WO2022166581A1 - 一种核苷酸衍生物及其药物组合物和用途 - Google Patents
一种核苷酸衍生物及其药物组合物和用途 Download PDFInfo
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000005874 benzothiadiazolyl group Chemical group 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960004774 citicoline sodium Drugs 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 125000006637 cyclobutyl carbonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- VEIYJWQZNGASMA-UHFFFAOYSA-N cyclohex-3-en-1-ylmethanol Chemical compound OCC1CCC=CC1 VEIYJWQZNGASMA-UHFFFAOYSA-N 0.000 description 1
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006641 cyclooctyl carbonyl group Chemical group 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006638 cyclopentyl carbonyl group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 210000003540 papillary muscle Anatomy 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- YWAFNFGRBBBSPD-OCMLZEEQSA-M sodium;[[(2r,3s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound [Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 YWAFNFGRBBBSPD-OCMLZEEQSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000005503 thioxanyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
Definitions
- the present invention relates to, but is not limited to, the technical field of medicinal chemistry, in particular to the use of a nucleotide derivative and its pharmaceutical composition and the treatment of cardiovascular and cerebrovascular diseases.
- CVD cardiovascular diseases
- Nucleotide substances participate in the molecular mechanism of gene information retention, replication and transcription in organisms, and play an important role in the regulation of cell structure, metabolism, energy and function, and are used to supplement endogenous substances or antagonize Enzymes in vivo, such as citicoline sodium, adenosine triphosphate disodium, cyclic adenosine monophosphate, riboflavin sodium phosphate, sodium phosphate creatine, etc., have good clinical effects. These endogenous substances or their structural analogs can enhance myocardial contractility, causing increased blood pressure and increased cardiac output. And can relax smooth muscle, dilate coronary blood vessels, promote the activity of respiratory chain oxidase and improve myocardial hypoxia.
- nucleotides and their analogs are highly water-soluble and polar, not only have low bioavailability, but also have poor cell membrane penetration, are difficult to enter into cells, and cannot exert their effects through the blood-brain barrier.
- Nucleotides and their analogs contain multiple active groups in their molecules, which can be modified in various ways to improve their pharmacokinetic characteristics and even biological activities, so as to exert better or even various clinical therapeutic effects . Therefore, there remains a need in the art for nucleotide derivatives of novel structures.
- the inventors developed a new class of nucleotide derivatives. During the research process, it was completely beyond the expectation of those skilled in the art that such derivatives have the functions of improving myocardial hypoxia, dilating coronary arteries, enhancing myocardial contractility, Prominent role in increasing cardiac output.
- One aspect of the present invention provides a nucleotide derivative, tautomer, stereoisomer, solvate, or a pharmaceutically acceptable salt thereof as shown in (I):
- Y 1 , Y 2 and Y 3 are each independently O, N(H) or S;
- R3 and R4 are each independently selected from H, or from the following groups substituted or unsubstituted with one or more groups A : alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, non- Aromatic cycloalkenylcarbonyl, arylcarbonyl or heteroarylcarbonyl;
- R 1 is selected from C6-C20 aryl substituted or unsubstituted by one or more groups A, or in,
- Y 4 is O or S
- R 5 and R 6 are each independently selected from hydrogen, or from the following groups substituted or unsubstituted by one or more groups B: C1-C8 alkyl, benzyl;
- R 7 is selected from the following groups substituted or unsubstituted by one or more groups B: C2-C20 alkenyl, C2-C20 alkynyl, non-aromatic C3-C8 cycloalkenyl, 3-8 membered heterocycle Alkyl, non-aromatic 3-8 membered heterocyclic group containing at least one double bond; alternatively, R 7 is alkyl substituted with one or more groups B, or substituted with one or more groups B Aryl;
- R2 is wherein, the above-mentioned Y 4 , R 5 , R 6 and R 7 are as defined above;
- the group A is one or more of the following groups: alkyl, cycloalkyl, alkoxy, aryloxy, alkylthio, alkylamino, alkylcarbonyl, aminoalkyl, hydroxyalkyl, Aminoalkylcarbonyl, heterocycloalkyl, heterocycloalkylmethylene, monoalkylaminomethylene, dialkylaminomethylene, halogen, amino, mercapto, hydroxyl, carboxyl, cyano and nitro;
- the group B is one or more of the following groups: hydroxyl, amino, mercapto, nitro, halogen, carboxyl, aldehyde, alkanoyloxy, aminocarbonyl and guanidine.
- the present invention provides a nucleotide derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salts thereof of formula (II):
- the present invention provides a nucleotide derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salts thereof of formula (III):
- Y 1 is O
- Y 1 is N(H);
- Y 1 is S.
- Y 2 is O
- Y 2 is N(H);
- Y 2 is S.
- Y 3 is N(H);
- Y 3 is O
- Y 3 is S.
- R 1 is C6-C20 aryl substituted or unsubstituted by one or more groups A;
- R 1 is selected from phenyl substituted or unsubstituted by one or more groups A, and by one or more groups A substituted or unsubstituted naphthyl;
- R 1 is selected from phenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, naphthyl, or phenoxyphenyl;
- R 1 is in
- the above Y is O
- the above Y is S
- R 5 and R 6 above are each independently selected from hydrogen, C1-C8 alkyl, or benzyl.
