WO2020010900A1 - 化合物用于制备预防、治疗或改善疼痛的药物的用途 - Google Patents

化合物用于制备预防、治疗或改善疼痛的药物的用途 Download PDF

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WO2020010900A1
WO2020010900A1 PCT/CN2019/084604 CN2019084604W WO2020010900A1 WO 2020010900 A1 WO2020010900 A1 WO 2020010900A1 CN 2019084604 W CN2019084604 W CN 2019084604W WO 2020010900 A1 WO2020010900 A1 WO 2020010900A1
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group
compound
formula
alkyl
iia
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English (en)
French (fr)
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段建新
李安蓉
孟繁英
唐纳德T·荣
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Shenzhen Ascentawits Pharmaceutical Technology Co Ltd
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Shenzhen Ascentawits Pharmaceutical Technology Co Ltd
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Priority to EP19834376.6A priority Critical patent/EP3821884A4/en
Priority to US17/258,724 priority patent/US20210283151A1/en
Priority to CN201980001988.4A priority patent/CN110896605B/zh
Priority to KR1020217003089A priority patent/KR102689740B1/ko
Priority to CA3105884A priority patent/CA3105884C/en
Priority to JP2021500604A priority patent/JP7153972B2/ja
Priority to CN202210621699.8A priority patent/CN115317492A/zh
Publication of WO2020010900A1 publication Critical patent/WO2020010900A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/564—Three-membered rings

Definitions

  • the invention relates to the use of compounds disclosed in patent application PCT / US2016 / 021581, patent application PCT / US2016 / 025665 and patent application PCT / US2016 / 062114 in the preparation of a medicament for the prevention, treatment or improvement of pain.
  • Opioids are alkaloids derived from opium (poppy) and derivatives in vivo and in vitro. They interact with central specific receptors to relieve pain and have strong analgesic effects; however, long-term use can easily lead to tolerance and dependence. And addictive, with respiratory depression, central sedation and other adverse reactions, currently used for acute
  • Non-steroidal anti-inflammatory drugs are a class of anti-inflammatory drugs that do not contain a steroid structure. They have anti-inflammatory, anti-rheumatic, analgesic, antipyretic, and anti-coagulant effects. They are widely used in clinical practice for osteoarthritis and rheumatoid Relief of arthritis, various fevers, and various pain symptoms; but only exerts a moderate analgesic effect, and is suitable for mild and moderate chronic dull pain, but it is not effective for directly stimulating sharp pain caused by sensory ends, and also has Gastrointestinal bleeding and cardiac toxicity.
  • the present invention is based on the patent application PCT / US2016 / 021581 (WO2016 / 145092), patent application PCT / US2016 / 025665 (WO2016 / 161342), and patent application PCT / US2016 / 062114 (WO2017 / 087428).
  • Compounds or pharmaceutically acceptable salts or solvates of these compounds provide the use of said compounds or their pharmaceutically acceptable salts or solvates in the manufacture of a medicament for the prevention, treatment or amelioration of pain.
  • the aldosterone reductase AKR1C3 needs to bind to a specific substrate.
  • aldehyde ketone reductase AKR1 C3 plays an important catalytic role in the biochemical pathway of prostaglandin H2 / D2 to prostaglandin E2 / F2:
  • the inventors designed experiments for verification.
  • the experiments confirmed that the above-mentioned specific substrate, that is, the DNA alkylating agent that over-expresses the aldehyde ketone reductase AKR1C3 can inhibit the activity of the aldehyde ketone reductase AKR1C3. It was confirmed that it can reduce the content of prostaglandin E2 / F2 in the blood, and based on this, it can be proved that the specific substrate mentioned above has analgesic effect.
  • the technical scheme provided by the present invention is as follows.
  • the invention provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the prevention, treatment or improvement of pain,
  • X 10 is O, S, SO or SO 2 ;
  • X, Y and Z are each independently hydrogen, CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6- C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered hetero Ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl Or an ether, or R 13 and R 14 together with the nitrogen atom to which they are bonded form a 5-7 membered heterocyclic group;
  • T comprises an amino phosphate alkylating agent
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, ether group are optionally substituted.
  • X 10 is S.
  • T is OP (Z 1 ) (NR 30 CH 2 CH 2 X 1 ) 2 , OP (Z 1 ) (NR 30 2 ) (N (CH 2 CH 2 X 1 ) 2 ), OP (Z 1 ) (N (CH 2 ) 2 ) 2 or OP (Z 1 ) (N (CH 2 CH 2 X 1 ) 2 ) 2 , wherein R 30 are each independently hydrogen or C 1 -C 6 Alkyl, or two R 30 groups together with the nitrogen atom to which they are bonded form a 5-7 membered heterocyclic group, Z 1 is O or S, and X 1 is Cl, Br or OMs or other leaving group.
  • T is OP (Z 1 ) (NHCH 2 CH 2 Cl) 2 , OP (Z 1 ) (NHCH 2 CH 2 Br) 2 , OP (Z 1 ) (NH 2 ) ( N (CH 2 CH 2 X 1 ) 2 ), OP (Z 1 ) (N (CH 2 ) 2 ) 2 or OP (Z 1 ) (N (CH 2 CH 2 Cl) 2 ) 2 , where Z 1 is O Or S, and X 1 is Cl, Br, or OMs.
  • Z 1 is O or S.
  • T is OP (O) (N (CH 2 CH 2 )) 2 , OP (O) (NHCH 2 CH 2 Cl) 2 , OP (O) (NHCH 2 CH 2 Br) 2 or OP (O) (NH 2 ) (N (CH 2 CH 2 Cl) 2 ).
  • Z is hydrogen
  • X is hydrogen
  • Y is hydrogen or a halogen group.
  • A is optionally substituted C 6 -C 10 aryl.
  • A is optionally substituted phenyl.
  • A is optionally substituted 5-15 membered heteroaryl.
  • A is optionally substituted pyridyl.
  • R is hydrogen
  • R is C 1 -C 6 alkyl.
  • R is methyl.
  • the compounds include individual non-image isomers and other geometric isomers and image isomers, as well as image isomers, non-image isomers, and geometric isomers other than image isomers Mixture of things.
  • the present invention encompasses the information provided in PCT application PCT / US2016 / 021581 on the use of the compound shown above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the prevention, treatment or amelioration of pain.
  • the present invention provides the use of a compound of formula II or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the prevention, treatment or improvement of pain,
  • X 10 is O, S, SO or SO 2 ;
  • X, Y and Z are each independently hydrogen, CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6- C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • Each R is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 -15-membered heterocyclic ring, 5-15-membered heteroaryl, ether, -CONR 13 R 14 or -NR 13 COR 14 ;
  • R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocyclic ring, 5-15 membered heteroaryl Or an ether, or R 13 and R 14 together with the nitrogen atom to which they are bonded form a 5-7 membered heterocyclic group;
  • L 1 and D are defined as follows:
  • L 1 is selected from:
  • R 40 and R 41 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 Aryl, 4-15 membered heterocyclic ring or 5-15 membered heteroaryl;
  • R 42 is C 2 -C 3 alkyl or heteroalkyl substituted with 1-3 C 1 -C 6 alkyl optionally
  • V (-) is any anion, preferably a pharmaceutically acceptable anion;
  • D is the part that makes D-OH an anticancer drug, where OH is an aliphatic or phenolic hydroxyl group, or an OH moiety attached to a phosphorus atom as provided herein; in other words, D is an anticancer drug D-OH removal Groups remaining after the hydroxyl group;
  • L 1 is:
  • R 40 is as defined above, R 43 is hydrogen or forms a heterocyclic ring with D, and the phenyl moiety is optionally substituted;
  • D is the part that makes D-NR 43 H an anti-cancer drug; in other words, D is a group remaining after de-amino or amine of the anti-cancer drug D-NR 43 H;
  • L 1 is a bond, -OC (R 40 R 41 ) 2- , -OC (R 40 R 41 ) -NR 40 R 41 (+)-C (R 40 R 41 ) -or
  • R 40 , R 41 and V are as defined above;
  • D is an anticancer drug containing a primary or secondary amine, wherein the primary or secondary amine is bonded to L 1 ;
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, ether group are optionally substituted.
  • X 10 is S.
  • D is part of the cytotoxic agent HNR 43 -D containing a primary or secondary amine group; in other words, D is a cytotoxic agent HNR 43 -D which removes the primary or secondary amine group Remaining groups after the secondary amine group.
  • D is part of the cytotoxic agent HO-D containing at least one hydroxyl group; in other words, D is the group remaining after the cytotoxic agent HO-D has dehydroxylated.
  • HO-D is a cytotoxic agent containing at least one hydroxyl group; in other words, D is a part of HO-D, a cytotoxic agent containing at least one hydroxyl group, or D is a cell Remaining group after detoxification of the toxic agent HO-D; in IIA-6-i, DNR 40 R 41 is a drug; in other words, D is a part that makes DNR 40 R 41 an anticancer drug, or D is an anticancer drug Drug DNR 40 R 41 is part of NR 40 R 41 ; and in IIA-6, D is a drug containing a secondary amine, wherein the secondary amine is bonded to a methylene group, in other words, D is a drug containing a secondary amine, and The secondary amine contained therein is bonded to a methylene group and further to -NR 40 R 41 , as shown above.
  • DNR 40 R 41 is a drug; in other words, D is such that DNR 40 R 41 is part of an anticancer drug, or D is an anticancer drug DNR 40 R 41 out of NR 40 R 41 ; in IIA-7, D is a drug containing a secondary amine, wherein the secondary amine is bonded to a methylene group, as shown above.
  • Z is hydrogen
  • X is hydrogen
  • Y is hydrogen or a halogen group.
  • A is optionally substituted C 6 -C 10 aryl.
  • A is optionally substituted phenyl.
  • A is optionally substituted 5-15 membered heteroaryl.
  • A is optionally substituted pyridyl.
  • each R is hydrogen
  • one of the R groups is hydrogen and the other is a C 1 -C 6 alkyl, or wherein the R groups are all non-hydrogen substituents as defined above.
