WO2018219295A1 - 二肽基肽酶iv抑制剂的氘代1,2,4-三嗪衍生物 - Google Patents

二肽基肽酶iv抑制剂的氘代1,2,4-三嗪衍生物 Download PDF

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WO2018219295A1
WO2018219295A1 PCT/CN2018/089027 CN2018089027W WO2018219295A1 WO 2018219295 A1 WO2018219295 A1 WO 2018219295A1 CN 2018089027 W CN2018089027 W CN 2018089027W WO 2018219295 A1 WO2018219295 A1 WO 2018219295A1
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Prior art keywords
compound
pharmaceutically acceptable
dipeptidyl peptidase
acceptable salt
less
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PCT/CN2018/089027
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English (en)
French (fr)
Inventor
刘刚
李硕
温晓明
胡春云
黄伟鑫
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深圳信立泰药业股份有限公司
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Publication of WO2018219295A1 publication Critical patent/WO2018219295A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicinal chemistry, in particular to a series of substituted 1,2,4-triazine derivatives of dipeptidyl peptidase IV (DPP-IV) inhibitors.
  • DPP-IV dipeptidyl peptidase IV
  • Dipeptidyl Peptidase IV (DPP-IV, EC 3.4.14.5) is a serine protease that hydrolyzes N-terminally from the N-position of the N-terminus of L-valine and L-alanine-containing peptides. Peptide. Although the function of DPP-IV has not been fully elucidated, it is considered to be a major physiological regulator of certain regulatory polypeptides, neuropeptides, circulating hormones, and chemokines. DPP-IV, although a multi-effect enzyme, has many substrates, but is best known as incretin, which includes glucagon-like peptide-1 (GLP-1) and glycoprotein-dependent insulin releasing peptide (GIP). ).
  • GLP-1 glucagon-like peptide-1
  • GIP glycoprotein-dependent insulin releasing peptide
  • Incretin is an intestinal hormone that secretes and promotes the intake of nutrients within minutes of ingestion of nutrients.
  • GLP-1 and GIP have the same effect on ⁇ cells, which can improve ⁇ cell function, including promoting glucose-dependent insulin secretion, inducing ⁇ cell proliferation, and enhancing anti-apoptotic effects.
  • GLP-1 Unlike GIP, GLP-1 still promotes insulin secretion in type 2 diabetes. Therefore, increasing GLP-1 is a promising means of treating type 2 diabetes.
  • the use of GLP-1 in patients with type 2 diabetes can significantly reduce blood glucose.
  • GLP-1 as a substrate for DPP-IV is rapidly hydrolyzed and inactivated in vivo, so the development of DPP-IV inhibitors is of great significance for the treatment of diabetes. .
  • DPP-IV inhibitor research has made great progress, and DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use.
  • DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use.
  • the most striking feature of DPP-IV inhibitors is that since incretin is secreted only after eating in the body, DPP-IV inhibitors are not easy to increase insulin levels when inappropriate, resulting in many side effects of hypoglycemic drugs.
  • long-acting DPP-IV inhibitors have been particularly attractive. Long-acting DPP-IV inhibitors are more convenient to use and have the ideal hypoglycemic effect, which makes them more popular in patients with type 2 diabetes.
  • Trelagliptin is a weekly DPP-IV inhibitor developed by Takeda Pharmaceutical Co., Ltd. The safety and efficacy of this drug has been confirmed in the clinic and has been approved for marketing in Japan. However, drugs that are too long-lasting tend to In long-term use, due to the strong drug effect, it may cause some adverse reactions in the human body, as well as some side effects caused by long-term maintenance of high blood drug concentration.
  • PCT/CN2010/080370 describes a series of DPP-IV inhibitors of new mother core structures.
  • the preferred compound I represented by the following formula is represented by the chemical name: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-
  • the 1,2,4-triazin-4(5H)-yl)methyl)-4-fluorobenzonitrile chemistry is:
  • the deuteration strategy of drug molecules is an attractive method because the substitution of one or more hydrogen atoms by helium atoms may slow down the rate of CYP-mediated drug metabolism; moreover, helium is safe, stable, non-radiative.
  • Hydrogen isotope is also beneficial for the development of new drugs, such as Teva's Huntington's disease drug AUSTEDO. Compared with hydrogen, bismuth and carbon form stronger chemical bonds, so the bond energy of C-D bond oxidation can be improved.
  • DPP-IV dipeptidyl peptidase IV
  • substitution means that some or all of the hydrogen on the compound is replaced by deuterium. That is, R 1 to R 19 are selected from hydrazine or hydrogen, and at least one of R 1 to R 19 is hydrazine.
  • the total relative amount of " ⁇ " in the above proposed compounds will be less than 49.9% of the compound. In other embodiments, the total relative amount of " ⁇ " will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5% of the compound. Less than 3%, less than 1%, or less than 0.5%.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 16 and R 17 are fluorene.
  • the IR compound of the present invention is preferably a compound of the right type. Compared to the hydrazine substitution at other sites, it is expected to have a more pronounced effect of reducing system clearance and increasing the biological half-life of the compound.
  • R 4 and R 5 are both deuterium, and/or R 6 , R 7 and R 8 are both deuterium, and/or R 9 and R 10 are both deuterium, and/or R 16 and R 17 is also awkward.
  • Specific preferred compounds include, but are not limited to, the following compounds:
  • the invention also provides pharmaceutically acceptable salts of the compounds of the invention.
  • the salt of the compound of the present invention is formed between an acid and a basic group of the compound such as an amino function, or between a base and an acidic group of the compound such as a carboxyl function.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to tissue contact suitable for use in humans or other mammals for a sufficient medical reason without undue toxicity, irritation, allergic response, etc., and reasonable The compound/risk ratio is proportional to the compound.
  • “Pharmaceutically acceptable salt” refers to any salt which is non-toxic and which, when administered, is capable of providing the compound of the invention either directly or indirectly.
  • Commonly used to form pharmaceutically acceptable salts include: sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, cokes Phosphate, hydrochloride, bromate, iodate, acetate, propionate, citrate, octanoate, acrylate, formate, isobutyrate, citrate, heptanoate , propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- Diacid salt, hexyne-1,6-diacid salt, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, sulfonate, xylene s
  • Preferred pharmaceutically acceptable salts are, for example, benzoates and the like.
  • Particular preferred pharmaceutically acceptable salts of the compounds include, but are not limited to, the pharmaceutically acceptable salts of the following compounds:
  • At least one compound described herein and/or at least one pharmaceutically acceptable salt thereof for use as an agent for ameliorating and/or for inhibiting DPPIV enzymes in a patient, such as a mammal, in need of inhibition of DPP-IV And a method comprising administering an effective amount of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof.
  • the invention further encompasses the use of at least one compound and/or at least one pharmaceutically acceptable salt thereof as a dipeptidyl peptidase IV activity inhibitor.
  • a subject is a mammal, such as a human, male or female, in need of inhibition of dipeptidyl peptidase-IV enzyme activity.
  • other mammals can also be treated in accordance with the methods of the invention.
  • mammals including but not limited to: cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovid, ovine, equine, canine, feline, rodent or murine animals treatment.
  • this method can also be applied to other species, such as birds (such as chicken).
  • compositions comprising at least one compound described herein and/or at least one pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention also provides a process for the preparation of a medicament for inhibiting DPP-IV activity in a human or animal comprising combining at least one compound and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention includes any composition prepared by mixing at least one compound of the formula (IR) and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • Dipeptidyl peptidase-IV is a cell surface protein involved in many biological functions. It has a wide distribution of tissues (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelial cells, lymphocytes and bone marrow cells, serum), and expression levels of DPP-IV in different tissues and cell types. different. DPP-IV is identical to the T cell activation marker CD26 and can cleave a large number of immunoregulatory, endocrine and neuropeptides in vitro. This suggests that DPP-IV plays a potential role in a variety of disease processes in humans or other species.
  • the compounds of the present invention and/or pharmaceutically acceptable salts thereof are useful for the treatment of the following diseases, disorders and symptoms.
  • Type II diabetes and related diseases Studies have shown that in vivo glucagon GLP-1 and GIP are rapidly degraded by DPP-IV. DPP-IV(-/-) deficient mice and preliminary clinical trials have shown that inhibition of DPP-IV increases the steady-state concentration of GLP-1 and GIP, thereby increasing glucose tolerance. Similar to GLP-1 and GIP, it is likely that other glucagon family polypeptides (such as PACAP) involved in glycemic regulation will also be inactivated by DPP-IV degradation. Inactivation of these polypeptides by DPP-IV also plays a role in glucose homeostasis.
  • glucagon family polypeptides such as PACAP
  • the DPP-IV inhibitor of the present invention is effective for treating type II diabetes, and for treating and preventing a large number of complications accompanying type II diabetes, including but not limited to, X syndrome (also called metabolic syndrome), low reactivity Blood sugar and type 2 diabetes dyslipidemia.
  • X syndrome also called metabolic syndrome
  • Obesity discussed below, is another symptom that is often associated with type 2 diabetes, and the compounds of the invention may also have therapeutic effects.
  • the compound of the present invention and/or a pharmaceutically acceptable salt thereof is effective for treating or preventing one or more of the following diseases or symptoms: (1) hyperglycemia, (2) impaired glucose tolerance, and (3) insulin resistance, (4) Obesity, (5) dyslipidemia, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL, (11) High and low density lipoprotein levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative Colitis, (16) other inflammation, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative diseases, (20) retinopathy, (21) nephropathy, (22) neurological diseases, (23) X syndrome, (24) ovarian high androgen (polycystic ovary syndrome), (25) type II diabetes, (26) growth hormone deficiency, (27) neutropenia, (2
  • the "disease” is preferably diabetes and related metabolic diseases among diseases which can be treated by the above DPP-IV, and diabetes is a group of metabolic diseases characterized by hyperglycemia. Usually caused by impaired insulin secretion or impaired biological effects, including type I diabetes, ie insulin-dependent diabetes mellitus, and II diabetes, ie non-insulin-dependent diabetes mellitus.
  • the administration of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof includes: oral administration, injection (e.g., intramuscular injection, intraperitoneal injection, intravenous injection, lateral ventricle injection, cerebral cistern injection or infusion, subcutaneous Injection, or implantation), inhalation spray, nasal mucosal administration, vaginal administration, rectal administration, sublingual administration, or topical administration.
  • injection e.g., intramuscular injection, intraperitoneal injection, intravenous injection, lateral ventricle injection, cerebral cistern injection or infusion, subcutaneous Injection, or implantation
  • inhalation spray e.g., nasal mucosal administration, vaginal administration, rectal administration, sublingual administration, or topical administration.
  • the compounds of the present invention can be prepared, either singly or together, in suitable unit formulations, including pharmaceutically acceptable non-toxic carriers for conventional use, and adjuvants and excipients which are suitable for different routes of administration.
  • At least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof is effective for a warm-blooded animal (e.g., mouse, rat, horse, cow, sheep, dog, cat, etc.) in addition to a therapeutic effect on humans. .
  • a warm-blooded animal e.g., mouse, rat, horse, cow, sheep, dog, cat, etc.
  • compositions containing at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof can be prepared in different unit dosage forms depending on the mode of administration, and can be prepared by well-known techniques of pharmacy.
  • at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof is combined with a carrier comprising one or more essential excipients.
  • the preparation of the pharmaceutical composition comprises uniformly and intimately combining at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof with a liquid carrier or/and a microsolid carrier, Then, if necessary, the product is made into the desired dosage form.
  • the at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof is present in an amount sufficient to produce the desired therapeutic effect on the development and progression of the disease.
  • the pharmaceutical composition containing at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof can be formulated into a form suitable for oral administration such as a tablet, a buccal tablet, a throat, an aqueous or oily substance.
  • a form suitable for oral administration such as a tablet, a buccal tablet, a throat, an aqueous or oily substance.
  • compositions suitable for oral administration can be prepared by known pharmaceutical formulation procedures.
  • the pharmaceutical composition comprises one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives.
  • Tablets are prepared by mixing the active ingredient with a non-toxic, pharmaceutically acceptable formulation suitable for the preparation of tablets.
  • excipients may include inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulation and disintegrants (such as corn starch or alginic acid); binders (such as starch, gelatin, or Acacia); a lubricant (such as magnesium stearate, stearic acid or talc).
  • These tablets may be uncoated or may be extended by the known coating technique to prolong the disintegration of the tablet in the gastrointestinal tract and the absorption of the drug, thereby allowing the drug to exert a sustained action over a longer period of time.
  • a delay material such as glyceryl stearate or glyceryl stearic acid can be employed.
  • Tablet coating can also be employed to make it a permeable tablet to control the release of the drug, such as sustained release or delayed release.
  • the preparation for oral use may also be a hard gelatin capsule characterized in that the hard gelatin is at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof and an inert solid diluent (such as calcium carbonate, calcium phosphate) Or kaolin; or a soft gelatin capsule, characterized in that the soft capsule is at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof with water or an oily medium (such as peanut oil) , liquid paraffin, and / or olive oil) are mixed.
