US2005058620A1PendingUtilityA1

Modified bio-related substance, process for producing the same, and intermediate

Assignee: NOF CORPPriority: Nov 20, 2002Filed: Nov 20, 2003Published: Mar 17, 2005

Est. expiryNov 20, 2022(expired)· nominal 20-yr term from priority

Inventors:Ken-Ichiro Nakamoto Syunsuke Ohashi Yuji Yamamoto Kenji Sakanoue Chika Itoh Tohru Yasukohchi

C08G 65/2609C08G 65/329A61P 43/00A61K 47/60C08G 65/32C08G 65/26

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References

Claims

Abstract

A modified bio-related substance, wherein at least one poly(alkylene glycol)oxy group represented by the following formula (1) is combined in a molecule: wherein R is a hydrocarbon group having 1 to 24 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 4 carbon atoms, R and OA 2 are the same or different from each other in one molecule, n and m are each average number of moles of the oxyalkylene group added, n represents 0 to 1000, and m represents 10 to 1000.

Claims

exact text as granted — not AI-modified

1 . A modified bio-related substance, wherein at least one poly(alkylene glycol)oxy group represented by the following formula (1):

wherein R is a hydrocarbon group having 1 to 24 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 4 carbon atoms, R and OA 2 are the same or different from each other in one molecule, n and m are each average number of moles of the oxyalkylene group added, n represents 0 to 1000, and m represents 10 to 1000, is combined in a molecule.

2 . The modified bio-related substance according to claim 1 , wherein in the formula (1), R is a hydrocarbon group having 1 to 10 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 3 carbon atoms, n is 0 to 500, and m is 10 to 1000.

3 . The modified bio-related substance according to claim 1 , wherein in the formula (1), R is a methyl group, OA 1 and OA 2 are each an oxyethylene group, n is 0 to 50, and m is 20 to 800.

4 . The modified bio-related substance according to claim 1 , wherein in the formula (1), n is 0.

5 . The modified bio-related substance according to claim 1 , wherein in the formula (1), n is 1 to 50.

6 . The modified bio-related substance according to claim 1 , wherein the bio-related substance has a physiological activity on a body.

7 . The modified bio-related substance according to claim 1 , wherein the bio-related substance is a protein or a polypeptide.

8 . The modified bio-related substance according to claim 1 , wherein the bio-related substance is an anticancer drug.

9 . The modified bio-related substance according to claim 1 , wherein the bio-related substance is an antifungal drug.

10 . The modified bio-related substance according to claim 1 , wherein the bio-related substance is a phospholipid.

11 . The modified bio-related substance according to claim 3 , wherein in the formula (1), n is 0.

12 . The modified bio-related substance according to claim 3 , wherein in the formula (1), n is 1 to 50.

13 . The modified bio-related substance according to claim 11 , wherein the bio-related substance has a physiological activity on a body.

14 . The modified bio-related substance according to claim 11 , wherein the bio-related substance is a protein or a polypeptide.

15 . The modified bio-related substance according to claim 11 , wherein the bio-related substance is an anticancer drug.

16 . The modified bio-related substance according to claim 11 , wherein the bio-related substance is an antifungal drug.

17 . The modified bio-related substance according to claim 11 , wherein the bio-related substance is a phospholipid.

18 . The modified bio-related substance according to claim 12 , wherein the bio-related substance has a physiological activity on a body.

19 . The modified bio-related substance according to claim 12 , wherein the bio-related substance is a protein or a polypeptide.

20 . The modified bio-related substance according to claim 12 , wherein the bio-related substance is an anticancer drug.

21 . The modified bio-related substance according to claim 12 , wherein the bio-related substance is an antifungal drug.

22 . The modified bio-related substance according to claim 12 , wherein the bio-related substance is a phospholipid.

23 . An intermediate for a modified bio-related substance, which is represented by the following formula (2):

wherein R is a hydrocarbon group having 1 to 24 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 4 carbon atoms, R and OA 2 are the same or different from each other in one molecule, n and m are each average number of moles of the oxyalkylene group added, n represents 0 to 1000, m represents 10 to 1000, and X represents a functional group capable of chemically reacting with an unmodified bio-related substance.