  • R is methyl
  • R 40 , R 41 and R 43 are each independently hydrogen or methyl and R 42 is -CH 2 -CH 2 -or CH 2 -C (Me) 2- .
  • D does not include amino phosphate alkylating agents, such as -P (Z 1 ) (NR 30 CH 2 CH 2 X 1 ) 2 , -P (Z 1 ) (NR 30 2 ) (N (CH 2 CH 2 X 1 ) 2 ), -P (Z 1 ) (N (CH 2 CH 2 )) 2 or -P (Z 1 ) (N (CH 2 CH 2 X 1 ) 2 ) 2 , wherein each R 30 is independently hydrogen or C 1 -C 6 alkyl, or 2 R 30 together with the nitrogen atom to which it is bonded form a 5-7 membered heterocyclic group, Z 1 is O or S, and X 1 is Cl, Br or OMs, or another leaving group.
  • amino phosphate alkylating agents such as -P (Z 1 ) (NR 30 CH 2 CH 2 X 1 ) 2 , -P (Z 1 ) (NR 30 2 ) (N (CH 2 CH 2 X 1 ) 2 ), -
  • the compounds include individual non-image isomers and other geometric isomers and image isomers, as well as image isomers, non-image isomers, and geometric isomers other than image isomers Mixture of things.
  • the present invention encompasses the information provided in PCT application PCT / US2016 / 025665 on the use of the compound shown above or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the prevention, treatment or amelioration of pain.
  • the compound I is a compound AST-3424 as shown below:
  • the compounds may also be used in the form of a salt, that is, the present invention provides the use of a pharmaceutically acceptable salt of the compound shown in the manufacture of a medicament for the prevention, treatment or improvement of pain.
  • the salt may be a basic salt, including the compound formed with an inorganic base (such as an alkali metal hydroxide, an alkaline earth metal hydroxide, etc.) or with an organic base (such as monoethanolamine, diethanolamine, or triethanolamine, etc.) Of salt.
  • the salt may be an acid salt, including the compound and an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid, etc.) or an organic acid (such as methanesulfonic acid). , Trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, etc.).
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid, etc.
  • organic acid such as methanesulfonic acid
  • the compounds can also be used in the form of solvates, that is, the present invention provides the use of a pharmaceutically acceptable solvate of the compound shown in the manufacture of a medicament for the prevention, treatment or improvement of pain.
  • the solvate is a hydrate, an alcoholate, or the like.
  • the pain is pain caused by cancer, including but not limited to: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, Colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenocarcinoma, sebaceous adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic Cancer, myeloid cancer, bronchial cancer, osteoblastic cancer, epithelial cancer, bile duct cancer, chorionic cancer, embryo cancer, seminoma, Wilms cancer, glioblastoma, astrocytoma, neural tuber cells Tumor, craniopharyngioma, ependymal tumor, pineal tumor,
  • cancer including but not limited to
  • the pain is pain caused by inflammation.
  • the medicaments produced may also include other compounds or agents in combination with the compounds shown.
  • Other compounds or agents can also be used to prevent, treat or improve pain.
  • the medicament prepared comprises the indicated compound or a salt or solvate thereof in a specific dosage range, and / or the medicament prepared is administered in a specific dosage form and a specific mode of administration.
  • the dosage of a drug for the prevention, treatment or amelioration of pain or the indicated compound or its salt or solvate contained in the drug usually depends on the specific compound administered, the patient, the specific disease or disorder and its severity, the route of administration And frequency, and need to be determined by the attending physician according to the specific situation.
  • the dose may be 0.1 to 30 mg / 7 days, preferably 1 to 10 mg / 7 days, and further preferably 5 mg / day; the dose may be divided every 7 days.
  • the medicaments produced may also include pharmaceutically acceptable excipients or excipients.
  • the medicament may be in any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric tablets, chewable tablets, orally disintegrating tablets, capsules, dragees, granules, dry powders, oral solutions, small needles for injection Lyophilized powder for injection or large infusion.
  • the pharmaceutically acceptable excipients or excipients in the medicine may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, adhesives Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, encapsulants, and pigments.
  • the present invention also relates to a method for the prevention, treatment or amelioration of pain, which method comprises administering to a subject in need thereof an effective amount of a compound of the present invention Or a pharmaceutically acceptable salt or solvate thereof.
  • the subject is a mammal, more preferably a human.
  • the pain is pain caused by cancer.
  • Cancer includes, but is not limited to, lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, Bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenocarcinoma, sebaceous adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, myeloid carcinoma, Bronchial cancer, osteoblast cancer, epithelial cancer, bile duct cancer, chorionic cancer, embryo cancer, seminoma, Wilms cancer, glioblastoma, astrocytoma, neuroblastoma, craniopharyngioma , Ependymal tumor, pineal tumor, hematopoietic tumor, vocal cord neuroma,
  • the present invention also provides a medicament for preventing, treating or improving pain caused by cancer or inflammation, which contains the compound of formula I or formula II as defined above.
  • the present invention also provides a method for treating pain caused by cancer or inflammation, comprising the steps of applying the above-mentioned medicine; and the step of measuring the AKR1C3 reductase content of a patient's cancer cells using an AKR1C3 antibody If it is determined that the AKR1C3 reductase content is equal to or greater than a predetermined value, the above-mentioned drug is administered to the patient.
  • Figure 1 shows the effect of AST-3424 on the production of reduced progesterone.
  • C x -C y or “C xy " before a group refers to the range of the number of carbon atoms present in the group.
  • C 1 -C 6 alkyl refers to an alkyl group having at least 1 and up to 6 carbon atoms.
  • Alkoxy refers to -O-alkyl
  • “Amine” refers to NR p R q , where R p and R q are independently hydrogen or C 1 -C 6 alkyl, or R p and R q together with the nitrogen atom to which they are bonded form a 4-15 membered heterocyclic ring .
  • Aryl refers to an aromatic having 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthracenyl) Group.
  • aryl when the point of attachment is at an aromatic carbon atom Or “Ar” applies (for example, 5,6,7,8 tetrahydronaphthalen-2-yl is an aryl group because its attachment point is at the 2-position of the aromatic phenyl ring).
  • the C 6 -C 10 aryl group may be a phenyl group, a naphthyl group, and various substituted phenyl or naphthyl groups.
  • Heteroaryl refers to an aromatic group having 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and includes a single ring (e.g., imidazolyl-2-yl and Imidazol-5-yl) and polycyclic systems (such as imidazopyridyl, benzotriazolyl, benzimidazol-2-yl, and benzimidazol-6-yl).
  • heteroaryl e.g., 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl.
  • the nitrogen and / or sulfur ring atoms of the heteroaryl are optionally oxidized to provide an N-oxide (N ⁇ O), sulfinyl, or sulfonyl moiety.
  • heteroaryl or 5-15 membered heteroaryl includes, but is not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene Benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzothienyl, benzene Benzimidazolyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl , Furyl, furyl, imidazolidinyl, imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl, indolyl, indazinyl, indolyl
  • Alkyl refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms and in some embodiments 1 to 6 carbon atoms.
  • C xyalkyl refers to an alkyl group having x to y carbon atoms.
  • This term includes, for example, straight-chain and branched-chain hydrocarbon groups such as methyl (CH 3- ), ethyl (CH 3 CH 2- ), n-propyl (CH 3 CH 2 CH 2- ), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2- ), isobutyl ((CH 3 ) 2 CHCH 2- ), second butyl ((CH 3 ) ( CH 3 CH 2 ) CH-), third butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2- ), and neopentyl ((CH 3 ) 3 CCH 2- ).
  • straight-chain and branched-chain hydrocarbon groups such as methyl (CH 3- ), ethyl (CH 3 CH 2- ), n-propyl (CH 3 CH 2 CH 2- ), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2
  • Cycloalkyl refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or polycyclic rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the attachment point is at a non-aromatic carbon atom (e.g. 5,6,7, 8-tetrahydronaphthalen-5-yl).
  • cycloalkyl or C 3 -C 8 cycloalkyl groups include cycloalkenyl.
  • cycloalkyl or C 3 -C 8 cycloalkyl include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.
  • Heterocyclic or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” means a heteroatom having from 1 to 14 carbon atoms and from 1 to 6 selected from the group consisting of nitrogen, sulfur or oxygen Saturated or partially saturated cyclic groups and includes monocyclic and polycyclic ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For polycyclic systems with aromatic and / or non-aromatic rings, the terms “heterocyclic”, “heterocyclic” when there is at least one ring heteroatom and the point of attachment is at an atom of the non-aromatic ring , "Heterocycloalkyl” or “heterocyclyl” applies (e.g., 1,2,3,4-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-6-yl and Decahydroquinoline-6-yl).
  • the heterocyclyl herein is a 3-15 member, 4-14 member, 5-13 member, 7-12 or 5-7 member heterocyclic ring.
  • the heterocycle contains 4 heteroatoms. In some other embodiments, the heterocyclic ring contains 3 heteroatoms. In another embodiment, the heterocyclic ring contains up to 2 heteroatoms. In some embodiments, the nitrogen and / or sulfur atom of the heterocyclyl is optionally oxidized to provide an N-oxide, sulfinyl, sulfonyl moiety.
  • Heterocyclyl includes, but is not limited to, tetrahydropyranyl, hexahydropyridyl, N-methylhexahydropyridin-3-yl, hexahydropyrazinyl, N-methylpyrrolidin-3-yl, 3 -Pyrrolidinyl, 2-pyrrolidinone-l-yl, morpholinyl and pyrrolidinyl.
  • Prefix indicating the number of carbon atoms e.g., C 3 - 10 refers to the total number of carbon number outside the impurity atoms in the heterocyclyl moiety atoms.
  • the divalent heterocyclic group will have a suitably adjusted hydrogen content.
  • “Ether” refers to 1 to 3 C 1 -C 6 alkoxy-substituted C 1 -C 6 alkyl. Alkoxy refers to -O-alkyl.
  • Halo refers to one or more of fluorine, chlorine, bromine and iodine.