  • an oily medium such as peanut oil
  • the DPP-IV inhibitor compound of the present invention may be combined with a carrier to prepare a dosage form which prevents rapid elimination of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof, such as a delayed release tablet and a package. Clothes piece. Other active compounds are also included in the dosage form to achieve the desired combination of properties.
  • Oral pharmaceutical dosage forms can be solid, gel or liquid.
  • solid dosage agents include, but are not limited to, tablets, capsules, granules, and mixed powders. More specific examples of oral tablets include compressed tablets, chewable tablets and enteric coated tablets, sugar coated tablets or film coated tablets. Examples of capsules include hard or soft capsules. Granules and powders can be formulated as non-effervescent or effervescent agents. Each dosage form can be combined with other known common ingredients.
  • the DPP-IV inhibitors of the invention are formulated into a solid dosage form, such as a capsule or tablet.
  • Tablets, pills, capsules, tablets, and the like may optionally contain one or more of the following ingredients or compounds of similar nature: a binder; a diluent; a disintegrant; a lubricant; a glidant; a sweetener and Flavoring agent.
  • Useful binders include, but are not limited to, microcrystalline cellulose, tragacanth, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste.
  • Useful lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stone pine and stearic acid.
  • Useful diluents include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate.
  • Useful glidants include, but are not limited to, colloidal silica.
  • Useful disintegrants include, but are not limited to, croscarmellose sodium, sodium carboxymethyl starch, alginic acid, corn starch, potato starch, soap clay, methyl cellulose, agar and carboxymethyl cellulose.
  • Useful colorants include, but are not limited to, water soluble FD dyes and C dyes approved for use, mixtures of water soluble FD dyes and C dyes, and aluminum hydroxide suspensions of water insoluble FD dyes and C dyes.
  • Useful sweeteners include, but are not limited to, sucrose, lactose, mannitol, artificial sweeteners such as cyclamate and saccharin, and any amount of spray-dried perfume.
  • Useful flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic blends with good mouthfeel (including but not limited to: peppermint, methyl salicylate).
  • Useful humectants include, but are not limited to, propylene glycol stearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Useful antiemetic coating agents include, but are not limited to, fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalate.
  • Useful film coating agents include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate.
  • At least one compound of the invention (IR) and/or at least one pharmaceutically acceptable salt is provided in the form of an optional composition which is formulated to protect the compound from the acidic environment of the stomach. Destroyed form.
  • the composition can be formulated as an enteric coating to maintain its integrity in the stomach and release the active compound in the intestinal tract.
  • the compositions may also be formulated in combination with an antacid or other similar ingredients.
  • a liquid carrier such as a fatty oil may optionally be added.
  • the unit dosage form may optionally also include a variety of other ingredients which modify the physical properties of the formulation, such as sugar coating or enteric solvent coating.
  • At least one compound or/and at least one pharmaceutically acceptable salt thereof of the present invention can be administered by making an elixirs, suspensions, syrups, coatings, chewables or the like.
  • a syrup may optionally include, in addition to at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof, a sweetener sucrose, a preservative, a colorant, and a perfume.
  • Examples of pharmaceutically acceptable carriers contained in a tablet comprising at least one compound of the invention or/and at least one pharmaceutically acceptable salt thereof include, but are not limited to, binders, lubricants, diluents, granules Degreasers, colorants, flavoring and wetting agents.
  • Enteric coated tablets can maintain their integrity in the acidic environment of the stomach due to enteric coating, and dissolve or disintegrate the active compound in the neutral or alkaline environment of the intestinal tract.
  • Sugar-coated tablets can be compressed into tablets of different layers with a pharmaceutically acceptable carrier.
  • the film-coated tablets can be tabletted with a polymer or other suitable coating. Multiple compression tablets can be made by multiple compressions using the pharmaceutically acceptable carriers described above. Colorants may also be used in the manufacture of tablets. Flavoring and sweetening agents are also useful in tablets, particularly in the manufacture of chewable tablets and lozenges.
  • Liquid oral preparations include, but are not limited to, aqueous solutions, emulsions, suspensions, solutions, and/or suspensions prepared by reconstitution of non-effervescent granules, and effervescent agents prepared by reconstitution of effervescent granules.
  • Aqueous solutions include, but are not limited to, tinctures and syrups.
  • the elixirs described herein refer to aqueous alcohol preparations which clarify the sweetness.
  • Pharmaceutically acceptable carriers useful in elixirs include, but are not limited to, solvents. Specific examples of the solvent include glycerin, sorbitol, ethanol, and syrup.
  • a syrup as used herein refers to a concentrated sugar solution, such as sucrose. The syrup may optionally further comprise a preservative.
  • An emulsion refers to a two-phase system in which a liquid is uniformly dispersed in the form of small liquid beads into another liquid phase.
  • the emulsion can optionally be, but is not limited to, a water-in-oil or oil-in-water emulsion.
  • Pharmaceutically acceptable carriers useful in emulsions include, but are not limited to, non-aqueous liquids, emulsifiers, and preservatives.
  • Pharmaceutically acceptable carriers for reconstitution into non-effervescent granules in liquid oral dosage forms include diluents, sweeteners and wetting agents.
  • Pharmaceutically acceptable carriers for effervescent granules include: an organic acid and a carbon dioxide generating material for reconstitution into a liquid oral dosage form.
  • Coloring agents and flavoring agents may optionally be added to each of the above dosage forms.
  • preservatives include: glycerin, propyl parabens, benzoic acid, sodium benzoate and ethanol.
  • emulsifiers that may be used include: gelatin, gum arabic, tragacanth, soap clay, and surfactants (such as polyoxyethylene sorbitan monooleate).
  • suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, magnesium aluminum silicate, and gum arabic.
  • Diluents include: lactose and sucrose.
  • Sweeteners include: sucrose, syrup, glycerin and artificial sweeteners such as sodium cyclamate and saccharin.
  • humectants that may be used include: propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene alkyl ether.
  • organic acids that may be used include: citric acid and tartaric acid.
  • Illustrative examples of carbon dioxide generating materials that may be used in the effervescent agent include sodium hydrogencarbonate and sodium carbonate.
  • Colorants include water soluble FD dyes and C dyes that have been approved for use, and mixtures thereof.
  • flavoring agents that may be used include: a mixture of a natural flavor extracted from a plant such as a fruit and a synthetic compound having a good mouthfeel.
  • a solution or suspension for preparing a solid dosage form such as propylene carbonate, vegetable oil or triglyceride, is easier to encapsulate.
  • Solutions for the preparation of liquid dosage forms, such as polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable carrier such as water to facilitate administration.
  • the active compound or its salt can be dissolved or dispersed in vegetable oils, ethylene glycol, triglycerides, propylene glycol esters (such as propylene carbonate) and other similar carriers, and the liquid or suspension can be filled into a hard Or a soft coffin to make a liquid or semi-solid oral preparation; the above solution or suspension is enclosed in a hard or soft capsule shell.
  • the invention also includes compositions for administration of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof, by parenteral administration.
  • Non-digestive routes of administration generally refer to administration by injection (including subcutaneous, intramuscular or intravenous).
  • the injection can be formulated into any convenient administration form such as a solution or suspension, a solid which is suitable for dissolution or suspension in a liquid before injection, or an emulsion.
  • Adjuvants for making the compounds of the present invention into injections include, but are not limited to, water, saline, dextrose, glycerol or ethanol.
  • a small amount of non-toxic auxiliary ingredients such as wetting agents and emulsifiers, pH buffers, stabilizers, solubilizers and the like (such as sodium acetate, sorbitan monolaurate) may also be optionally added to the injection. , triethanolamine oleic acid and cyclodextrin). It can also be formulated as an implant with sustained release properties which maintains the concentration of the drug at a stable level.
  • the amount of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof in the above parenteral dosage form depends on its particular nature, the activity of the compound, and the needs of the patient.
  • routes of administration for parenteral administration include intravenous, subcutaneous or intramuscular administration.
  • Formulations for parenteral administration include: sterile solutions for injection, sterile soluble dry powders, such as lyophilized powder (dissolved with a solvent before use), tablets for subcutaneous injection, sterile suspension for injection, sterile non-soluble dry powder (Dispersed with solvent before use) and sterilized emulsion for injection.
  • the solution for injection may be an aqueous solution or a non-aqueous solution.
  • Suitable carriers for the preparation of intravenous administration include, but are not limited to, physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents (such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof).
  • physiological saline physiological saline
  • PBS phosphate buffered saline
  • thickening and solubilizing agents such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.
  • a pharmaceutically acceptable carrier which can be used in the preparation of a parenteral dosage form, including but not limited to: aqueous solvents, nonaqueous solvents, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying Agents, isolation or chelating agents and other pharmaceutically acceptable substances.
  • Possible water solvents include: sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, glucose injection and lactated Ringer's injection.
  • Non-aqueous solvents that may be used include: vegetable oils, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Formulations for parenteral administration may be added to bacteriostats or fungicides, especially when the pharmaceutical preparations are available in a variety of packaging sizes.
  • Antibacterial agents which may be used include: phenols or cresols, mercury preparations, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Isotonic agents which may be used include: sodium chloride and isotonic agents of glucose. Buffers that may be used include: phosphates and citrates. Possible antioxidants include sodium bisulfate. Local anesthetics that may be used include procaine hydrochloride. Suspending and dispersing agents which may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Emulsifiers that may be used include: sorbate 80 (Tween 80). Metal ion separation or chelating agents that may be used include ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • Pharmaceutically acceptable carriers for increasing water solubility include: ethanol, polyethylene glycol, and propylene glycol.
  • Carriers for adjusting pH adjustment include sodium hydroxide, hydrochloric acid, citric acid or lactic acid.
  • concentration of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof in the parenterally administered preparation can be appropriately adjusted in order to enable the injection to produce a good pharmacological action.
  • concentration and/or dosage of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof will depend on the weight, age and physical condition of the patient or animal being administered.
  • a unit dose of the injectable preparation may be enclosed in an ampoule, vial or needle syringe.
  • Non-oral administration preparations should be sterilized by conventional methods.
  • Injections can be used for topical or systemic administration.
  • at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof is capable of producing a pharmacological agent in a dose ranging from 0.1% w/w to 90% w/w or higher, for example, in a tissue to be administered
  • concentration of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof is greater than 1% w/w.
  • At least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof may be administered once or in divided doses. The exact dose and duration of administration of the drug will depend on the site of the parenteral administration, the carrier and other variables that can be determined by known treatment regimens or by extrapolation from in vitro and in vivo data.
  • the patient's age is different and the dose is different.
  • the patient's medication regimen should be adjusted at any time based on the needs of the individual's medication and the judgment of the professional. Therefore, the specific drug concentration can be referred to the above drug concentration range, but it is not limited to this concentration range.
  • the at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof may be prepared into a suspension or other suitable preparation by micronization, or may be derivatized into a more soluble active product or prepared as a prodrug.
  • the dosage form of the final mixture will depend on a number of factors, including the intended mode of administration and the solubility of the compound in the chosen carrier or solvent.
  • the effective concentration of the drug to achieve a symptom that alleviates the disease can be determined empirically.
  • At least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof may also be formulated as a lyophilized powder which, when used, is reconstituted into a solution, emulsion or other mixture.
  • the lyophilized powder can also be made into a solid or a gel.
  • the preparation of the lyophilized powder comprises the steps of: glucose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose or other suitable material, about 1-20%, for example 5% to 15%, dissolved in a suitable buffer such as citrate, sodium phosphate and/or potassium phosphate and/or other conventionally known buffers (approximately neutral pH).
  • a suitable buffer such as citrate, sodium phosphate and/or potassium phosphate and/or other conventionally known buffers (approximately neutral pH).
  • At least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof is then added to the above solution, for example, at a temperature above room temperature (30-35 ° C), and stirred until it is completely dissolved.
  • the solution is then diluted with buffer to the desired concentration, filtered to remove bacteria and removed, ensuring that the solution is sterile and sub-packed into small glass vials for lyophilization.
  • Each vial may contain a single dose or multiple doses of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof.
  • At least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof can also be administered by making a topical composition.
  • the composition can be used for topical administration as well as for systemic administration.
  • the topical composition can be formulated into a solution, a suspension, an emulsion or the like, and the mixture can be formulated into a preparation such as a cream, a gel, an ointment, an emulsion, a solution, an elixir, a lotion, a suspension. , elixirs, pastes, foams, aerosols, enemas, sprays, suppositories, bandages, dermal patches or any other formulation suitable for topical administration.
  • the at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof may also be formulated into an aerosol for topical administration, such as an inhalant, for example, a gas of a steroid which treats an inflammatory disease, particularly asthma.
  • an inhalant for example, a gas of a steroid which treats an inflammatory disease, particularly asthma.
  • aerosols Preparation of aerosols.