24 . The intermediate according to claim 23 , wherein in the formula (2), R is a hydrocarbon group having 1 to 10 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 3 carbon atoms, n is 0 to 500, and m is 10 to 1000.

25 . The intermediate according to claim 23 , wherein in the formula (2), R is a methyl group, OA 1 and OA 2 are each an oxyethylene group, n is 0 to 50, and m is 20 to 800.

26 . The intermediate according to claim 23 , wherein in the formula (2), n is 0.

27 . The intermediate according to claim 23 , wherein in the formula (2), n is 1 to 50.

28 . The intermediate according to claim 23 , wherein the functional group is a functional group capable of reacting with an amino group, a mercapto group, an unsaturated bond, or a carboxyl group of the unmodified bio-related substance.

29 . The intermediate according to claim 23 , wherein X is a group selected from the group (I):

wherein Z represents a simple alkylene group or an alkylene group containing an ether bond, an ester bond, a urethane bond, an amide bond, a carbonate bond, or a secondary amino group and Y represents a hydrocarbon group having 1 to 10 carbon atoms which may contain fluorine atom(s).

30 . The intermediate according to claim 23 , wherein X is a group selected from the group (II):
Group (II) —Z—NH 2 (g) —NH 2 (j) Z—COOH (k) wherein Z represents a simple alkylene group or an alkylene group containing an ether bond, an ester bond, a urethane bond, an amide bond, a carbonate bond, or a secondary amino group.

31 . A process for producing a modified bio-related substance wherein at least one poly(alkylene glycol)oxy group represented by the following formula (1):

32 . The process according to claim 31 , wherein the bio-related substance has a physiological activity on a body.

33 . The process according to claim 31 , wherein the bio-related substance is a protein or a polypeptide.

34 . The process according to claim 31 , wherein the bio-related substance is an anticancer drug.

35 . The process according to claim 31 , wherein the bio-related substance is an antifungal drug.

36 . The process according to claim 31 , wherein the bio-related substance is a phospholipid.

37 . The intermediate according to claim 29 , wherein X is a group represented by (a) in the group (I).

38 . The intermediate according to claim 29 , wherein X is a group represented by (d) in the group (I).

39 . The intermediate according to claim 29 , wherein X is a group represented by (e) in the group (I).

40 . The intermediate according to claim 29 , wherein X is a group represented by (f) in the group (I).

41 . The intermediate according to claim 25 , wherein in the formula (2), n is 0.

42 . The intermediate according to claim 25 , wherein in the formula (2), n is 1 to 50.

43 . The intermediate according to claim 41 , wherein the functional group is a functional group capable of reacting with an amino group, a mercapto group, an unsaturated bond, or a carboxyl group of the unmodified bio-related substance.

44 . The intermediate according to claim 41 , wherein X is a group selected from the group (I):

45 . The intermediate according to claim 41 , wherein X is a group selected from the group (II):
Group (II) —Z—NH 2 (g) —NH 2 (j) —Z—COOH (k) wherein Z represents a simple alkylene group or an alkylene group containing an ether bond, an ester bond, a urethane bond, an amide bond, a carbonate bond, or a secondary amino group.

46 . The intermediate according to claim 42 , wherein the functional group is a functional group capable of reacting with an amino group, a mercapto group, an unsaturated bond, or a carboxyl group of the unmodified bio-related substance.

47 . The intermediate according to claim 42 , wherein X is a group selected from the group (I):

48 . The intermediate according to claim 42 , wherein X is a group selected from the group (II):
Group (II) —Z—NH 2 (g) —NH 2 (j) —Z—COOH (k) wherein Z represents a simple alkylene group or an alkylene group containing an ether bond, an ester bond, a urethane bond, an amide bond, a carbonate bond, or a secondary amino group.

49 . The intermediate according to claim 44 , wherein X is a group represented by (e) in the group (I).

