USE OF COMPOUND IN DRUG FOR PREVENTING, TREATING, OR ALLEVIATING PAIN

Abstract

The present invention provides a use of a compound shown in Formula I/II in a drug for preventing, treating or alleviating pain

##STR00001##

Claims

1. A method of preventing, treating or alleviating pain in a subject comprising the step of administering to the subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, or a solvate thereof, ##STR00017## wherein X.sup.10 is O, S, SO, or SO.sub.2; A is C.sub.6-C.sub.10 aryl or substituted aryl, 5-15 membered heteroaryl or substituted heteroaryl, or —N═CR.sup.1R.sup.2, wherein each R.sup.1 and R.sup.2 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each X, Y, and Z independently is hydrogen, CN, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; R is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each R.sup.13 and R.sup.14 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl or ether, or R.sup.13 and R.sup.14 together with the nitrogen atom to which they are bonded to form 5-7 membered heterocyclyl group; T comprises a phosphoramidate alkylating agent; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, and ether groups are optionally substituted, thereby preventing, treating or alleviating pain in the subject.

2. The method according to claim 1, wherein in the compound of formula I, T is OP(Z.sup.1)(NR.sup.30CH.sub.2CH.sub.2X.sup.1).sub.2, OP(Z.sup.1)(NR.sup.30.sub.2)(N(CH.sub.2CH.sub.2X.sup.1).sub.2), OP(Z.sup.1)(N(CH.sub.2).sub.2).sub.2 or OP(Z.sup.1)(N(CH.sub.2CH.sub.2X.sup.1).sub.2).sub.2, wherein each R.sup.30 independently is hydrogen or C.sub.1-C.sub.6 alkyl or two R.sup.30 groups together with the nitrogen atom to which they are bonded to form 5-7 membered heterocyclyl group, Z.sup.1 is O or S, and X.sup.1 is Cl, Br, or OMs or other leaving groups.

3. The method according to claim 1, wherein in the compound of formula I, T is OP(Z.sup.1)(NHCH.sub.2CH.sub.2Cl).sub.2, OP(Z.sup.1)(NHCH.sub.2CH.sub.2Br).sub.2, OP(Z.sup.1)(NH.sub.2)(N(CH.sub.2CH.sub.2X.sup.1).sub.2), OP(Z.sup.1)(N(CH.sub.2).sub.2).sub.2 or OP(Z.sup.1)(N(CH.sub.2CH.sub.2Cl).sub.2).sub.2, wherein Z.sup.1 is O or S, and X.sup.1 is Cl, Br, or OMs.

4. The method according to claim 1, wherein in the compound of formula I, T is OP(O)(N(CH.sub.2CH.sub.2)).sub.2, OP(O)(NHCH.sub.2CH.sub.2Cl).sub.2, OP(O)(NHCH.sub.2CH.sub.2Br).sub.2 or OP(O)(NH.sub.2)(N(CH.sub.2CH.sub.2Cl).sub.2).

5. The method according to claim 1, wherein the compound of formula I is ##STR00018##

6. A method of preventing, treating or alleviating pain in a subject comprising the step of administering to the subject in need thereof an effective amount of a compound of formula II or a pharmaceutically acceptable salt, or a solvate thereof, ##STR00019## wherein X.sup.10 is O, S, SO, or SO.sub.2; A is C.sub.6-C.sub.10 aryl or substituted aryl, 5-15 membered heteroaryl or substituted heteroaryl, or —N═CR.sup.1R.sup.2, wherein each R.sup.1 and R.sup.2 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14 or —NR.sup.13COR.sup.14; each X, Y, and Z independently is hydrogen, CN, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each R independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each R.sup.13 and R.sup.14 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether, or R.sup.13 and R.sup.14 together with the nitrogen atom to which they are bonded to form 5-7 membered heterocyclyl group; L.sup.1 is selected from the group consisting of: ##STR00020## wherein R.sup.40 and R.sup.41 are independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, or 5-15 membered heteroaryl; R.sup.42 is C.sub.2-C.sub.3 alkylene or heteroalkylene optionally substituted with 1-3 C.sub.1-C.sub.6 alkyl; V(−) is any anion, preferably, a pharmaceutically acceptable anion; and D is a moiety such that D-OH is an anticancer drug wherein OH is an aliphatic or a phenolic hydroxy group or is an OH moiety attached to a phosphorous atom as provided herein; in other words, D is the remaining group in the anticancer drug D-OH after the hydroxyl group is removed therefrom; alternatively L.sup.1 is: ##STR00021## wherein R.sup.40 is defined as above, R.sup.43 is hydrogen or together with D forms a heterocycle, and the phenyl moiety is optionally substituted, and D is a moiety such that D-NR.sup.43H is an anticancer drug; in other words, D is the remaining group in the anticancer drug D-NR.sup.43H after amino or amine is removed therefrom; alternatively L.sup.1 is a bond, —O—C(R.sup.40R.sup.41).sub.2—, —O—C(R.sup.40R.sup.41)—NR.sup.40R.sup.41(+)—C(R.sup.40R.sup.41)— or ##STR00022## wherein R.sup.40, R.sup.41 and V are defined as above, and D is an anticancer drug containing a primary or a secondary amine, wherein the primary or the secondary amine is bonded to L.sup.1; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, and ether groups are optionally substituted, thereby preventing, treating or alleviating pain in the subject.