- R 5 and R 6 are each independently selected from: hydrogen, methyl, ethyl, and benzyl;
- R 7 is the following groups substituted or unsubstituted with one or more groups B: C2-C20 alkenyl, non-aromatic C3-C8 cycloalkenyl, 3-8 membered heterocycloalkane 3-8 membered heterocyclic group that is non-aromatic and contains at least one double bond;
- R 7 above is alkyl substituted with one or more groups B, or aryl substituted with one or more groups B;
- R 7 is selected from 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, 2-vinyl-3-butenyl, 3-butenyl, 2-butenyl, cyclohexenylmethyl, furan-2-ylmethyl, hexahydropyran-4-ylmethyl, 2-methyl-2-butenyl.
- R 2 is Wherein, the above-mentioned Y 4 , R 5 , R 6 and R 7 are as defined above.
- both R 3 and R 4 are hydrogen
- one of R 3 and R 4 is hydrogen, and the other is the following group substituted or unsubstituted with one or more groups A: alkylcarbonyl , alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, non-aromatic cycloalkenylcarbonyl, arylcarbonyl or heteroarylcarbonyl;
- both R 3 and R 4 are the following groups substituted or unsubstituted with one or more groups A: alkylcarbonyl, alkenylcarbonyl, alkyne Hydrocarbylcarbonyl, cycloalkylcarbonyl, non-aromatic cycloalkenylcarbonyl, arylcarbonyl or heteroarylcarbonyl;
- the group A is: alkyl, cycloalkyl, alkoxy, aryloxy, alkylthio, alkylamino, trifluoromethyl, alkylcarbonyl, aminoalkyl, hydroxyalkyl, aminoalkylcarbonyl , heterocycloalkyl, heterocycloalkylmethylene, monoalkylaminomethylene, dialkylaminomethylene, halogen, amino, mercapto, hydroxyl, carboxyl, cyano and nitro;
- the group B is: hydroxyl group, amino group, mercapto group, nitro group, halogen group, carboxyl group, aldehyde group, alkanoyloxy group, alkanoyloxyalkyl group, aminocarbonyl group and guanidine group.
- nucleotide derivatives provided by the present invention are selected from the following compounds:
- the present invention provides pharmaceutical compositions comprising the aforementioned nucleotide derivatives, tautomers, stereoisomers, solvates, and pharmaceutically acceptable salts thereof.
- the present invention discloses a pharmaceutical composition, which uses the compound, isomer or a pharmaceutically acceptable salt thereof described in the present invention as an active ingredient or main active ingredient, supplemented by a pharmaceutically acceptable vector composition.
- the present invention provides the use of the above-mentioned pharmaceutical composition for preparing a medicament for treating and preventing cardiovascular and cerebrovascular diseases.
- the present invention provides that the above-mentioned pharmaceutical composition can be used to treat and prevent diseases related to cardiovascular and cerebrovascular diseases; the above-mentioned cardiovascular and cerebrovascular-related diseases include but are not limited to: angina pectoris, acute myocardial infarction, myocardial hypoxia and the like.
- the nucleotide derivatives of the present invention can be formulated into pharmaceutical compositions for administration to a patient according to a variety of suitably selected modes of administration, including systemic, such as oral, inhalation, or parenteral, via Intravenous, intramuscular, transdermal or subcutaneous, etc.
- the nucleotide derivatives of the present invention can be prepared as pharmaceutical compositions, including but not limited to tablets, capsules or solutions for oral administration, or solutions for transdermal administration, sprays agent, lotion, ointment, latex or gel.
- solvated forms eg, hydrated, ethanolate forms.
- solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
- the alkylcarbonyl group is a C1-C20 alkylcarbonyl group, including but not limited to: formyl, acetyl, propionyl, 2-methylpropionyl, butyryl, 3-methylbutyryl Acyl.
- the alkenylcarbonyl group is a C2-C20 alkenylcarbonyl group, including but not limited to: acryloyl, 2-butenoyl, 3-butenoyl, 4-pentenoyl, 3-pentenoyl alkenoyl.
- the alkynylcarbonyl group is a C2-C20 alkynylcarbonyl group, including but not limited to: 2-butynoyl, 2-pentynoyl, and 3-pentynoyl.
- the cycloalkylcarbonyl group may be a C3-C8 cycloalkylcarbonyl group, including but not limited to: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl carbonyl, or cyclooctylcarbonyl.
- the non-aromatic cycloalkenylcarbonyl can be non-aromatic C3-C8 cycloalkenyl, including but not limited to: cyclopentenylcarbonyl, cyclohexenylcarbonyl.
- the arylcarbonyl group may be a C6-C20 arylcarbonyl group, including but not limited to: benzoyl, naphthoyl, anthracenyl, or bibenzoyl and the like.
- the heteroaryl group in the heteroarylcarbonyl group may be selected from the following groups: thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, Isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thitriazolyl, oxtriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl , tetrazinyl, purinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl and indolyl.
- the C1-C8 alkyl groups include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, heptyl, octyl, or 2,2-diethylethyl;
- the C2-C18 alkynyl group includes, but is not limited to, 1-butyn
- the 3-8 membered heterocyclic hydrocarbon group or the non-aromatic 3-8 membered heterocyclic group containing at least one double bond means that the heterocyclic ring includes at least one or more atoms selected from the following groups: : oxygen, nitrogen and sulfur; the 3-8-membered heterocyclic hydrocarbon group or non-aromatic 3-8-membered heterocyclic group containing at least one double bond includes but is not limited to: oxiranyl, aziridinyl, Thietanyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrole Alkyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl
- the C6-C20 aryl group is benzene, naphthalene, anthracene, or biphenyl and the like.
