阅读说明：本技术 一种替瑞帕肽类似物 (Tirapapotide analogue ) 是由 周述靓 王鹏 邓岚 于 2019-09-25 设计创作，主要内容包括：本发明涉及医药合成领域,公开了一种替瑞帕肽类似物。本发明所述替瑞帕肽类似物,用于制备治疗疾病的药物组合物,所述药物组合物在制备治疗下述至少一种疾病的药物中的用途,所述疾病包括II型糖尿病、糖耐量受损、I型糖尿病、肥胖、高血压、代谢综合征、血脂异常、认知障碍、动脉粥样硬化、心肌梗塞、冠状动脉心脏病、心血管疾病、中风、炎性肠道综合征和/或消化不良或胃溃疡、肝纤维化疾病和肺纤维化疾病。(The invention relates to the field of medicine synthesis, and discloses a tirapapeptide analogue. The tirapapeptide analogues of the present invention are useful for the preparation of a pharmaceutical composition for the treatment of a disease comprising type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis disease and pulmonary fibrosis.)

1. A tirapatide analog having structural formula I:

Tyr-AA1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-AA1-Leu-

Asp-Lys-Ile-Ala-Gln-Lys(R)-Ala-AA2-Val-Gln-Trp-Leu-Ile-Ala-

Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA3

structure I

AA in Structure I₁Comprises the following steps:

wherein X₁And X₂Is a compound of formula (I) in the formula (H),

or is CH₃、CH(CH₃)₂、C(CH₃)₃、CH(CH₂CH₃)₂、C(CH₂CH₃)₃、CH(CH₂CH₂CH₃)₂、C(CH₂CH₂CH₃)₃、CH(CH(CH₃))₂、C(CH(CH₃))₃、

Or is CH₂CH₃、CH₂CH(CH₃)₂、CH₂C(CH₃)₃、CH₂CH(CH₂CH₃)₂、CH₂C(CH₂CH₃)₃、CH₂CH(CH₂CH₂CH₃)₂、CH₂C(CH₂CH₂CH₃)₃、CH₂CH(CH(CH₃))₂、CH₂C(CH(CH₃))₃、

AA in Structure I₂Is Phe, or is 1-Nal, or is 2-Nal

AA in Structure I₃Is NH₂Or is OH

R in structure I is HO₂C(CH₂)_n1CO-(γGlu)_n2-(PEG_n3(CH2)_n4CO)_n5-

Wherein: n1 is an integer from 10 to 20;

n2 is an integer from 1 to 5;

n3 is an integer from 1 to 30;

n4 is an integer from 1 to 5;

n5 is an integer from 1 to 5.

2. A tirapatide analog according to claim 1, comprising a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex of the analog, a prodrug based on the compound, or a mixture of any of the foregoing.

3. A tirapapeptide analog according to claim 1 and claim 2 for use in the preparation of a pharmaceutical composition for the treatment of a disease.

4. The pharmaceutical composition according to claim 3, for use in the manufacture of a medicament for the treatment of at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis diseases and pulmonary fibrosis diseases.

5. The pharmaceutical composition according to claim 4, for use in the preparation of a medicament for the treatment of delayed efficacy and/or prevention of exacerbation of type II diabetes.

6. The pharmaceutical composition of claim 6, for use in the preparation of a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta-cell mass, and/or restoring glucose sensitivity to beta cells.

7. The tirapapeptide analog of claim 1, comprising the analog for use in a method of modulating blood glucose in vivo.

Technical Field

The invention relates to a tirapapeptide analogue and application thereof, wherein the analogue is a dual incretin peptide analogue compound for exciting human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors.

Background

GIP is a 42 amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from and protecting pancreatic beta cells in the presence of glucose. GLP-1 is a 37 amino acid peptide that stimulates insulin secretion, protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying, and food intake, resulting in weight loss. GIP and GLP-1 are known as incretins; incretin receptor signaling plays a key physiologically relevant role in glucose homeostasis. In normal physiology, GIP and GLP-1 are secreted from the intestinal tract after a meal, and these incretins enhance physiological responses to food, including satiety, insulin secretion, and nutrient handling.

The most common side effect of GLP-1 analogs is that administration does not achieve full-effect glycemic control and weight loss, whereas GIP alone has a very modest glucose lowering capacity in type 2 diabetics. Both native GIP and GLP-1 can be rapidly inactivated by the ubiquitous protease DPP IV and therefore can only be used for short-term metabolic control.

It is reported in WO 2013/164483 and WO 2014/192284 that certain GIP/GLP-1 analogs exhibit both GIP and GLP-1 activity and that such analogs can be found to achieve better glycemic control and weight loss.

Disclosure of Invention

The invention provides a tirapapeptide analogue and application thereof, wherein the analogue is a dual incretin peptide analogue compound for exciting human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors.

To achieve the above object, the present invention provides, in a first aspect, a compound of structure I, a pharmaceutically acceptable salt, solvate, chelate or non-covalent complex thereof, a prodrug based on the compound, or any mixture thereof.

