Pyridines and their use in the treatment of cancer

Abstract

There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein L, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n have meanings provided in the description, which compounds are useful in the treatment of cancers. ##STR00001##

Claims

1. A compound of formula I ##STR00032## or a pharmaceutically acceptable salt thereof, wherein: L represents S(O).sub.2; n represents 0 to 5; R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, R.sup.a1, CN, -A.sup.a1-C(Q.sup.a1)R.sup.b1, -A.sup.b1-C(Q.sup.b1)N(R.sup.c1)R.sup.d1, -A.sup.c1-C(Q.sup.c1)OR.sup.e1, -A.sup.d1-S(O).sub.pR.sup.f1, -A.sup.e1-S(O).sub.pN(R.sup.g1)R.sup.h1, -A.sup.f1-S(O).sub.pOR.sup.i1, N.sub.3, N(R.sup.j1)R.sup.k1, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.11 or SR.sup.m1; each A.sup.a1 to A.sup.f1 independently represents a single bond, N(R.sup.p1) or O; each Q.sup.a1 to Q.sup.c1 independently represents O, S, NR.sup.n1 or N(OR.sup.o1); each R.sup.a1 and R.sup.f1 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; each R.sup.p1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.g1, R.sup.h1, R.sup.i1, R.sup.j1, R.sup.k1, R.sup.l1, R.sup.m1, R.sup.n1 and R.sup.o1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; or any of R.sup.c1 and R.sup.d1, R.sup.g1 and R.sup.h1 and/or R.sup.j1 and R.sup.k1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, or C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.4 independently represents halo, R.sup.a2, CN, -A.sup.a2-C(Q.sup.a2)R.sup.b2, -A.sup.b2-C(Q.sup.b2)N(R.sup.c2)R.sup.d2, -A.sup.c2-C(Q.sup.c2)OR.sup.e2, -A.sup.d2-S(O).sub.qR.sup.f2, -A.sup.e2-S(O).sub.qN(R.sup.g2)R.sup.h2, -A.sup.f2-S(O).sub.qOR.sup.i2, N.sub.3, N(R.sup.j2)R.sup.k2, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l2 or SR.sup.m2; each Q.sup.a2 to Q.sup.c2 independently represents O, S, NR.sup.n2 or N(OR.sup.o2); each A.sup.a2 to A.sup.f2 independently represents a single bond, N(R.sup.p2) or O; each R.sup.a2 and R.sup.f2 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; each R.sup.p2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b2, R.sup.e2, R.sup.d2, R.sup.e2, R.sup.g2, R.sup.h2, R.sup.i2, R.sup.j2, R.sup.k2, R.sup.l2, R.sup.m2, R.sup.n2 and R.sup.o2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; or any two R.sup.c2 and R.sup.d2, R.sup.g2 and R.sup.h2 and/or R.sup.j2 and R.sup.k2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C.sub.1-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, and O; each G.sup.1a, G.sup.1b, G.sup.2a and G.sup.2b independently represents halo, CN, N(R.sup.a3)R.sup.b3, OR.sup.c3, SR.sup.d3 or O; each R.sup.a3, R.sup.b3, R.sup.c3 and R.sup.d2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; or R.sup.a3 and R.sup.b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C.sub.1-3alkyl optionally substituted by one or more fluoro, C.sub.2-3alkenyl optionally substituted by one or more fluoro, C.sub.2-3alkynyl optionally substituted by one or more fluoro, and O; and each p and q independently represents 1 or 2, with the proviso that the compound of formula I is not a compound selected from the list consisting of compounds: (1) 6-methoxy-3-nitro-2-(phenylsulphonyl)pyridine; (2) 6-methoxy-3-nitro-2-tosylpyridine; (3) 5-methyl-3-nitro-2-(phenylsulphonyl)pyridine; (4) 3-nitro-2-tosylpyridine; (5) 2-((4-chlorophenyl)sulphonyl)-6-methoxy-3-nitropyridine; (6) 3-nitro-2-(phenylsulphonyl)pyridine; (7) 2-methyl-3,5-dinitro-6-(phenylsulphonyl)pyridine; and (8) N-(2-((5-chloro-3-nitropyridin-2-yl)sulphonyl)phenyl)acetamide.