50 . The intermediate according to claim 47 , wherein X is a group represented by (e) in the group (I).

51 . A polyalkylene glycol derivative substantially containing no secondary hydroxyl group and being a starting material for the intermediate according to claim 23 , which is represented by the following formula (p):

52 . The polyalkylene glycol derivative according to claim 51 , wherein in the formula (p), R is a hydrocarbon group having 1 to 10 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 3 carbon atoms, n represents 0 to 500, and m represents 10 to 1000.

53 . The polyalkylene glycol derivative according to claim 51 , wherein in the formula (p), R is a methyl group, OA 1 and OA 2 are each an oxyethylene group, n represents 0 to 50, and m represents 20 to 800.

54 . The polyalkylene glycol derivative according to claim 51 , wherein in the formula (p), n represents 0.

55 . The polyalkylene glycol derivative according to claim 51 , wherein in the formula (p), n represents 1 to 50.

56 . The polyalkylene glycol derivative according to claim 51 , wherein polydispersity Mw/Mn in all the peaks from the starting point of elution to the end point of elution satisfies the relationship:
Mw/Mn≦1.07
in gel permeation chromatography of the polyalkylene glycol derivative represented by the formula (p).

57 . The polyalkylene glycol derivative of the formula (p) according to claim 51 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mpx1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

58 . The polyalkylene glycol derivative of the formula (p) according to claim 56 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mpx1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

59 . The polyalkylene glycol derivative according to claim 53 , wherein in the formula (p), n is 0.

60 . The polyalkylene glycol derivative according to claim 53 , wherein in the formula (p), n is 1 to 50.

61 . The polyalkylene glycol derivative according to claim 54 , which satisfies the following parameter:
M2/(M1+M2)×100≦10 M1: an integral value of the methyl group originated from the mesyl group derived from the hydroxyl group at the 1-position directly bonded to the glycerin skeleton when a compound represented by the formula (p) is reacted with methanesulfonyl chloride to obtain a mesylated compound and a nuclear magnetic resonance spectrum thereof is measured as a deuterated methanol solution, M2: an integral value of the methyl group originated from the mesyl group derived from the hydroxyl group of the polyalkylene glycol chain.

62 . The polyalkylene glycol derivative according to claim 59 , wherein polydispersity Mw/Mn in all the peaks from the starting point of elution to the end point of elution satisfies the relationship:
Mw/Mn≦1.07
in gel permeation chromatography of the polyalkylene glycol derivative represented by the formula (p).

63 . The polyalkylene glycol derivative of the formula (p) according to claim 59 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mp×1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

64 . The polyalkylene glycol derivative of the formula (p) according to claim 62 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mp×1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

65 . The polyalkylene glycol derivative according to claim 64 , which satisfies the following parameter:
M2/(M1+M2)×100≦10 M1: an integral value of the methyl group originated from the mesyl group derived from the hydroxyl group at the 1-position directly bonded to the glycerin skeleton when a compound represented by the formula (p) is reacted with methanesulfonyl chloride to obtain a mesylated compound and a nuclear magnetic resonance spectrum thereof is measured as a deuterated methanol solution, M2: an integral value of the methyl group originated from the mesyl group derived from the hydroxyl group of the polyalkylene glycol chain.

66 . The polyalkylene glycol derivative according to claim 60 , wherein polydispersity Mw/Mn in all the peaks from the starting point of elution to the end point of elution satisfies the relationship:
Mw/Mn ≦1.07
in gel permeation chromatography of the polyalkylene glycol derivative represented by the formula (p).

67 . The polyalkylene glycol derivative of the formula (p) according to claim 60 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mp×1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

68 . The polyalkylene glycol derivative of the formula (p) according to claim 66 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mp×1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

69 . The polyalkylene glycol derivative according to claim 61 , wherein polydispersity Mw/Mn in all the peaks from the starting point of elution to the end point of elution satisfies the relationship:
Mw/Mn≦1.07
in gel permeation chromatography of the polyalkylene glycol derivative represented by the formula (p).