- the 3-8 membered heteroaryl group may be selected from: pyrimidine, furan, thiazole, thiophene, pyridine, pyrrole, imidazole.
- the alkyl group in the group A, alkylcarbonyl group, aminoalkyl group, hydroxyalkyl group or the alkyl group in the aminoalkylcarbonyl group may be a C1-C18 alkyl group, examples include but not Limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, dodecyl, hexadecyl alkyl, octadecyl, or 2,2-diethylethyl.
- the cycloalkyl group in the group A may be a C3-C8 cycloalkyl group, examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl base, or cyclooctyl.
- the alkoxy group in the group A can be C1-C18 alkoxy group, examples include but are not limited to: methoxy group, ethoxy group, n-propoxy group, isopropoxy group , n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, neopentyloxy, n-hexyloxy, dodecyloxy, tetradecyloxy, hexadecane oxy, octadecyloxy, or 2,2-diethylethoxy.
- the alkylthio group in the group A may be a C1-C18 alkylthio group, examples include but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio , n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, n-pentylthio, neopentylthio, n-hexylthio, dodecylthio, tetradecylthio, hexadecane Thio, octadecylthio, or 2,2-diethylethylthio
- the alkylamino group in the group A may be a monoalkylamino group or a dialkylamino group, wherein the alkyl group is as described above.
- the halogen in the group A is fluorine, chlorine, bromine or iodine.
- the heterocycle in the heterocycloalkyl group and the heterocycloalkylmethylene group in the group A can be oxiranyl, aziridinyl, thiirane, nitrogen tetrahydrofuranyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazepine Heterohexanyl, homopiperazinyl, azepanyl, oxepanyl, thiepanyl, oxazepanyl, dia
- the pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts, such as hydrochloride, sulfate, or phosphate; organic acid salts, such as methanesulfonate, ethanesulfonate, besylate, besylate, citrate, or acetate, etc.
- pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms, which are within the scope of sound medical judgment, suitable for use in humans and animals tissue exposure without undue toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient.
- Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, penetration enhancers, and the like.
- stereoisomers refers to compounds that have the same chemical composition, but differ in the arrangement of atoms or groups in space.
- solvate means that certain compounds may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent and are intended to be included within the scope of the present invention.
- the compounds in this application may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- N-Boc-L-alanine (3.8 g, 20 mmol) was dissolved in dichloromethane (40 mL), compound DSC12-0104 (3.0 g, 30 mmol) was added, and 1-(3-dimethylaminopropyl) was added under stirring )-3-ethylcarbodiimide hydrochloride (EDCI, 5.8 g, 30 mmol) and 4-dimethylaminopyridine (3.7 g, 30 mmol).
- phenyl dichlorophosphate (4.2 g, 20 mmol) was dissolved in dichloromethane (40 mL), cooled to below -5 °C, the above-mentioned standby was dropped into the system, the dropwise addition was completed, triethylamine (2.2 g, 22 mmol), the temperature of the dropwise addition process was controlled not to be higher than 10° C., the dropwise addition was completed, and the reaction was carried out for 2 hours.
- a dichloromethane solution (10 mL) of pentafluorophenol (3.7 g, 20 mmol) was added dropwise, and the dropwise addition was completed, and triethylamine (2.0 g, 20 mmol) was added dropwise again.
- N-Boc-L-alanine 9.46 g, 50 mmol
- anhydrous tetrahydrofuran 70 mL
- diisopropylethylamine 12.92 g, 100 mmol
- the reaction mixture was then cooled to 0°C and stirred for an additional 30 minutes before acetic anhydride (51.0 g, 50 mmol) was added.
- Step 2-Step 4 Preparation of compound DSC12-06
- Example 7 The effect of DSC12-01 on hypoxia tolerance in healthy newborn pigs
- Test method 31 healthy pigs (weight 0.5-2.5kg) born 3-7 days old, male or female. Randomly divided into 4 groups. After anesthetized neonatal pigs, tracheal intubation was performed, and mechanical respiration was performed, and 100% oxygen was inhaled. A midline longitudinal incision was made in the neck, and the bilateral carotid arteries were separated, with silk thread indwelling. After the basal state of neonatal pigs was stable for 20 minutes, the blood flow of bilateral common carotid arteries was blocked with arterial clips, and the inhaled gas of mechanical respiration was changed to a mixture of 6% oxygen and 94% nitrogen for 30 minutes, and then 100% oxygen was inhaled, and at the same time, the two sides were restored.
- the blood supply of the lateral common carotid artery was sutured.
- the administration group: n 9, after intravenous injection of DSC12-01 (2.00 mg/kg), the bilateral common carotid arteries were blocked and 6% oxygen was inhaled;
- Meglumine cyclophosphate (MCA) group: n 9, intravenous injection of MCA (1.75 mg /kg) and then blocked the bilateral common carotid arteries and inhaled 6% oxygen.
- MCA Meglumine cyclophosphate
- the optical density value of Western blot results was analyzed.
- the optical density value of iNOS expression in myocardial tissue of sham operation group was 0.17 ⁇ 0.03
- the optical density value of iNOS expression in myocardial tissue of ischemia-hypoxia group was 0.39 ⁇ 0.07, the difference was significant, P ⁇ 0.01
- the optical density value of iNOS expression in the myocardial tissue of the administration group was 0.19 ⁇ 0.04, the difference was significant, P ⁇ 0.01.