  • C xy alkenyl refers to an alkenyl group having x to y carbon atoms and is intended to include, for example, vinyl, propenyl, 1,3-butadienyl, and the like.
  • Alkynyl refers to a straight-chain monovalent hydrocarbon group or branched monovalent hydrocarbon group of 2 to 10 carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and containing at least one triple bond.
  • alkynyl is also intended to include these hydrocarbon groups having one triple bond and one double bond.
  • C 2-6 alkynyl includes ethynyl, propynyl, and the like.
  • Amino phosphate alkylating agent refers to an alkylating agent comprising one or more Z 5 -X 5 -Y 5 moieties bonded to an -OP (Z1) moiety, where Z 5 is such as nitrogen, sulfur or oxygen For heteroatoms, X 5 is optionally substituted ethylene, Y 5 is halo or another leaving group, or Z 5 -X 5 -Y 5 together form an aziridinyl (NCH 2 CH 2 ) moiety And Z 1 is as defined above.
  • This alkylating agent can react with DNA or another nucleic acid or protein. In some cases, the alkylating agent can crosslink the DNA.
  • a group may be substituted with one or more substituents (eg, 1, 2, 3, 4 or 5 substituents).
  • the substituent is selected from the group consisting of chlorine, fluorine, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -CO 2 H and its salts, and C 1 -C 6 alkyl esters.
  • Alkylene refers to a divalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms and in some embodiments 1 to 6 carbon atoms.
  • C uv alkylene refers to an alkylene group having u to v carbon atoms.
  • Alkylidene and Alkylene include branched and straight chain hydrocarbon groups.
  • C 1 -C 6 alkylene include methylene, ethyl stretching, stretch propyl, 2-methyl-propyl stretched, stretch-pentyl and the like.
  • Heteroalkyl refers to an alkylene in which a chain carbon atom is replaced by a heteroatom such as O, S, N, or P or a heteroatom-containing substituent.
  • Drugs as referred to herein with respect to D include, but are not limited to, gemcitabine, erlotinib, meturedepa, uredepa, hexamethamine ( altretamine), imatinib, triethylenemelamine, trimethylmelamine, chlorambucil, chlornaphazine, estramustine, gefitinib gefitinib), mechlorethamine, nitrogen mustard oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trifoten (trofosfamide), uracil mustard, carmustine, chlorozotocin, fotemustine, nimustine, ramustine ranimustine, dacarbazine, mannomustine, miobronitol, mitolactol, pipepobroman, aclacinomycins ), Actinomycin, anthramycin, azaseri ne), bleomycin, c
  • administering means direct administration or administration (which can be administered or administered to a patient by a medical professional or can be self-administered or administered) and / or indirect administration or administration, which can be the act of prescribing a drug.
  • direct administration or administration which can be administered or administered to a patient by a medical professional or can be self-administered or administered
  • indirect administration or administration which can be the act of prescribing a drug.
  • a physician instructing a patient to self-administer or administer a drug and / or provide a prescription for a drug to a patient is administering or administering the drug to the patient.
  • Cancer refers to potentially unrestricted growth leukemia, lymphoma, cancer, and other malignancies (including solid tumors) that can locally expand through invasion and systemically through metastasis.
  • malignancies including solid tumors
  • Examples of cancer include, but are not limited to, adrenal gland, bone, brain, breast, bronchi, colon and / or rectum, gallbladder, head and neck, kidney, throat, liver, lung, nervous tissue, pancreas, prostate, parathyroid, Cancer of the skin, stomach and thyroid.
  • cancers include acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, cervical epithelial differentiation and carcinoma in situ, Ewing's sarcoma, epidermoid carcinoma, giant cell tumor, multiple Glioblastoma, hair cell tumor, intestinal ganglioma, proliferative corneal neurotumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemia, lymphoma, malignant carcinoid tumor, malignant melanoma , Malignant hypercalcemia, equine tumor, medullary epithelial cancer, metastatic skin cancer, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteosarcoma, osteoblastic and other sarcomas, Ovarianoma, pheochromocytoma, polycythemia vera, primary
  • “Inflammation” is preferably due to the arachidonic acid-coxidase-prostaglandin pathway described above, and painful inflammation is initiated by prostaglandin E2 / F2.
  • Patient and “individual” are used interchangeably and refer to a mammal in need of cancer treatment. Usually, the patient is human. Usually, the patient is a human diagnosed with cancer. In certain embodiments, “patient” or “individual” may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, for screening, characterizing, and evaluating drugs and therapies Or rat.
  • Prodrug refers to a compound that is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property after administration or administration.
  • prodrugs are chemically modified in a way that makes them less active or inactive relative to the drug, but chemical modification causes the corresponding drug to be produced through metabolism or other biological processes after the prodrug is administered.
  • Prodrugs may have altered metabolic stability or delivery characteristics, fewer side effects or lower toxicity, or improved flavors relative to the active drug (see, for example, reference Nogrady, 1985, Medical Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392, which is incorporated herein by reference).
  • Prodrugs can be synthesized using reactants other than the corresponding drugs.
  • Solid tumor refers to a solid tumor including, but not limited to, metastatic tumors in bone, brain, liver, lung, lymph nodes, pancreas, prostate, skin, and soft tissue (sarcoma).
  • a “therapeutically effective amount" of a drug refers to a drug that, when administered or administered to a patient with cancer, will have the desired therapeutic effect (e.g., amelioration, improvement, alleviation or elimination of the clinical manifestations of one or more cancers in the patient) The amount.
  • the therapeutic effect need not occur by administering or administering one dose, and may occur only after administering or administering a series of doses. Thus, a therapeutically effective amount can be administered or administered one or more times.
  • a condition or "treatment" of a patient means taking steps to obtain beneficial or desired results (including clinical results).
  • beneficial or desirable clinical outcomes include, but are not limited to, the alleviation or improvement of one or more symptoms of cancer; the reduction in the extent of the disease; the delay or slowing of disease progression; the improvement, alleviation, or stabilization of the disease state; Or other beneficial results.
  • treatment of cancer may result in a partial response or stabilization of the disease.
  • Tumor cell refers to a tumor cell of any suitable species (eg, a mammal, such as a mouse, dog, cat, horse, or human).
  • Negative control Sample ( ⁇ L) PBS 68 58 NADPH (20mM) 10 10 AKR1C3 (250 ⁇ g / mL) 10 10 AST-3424 (250 ⁇ M) 0 10
  • Step 2 Pre-incubate the above duplicates at 37 ° C for 30 minutes and 60 minutes.
  • Step 3 add another 10 ⁇ L of 20 mM NADPH PBS phosphate buffered saline solution and 2 ⁇ L of 250 ⁇ M progesterone 50% MeOH / H2O solution to each Eppendorf tube and mix gently.
  • Step 4 Immediately transfer 50 ⁇ L of the mixture from the above step to 100 ⁇ L of a 1 ⁇ g / mL propranolol (internal standard IS) 100% acetonitrile solution.
  • Step 5 Incubate the remaining sample at 37 ° C for 30 minutes, and add 100 ⁇ L of 1 ⁇ g / mL propranolol (internal standard IS) 100% acetonitrile solution.
  • Step 6 For all samples, add 100 ⁇ L of reagent water, vortex for 5 minutes at 1100 rpm, and centrifuge at 15000 rpm for 10 minutes at room temperature.
  • Step 7 Load all samples onto LC / MS to determine the reduced progesterone, i.e., 20 ⁇ -dihydroprogesterone.
  • test conditions of the LC-MS instrument are the test conditions of the LC-MS instrument.
  • Step 9 Calculation of reduced progesterone (20 ⁇ -dihydroprogesterone): Determine the area of reduced progesterone, namely 20 ⁇ -dihydroprogesterone and propranolol, in each sample by LC / MS. The peak area ratio of reduced progesterone to propranolol (that is, the ratio in the table above) was calculated, and the ratio when time was 0 was set to 0%.
  • AKR1C3 activity (%) [(amount of reduced progesterone after sample normalization) 30min- (amount of reduced progesterone after sample normalization) 0min] / [(amount of reduced progesterone after normalization of negative control group) 30min- (negative control The amount of reduced progesterone after group normalization was 0 min] * 100.
  • AST-3424 at a concentration of 5 ⁇ M basically inhibited the activity of AKR1C3: compared with the negative control, the production of reduced progesterone, namely 20 ⁇ -dihydroprogesterone, was reduced to 3.9% and 9.2% prove that the AST-3424 compound and its similar compounds disclosed in PCT / US2016 / 021581, PCT / US2016 / 025665 and PCT / US2016 / 062114 are inhibitors of the AKR1C3 enzyme.
  • Prostaglandins E2 and F2 in serum samples were analyzed by conventional ELISA methods. The measurement results are shown in the following table.
  • Pain caused directly by tumors and bone infiltration and metastasis include: direct bone involvement and direct activation of local nociceptors; tumors compress adjacent nerves, blood vessels, and soft tissues; tumors release PGE1, PGF2 during bone infiltration, and PGF2 is Strong pain factor.
  • the above animal in vivo experiments show that the AST-3424 compound can significantly reduce the content of PGF2, thereby achieving the effect of treating / improving pain caused by cancer or tumor.

