WO2022111642A1 - Procédé de préparation d'un dérivé acylé d'insuline ou d'un analogue de celui-ci - Google Patents
Procédé de préparation d'un dérivé acylé d'insuline ou d'un analogue de celui-ci Download PDFInfo
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- WO2022111642A1 WO2022111642A1 PCT/CN2021/133639 CN2021133639W WO2022111642A1 WO 2022111642 A1 WO2022111642 A1 WO 2022111642A1 CN 2021133639 W CN2021133639 W CN 2021133639W WO 2022111642 A1 WO2022111642 A1 WO 2022111642A1
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- Prior art keywords
- compound
- insulin
- formula
- integer
- groups
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 154
- 238000000034 method Methods 0.000 title claims abstract description 48
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- 108090001061 Insulin Proteins 0.000 claims abstract description 44
- 229940125396 insulin Drugs 0.000 claims abstract description 43
- 239000004026 insulin derivative Substances 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 101000976075 Homo sapiens Insulin Proteins 0.000 claims description 19
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 19
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- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
Definitions
- the present disclosure relates to the field of biomedicine, in particular to a method for preparing an acylated derivative of insulin or an analog thereof.
- Diabetes mellitus is a metabolic syndrome characterized by hyperglycemia caused by defective insulin secretion and/or insufficient insulin action. Diabetes itself is not serious, but complications caused by poor blood sugar control or disease progression, such as myocardial infarction, cerebral hemorrhage, blindness, renal failure and lower limb amputation, can seriously reduce the quality of life of patients and even endanger their lives. It is true that diabetes has become the third largest disease besides cardiovascular and cerebrovascular diseases and malignant tumors. The World Health Organization (WHO) currently defines diabetes as: fasting blood glucose ⁇ 7.0 mmol/L, or elevated blood glucose treated with medication, or a history of diabetes diagnosis.
- WHO World Health Organization
- HbA 1c glycated hemoglobin
- Long-acting insulin is an exogenous insulin modified from human insulin, which is characterized by stable onset of action and long duration of drug effect, and the risk of causing nocturnal hypoglycemia is significantly lower than that of neutral protamine zinc insulin (neutral protamine zinc insulin). protamine hagedorn, NPH).
- Detemir Insulin Detemir, Novo Nordisk
- Insulin Degludec Insulin Degludec
- Glargine Insulin Glargine, Sanofi original research, Eli Lilly imitation
- WO2018024186A discloses a novel long-acting insulin, the preparation process of which still needs to be improved in the following aspects: 1) the active ester compound used for acylation of insulin has poor stability and cannot be produced on a large scale; 2) the active ester compound is used for insulin acylation. The modification rate of acylation is too low, and the production cost is too high. In view of the above problems, there is an urgent need for active ester compounds suitable for scale-up production and methods for preparing acylated derivatives of insulin or its analogs in high yields.
- the present disclosure carries out structural improvement design for the active ester compound, and obtains the active ester compound that can be produced in kilograms, with stable production process and controllable quality.
- the method for acylating and condensing an active ester compound with insulin or its analogs provided by the present disclosure not only has high yield, but also has a stable process, can greatly reduce the production cost of acylated derivatives of insulin or its analogs, and can realize large-scale production. commercialized production.
- the present disclosure provides a method of preparing an acylated derivative of insulin or an insulin analog comprising the step of reacting a compound of formula (I) with insulin or an insulin analog:
- R is R 1 are independently electron withdrawing groups, and q is an integer from 1 to 4;
- W is a diacyl structure with -OC(CH 2 ) n CO-, where n is an integer from 2 to 10; W is one of its acyl groups with the A-chain or B-chain N-terminal amino acid of insulin or insulin analogs
- the ⁇ -amino group of the residue or the ⁇ -amino group of a lysine residue present on the B-chain forms an amide bond;
- X is a diamino compound containing a carboxylic acid group, and X is connected with one of its amino groups to an acyl group in W to form an amide bond;
- Y is -A( CH2 ) m- , wherein A is absent or CO-; m is an integer from 6 to 32;
- Z is -COOH
- insulin is natural insulin
- insulin analog is a polypeptide molecule comprising 1 or more amino acid deletions, additions, substitutions or combinations thereof relative to natural insulin, for example, comprising 1 to 10 amino acid deletions, additions, substitutions or the like combination.