2. A compound as claimed in claim 1, wherein each R.sup.4 independently represents halo, N(R.sup.j2)R.sup.k2, OR.sup.12, or R.sup.a2.

3. A compound as claimed in claim 1, wherein each R.sup.1, R.sup.2 and R.sup.3 each independently represents H, halo, R.sup.a1, N(R.sup.j1)R.sup.k1, OR.sup.l1 or SR.sup.m1.

4. A compound as claimed in claim 1, wherein each R.sup.a2 independently represents C.sub.1-6 alkyl optionally substituted by one or more fluoro, and each R.sup.j2, R.sup.k2 and R.sup.l2 independently represents H or C.sub.1-6 alkyl optionally substituted by one or more fluoro.

5. A compound as claimed in claim 1, wherein n represents 0 or 1.

6. A compound as claimed in claim 1, wherein n represents at least 1 and one R.sup.4 group is present in the 4-position.

7. A compound as claimed in claim 1, wherein each R.sup.4 independently represents halo or C.sub.1-6 alkyl optionally substituted by one or more fluoro.

8. A compound as claimed in claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, R.sup.a1, N(R.sup.j1)R.sup.k1 or OR.sup.l1.

9. A compound as claimed in claim 1, wherein each R.sup.a1, R.sup.j1, R.sup.k1, R.sup.l1 and R.sup.m1 independently represent C.sub.1-6 alkyl optionally substituted by one or more fluoro.

10. A compound as claimed in claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, N(R.sup.j1)R.sup.k1 or OR.sup.l1.

11. A compound as claimed in claim 1, wherein: R.sup.2 and R.sup.3 represent H; and/or R.sup.1 represents H, chloro, N(C.sub.1-6 alkyl)C.sub.1-6 alkyl or OC.sub.1-6 alkyl, wherein the latter two groups are optionally substituted by one or more fluoro.

12. A compound as claimed in claim 1, wherein: R.sup.2 and R.sup.3 represent H; and/or R.sup.1 represents H or OC.sub.1-6 alkyl optionally substituted by one or more fluoro.

13. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I ##STR00033## or a pharmaceutically acceptable salt thereof, wherein: L represents S(O).sub.2; n represents 0 to 5; R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, R.sup.a1, CN, -A.sup.a1-C(Q.sup.a1)R.sup.b1, -A.sup.b1-C(Q.sup.b1)N(R.sup.c1)R.sup.d1, -A.sup.d1-C(Q.sup.c1)OR.sup.e1, -A.sup.d1-S(O).sub.pR.sup.f1, -A.sup.c1-S(O).sub.pN(R.sup.g1)R.sup.h1, -A.sup.f1-S(O).sub.pOR.sub.i1, N.sub.3, N(R.sup.j1)R.sup.k1, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l1 or SR.sup.m1; each A.sup.a1 to A.sup.f1 independently represents a single bond, N(R.sup.p1) or O; each Q.sup.a1 to Q.sup.c1 independently represents O, S, NR.sup.n1 or N(OR.sup.o1); each R.sup.a1 and R.sup.f1 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; each R.sup.p1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.g1, R.sup.h1, R.sup.i1, R.sup.j1, R.sup.k1, R.sup.l1, R.sup.m1, R.sup.n1 and R.sup.o1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; or any of R.sup.c1 and R.sup.d1, R.sup.g1 and R.sup.h1 and/or R.sup.j1 and R.sup.k1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, or C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.4 independently represents halo, R.sup.a2, CN, -A.sup.a2-C(Q.sup.a2)R.sup.b2, -A.sup.b2-C(Q.sup.b2)N(R.sup.c2)R.sup.d2, -A.sup.c2-C(Q.sup.c2)OR.sup.e2, -A.sup.d2-S(O).sub.qR.sup.f2, -A.sup.e2-S(O).sub.qN(R.sup.g2)R.sup.h2, -A.sup.f2-S(O).sub.qOR.sup.i2, N.sub.3, N(R.sup.j2)R.sup.k2, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l2 or SR.sup.m2; each Q.sup.a2 to Q.sup.c2 independently represents O, S, NR.sup.n2 or N(OR.sup.o2); each A.sup.a2 to A.sup.f2 independently represents a single bond, N(R.sup.p2) or O; each R.sup.a2 and R.sup.f2 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; each R.sup.p2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b2, R.sup.c2, R.sup.d2, R.sup.e2, R.sup.g2, R.sup.h2, R.sup.i2, R.sup.j2, R.sup.k2, R.sup.l2, R.sup.m2, R.sup.n2 and R.sup.o2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; or any two R.sup.c2 and R.sup.d2, R.sup.g2 and R.sup.h2 and/or R.sup.j2 and R.sup.k2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C.sub.1-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, and O; each G.sup.1a, G.sup.1b, G.sup.2a and G.sup.2b independently represents halo, CN, N(R.sup.a3)R.sup.b3, OR.sup.c3, SR.sup.d3 or O; each R.sup.a3, R.sup.b3, R.sup.c3 and R.sup.d3 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; or R.sup.a3 and R.sup.b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C.sub.1-3alkyl optionally substituted by one or more fluoro, C.sub.2-3alkenyl optionally substituted by one or more fluoro, C.sub.2-3alkynyl optionally substituted by one or more fluoro, and O; and each p and q independently represents 1 or 2.