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Abstract

本发明提供式（I）/（II）化合物在制备预防、治疗或改善疼痛的药物中的用途。

Description

化合物用于制备预防、治疗或改善疼痛的药物的用途 技术领域
本发明涉及专利申请PCT/US2016/021581、专利申请PCT/US2016/025665和专利申请PCT/US2016/062114中公开的化合物在制备预防、治疗或改善疼痛的药物中的用途。
背景技术
疼痛是一种因实际的或潜在的组织损伤而产生的痛苦感觉，既是机体的一种保护性反应，也是临床许多疾病的常见症状。
疼痛的治疗在医学上是非常重要的。传统镇痛药物主要包括阿片类药物和非甾体抗炎药。阿片类药物是从阿片(罂粟)中提取的生物碱及体内外的衍生物，其与中枢特异性受体相互作用，能缓解疼痛，镇痛作用强；但是长期使用易导致耐受性、依赖性和成瘾性，并有呼吸抑制、中枢镇静等不良反应，目前用于急性
Figure PCTCN2019084604-appb-000001
锐痛和癌性剧痛等。非甾体抗炎药是一类不含有甾体结构的抗炎药，具有抗炎、抗风湿、止痛、退热和抗凝血等作用，在临床上广泛用于骨关节炎、类风湿性关节炎、多种发热和各种疼痛症状的缓解；但是仅发挥中等程度镇痛作用，适用于轻度和中度的慢性钝痛，但对直接刺激感觉末梢引起的锐痛无效，此外还具有消化道出血和心脏毒性等不良反应。
因此本领域仍需要开发新型的镇痛药物。
发明内容
为了解决上述技术问题，本发明基于专利申请PCT/US2016/021581(WO2016/145092)、专利申请PCT/US2016/025665(WO2016/161342)和专利申请PCT/US2016/062114(WO2017/087428)中公开的化合物或者这些化合物的药学上可接受的盐或溶剂合物，提供所述化合物或者其药学上可接受的盐或溶剂合物在制备预防、治疗或改善疼痛的药物中的用途。
已经证明，专利申请PCT/US2016/021581、PCT/US2016/025665和PCT/US2016/062114中公开的化合物作为国际首创的、高度肿瘤选择性的小分子靶向治疗药物，在多种临床前细胞和动物模型中已表现出非常出色的抗癌效果。这些化合物作为醛酮还原酶AKR1C3特异性底物，可仅在AKR1C3高表达的癌细胞内快速有效地还原，从而释放细胞毒素导致高选择性的癌细胞杀伤药效。
研发团队构想，由于上述发明申请公开的化合物作为醛酮还原酶AKR1C3特异性底物(以下简称特异性底物)，其实际是一种抗癌烷化剂前药，其特异性的在醛酮还原酶AKR1C3的作用下被活化并代谢得到具有细胞毒性的烷化剂，以AST-2870(上述PCT/US2016/021581中公开的化合物TH-2870)为例：
也就是说，醛酮还原酶AKR1C3需要和特异性底物结合。
根据研究文献(Samad T A,Moore K A,Sapirstein A,et al.Interleukin-1[beta]-mediated induction of Cox-2in the CNS contributes to  inflammatory pain hypersensitivity[J].Nature,2001,410(6827):471-5.；Baojian Z,Yanbing Y,Gele A,et al.Tanshinone IIA Attenuates Diabetic Peripheral Neuropathic Pain in Experimental Rats via Inhibiting Inflammation[J].Evidence-Based Complementary and Alternative Medicine,2018,2018:1-8.；Lovering A,Ride J,Bunce C,et al.Crystal Structures of Prostaglandin D2 11-Ketoreductase(AKR1C3)in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin[J].Cancer Research,2004,64(5):1802-1810.；Matsuura K,Shiraishi H,Hara A,et al.Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform(AKR1C3)that exhibits high prostaglandin D2 11-ketoreductase activity.[J].Journal of Biochemistry,1998,124(5):940-6.)可知醛酮还原酶AKR1C3在前列腺素H2/D2转化为前列腺素E2/F2的生化路径中扮演重要的催化作用：
Figure PCTCN2019084604-appb-000002
发明人设想，由于特异性底物能够和醛酮还原酶AKR1C3结合，能不能成为醛酮还原酶AKR1C3的抑制剂，从而发挥降低前列腺素E2/F2水平，起到预防、治疗或改善癌症或炎症引起的疼痛的作用呢？
Figure PCTCN2019084604-appb-000003
对于以上设想，发明人设计了实验进行验证，实验证实上述的特异性底物即以过表达醛酮还原酶AKR1C3为标靶的DNA烷化剂能抑制醛酮还原酶AKR1C3的活性，而且动物实验证实，其能降低血液中的前列腺素E2/F2的含量，据此，可以证明上述的特异性底物具有止疼作用。
关于上述化合物的止疼作用，特别是它们在制备预防、治疗或改善癌症或炎症引起的疼痛的药物中的用途，本发明提供的技术方案如下。
一方面，本发明提供式I化合物或者其药学上可接受的盐或溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途，
Figure PCTCN2019084604-appb-000004
其中，
X 10是O、S、SO或SO 2；
A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
R是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14与其所键结的氮原子一起形成5-7元杂环基；
T包含胺基磷酸酯烷化剂；且
其中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基视情况经取代。
优选地，其中，所述化合物具有式I-A
Figure PCTCN2019084604-appb-000005
其余变量如上文所定义。
或者，X 10是S。
更优选地，在所述化合物中，T是OP(Z 1)(NR 30CH 2CH 2X 1) 2、OP(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2)、OP(Z 1)(N(CH 2) 2) 2或OP(Z 1)(N(CH 2CH 2X 1) 2) 2，其中R 30各自独立地是氢或C 1-C 6烷基，或2个R 30基团与其所键结的氮原子一起形成5-7元杂环基，Z 1是O或S，且X 1是Cl、Br或OMs或其他离去基团。
进一步优选地，在所述化合物中，T是OP(Z 1)(NHCH 2CH 2Cl) 2、OP(Z 1)(NHCH 2CH 2Br) 2、OP(Z 1)(NH 2)(N(CH 2CH 2X 1) 2)、OP(Z 1)(N(CH 2) 2) 2或OP(Z 1)(N(CH 2CH 2Cl) 2) 2，其中Z 1是O或S，且X 1是Cl、Br或OMs。
根据本发明的具体实施方式，在所述化合物中，Z 1是O或S。
根据本发明的具体实施方式，在所述化合物中，T是OP(O)(N(CH 2CH 2)) 2、OP(O)(NHCH 2CH 2Cl) 2、OP(O)(NHCH 2CH 2Br) 2或OP(O)(NH 2)(N(CH 2CH 2Cl) 2)。
根据本发明的具体实施方式，在所述化合物中，Z是氢。
根据本发明的具体实施方式，在所述化合物中，X是氢。
根据本发明的具体实施方式，在所述化合物中，Y是氢或卤基。
优选地，在所述化合物中，A是视情况经取代的C 6-C 10芳基。
更优选地，在所述化合物中，A是视情况经取代的苯基。
优选地，在所述化合物中，A是视情况经取代的5-15元杂芳基。
更优选地，在所述化合物中，A是视情况经取代的吡啶基。
更优选地，在所述化合物中，A是-N＝CR 1R 2，其中R 1和R 2如上文所定义。
根据本发明的具体实施方式，在所述化合物中，R是氢。
优选地，在所述化合物中，R是C 1-C 6烷基。
根据本发明的具体实施方式，在所述化合物中，R是甲基。关于本文所述用途，所述化合物包括个别非镜像异构物及其他几何异构物及镜像异构物、及镜像异构物、非镜像异构物及除非镜像异构物以外的几何异构物的混合物。
本发明上文所示式I化合物见PCT申请PCT/US2016/021581，其国际公开文本为WO2016/145092，对应的中国专利申请为CN201680015078.8，其该公开文本为CN107530556A，该专利申请的全部内容以引用方式并入本文。在该PCT申请中，就化合物的通式结构、基团取代情况、优选通式结构、优选具体化合物等等均进行了详细说明，所涉及到的全部内容均在此引用。因此，本发明就上文所示化合物或者其药学上可接受的盐或溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途涵盖了PCT申请PCT/US2016/021581中提供的关于化合物或者其药学上可接受的盐或溶剂合物的全部内容。
另一方面，本发明提供式II化合物或者其药学上可接受的盐或溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途，
Figure PCTCN2019084604-appb-000006
其中
X 10是O、S、SO或SO 2；
A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
每个R独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15 元杂环、5-15元杂芳基或醚，或者R 13和R 14与其所键结的氮原子一起形成5-7元杂环基；
L 1和D定义如下：
L 1选自：
Figure PCTCN2019084604-appb-000007
其中，R 40和R 41独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环或5-15元杂芳基；R 42是视情况经1-3个C 1-C 6烷基取代的C 2-C 3伸烷基或伸杂烷基；V(-)为任何阴离子，较佳为医药学上可接受的阴离子；和
D是使得D-OH为抗癌药物的部分，其中OH为脂族羟基或酚羟基，或为如本文提供的附接至磷原子的OH部分；换言之，D是抗癌药物D-OH脱去羟基后剩余的基团；