- R 1 is selected from C 1 -C 6 alkanoyl, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, halogen, nitro, cyano, sulfonic acid, or carboxyl.
- C1 - C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
- halogens include, but are not limited to, F, Cl, Br, I.
- R 1 is selected from acetyl, propionyl, halo, or nitro. In some embodiments, R 1 is selected from acetyl, propionyl, F, Cl, or nitro.
- R 1 is propionyl
- q is 1, 2, or 3; eg, q is 1.
- W forms an amide bond with the epsilon-amino group of a lysine residue present on the B-chain.
- n is an integer from 2 to 5, eg, n is 2.
- X is -HN( CH2 )pCH(COOH)NH-, wherein p is an integer from 2 to 10.
- p is an integer from 2 to 6.
- p is an integer from 2 to 4, eg, p is 4.
- n is an integer from 10 to 16, eg, m is an integer from 12 to 14.
- R has a structure selected from the group consisting of:
- the compound of formula (I) is a compound of formula (Ia) or a compound of formula (Ib):
- the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations.
- the compound of formula (I) is:
- the method includes the steps of:
- the catalyst is 1,2,4-triazole; at a reaction temperature of 0-25° C., for example, about 0° C.; reaction for 1-8 hours, for example, for about 4 hours; the catalyst is reacted with
- the equivalence ratio of insulin or insulin analog is (1-12):1, eg, about 8:1.
- the organic solvent is isopropanol.
- the organic solvent is N,N-dimethylformamide.
- the insulin or insulin analog in step (b), is in solution, eg, in 50 mM Tris-HCl buffer (pH 8.5).
- the insulin or insulin analog solution in step (b), is pre-cooled to 0-25°C prior to the reaction, such as pre-cooled to 0-20°C, 0-15°C, 0-10°C or 0- 5°C. In some embodiments, the insulin or insulin analog solution is pre-cooled to about 0°C prior to the reaction.
- the equivalent ratio of the compound of formula (I) to insulin or insulin analog is about 1:1, about 2:1, about 3:1, or about 4:1, such as about 2:1.
- the catalyst is 1,2,4-triazole.
- the equivalent ratio of catalyst to insulin or insulin analog is (1-12):1, eg, about 11:1, about 10:1, about 9:1, about 8:1 1. About 7:1, about 6:1, or about 5:1.
- step (c) the equivalent ratio of catalyst to insulin or insulin analog is about 8:1.
- the reaction temperature is 0-20°C, 0-15°C, 0-10°C, or 0-5°C.
- step (c) the reaction temperature is about 0°C.
- step (c) the reaction is carried out for 1-8 hours, 2-8 hours, 2-7 hours, 3-7 hours, 3-6 hours, 3-5 hours, 3-4 hours, or 4-5 hours. In some embodiments, in step (c), the reaction is carried out for about 4 hours.
- the method includes the steps of:
- the insulin or insulin analog is present in solution, for example in about 50 mM Tris-HCl buffer (about pH 8.5);
- the insulin or insulin analog solution is pre-cooled to 0-25°C before the reaction, for example, pre-cooled to 0-20°C, 0-15°C, 0-10°C, 0-5°C , 0°C.
- the insulin is human insulin, porcine insulin, or bovine insulin.
- the insulin analog is a deletion, addition, Substituted polypeptide molecules or combinations thereof.
- insulin analogs include, but are not limited to: (i) insulin aspart, which differs from human insulin in that the B28 proline is replaced by aspartic acid; (ii) insulin lispro, which differs from human insulin in the The penultimate lysine and proline residues on the C-terminus are reversed; (iii) insulin lysine, which differs from human insulin in that the asparagine of B3 is replaced by lysine and the lysine of B29 is replaced by Glutamate replacement; (iv) insulin glargine, which differs from human insulin in that the asparagine of A21 is replaced by glycine and the B chain is extended by two arginines at the carboxy terminus.