Tyr-AA1-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-AA1-Leu-

Asp-Lys-Ile-Ala-Gln-Lys(R)-Ala-AA2-Val-Gln-Trp-Leu-Ile-Ala-

Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AA3

Structure I

AA in Structure I₁Comprises the following steps:

wherein X₁And X₂Is a compound of formula (I) in the formula (H),

or is CH₃、CH(CH₃)₂、C(CH₃)₃、CH(CH₂CH₃)₂、C(CH₂CH₃)₃、CH(CH₂CH₂CH₃)₂、C(CH₂CH₂CH₃)₃、CH(CH(CH₃))₂、C(CH(CH₃))₃、

Or is CH₂CH₃、CH₂CH(CH₃)₂、CH₂C(CH₃)₃、CH₂CH(CH₂CH₃)₂、CH₂C(CH₂CH₃)₃、CH₂CH(CH₂CH₂CH₃)₂、CH₂C(CH₂CH₂CH₃)₃、CH₂CH(CH(CH₃))₂、CH₂C(CH(CH₃))₃、

AA in Structure I₂Is Phe, or is 1-Nal, or is 2-Nal

AA in Structure I₃Is NH₂Or is OH

R in structure I is HO₂C(CH₂)_n1CO-(γGlu)_n2-(PEG_n3(CH2)_n4CO)_n5-

Wherein: n1 is an integer from 10 to 20;

n2 is an integer from 1 to 5;

n3 is an integer from 1 to 30;

n4 is an integer from 1 to 5;

n5 is an integer from 1 to 5;

the invention also provides pharmaceutical compositions comprising a compound according to the invention and the use of a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for the treatment of a disease.

Preferably, the use of the pharmaceutical composition in the manufacture of a medicament for the treatment of at least one of type II diabetes, impaired glucose tolerance, type I diabetes, obesity, hypertension, metabolic syndrome, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, cardiovascular disease, stroke, inflammatory bowel syndrome and/or dyspepsia or gastric ulcer, liver fibrosis diseases and pulmonary fibrosis diseases.

Preferably, the pharmaceutical composition is applied to the preparation of medicines for treating delayed drug effect and/or preventing worsening of type II diabetes.

Preferably, the use of the pharmaceutical composition for the manufacture of a medicament for reducing food intake, reducing beta cell apoptosis, increasing islet beta cell function, increasing beta cell mass, and/or restoring glucose sensitivity to beta cells.

The invention still further provides methods of administering the compounds to a subject for the modulation of blood glucose in vivo.

Further details of the invention are set forth below, or some may be appreciated in embodiments of the invention.

Unless otherwise indicated, the amounts of the various ingredients, reaction conditions, and the like used herein are to be construed in any case to mean "about". Accordingly, unless expressly stated otherwise, all numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in the respective experimental conditions.

Herein, when a chemical structural formula and a chemical name of a compound are ambiguous or ambiguous, the compound is exactly defined by the chemical structural formula. The compounds described herein may contain one or more chiral centers, and/or double bonds and the like, and stereoisomers, including isomers of double bonds (e.g., geometric isomers), optical enantiomers, or diastereomers, may also be present. Accordingly, any chemical structure within the scope of the description, whether partial or complete, including similar structures as described above, includes all possible enantiomers and diastereomers of the compound, including any stereoisomer alone (e.g., pure geometric isomers, pure enantiomers, or pure diastereomers), as well as any mixture of such stereoisomers. Mixtures of these racemates and stereoisomers may also be further resolved into the enantiomers or stereoisomers of their constituent members by those skilled in the art using non-stop separation techniques or methods of chiral molecular synthesis.

The compounds of formula I include, but are not limited to, optical isomers, racemates and/or other mixtures of these compounds. In the above case, a single enantiomer or diastereomer, such as an optical isomer, can be obtained by asymmetric synthesis or racemate resolution. Resolution of the racemates can be accomplished by various methods, such as conventional recrystallization from resolution-assisting reagents, or by chromatographic methods. In addition, the compounds of formula I also include cis and/or trans isomers with double bonds.

The compounds of the present invention include, but are not limited to, the compounds of formula I and all of their pharmaceutically acceptable different forms. The pharmaceutically acceptable different forms of these compounds include various pharmaceutically acceptable salts, solvates, complexes, chelates, non-covalent complexes, prodrugs based on the above and any mixtures of these forms.

The compound shown in the structure I provided by the invention has stable property, is not easily degraded by dipeptidyl peptidase IV (DPP-IV) in vivo, is a GIP/GLP-I dual agonist analogue, and has obvious effects of reducing blood sugar and weight.

Detailed Description

The invention discloses a GIP/GLP-1 analogue and application thereof, and a person skilled in the art can appropriately improve related parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the process of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the compounds and processes described herein, as well as other changes and combinations of the foregoing, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.

The Chinese names corresponding to the English abbreviations related in the invention are shown in the following table:

english abbreviation	Name of Chinese	English abbreviation	Name of Chinese
				Fmoc	9-fluorenylmethoxycarbonyl group	OtBu	Tert-butoxy radical
tBu	Tert-butyl radical	Boc	Boc-acyl
				Trt	Trityl radical	Pbf	(2, 3-dihydro-2, 2, 4, 6, 7-pentamethylbenzofuran-5-yl) sulfonyl group
Ala	Alanine	Leu	Leucine
				Arg	Arginine	Lys	Lysine
Asn	Asparagine	Met	Methionine
				Asp	Aspartic acid	Phe	Phenylalanine
Cys	Cysteine	Pro	Proline
				Gln	Glutamine	Ser	Serine
Glu	Glutamic acid	Thr	Threonine
				Gly	Glycine	Trp	Tryptophan
His	Histidine	Tyr	Tyrosine
				Ile	Isoleucine	Val	Valine
Dap	2, 3-diaminopropionic acid	Dab	2, 4-diaminobutyric acid
				Orn	Ornithine	Dah	2, 7-Diaminoheptanoic acid
Dhthr	Dehydroxythreonine	Dhval	2, 3-didehydro valine