7. The method according to claim 6, wherein the compound of formula II is a compound of formula II-A, ##STR00023## wherein the remaining variables are as defined in claim 6.

8. The method according to claim 6, wherein the compound of formula II is a compound of formula IIA-1: ##STR00024## wherein the remaining variables are as defined in claim 6, and D is a moiety of the cytotoxic agent HNR.sup.43-D containing a primary or a secondary amine group; in other words, D is the remaining group in the cytotoxic agent HNR.sup.43-D after the primary or a secondary amine group is removed therefrom; alternatively, the compound is of formula III-2 or IIIA-3: ##STR00025## wherein the remaining variables are as defined in claim 6, and D is a moiety of the cytotoxic agent HO-D containing at least one hydroxyl group; in other words, D is the remaining group in the cytotoxic agent HO-D after the hydroxyl group is removed therefrom; alternatively, the compound is of formula IIA-4, IIA-6 or IIA-6-i: ##STR00026## wherein the variables are as defined in claim 6; wherein in IIA-4, HO-D is cytotoxic agent containing at least one hydroxyl group; in other words, D is a moiety of the cytotoxic agent HO-D containing at least one hydroxyl group, or D is the remaining group in the cytotoxic agent HO-D after the hydroxyl group(s) is/are removed therefrom; in IIA-6-i, DNR.sup.40R.sup.41 is a drug; in other words, D is a moiety such that DNR.sup.40R.sup.41 is an anticancer drug or D is the remaining moiety in the anticancer DNR40R.sup.41 after NR.sup.40R.sup.41 is removed therefrom; and in IIA-6, D is a drug containing a secondary amine, wherein the secondary amine is bonded to the methylene group; in other words, D is a drug containing a secondary amine, and is bonded via the secondary amine contained therein to the methylene group so as to be linked to —NR.sup.40R.sup.41 as shown in the above formula IIA-4, IIA-6 or IIA-6-I; alternatively, the compound is of IIA-5 or IIA-7: ##STR00027## wherein the variables are as defined in claim 6; wherein in IIA-5, DNR.sup.40R.sup.41 is a drug; in other words, D is a moiety such that DNR.sup.40R.sup.41 is an anticancer drug or D is the remaining moiety in the anticancer DNR40R.sup.41 after NR.sup.40R.sup.41 is removed therefrom; and IIA-7, D is a drug containing a secondary amine, wherein the secondary amine is bonded to the methylene group as shown in the above formula IIA-5 or IIA-7.

9. The method according to claim 6, wherein in the compound of formula II, Z is hydrogen, or X is hydrogen, or Y is hydrogen/halo.

10. The method according to claim 6, wherein in the compound of formula II, A is substituted or unsubstituted C.sub.6-C.sub.10 aryl, or phenyl, or 5-15 membered heteroaryl, or pyridyl, or —N═CR.sup.1R.sup.2, wherein R.sup.1 and R.sup.2 are as defined in claim 6.

11. The method according to claim 6, wherein in the compound of formula II, each R is hydrogen, or one of the R groups is hydrogen and the other R group is C.sub.1-C.sub.6 alkyl, or both R groups are non-hydrogen substituents as defined in claim 6, or R is methyl.

12. The method according to claim 6, wherein in the compound of formula II, each of R.sup.40, R.sup.41 and R.sup.43 is independently hydrogen or methyl and R.sup.42 is —CH.sub.2—CH.sub.2— or —CH.sub.2—C(Me).sub.2-.