70 . The polyalkylene glycol derivative of the formula (p) according to claim 61 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mp×1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

71 . The polyalkylene glycol derivative of the formula (p) according to claim 69 , which is produced using a compound of the formula (4) as a starting material and satisfies the following parameter:
Hrd/Mp×1000000≦3 Mp: a molecular weight corresponding to the peak top obtained from gel permeation chromatography of the formula (p), Hrd: a ratio of hydroxyl group residue contained in the alkyl group R at the polyoxyalkylene chain terminal end at the 2- and 3-positions in the compound of the formula (4).

72 . A process for producing the polyalkylene glycol derivative of the formula (p) comprising the following step (A):
Step (A): a step of subjecting the compound represented by the formula (4): wherein R is a hydrocarbon group having 1 to 24 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 4 carbon atoms, R and OA2 are the same or different from each other in one molecule, n and m are each average number of moles of the oxyalkylene group added, n represents 0 to 1000, and m represents 10 to 1000, to a hydrogenative reduction reaction under a condition that a water content in a reaction system is 1% or less.

73 . The process according to claim 72 , wherein in the step (A), palladium is used as a hydrogenative reduction catalyst, palladium is added in an amount of 1 to 20 wt % based on the compound of the formula (4), and the reaction is carried out at a temperature of 40° C. or lower.

74 . The process according to claim 72 , wherein as previous steps of the step (A), the following steps (B1) and (B2) are carried out:
Step (B1): a step of adding a dehalogenating agent and a compound represented by the formula (6) to a compound represented by the formula (5) and reacting them at 20 to 60° C. to obtain a compound of the formula (7), provided that each charged molar ratio satisfies the following relationship: Vc≧3Va Vb&gt;Vc Va: number of moles of the compound represented by the formula (5) Vb: number of moles of the dehalogenating agent Vc: number of moles of the compound represented by the formula (6); Step (B2): a step of adding a compound represented by the formula (8) to the compound of the formula (7) and reacting them at 20 to 80° C. to obtain a compound of the formula (4), provided that each charged molar ratio satisfies the following relationship: Vd&gt;Vc Vd: number of moles of the compound represented by the formula (8); wherein R is a hydrocarbon group having 1 to 24 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 4 carbon atoms, n and m are each average number of moles of the oxyalkylene group added, n represents 0 to 1000, m represents 10 to 1000, W is a halogen atom selected from Cl, Br and I, R 1 is a hydrocarbon group having 1 to 10 carbon atoms, and M is potassium or sodium.

75 . The process according to claim 74 , comprising a step (B3) as a successive step of the step (B2):
Step (B3): a step of filtrating the reaction liquid or washing the reaction liquid with an aqueous inorganic salt solution having a concentration of 10 wt % or more.

76 . The process according to claim 75 , wherein the steps (B1) to (B3) are repeated after the step (B3).

77 . The process according to claim 75 , wherein as previous steps of the steps (B1) to (B3), the following steps (C1) and (C2) are carried out:
Step (C1): a step of adding sodium or potassium in an amount of 5 to 50 mol % based on a compound represented by the formula (9): wherein OA 1 is an oxyalkylene group having 2 to 4 carbon atoms,
and dissolving the former at 10 to 50° C.;
Step (C2): a step of reacting an alkylene oxide at 50 to 130° C.

78 . The process according to claim 76 , wherein as previous steps of the steps (B1) to (B3), the following steps (C1) and (C2) are carried out:
Step (C1): a step of adding sodium or potassium in an amount of 5 to 50 mol % based on the compound represented by the formula (9): wherein OA 1 is an oxyalkylene group having 2 to 4 carbon atoms,
and dissolving the former at 10 to 50° C.;
Step (C2): a step of reacting an alkylene oxide at 50 to 130° C.

79 . A modified bio-related substance, which is obtained by the process according to claim 31 .