或者
L 1为：
Figure PCTCN2019084604-appb-000008
其中R 40如上文所定义，R 43为氢或与D一起形成杂环，且苯基部分视情况经取代；和
D是使得D-NR 43H为抗癌药物的部分；换言之，D是抗癌药物D-NR 43H脱去氨基或胺后剩余的基团；
或者
L 1是键、-O-C(R 40R 41) 2-、-O-C(R 40R 41)-NR 40R 41(+)-C(R 40R 41)-或
Figure PCTCN2019084604-appb-000009
其中R 40、R 41和V如上文所定义；和
D是含有伯胺或仲胺的抗癌药物，其中该伯胺或该仲胺键接至L 1；且
其中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基视情 况经取代。
优选地，其中，所述化合物具有式II-A
Figure PCTCN2019084604-appb-000010
其余变量如上文所定义。
在另一实施例中，X 10为S。
更优选地，其中，所述化合物具有式IIA-1：
Figure PCTCN2019084604-appb-000011
其余变量如上文所定义，且D是含有一级胺基或二级胺基的细胞毒性剂HNR 43-D的一部分；换言之，D是细胞毒性剂HNR 43-D脱去一级胺基或二级胺基后剩余的基团。
或者，更优选地，其中，所述化合物具有式IIA-2或IIA-3：
Figure PCTCN2019084604-appb-000012
Figure PCTCN2019084604-appb-000013
其余变量如上文所定义，且D是含有至少一个羟基的细胞毒性剂HO-D的一部分；换言之，D是细胞毒性剂HO-D脱去羟基后剩余的基团。
或者，更优选地，其中，所述化合物具有式IIA-4、IIA-6或IIA-6-i：
Figure PCTCN2019084604-appb-000014
其中变量如上文所定义；其中，IIA-4中，HO-D为含有至少一个羟基的 细胞毒性剂；换言之，D是含有至少一个羟基的细胞毒性剂HO-D的一部分，或者说D是细胞毒性剂HO-D脱去羟基后剩余的基团；在IIA-6-i中，DNR 40R 41是药物；换言之，D是使得DNR 40R 41为抗癌药物的部分，或者D是抗癌药物DNR 40R 41脱离NR 40R 41的部分；且在IIA-6中，D是含有仲胺的药物，其中该仲胺键接至亚甲基，换言之，D是含有仲胺的药物，且通过其含有的仲胺键接至亚甲基、进而与-NR 40R 41相连，如以上所示。
或者，更优选地，其中，所述化合物具有式IIA-5或IIA-7：
Figure PCTCN2019084604-appb-000015
其中变量如上文所定义；其中，在IIA-5中，DNR 40R 41是药物；换言之，D是使得DNR 40R 41为抗癌药物的部分，或者D是抗癌药物DNR 40R 41脱离NR 40R 41的部分；在IIA-7中，D是含有仲胺的药物，其中该仲胺键接至亚甲基，如以上所示。
根据本发明的具体实施方式，在所述化合物中，Z是氢。
根据本发明的具体实施方式，在所述化合物中，X是氢。
根据本发明的具体实施方式，在所述化合物中，Y是氢或卤基。
优选地，在所述化合物中，A是视情况经取代的C 6-C 10芳基。
更优选地，在所述化合物中，A是视情况经取代的苯基。
优选地，在所述化合物中，A是视情况经取代的5-15元杂芳基。
更优选地，在所述化合物中，A是视情况经取代的吡啶基。
更优选地，在所述化合物中，A是-N＝CR 1R 2，其中R 1和R 2如上文所定义。
根据本发明的具体实施方式，在所述化合物中，每个R是氢。
优选地，在所述化合物中，R基团中的一个是氢且另一个是C 1-C 6烷基，或其中R基团均是如上文所定义的非氢取代基。
根据本发明的具体实施方式，在所述化合物中，R是甲基。
优选地，在所述化合物中，R 40、R 41和R 43各自独立地是氢或甲基且R 42是-CH 2-CH 2-或CH 2-C(Me) 2-。
特别地，如本文中所用，D不包括胺基磷酸酯烷基化剂，诸如-P(Z 1)(NR 30CH 2CH 2X 1) 2、-P(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2)、-P(Z 1)(N(CH 2CH 2)) 2或-P(Z 1)(N(CH 2CH 2X 1) 2) 2，其中每个R 30独立地是氢或C 1-C 6烷基，或2个R 30与其所结合的氮原子一起形成5-7元杂环基，Z 1是O或S，且X 1是Cl、Br或OMs，或另一离去基团。
关于本文所述用途，所述化合物包括个别非镜像异构物及其他几何异构物及镜像异构物、及镜像异构物、非镜像异构物及除非镜像异构物以外的几何异构物的混合物。
本发明上文所示式II化合物见PCT申请PCT/US2016/025665，其国际公开文本为WO2016/161342，对应的中国申请为CN201680020013.2，其公开文本为CN108136214A，该专利申请的全部内容以引用方式并入本文。在该PCT申请中，就化合物的通式结构、基团取代情况、优选通式结构、优选具体化合物等等均进行了详细说明，所涉及到的全部内容均在此引用。因此，本发明就上文所示化合物或者其药学上可接受的盐或溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途涵盖了PCT申请PCT/US2016/025665中提供的关于化合物或者其药学上可接受的盐或溶剂合物的全部内容。
根据本发明的具体实施方式，所述化合物I为如下所示的化合物AST-3424：
Figure PCTCN2019084604-appb-000016
AST-3424(前述三个PCT申请中的2870化合物的S构型异构体)
关于本文所述用途，所述化合物还可以盐的形式使用，即本发明提供所示化合物的药学上可接受的盐在制备用于预防、治疗或改善疼痛的药物中的用途。其中，所述盐可以为碱式盐，包括所述化合物与无机碱(例如碱金属氢氧化物、碱土金属氢氧化物等)或与有机碱(例如单乙醇胺、二乙醇胺或三乙醇胺等)形成的盐。或者，所述盐可以为酸式盐，包括所述化合物与无机酸(例如盐酸、氢溴酸、氢碘酸、硝酸、高氯酸、硫酸或磷酸等)或与有机酸(例如甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、富马酸、草酸、马来酸、柠檬酸等)形成的盐。选择和制备化合物的可接受的盐和溶剂化物等是本领域公知技术。
关于本文所述用途，所述化合物还可以溶剂合物的形式使用，即本发明提供所示化合物的药学上可接受的溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途。其中，所述溶剂合物为水合物、醇合物等。
关于本文所述用途，所述疼痛为癌症引起的疼痛，癌症包括但不限于：肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列 腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、子宫内膜癌、胶质瘤、结直肠癌、甲状腺癌、尿路上皮癌或多发性骨髓瘤。
显然根据以上本申请发明人的实验证实以及相关研究文献可知，关于本文所述用途，所述疼痛为炎症引起的疼痛。
关于本文所述用途，所制得的药物还可包含与所示化合物联合使用的其他化合物或药剂。其他化合物或药剂也可用于预防、治疗或改善疼痛。
关于本文所述用途，所制得的药物包含特定剂量范围的所示化合物或其盐或溶剂合物，和/或，所制得的药物为特定剂型、特定给药方式施用。
用于预防、治疗或改善疼痛的药物或该药物中包含的所示化合物或其盐或溶剂合物的剂量通常取决于施用的具体化合物、患者、具体疾病或病症及其严重程度、给药途径和频率等，并且需要由主治医师根据具体情况判定。例如，在通过口服途径施用本发明提供的化合物或药物时，其剂量可为0.1至30mg/7天，优选1至10mg/7天，进一步优选5mg/天；所述剂量可以分每7天1至2次给药，优选1次。
关于本文所述用途，所制得的药物还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
基于本发明提供的所述用途，本发明还涉及一种疼痛的预防、治疗或改善方法，所述方法包括向有此需要的受试者施用预防、治疗或改善有效量的本发明 所示化合物或者其药学上可接受的盐或溶剂合物。优选地，所述受试者是哺乳动物，更优选是人。所述疼痛为癌症引起的疼痛，癌症包括但不限于：肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、子宫内膜癌、胶质瘤、结直肠癌、甲状腺癌、尿路上皮癌或多发性骨髓瘤。
基于本发明提供的所述用途，本发明还提供一种含有上文定义的式I或式II化合物且用于预防、治疗或改善癌症或炎症引起的疼痛的药物。
基于本发明提供的所述用途，本发明还提供一种治疗癌症或炎症引起的疼痛的方法，其包含施加上述的药物的步骤；以及使用AKR1C3抗体测定患者的癌细胞的AKR1C3还原酶含量的步骤，若测得该AKR1C3还原酶含量等于或大于预定值，则向该患者投与上述的药物。
附图说明
图1为AST-3424是否施加对还原黄体酮生成过程的影响实验
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
本发明所示化合物以及合成方法见专利申请PCT/US2016/021581(WO2016/145092)、专利申请PCT/US2016/025665(WO2016/161342)和专利申请PCT/US2016/062114(WO2017/087428)。
提供以下定义以帮助阅读者。除非另有定义，否则本文所用的所有业内术语、符号及其他科学或医学术语或术语学均意欲具有熟习化学及医学领域的技术者通常所了解的含义。在一些情形下，为清楚和/或供及时参考，具有 通常所了解含义的术语定义于本文中，且本文中此等定义的纳入不应解释为表示与如业内通常所了解的术语的定义有实质差异。
所有数值指定(例如pH、温度、时间、浓度及重量)(包括其中每一者的范围)通常可为适当以0.1、1.0或10.0的增量改变(+)或(-)的近似值。所有数值指定均可理解为前面有术语“约”。本文所述试剂为实例性的且此等的同等物可为业内所已知。
基团前的“C x-C y”或“C x-y”是指存在于该基团中的碳原子数目的范围。举例而言，C 1-C 6烷基是指具有至少1个且最多6个碳原子的烷基。
“烷氧基”是指-O-烷基。
“胺基”是指NR pR q，其中R p及R q独立是氢或C 1-C 6烷基，或R p及R q与其所键结的氮原子一起形成4-15元杂环。
“芳基”是指具有6至14个碳原子且不含环杂原子且具有单环(例如，苯基)或多个缩合(稠合)环(例如，萘基或蒽基)的芳香族基团。对于包括不具有环杂原子之具有芳香族环及非芳香族环之稠合、桥连及螺环系统之多环系统而言，当附接点位于芳香族碳原子处时，术语“芳基”或“Ar”适用(例如，5,6,7,8四氢萘-2-基是芳基，此乃因其附接点是位于芳香族苯基环的2位处)。