13. The method according to claim 6, wherein in the compound of formula II, D excludes a phosphoramidate alkylating agent such as —P(Z.sup.1)(NR.sup.30CH.sub.2CH.sub.2X.sup.1).sub.2, —P(Z.sup.1)(NR.sup.30.sub.2)(N(CH.sub.2CH.sub.2X.sup.1).sub.2), —P(Z.sup.1)(N(CH.sub.2CH.sub.2)).sub.2 or —P(Z.sup.1)(N(CH.sub.2CH.sub.2X.sup.1).sub.2).sub.2, wherein each R.sup.30 independently is hydrogen or C.sub.1-C.sub.6 alkyl or 2R.sup.30s together with the nitrogen atom to which they are bonded to form 5-7 membered heterocyclyl group, Z.sup.1 is O or S, and X.sup.1 is Cl, Br, or OMs or another leaving group.

14. The method according to claim 1, wherein the pharmaceutically acceptable salt is a basic salt or an acid salt or the solvate is hydrate or alcoholate; or the pain is a pain caused by cancer or inflammation.

15-16. (canceled)

17. A pharmaceutical composition comprising the compound of formula I ##STR00028## wherein X.sup.10 is O, S, SO, or SO.sub.2; A is C.sub.6-C.sub.10 aryl or substituted aryl, 5-15 membered heteroaryl or substituted heteroaryl, or —N═CR.sup.1R.sup.2, wherein each R.sup.1 and R.sup.2 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each X, Y, and Z independently is hydrogen, CN, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; R is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each R.sup.13 and R.sup.14 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl or ether, or R.sup.13 and R.sup.14 together with the nitrogen atom to which they are bonded to form 5-7 membered heterocyclyl group; T comprises a phosphoramidate alkylating agent; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, and ether groups are optionally substituted, and a pharmaceutically acceptable auxiliary or excipient, for prevention, treatment or alleviation of pain caused by cancer or inflammation.

18. A method for treatment of pain caused by cancer or inflammation, the method comprising a step of administering the pharmaceutical composition of claim 17 to a subject in need of such treatment, thereby treating the pain in the subject; and a step for measuring the content of AKR1C3 reductase of cancer cells in the subject using AKR1C3 antibodies, where the content of AKR1C3 reductase is measured to be equal to or greater than the predetermined value.

19. The method according to claim 6, wherein the salt is a basic salt or an acid salt; or the solvate is hydrate or alcoholate; or the pain is a pain caused by cancer or inflammation.

20. A pharmaceutical composition comprising the compound of formula II ##STR00029## wherein X.sup.10 is O, S, SO, or SO.sub.2; A is C.sub.6-C.sub.10 aryl or substituted aryl, 5-15 membered heteroaryl or substituted heteroaryl, or —N═CR.sup.1R.sup.2, wherein each R.sup.1 and R.sup.2 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14 or —NR.sup.13COR.sup.14; each X, Y, and Z independently is hydrogen, CN, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each R independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR.sup.13R.sup.14, or —NR.sup.13COR.sup.14; each R.sup.13 and R.sup.14 independently is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether, or R.sup.13 and R.sup.14 together with the nitrogen atom to which they are bonded to form 5-7 membered heterocyclyl group; L.sup.1 is selected from the group consisting of: ##STR00030## wherein R.sup.40 and R.sup.41 are independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, 4-15 membered heterocycle, or 5-15 membered heteroaryl; R.sup.42 is C.sub.2-C.sub.3 alkylene or heteroalkylene optionally substituted with 1-3 C.sub.1-C.sub.6 alkyl; V(−) is any anion, preferably, a pharmaceutically acceptable anion; and D is a moiety such that D-OH is an anticancer drug wherein OH is an aliphatic or a phenolic hydroxy group or is an OH moiety attached to a phosphorous atom as provided herein; in other words, D is the remaining group in the anticancer drug D-OH after the hydroxyl group is removed therefrom; alternatively L1 is: ##STR00031## wherein R.sup.40 is defined as above, R.sup.43 is hydrogen or together with D forms a heterocycle, and the phenyl moiety is optionally substituted, and D is a moiety such that D-NR.sup.43H is an anticancer drug; in other words, D is the remaining group in the anticancer drug D-NR.sup.43H after amino or amine is removed therefrom; alternatively L1 is a bond, —O—C(R.sup.40R.sup.41).sub.2—, —O—C(R.sup.40R.sup.41)—NR.sup.40R.sup.41(+)—C(R.sup.40R.sup.41)— or ##STR00032## wherein R.sup.40, R.sup.41 and V are defined as above, and D is an anticancer drug containing a primary or a secondary amine, wherein the primary or the secondary amine is bonded to L.sup.1; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, and ether groups are optionally substituted, and a pharmaceutically acceptable auxiliary or excipient, for prevention, treatment or alleviation of pain caused by cancer or inflammation.