  • These formulations for administration by the respiratory tract may be formulated as an aerosol, spray solution or inhalation dry powder, either alone or in combination with an inert carrier such as lactose.
  • the particle diameter of the formulation when administered through the respiratory tract should be less than 50 microns, preferably less than 10 microns.
  • the at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof may also be formulated for topical administration, such as topical application to the skin and mucous membranes, for example, for gels, emulsions and lotions. For eye diseases, or for intracerebral or intraspinal administration. Methods for topical administration include transdermal administration, ocular or mucosal administration or inhalation administration.
  • the nasal drops of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof may be formulated into a nasal mucosal administration product alone or in combination with other pharmaceutically acceptable adjuvants.
  • rectal administration forms for producing systemic effects are suppositories, tablets and capsules.
  • the rectal suppository as used herein refers to a solid preparation which can be inserted into the rectum, softened and melted under body temperature to release one or more pharmacologically active ingredients having therapeutic effects.
  • the pharmaceutically acceptable materials for use in suppositories are bases or excipients, as well as materials which increase the melting point of the suppository.
  • the base comprises: cocoa butter (cocoa butter), glycerin gum, polyethylene glycol and monoglyceride, a mixture of diglycerides and triglycerides in suitable proportions and fatty acids. Mixtures of different matrices can also be used. Substances that increase the melting point of suppositories include blubber and wax. Suppositories can be prepared by molding. The standard weight of rectal suppositories is about 2-3 mg. The preparation of tablets and capsules for rectal administration and the preparation of pharmaceutically acceptable excipients are consistent with the preparation of tablets and capsules for oral administration.
  • the compound of the present invention inhibits the activity of DPP-IV enzyme, and the dose for the treatment and prevention of the disease is generally about 0.1 to 1000 mg/day, and may be administered in a single administration or in multiple administrations.
  • the dosage administered is from about 0.1 to about 250 mg/day, such as from about 0.5 to about 100 mg/day. Suitable dosages can range from about 0.1 to 1000 mg/kg/day, from about 0.1 to 500 mg/kg/day, or from about 0.1 to 50 mg/day. The dose administered in the above range may be 0.1-0.5, 0.5-5 or 5-50 mg/day.
  • the tablet composition contains 1.0 to 1000 mg of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof, and the amount of the active ingredient in the tablet can be adjusted according to the symptoms of the treated patient.
  • the content of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof in the tablet may be, for example, 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0. , 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 mg.
  • the method of administering at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof may be 1-2 times a day, such as once or several times a day.
  • At least one compound of the invention in an animal test for treating or preventing diabetes and/or hyperglycemia or hypertriglyceridemia or other disease with at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof The test results for and/or at least one pharmaceutically acceptable salt thereof are generally satisfactory.
  • the dosage to be administered is about 0.1-3000 mg/day, and the administration method may be once or twice daily, 2-6 times, or in a sustained release dosage form, or once every 2 days, once every 3 days, Once every 4 days, once every 5 days, etc.
  • the total daily dose is from about 1 mg to about 1000 mg, for example from about 1 mg to about 50 mg.
  • the total daily dose is generally from about 1 mg to about 50 mg, and the dosage regimen can be adjusted to show that the drug produces the best therapeutic effect.
  • the particular dosage administered and the number of administrations will vary depending on the particular patient, depending on a number of influencing factors, including: at least one compound of the invention and/or at least one pharmaceutically acceptable
  • the activity of the salt, the metabolic stability and duration of action of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof, the age, weight, health, sex, diet, mode of administration and time of the patient, the drug The clearance rate, the combination of the drug, the severity of the disease, and the condition the patient is receiving.
  • the compound of the present invention and/or a pharmaceutically acceptable salt thereof can also be used in combination with other drugs for the treatment of the above diseases, disorders and symptoms.
  • the compound of the present invention and/or a pharmaceutically acceptable salt thereof can be used in combination with one or more other drugs for the therapeutic treatment of a compound of the formula (IR) and/or a pharmaceutically acceptable salt thereof or other drug A disease or condition, especially if the combination is more safe or more effective than using the drug alone.
  • These other drugs are used in conventional dosages and in a conventional manner, together with at least one compound of the formula (IR) and/or at least one pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains at least one drug and at least one formula (IR) A compound and/or at least one pharmaceutically acceptable salt thereof.
  • the combination therapy may also be administered at least one compound of the formula (IR) and/or at least one pharmaceutically acceptable salt thereof and the other drug or drugs in different dosing cycles.
  • the compounds of the invention and the other active ingredients may be administered in lower doses than those employed alone.
  • pharmaceutical compositions of the invention include, but are not limited to, a combination of one or more additional active ingredients with at least one compound of formula (IR) and/or at least one pharmaceutically acceptable salt thereof.
  • DPP-IV dipeptidyl peptidase IV
  • insulin sensitizers including but not limited to PPAR gamma agonists, such as glitazones (eg, troglitazone, pioglitazone, en Glitazone, MCC-555, rosiglitazone, baglitazone, etc.) and other PPAR ligands, including PPAR ⁇ / ⁇ dual agonists, such as KRP-297 and moglitastat, and PPAR ⁇ agonists, such as Norfic acid derivatives (eg, gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin and phenform
  • At least one compound or/and at least one pharmaceutically acceptable salt thereof of the present invention may also be combined with other active substances which have no effect on their therapeutic effects or which enhance their action, such as antacids, H2 receptor blockers and diuretics.
  • active substances such as antacids, H2 receptor blockers and diuretics.
  • at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof is used for the treatment of asthma or hypertension, it can be used in combination with other bronchodilators or antihypertensive agents, respectively.
  • compositions of the present invention comprise one or more additional active ingredients and at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof.
  • the weight ratio of at least one compound of the invention and/or at least one pharmaceutically acceptable salt thereof to at least one other active ingredient may vary, depending on the effective dose of each ingredient. For example, an effective dose of each active ingredient can be used.
  • the weight ratio of the compound of the invention to the other active ingredient is, for example, from 1000:1 Up to 1:1000, for example from 200:1 to 1:200.
  • the weight ratio is generally within the above range, but an effective dose of each active ingredient can be used in each case.
  • the combination of at least one compound of the present invention and/or at least one pharmaceutically acceptable salt thereof with other active ingredients may be administered separately or in combination.
  • administration of one of the components may precede, simultaneously, or after the other components.
  • D means ⁇ .
  • Intervention and “treatment” are used interchangeably, both of which include therapeutic and prophylactic use. Both terms are meant to reduce, inhibit, alleviate, reduce, arrest, or stabilize the onset or progression of a disease (eg, a disease or condition as discussed herein), reduce the severity of the disease, or improve the condition associated with the disease.
  • a disease eg, a disease or condition as discussed herein
  • compound when referring to a compound of the invention, refers to a group of molecules having the same chemical structure, except that there may be isotopic variations in the constituent atoms of the molecule.
  • a compound represented by a specific chemical structure containing a specified ruthenium atom will simultaneously include a relatively small amount of isotope having a hydrogen atom at one or more of the specified oxime positions in the structure.
  • Number body The relative amount of the isotopic isotope in the compounds of the invention will depend on a number of factors, including the isotopic purity of the deuteration reactant used to make the compound, and the efficiency of the rhodium combination in the various synthetic steps used to prepare the compound.
  • the compounds of the invention contain one or more asymmetric carbon atoms.
  • the compounds of the invention may exist as separate enantiomers as well as as mixtures of enantiomers.
  • the compounds of the invention will include not only the racemic mixture, but also the individual individual enantiomers which are substantially free of other enantiomers.
  • compound refers to a use that has sufficient stability to permit manufacture and maintain the integrity of the compound for a sufficient period of time for the purposes detailed herein (eg, to make a therapeutic product, to make a treatment)
  • a compound of an intermediate, a separable or storable intermediate compound, or a compound that treats a disease or condition in response to a therapeutic agent e.g., to make a therapeutic product, to make a treatment
  • the deuterated drug of the present invention can reduce the formation of toxic metabolites and increase the production of active metabolites, thereby reducing toxic side effects or improving therapeutic effects.
  • the deuterated drug of the present invention can reduce the system clearance rate and increase the biological half life of the compound. This advantage of the deuterated drug of the present invention can maintain the same therapeutic level while reducing the dosage used, thereby reducing toxic side effects or improving the therapeutic effect.
  • the deuterated drug of the present invention can reduce the metabolic ratio of the drug in the gastrointestinal tract or the liver, so that most of the unmetabolized drugs enter the systemic circulation.
  • the deuterated drug of the present invention can reduce the dosage of the drug, produce a lower metabolic load, and improve the tolerance of the drug.
  • the IR compound of the present invention is preferably a compound of the right type
  • the present process produces a compound of Example 3 of deuterated PCT/CN2010/080370, preferably R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 16 and R 17 moieties or both deuterium or hydrogen.
  • the preparation of deuterated benzoate is exemplified.
  • other forms of salts can be prepared.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, Nitrate, etc., and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, tannic acid Salt, benzoate, mandelate, methanesulfonate, ethanesulfonate, tosylate, sulfosalicylate, etc., or by other methods described in the literature, such as ion exchange These salts.
  • salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, besylate, benzoate, heavy sulfate, Borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumaric acid Salt, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate , laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectate, persul
  • PCT/CN2010/080370 Example 3 compound free base as raw material (500mg), C 2 H 5 OD as solvent (10mL), DBU (445mg, 2eq.) as a base, stirred at 23+-0.5 ° C for 24h, at room temperature , vacuum dry solvent. Dissolve with DCM, wash twice with a saturated solution of NH 4 Cl in D 2 O to remove DBU and dry Na 2 SO 4 .
  • the benzoic acid salt of the compound of Example 3 of PCT/CN2010/080370 was used as a raw material (500 mg), CH 3 COOD was used as a solvent (100 mg/mL), and stirred at 50 ° C for 24 h to 36 h, and the solvent was evaporated in vacuo.
  • DCM was added to dissolve, a small amount of water was added, and extracted with saturated aqueous Na 2 CO 3 in an ice bath was adjusted to pH9-10 with DCM, the combined organic phases were dried over anhydrous Na 2 SO 4.
  • IR8 benzoate Dissolve IR8 and benzoic acid in DCM separately, slowly add an equivalent of benzoic acid DCM solution to IR8 solution under ice bath, stir for 1 h, and spin dry under vacuum; Acid salt (PCT/CN2010/080370 Example 3 Compound-d3_BA).
  • the D- glutamine (5.84g, 40mmol) was dissolved in 1N NaOH (84mL) in an ice bath was added dropwise (Boc) 2 O (14mL, 60mmol) in dioxane (40 mL) was stirred after 30min, Remove the ice bath and stir for 4 h. Concentrated under reduced pressure to a half volume, the ice bath was adjusted with 1N KHSO 4 to pH 2-3, and extracted with EtOAc (60mL * 3), the organic phase was dried with Na 2 SO 4, and concentrated to give 8.6 g of a clear oil, yield 87%.
  • IR12 and benzoic acid were respectively dissolved in DCM, and a benzoic acid solution was slowly added dropwise to the IR12 solution under ice bath, stirred for 1 hour, and then the solvent was removed in vacuo to give the compound IR12_BA.
  • IR11 was used as a raw material (180 mg), C 2 H 5 OD was used as a solvent (50 mg/mL), DBU (190 mg) was used as a base, and stirred at 23 ° C for 24 hours, and the solvent was evaporated to dryness at room temperature under vacuum. Then it was dissolved in DCM, washed twice with a saturated solution of NH 4 Cl in D 2 O to remove DBU and dried Na 2 SO 4 . Purification by column chromatography, wet loading (DCM / MeOH, 20/1). The pale yellow solid compound IR13 (55 mg, yield 30%) was obtained.
  • the benzene IR11 was used as a raw material (125 mg), CH 3 COOD was used as a solvent (2 mL), and the mixture was stirred at 50 ° C for 24 hours, and the solvent was evaporated to dryness.
  • DCM was added to dissolve, a small amount of water was added, and extracted with saturated aqueous Na 2 CO 3 in an ice bath was adjusted to pH9-10 with DCM, the combined organic phases were dried over anhydrous Na 2 SO 4. Purification by column chromatography, wet-up (DCM / MeOH, 20/1) to afford compound IR14 (42mg, yield: 35%).
  • IR14_BA was obtained by the method of Example 4.
  • IR11 was used as a raw material (300 mg), C 2 H 5 OD was used as a solvent (8 mL), and DBU (280 mg) was used as a base, and stirred at 23 ° C for 24 hours, and the solvent was evaporated to dryness at room temperature under vacuum. Dissolve with DCM, wash twice with a saturated solution of NH 4 Cl in D 2 O to remove DBU and dry Na 2 SO 4 . Filter, remove solvent and dry in vacuum. The dried (210mg) was dissolved in CH 3 COOD (3mL), stirred 24h 50 °C.