Abstract
一种核苷酸衍生物及其药物组合物和用途。具体涉及一种如通式(I)所示的核苷酸衍生物或其互变异构体、立体异构体、溶剂化物、其药学上可接受盐,以及它们在制备心脑血管方面疾病的药物中的应用,其中通式(I)各基团的定义详见说明书。
Description
本发明涉及但不限于药物化学技术领域,尤指一种核苷酸衍生物及其药物组合物和心脑血管方面疾病治疗方面的用途。
随着社会经济水平的提高,全球化和城镇化程度的加深,人们饮食习惯等生活方式发生了重大转变。同时随着全球老龄化程度加剧,越来越多证据表明非传染性疾病,特别是心血管病(cardiovascular disease,CVD)已经成为全球疾病负担的主要原因。2019年全球疾病、伤害和风险因素负担研究(Global Burden of Disease,GBD)显示,2019年CVD在全球共造成1856.21万死亡,已经成为全球第一大死因。
2019年,中国CVD患病人数为1.20亿,新发病例数1234.11万,死亡458.43万;病率、发病率和死亡率从1990年的4235.43/10万、447.81/10万和204.75/10万,分别升至2019年的8460.08/10万、867.65/10万和322.30/10万。患病率、发病率和死亡率均随年龄呈上升趋势。未来,由于高血压、饮食因素、空气污染和烟草等原因,加上人口老龄化迅速,中国CVD疾病负担仍然十分严峻。
核苷酸类物质参与生物体中基因信息的保留、复制和转录的分子机制,在细胞的结构、代谢、能量和功能的调节等方面起着十分重要作用,用于补充内源性物质或拮抗生物体内的酶,如胞磷胆碱钠、三磷酸腺苷二钠、环磷腺苷、核黄素磷酸钠、磷酸肌酸钠等具有很好的临床效果。这些内源性物质或其结构类似物能使心肌收缩力增强,引起血压升高,心输出量增高。并能舒张平滑肌、扩张冠状动脉血管、促进呼吸链氧化酶的活性及改善心肌缺氧等。
然而,很多核苷酸及其类似物水溶性和极性较强,不仅生物利用度低,而 且细胞膜穿透性差、难以进入细胞内以及通过血脑屏障而不能发挥其作用。核苷酸及其类似物的化合物分子中含多个活泼基团,可进行多种方式的修饰以改善其药代动力学特征甚至生物活性,从而发挥更好的甚至各种不同的临床治疗效果。因此,本领域仍需要新型结构的核苷酸衍生物。
发明内容
本发明人开发了一类新的核苷酸衍生物,在研究过程中,完全出乎本领域技术人员预料的发现,这类衍生物具有改善心肌缺氧、扩张冠脉、增强心肌收缩力、增加心排血量方面的突出作用。
本发明一方面提供一种如(I)所示的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐:
式(I)中,
Y
1、Y
2和Y
3各自独立地为O、N(H)或S;
R
3和R
4各自独立地选自H、或选自被一个或者多个基团A取代或未取代的下列基团:烷基羰基、烯烃基羰基、炔烃基羰基、环烷基羰基、非芳香的环烯烃基羰基、芳基羰基或杂芳基羰基;
上述Y
4为O或S;
上述R
5和R
6各自独立地选自氢、或选自被一个或者多个基团B取代或 未取代的下列基团:C1-C8的烷基、苄基;
上述R
7选自被一个或者多个基团B取代或未取代的下列基团:C2-C20烯烃基、C2-C20炔烃基、非芳香的C3-C8环烯烃基、3-8元杂环烷基、非芳香的且包含至少一个双键的3-8元杂环基;或者,R
7为被一个或者多个基团B取代的烷基、或者被一个或多个基团B取代的芳基;
所述基团A为下列基团中一种或多种:烷基、环烷基、烷氧基、芳氧基、烷硫基、烷氨基、烷基羰基、氨基烷基、羟基烷基、氨基烷基羰基、杂环烷基、杂环烷基亚甲基、单烷胺基亚甲基、双烷胺基亚甲基、卤素、氨基、巯基、羟基、羧基、氰基和硝基;
所述基团B为下列基团中一种或多种:羟基、氨基、巯基、硝基、卤素、羧基、醛基、烷酰氧基、氨基羰基和胍基。
在一些实施方案中,本发明提供一种如式(II)所示的核苷酸衍生物、互变异构体、立体异构体、溶剂化物及其药学上可接受的盐:
式(II)中取代基的定义如前所述。
在一些实施方案中,本发明提供一种如式(Ⅲ)所示的核苷酸衍生物、互变异构体、立体异构体、溶剂化物及其药学上可接受的盐:
式(Ⅲ)中取代基的定义如前所述。
在一些实施方案中,上述式(I)-(Ⅲ)中,Y
1为O;
在一些实施方案中,上述式(I)和/或(II)中,Y
1为N(H);
在一些实施方案中,上述式(I)和/或(II)中,Y
1为S。
在一些实施方案中,上述式(I)-(Ⅲ)中,Y
2为O;
在一些实施方案中,上述式(I)和/或(II)中,Y
2为N(H);
在一些实施方案中,上述式(I)和/或(II)中,Y
2为S。
在一些实施方案中,上述式(I)-(Ⅲ)中,Y
3为N(H);
在一些实施方案中,上述式(I)和/或(II)中,Y
3为O;
在一些实施方案中,上述式(I)和/或(II)中,Y
3为S。
在一些实施方案中,上述式(I)-(Ⅲ)中,R
1为被一个或者多个基团A取代或未取代的C6-C20的芳基;
进一步地,在一些更具体地实施方案中,上述式(I)-(Ⅲ)中,R
1选自被一个或者多个基团A取代或未取代的苯基、被一个或者多个基团A取代或未取代的萘基;
更进一步地,在一些更具体地实施方案中,上述式(I)-(Ⅲ)中,R
1选自苯基、邻溴苯基、间溴苯基、对溴苯基、萘基、或苯氧基苯基;