21. A method for treatment of pain caused by cancer or inflammation, the method comprising a step of administering the pharmaceutical composition of claim 20 to a subject in need of such treatment, thereby treating the pain in the subject; and a step for measuring the content of AKR1C3 reductase of cancer cells in a subject using AKR1C3 antibodies, where the content of AKR1C3 reductase is measured to be equal to or greater than the predetermined value.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0100] FIG. 1 depicts the experiment showing the effect of application of AST-3424 on the production of reduced progesterone.

DETAILED DESCRIPTION OF THE INVENTION

[0101] The present invention will be described below with reference to specific examples. Those skilled in the art could understand that these examples are only used for describing the invention and do not in any way limit its scope.

[0102] The experimental methods in the following examples are all conventional methods unless otherwise specified. The raw materials of the medicaments, the reagents and the like used in the following examples are all commercially available products unless otherwise specified.

[0103] The compounds shown in the present invention and the methods for synthesizing the same are disclosed in Patent Application No. PCT/US2016/021581 (WO2016/145092), Patent Application No. PCT/US2016/025665 (WO2016/161342), and Patent Application No. PCT/US2016/062114 (WO2017/087428).

[0104] The following definitions are provided to assist the reader. Unless otherwise defined, all terms of art, notations, and other scientific or medical terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the chemical and medical arts. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not be construed as representing a substantial difference over the definition of the term as generally understood in the art.

[0105] All numerical designations, e.g., pH, temperature, time, concentration, and weight, including ranges of each thereof, are approximations that typically may be varied (+) or (−) by increments of 0.1, 1.0, or 10.0, as appropriate. All numerical designations may be understood as preceded by the term “about”. Reagents described herein are exemplary and equivalents of such may be known in the art.

[0106] “C.sub.x-C.sub.y” or “C.sub.x-y” before a group refers to a range of the number of carbon atoms that are present in that group. For example, C.sub.1-C.sub.6 alkyl refers to an alkyl group having at least 1 and up to 6 carbon atoms.

[0107] “Alkoxy” refers to —O-Alkyl.

[0108] “Amino” refers to NR.sup.pR.sup.q wherein R.sup.p and R.sup.q independently are hydrogen or C.sub.1-C.sub.6 alkyl, or R.sup.p and R.sup.q together with the nitrogen atom to which they are bonded to form a 4-15 membered heterocycle.

[0109] “Aryl” refers to an aromatic group of from 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 anthryl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term “aryl” or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).

[0110] According to specific embodiments of the present application, C.sub.6-C.sub.10 aryl can be phenyl, naphthyl and various substituted phenyl or naphthyl.

[0111] “Heteroaryl” refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl-2-yl and imidazol-5-yl) and multiple ring systems (e.g. imidazopyridyl, benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, the term “heteroaryl” applies if there is at least one ring heteroatom, and the point of attachment is at an atom of an aromatic ring (e.g. 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N.fwdarw.O), sulfinyl, or sulfonyl moieties. The term heteroaryl or 5-15 membered heteroaryl includes, but is not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzothienyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl and xanthenyl.

[0112] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. “C.sub.x-y alkyl” refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH.sub.3—), ethyl (CH.sub.3CH.sub.2—), n-propyl (CH.sub.3CH.sub.2CH.sub.2—), isopropyl ((CH.sub.3).sub.2CH—), n-butyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2—), isobutyl ((CH.sub.3).sub.2CHCH.sub.2—), sec-butyl ((CH.sub.3)(CH.sub.3CH.sub.2)CH—), tert-butyl ((CH.sub.3).sub.3C—), n-pentyl (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2—), and neopentyl ((CH.sub.3).sub.3CCH.sub.2—).

[0113] “Cycloalkyl” refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term “cycloalkyl” applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8-tetrahydronaphthalene-5-yl). The term “cycloalkyl” or “C.sub.3-C.sub.8 cycloalkyl” includes cycloalkenyl groups. Examples of cycloalkyl groups or C.sub.3-C.sub.8 cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and cyclohexenyl.

[0114] “Heterocyclic” or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom, and the point of attachment is at an atom of a non-aromatic ring (e.g. 1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In some embodiments, the heterocyclic groups herein are 3-15 membered, 4-14 membered, 5-13 membered, 7-12 membered, or 5-7 membered heterocycles. In some other embodiments, the heterocycles contain 4 heteroatoms. In some other embodiments, the heterocycles contain 3 heteroatoms. In another embodiment, the heterocycles contain up to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties. Heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g., C.sub.3-10) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms. A divalent heterocyclic radical will have the appropriately adjusted hydrogen content.