80 . A process for producing an intermediate for a modified bio-related substance, represented by the formula (2), wherein the polyalkylene glycol derivative according to claim 51 is used as a starting material:

wherein R is a hydrocarbon group having 1 to 24 carbon atoms, OA 1 and OA 2 are each an oxyalkylene group having 2 to 4 carbon atoms, R and OA 2 are the same or different from each other in one molecule, n and m are each average number of moles of the oxyalkylene group added, n represents 0 to 1000, m represents 10 to 1000, and X represents a functional group capable of chemically reacting with an unmodified bio-related substance.

81 . An intermediate for a modified bio-related substance, which is obtained by the process according to claim 80 .

82 . A polyalkylene glycol derivative of the formula (p), which is obtained by the process according to claim 72 .

83 . A process for producing a polyalkylene glycol derivative of the formula (11), comprising the following step (AA):
Step (AA): a step of subjecting a compound represented by the formula (10) to a hydrogenative reduction reaction under a condition that a water content in a reaction system is 1% or less: wherein G is a residual group of a compound having 2 to 4 hydroxyl groups; R 2 is a hydrocarbon group having 1 to 4 carbon atoms; m1, m2, and m3 represent each average number of moles of an oxyethylene group added and satisfy the following relationship: 0≦m1≦1000, 0≦m2≦1000, 0≦m3≦1000, 10≦m1+m2+m3≦1000; X 1 is an amino group, a carboxyl group, or a protected group thereof; and g1, g2, and g3 represent each an integer and satisfy the following relational equations: 1≦g1≦3, 0≦g2, 0≦g3, 2≦g1+g2+g3≦4.

84 . A process for producing a polyalkylene glycol derivative of the formula (11) according to claim 83 , wherein in the step (AA), palladium is used as a hydrogenative reduction catalyst, palladium is added in an amount of 1 to 20 wt % based on the compound of the formula (10), and the reaction is carried out at a temperature of 40° C. or lower.

85 . A process for producing a polyalkylene glycol derivative of the formula (16), wherein the following steps (BB1) and (BB2) are carried out:
Step (BB1): a step of adding a dehalogenating agent and a compound represented by the formula (14) to a compound represented by the formula (12) and reacting them at 20 to 60° C. to obtain a compound of the formula (13), provided that each charged molar ratio satisfies the following relationship: Vj≧1.5×Vh×g5 Vi&gt;Vj Vh: number of moles of the compound represented by the formula (12) Vi: number of moles of the dehalogenating agent Vj: number of moles of the compound represented by the formula (14); Step (BB2): a step of adding a compound represented by the formula (15) to the compound of the formula (13) and reacting them at 20 to 80° C. to obtain a compound of the formula (16), provided that each charged molar ratio satisfies the following relationship: Vk&gt;Vj Vk: number of moles of the compound represented by the formula (15): wherein G is a residual group of a compound having 2 to 4 hydroxyl groups; R 2 is a hydrocarbon group having 1 to 4 carbon atoms; m1, m2, and m3 represent each average number of moles of an oxyethylene group added and satisfy the following relationship: 0≦m1&lt;1000, 0≦m2≦1000, 0≦m3≦1000, 10≦m1+m2+m3≦1000; X 1 is an amino group, a carboxyl group, or a protected group thereof; g4, g5, and g6 represent each an integer and satisfy the following relational equations: 0≦g4, 1≦g5≦3, 0≦g6, 2≦g4+g5+g6≦4; W is a halogen atom selected from Cl, Br and I; R 3 is a hydrocarbon group having 1 to 10 carbon atoms; and M is potassium or sodium.

86 . The process for producing a polyalkylene glycol derivative of the formula (16) according to claim 85 , comprising a step (BB3) as a successive step of the step (BB2):
Step (BB3): a step of filtrating the reaction liquid or washing the reaction liquid with an aqueous inorganic salt solution having a concentration of 10 wt % or more.

87 . The process for producing a polyalkylene glycol derivative of the formula (16) according to claim 86 , wherein the steps (BB1) to (BB3) are repeated after the step (B3).

88 . A composition, which contains a polyalkylene glycol represented by the following formula (p) and substantially does not contain polyalkylene glycol derivative having a secondary hydroxyl group:

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