof, provided that when

(i) R¹, R⁵ and R⁶ are methyl, and R² and R³ are H, then R⁴ is not 3,4—

F₂C₆H₃, 3,4—

Cl₂C₆H₃, p-t-butylphenyl, 2,3-(MeO)₂C₆H₃, 2,5-(MeO)₂C₆H₃, or 3-pyridyl;

(ii) R¹, R⁵ and R⁶ are methyl or R⁵ and R⁶ are taken together as —

(CH₂)₆— and

—

(CH₂)₇—

, then R⁴ not 3-(MeO)C₆H₄.

33. The method of claim 26, wherein the compound is selected from the group consisting of:

(a) 4-(3′

-Thienyl)-α

,α

,1-trimethyl-4-piperidinemethanol;

(b) 4-(3′

-Chlorophenyl)-α

,1-dimethylpiperidinemethanol;

(c) 4-(3′

-Chlorophenyl)-α

,α

,1-trimethyl-4-piperidinemethanol;

(d) 4-(3′

-Bromophenyl)-α

,1-dimethylpiperidinemethanol;

(e) 4-(3′

-Bromophenyl)-α

,α

,1-trimethyl-4-piperidinemethanol;

(f) 4-(2-Thienyl)-α

,1-dimethylpiperidinemethanol;

(g) 4-(3-Thienyl)-α

,1-dimethylpiperidinemethanol;

(h) 4-(3′

-Chlorophenyl)-α

,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1-methanol;

(i) 3-(3′

-Chlorophenyl)-α

,α

,1-trimethyl-3-pyrrolidinemethanol;

(j) 4(4′

-Trifluoromethylphenyl)-α

,1-dimethylpiperidinemethanol;

or a pharmaceutically suitable salt thereof.

35. The method of claim 26, wherein the compound administered does not show significant activity at mu, kappa, delta, or sigma receptor sites in the brain.

36. The method of claim 26, wherein the compound administered lacks addictive or respiratory depressant properties.

37. The method of claim 26, wherein the compound administered does not inhibit prostaglandin synthesase activity.

38. The method of claim 26, wherein the compound administered does not exhibit an anti-inflammatory effect in vivo.

39. The method of claim 26, wherein the compound administered inhibits uptake of serotonin, norepinephrine, or dopamine.

40. The method of claim 26, wherein the compound administered does not exhibit anticholinergic side effects, sedation, or motor impairment.

41. The method of claim 26, wherein the treatment is a maintenance treatment to prevent the reoccurrence of neuropathic pain.

43. The method of claim 26, wherein the compound is in the form of a dosage unit.

44. The method of claim 26, wherein the patient is a human.

45. The method of claim 43, wherein the dosage is 50-1000 mg.

46. The method of claim 43, wherein the dosage unit is an immediate release tablet, controlled release tablet, capsule, oral solution, oral suspension, or pill.

47. The method of claim 26, wherein the compound is suitable for orally delivery.

48. The method of claim 26, wherein the compound is suitable for parental delivery.

49. The method of claim 26, wherein the compound is suitable for intravenous delivery, transdermal delivery, intranasal delivery, rectal suppository delivery, or transmucosal delivery.

50. The method of claim 26, wherein the neuropathic pain is caused by a disorder selected from carpal tunnel syndrome, cervical or lumbar radiculopathy, complex regional pain syndrome, spinal cord injury, or stump pain.

51. The method of claim 26, wherein the neuropathic pain is caused by a disorder selected from metabolic or toxic diseases.

52. The method of claim 26, wherein the neuropathic pain is caused by endocrinologic disorder.

53. The method of claim 52, wherein the endocrinologic disorder is selected from diabetes mellitus, diabetic neuropathy, amyloidosis, or amyloid polyneuropathy.

54. The method of claim 26, wherein the neuropathic pain is caused by a malignant tumor, Eosinophilia-myalgia syndrome, monoclonal gammopathy, mulitiple sclerosis stroke, postherpetic neuralgia, neuropathy with monoclonal protein, vasculitic neuropathy, neuropathy associated with Guillain-Barré

syndrome, neuropathy associated with Fabry'"'"'s disease, entrapment due to anatomic abnormality, trigeminal, CNS neuralgia, malignancy, inflammatory condition, autoimmune disorder, idiopathic distal small-fiber neuropathy, toxin, drug, dietary or absorption abnormality, immuno-globulinemia, hereditary abnormality, mastectomy, or amputation.

55. The method of claim 26, wherein the neuropathic pain is caused by a viral infection.

56. The method of claim 54, wherein the viral infection is HIV infection or herpes.

57. The method of claim 54, wherein said autoimmune disorder is selected from a group consisting of demyelinating inflammatory disorder, rheumatoid arthritis, systemic lupus erythematosus, or Sjö

gren'"'"'s syndrome.