[0115] “Ether” refers to a C.sub.1-C.sub.6 alkyl group substituted with 1-3 C.sub.1-C.sub.6 alkoxy groups, wherein alkoxy refers to —O-alkyl.

[0116] “Halo” refers to one or more of fluoro, chloro, bromo, and iodo.

[0117] “Alkenyl” refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=—). For example, C.sub.x-y alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include, for example, ethenyl, propenyl, 1,3-butadienyl, and the like.

[0118] “Alkynyl” refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and containing at least one triple bond. The term “alkynyl” is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, C.sub.2-6 alkynyl includes ethynyl, propynyl, and the like.

[0119] “Phosphoramidate alkylating agent” refers to an alkylating agent comprising one or more Z.sup.5—X.sup.5—Y.sup.5 moieties bonded to an —O—P(Z1) moiety, where Z.sup.5 is a heteroatom such as nitrogen, sulfur or oxygen, X.sup.5 is optionally substituted ethylene, Y.sup.5 is halo or another leaving group, or Z.sup.5—X.sup.5—Y.sup.5 together form an aziridinyl (NCH.sub.2CH.sub.2) moiety, and Z.sup.1 is defined as above. Such an alkylating agent can react with a DNA or another nucleic acid or protein. In some instances an alkylating agent can be cross-linked with DNA.

[0120] The term “optionally substituted” refers to a substituted or unsubstituted group. The group may be substituted with one or more substituents, such as e.g., 1, 2, 3, 4 or 5 substituents. Preferably, the substituents are selected from the group consisting of oxo, halo, —CN, NO.sub.2, —N.sub.2+, —CO.sub.2R.sup.100, —OR.sup.100, —SR.sup.100, —SOR.sup.100, —SO.sub.2R.sup.100, —NR.sup.100SO.sub.2R.sup.100, —NR.sup.101R.sup.102, —CONR.sup.101R.sup.102, —SO.sub.2NR.sup.101R.sup.102, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, —CR.sup.100═C(R.sup.100).sub.2, —CCR.sup.100, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocyclyl, C.sub.6-C.sub.12 aryl and C.sub.2-C.sub.12 heteroaryl, or a divalent substituent such as —O—(CH.sup.2)—O—, —O—(CH.sub.2).sub.2—O—, and, 1-4 methyl substituted version thereof, wherein each R.sup.100, R.sup.101, and R.sup.102 independently is hydrogen or C.sub.1-C.sub.8 alkyl; C.sub.3-C.sub.12 cycloalkyl; C.sub.3-C.sub.10 heterocyclyl; C.sub.6-C.sub.12 aryl; or C.sub.2-C.sub.12 heteroaryl; or R.sup.100 and R.sup.102 together with the nitrogen atom to which they are attached to form a 5-7 membered heterocycle; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1-3 C.sub.1-C.sub.6 alkyl, 1-3 C.sub.1-C.sub.6 haloalkyl or 1-3 C.sub.1-C.sub.6 alkoxy groups. Preferably, the substituents are selected from the group consisting of chloro, fluoro, —OCH.sub.3, methyl, ethyl, iso-propyl, cyclopropyl, —CO.sub.2H and salts and C.sub.1-C.sub.6 alkyl esters thereof, CONMe.sub.2, CONHMe, CONH.sub.2, —SO.sub.2Me, —SO.sub.2NH.sub.2, —SO.sub.2NMe.sub.2, —SO.sub.2NHMe, —NHSO.sub.2Me, —NHSO.sub.2CF.sub.3, —NHSO.sub.2CH.sub.2Cl, —NH.sub.2, —OCF.sub.3, —CF.sub.3 and —OCHF.sub.2.

[0121] “Alkylene” refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. “C.sub.u-v alkylene” refers to alkylene groups having from u to v carbon atoms. The alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups. For example, “C.sub.1-6 alkylene” includes methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

[0122] “Heteroalkylene” refers to an alkylene wherein a chain carbon atom is replaced with a heteroatom such as O, S, N, or P, or a heteroatom containing substituent.

[0123] The “drugs” regarding D herein includes without limitation, gemcitibine, erlotinib, meturedepa, uredepa, altretamine, imatinib, triethylenemelamine, trimethylmelamine, chlorambucil, chlornaphazine, estramustine, gefitinib, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycins, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carubicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, daunomycin, 6-diazo-5-oxo-1-norleucine, mycophenolic acid, nogalamycin, olivomycin, peplomycin, plicamycin, porfiromycin, puromycin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-fluorouracil, tegafur, L-asparaginase, pulmozyme, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, defofamide, demecolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, flutamide, hydroxyurea, interferon-alpha, interferon-beta, interferon-gamma, interleukin-2, lentinan, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, paclitaxel, tamoxifen, erlotonib, teniposide, tenuazonic acid, triaziquone, 2,2′,2″-trichlorotriethylamine, urethan, vinblastine, and vincristine.