根据本申请的具体实施方式，C 6-C 10芳基可以是苯基、萘基及各种取代的苯基或萘基。
“杂芳基”是指具有1至14个碳原子及1至6个选自由氧、氮及硫组成的群的杂原子的芳香族基团且包括单环(例如咪唑基-2-基及咪唑-5-基)及多环系统(例如咪唑并吡啶基、苯并三唑基、苯并咪唑-2-基及苯并咪唑-6-基)。对于包括具有芳香族及非芳香族环的稠合、桥连及螺环系统的多环系统而言，若存在至少一个环杂原子且附接点是位于芳香族环的原子处，则应用术语“杂芳基”(例如1,2,3,4-四氢喹啉-6-基及5,6,7,8-四氢喹啉-3-基)。在一些实施例中，杂芳基的氮和/或硫环原子视情况经氧化以提供N-氧化物(N→O)、亚磺酰基或磺酰基部分。术语杂芳基或5-15元杂芳基包括(但不限于)吖啶基、吖辛因基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基(benzothiophenyl)、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并噻吩基(benzothienyl)、苯并咪唑啉基、咔唑基、NH-咔唑基、咔啉基、苯并二氢吡喃基(chromanyl)、苯并吡喃基(chromenyl)、噌啉基(cinnolinyl)、二噻嗪基、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑并吡啶基、咪唑基、吲唑基、二氢吲哚基(indolenyl)、吲哚啉基、吲嗪基、吲哚基、异苯并呋喃基、异苯并二氢吡喃基(isochromanyl)、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基(isoquinolinyl)、异喹啉基(isoquinolyl)、异噻唑基、异恶唑基、萘啶基、八氢异喹啉基、恶二唑基、恶唑啶基、恶唑基、嘧啶基、啡啶基、啡啉基、吩嗪基、吩噻嗪基、吩恶噻基、吩恶嗪基、酞嗪基、六氢吡嗪基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑啶基、吡唑啉基、吡唑基、唑嗪基、吡啶并恶唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喏啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、噻二嗪基、噻二唑基、噻蒽基、噻唑基、噻吩基(thienyl)、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、噻吩基(thiophenyl)、三嗪基及呫吨基。
“烷基”是指具有1至10个碳原子且在一些实施例中具有1至6个碳原子的单价饱和脂肪族烃基。“C x-y烷基”是指具有x至y个碳原子的烷基。此术语 包括(举例而言)直链及具支链烃基，例如甲基(CH 3-)、乙基(CH 3CH 2-)、正丙基(CH 3CH 2CH 2-)、异丙基((CH 3) 2CH-)、正丁基(CH 3CH 2CH 2CH 2-)、异丁基((CH 3) 2CHCH 2-)、第二丁基((CH 3)(CH 3CH 2)CH-)、第三丁基((CH 3) 3C-)、正戊基(CH 3CH 2CH 2CH 2CH 2-)及新戊基((CH 3) 3CCH 2-)。
“环烷基”是指具有3至14碳原子且没有环杂原子且具有单环或包括稠合、桥连及螺环系统的多环的饱和或部分饱和环状基团。对于不具有环杂原子的具有芳香族及非芳香族环的多环系统而言，当附接点是位于非芳香族碳原子处时，术语“环烷基”适用(例如5,6,7,8-四氢萘-5-基)。术语“环烷基”或C 3-C 8环烷基包括环烯基。环烷基或C 3-C 8环烷基的实例包括(例如)金刚烷基、环丙基、环丁基、环戊基、环辛基及环己烯基。
“杂环状”或“杂环”或“杂环烷基”或“杂环基”是指具有1至14个碳原子及1至6个选自由氮、硫或氧组成的群的杂原子的饱和或部分饱和环状基团且包括单环及包括稠合、桥连及螺环系统的多环系统。对于具有芳香族及/或非芳香族环的多环系统而言，当存在至少一个环杂原子且附接点是位于非芳香族环的原子处时，术语“杂环状”、“杂环”、“杂环烷基”或“杂环基”适用(例如1,2,3,4-四氢喹啉-3-基、5,6,7,8-四氢喹啉-6-基及十氢喹啉-6-基)。在一些实施例中，此处杂环基是3-15元、4-14元、5-13元、7-12或5-7元杂环。在一些其他实施例中，杂环含有4个杂原子。在一些其他实施例中，杂环含有3个杂原子。在另一实施例中，杂环含有最多2个杂原子。在一些实施例中，杂环基的氮及/或硫原子视情况经氧化以提供N-氧化物、亚磺酰基、磺酰基部分。杂环基包括(但不限于)四氢吡喃基、六氢吡啶基、N-甲基六氢吡啶-3-基、六氢吡嗪基、N-甲基吡咯啶-3-基、3-吡咯啶基、2-吡咯啶酮-l-基、吗啉基及吡咯啶基。指示碳原子数的前缀(例如，C 3- 10)是指杂环基部分中除杂原子数之外的总碳原子数。二价杂环基将具有适当调整的氢含量。
“醚”是指经1-3个C 1-C 6烷氧基取代的C 1-C 6烷基。烷氧基是指-O-烷基。
“卤基”是指氟、氯、溴及碘中的一或多者。
“烯基”是指具有2至10个碳原子且在一些实施例中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C＝<)的直链或具支链烃基。举例而言，C x-y烯基是指具有x至y个碳原子的烯基且意欲包括(例如)乙烯基、丙烯基、1,3-丁二烯基及诸如此类。
“炔基”是指2至10个碳原子且在一些实施例中2至6个碳原子或2至4个碳原子且含有至少一个三键的直链单价烃基或具支链单价烃基。术语“炔基”亦意欲包括具有一个三键及一个双键的这些烃基。举例而言，C 2-6炔基包括乙炔基、丙炔基及诸如此类。
“胺基磷酸酯烷化剂”是指包含一或多个键结至-O-P(Z1)部分的Z 5-X 5-Y 5部分的烷化剂，其中Z 5是诸如氮、硫或氧等杂原子，X 5是视情况经取代的伸乙基，Y 5是卤基或另一离去基，或Z 5-X 5-Y 5一起形成氮丙啶基(NCH 2CH 2)部分且Z 1如上文所定义。此一烷化剂可与DNA或另一核酸或蛋白质反应。在一些情形下，烷化剂可交联DNA。
术语“视情况经取代”是指经取代或未经取代的基团。基团可经一或多个取代基(例如1、2、3、4或5个取代基)取代。较佳地，取代基选自由以下组成的群：侧氧基、卤基、-CN、NO 2、-N 2+、-CO 2R 100、-OR 100、-SR 100、-SOR 100、-SO 2R 100、-NR 100SO 2R 100、-NR 101R 102、-CONR 101R 102、-SO 2NR 101R 102、C 1-C 6烷基、C 1-C 6烷氧基、-CR 100＝C(R 100) 2、-CCR 100、C 3-C 10环烷基、C 3-C 10杂环基、C 6-C 12芳基及 C 2-C 12杂芳基或诸如-O-(CH 2)-O-、-O-(CH 2) 2-O-及其1-4个甲基经取代的形式等二价取代基，其中R 100、R 101及R 102各自独立是氢或C 1-C 8烷基；C 3-C 12环烷基；C 3-C 10杂环基；C 6-C 12芳基；或C 2-C 12杂芳基；或R 100及R 102与其附接至的氮原子一起形成5-7元杂环；其中烷基、环烷基、杂环基、芳基或杂芳基各自视情况经1-3个卤基、1-3个C 1-C 6烷基、1-3个C 1-C 6卤烷基或1-3个C 1-C 6烷氧基取代。较佳地，取代基选自由以下组成的群：氯、氟、-OCH3、甲基、乙基、异丙基、环丙基、-CO 2H及其盐及C 1-C 6烷基酯、CONMe 2、CONHMe、CONH 2、-SO 2Me、-SO 2NH 2、-SO 2NMe 2、-SO 2NHMe、-NHSO 2Me、-NHSO 2CF 3、-NHSO 2CH 2Cl、-NH 2、-OCF 3、-CF 3及-OCHF 2。
“伸烷基”(Alkylene)是指具有1至10个碳原子且在一些实施例中具有1至6个碳原子的二价饱和脂肪族烃基。“C u-v伸烷基”是指具有u至v个碳原子的伸烷基。亚烷基(Alkylidene)及伸烷基(Alkylene)包括具支链及直链烃基。举例而言，“C 1-C 6伸烷基”包括亚甲基、伸乙基、伸丙基、2-甲基伸丙基、伸戊基及诸如此类。
“伸杂烷基”是指其中链碳原子经诸如O、S、N或P等杂原子或含有杂原子的取代基替代的伸烷基。
在本文中关于D所述的“药物”包括(但不限于)吉西他滨(gemcitabine)、埃罗替尼(erlotinib)、美妥替哌(meturedepa)、乌瑞替派(uredepa)、六甲蜜胺(altretamine)、伊马替尼(imatinib)、曲他胺(triethylenemelamine)、三甲密胺、苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、雌氮芥(estramustine)、吉非替尼(gefitinib)、氮芥(mechlorethamine)、氮芥氧化物盐酸盐、美法仑(melphalan)、新氮芥(novembichin)、芬司特瑞(phenesterine)、泼尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard)、卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、达喀尔巴嗪(dacarbazine)、甘露氮芥(mannomustine)、二溴甘露醇(mitobronitol)、二溴卫矛醇(mitolactol)、哌泊溴烷(pipobroman)、阿克拉霉素(aclacinomycins)、放射菌素(actinomycin)、安曲霉素(anthramycin)、偶氮丝胺酸(azaserine)、博莱霉素(bleomycin)、放线菌素C(cactinomycin)、卡柔比星(carubicin)、嗜癌菌素(carzinophilin)、色霉素(chromomycin)、放线菌素d(dactinomycin)、道诺霉素(daunorubicin)、柔红霉素(daunomycin)、6-重氮-5-侧氧基-1-正白胺酸、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、普卡霉素(plicamycin)、泊非罗霉素(porfiromycin)、嘌呤霉素(puromycin)、链黑霉素(streptonigrin)、链脲菌素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、左柔比星(zorubicin)、迪诺特宁(denopterin)、蝶罗呤(pteropterin)、曲美沙特(trimetrexate)、氟达拉宾(fludarabine)、6-巯基嘌呤、硫米嘌呤(thiamiprine)、硫鸟嘌呤、安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、5-氟尿嘧啶、替加氟(tegafur)、L-天冬酰胺酶、百慕时(pulmozyme)、醋葡醛内酯、醛磷酰胺糖苷、胺基乙酰丙酸、安吖啶(amsacrine)、贝斯布西(bestrabucil)、比生群(bisantrene)、得佛酰胺(defofamide)、地美可辛(demecolcine)、地吖 醌(diaziquone)、艾弗鸟胺酸(elfornithine)、依利醋铵(elliptinium acetate)、依托格鲁(etoglucid)、氟他胺(flutamide)、羟基尿素(hydroxyurea)、干扰素-α、干扰素-β、干扰素-γ、介白素-2、蘑菇多醣(lentinan)、丙脒腙(mitoguazone)、米托蒽醌(mitoxantrone)、莫哌达醇(mopidamol)、二胺硝吖啶(nitracrine)、喷司他丁(pentostatin)、蛋胺氮芥(phenamet)、吡柔比星(pirarubicin)、鬼臼酸(podophyllinic acid)、2-乙基酰肼、丙卡巴肼(procarbazine)、雷佐生(razoxane)、西索菲兰(sizofiran)、锗螺胺(spirogermanium)、太平洋紫杉醇(paclitaxel)、他莫昔芬(tamoxifen)、埃罗替尼(erlotonib)、替尼泊苷(teniposide)、细交链孢菌酮酸(tenuazonic acid)、三亚胺醌、2,2',2"-三氯三乙胺、尿烷、长春碱(vinblastine)及长春新碱(vincristine)。