在一些实施方案中,上述Y
4为O;
在一些实施方案中,上述Y
4为S;
在一些实施方案中,上述R
5和R
6各自独立地选自氢、C1-C8烷基、或苄基。
进一步地,在一些更具体地实施方案中,上述R
5和R
6各自独立地选自:氢、甲基、乙基、和苄基;
在一些实施方案中,上述R
7为被一个或者多个基团B取代或未取代的下列基团:C2-C20烯烃基、非芳香的C3-C8环烯烃基、3-8元杂环烷基、非芳香的且包含至少一个双键的3-8元杂环基;
在一些实施方案中,上述R
7为被一个或者多个基团B取代的烷基、或者被一个或多个基团B取代的芳基;
进一步地,在一些更具体地实施方案中,上述R
7选自2-乙基-1-丁烯基、2-乙基-3-丁烯基、2-乙烯基-3-丁烯基、3-丁烯基、2-丁烯基、环己烯基甲基、呋喃-2-基甲基、六氢吡喃-4-基甲基、2-甲基-2-丁烯基。
在一些实施方案中,上述式(I)-(Ⅲ)中,R
3和R
4均为氢;
在一些实施方案中,上述式(I)-(Ⅲ)中,R
3和R
4其中一个为氢,另一个为被一个或者多个基团A取代或未取代的下列基团:烷基羰基、烯烃基羰基、炔烃基羰基、环烷基羰基、非芳香的环烯烃基羰基、芳基羰基或杂芳基羰基;
在一些实施方案中,上述式(I)-(Ⅲ)中,R
3和R
4均为被一个或者多个基团A取代或未取代的下列基团:烷基羰基、烯烃基羰基、炔烃基羰基、环烷基羰基、非芳香的环烯烃基羰基、芳基羰基或杂芳基羰基;
所述基团A为:烷基、环烷基、烷氧基、芳氧基、烷硫基、烷氨基、三 氟甲基、烷基羰基、氨基烷基、羟基烷基、氨基烷基羰基、杂环烷基、杂环烷基亚甲基、单烷胺基亚甲基、双烷胺基亚甲基、卤素、氨基、巯基、羟基、羧基、氰基和硝基;
所述基团B为:羟基、氨基、巯基、硝基、卤素、羧基、醛基、烷酰氧基、烷酰氧基烷基、氨基羰基和胍基。
在一些实施方案中,本发明提供的上述核苷酸衍生物,选自下列化合物:
另一方面,在一些实施方案中,本发明提供了包含上述核苷酸衍生物、互变异构体、立体异构体、溶剂化物及其药学上可接受的盐的药物组合物。
在一些实施方案中,本发明公开了一种药物组合物,其以本发明所述的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分,辅以药学上可接受的载体组成。
第三方面,在一些实施方案中,本发明提供了上述药物组合物可用于在制备治疗和预防心脑血管方面疾病药物中的用途。
在一些实施方案中,本发明提供了上述药物组合物可用于治疗和预防与心脑血管相关病症的疾病;上述心脑血管相关病症包括但不限于:心绞痛、急性心肌梗死、心肌缺氧等。
在一些实施方案中,本发明所述核苷酸衍生物可以被制备为药用组合物,按照多种合适选择的给予方式给患者用药,这些途径包括全身例如口服、吸入或胃肠外,通过静脉内、肌肉、透皮或皮下等。
在一些实施方案中,本发明所述核苷酸衍生物可以被制备为药用组合物的制剂包括但不限于口服的片剂、胶囊或溶液等,或用于透皮给药的溶液、喷 剂、乳液、软膏、乳胶或凝胶。
定义:
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在,例如水合物、乙醇合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。
在本申请的实施方案中,所述烷基羰基为C1-C20烷基羰基,包括但不限于:甲酰基、乙酰基、丙酰基、2-甲基丙酰基、丁酰基、3-甲基丁酰基。
在本申请的实施方案中,所述烯烃基羰基为C2-C20烯烃基羰基,包括但不限于:丙烯酰基、2-丁烯酰基、3-丁烯酰基、4-戊烯酰基、3-戊烯酰基。
在本申请的实施方案中,所述炔烃基羰基为C2-C20炔烃基羰基,包括但不限于:2-丁炔酰基、2-戊炔酰基、3-戊炔酰基。
在本申请的实施方案中,所述环烷基羰基可以为C3-C8环烷基羰基包括但不限于:环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基、环庚基羰基、或环辛基羰基。
在本申请的实施方案中,所述非芳香的环烯烃基羰基可以非芳香的C3-C8环烯烃基包括但不限于:环戊烯基羰基、环己烯基羰基。
在本申请的实施方案中,所述芳基羰基可以为C6-C20芳基羰基包括但不限于:苯甲酰基、萘甲酰基、蒽甲酰基、或联苯甲酰基等。
在本申请的实施方案中,所述杂芳基羰基中的杂芳基可以选自下列基团:噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、噻三唑基、噁三唑基、吡啶基、嘧啶 基、吡嗪基、哒嗪基、三嗪基、四嗪基、嘌呤基、苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并三唑基、苯并咪唑基和吲哚基。
在本申请的实施方案中,所述C1-C8烷基包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、新戊基、正己基、庚基、辛基、或2,2-二乙基乙基;所述C2-C20烯烃基包括但不限于烯丙基、2-丁烯基(-CH2-CH=CH-CH
3)、2-甲基-2-戊烯基(-CH
2-C(CH
3)=CH-CH
2-CH
3)、5-己烯基(-CH
2CH
2CH
2CH=CH