14. The method of claim 13, wherein the cancer is selected from the group consisting of: soft tissue cancers; gastrointestinal cancers; genitourinary tract cancers; liver cancers; bone cancers; cancers of the head and/or nervous system; gynecological cancers; haematologic cancers; skin cancers; neurofibromatosis and adrenal gland cancer.

15. The method of claim 13, wherein the cancer is a solid tumor cancer.

16. The method of claim 14, wherein the cancer is selected from the group consisting of: sarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, bronchogenic carcinoma, alveolar or bronchiolar carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, esophageal cancer, stomach cancer, pancreatic cancer, small bowel cancer, large bowel cancer, kidney cancer, bladder cancer, urethra cancer, prostate cancer, testis cancer, hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, giant cell tumor, malignant giant cell tumor, chordoma, osteochronfroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, skull cancer, meninges cancer, brain cancer, spinal cord cancer, neuroblastomas, uterus cancer, cervix cancer, ovary cancer, vulva cancer, vagina cancer, fallopian tube cancer, the blood and bone marrow cancer, lymphoma, malignant lymphoma, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

17. A pharmaceutical composition comprising a compound, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier, wherein the compound is of formula I ##STR00034## or a pharmaceutically acceptable salt thereof, wherein: L represents S(O).sub.2; n represents 0 to 5; R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, R.sup.a1, CN, A.sup.a1-C(Q.sup.a1)R.sup.b1, -A.sup.b1-C(Q.sup.b1)N(R.sup.c1)R.sup.d1, -A.sup.e1-C(Q.sup.e1)OR.sup.e1, -A.sup.d1-S(O).sub.pR.sup.f1, A.sup.e1-S(O).sub.pN(R.sup.g1)R.sup.h1, -A.sup.f1-S(O).sub.pOR.sup.i1, N.sub.3, N(R.sup.j1)R.sup.k1, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l1 or SR.sup.m1; each A.sup.a1 to A.sup.f1 independently represents a single bond, N(R.sup.p1) or O; each Q.sup.a1 to Q.sup.c1 independently represents O, S, NR.sup.n1 or N(OR.sup.o1); each R.sup.a1 and R.sup.f1 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; each R.sup.p1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.g1, R.sup.h1, R.sup.i1, R.sup.j1, R.sup.k1, R.sup.l1, R.sup.m1, R.sup.n1, and R.sup.o1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; or any of R.sup.c1 and R.sup.d1, R.sup.g1 and R.sup.h1 and/or R.sup.j1 and R.sup.k1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, or C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.4 independently represents halo, R.sup.a2, CN, -A.sup.a2-C(Q.sup.a2)R.sup.b2, -A.sup.b2-C(Q.sup.b2)N(R.sup.c2)R.sup.d2, -A.sup.c2-C(Q.sup.c2)OR.sup.c2, -A.sup.d2-S(O).sub.qR.sup.f2, -A.sup.e2-S(O).sub.qN(R.sup.g2)R.sup.h2, -A.sup.f2-S(O).sub.qOR.sup.i2, N.sub.3, N(R.sup.j2)R.sup.k2, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l2 or SR.sup.m2; each Q.sup.a2 to Q.sup.c2 independently represents O, S, NR.sup.n2 or N(OR.sup.o2); each A.sup.a2 to A.sup.f2 independently represents a single bond, N(R.sup.p2) or O; each R.sup.a2 and R.sup.f2 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; each R.sup.p2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b2, R.sup.c2, R.sup.d2, R.sup.e2, R.sup.g2, R.sup.h2, R.sup.i2, R.sup.j2, R.sup.k2, R.sup.l2, R.sup.m2, R.sup.n2 and R.sup.o2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; or any two R.sup.c2 and R.sup.d2, R.sup.g2 and R.sup.h2 and/or R.sup.j2 and R.sup.k2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C.sub.1-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, and O; each G.sup.1a, G.sup.1b, G.sup.2a and G.sup.2b independently represents halo, CN, N(R.sup.a3)R.sup.b3, OR.sup.c3, SR.sup.d3 or O; each R.sup.a3, R.sup.b3, R.sup.c3 and R.sup.d3 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; or R.sup.a3 and R.sup.b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C.sub.1-3alkyl optionally substituted by one or more fluoro, C.sub.2-3alkenyl optionally substituted by one or more fluoro, C.sub.2-3alkynyl optionally substituted by one or more fluoro, and O; and each p and q independently represents 1 or 2, with the proviso that the compound of formula I is not compound (1): 6-methoxy-3-nitro-2-(phenylsulphonyl)pyridine.