  • the other compounds of the present invention can be prepared by appropriately adjusting the substitution sites by the above-mentioned general production methods and preparation methods of specific compounds and salts thereof.
  • DPP-IV kit DPP-IV-Glo meter sion compound data, Promega, Cat#G8351
  • test compound was dissolved in 100% DMSO to prepare a stock solution at a concentration of 10 mM.
  • the drug was at a final concentration of 20 ⁇ M, and was diluted with a 5-fold gradient of Tris-HCl (pH 8.0) buffer for a total of 10 doses.
  • DPP-IV-Glo TM reagent 100 ⁇ l of DPP-IV-Glo TM substrate was added to 50 ml of fluorescein detection reagent in the previous step, and vortexed, and the concentration of the substrate in the system was 20 ⁇ M;
  • the DPP-IV-Glo TM reagent is placed at room temperature for 30-60 minutes;
  • Mass Spectrometer The Thermo Fisher Scientific TSQ QUANTUM Ultra EMR tandem mass spectrometer was equipped with an electrospray ionization source (ESI) and an Xcalibur workstation.
  • ESI electrospray ionization source
  • the ion source was an electrospray ionization source (ESI source), positive ion detection; source spray voltage 3500 V; gasification chamber temperature 200 ° C; ion transport capillary temperature 350 ° C; auxiliary gas 10 Arb; sheath gas 30 Arb, collision pressure 1.5 mTorr.
  • the scanning method is Selective Reaction Monitoring (SRM), and the ion response, Tube Lens and collision energy for quantitative analysis are shown in Table 1.
  • Cmax peak concentration, AUC 0-t concentration-time curve area, CL clearance rate, T 1/2 is half-life time, BA stands for benzoate.
  • the pharmacokinetic parameters of each compound showed that the compounds IR8, IR12 and IR14 in this experiment showed a significant increase in Cmax, AUC 0-t and half-life T 1/2 compared with the benzoate of the positive control compound I.
  • the clearance rate refers to the volume of drug-containing plasma eliminated from the body per unit time or the apparent volume of drug removed from the body per unit time. Reflecting the body's ability to remove drugs, the greater the clearance rate, the stronger the body's ability to excrete substances, that is, the faster the drug is removed from the plasma, the shorter its half-life is. Too low a clearance rate will affect the elimination of drugs and lead to accumulation of poisoning.
  • the positive control compound I has a high clearance rate compared with IR8, IR12 and IR14, indicating that the body has a strong ability to scavenge compound I, and the rate of elimination from the body is fast, and the residence time in the body is short.
  • IR8, IR12 and IR14 are expected to have better long-term in vivo time.

Abstract

二肽基肽酶IV（DPP-IV）抑制剂的取代1,2,4-三嗪衍生物，所述衍生物具有以下结构式（IR），其中R 1-R 19的部分或者全部氢被氘取代，其可用于制备改善或治疗糖尿病的药物。

Description

二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物 技术领域
本发明属于医药化学技术领域，特别涉及一系列二肽基肽酶IV(DPP-IV)抑制剂的取代1,2,4-三嗪衍生物。
背景技术
二肽基肽酶IV(Dipeptidyl Peptidase,DPP-IV,EC3.4.14.5)是一个丝氨酸蛋白酶，从含有L-脯氨酸和L-丙氨酸的多肽N端倒数第二位水解N端二肽。尽管DPP-IV的功能未被完全阐明，它被认为是某些调节多肽、神经肽、循环激素和趋化因子的主要生理性调节因子。尽管作为多效酶，DPP-IV有诸多底物，但最为人所知的是肠促胰素，它包括胰高血糖素样肽-1(GLP-1)和糖依赖性胰岛素释放肽(GIP)。肠促胰素是在摄入营养物的几分钟内分泌并促进摄入营养物的处置的肠道激素。GLP-1和GIP对β细胞的作用相同，可改善β细胞功能，包括促进葡萄糖依赖的胰岛素分泌、诱导β细胞增殖、增强抗凋亡作用。
与GIP不同，GLP-1在Ⅱ型糖尿病中仍是促进胰岛素分泌的，因此，提高GLP-1是一种有前景的治疗Ⅱ型糖尿病的手段。Ⅱ型糖尿病患者中使用GLP-1可明显降低血糖，然而GLP-1作为DPP-IV的底物在体内会迅速被水解而失活，因此研制DPP-IV抑制剂对治疗糖尿病具有非常重要的意义。
目前，DPP-IV抑制剂的研究取得了较大的进展，包括西他列汀、沙格列汀、阿格列汀在内的DPP-IV抑制剂已经批准上市，进入临床使用。DPP-IV抑制剂最显著的特点是，由于肠促胰岛素只在机体进食后分泌，DPP-IV抑制剂不易在不适当的时候增加胰岛素水平，产生许多降糖药共同的副作用低血糖。近几年，长效DPP-IV抑制剂特别引人注目。长效DPP-IV抑制剂使用更方便，同时具备理想的降糖效果，这会使其在II型糖尿病患者中更受欢迎。Trelagliptin是由武田制药有限公司开发的一个一周一次DPP-IV抑制剂，该药的安全性和有效性在临床中得到了确认，目前已在日本获批上市，然而，过于长效的药物往往会在长期使用中，由于药效强可能导致人体的某些不良反应，以及长期维持高血药浓度而带来的某些副作用。
PCT/CN2010/080370描述了一系列的新母核结构的DPP-IV抑制剂。其中，包括优选的下式结构式所示的化合物I，化学名称为：(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苄腈化学为：
Figure PCTCN2018089027-appb-000001
药物分子的氘代策略是一个有吸引力的方法，因为氘原子替代一个或更多的氢原子后有可能会减慢CYP介导的药物代谢速度；而且，氘是安全、稳定、非辐射的氢的同位素，也有利于发展新药，例如梯瓦的亨廷顿舞蹈症药物AUSTEDO。相比于氢，氘和碳形成了更强的化学键，因此可以提高C-D键抗氧化的键能。
但对于具体化合物，氘代后的效果不可预测。甚至，氘效果的可变性还导致专家质疑或抛弃了氘修饰作为可行的药物设计策略以抑制有害代谢的想法(例如，JM Fukuto et al.,J. Med.Chem.1991,34,2871-76)。
由此可见，对于特定的化合物的选择及特定的氘代策略选择，以期获得优异效果的化合物用于制备临床药物，还需克服大量的困难。
发明内容
鉴于现有技术存在的问题，本发明提供了一系列二肽基肽酶IV(DPP-IV)抑制剂的取代1,2,4-三嗪衍生物，其具有以下结构式：
Figure PCTCN2018089027-appb-000002
所述取代是指化合物上的部分或者全部氢被氘取代。即R 1至R 19选自氘或者为氢，且至少R 1至R 19中一个以上为氘。
以上提出的化合物中的“氘”总的相对量将少于化合物的49.9％。在其他实施方式中，“氘”总的相对量将少于化合物的47.5％、少于40％、少于32.5％、少于25％、少于17.5％、少于10％、少于5％、少于3％、少于1％、或者少于0.5％。
优选的所述R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 16和R 17中一个以上为氘。
即本发明的IR化合物优选为右式化合物
Figure PCTCN2018089027-appb-000003
相较于其他位点的氘取代，预期具有更为明显的降低系统清除率，增加化合物的生物半衰期的效果。
更为优选的化合物为：R 4和R 5同时为氘，和/或R 6、R 7和R 8同时为氘，和/或者R 9和R 10同时为氘，和/或者R 16和R 17同时为氘。
具体的优选化合物，包括但不限于以下化合物：
Figure PCTCN2018089027-appb-000004
Figure PCTCN2018089027-appb-000005
本发明也提供了本发明中化合物的药学可接受的盐。
本发明中化合物的盐形成于酸和化合物的碱性基团例如氨基官能团之间，或者碱和化合物的酸性基团例如羧基官能团之间。根据另一个优选实施方式，化合物是药学可接受的酸加成盐。
本文所用的术语“药学可接受的”，是指在有足够医学理由的范围内，适合于人类或其他哺乳动物的组织接触使用而没有不适当的毒性、刺激、过敏性反应等，以及与合理的利益/风险比率相称的化合物。“药学可接受的盐”指任何没有毒性的盐，其在给药时，能够直接地或间接地提供本发明的化合物。
通常被用来形成药学可接受的盐包括：硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、一氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、盐酸盐、溴酸盐、碘酸盐、醋酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸酯、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、反丁烯二酸盐、顺丁烯二酸盐、丁炔-1，4-二酸盐、己炔-1，6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、顺丁烯二酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐等。
优选的药学可接受的盐例如苯甲酸盐等。
具体的优选化合物药学可接受的盐，包括但不限于以下化合物药学可接受的盐：