向患者“投与”或“施用”药物是指直接投与或施用(其可由医学专业人士向患者投与或施用或者可自投与或施用)及/或间接投与或施用，其可是开处药物的行为。举例而言，指示患者自投与或施用药物及/或将药物的处方提供给患者的医师是向患者投与或施用药物。
“癌症”是指可通过侵袭而局部扩展且通过转移而全身扩展的潜在无限制生长的白血病、淋巴瘤、癌及其他恶性肿瘤(包括实体肿瘤)。癌症的实例包括(但不限于)肾上腺、骨、脑、乳房、支气管、结肠及/或直肠、胆囊、头及颈、肾、喉、肝、肺、神经组织、胰脏、前列腺、副甲状腺、皮肤、胃及甲状腺的癌症。癌症的某些其他实例包括急性及慢性淋巴细胞及粒细胞肿瘤、腺癌、腺瘤、基底细胞癌、子宫颈上皮分化不良及原位癌、尤文氏肉瘤、表皮样癌、巨细胞瘤、多型性神经胶母细胞瘤、毛细胞肿瘤、肠神经节细胞瘤、增生性角膜神经肿瘤、胰岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性黑色素瘤、恶性高钙血症、马方样体型肿瘤、髓样上皮癌、转移性皮肤癌、黏膜神经瘤、骨髓瘤、蕈状肉芽肿、神经胚细胞瘤、骨肉瘤、骨原性及其他肉瘤、卵巢瘤、嗜铬细胞瘤、真性红血球增多症、原发性脑瘤、小细胞肺癌、溃疡型及乳头型二者的鳞状细胞癌、增生、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞肿瘤、局部皮肤病灶、网状细胞肉瘤及威尔姆氏肿瘤。
“炎症”优选由于上述花生四烯酸-环氧合酶-前列腺素途径的，由前列腺素E2/F2引发疼痛的炎症。
“患者”及“个体”可互换使用，是指需要癌症治疗的哺乳动物。通常，患者是人类。通常，患者是诊断患有癌症的人类。在某些实施例中，“患者”或“个体”可指用于筛选、表征及评估药物及疗法的非人类哺乳动物，例如非人类灵长类动物、狗、猫、兔、猪、小鼠或大鼠。
“前药”是指投与或施用之后经新陈代谢或以其他方式转化为关于至少一种性质的生物学活性或活性更高的化合物(或药物)的化合物。相对于药物，前药以使其相对于药物活性较低或无活性的方式化学修饰，但化学修饰使得在前药投与之后通过代谢或其他生物过程产生相应药物。前药可相对于活性药物具有改变的代谢稳定性或输送特征、较少副作用或较低毒性或经改良的风味(参见(例如)参考文献Nogrady，1985，Medicinal Chemistry A Biochemical Approach，0xford University Press，New York，第388页至392页，其以引用式并入本文中)。前药可使用除相应药物以外的反应物来合成。
“实体肿瘤”是指包括(但不限于)骨、脑、肝、肺、淋巴结、胰脏、前列腺、皮肤及软组织(肉瘤)中的转移肿瘤的实体肿瘤。
药物的“治疗有效量”是指当向患有癌症的患者投与或施用时，将具有预期的治疗效应(例如患者中一或多种癌症的临床表现的缓和、改善、缓解或消除)的药物的量。治疗效应不必通过投与或施用一个剂量而出现，且可仅在投与或施用一系列剂量后出现。因此，治疗有效量可以一或多次来投与或施用。
病况或患者的“治疗”是指采取步骤以获得有益或期望结果(包括临床结果)。出于本发明的目的，有益或期望临床结果包括(但不限于)一或多种癌症症状的缓和或改善；疾病程度的减弱；疾病进展的延迟或减缓；疾病状态的改善、缓解或稳定；或其他有益结果。在一些情形下，癌症的治疗可使得部分反应或稳定疾病。
“肿瘤细胞”是指任何适当物种(例如，哺乳动物，例如鼠类、犬、猫、马或人类)的肿瘤细胞。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
以下提供体外实验和食蟹猴体内实验来验证化合物的止痛作用。
体外实验
实验仪器：
Waters Acquity I Class UPLC超高效液相色谱仪配有Xevo G2-XS Q Tof HRMS四极杆飞行时间高分辨率质谱仪。
缓冲液和物料：
1.PBS磷酸缓冲盐溶液，
2. 20mM NADPH的PBS磷酸缓冲盐溶液
3. 250μg/mL AKR1C3的PBS磷酸缓冲盐溶液
4. 250μM AST-3424的50％MeOH/H2O溶液
5. 250μM黄体酮(progesterone)的50％MeOH/H2O溶液
6. 1μg/mL普萘洛尔(propranolol)的100％乙腈溶液
实验操作流程
步骤1，将反应混合物按照下表一式四份(n＝4)制成Eppendorf管，轻轻混合。
物料 阴性对照(μL) 样本(μL)
PBS 68 58
NADPH(20mM) 10 10
AKR1C3(250μg/mL) 10 10
AST-3424(250μM) 0 10
步骤2，将以上一式两份混合物在37℃下预孵育30分钟，60分钟。
步骤3，在每个Eppendorf管中加入另外10μL的20mM NADPH的PBS磷酸缓冲盐溶液和2μL的250μM黄体酮(progesterone)的50％MeOH/H2O溶液并轻轻混合。
步骤4，立即将以上步骤中的50μL混合物转移到100μL的1μg/mL普萘洛尔(propranolol，内标IS)的100％乙腈溶液中。
步骤5，将剩余样品在37℃下孵育30分钟，并加入100μL1μg/mL普萘洛尔(propranolol，内标IS)的100％乙腈溶液。
步骤6，对于所有样品，加入100μL试剂水，以1100rpm涡旋混合5分钟，并在室温下以15000rpm离心10分钟。
步骤7，将所有样品加载到LC/MS上以测定还原的黄体酮即20α-二氢孕 酮的含量。
LC-MS仪器的测试条件为
Figure PCTCN2019084604-appb-000017
液相洗脱梯度
Time(min) A(％) B(％)
0.00 90.0 0.0
1.5 5.0 95.0
2.00 5.0 95.0
2.30 90.0 10.0
3.00 90.0 10.0
四极杆飞行时间质谱参数
项目 参数
毛细管电压(Capilary kV) 2.5
进样锥电压(Sampling ConeV) 40
源温度Source temperature(℃) 100
进样锥气体流速Cone Gas(L/h) 50
脱溶剂气体流速Desolvation Gas(L/h) 600
电离方式(Interface Type) ES,Positive
分析器模式(Analyser Mode) Sensitivity
扫描范围(Scan Range) 50-800m/z
步骤9，还原黄体酮(20α-二氢孕酮)的计算：通过LC/MS测定每种样品中还原黄体酮即20α-二氢孕酮和普萘洛尔峰面积。计算还原黄体酮与普萘洛尔的峰面积比(即上表中的比率)，并将时间为0时的比率设定为0％。
AKR1C3活性(％)＝[(样品标准化后的还原黄体酮量)30min-(样品标准化后的还原黄体酮量)0min]/[(阴性对照组标准化后的还原黄体酮量)30min-(阴性对照组标准化后还原黄体酮量)0min]*100。
根据以上计算得到上表的AKR1C3活性结果。
实验结果
Figure PCTCN2019084604-appb-000018
实验结果分析与总结
AST-3424对AKR1C3活性的影响结果表
Figure PCTCN2019084604-appb-000019
AST-3424对还原黄体酮生产过程的的影响，如图1所示。
经过以上的体外实验证实，预孵育30分钟和60分钟后，5μM浓度的AST-3424基本上抑制了AKR1C3活性：与阴性对照相比，还原黄体酮即20α-二氢孕酮的产生分别降低至3.9％和9.2％，证明了AST-3424化合物及其类似的利申请PCT/US2016/021581、PCT/US2016/025665和PCT/US2016/062114中公开的化合物是AKR1C3酶的抑制剂。
二，体内实验
3只食蟹猴，按下表进行实验。
Figure PCTCN2019084604-appb-000020
从广西雄森灵长类开发实验有限公司购入4只雄性食蟹猴，所有动物均为体检合格、无异常的健康食蟹猴。其中3只用于给药实验，其余的动物用于制备空白血浆。
给药前、给药开始后6、24、48和72小时。经股静脉或其他合适的静脉采血1mL，置于无抗凝剂采血管中，血液样本采集后置于冰上，静置30-60分钟离心分离血清(离心条件：3500转/分钟，10分钟，2-8℃)。收集的血清分析前存放于–80℃。
血清样本中前列腺素E2和F2由常规的ELISA方法进分析。测定结果如下表。
食蟹猴单次静脉滴注给药后的血清中前列腺素E2和F2的浓度结果
Figure PCTCN2019084604-appb-000021
Figure PCTCN2019084604-appb-000022
食蟹猴给予0.58mg/kg的AST3424后，前列腺素E2和F2均降低，在24小时时出现波动性的增高，推测与动物本身分泌前列腺素E2和F2的时间特点有关，表明给予AST3424后能抑制食蟹猴分泌前列腺素E2和F2。
肿瘤直接引起的疼痛和骨骼的浸润和转移产生疼痛的原因包括:骨骼直接受累和局部伤害感受器的直接激活；肿瘤压迫邻近的神经、血管和软组织；肿瘤骨浸润时释放PGE1、PGF2,而PGF2是强烈的致痛因子，以上的动物体内实验表明AST-3424化合物可以大幅降低PGF2的含量，从而达到治疗/改善癌症或肿瘤引起的疼痛的效果。
三，实验结论