2)、或2-丁炔基(-CH
2-CC-CH
3);所述C2-C18炔烃基包括但不限于1-丁炔-4-基。
在本申请的实施方案中,所述3-8元杂环烃基或非芳香的且包含至少一个双键的3-8元杂环基是指该杂环至少包括一个或多个选自下列原子:氧、氮和硫;所述3-8元杂环烃基或非芳香的且包含至少一个双键的3-8元杂环基包括但不限于:环氧乙烷基、吖丙啶基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁基、1,3-二硫杂环丁基、吡咯烷基、二氢-1H-吡咯基、二氢呋喃基、四氢呋喃基、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基、异喹啉基、四氢异喹啉基、吗啉基、硫吗啉基、1,1-二氧代-硫吗啉基、二氢吡喃基、四氢吡喃基、六氢噻喃基、六氢嘧啶基、氧杂氮杂环己烷基、噻嗪烷基、噻噁烷基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、硫氮杂环庚烷基、四氢噻喃基、噁唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷酮基、噁唑烷酮基等。
在本申请的实施方案中,所述C6-C20芳基为苯、萘、蒽、或联苯等。
在本申请的实施方案中,所述3-8元杂芳基可以选自:嘧啶、呋喃、噻唑、噻吩、吡啶、吡咯、咪唑。
在本申请的实施方案中,所述基团A中的烷基、烷基羰基、氨基烷基、羟基烷基或氨基烷基羰基中的烷基可以是C1-C18烷基,示例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、新戊基、正己基、十二烷基、十六烷基、十八烷基、或2,2-二乙基乙基。
在本申请的实施方案中,所述基团A中的环烷基可以是C3-C8环烷基, 示例包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基、或环辛基。
在本申请的实施方案中,所述基团A中的烷氧基可以是C1-C18烷氧基,示例包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、异丁氧基、叔丁氧基、正戊氧基、新戊氧基、正己氧基、十二烷氧基、十四烷氧基、十六烷氧基、十八烷氧基、或2,2-二乙基乙氧基。
在本申请的实施方案中,所述基团A中的烷硫基可以是C1-C18烷硫基,示例包括但不限于:甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、仲丁硫基、异丁硫基、叔丁硫基、正戊硫基、新戊硫基、正己硫基、十二烷硫基、十四烷硫基、十六烷硫基、十八烷硫基、或2,2-二乙基乙硫基
在本申请的实施方案中,所述基团A中的烷胺基可以是单烷基氨基或二烷基氨基,其中的烷基如上所述。
在本申请的实施方案中,所述基团A中的卤素为氟、氯、溴或碘。
在本申请的实施方案中,所述基团A中杂环烷基、杂环烷基亚甲基中的杂环可以是环氧乙烷基、吖丙啶基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁基、1,3-二硫杂环丁基、四氢呋喃基、四氢噻吩基、哌啶基、哌嗪基、吗啉基、硫吗啉基、1,1-二氧代-硫吗啉基、四氢吡喃基、六氢噻喃基、六氢嘧啶基、氧杂氮杂环己烷基、高哌嗪基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、硫氮杂环庚烷基。
在本申请的实施方案中,所述的药学上可接受的盐,包括但不限于,无机酸盐,例如盐酸盐、硫酸盐、或磷酸盐等;有机酸盐,例如甲磺酸盐、乙磺酸盐、苯磺酸盐、苯甲磺酸盐、枸橼酸盐、或乙酸盐等。
在本申请的实施方案中,所述的药学上可接受的,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。
术语“立体异构体”指具有同一化学构成,但是原子或基团在空间的排列不同的化合物。
属于“溶剂化物”指某些化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。
本申请书中的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
以下实施例可以使本领域技术人员更全面地理解本发明,但不以任何方式限制本发明,所有化合物的结构均经MS确定。
实施例1:2-乙基-3-烯-1-基((S)-(2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟四氢呋喃-2-基)甲氧基)(苯氧基)磷酰)-L-丙氨酸酯(化合物DSC12-01)的合成
反应式:
制备方法:
步骤1:化合物DSC12-0104的制备
氮气氛围下,将2,5-二氢呋喃(7.0g,100mmol)溶解在无水四氢呋喃(50mL)中,冷却至0℃。加入2mol/L的乙基氯化镁的无水四氢呋喃溶液(38mL,76.9mmol),并将所得混合物在25℃下搅拌10分钟,然后加入乙烯双(1-茚基)二氯化锆(130mg,0.31mmol)。使混合物在氮气氛围下搅拌40小时。随后向体系加入水,用二氯甲烷萃取3次,合并有机相,无水硫酸钠干燥,过滤,浓缩,剩余物真空蒸馏得化合物DSC12-0104(3.21g),收率32.1%。ESI-MS(+):m/z=101.09。