[0124] “Administering” or “administration of” a drug to a patient (and grammatical equivalents of this phrase) refers to direct administration, which may be administered to a patient by a medical professional or may be self-administered, and/or indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.

[0125] “Cancer” refers to leukemias, lymphomas, carcinomas, and other malignant tumors, including solid tumors, of potentially unlimited growth that can expand locally by invasion and spread throughout the bodyby metastasis. Examples of cancers include, but are not limited to, cancer of the adrenal gland, bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head and neck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate, parathyroid, skin, stomach, and thyroid. Certain other examples of cancers include, acute and chronic lymphocytic and granulocytic tumors, adenocarcinoma, adenoma, basal cell carcinoma, poor cervical intraepithelial differentiation and in situ carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant cell tumor, glioblastoma multiforma, hairy-cell tumor, intestinal ganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma, Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid, malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor, medullary epithelial carcinoma, metastatic skin carcinoma, mucosal neuroma, myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic and other sarcoma, ovarian tumor, pheochromocytoma, polycythermia vera, primary brain tumor, small-cell lung tumor, squamous cell carcinoma of both ulcerating and papillary type, hyperplasia, seminoma, soft tissue sarcoma, retinoblastoma, rhabdomyosarcoma, renal cell tumor, topical skin lesion, reticulum cell sarcoma, and Wilm's tumor.

[0126] “Inflammation” is preferably the inflammation which causes pain due to the prostaglandin E2/F2 from the above-mentioned arachidonic acid-cyclooxygenase-prostaglandin pathway.

[0127] “Patient” and “subject” are used interchangeably to refer to a mammal in need of treatment for cancer. Generally, the patient is a human. Generally, the patient is a human diagnosed with cancer. In certain embodiments, a “patient” or “subject” may refer to a non-human mammal used in screening, characterizing, and evaluating drugs and therapies, such as, a non-human primate, a dog, cat, rabbit, pig, mouse or a rat.

[0128] “Prodrug” refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property. A prodrug, relative to the drug, is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered. A prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may be synthesized using reactants other than the corresponding drug.

[0129] “Solid tumor” refers to solid tumors including, but not limited to, metastatic tumors in bone, brain, liver, lungs, lymph node, pancreas, prostate, skin and soft tissue (sarcoma).

[0130] “Therapeutically effective amount” of a drug refers to an amount of a drug that, when administered to a patient with cancer, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of cancer in the patient. A therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0131] “Treatment of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or improvement of one or more symptoms of cancer; diminishment of extent of disease; delay or slowing of disease progression; alleviation, palliation, or stabilization of the disease state; or other beneficial results. Treatment of cancer may, in some cases, result in partial response or stable disease.

[0132] “Tumor cells” refers to tumor cells of any appropriate species, e.g., mammalian such as murine, canine, feline, equine or human.

[0133] The above description of embodiments of the present invention does not limit the present invention. Those skilled in the art can make various modifications and changes according to the present invention, and any modification and change within the spirit of the present invention shall be covered in the scope of the claims appended to the present invention.

[0134] An in vitro experiment and an in vivo experiment in cynomolgus monkeys are provided below to verify the analgesic effects of the compounds.

In Vitro Experiments

[0135] Experimental apparatus: Waters Acquity I Class UPLC Ultra Performance Liquid Chromatograph equipped with a Xevo G2-XS Q Tof HRMS Quadrupole Time-of-flight High-Resolution Mass Spectrometer

[0136] Buffers and Materials:

[0137] 1. PBS phosphate buffered saline solution,

[0138] 2. PBS phosphate buffered saline solution of 20 mM NADPH

[0139] 3. PBS phosphate buffered saline solution of 250 μg/mL AKR1C3

[0140] 4. 50% MeOH/H2O solution of 250 μM AST-3424

[0141] 5. 50% MeOH/H2O solution of 250 μM progesterone

[0142] 6. 100% acetonitrile solution of 1 μg/mL propranolol

Experimental Procedures

[0143] In step 1, the reaction mixtures were prepared into Eppendorf tubes in quadruplicate (n=4) according to the table below and mixed gently.