18. A combination product comprising: (A) a compound; and (B) one or more other therapeutic agent that is useful in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier, wherein the compound is of formula I ##STR00035## or a pharmaceutically acceptable salt thereof, wherein: L represents S(O).sub.2; n represents 0 to 5; R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, R.sup.a1, CN, -A.sup.a1-C(Q.sup.a1)R.sup.b1, -A.sup.b1-C(Q.sup.b1)N(R.sup.c1)R.sup.d1, -A.sup.c1-C(Q.sup.c1)OR.sup.e1, -A.sup.d1-S(O).sub.pR.sup.f1, -A.sup.c1-S(O).sub.pN(R.sup.g1)R.sup.h1, -A.sup.f1-S(O).sub.pOR.sup.i1, N.sub.3, N(R.sup.j1)R.sup.k1, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l1 or SR.sup.m1; each A.sup.a1 to A.sup.f1 independently represents a single bond, N(R.sup.p1) or O; each Q.sup.a1 to Q.sup.c1 independently represents O, S, NR.sup.n1 or N(OR.sup.o1); each R.sup.a1 and R.sup.f1 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; each R.sup.p1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.g1, R.sup.h1, R.sup.i1, R.sup.j1, R.sup.k1, R.sup.l1, R.sup.m1, R.sup.n1 and R.sup.o1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; or any of R.sup.c1 and R.sup.d1, R.sup.g1 and R.sup.h1 and/or R.sup.j1 and R.sup.k1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, or C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.4 independently represents halo, R.sup.a2, CN, -A.sup.a2-C(Q.sup.a2)R.sup.b2, -A.sup.b2-C(Q.sup.b2)N(R.sup.c2)R.sup.d2, -A.sup.c2-C(Q.sup.c2)OR.sup.e2, -A.sup.d2-S(O).sub.qR.sup.f2, -A.sup.e2-S(O).sub.qN(R.sup.g2)R.sup.h2, -A.sup.f2-S(O).sub.qOR.sup.12, N.sub.3, N(R.sup.j2)R.sup.k2, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l2 or SR.sup.m2; each Q.sup.a2 to Q.sup.c2 independently represents O, S, NR.sup.n2 or N(OR.sup.o2); each A.sup.a2 to A.sup.f2 independently represents a single bond, N(R.sup.p2) or O; each R.sup.a2 and R.sup.f2 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; each R.sup.p2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b2, R.sup.c2, R.sup.d2, R.sup.e2, R.sup.g2, R.sup.h2, R.sup.i2, R.sup.j2, R.sup.k2, R.sup.l2, R.sup.m2, R.sup.n2 and R.sup.o2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; or any two R.sup.c2 and R.sup.d2, R.sup.g2 and R.sup.h2 and/or R.sup.j2 and R.sup.k2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C.sub.1-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, and O; each G.sup.1a, G.sup.1b, G.sup.2a and G.sup.2b independently represents halo, CN, N(R.sup.a3)R.sup.b3, OR.sup.c3, SR.sup.d3 or O; each R.sup.a3, R.sup.b3, R.sup.c3 and R.sup.d3 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; or R.sup.a3 and R.sup.b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C.sub.1-3alkyl optionally substituted by one or more fluoro, C.sub.2-3alkenyl optionally substituted by one or more fluoro, C.sub.2-3alkynyl optionally substituted by one or more fluoro, and O; and each p and q independently represents 1 or 2.