Figure PCTCN2018089027-appb-000006
Figure PCTCN2018089027-appb-000007
在一些具体例子中，此处描述的至少一种化合物和/或其至少一个药学上可接受的盐作为改善和/或用于抑制需要抑制DPP-IV的患者如哺乳动物体内DPPIV酶药物的应用及方法，包括给予有效剂量的本发明的至少一种化合物和/或其至少一个药学上可接受的盐。本发明还包括至少一种化合物和/或其至少一个药学上可接受的盐作为二肽基肽酶IV活性抑制剂的用途。
在一些实例中，治疗对象是指需要抑制二肽基肽酶-IV酶活性的哺乳动物，如人类，男 性或女性。除了灵长类哺乳动物(如人类)外，其他哺乳动物也可以根据本发明的方法进行治疗。例如，哺乳动物，包括但不限于：牛，绵羊，山羊，马，狗，猫，豚鼠，老鼠或其它牛科、羊科、马科、犬科，猫科，啮齿类或鼠类动物都可以治疗。不过，该方法也可实行于其他物种，如鸟类(如鸡)。
本发明还提供了组合物，包括此处描述的至少一种化合物和/或其至少一个药学上可接受的盐和药学可接受载体。
本发明还提供了制备抑制人或动物体内DPP-IV活性的药剂的方法，包括把至少一种化合物和/或其至少一个药学上可接受的盐和至少一种药学可接受的载体的组合。
本发明的药物组合物包括任何通过把至少一种式(IR)的化合物和/或其至少一个药学上可接受的盐和至少一种药学可接受的载体混合而制成的组合物。
二肽基肽酶-IV(DPP-IV)是细胞表面蛋白，参与诸多生物功能。它有广泛的组织分布(肠，肾，肝，胰腺，胎盘，胸腺，脾，上皮细胞，血管内皮细胞，淋巴细胞和骨髓细胞，血清)，不同的组织和细胞类型中DPP-IV的表达水平不同。DPP-IV与T细胞活化标志物CD26相同，在体外可以剪切大量免疫调节、内分泌和神经多肽。这表明DPP-IV在人类或其他种属的多种疾病过程中起潜在作用。
因此，本发明的化合物和/或其药学上可接受的盐可用于治疗以下疾病、失调和症状。
II型糖尿病及相关疾病：研究证明，在体内肠降血糖素GLP-1的和GIP被DPP-IV迅速降解失活。DPP-IV(-/-)缺陷小鼠和初步临床试验表明，抑制DPP-IV能增加GLP-1和GIP的稳态浓度，从而提高糖耐量。与GLP-1和GIP类似，很可能其他参与血糖调节的胰高血糖素家族多肽(如PACAP)也会被DPP-IV降解失活。DPP-IV对这些多肽的灭活也在葡萄糖动态平衡中发挥作用。
因此，本发明的DPP-IV抑制剂能有效治疗II型糖尿病，以及治疗和预防伴随II型糖尿病的大量并发症，包括但不限于，X综合症(也称为代谢综合症)，反应性低血糖和II型糖尿病血脂异常。以下讨论的肥胖，是另一个经常与II型糖尿病并发的症状，本发明的化合物也可能对其有治疗作用。
本发明的化合物和/或其药学上可接受的盐能有效治疗或预防下列一种或多种疾病或症状：(1)高血糖，(2)糖耐量降低，(3)胰岛素抵抗，(4)肥胖，(5)血脂代谢紊乱，(6)血脂异常，(7)高血脂，(8)高甘油三酯血症，(9)高胆固醇血症，(10)低HDL水平，(11)高低密度脂蛋白水平，(12)动脉粥样硬化及其后遗症，(13)血管再狭窄，(14)肠易激综合症，(15)炎症性肠病，包括克罗恩病和溃疡性结肠炎，(16)其他炎症，(17)胰腺炎，(18)腹部肥胖，(19)神经退行性疾病，(20)视网膜病变，(21)肾病，(22)神经性疾病，(23)X综合征，(24)卵巢高雄激素(多囊卵巢综合征)，(25)II型糖尿病，(26)生长激素缺乏，(27)中性粒细胞减少，(28)神经元疾病，(29)肿瘤转移，(30)良性前列腺肥大，(32)牙龈炎，(33)高血压，(34)骨质疏松症，以及其他抑制DPP-IV能治疗的症状。
所述“疾病”在上述DPP-IV所能治疗的疾病中优选糖尿病及相关代谢疾病，糖尿病是一组以高血糖为特征的代谢性疾病。多是由于胰岛素分泌缺陷或其生物作用受损而引起，包括I型糖尿病，即胰岛素依赖型糖尿病，和II糖尿病，即非胰岛素依赖型糖尿病。
本发明的至少一种化合物和/或其至少一个药学上可接受的盐的给药方式包括：口服，注射(如肌肉注射，腹腔注射，静脉注射，侧脑室注射，脑池注射或输液，皮下注射，或植入)，吸入喷雾，鼻粘膜给药，阴道给药，直肠给药，舌下含服，或局部给药。本发明的化合物可单独或一起制成适宜的单位制剂，该制剂包括常规应用的药学可接受的无毒载体，适合不同给药途径的佐剂和赋形剂。本发明的至少一种化合物和/或其至少一个药学上可接受的盐除了对人类有治疗作用外，对于恒温动物(如小鼠、大鼠、马、牛、羊、狗、猫等 也有效。
含有本发明的至少一种化合物和/或其至少一个药学上可接受的盐的药物组合物可以根据不同的给药方式制成不同单位剂量形式，可通过药剂学公知技术制备。在一些示例中，本发明的至少一种化合物和/或其至少一个药学上可接受的盐与包括一种或多种必要的辅料地载体相结合起来。
在一些实例中，药物组合物的制备过程包括，把本发明的至少一种化合物和/或其至少一个药学上可接受的盐与液体载体或/和微小的固体载体均匀、紧密地结合起来，然后必要时将产品做成所需的剂型。在一些实例中，本发明的至少一种化合物和/或其至少一个药学上可接受的盐的含量应足以对疾病的发生和进程产生预期的治疗效果。
含有本发明的至少一种化合物和/或其至少一个药学上可接受的盐的药物组合物可以制成适合口服给药的剂型，如：片剂，口含片，润喉剂，水性或油性混悬剂，分散粉剂或颗粒剂，乳剂，硬胶囊或软胶囊，糖浆剂或酏剂。
适于口服的药物组合物可通过已知的药物制剂工艺制备。为了得到美观可口的药物制剂，该药物组合物中包括一种或几种物质，选自甜味剂、调味剂、着色剂和防腐剂。片剂是由活性成分的药物与无毒的，药学可接受的，适合制备片剂的制剂辅药混合制成。这些辅料可能包括，惰性稀释剂(如碳酸钙，碳酸钠，乳糖，磷酸钙或磷酸钠)；制粒和崩解剂(如玉米淀粉或海藻酸)；粘合剂(如淀粉，明胶，或阿拉伯胶)；润滑剂(如硬脂酸镁，硬脂酸或滑石粉)。这些片剂可以不包衣也可以通过已知的包衣技术来延长片剂在胃肠道中的崩解和药物的吸收，从而使药物在一个较长时间内产生持续作用。例如，可采用延迟材料，如硬脂酸甘油酯或甘油硬脂酸。也可以采用片剂包衣，使其成为渗透性的片剂以控制药物的释放，如持续释放或延迟释放。
口服使用的制剂也可以是硬明胶胶囊，其特征在于该硬明胶系将本发明的至少一种化合物和/或其至少一个药学上可接受的盐与惰性固体稀释剂(例碳酸钙，磷酸钙或高岭土)混合制成的；也可以是软明胶胶囊，其特征在于该软胶囊是将本发明的至少一种化合物和/或其至少一个药学上可接受的盐与水或油性介质(如花生油，液体石蜡，和/或橄榄油)混合后制成。
本发明的DPP-IV抑制剂类化合物，可以与载体结合制成防止本发明的至少一种化合物和/或其至少一个药学上可接受的盐被机体快速清除的剂型，如延迟释放片和包衣片。该剂型中也进一步包含其它活性化合物，以获得所期望的特性组合。
口服药物剂型可以是固体剂，凝胶剂或液体剂。固体剂的例子包括但不限于：片剂，胶囊，颗粒和混合散剂。口服片剂更特殊的例子包括压缩片，咀嚼片和肠衣片，糖衣片或薄膜包衣片。胶囊的例子包括硬胶囊或软胶囊。颗粒剂和粉剂可以做成非泡腾剂或泡腾剂。每种剂型都可与其它已知的常用成分联合应用。
在某些实施例中，本发明的DPP-IV抑制剂被制成固体剂型，例如胶囊或片剂。片剂，丸剂，胶囊，锭片等可以任选包含一种或多种下列的成分或者类似性质的化合物：粘结剂；稀释剂；崩解剂；润滑剂；助流剂；甜味剂及调味剂。
可用的粘合剂包括但不限于：微晶纤维素，黄蓍胶，葡萄糖溶液，阿拉伯胶浆，明胶溶液，蔗糖和淀粉糊。
可用的润滑剂包括但不限于：滑石粉，淀粉，硬脂酸镁，硬脂酸钙，石松和硬脂酸。
可用的稀释剂包括但不限于：乳糖，蔗糖，淀粉，高岭土，盐，甘露醇和磷酸二钙。
可用的助流剂包括但不限于：胶体二氧化硅。
可用的崩解剂包括但不限于：交联羧甲基纤维素钠，羧甲基淀粉钠，褐藻酸，玉米淀粉，马铃薯淀粉，皂粘土，甲基纤维素，琼脂和羧甲基纤维素。
可用的着色剂包括但不限于：批准应用的水溶性FD染料和C染料，水溶性FD染料 和C染料的混合物，以及水不溶性FD染料和C染料的氢氧化铝混悬液。
可用的甜味剂包括但不限于：蔗糖，乳糖，甘露醇，人工甜味剂(如甜蜜素和糖精)，以及任意量的喷雾干燥香料。
可用的矫味剂包括但不限于：从植物(如水果)中提取的天然香料，口感良好的人工合成混合物(包括但不限于：薄荷，水杨酸甲酯)。
可用的湿润剂包括但不限于：丙二醇硬脂酸酯，去水山梨醇单油酸酯，二甘醇单月桂酸酯和聚氧乙烯十二烷基醚。
可用的镇吐包衣剂包括但不限于：脂肪酸，脂肪，蜡，虫胶，氨化虫胶和纤维素醋酸邻苯二甲酸酯。
可用的薄膜包衣剂包括但不限于：羟乙基纤维素，羧甲基纤维素钠，聚乙二醇4000和纤维素醋酸邻苯二甲酸酯。
如果需要口服，本发明的至少一种式(IR)化合物和/或至少一种药学上可接受的盐任选组合物形式提供，该组合物被制成保护该化合物在胃部酸性环境中不被破坏的形式。例如，该组合物可制成肠溶包衣制剂，以保持其在胃中的完整性，并在肠道内释放活性化合物。组合物也可以制成和抗酸剂或其他类似成分的组合制剂。
当制备的剂型是胶囊剂时，可以任选加入一种液体载体如脂肪油。此外，单位制剂形式还可以任选包括多种其它的成分，该等成分改变制剂的物理性质，其例子如糖包衣或肠溶剂包衣。
本发明的至少一种化合物或/和至少一种其药学上可接受的盐可以通过制成酏剂，悬浊液，糖浆剂，包衣，咀嚼剂或类似的方式给药。糖浆剂除了含有本发明的至少一个化合物和/或其至少一个药学上可接受的盐外，还可任选地包括甜味剂蔗糖，防腐剂，着色剂和香料。
包含本发明的至少一种化合物或/和至少一种其药学上可接受的盐的片剂中包含的药学可接受载体的例子，包括但不限于：粘合剂，润滑剂，稀释剂，崩解剂，着色剂，调味剂和润湿剂。肠衣片因有肠溶包衣，在胃的酸性环境中可以保持其完整性，并在肠道的中性或碱性环境中才溶解或崩解释放活性化合物。糖衣片可用药学可接受载体压成不同层的片剂。薄膜衣片可以用聚合物或其他合适的包衣来压片。多重压缩片剂可以用前述药学可接受载体通过多次压片制成。着色剂在片剂的制作中也可能被用到。调味剂和甜味剂也可用于片剂，特别是在制作咀嚼片及锭剂中非常有用。
液体口服制剂包括但不限于：水溶液剂，乳剂，混悬剂，溶液，和/或由非泡腾颗粒复溶制成的混悬剂，和由泡腾颗粒复溶制成的泡腾剂。
水溶液剂包括但不限于：酏剂和糖浆剂。此处所述的酏剂是指澄清有甜味的含水酒精制剂。酏剂中可用的药学可接受载体包括但不限于溶剂。溶剂的特别的例子包括：甘油，山梨醇，乙醇和糖浆。此处所述的糖浆剂是指浓缩的糖溶液，如蔗糖。糖浆可以任选进一步包含防腐剂。
乳剂是指一种液体以小液珠的形式均匀分散到另一种液相中的两相体系。乳液可以任选是，但不限于，油包水或水包油乳剂。乳剂中可用的药学可接受载体包括但不限于：非水液体，乳化剂和防腐剂。
复溶成液体口服剂型的非泡腾颗粒剂中所需的药学可接受载体包括：稀释剂，甜味剂和润湿剂。
泡腾颗粒剂的药学可接受载体包括：有机酸和产生二氧化碳的物质，该颗粒剂用于复溶成液体口服剂型。
上述各种剂型都可任选加入着色剂和调味剂。
可能用到的防腐剂的示例性例子包括：甘油，对羟苯甲酸丙酯类，苯甲酸，苯甲酸钠 和乙醇。
乳剂中可能用到的非水相液体的示例性例子包括：矿物油和棉籽油。
可能用到的乳化剂的示例性例子包括：明胶，阿拉伯胶，黄蓍胶，皂粘土和表面活性剂(如聚氧乙烯去水山梨醇单油酸酯)。
可能用到的助悬剂的示例性例子包括：羧甲基纤维素钠，果胶，黄蓍胶，硅酸镁铝和阿拉伯胶。稀释剂包括：乳糖和蔗糖。甜味剂包括：蔗糖，糖浆，甘油和人造甜味剂(如甜蜜素和糖精)。
可能用到的湿润剂的示例性例子包括：丙二醇单硬脂酸酯，失水山梨醇单油酸酯，二甘醇单月桂酸酯和聚氧乙烯烷基醚。
可能用到的有机酸的示例性例子包括：柠檬酸和酒石酸。
泡腾剂中可能用到的产生二氧化碳的物质的示例性例子包括碳酸氢钠和碳酸钠。着色剂包括已批准使用的水溶性FD染料和C染料，及其它们的混合物。
可能用到的调味剂的示例性例子包括：从植物(如水果)中提取的天然香料和口感良好的人工合成化合物的混合物。
用于制备固体剂型的溶液或悬浊液，如碳酸丙烯酯，植物油或甘油三酸脂，装入胶囊较容易。用于制备液体剂型的溶液(如聚乙二醇)，可用足够量的药学可接受载体(如水)进行稀释，以便于给药。
此外，可将活性化合物或其盐溶解或分散到植物油，乙二醇，甘油三酸脂，丙二醇酯(如碳酸丙烯酯)和其它类似的载体中，并将液体或混悬液装入硬质或软质曩材中，以制成液体或半固体口服制剂；把上述溶液或悬液封入硬或软胶囊壳。
本发明还包括本发明的至少一个化合物和/或其至少一个药学上可接受的盐通过非消化道给药的组合物。非消化道给药途径通常指注射(包括皮下，肌内或静脉注射)给药。注射剂可被制成任意方便给药的剂型，如溶液或混悬液，注射前适于溶解或混悬在液体中的固体，或制成乳剂。
用于将本发明化合物制成注射剂的辅药包括但不限于：水，盐水，葡萄糖，甘油或乙醇。该注射剂中也可以选择性加入少量无毒的辅助成分，如润湿剂和乳化剂，pH值缓冲剂，稳定剂，助溶剂和其他类似物质(如醋酸钠，失水山梨醇单月桂酸酯，三乙醇胺油酸和环糊精)。也可将其制成缓释特性的植入剂，该剂型可以使药物的浓度维持在一个稳定水平。本发明的至少一个化合物和/或其至少一个药学上可接受的盐在上述非消化道给药剂型中的含量取决于其特定的性质，该化合物的活性以及患者的需要。