TABLE-US-00001 Negative Materials controls (μL) Samples (μL) PBS 68 58 NADPH (20 mM) 10 10 AKR1C3 (250 μg/mL) 10 10 AST-3424 (250 μM) 0 10

[0144] In step 2, the above mixtures were pre-incubated in duplicate at 37° C. for 30 minutes and 60 minutes.

[0145] In step 3, another 10 μL of PBS phosphate buffered saline solution of 20 mM NADPH and 2 μL of 50% MeOH/H.sub.2O solution of 250 μM progesterone were added to each Eppendorf tube and mixed gently.

[0146] In step 4, 50 μL of the mixture in the above step was immediately transferred to 100 μL of 100% acetonitrile solution of 1 μg/mL propranolol (internal standard (IS)).

[0147] In step 5, the remaining samples were incubated at 37° C. for 30 minutes, and 100 μL of 100% acetonitrile solution of 1 μg/mL propranolol (internal standard (IS)) was added.

[0148] In step 6, 100 μL of reagent water was added to all the samples, vortexed at 1,100 rpm for 5 minutes, and centrifuged at 15,000 rpm for 10 minutes at room temperature.

[0149] In step 7, all the samples were loaded on LC/MS to determine the content of reduced progesterone, namely 20α-dihydroprogesterone.

[0150] The test conditions for the LC-MS apparatus are shown below

TABLE-US-00002 Items Conditions Apparatus: Waters Acquity I Class Liquid Chromatograph Chromatographic Acquity UPLC BEHC18 Chromatographic Column column: (50*2.1 mm, 1.7 μm) Flow rate: 0.4 mL/min Injection volume: 3 μL The composition of A: 0.1% (V/V) formic acid aqueous solution the mobile phase: B: 0.1% (V/V) formic acid acetonitrile solution The temperature of 40° C. the column oven: Detector: Quadrupole Time-of-flight Mass Spectrometer Q-TOF MS

[0151] The Gradient of Elution of the Liquid Phase

TABLE-US-00003 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

[0152] Parameters of the Quadrupole Time-of-Flight Mass Spectrometer

TABLE-US-00004 Items Parameters Capillary voltage (kV) 2.5 Cone voltage (V) 40 Source temperature (° C.) 100 Flow rate of cone gas (L/h) 50 Flow rate of desolvation gas 600 (L/h) Ionization mode (Interface ES, Positive type) Analyser mode Sensitivity Scan range 50-800 m/z

[0153] In step 9, the reduced progesterone (20α-dihydroprogesterone) is calculated: the peak area of the reduced progesterone, namely 20α-dihydroprogesterone and propranolol, in each sample was determined by LC/MS. The peak area ratios of reduced progesterone to propranolol (i.e., the ratios in the above table) were calculated, and when the time is 0 the ratio is set to 0%.

AKR1C3 activity (%)=[(the amount of reduced progesterone after normalization of the sample) 30 min−(the amount of reduced progesterone after normalization of the sample) 0 min]/[(the amount of reduced progesterone after normalization of the negative control group) 30 min−(the amount of reduced progesterone after normalization of the negative control group) 0 min]*100.

[0154] The AKR1C3 activity results in the above table were calculated according to the above formula.

Experimental Results

[0155]

TABLE-US-00005 The peak areas of the liquid phase Duration Progesterone Reduced progesterone Propranolol AKR1C3 Incubation Reaction AST-3424 Values Averages Values Averages Ratios* Values Averages activity % Negative 30 min 0 Absent 36658 36835 150 158 0.0034 51141 46879 0 control 37011 166 42616 groups 60 min 35244 35125 87 83 0.0019 42794 43650 0 35006 79 44506 30 min 30 min 28675 26228 5616 6617 0.1506 43589 43935 100 23780 7617 44280 60 min 25917 26492 6747 6051 0.1343 44258 45067 100 27067 5354 45876 Samples 30 min 0 154017 37107 37438 70 72 0.0017 43247 43436 0 154843 37769 74 43625 60 min 108351 38050 37989 58 64 0.0015 43907 43697 0 107508 37928 70 43487 30 min 30 min 104748 35187 35210 344 331 0.0074 45657 45051 3.9 110630 35234 319 44445 60 min  52296 32636 32520 622 616 0.0137 45395 45101 9.2  51309 32404 610 44807

Analysis and Summary of the Experimental Results

[0156] Table: The effect of AST-3424 on AKR1C3 activity

TABLE-US-00006 % AKR1C3 activity The time of 0 μM 5 μM incubation (min) AST-3424 AST-3424 30 100% 3.9% 60 100% 9.2%

[0157] The effect of AST-3424 on the production of reduced progesterone is shown in FIG. 1.