19. A kit-of-parts comprising: (a) a pharmaceutical formulation comprising a compound, and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier; and (b) one or more other therapeutic agent that is useful in the treatment of cancer, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, wherein the compound is of formula I ##STR00036## or a pharmaceutically acceptable salt thereof, wherein: L represents S(O).sub.2; n represents 0 to 5; R.sup.1, R.sup.2 and R.sup.3 each independently represent H, halo, R.sup.a1, CN, -A.sup.a1-C(Q.sup.a1)R.sup.b1, -A.sup.b1-C(Q.sup.b1)N(R.sup.c1)R.sup.d1, -A.sup.c1-C(Q.sup.c1)OR.sup.e1, -A.sup.d1-S(O).sub.pR.sup.f1, -A.sup.e1-S(O).sub.pN(R.sup.g1)R.sup.h1, -A.sup.f1-S(O).sub.pOR.sup.i1, N.sub.3, N(R.sup.j1)R.sup.k1, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.l1 or SR.sup.m1; each A.sup.a1 to A.sup.f1 independently represents a single bond, N(R.sup.p1) or O; each Q.sup.a1 to Q.sup.c1 independently represents O, S, NR.sup.n1 or N(OR.sup.o1); each R.sup.a1 and R.sup.f1 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; each R.sup.p1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.g1, R.sup.h1, R.sup.i1, R.sup.j1, R.sup.k1, R.sup.l1, R.sup.m1, R.sup.n1 and R.sup.o1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b; or any of R.sup.1 and R.sup.d1, R.sup.g1 and R.sup.h1 and/or R.sup.j1 and R.sup.k1 are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, or C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.4 independently represents halo, R.sup.a2, CN, -A.sup.a2-C(Q.sup.a2)R.sup.b2, -A.sup.b2-C(Q.sup.b2)N(R.sup.c2)R.sup.d2, -A.sup.c2-C(Q.sup.c2)OR.sup.e2, -A.sup.d2-S(O).sub.qR.sup.f2, -A.sup.e2-S(O).sub.qN(R.sup.g2)R.sup.h2, -A.sup.f2-S(O).sub.qOR.sup.i2, N.sub.3, N(R.sup.j2)R.sup.k2, N(H)CN, NO.sub.2, ONO.sub.2, OR.sup.12 or SR.sup.m2, each Q.sup.a2 to Q.sup.c2 independently represents O, S, NR.sup.n2 or N(OR.sup.o2); each A.sup.a2 to A.sup.f2 independently represents a single bond, N(R.sup.p2) or O; each R.sup.a2 and R.sup.f2 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; each R.sup.p2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; each R.sup.b2, R.sup.c2, R.sup.d2, R.sup.e2, R.sup.g2, R.sup.h2, R.sup.i2, R.sup.j2, R.sup.k2, R.sup.l2, R.sup.m2, R.sup.n2 and R.sup.o2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b; or any two R.sup.c2 and R.sup.d2, R.sup.g2 and R.sup.h2 and/or R.sup.j2 and R.sup.k2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halogen, C.sub.1-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, C.sub.2-3alkyl optionally substituted by one or more halogens, and O; each G.sup.1a, G.sup.1b, G.sup.2a and G.sup.2b independently represents halo, CN, N(R.sup.a3)R.sup.b3, OR.sup.c3, SR.sup.d3 or O; each R.sup.a3, R.sup.b3, R.sup.c3 and R.sup.d3 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more fluoro, C.sub.2-6 alkenyl optionally substituted by one or more fluoro, or C.sub.2-6 alkynyl optionally substituted by one or more fluoro; or R.sup.a3 and R.sup.b3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from fluoro, C.sub.1-3alkyl optionally substituted by one or more fluoro, C.sub.2-3alkenyl optionally substituted by one or more fluoro, C.sub.2-3alkynyl optionally substituted by one or more fluoro, and O; and each p and q independently represents 1 or 2.