步骤2:化合物DSC12-0103的制备
将N-Boc-L-丙氨酸(3.8g,20mmol)溶于二氯甲烷(40mL),加入化合物DSC12-0104(3.0g,30mmol),搅拌下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI,5.8g,30mmol)和4-二甲氨基吡啶(3.7g,30mmol)。加入完毕,室温反应4小时,用饱和磷酸二氢钠洗涤,分出有机相,无水硫酸钠干燥,过滤,浓缩,剩余物为化合物DSC12-0103(4.1g),收率75.6%。ESI-MS(+):m/z=272.18。
步骤3:化合物DSC12-0102的制备
将化合物DSC12-0103(5.4g,20mmol)溶于二氯甲烷(20mL)中,冷却至0℃左右,加入三氟乙酸/水(10:1,3mL),搅拌1小时,备用。
氮气保护下,将二氯磷酸苯酯(4.2g,20mmol)溶于二氯甲烷(40mL),降温至-5℃以下,将上述备用液滴入体系,滴加完毕,加入三乙胺(2.2g,22mmol),滴加过程控制体系温度不高于10℃,滴加完毕,反应2小时。滴加五氟苯酚(3.7g,20mmol)的二氯甲烷溶液(10mL),滴加完毕,再次滴加三乙胺(2.0g,20mmol)。滴加完毕,系升温室温反应。反应结束后,加入硫酸氢钠的水溶液,搅拌30分钟,分出有机相,有机相水洗后浓缩至干。
上述浓缩干的剩余物加入环己烷(50mL)24,体系加热80℃搅拌1小时,加入三乙胺(0.25g,2.5mmol),缓慢降温至30℃搅拌5小时。体系过滤得到固体,固体中加入异丙醇(20mL),降温至0℃打浆2小时,过滤得化合物DSC12-0103(4.5g),收率45.6%。ESI-MS(+):m/z=494.11。
步骤4:化合物DSC12-0101的制备
氮气保护下,反应瓶中依次加入无水乙腈(50mL)、化合物DSC12-0102(2.5g,5mmol)和DSC12-01SM1(1.7g,5mmol),然后加入无水氯化镁(1.0g,10mmol),体系加热至50℃,加入二异丙基乙胺(1.6g,12.5mmol),体系继续50℃反应。TLC监测反应完毕,体系浓缩,剩余物加入二氯甲烷和水,分出有机相,无水硫酸钠干燥,过滤,浓缩,剩余物过柱纯化得化合物DSC12-0101(1.1g),收率34.1%。ESI-MS(+):m/z=641.24。
步骤5:化合物DSC12-01的制备
反应瓶中加入四氢呋喃(20mL)、化合物DSC12-0101(1.0g,1.56mmol)、和浓盐酸(3mL)。加入完毕,体系室温搅拌15小时。用1N的氢氧化钠溶液调节体系至中性,减压浓缩,剩余物加入二氯甲烷和水,分出有机相,无水硫酸钠干燥,过滤,浓缩,剩余物过柱纯化,得化合物DSC12-01(0.32g),收率34.2%。ESI-MS(+):m/z=601.21。
实施例2:丁基-3-烯-1-基((S)-((2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(化合物DSC12-02)的合成
反应式:
制备方法:
以3-丁烯-1-醇为起始物料,参考实施例1步骤2至步骤5的操作工序,制备得化合物DSC12-02(0.24g),总收率6.2%。ESI-MS(+):m/z=573.18。
实施例3:呋喃-2-基甲基((S)-(2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(化合物DSC12-03)的合成
反应式:
制备方法:
以糠醇为起始物料,参考实施例1步骤2至步骤5的操作工序,制备得化合物DSC12-03(0.17g),总收率7.0%。ESI-MS(+):m/z=599.16。
实施例4:环己-3-烯-1-基甲基((S)-(2R,3S,4R,5R)-5-(4-氨基 吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(化合物DSC12-04)的合成
反应式:
制备方法:
以3-环己烯-1-甲醇为起始物料,参考实施例1步骤2至步骤5的操作工序,制备得化合物DSC12-04(0.27g),总收率7.8%。ESI-MS(+):m/z=613.21。
实施例5:2-乙烯基-3-烯-1-基((S)-(2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(化合物DSC12-05)的合成
反应式:
制备方法:
以2-乙烯基-3-丁烯-1-醇为起始物料,参考实施例1步骤2至步骤5的操 作工序,制备得化合物DSC12-05(0.22g),总收率8.3%。ESI-MS(+):m/z=599.19。
实施例6:2-乙基-1-烯-1-基((S)-((2R,3S,4R,5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯(化合物DSC12-06)的合成
反应式:
制备方法:
步骤1:化合物DSC12-0603的制备
