FIELD OF INVENTION

The present invention provides compounds suitable as therapeutic agents and intermediates thereto, pharmaceutical compositions of such compounds and methods of treating cancer in cancer patients, and so relates to the fields of biology, chemistry, and medicine.

BACKGROUND

Cancer is one of the major causes of human morbidity and mortality. Cancer treatment is challenging because it is difficult to kill cancer cells without damaging or killing normal cells. Damaging or killing normal cells during cancer treatment is a cause of adverse side effects in patients and can limit the amount of anti-cancer drug administered to a cancer patient.

Aldo-keto reductase family 1 member C3 is an enzyme that in humans is encoded by the AKR1C3 gene. This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors.

Many cancer cells overexpress AKR1C3 reductase relative to normal cells (See, Cancer Res 2010; 70:1573-1584, Cancer Res 2010; 66: 2815-2825). PR 104:


has been shown to be a weak substrate for AKR1C3 and was tested in the clinical trials as the water soluble phosphate prodrug PR 104P. This compound is not a selective AKR1C3 activated prodrug as it can also be activated under hypoxic conditions. PR 104 was ineffective in clinical trials.

There remains a need for compounds suitable for treating cancer patients, including for selective AKR1C3 reductase activated prodrugs for treating cancer patients. The present invention meets this need.

SUMMARY

In one aspect, provided herein are compounds of formula I:


pharmaceutically acceptable salts, and solvates of each thereof, wherein
X10is O, S, SO, or SO2;
A is C6-C10aryl, 5-15 membered heteroaryl, or —N═CR1R2;
each R1and R2independently is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR13R14, or —NR13COR14;
each X, Y, and Z independently is hydrogen, CN, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C5cycloalkyl, C6-C10aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR13R14, or —NR13COR4;
each R independently is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C6-C10aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR13R14or —NR13COR14;
each R13and R14independently is hydrogen, C1-C6alkyl, C3—C8cycloalkyl, C6-C10aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;
wherein L1and D are defined as follows:
L1is selected from:


R40and R41are independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C6-C10aryl, 4-15 membered heterocycle, or 5-15 membered heteroaryl
R42is C2-C3alkylene or heteroalkylene optionally substituted with 1-3 C1-C6alkyl groups,
V(−) is any anion, preferably, a pharmaceutically acceptable anion,
D is a moiety such that D-OH is an anti cancer drug wherein OH is an aliphatic or a phenolic hydroxy group or is an OH moiety attached to a phosphorous atom as provided herein; or
L1is:


R40is defined as above, R43is hydrogen or together with D forms a heterocycle ring, and the phenylene moiety is optionally substituted, and
D is a moiety such that D-NR43H is an anti cancer drug; or
L1is a bond, —O—CR40R412—, —O—C(R40R41)—NR40R41(+)—C(R40R41)—, or


wherein R40and R41are defined as above, and
D is an anticancer drug containing a tertiary or a secondary nitrogen atom, wherein the tertiary or the secondary nitrogen atom is bonded to L1,
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, and ether groups are optionally substituted.

In another embodiment, provided herein is a compound of formula I-A



In another embodiment, X10is S.

Illustrative and non-limiting examples of D, and how D is bonded to L1is provided herein. Based on this information, other D useful moieties and their bonding to L1in accordance with this invention will be apparent to a skilled artisan.

As used herein, D excludes a phosphoramidate alkylator such as —P(Z1)(NR30CH2CH2X1)2, —P(Z1)(NR302)(N(CH2CH2X)2), —P(Z)(N(CH2CH2))2, or —P(Z1)(N(CH2CH2XI)2)2, wherein each R30independently is hydrogen or C1-C6alkyl or 2 R30s together with the nitrogen atom they are bound to form 5-7 membered heterocyclyl group, Z1is O or S, and X1is Cl, Br, or OMs or another leaving group.

In some embodiment, the compounds provided herein have an anti-cancer cellular cytotoxicity or anti-proliferation effect that is at least half, at least 20%, at least 10%, at least 5%, at least 1%, or at least 0.1% of the corresponding anti cancer agent: DOH, DNH2, and the likes, as utilized herein. Methods of determining the cytotoxicity or the anti-proliferation effect of compounds are well known to the skilled artisan and also described herein. In some embodiment, those hydroxy and amino (including secondary and tertiary amino groups) groups in an anti cancer agents are derivatized as provided herein such that upon derivatization and forming the compounds of this invention, the cytotoxity or the antiproliferation effect of the derivative (i.e., the compound provided herein) is at least half, at least 20%, at least 10%, at least 5%, at least 1%, or at least 0.1% of the corresponding anti cancer agent utilized. Skilled artisan are aware of which hydroxy and/or amino groups (including secondary and tertiary amino groups) of an anti cancer agent are responsible for at least some or a substantial part of the anti cancer activity of that agent. For example, and without limitation, masking the amino group in an anthracycline as provided herein, is contemplated to reduce the cytotoxicity of the anthracycline.

The compounds provided herein include individual diastereomers and other geometric isomers, and enantiomers, and mixtures of enantiomers, diastereomers, and geometric isomers other than diastereomers.

In another aspect, provided herein is a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient. In another aspect, provided herein is a unit dose of the pharmaceutical composition provided herein.

In another aspect, provided herein is a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable composition as provided herein. In one embodiment, the cancer is one wherein AKR1C3reductase levels are high or are higher than usual in such a cancer. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is non small cell lung cancer or melanoma. In a further aspect, the method comprises determining the AKR1C3reductase level of the cancer by methods using an AKR1C3antibody, and administering a therapeutically effective amount of a compound or a pharmaceutically acceptable composition provided herein to said patient if said level is equal to or greater than a predetermined value. In one aspect, the method comprises prior to administration, determining a intratumoral AKR1C3reductase level in a sample isolated from the patient and selecting the patient for the therapy if the level is equal to or greater than a predetermined level. In some embodiments, a therapeutically effective amount of a cancer treatment other than a treatment comprising administration of a compound or a pharmaceutically acceptable composition provided herein is administered if the level does not exceed or is less than said predetermined value. Methods of determining the therapeutically effective amount, appropriate mode of administration of the compounds and compositions provided herein will be apparent to the skilled artisan upon reading this disclosure and based on other methods known to them. AKR1C3levels are measured following routine methods well known to the skilled artisan.