- the insulin analog is human insulin with a threonine deletion at position 30 of the B chain (also known as Des(B30) human insulin), and the amino acid sequences of the A and B chains of Des(B30) human insulin are shown below :
- a chain GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1);
- Chain B FVNQHLCGSHLVEALYLVCGERGFFYTPK (SEQ ID NO: 2).
- the method for preparing acylated derivatives of insulin or insulin analogs further comprises the formula
- X' and Z' respectively represent the form in which all carboxyl groups in X and Z are protected by protective groups, and the protective groups are C 1 -C 6 alkyl groups, such as C 1 -C 4 alkyl groups; R is as in formula (I) definition.
- C1 - C6 alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl , 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl or 2,3-dimethylbutyl base butyl.
- C1 - C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
- the protecting group is methyl or tert-butyl.
- the method of preparing an acylated derivative of insulin or an insulin analog further comprises the step of reacting a compound of formula (III) with a compound of formula (IV) to obtain the compound of formula (I') ,
- W' is -OC(CH 2 ) n COOH, n is an integer from 2 to 10; X', Y, Z' are as defined above; R 1 are independently electron withdrawing groups, and q is 1 to 4 the integer.
- R 1 is selected from C 1 -C 6 alkanoyl, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, halogen, nitro, cyano, sulfonic acid, or carboxyl. In some embodiments, R 1 is selected from acetyl, propionyl, halo, or nitro. In some embodiments, R 1 is selected from acetyl, propionyl, F, Cl, or nitro. In some embodiments, R 1 is propionyl. In some embodiments, q is 1, 2, or 3; eg, q is 1.
- the method of an acylated derivative of insulin or an insulin analog further comprises the step of reacting a compound of formula (III) with a compound of formula (IV) to provide said compound of formula (I'),
- W' is -OC(CH 2 ) n COOH, and n is an integer from 2 to 10;
- Y is -A( CH2 ) m- , wherein A is absent or CO-; m is an integer from 6 to 32;
- X' and Z' respectively represent the form in which all carboxyl groups in X and Z are protected by protective groups, and the protective groups are C 1 -C 6 alkyl groups, such as C 1 -C 4 alkyl groups;
- X is a dicarboxylic acid group containing a carboxylic acid group. Amino compound, X is connected with an acyl group in W to form an amide bond with one of its amino groups;
- Z is -COOH
- R 1 are independently electron withdrawing groups, and q is an integer from 1 to 4.
- R 1 is selected from C 1 -C 6 alkanoyl, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, halogen, nitro, cyano, sulfonic acid, or carboxyl. In some embodiments, R 1 is selected from acetyl, propionyl, halo, or nitro. In some embodiments, R 1 is selected from acetyl, propionyl, F, Cl, or nitro. In some embodiments, R 1 is propionyl. In some embodiments, q is 1, 2, or 3; eg, q is 1.
- R has a structure selected from the group consisting of:
- n is an integer from 2 to 5, eg, n is 2.
- X is -HN( CH2 )pCH(COOH)NH-, wherein p is an integer from 2 to 10.
- p is an integer from 2 to 6.
- p is an integer from 2 to 4, eg, p is 4.
- m is an integer from 10 to 16, eg, m is an integer from 12 to 14.
- the methods of the present disclosure achieve an acylation modification rate of insulin or insulin analog of at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% .
- the acylation modification rate can be determined by Phenomenex Gemini C18 liquid chromatography and calculated by the following formula: In the formula, is the average value of the ratio of the concentration of the reference solution to the main peak area; is the average value of the main peak area in the test solution; C i is the concentration of the test solution.