以上的体外和体内实验证实上述的特异性底物即以过表达醛酮还原酶AKR1C3为标靶的DNA烷化剂能抑制醛酮还原酶AKR1C3的活性，而且动物实验证实，其能降低血液中的前列腺素E2/F2的含量，据此，可以证明上述的AST-3424化合物及其类似的利申请PCT/US2016/021581、PCT/US2016/025665和PCT/US2016/062114中公开的化合物是AKR1C3酶的抑制剂，其能阻断前列腺素E2/F2的生成，降低其含量，具有止疼作用。

Claims (18)

  1. 式I化合物或者其药学上可接受的盐或溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途，
    Figure PCTCN2019084604-appb-100001
    其中，
    X 10是O、S、SO或SO 2；
    A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    R是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14基团与其所键结的氮原子一起形成5-7元杂环基；
    T包含胺基磷酸酯烷化剂；且
    其中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基视情况经取代。
  2. 根据权利要求1中任一项所述的用途，其中，在所述式I化合物中，T是OP(Z 1)(NR 30CH 2CH 2X 1) 2、OP(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2)、OP(Z 1)(N(CH 2) 2) 2或OP(Z 1)(N(CH 2CH 2X 1) 2) 2，其中R 30各自独立地是氢或C 1-C 6烷基，或2个R 30基团与其所键结的氮原子一起形成5-7元 杂环基，Z 1是O或S，且X 1是Cl、Br或OMs或其他离去基团。
  3. 根据权利要求1中任一项所述的用途，其中，在所述式I化合物中，T是OP(Z1)(NHCH2CH2Cl)2、OP(Z1)(NHCH2CH2Br)2、OP(Z1)(NH2)(N(CH2CH2X1)2)、OP(Z1)(N(CH2)2)2或OP(Z1)(N(CH2CH2Cl)2)2，其中Z1是O或S，且X1是Cl、Br或OMs。
  4. 根据权利要求1中任一项所述的用途，其中，在所述式I化合物中，T是OP(O)(N(CH2CH2))2、OP(O)(NHCH2CH2Cl)2、OP(O)(NHCH2CH2Br)2或OP(O)(NH2)(N(CH2CH2Cl)2)。
  5. 根据权利要求1中任一项所述的用途，其中，所述式I化合物为
    Figure PCTCN2019084604-appb-100002
  6. 式II化合物或者其药学上可接受的盐或溶剂合物在制备用于预防、治疗或改善疼痛的药物中的用途，
    Figure PCTCN2019084604-appb-100003
    其中
    X 10是O、S、SO或SO 2；
    A是C 6-C 10芳基或取代芳基、5-15元杂芳基或取代杂芳基或-N＝CR 1R 2；其中，R 1和R 2各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    X、Y和Z各自独立地是氢、CN、卤基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    每个R独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基、醚、-CONR 13R 14或-NR 13COR 14；
    R 13和R 14各自独立地是氢、C 1-C 6烷基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环、5-15元杂芳基或醚，或者R 13和R 14与其所键结的氮原子一起形成5-7元杂环基；
    L 1和D如说明书中定义，具体定义如下
    L 1选自：
    Figure PCTCN2019084604-appb-100004
    其中，R 40和R 41独立地是氢、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、C 6-C 10芳基、4-15元杂环或5-15元杂芳基；
    R 42是视情况经1-3个C 1-C 6烷基取代的C 2-C 3伸烷基或伸杂烷基；V(-)为任何阴离子，较佳为医药学上可接受的阴离子；和
    D是使得D-OH为抗癌药物的部分，其中OH为脂族羟基或酚羟基，或为如本文提供的附接至磷原子的OH部分；换言之，D是抗癌药物D-OH脱去羟基后剩余的基团；
    或者
    L 1为：
    Figure PCTCN2019084604-appb-100005
    其中R 40如上文所定义，R 43为氢或与D一起形成杂环，且苯基部分视情况经取代；和
    D是使得D-NR 43H为抗癌药物的部分；换言之，D是抗癌药物D-NR 43H脱去氨基或胺后剩余的基团；
    或者
    L 1是键、-O-C(R 40R 41)-、-O-C(R 40R 41)-NR 40R 41(+)-C(R 40R 41)-或
    Figure PCTCN2019084604-appb-100006
    其中R 40、R 41和V如上文所定义；和
    D是含有伯胺或仲胺的抗癌药物，其中该伯胺或该仲胺键接至L 1；且
    其中所述烷基、烯基、炔基、环烷基、芳基、杂环、杂芳基、醚基视情况经取代。
  7. 根据权利要求6中任一项所述的用途，其中，
    所述式II化合物为式II-A
    Figure PCTCN2019084604-appb-100007
    其余变量如权利要求6所定义。
  8. 根据权利要求6中任一项所述的用途，其中，所述式II化合物为式IIA-1：
    Figure PCTCN2019084604-appb-100008
    其余变量如权利要求6所定义，且D是含有一级胺基或二级胺基的细胞毒性剂HNR 43-D的一部分；换言之，D是细胞毒性剂HNR 43-D脱去一级胺基或二级胺基后剩余的基团；
    或
    为式IIA-2或IIA-3：
    Figure PCTCN2019084604-appb-100009
    其余变量如权利要求6所定义，且D是含有至少一个羟基的细胞毒性剂HO-D的一部分；换言之，D是细胞毒性剂HO-D脱去羟基后剩余的基团；
    或
    为式IIA-4、IIA-6或IIA-6-i：
    Figure PCTCN2019084604-appb-100010
    Figure PCTCN2019084604-appb-100011
    其中变量如权利要求6所定义；其中，在IIA-4中，HO-D为含有至少一个羟基的细胞毒性剂；换言之，D是含有至少一个羟基的细胞毒性剂HO-D的一部分，或者说D是细胞毒性剂HO-D脱去羟基后剩余的基团；在IIA-6-i中，DNR 40R 41是药物；换言之，D是使得DNR 40R 41为抗癌药物的部分，或者D是抗癌药物DNR 40R 41脱离NR 40R 41的部分；且在IIA-6中，D是含有仲胺的药物，其中该仲胺键接至亚甲基，换言之，D是含有仲胺的药物，且通过其含有的仲胺键接至亚甲基、进而与-NR 40R 41相连，如以上式IIA-4、IIA-6或IIA-6-i所示；
    或
    为式IIA-5或IIA-7：
    Figure PCTCN2019084604-appb-100012
    其中变量如权利要求6所定义；其中，在IIA-5中，DNR 40R 41是药物；换言之，D是使得DNR 40R 41为抗癌药物的部分，或者D是抗癌药物DNR 40R 41脱离NR 40R 41的部分；在IIA-7中，D是含有仲胺的药物，其中该仲胺键接至亚甲基，如以上式IIA-5或IIA-7所示。
  9. 根据权利要求6-8中任一项所述的用途，其中，式II化合物中Z是氢或X是氢或Y是氢/卤基。
  10. 根据权利要求6-8中任一项所述的用途，其中，式II化合物中A是取代/未取代的C6-C10芳基或苯基或5-15元杂芳基或吡啶基或-N＝CR1R2，R1和R2如权利要求6所定义。
  11. 根据权利要求6-8中任一项所述的用途，其中，式II化合物 中，每个R是氢或R基团中的一个是氢且另一个是C1-C6烷基，或其中R基团均是如权利要求6所定义的非氢取代基或R是甲基。
  12. 根据权利要求6-8中任一项所述的用途，其中，式II化合物中R 40、R 41和R 43各自独立地是氢或甲基且R 42是-CH 2-CH 2-或CH 2-C(Me) 2-。
  13. 根据权利要求6-8中任一项所述的用途，其中，式II化合物中D不包括胺基磷酸酯烷基化剂，诸如-P(Z 1)(NR 30CH 2CH 2X 1) 2、-P(Z 1)(NR 30 2)(N(CH 2CH 2X 1) 2)、-P(Z 1)(N(CH 2CH 2)) 2或-P(Z 1)(N(CH 2CH 2X 1) 2) 2，其中每个R 30独立地是氢或C 1-C 6烷基，或2个R 30与其所结合的氮原子一起形成5-7元杂环基，Z 1是O或S，且X 1是Cl、Br或OMs，或另一离去基团。
  14. 根据权利要求1至13中任一项所述的用途，其中，所述盐为碱式盐或酸式盐。
  15. 根据权利要求1至3中任一项所述的用途，其中，所述溶剂合物为水合物或醇合物。
  16. 根据权利要求1至13中任一项所述的用途，其中，所述疼痛为癌症或炎症引起的疼痛。
  17. 一种含有上述1-13中定义的式I或式II化合物且用于预防、治疗或改善癌症或炎症引起的疼痛的药物。
  18. 治疗癌症或炎症引起的疼痛的方法，其包含施加权利要求18所述的药物的步骤；以及使用AKR1C3抗体测定患者的癌细胞的AKR1C3还原酶含量的步骤，若测得该AKR1C3还原酶含量等于或大于预定值，则向该患者投与权利要求18所述的药物。
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CN112004799B (zh) * 2019-07-01 2023-05-02 深圳艾欣达伟医药科技有限公司 Akr1c3抑制剂及医药用途
WO2021000862A1 (zh) * 2019-07-01 2021-01-07 深圳艾欣达伟医药科技有限公司 Akr1c3抑制剂及医药用途
CN119744178A (zh) * 2022-10-12 2025-04-01 深圳艾欣达伟医药科技有限公司 Akr1c3激活抗癌前药化合物与镇痛药物联用治疗伴有疼痛的癌症患者
WO2025113661A1 (zh) * 2023-12-01 2025-06-05 深圳艾欣达伟医药科技有限公司 含有氮丙啶结构的dna烷化剂前药与抗过敏药物联用治疗肿瘤、癌症

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