[0158] The aforementioned in vitro experiment proves that after pre-incubation for 30 minutes and 60 minutes, AST-3424 at a concentration of 5 μM basically inhibited AKR1C3 activity: compared with the negative control groups, the production of the reduced progesterone, namely 20α-dihydroprogesterone, was reduced to 3.9% and 9.2%, respectively, proving that the compound AST-3424 and the similar compounds disclosed in the patent applications No. PCT/US2016/021581, PCT/US2016/025665 and PCT/US2016/062114 are inhibitors of AKR1C3 enzyme.

II. In Vivo Experiment

[0159] An experiment with three cynomolgus monkeys was performed according to the table below.

TABLE-US-00007 Administration The concentration of the solution of The The dosage of the the test volume of Amount Test test substance substance administration Mode of Collected Group Male substance (mg/kg) (mg/mL) (mL/kg) administration Sample 1 3 AST3424 1/Compound 0.2 5 Intravenous Plasma/ infusion serum

[0160] Four male cynomolgus monkeys were purchased from Guangxi Xiongsen Primate Development and Experiment Co., Ltd., and all of them were healthy cynomolgus monkeys that had passed the physical examination and have no abnormalities. Among them, three cynomolgus monkeys were used in the experiment of administration and the remaining one was used for preparing blank plasma.

[0161] Before administration, and 6, 24, 48 and 72 hours after the start of administration, 1 mL of blood was collected from the femoral vein or other suitable vein, and placed in a blood collection tube without anticoagulant. After collected, the blood sample was placed on ice and allowed to stand for 30-60 minutes before being centrifuged at 3,500 rpm for 10 minutes at 2-8° C. to separate the serum. The collected serum was stored at −80° C. before being analyzed.

[0162] Prostaglandins E2 and F2 in serum samples were analyzed by conventional ELISA methods. The measurement results are as follows.

[0163] The concentrations of prostaglandins E2 and F2 in the serum after single administration to cynomolgus monkeys by intravenous infusion

TABLE-US-00008 The measured concentration of prostaglandin F2 (pg/ml) Time point 101 102 103 Mean SD Before 1828.51 310.17 1125.58 1088.09 759.86 administration  6 h 165.32 260.80 300.65 242.26 69.54 24 h 816.63 3460.25 4208.19 2828.36 1781.89 48 h 183.73 216.12 541.05 313.63 197.61 72 h 441.76 968.01 1369.67 926.48 465.35 The measured concentration of prostaglandin E2 (pg/ml) Time point 101 102 103 Mean SD Before 713.91 233.63 461.26 469.60 240.25 administration  6 h 210.67 214.73 670.73 365.38 264.45 24 h 450.48 822.21 2735.20 1335.97 1225.95 48 h 322.13 168.84 276.35 255.78 78.69 72 h 408.15 521.78 663.03 530.99 127.69

[0164] After 0.58 mg/kg of AST3424 was administered to cynomolgus monkeys, both prostaglandins E2 and F2 decreased; they fluctuatingly increased at 24 h, which was speculated to be related to the time characteristics of the secretion of prostaglandins E2 and F2 by the cynomolgus monkeys themselves. This demonstrates that AST3424 can inhibit the secretion of prostaglandins E2 and F2 by cynomolgus monkeys.

[0165] The causes of pain directly arising from a tumor and bone infiltration and metastasis include the following: direct bone involvement and direct activation of local nociceptors; compression of adjacent nerves, blood vessels and soft tissues by the tumor; and release of PGE1 and PGF2 from bone infiltration by the tumor. PGF2 is a strong pain-causing factor. The aforementioned animal experiment shows that the AST-3424 compound can greatly reduce the content of PGF2, thereby achieving the effect of treating/alleviating the pain caused by cancer or tumor.

III. Experiment Conclusion

[0166] The above in vitro and in vivo experiments verify that the aforementioned specific substrate, namely DNA alkylating agent targeting overexpressed aldo-keto reductase AKR1C3, can inhibit the activity of the aldo-keto reductase AKR1C3. Moreover, the animal experiment proves that the specific substrates can reduce the content of prostaglandin E2/F2 in the blood. Accordingly, it can be proved that the aforementioned compound AST-3424 and the similar compounds disclosed in the patent applications No. PCT/US2016/021581, PCT/US2016/025665 and PCT/US2016/062114 are inhibitors of AKR1C3 enzyme, which can block the production of prostaglandin E2/F2, reduce its content, and has an analgesic effect.