- the present disclosure also provides a compound of formula (I):
- R is R 1 are independently electron withdrawing groups, and q is an integer from 1 to 4;
- W is a diacyl structure with -OC( CH2 )nCO-, wherein n is an integer from 2 to 10;
- X is a diamino compound containing a carboxylic acid group, and X is connected with one of its amino groups to an acyl group in W to form an amide bond;
- Y is -A( CH2 ) m- , wherein A is absent or CO-; m is an integer from 6 to 32;
- Z is -COOH.
- R 1 is selected from C 1 -C 6 alkanoyl, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, halogen, nitro, cyano, sulfonic acid, or carboxyl.
- C1 - C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
- halogens include, but are not limited to, F, Cl, Br, I.
- R 1 is selected from acetyl, propionyl, halo, or nitro. In some embodiments, R 1 is selected from acetyl, propionyl, F, Cl, or nitro.
- R 1 is propionyl
- q is 1, 2, or 3; eg, q is 1.
- n is an integer from 2 to 5, eg, n is 2.
- X is -HN( CH2 )pCH(COOH)NH-, wherein p is an integer from 2 to 10.
- p is an integer from 2 to 6.
- p is an integer from 2 to 4, eg, p is 4.
- n is an integer from 10 to 16, eg, m is an integer from 12 to 14.
- R has a structure selected from the group consisting of:
- the compound of formula (I) is a compound of formula (Ia) or a compound of formula (Ib):
- the compound of formula (I) is:
- acylation modification rate can be determined by Phenomenex Gemini C18 liquid chromatography and calculated by the following formula: In the formula, is the average value of the ratio of the concentration of the reference solution to the main peak area; is the average value of the main peak area in the test solution; C i is the concentration of the test solution.
- X' and Z' respectively represent the form in which all carboxyl groups in X and Z are protected by protective groups, and the protective groups are C 1 -C 6 alkyl groups, such as C 1 -C 4 alkyl groups; R, W, X, Y and Z are as defined in formula (I).
- the protecting group is methyl or tert-butyl.
- the compound of formula (I') is:
- the present disclosure also provides a method for preparing the compound of formula (I), which comprises the step of removing the carboxyl protecting group from the compound of formula (I') to obtain the compound of formula (I).
- the method of preparing a compound of formula (I) further comprises the step of reacting a compound of formula (III) with a compound of formula (IV) to obtain said compound of formula (I'),
- W' is -OC(CH 2 ) n COOH, n is an integer from 2 to 10; X', Y, Z' are as defined above; R 1 are independently electron withdrawing groups, and q is 1 to 4 the integer.
- R 1 is selected from C 1 -C 6 alkanoyl, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, halogen, nitro, cyano, sulfonic acid, or carboxyl. In some embodiments, R 1 is selected from acetyl, propionyl, halo, or nitro. In some embodiments, R 1 is selected from acetyl, propionyl, F, Cl, or nitro. In some embodiments, R 1 is propionyl. In some embodiments, q is 1, 2, or 3; eg, q is 1.
- the present disclosure also provides a method for preparing a compound of formula (I'), comprising the step of reacting a compound of formula (III) with a compound of formula (IV) to obtain said compound of formula (I'),
- W' is -OC(CH 2 ) n COOH, and n is an integer from 2 to 10;
- Y is -A( CH2 ) m- , wherein A is absent or CO-; m is an integer from 6 to 32;
- X' and Z' respectively represent the form in which all carboxyl groups in X and Z are protected by protective groups, and the protective groups are C 1 -C 6 alkyl groups, such as C 1 -C 4 alkyl groups;
- X is a dicarboxylic acid group containing a carboxylic acid group. Amino compound, X is connected with an acyl group in W to form an amide bond with one of its amino groups;
- Z is -COOH
- R 1 are independently electron withdrawing groups, and q is an integer from 1 to 4.
- R 1 is selected from C 1 -C 6 alkanoyl, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, halogen, nitro, cyano, sulfonic acid, or carboxyl. In some embodiments, R 1 is selected from acetyl, propionyl, halo, or nitro. In some embodiments, R 1 is selected from acetyl, propionyl, F, Cl, or nitro. In some embodiments, R 1 is propionyl. In some embodiments, q is 1, 2, or 3; eg, q is 1.