58. The method of claim 54, wherein toxin or drug is selected from the group consisting of arsenic, lead, mercury, thallium, alcohol, vincrisitne, cisplatinum, or dideoxynucleoside.

27. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

when m is 2;

R¹ is CH₃, C₂H₅, n—

C₃H₇ or allyl;

R² and R³ independently are H or alkyl of 1-4 carbon atoms;

or R¹ and R² taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;

or R² and R³ taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;

R⁴ is;

(a)

(b) 1-naphthyl optionally substituted with one or two substituents, the same or different, selected from F, Cl, Br;

perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the alkyl-containing groups being 1-12 carbon atoms.

(c) 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms,

(d) 2-, or 3-thienyl optionally substituted with Cl, Br, or alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted with alkyl it is other than the 5-position, or

(e) 2-, or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br or CF₃;

R⁵ independently is alkyl of 1-4 carbon atoms or when taken together with R⁶ is a branched or unbranched alkylene bridge of 3-11 carbon atoms;

R⁶ independently is alkyl of 1-4 carbon atoms, or when taken together with R⁵ is a branched or unbranched alkylene bridge of 3-11 carbon atoms;

R⁷ is H, alkyl of 1-4 carbon atoms, alkanoyl, or —

CH₂phenyl.

28. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

m is 1 or 3;

R¹ independently is CH₃, C₂H₅, n—

C₃H₇, or allyl;

R² and R³ independently are H or alkyl of 1-4 carbon atoms;

or R¹ and R² taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;

or R² and R³ taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;

R⁴ is;

(a) phenyl or

 

where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;

(b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;

(c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;

(d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;

(e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;

or

(f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF₃;

R⁵ independently is alkyl of 1-4 carbon atoms, or when taken together with R⁶ is a branched or unbranched alkylene bridge of 3-11 carbon atoms;

R⁶ independently is H, alkyl of 1-4 carbon atoms, or when taken together with R⁵ is a branched or unbranched alkylene bridge of 3-11 carbon atoms;

R⁷ is H, alkyl of 1-4 carbon atoms, alkanoyl, or —

CH₂phenyl;

or a pharmaceutically suitable salt or N-oxide thereof.

29. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

m is 2;

R⁶ is H;

R¹ independently is CH₃, C₂H₅, n—

C₃H₇, or allyl;

R² and R³ independently are H or alkyl of 1-4 carbon atoms;

or R¹ and R² taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;

or R² and R³ taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;

R⁴ is;

(a) phenyl or

 

where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;

(b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;

(c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;

(d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;

(e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;

or

(f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CE₃;

R⁵ independently is alkyl of 1-4 carbon atoms;

R⁷ is H, alkyl of 1-4 carbon atoms, alkanoyl, or —

CH₂phenyl;

or

a pharmaceutically suitable salt or N-oxide thereof.

30. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

m is 2;

R⁶ is H;

R¹ is methyl;

R² and R³ independently are H or alkyl of 1-4 carbon atoms;

or R² and R³ taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;

R⁴ is;

(a)

 

where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;

(b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;

(c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;

(d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;

(e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;

or

(f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF₃;

R⁵ independently is alkyl of 1-4 carbon atoms;

R⁷ is H, alkyl of 1-4 carbon atoms, alkanoyl, or —

CH₂phenyl;

or

a pharmaceutically suitable salt or N-oxide thereof.

31. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

m is 2;

(a) R¹ is CH₃;

(b) R² and R³ are H;

(c) R⁴ is 2- or 3-thienyl,

 

where X is Cl, Br, F, CF₃;

(d) R⁵ is CH₃;

(e) R⁶ is H or CH₃; and

(f) R⁷ is H.

32. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein;

m is 1 or 3;

(a) R¹ is CH₃;

(b) R², R³ and R⁷ are H;

(c) R⁴ is

 

where X is Cl, Br, F or CF₃;

or

(d) R⁵ is CH₃; and

(e) R⁶ is H or CH₃.

34. A method for the treatment neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:

or its pharmaceutically acceptable salt or prodrug thereof, wherein;

X¹ and X² are independently O or NR²; and

R¹ is H, alkyl, lower alkyl (such as a C₁ to C₆ optionally substituted branched or straight-chained alkyl);

alkenyl, alkynyl, acyl, —

C(O)R⁵, —

C(O)NR⁵R⁶, —

C(O)OR⁵, —

C(O)SR⁵, —

C(S)R⁵, —

C(S)NR⁵R⁶, —

C(S)OR⁵, —

C(S)SR⁵, —

C(NR⁷)R⁵, —

C(NR⁷)NR⁵R⁶, —

C(NR⁷)OR⁵, —

C(NR⁷)SR⁵ or phosphate; and

R², R⁵, R⁶ and R⁷ are independently H or alkyl.