在三口瓶中,将N-Boc-L-丙氨酸(9.46g,50mmol)溶解在无水四氢呋喃(70mL)中。向该溶液中加入二异丙基乙胺(12.92g,100mmol)。然后在加入乙酸酐(51.0g,50mmol)之前将该反应混合物冷却至0℃并再搅拌30分钟。然后加入2-乙基丁醛(5.51g,55mmol)继续维持0℃搅拌4h,蒸出四氢呋喃,体系加入饱和碳酸氢钠,用乙酸乙酯萃取3次,饱和食盐水洗涤3次,有机相无水硫酸钠干燥,过滤,减压蒸干,得化合物DSC12-0603(11.6g),收率85.6%。ESI-MS(+):m/z=272.18。
步骤2-步骤4:化合物DSC12-06的制备
参考实施例1步3至步骤5的操作工序,制备得化合物DSC12-06(0.15g),总收率7.1%。ESI-MS(+):m/z=601.21。
按照与上述实施例同样的方法,使市售化合物或由市售化合物适当合成的中间体化合物,合成了下列实施例化合物。
实施例7:DSC12-01对健康新生猪耐缺氧的影响
试验方法:出生3-7天的健康猪31只(体重0.5-2.5kg,),雌雄不限。随机分成4组。麻醉新生猪后气管插管,进行机械呼吸,吸入100%氧气。颈正中纵切口,分离双侧颈动脉,带丝线留置。新生猪基础状态平稳20min后,用动脉夹阻断双侧颈总动脉血流,同时机械呼吸的吸入气体改为6%氧气94%氮气混合气,持续30min,然后吸入100%氧气,同时恢复双侧颈总动脉血供,缝合切口。其中,假手术组:n=4,只游离双侧颈动脉;缺氧缺血组:n=9,双侧颈总动脉暂时性阻断,同时控制呼吸吸入6%氧气;给药组:n=9,静注DSC12-01(2.00mg/kg)后再阻断双侧颈总动脉和吸入6%氧气;环磷腺苷葡胺(MCA)组:n=9,静注MCA(1.75mg/kg)后再阻断双侧颈总动脉和吸入6%氧气。
肌钙蛋白测定:新生猪麻醉平稳后20min和缺氧缺血10h后,分别按照肌钙蛋白I测定试剂盒的说明书操作,用化学发光法测定肌钙蛋白I含量。结 果见表3:
表3肌钙蛋白I含量测定结果
由上可见:四组动物在麻醉后缺氧缺血前肌钙蛋白I值无显著性差异(P>0.05);在缺氧缺血后10h,缺氧缺血组血液样本内肌钙蛋白I值显著高于假手术组(P<0.01),给药组和MCA组肌钙蛋白I值显著降低(P<0.01);同时,给药组肌钙蛋白I值比MCA组更低(P<0.01),显示出化合物DSC12-01在此方面更加有效。
Western blot方法:麻醉处死新生猪,在左室前乳头肌伴同前壁取心肌组织,超声粉碎,离心取上清,BCA法测定蛋白浓度,电泳、转印、5%脱脂奶粉溶液封闭在4℃冰箱过夜,一抗iNOS和β-actin孵育2h,二抗孵育2h,ECL扫描测光密度值。
统计学处理采用SPSS11.0统计软件处理,计量资料以均数±标准差(x± s)表示,两组间比较采用成组t检验,三组间比较采用单因素方差分析,P<0.05为差异有统计学意义。
对Western blot结果进行光密度值分析,假手术组心肌组织iNOS表达的光密度值为0.17±0.03,缺血缺氧组心肌组织iNOS表达的光密度值为0.39±0.07,二者差异显著,P<0.01;与缺血缺氧组相比,给药组心肌组织iNOS表达的光密度值为0.19±0.04,二者差异显著,P<0.01。
虽然本发明已以较佳实施例揭示如上,然其并非用以限定本发明,任何本领域技术人员,在不脱离本发明的精神和范围内,当可作些许的修改和完善,因此本发明的保护范围当以权利要求书所界定的为准。
Claims (6)
- 一种如(I)所示的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐:式(I)中,Y 1、Y 2和Y 3各自独立地为O、N(H)或S;R 3和R 4各自独立地选自H、或选自被一个或者多个基团A取代或未取代的下列基团:烷基羰基、烯烃基羰基、炔烃基羰基、环烷基羰基、非芳香的环烯烃基羰基、芳基羰基或杂芳基羰基;上述Y 4为O或S;上述R 5和R 6各自独立地选自氢、或选自被一个或者多个基团B取代或未取代的下列基团:C1-C8的烷基、苄基;上述R 7选自被一个或者多个基团B取代或未取代的下列基团:C2-C20烯烃基、C2-C20炔烃基、非芳香的C3-C8环烯烃基、3-8元杂环烷基、非芳香的且包含至少一个双键的3-8元杂环基;或者,R 7为被一个或者多个基团B取代的烷基、或者被一个或多个基团B取代的芳基;所述基团A为下列基团中一种或多种:烷基、环烷基、烷氧基、芳氧基、烷硫基、烷氨基、烷基羰基、氨基烷基、羟基烷基、氨基烷基羰基、杂环烷基、杂环烷基亚甲基、单烷胺基亚甲基、双烷胺基亚甲基、卤素、氨基、巯基、羟基、羧基、氰基和硝基;所述基团B为下列基团中一种或多种:羟基、氨基、巯基、硝基、卤素、羧基、醛基、烷酰氧基、氨基羰基和胍基。
- 包含如权利要求1~4中任一项所述的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐的药物组合物。
- 权利要求1~4中任一项所述的核苷酸衍生物、互变异构体、立体异构体、溶剂化物、或其药学上可接受盐,或者权利要求5所述的药物组合物在制备用于心脑血管的辅助治疗药物中的应用。
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