- R has a structure selected from the group consisting of:
- n is an integer from 2 to 5, eg, n is 2.
- X is -HN( CH2 )pCH(COOH)NH-, wherein p is an integer from 2 to 10.
- p is an integer from 2 to 6.
- p is an integer from 2 to 4, eg, p is 4.
- m is an integer from 10 to 16, eg, m is an integer from 12 to 14.
- acylated derivatives of insulin analogs of the present disclosure may be conventionally named N ⁇ -(HOOC( CH2 ) 14CO ) -N ⁇ - ( OCCH2CH2CO- ( N ⁇ B29 - Des (B30) Human insulin))-Lys-OH, which has a specific structure of the following formula (IIa):
- acylated derivatives of insulin analogs of the present disclosure may be conventionally named lysine B29( N ⁇ - ( N ⁇ -hexadecanediacid-L-lysine- N ⁇ - oxobutyryl)) des(B30) human insulin, which has the structure shown in formula (IIb):
- the yield of the acylated derivative of the insulin analog is not less than 55%, eg, the yield is about 55% to about 60%, about 55% to about 65% , about 55% to about 70%, about 57% to about 70%, about 55% to about 80%, about 55% to about 90%, about 55% to about 100%, about 60% to about 80%, about 60% to about 90%, about 65% to about 85%, about 65% to about 95%, about 70% to about 75%. In some specific embodiments, the yield of the acylated derivative of the insulin analog is from about 57% to about 70% according to the preparation methods provided by the present disclosure.
- the acylation modification rate of the acylated derivative of the insulin analog is not less than 45%, eg, the modification rate is about 45% to about 55%, about 45% to about 60% %, about 45% to about 70%, about 45% to about 80%, about 45% to about 90%, about 45% to about 100%, about 50% to about 65%, about 50% to about 75%, About 50% to about 85%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%.
- the acylation modification rate of the acylated derivative of the insulin analog is from about 60% to about 70%.
- the yield of the acylated derivative of the insulin analog is not less than 55% and the acylation modification rate is not less than 45%, eg, the yield is from about 55% to about 60%. %, about 55% to about 65%, about 55% to about 70%, about 57% to about 70%, about 55% to about 80%, about 55% to about 90%, about 55% to about 100%, About 60% to about 80%, about 60% to about 90%, about 65% to about 85%, about 65% to about 95%, about 70% to about 75%; acylation modification rate of about 45% to about 55%, about 45% to about 60%, about 45% to about 70%, about 45% to about 80%, about 45% to about 90%, about 45% to about 100%, about 50% to about 65% , about 50% to about 75%, about 50% to about 85%, about 50% to about 95%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%.
- references in this disclosure to one or more embodiments means that one or more of the particular features described in that embodiment are included in at least one embodiment of the disclosure, and in addition, the feature may also be included in one or more embodiments Combinations in any manner, ie combinations of features of different embodiments, are also included within the scope of this disclosure and constitute different embodiments.
- insulin refers to natural insulin, such as human insulin, porcine insulin or bovine insulin.
- insulin analog refers to a polypeptide molecule comprising one or more amino acid deletions, additions, substitutions, or combinations thereof relative to native insulin.
- "insulin derivative" or "derivative of an insulin analog" refers to a polypeptide molecule to which one or more organic substituents (e.g., fatty acids) are attached to one or more amino acids on insulin or insulin analogs.
- organic substituents e.g., fatty acids
- the term “about” means that the index value is within an acceptable error range of the particular value determined by one of ordinary skill in the art, which value depends in part on how the measurement or determination is made (ie, the limits of the measurement system). For example, “about” can mean within 1 or more than 1 standard deviation in every practice in the art. Alternatively, “about” or “substantially comprising” can mean a range of up to ⁇ 20%, eg, a pH of about 5.5 means pH 5.5 ⁇ 1.1. Furthermore, particularly with respect to biological systems or processes, the term can mean at most one order of magnitude or at most five times the value.