非消化道给药的给药途径包括经静脉，皮下或肌内给药。非消化道给药制剂包括：注射用无菌溶液剂，无菌可溶性干粉，如冻干粉(用前用溶剂溶解)，皮下注射用片，注射用灭菌混悬剂，无菌非可溶性干粉(用前用溶剂分散)和注射用灭菌乳剂。注射用溶液可以是水溶液也可以是非水溶液。
用于制备静脉给药制剂的合适载体包括但不限于：生理盐水，磷酸缓冲盐溶液(PBS)和含有增稠剂和增溶剂的溶液(如葡萄糖，聚乙二醇和聚丙二醇及其混合物)。
可用于制备非消化道给药剂型的药学可接受载体，包括但不限于：水溶剂，非水溶剂，抗菌剂，等渗剂，缓冲液，抗氧化剂，局部麻醉剂，悬浮剂和分散剂，乳化剂，分离或螯合剂及其它药学可接受物质。
可能用到的水溶剂包括：氯化钠注射液，林格注射液，等渗葡萄糖注射液，无菌水注射液，葡萄糖注射液和乳酸林格注射液。
可能用到的非水溶剂包括：植物油类，棉籽油，玉米油，芝麻油和花生油。
非消化道给药制剂可以加入抑菌剂或抑真菌剂，特别是当药物制剂的有多种包装规格时。可以选用的抗菌剂包括：酚类或甲酚类，汞制剂，苯甲醇，三氯叔丁醇，甲基和丙基 对羟基苯甲酸酯，硫柳汞，苯扎氯铵和苄索氯铵。
可能用到的等渗剂包括：氯化钠和葡萄糖等渗剂。可能用到的缓冲剂包括：磷酸盐和柠檬酸盐。可能用到的抗氧化剂包括硫酸氢钠。可能用到的局部麻醉剂包括盐酸普鲁卡因。可能用到的悬浮剂和分散剂包括：羧甲基纤维素钠，羟丙基甲基纤维素和聚乙烯吡咯烷酮。可能用到的乳化剂包括：山梨酯80(吐温80)。可能用到的金属离子分离或螯合剂包括，乙二胺四乙酸(EDTA)。
用于增加水溶性的药用载体包括：乙醇，聚乙二醇和丙二醇。用于调节pH调节的载体包括氢氧化钠，盐酸，柠檬酸或乳酸。
为了使注射剂能够产生良好的药理作用，非口服给药制剂中本发明的至少一个化合物和/或其至少一个药学上可接受的盐的浓度可以适当调节。本发明的至少一个化合物和/或其至少一个药学上可接受的盐的确切浓度和/或给药剂量应取决于用药患者或动物的体重，年龄和身体状况。
单位剂量的注射制剂可能是封装在安瓿，小瓶或有针注射器中。非口服给药制剂应经常规方法消毒灭菌。
注射剂可以用于局部或全身给药。例如，本发明的至少一个化合物和/或其至少一个药学上可接受的盐能够产生药理作用的剂量范围为0.1％w/w到90％w/w或更高，例如在给药组织中本发明的至少一个化合物和/或其至少一个药学上可接受的盐的浓度大于1％w/w。本发明的至少一个化合物和/或其至少一个药学上可接受的盐可以一次给药也可以减小剂量分次给药。药物确切的给药剂量和给药疗程取决于非消化道给药部位，载体和其它可通过已知的治疗方案或通过体内外试验数据外推来确定的变量。值得注意的是，患者年龄的不同，给药剂量也不同。应依据个体用药的需要，以及专业人员的判断随时调整患者的用药方案。因此，具体用药时可以参照上述药物浓度范围，但不能局限于该浓度范围。
本发明的至少一个化合物和/或其至少一个药学上可接受的盐可以通过微粉化制成悬液或其他合适的制剂，或者可以衍生成溶解性更好的活性产物或制备成前药。最终混合物的剂型取决于很多因素，包括预期的给药方式和该化合物在所选载体或溶剂中的溶解性。药物达到可缓解疾病症状时的有效浓度可以通过经验确定。
本发明的至少一个化合物和/或其至少一个药学上可接受的盐也可以制成冻干粉，用时再重新配置成溶液，乳剂或其他混合剂。冻干粉也可制成固体或凝胶。
制备无菌冻干粉首先要把化合物溶解到含有葡萄糖或其它适宜辅料的磷酸钠缓冲液中，然后将溶液进行过滤除菌，最后通过常规的工艺技术进行冻干得到所需的剂型。简言之，冻干粉的制备过程包括以下步骤：把葡萄糖，山梨醇，果糖，玉米糖浆，木糖醇，甘油，葡萄糖，蔗糖或其他合适的物质，约1-20％，例如5％至15％，溶解到适当的缓冲液中，如柠檬酸盐，磷酸钠和/或磷酸钾和/或其它常规已知的缓冲液(约为中性pH)。然后再在上述溶液中加入本发明的至少一个化合物和/或其至少一个药学上可接受的盐，例如在温度高于室温的条件下(30-35℃)，搅拌直至其完全溶解。然后再用缓冲液稀释上述溶液到需要的浓度，过滤除菌并除去微粒，确保溶液处于无菌状态后分装进小玻璃瓶冻干。每个小玻璃瓶中可以含有单剂量或多剂量的本发明的至少一个化合物和/或其至少一个药学上可接受的盐。
本发明的至少一个化合物和/或其至少一个药学上可接受的盐也可以通过制成局部用药组合物来给药。该组合物可以用于局部给药，也可以用于全身给药。该局部用药组合物可以制成溶液，混悬液，乳剂或类似物，该合剂可制成制剂，如乳膏剂，凝胶剂，软膏剂，乳剂，溶液剂，酏剂，洗剂，悬液，酊剂，糊剂，泡沫剂，气雾剂，灌肠剂，喷雾剂，栓剂，绷带，皮肤贴片或任何其他适合局部给药的制剂。也可以把本发明的至少一个化合物和/或其至少一个药学上可接受的盐制成气雾剂用于局部给药，如吸入剂，例如治疗炎性疾 病特别是哮喘的甾族化合物的气雾剂的制备)。这些通过呼吸道给药的制剂可以单独或与一种惰性载体(如乳糖)组合制成气雾剂，喷雾溶液剂或吸入干粉剂。通过呼吸道给药时制剂的颗粒直径应小于50微米，最好小于10微米。
本发明的至少一个化合物和/或其至少一个药学上可接受的盐也可以制成局部给药的剂型，如局部涂抹于皮肤和粘膜给药，例如制成凝胶剂，乳剂和洗剂用于眼部疾病，或者用于脑池内或椎管内给药。局部用药的方法包括透皮给药，眼部或粘膜给药或吸入给药。本发明的至少一个化合物和/或其至少一个药学上可接受的盐的滴鼻液可单独或与其它药学可接受的辅料组合制成鼻粘膜给药制剂。
根据治疗疾病的特点，也可以通过其他的给药方式给药，如局部涂药，皮肤贴片或直肠给药。例如，用于产生全身效应的直肠给药剂型有栓剂，片剂和胶囊剂。此处所述的直肠栓剂，是指可以插入直肠内，在体温条件下软化并融化释放一种或多种具有治疗作用的药理活性成分的固体制剂。栓剂中用到的药学可接受材料有基质或赋形剂，以及可提高栓剂熔点的物质。基质包括：可可脂(可可油)，甘油胶，聚乙二醇和甘油一酯，甘油二酯和甘油三酯适当比例的混合物和脂肪酸。也可以用不同基质的混合物。提高栓剂熔点的物质包括鲸脂和蜡。栓剂可以通过模压法制备。直肠栓剂的标准重量大约2-3mg。通过直肠给药的片剂和胶囊剂的制备方法和制备用的药学可接受辅料与制备通过口服给药的片剂和胶囊剂一致。
本发明化合物抑制DPP-IV酶活性，发挥疾病治疗与预防作用的剂量一般为约0.1-1000mg/日，可以单次给药也可以分多次给药。
例如，给药剂量为约0.1-约250mg/日，如约0.5-约100mg/日。适宜的剂量范围可为约0.1-1000mg/kg/日，约0.1-500mg/kg/日，或约0.1-50mg/日。在以上的范围内给药剂量可能为，0.1-0.5，0.5-5或5-50mg/日。对于口服给药来说，片剂组合物中含本发明的至少一个化合物和/或其至少一个药学上可接受的盐1.0-1000mg，根据治疗患者的症状可调节片剂中活性成分的含量，片剂中本发明的至少一个化合物和/或其至少一个药学上可接受的盐的含量例如可以为：1.0，5.0，10.0，15.0，20.0，25.0，50.0，75.0，100.0，150.0，200.0，250.0，300.0，400.0，500.0，600.0，750.0，800.0，900.0和1000.0mg。本发明的至少一个化合物和/或其至少一个药学上可接受的盐的给药方法可以为每天1-2次，如每天一次或数天一次。
在用本发明的至少一个化合物和/或其至少一个药学上可接受的盐治疗或预防糖尿病和/或高血糖或高甘油三酯血症或其它疾病的动物试验中，本发明的至少一个化合物和/或其至少一个药学上可接受的盐的试验结果普遍令人满意。给药的剂量约为：0.1-3000mg/日，给药的方法可以是每日一次或每日分2-6次给药，或以缓释剂型给药，或2天一次、3天一次、4天一次、5天一次等。对多数大型哺乳动物，日给药总剂量约为1mg-1000mg，例如约1mg-约50mg。对于体重为70kg的成年人来说，日给药总剂量一般为约1mg-约50mg，可调整给药方案以示药物产生最佳的疗效。
对于具体的患者来说，具体的给药剂量和给药次数应根据具体用药病人而变化，这取决于很多影响因素，包括：本发明的至少一个化合物和/或其至少一个药学上可接受的盐的活性，本发明的至少一个化合物和/或其至少一个药学上可接受的盐的代谢稳定性和作用时间长短，病人的年龄，体重，健康，性别，饮食，给药方式与时间，药物的清除率，药物的联合用药情况，疾病的严重程度，以及患者正在接受的治疗情况。
进一步地，本发明的化合物和/或其药学上可接受的盐还可与其他药物联合应用，用于上述疾病、失调和症状的治疗。
本发明的化合物和/或其药学上可接受的盐可与一个或多个其它药物联合使用，用于治疗式(IR)的化合物和/或其药学上可接受的盐或其他药物能有效治疗的疾病或症状，特别是联合使用药物更加安全或比单独使用药物更有效的情况。这些其他的药物以常用剂量和用 法使用，与至少一种式(IR)化合物和/或其至少一个药学上可接受的盐同时或先后使用。当至少一种式(IR)化合物和/或其至少一个药学上可接受的盐与一个或多个其他药物同时使用时，单位剂型的药物组合物含有至少一种药物和至少一个式(IR)化合物和/或其至少一个药学上可接受的盐。但是，联合用药疗法也可以是至少一个式(IR)化合物和/或其至少一个药学上可接受的盐和其他一个或多个药物按不同的给药周期给药。当与一个或多个其他活性成分联合使用时，本发明所述化合物和其他活性成分可使用比单独用药更低的剂量。因此，本发明的药物组合物，包括但不限于由一个或多个其它活性成分与至少一个式(IR)化合物和/或其至少一个药学上可接受的盐的组合。
无论分别给药或以同一药物组合物给药，可与至少一个式(IR)化合物和/或至少一个其药学上可接受的盐联合给药的其他活性成分，包括但不限于：(a)其他二肽基肽酶IV(简称DPP-IV)抑制剂；(b)胰岛素增敏剂，包括但不限于(i)PPARγ激动剂，如格列酮类(如曲格列酮、吡格列酮、恩格列酮、MCC-555，罗格列酮，巴格列酮等)和其他PPAR配体，包括PPARα/γ双重激动剂，如KRP-297和莫格列他，和PPARα激动剂，如非诺贝酸衍生物(例如，吉非罗齐，安妥明，非诺贝特和苯扎贝特)，(ii)双胍类如二甲双胍和苯乙双胍，和(iii)蛋白酪氨酸磷酸酶-1B(PTP-1B)抑制剂；(c)胰岛素或胰岛素类似物；(d)磺脲类药物和其他胰岛素促分泌剂，如格列苯磺丁脲，格列吡嗪，格列美脲和氯茴苯酸类，如那格列胺和瑞格列奈；(e)α-葡萄糖苷酶抑制剂(如阿卡波糖和米格列醇)；(f)胰高血糖素受体拮抗剂；(g)GLP-1，GLP-1类似物，如Exendin4，利拉鲁肽，和GLP-1受体激动剂；(h)GIP和GIP类似物，和GIP受体激动剂；(i)PACAP，PACAP类似物，和PACAP的受体激动剂；(j)降胆固醇药物，如(i)HMG-CoA还原酶抑制剂(洛伐他汀，辛伐他汀，普伐他汀，西伐他汀，氟伐他汀，阿托伐他汀，伊伐他汀和罗伐他汀和其他他汀类药物及其合适的盐)，(ii)螯合剂(例如，考来烯胺，考来替泊和交联葡聚糖的二烷基胺基烷基衍生物)，(iii)烟醇，烟酸或其盐，(iv)PPARα激动剂，如非诺贝酸衍生物(例如吉非罗齐，安妥明，非诺贝特和苯扎贝特)，(v)PPARα/γ双激动剂，如KRP-297，(vi)胆固醇吸收抑制剂，如β-谷甾醇和依泽替米贝，(vii)酰基辅酶A：胆固醇酰基转移酶抑制剂，如阿伐麦布，和(viii)抗氧化剂，如普罗布考；(k)PPARδ激动剂：(l)抗肥胖化合物，如芬氟拉明，右芬氟拉明，芬特明，西布曲明，奥利司他，神经肽Y1或Y5的拮抗剂，CB1受体逆激动剂和拮抗剂，肾上腺素受体激动剂，黑素皮质素受体激动剂，例如黑素皮质素-4受体激动剂，ghrelin拮抗剂，与黑色素浓集素(MCH)受体拮抗剂；(m)回肠胆汁酸转运抑制剂；(n)炎症条件下使用的药物，如阿司匹林，非甾体抗炎药如布洛芬，糖皮质激素，柳氮磺吡啶，以及选择性环氧合酶-2抑制剂；(o)降压药，如ACE抑制剂(例如依那普利，赖诺普利，卡托普利，喹那普利，群多普利)，A-II受体拮抗剂(例如氯沙坦，坎地沙坦，依贝沙坦，缬沙坦，替米沙坦，依普罗沙坦)，β受体阻滞剂和钙通道阻滞剂；和(p)葡萄糖激酶激活剂(GKAs)。
本发明的至少一种化合物或/和至少一种其药学上可接受的盐也可与其他活性物质合用，这些活性物质要对其治疗作用无影响，或能增强其作用，如抗酸药，H2受体阻滞剂和利尿药。例如，当本发明的至少一个化合物和/或其至少一个药学上可接受的盐用于治疗哮喘或高血压时，就可以分别与其他支气管扩张剂或抗高血压药物合用。
一些实例中，当本发明的至少一种化合物和/或其至少一个药学上可接受的盐与一个或多个其他药物同时应用的时候，使用药物组合物，其包含至少一种其它药物和本发明至少一种化合物和/或其至少一个药学上可接受的盐。因此，本发明的药物组合物包括一个或多个其它活性成分和本发明的至少一种化合物和/或其至少一个药学上可接受的盐。