- Step 1 in a 2L there-necked flask, add compound X12 (100.0g, 189.75mmol) and triethylamine (38.4g, 375mmol), then add ultra-dry tetrahydrofuran (Tetrahydrofuran, THF) (1L) to dissolve, cool down to -5 Stir at °C.
- Compound X12 can be synthesized according to the method described in patent publication WO2018024186A. Succinic anhydride (21.85 g, 218 mmol) was added to the reaction flask in batches. After the addition, the mixture was stirred at -5 °C to 5 °C for 30 min, and then transferred to room temperature and stirred for 16.5 h.
- Step 2 In a 3L three-necked flask, add compound X13 (119.0g), add 4-hydroxypropiophenone (34.2g), add DCM (2.38L) to dissolve, replace with argon for protection, cool down to 0°C in a cold trap, add 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) 45.12 g, after the addition was completed, the reaction was continued to be stirred at 0° C. for 30 min. The reaction solution was raised to room temperature and continued to be stirred for 2 hours, and the plate was sampled, and the reaction of compound X13 was basically complete.
- EDCI 1-ethyl-3 (3-dimethylpropylamine) carbodiimide
- reaction solution was directly concentrated under reduced pressure to obtain a crude compound X17 (221.61 g) with a purity of 62.05%. Purified by normal silica gel column (n-hexane/ethyl acetate) to obtain pure compound X17 (107.88 g) with a purity of 97.30%.
- Step 3 In a 2L single-neck flask, add compound X17 (107.8g), DCM (107.8mL), turn on stirring, add trifluoroacetic acid (646.8mL) to dissolve, and replace with argon for protection. Stir at room temperature for 3.5h, after TLC monitoring the basic reaction is complete, add isopropyl ether (2156mL) at one time to wash out, stir vigorously, and a white solid is precipitated (obvious exothermic phenomenon occurs during the washout process). After filtering, the filter cake was washed with isopropyl ether (200 mL ⁇ 3). The filter cake was vacuum dried overnight. Compound X18 (87.14 g) was obtained by weighing, and the purity was 97.25% by liquid phase detection.
- acetic acid was added dropwise to the reaction solution to adjust the pH to 7.0, and the reaction solution was transferred to a 3L glass bottle and sealed at -10°C
- acylated derivatives of Des(B30) human insulin modified with active ester compounds X15, X19, X20 and X21 were also prepared, and the modification process was the same as that of X18.
- Mobile phase A 0.02 mol/L anhydrous sodium sulfate-triethanolamine (100:1), pH 2.3 [weigh 2.84 g of anhydrous sodium sulfate, dissolve in water and dilute to 1000 mL, add 10 mL of triethanolamine and mix well, adjust pH with phosphoric acid value to 2.3];
- Injection volume 20 ⁇ L; sample temperature control: 5°C;
- System suitability solution Take a aliquot and cryopreserved system suitability solution, and use it directly after thawing at room temperature;
- Reference substance solution take the reference substance (for example, lysine B29 prepared according to the method described in WO2018024186A ( N ⁇ - (N ⁇ -hexadecane fatty acid-L-lysine- N ⁇ -oxobutyryl)) des (B30) human insulin) about 25mg, accurately weighed, placed in a 25mL volumetric flask, dissolved in a diluent and diluted to the mark, shaken to make a solution containing about 1mg per 1mL, as the reference solution (this solution Stable within 24h at 5°C ⁇ 3°C).
- the reference substance for example, lysine B29 prepared according to the method described in WO2018024186A ( N ⁇ - (N ⁇ -hexadecane fatty acid-L-lysine- N ⁇ -oxobutyryl) des (B30) human insulin
- test solution in the control solution of the reaction solution take an appropriate amount of the modified reaction solution, add the diluent [acetonitrile-water (1:1.7)] to dissolve and dilute to the mark, shake well, and prepare an acylated derivative containing insulin analogs per 1 mL
- the solution of about 1mg is used as the test solution (the solution is stable within 24h under the condition of 5°C ⁇ 3°C).
- Chromatographic column octadecylsilane bonded silica gel as filler (YMC-Pack ODS-AQ 5 ⁇ m 150 ⁇ 4.6mm is suitable); flow rate is 1.2mL per minute; column temperature is 10°C; detection wavelength is 200nm; injection volume is 10 ⁇ L; the diluent is methanol-acetonitrile (1:9), and the sample temperature is controlled at 10 °C.
- Relative retention time RT impurity /RT X15 (or X18)
- the content of each impurity was calculated according to the peak area normalization method.
- Table 4 shows the long-term stability test results of X15 and X18. It can be seen that from the beginning of the test to 6 months, the purity of the main peak of X18 is always more than 10% higher than that of X15, normalized total impurities; after 6 months of the stability test, the purity of the main peak of X15 decreased by 0.9% (normalized %). The normalized total impurity % increased by 0.9%); while the main peak purity % of X18 decreased by only 0.2% (normalized total impurity % increased by only 0.2%). X18 has better long-term stability than X15.
- Table 5 summarizes the comparison results of active compounds X15, X18, X19 and X20 in terms of synthesis process, quality, modification amount and modification rate, wherein X15 is the active ester described in patent publication WO2018024186A. It can be seen that the molecular structures of the active esters X18, X19 and X20 are relatively stable, the process stability is good, and they can be scaled up to kilogram production. The ester to insulin analog feed ratio was reduced by 50%. In addition, X18 has advantages in yield, purity and modification rate compared to X19 and X20.
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Abstract
La présente divulgation concerne un procédé de préparation d'un dérivé acylé d'insuline ou d'un analogue de celui-ci, comprenant l'étape consistant à faire réagir de l'insuline ou un analogue de celle-ci avec le composé de formule (I), et concerne également le composé de formule (I) et son procédé de préparation. Le procédé selon la présente divulgation a un rendement élevé et un procédé stable, peut réduire de façon significative le coût de production de dérivés acylés d'insuline ou de ses analogues, et permet une production commerciale à grande échelle.
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CN101389650A (zh) * | 2005-12-28 | 2009-03-18 | 诺沃-诺迪斯克有限公司 | 包含酰化胰岛素和锌的组合物以及制备所述组合物的方法 |
CN106496322A (zh) * | 2015-09-07 | 2017-03-15 | 江苏恒瑞医药股份有限公司 | 人胰岛素或其类似物的酰化衍生物的制备方法 |
WO2018024186A1 (fr) * | 2016-08-02 | 2018-02-08 | 江苏恒瑞医药股份有限公司 | Dérivé acylé de l'insuline humaine ou son analogue |
WO2019149245A1 (fr) * | 2018-02-01 | 2019-08-08 | 江苏恒瑞医药股份有限公司 | Composition pharmaceutique comprenant un dérivé acylé d'analogue d'insuline humaine et son procédé de préparation |
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- 2021-11-26 TW TW110144275A patent/TW202229324A/zh unknown
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101389650A (zh) * | 2005-12-28 | 2009-03-18 | 诺沃-诺迪斯克有限公司 | 包含酰化胰岛素和锌的组合物以及制备所述组合物的方法 |
CN106496322A (zh) * | 2015-09-07 | 2017-03-15 | 江苏恒瑞医药股份有限公司 | 人胰岛素或其类似物的酰化衍生物的制备方法 |
WO2018024186A1 (fr) * | 2016-08-02 | 2018-02-08 | 江苏恒瑞医药股份有限公司 | Dérivé acylé de l'insuline humaine ou son analogue |
WO2019149245A1 (fr) * | 2018-02-01 | 2019-08-08 | 江苏恒瑞医药股份有限公司 | Composition pharmaceutique comprenant un dérivé acylé d'analogue d'insuline humaine et son procédé de préparation |
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