本发明的至少一种化合物和/或其至少一个药学上可接受的盐与至少一种其他活性成分的重量比例可以是不同的，这取决于每种成分的有效剂量。例如，可以使用每个活性成 分各自的有效剂量。因此，例如，当本发明的至少一种化合物和/或其至少一个药学上可接受的盐与另外至少一种活性成分合用时，本发明化合物与另一活性成分的重量比例例如从1000：1至1：1000，例如从200：1至1：200范围内。本发明的至少一种化合物和/或其至少一个药学上可接受的盐与其他活性成分合用时，重量比例一般在上述范围内，但在每种情况下可使用每一个活性成分的有效剂量。
本发明的至少一种化合物和/或其至少一个药学上可接受的盐与其他活性成分的组合中，可以分别给药，也可联合给药。此外，其中一个成分的给药，可先于，同时，或后于其他成分。
本发明定义“D”是指氘。“改善”和“治疗”可互换地使用，二者都包括治疗和预防使用。两个术语都表示降低、抑制、减轻、减少、阻止、或者稳定疾病的发生或进展(例如，这里讨论的疾病或病症)，减轻疾病的严重程度或者改进和疾病相关的病状。
除非另外指出，当一个位置特别指明为“H”或“氢”，应理解为该位置具有天然丰度同位素组成的氢。除非另外声明，当一个位置特别指明是“D”或“氘”，应理解成该位置具有氘。
术语“化合物”，当指代本发明的化合物时，是指具有相同化学结构的一组分子，除了可能在该分子的组成原子上存在同位素变化。因此，本领域技术人员应该清楚，用含有指定氘原子的具体化学结构代表的化合物，将同时包括较少量在该结构中在指定的氘位置的一处或更多处具有氢原子的同位素异数体。该同位素异数体在本发明化合物中的相对量，将依赖于许多因素，包括用于制造化合物的氘化反应物的同位素纯度，以及用于制备化合物的各个合成步骤中的氘结合的效率。
本发明的化合物含有一个或多个不对称碳原子。这样，本发明的化合物可以作为单独的对映异构体以及对映异构体的混合物存在。因此，本发明的化合物将不仅包括消旋的混合物，还包括基本上不含其他对映异构体的单独的各对映异构体。
除非另外指出，当公开的化合物用没有明确说明立体化学的结构命名或者描述并具有一个或更多的手性中心时，应该理解为代表该化合物所有可能的立体异构体。
本文所用的术语“化合物”是指具有充分的稳定性以允许制造、并且在充分长的时间内保持化合物的完整性以用于本文详细说明的用途(例如，制成治疗产品、用于制造治疗化合物的中间产物、可分离或可储存的中间产物化合物、治疗应答于治疗试剂的疾病或病状)的化合物。
本发明相对于现有技术的有益效果包括但不限于：
(1)、本发明氘代药物可以减少毒性代谢产物的生成，增加活性代谢产物的生成，从而降低毒副作用或者提高治疗效果。
(2)、本发明氘代药物可以降低系统清除率，增加化合物的生物半衰期。本发明氘代药物的这种优点可以在减少使用剂量的同时保持相同的治疗水平，从而降低毒副作用或者提高治疗效果。
(3)、本发明氘代药物可以降低药物在胃肠道或肝脏中的代谢比例，使大多数未代谢的药物进入到体循环中。这种情况下，本发明氘代药物可以减少药物剂量的要求，产生较低的代谢负荷，提高药物的耐受性。
具体实施方式
下面结合具体实施例对本发明作进一步详细说明，但是本发明的内容不局限于实施例。
本发明的IR化合物优选为右式化合物
Figure PCTCN2018089027-appb-000008
本方法制备氘代PCT/CN2010/080370实施例3化合物，优选R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 16和R 17部分或者同时为氘或者氢。本例中举例了制备氘代苯甲酸盐。但是可以制备其他形式的盐。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。
示例性合成
实施例1化合物IR7的制备
Figure PCTCN2018089027-appb-000009
以PCT/CN2010/080370实施例3化合物游离碱为原料(500mg)，C 2H 5OD作溶剂(10mL)，DBU(445mg,2eq.)作碱，在23+-0.5℃搅拌24h，室温下，真空旋干溶剂。加DCM溶解，用NH 4Cl的D 2O饱和溶液洗两次除去DBU，无水Na 2SO 4干燥。浓缩，柱层析纯化，湿法上样(DCM/MeOH,20/1)，得到化合物IR7(84％)。 1H NMR(CDCl 3,400MHz):δ＝7.72-7.69(m,1H),7.13-7.09(m,1H),6.81-6.79(m,1H),3.32-3.28(m,1H),3.16-3.13(m,1H),3.03-2.97(m,1H),2.96-2.2.89(m,1H),2.43(s,3H),1.99-1.95(m,1H),1.83-1.76(m,1H),1.71-1.61(m,1H),1.32-1.22(m,1H)；HRMS(ESI)Calcd.for C 17H 18D 2FN 6O +[M+H +]345.1803,found 345.1802。
实施例2化合物IR8及IR8_BA的制备
Figure PCTCN2018089027-appb-000010
以PCT/CN2010/080370实施例3化合物苯甲酸盐为原料(500mg)，CH 3COOD作溶剂(100mg/mL)，50℃搅拌24h～36h，真空旋干溶剂。加DCM溶解，加入少量水，冰浴下用饱和Na 2CO 3水溶液调至pH9-10，用DCM萃取，合并有机相，无水Na 2SO 4干燥。浓缩，柱层析纯化，湿法上样(DCM/MeOH,20/1)，得到化合物IR8(48％)。化合物IR8： 1H NMR(MeOD-d4,500MHz):δ＝7.83-7.80(m,1H),7.26-7.22(m,1H),7.19-7.17(m,1H),5.36(s,2H),3.44-3.41(m,1H),3.23-3.21(m,1H),2.94-2.84(m,2H),2.73-2.68(m,1H),1.99-1.95(m,1H),1.80-1.75(m,1H),1.71-1.62(m,1H),1.33-1.26(m,1H)；HRMS(ESI)Calcd.for C 17H 17D 3FN 6O +[M+H +]346.1865,found 346.1867。
IR8苯甲酸盐的制备：将IR8和苯甲酸分别溶于DCM中，冰浴下向IR8溶液中缓慢滴加等当量的苯甲酸DCM溶液，搅拌1h，真空旋干；得到化合物IR8的苯甲酸盐(PCT/CN2010/080370实施例3化合物-d3_BA)。 1H NMR(MeOD-d4,400MHz):δ＝7.96-7.93(m,2H),7.82-7.79(m,1H),7.46-7.34(m,3H),7.27-7.22(m,2H),5.39-5.30(m,1H),3.66-3.62(m,1H),3.46-3.41(m,1H),3.22-3.19(m,1H),3.13-3.08(m,1H),2.99-2.93(m,1H),2.13-2.09(m,1H),1.87-1.70(m,2H),1.65-1.56(m,1H)。
实施例3化合物IR11的制备
Figure PCTCN2018089027-appb-000011
化合物2的合成
将D-谷氨酰胺(5.84g,40mmol)溶于1N NaOH(84mL)中，冰浴下滴加(Boc) 2O(14mL,60mmol)的二氧六环(40mL)溶液，搅拌30min后，撤去冰浴室温搅拌4h。减压浓缩至一半体积，冰浴，用1N KHSO 4调pH至2-3，再用EtOAc萃取(60mL*3)，有机相用Na 2SO 4干燥，浓缩得透明油状物8.6g，收率87％。
化合物3的合成
将化合物2(2.0g,8.12mmol)溶于THF(20mL)，加入DMAP(4mg,0.032mmol)，CDI(1.4g,8.44mmol)，70℃加热回流7h，冷却至室温，过滤，用THF洗，减压浓缩后真空干燥得白色固体1.41g，收率76％。
化合物4-d4的合成
将LiAlH 4(3.2g)溶于冰的THF(50mL)中，再缓慢滴加化合物3(5.0g)的THF(25mL)溶液，冰浴下搅拌2.5h；依次加入水(3.2g)，15％NaOH溶液(3.2g)，水(9.6g)，每次加完搅拌15分钟再加下一个。抽滤，滤饼用DCM/IPA(4/1,250mL)洗涤，合并滤液，减压浓缩，残留物经柱层析纯化得到420mg，收率12％。
化合物PCT/CN2010/080370实施例3化合物I-d4-Boc的合成
将化合物5(0.523mmol)与化合物4-d4(1.04mmol)研磨5分钟，在氮气氛围下加热到135℃反应13h，反应混合物用硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝10～50％)得到化合物6。
向碳酸钠(53mg,0.50mmol)、醋酸钯(3mg,0.013mmol)和N-甲基吡咯烷酮0.5mL的混合物中加入异丙醇3滴和水2滴，该混合物室温搅拌5分钟，向其中加入化合物6(0.496mmol)的NMP溶液(1.0mL)，并加热到140℃，再加入K 4[Fe(CN) 6].3H 2O(209mg,0.496mmol)，在140℃加热12h，冷却到室温，加入水10mL，乙酸乙酯萃取(20mL×2)，合并有机层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20～35％)得化合物I-d4-Boc。
化合物IR11的合成
将化合物PCT/CN2010/080370实施例3化合物I-d4-Boc(900mg,mmol)溶于EtOAc(20mL)，冰浴，加入3M HCl/EtOAc(15mL)，室温搅拌1.5h。向反应液中吹氮气除去HCl气体，旋干，加入水(5mL)溶解固体，用DCM(15mL)萃取，水相用氨水调pH至7-8，再用DCM(10mL*3)萃取，合并有机相，无水MgSO 4干燥，减压浓缩，经层析纯化得黄色固体410mg，收率59％，
化合物IR11： 1H NMR(MeOD-d4,500MHz):δ＝7.83-7.80(m,1H),7.27-7.23(m,2H),5.35(s,1H),3.31-3.21(m,1H),2.33(s,3H),2.08-2.03(m,1H),1.83-1.78(m,1H),1.73-1.68(m,1H),1.52-1.45(m,1H)。
实施例4化合物IR12及IR12_BA的制备
Figure PCTCN2018089027-appb-000012
反应条件：以IR8为原料(300mg)，C 2H 5OD作溶剂(50mg/mL)，DBU(2eq.)作碱，在23℃下搅拌24h，室温下真空旋干溶剂。加DCM溶解，加入少量水，冰浴下用饱和Na 2CO 3水溶液调至pH9-10，用DCM萃取，合并有机相，无水Na 2SO 4干燥。柱层析纯化，湿法上样(DCM/MeOH,20/1)。得到浅黄色固体化合物IR12(收率35％)。 1H NMR(MeOD-d4,500MHz):δ＝7.86-7.83(m,1H),7.29-7.26(m,1H),7.22-7.20(m,1H),3.47-3.44(m,1H),3.70-3.24(m,1H),2.97-2.87(m,1H),2.76-2.71(m,1H),2.02-1.99(m,1H),1.83- 1.78(m,1H),1.73-1.66(m,1H),1.36-1.29(m,1H)。
IR12的苯甲酸盐的制备：(0414)将IR12和苯甲酸分别溶于DCM中，冰浴下向IR12溶液中缓慢滴加苯甲酸溶液，搅拌1h,然后真空去除溶剂，得到化合物IR12_BA。 1H NMR(MeOD-d4,400MHz):δ＝7.95-7.93(m,2H),7.82-7.79(m,1H),7.44-7.41(m,1H),7.37-7.34(m,2H),7.28-7.22(m,2H),3.66-3.62(m,1H),3.45-3.40(m,1H),3.24-3.19(m,1H),3.14-3.09(m,1H),2.99-2.93(m,1H),2.13-2.09(m,1H),1.87-1.70(m,2H),1.65-1.56(m,1H)。
实施例5化合物IR13的制备
Figure PCTCN2018089027-appb-000013
反应条件：以IR11为原料(180mg)，C 2H 5OD作溶剂(50mg/mL)，DBU(190mg)作碱，在23℃下搅拌24h，室温下真空旋干溶剂。然后加入DCM溶解，用NH 4Cl的D 2O饱和溶液洗两次除去DBU，Na 2SO 4干燥。柱层析纯化，湿法上样(DCM/MeOH,20/1)。得到浅黄色固体化合物IR13(55mg，收率30％)。化合物IR13： 1H NMR(MeOD-d4,400MHz):δ＝7.83-7.80(m,1H),7.28-7.22(m,2H),3.20-3.17(m,1H),2.33-2.30(m,1H),2.08-2.01(m,1H),1.83-1.77(m,1H),1.73-1.66(m,1H),1.50-1.41(m,1H)；HRMS(ESI)Calcd.for C 17H 14D 6FN 6O +[M+H +]349.2054,found 349.2055。
实施例6化合物IR14的制备
Figure PCTCN2018089027-appb-000014
以苯IR11为原料(125mg)，CH 3COOD作溶剂(2mL)，50℃搅拌24h，真空旋干溶剂。加DCM溶解，加入少量水，冰浴下用饱和Na 2CO 3水溶液调至pH9-10，用DCM萃取，合并有机相，无水Na 2SO 4干燥。柱层析纯化，湿法上样(DCM/MeOH,20/1)，得到化合物IR14(42mg，收率35％)。化合物IR14： 1H NMR(MeOD-d4,500MHz):δ＝7.83-7.80(m,1H),7.26-7.22(m,1H),7.20-7.17(m,1H),5.36(s,2H),2.93-2.90(m,1H),2.00-1.95(m,1H),1.79-1.75(m,1H),1.68-1.62(m,1H),1.33-1.26(m,1H)；HRMS(ESI)Calcd.for C 17H 13D 7FN 6O +[M+H +]350.2117,found 350.2116。
通过实施例4的方法制备得到IR14_BA。
实施例7化合物IR15的制备
Figure PCTCN2018089027-appb-000015
以IR11为原料(300mg)，C 2H 5OD作溶剂(8mL)，DBU(280mg)作碱，在23℃搅拌24h，室温下真空旋干溶剂。加DCM溶解，用NH 4Cl的D 2O饱和溶液洗两次除去DBU，无水Na 2SO 4干燥。过滤，去除溶剂，真空干燥。将干燥物(210mg)溶于CH 3COOD(3mL),50℃搅拌24h。真空旋干溶剂，加DCM溶解，加入少量水，冰浴下用饱和Na 2CO 3水溶液调至pH9-10，用DCM萃取，合并有机相，无水Na 2SO 4干燥。柱层析纯化，湿法上样(DCM/MeOH,20/1)。得到浅黄色固体化合物IR15(91mg,两步收率30％)。 1H NMR(MeOD-d 4,400MHz):δ＝7.83-7.80(m,1H),7.27-7.18(m,2H),2.94-2.90(m,1H),2.00-1.94(m,1H),1.80-1.74(m,1H),1.69-1.62(m,1H),1.35-1.26(m,1H)；HRMS(ESI)Calcd.for C 17H 11D 9FN 6O +[M+H +]352.2242,found 352.2243。
本发明其他化合物可以通过上述通用制备方法和具体化合物及其盐的制备方法，对取代位做适当的调整后制备得到。
示例性药效和药代实验
实施例8体外药效实验
将上述其中三个氘代化合物IR11、IR12和IR14，及阳性对照物化合物I的苯甲酸盐，进行体外检测对人DPP-IV抑制活性检测，计算各个化合物分别对DPP IV的IC 50值。
1.实验方法：DPP-IV-Glo TM蛋白酶检测方法，
仪器
Envision多标记检测仪
试剂
1)DPP-IV试剂盒(DPP-IV-Glo测仪sion法合物分别对果数据，Promega,Cat#G8351)
2)DMSO(Sigma,Cat：154938-1L)
3)Dipeptidyl Peptidase IV(Sigma,Cat：D4943)
4)384孔板(PerkinElmer,OptiPlate-384MicroPlate)
2.试验内容
化合物配制方法
将待测化合物用100％DMSO溶解，配制成10mM浓度的储存液。反应体系中，药物最高终浓度20μM，用Tris-HCl(PH8.0)缓冲液5倍梯度稀释，共10个剂量。
DPP-IV-Glo TM蛋白酶检测方法
1)在使用之前，将DPP-IV-GloTT试剂盒中的缓冲液溶化并平衡至室温，并将低压冻干的荧光素检测试剂平衡至室温；
2)用110μl超纯水重悬底物，配制成浓度为10mM的底物储存液；
3)用DPP-IV-Glo TM的缓冲液50ml重悬荧光素检测试剂；
4)制备DPP-IV-Glo TM试剂：按比例将100μl DPP-IV-Glo TM的底物加入到上一步骤的50ml荧光素检测试剂中，涡旋混匀，该体系中底物的浓度为20μM；
5)用之前，将DPP-IV-Glo TM试剂置于室温30-60分钟；
6)制备样品：
Figure PCTCN2018089027-appb-000016
7)室温孵育10min；
8)在各样品孔中加入10μl的DPP IV-Glo TM检测试剂；
9)振荡300-500转30s，1000转/分离心10s，混匀；
10)反应5分钟后，用Envision多标记检测仪读板。
3.结果处理和分析方法
根据荧光强度F值计算抑制率，抑制率＝[1-(F样品-F空白)/(F阴性-F空白)]×100，结果用平均数±标准误(Mean±SEM)表示。根据抑制率，计算化合物IC50。
实验结果：化合物对DPP IV的IC 50值，详见以下表：
化合物对DPP IV抑制的IC 50值效果
Figure PCTCN2018089027-appb-000017
实验结果显示：优选的化合物IR12和化合物IR14相对于未进行的氘代的化合物I，在IC 50值有明显的减小，可能预期更好的DPP-IV体内效果。
实施例9体内药代实验
将上述其中三个氘代化合物IR8、IR12和IR14，及阳性对照物化合物I的苯甲酸盐，进行正式大鼠体内PK实验。
实验方法：1、LC-MS仪器
①液相色谱仪：美国Thermo Fisher Scientific公司Dionex Ultimate 3000 UPLC液相色谱仪，配有RS pump四元梯度泵，RS Column Compartment柱温箱，RS Autosampler自动进样器；
②质谱仪：美国Thermo Fisher Scientific公司TSQ QUANTUM Ultra EMR串联质谱仪，配有电喷雾离子化源(ESI)以及Xcalibur工作站。
2、液相条件
UPLC色谱柱：Thermo Hypersil Gold，100mm×2.1mm，1.9μm；柱温：40℃。
流动相为0.1％甲酸水溶液-甲醇＝60:40(v/v)，运行时间：3min，流速：0.3mL/min。
3、质谱条件
离子源为电喷雾电离源(ESI源)，正离子检测；源喷雾电压3500V；气化室温度200℃；离子传输毛细管温度350℃；辅气10Arb；鞘气30Arb，碰撞压力1.5mTorr。扫描方 式为选择反应监测(SRM)，用于定量分析的离子反应、Tube Lens及碰撞能见表1.
表1 分析物的SRM质谱条件
分析物 Q1(m/z) Q3(m/z) 碰撞能量(V) Tube Lens(V)
I 343.1 326.1 23 63
IR8 346.1 329.1 19 80
IR12 348.1 331.1 20 80
IR14 350.2 333.1 20 84
苯海拉明(IS) 256.1 167.2 20 61
实验方法：大鼠单次灌胃各化合物后主要药动学参数(n＝8，雌雄各半)如下表，表格数据为均值。
Figure PCTCN2018089027-appb-000018
注：C max达峰浓度，AUC 0-t浓度-时间曲线下面积，CL清除率，T 1/2为半衰期时间，BA代表苯甲酸盐。
各化合物药代参数显示，本次实验的化合物IR8、IR12和IR14与阳性对照物化合物I的苯甲酸盐相比，Cmax及AUC 0-t及半衰期T 1/2均有所明显的提高，清除率是指：单位时间从体内消除的含药血浆的体积或单位时间从体内消除的药物表观分布容积。反映机体清除药物的能力，清除率越大表示机体对物质的排泄能力越强，即相同剂量的药物，从血浆中消除的越快，一般其半衰期也越短。清除率太低会影响药物的排除，易产生积蓄中毒。阳性对照物化合物I与IR8、IR12和IR14相比清除率高，说明机体对化合物I的清除能力强，其从体内消除的速率快，在体内滞留时间短。预期IR8、IR12和IR14具有更好的体内长效时间。
在没有进一步说明的情况下，相信本领域的普通技术人员可以仅利用前面的说明和示范性的实施例，便制造和使用本发明的化合物，并实行权利要求所保护的方法。应该理解的是，前面的讨论和实施例仅仅呈现了某些优选实施方式的详细说明。对于本领域技术人员而言，可以在不脱离本发明的精神和范围的情况下做出各种修饰和同等物均属于本发明的保护范围内。

Claims (11)

  1. 二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述衍生物具有以下结构式：
    Figure PCTCN2018089027-appb-100001
    其中，R 1至R 19选自氘或者为氢，且至少R 1至R 19中一个以上为氘。
  2. 根据权利要求1所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述化合物中的“氘”总的相对量将少于化合物的49.9％。
  3. 根据权利要求1所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述化合物中的“氘”总的相对量将少于化合物的47.5％、少于40％、少于32.5％、少于25％、少于17.5％、少于10％、少于5％、少于3％、少于1％、或者少于0.5％。
  4. 根据权利要求1所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 16和R 17中一个以上为氘。
  5. 根据权利要求1所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述化合物中R 4和R 5同时为氘，和/或R 6、R 7和R 8同时为氘，和/或者R 9和R 10同时为氘，和/或者R 16和R 17同时为氘。
  6. 根据权利要求1所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述化合物结构如下：
    Figure PCTCN2018089027-appb-100002
    Figure PCTCN2018089027-appb-100003
  7. 根据权利要求1—6任一权利要求所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述化合物为其药学上可接受的盐，包括硫酸 盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、一氢磷酸盐、二氢磷酸盐、偏磷酸盐、焦磷酸盐、盐酸盐、溴酸盐、碘酸盐、醋酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸酯、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、反丁烯二酸盐、顺丁烯二酸盐、丁炔-1，4-二酸盐、己炔-1，6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、顺丁烯二酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐。
  8. 根据权利要求7所述的二肽基肽酶IV抑制剂的取代1,2,4-三嗪衍生物，其特征在于，所述化合物为其药学上可接受的盐，选自：
    Figure PCTCN2018089027-appb-100004
    Figure PCTCN2018089027-appb-100005
  9. 药物组合物，其特征在于，包含权利要求1到8任一项所述的至少一个化合物和/或其至少一个药学上可接受的盐，和至少一种药学上可接受的载体。
  10. 化合物作为改善或治疗对二肽基肽酶IV响应疾病药物的应用，其特征在于，包括，所述化合物包含权利要求1到8任一项所述的至少一个化合物和/或其至少一个药学上可接受的盐。
  11. 根据权利要求10所述的应用，其特征在于，对二肽基肽酶IV响应疾病包括：(1)高血糖或糖尿病，包括I型糖尿病、II型糖尿病，(2)糖耐量降低，(3)胰岛素抵抗，(4)肥胖，(5)血脂代谢紊乱，(6)血脂异常，(7)高血脂，(8)高甘油三酯血症，(9)高胆固醇血症，(10)低HDL水平，(11)高低密度脂蛋白水平，(12)动脉粥样硬化及其后遗症，(13)血管再狭窄，(14)肠易激综合症，(15)炎症性肠病，包括克罗恩病和溃疡性结肠炎，(16)其他炎症，(17)胰腺炎，(18)腹部肥胖，(19)神经退行性疾病，(20)视网膜病变，(21)肾病，(22)神经性疾病，(23)X综合征，(24)卵巢高雄激素(多囊卵巢综合征)，(25)II型糖尿病，(26)生长激素缺乏，(27)中性粒细胞减少，(28)神经元疾病，(29)肿瘤转移，(30)良性前列腺肥大，(32)牙龈炎，(33)高血压，(34)骨质疏松症。
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