20. A process for the preparation of a compound as defined in claim 1, which process comprises: (i) reaction of a compound of formula IIA ##STR00037## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1 and LG.sup.1 represents a suitable leaving group, with a compound of formula IIA ##STR00038## wherein R.sup.4 and n are as defined in claim 1 and M represents an alkali metal ion, in the presence of a suitable acid and in the presence of a suitable solvent, and optionally in the presence of a suitable phase transfer catalyst; (ii) reaction of a compound of formula IIB ##STR00039## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined are as defined in claim 1 and M represents an alkali metal ion, with a compound of formula IIIB ##STR00040## wherein R.sup.4 and n are as defined are as defined in claim 1 and LG.sup.1 represents a suitable leaving group, in the presence of a suitable acid and in the presence of a suitable solvent, and optionally in the presence of a suitable phase transfer catalyst; (iii) reaction of a compound of formula IIA with a compound of formula IIIA, in the presence of a suitable metal halide and in the presence of a suitable solvent; (iv) reaction of a compound of formula IIB with a compound of formula IIIB, in the presence of a suitable metal halide and in the presence of a suitable solvent; or (v) reaction of a compound of formula IV ##STR00041## wherein R.sup.1 to R.sup.4 and n are as defined in claim 1, with a suitable oxidising agent in the presence of a suitable solvent; (vi) reaction of a compound of formula V ##STR00042## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1 and LG.sup.3 represents a suitable leaving group with a compound of formula VI ##STR00043## wherein R.sup.4 and n are as defined in claim 1, in the presence of a suitable Lewis acid and in the presence of a suitable solvent; (vii) reaction of a compound of formula V with a compound of formula VI, in the presence of a suitable catalyst and a suitable base, and in the presence of a suitable solvent; (viii) reaction of a compound of formula V with a compound of formula VII ##STR00044## wherein R.sup.4 and n are as defined in claim 1 and LG.sup.4 represents a suitable leaving group, in the presence of a suitable catalyst and in the presence of a suitable solvent; (ix) reaction of a compound of formula IIB as defined in Step (ii) above with (a) a compound of formula VI having at least one R.sup.4 group, or (b) a compound of formula VI but having a group that may be converted to an R.sup.4 group, wherein the R.sup.4 group or group that may be converted to an R.sup.4 group is present ortho to the essential H substituent and represents a suitable directing group, in the presence of a suitable catalyst and/or oxidant, and in the presence of a suitable solvent, which step may further comprise conversion of the group that may be converted to an R.sup.4 group to the required R.sup.4 group.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows results obtained from the experiment described in Biological Example 1 for the compound of Example 1.

(2) FIG. 2 shows results obtained from the experiment described in Biological Example 2 (using the compound of Example 1).

(3) FIG. 3 shows results obtained from the experiment described in Biological Example 3 (using the compound of Example 1).

EXAMPLES

(4) The invention is illustrated by way of the following examples, in which the following abbreviations may be employed.

(5) aq aqueous

(6) BSA bovine serum albumin

(7) conc concentrated

(8) DMA N,N-dimethylacetamide

(9) DMF N,N-dimethylformamide

(10) DMSO dimethyl sulphoxide

(11) DTNB 5,5-dithio-bis-(2-nitrobenzoic acid)

(12) EDTA ethylenediaminetetraacetic acid

(13) GSSG glutathione disulfide

(14) HPLC high performance liquid chromatography

(15) HRMS high resolution mass spectrometry

(16) mCPBA meta-chloroperbenzoic acid

(17) NADPH nicotinamide adenine dinucleotide phosphate

(18) NMR nuclear magnetic resonance

(19) PBS phosphate buffered saline

(20) rt room temperature

(21) Starting materials and chemical reagents specified in the syntheses described below are commercially available from a number of suppliers, such as Sigma Aldrich.

(22) In the event that there is a discrepancy between nomenclature and the structure of compounds as depicted graphically, it is the latter that presides (unless contradicted by any experimental details that may be given and/or unless it is clear from the context).

(23) Final compounds are named using ChemBioDraw Ultra 14.

Example 1: 2-((4-Chlorophenyl)sulphonyl)-6-methoxy-3-nitropyridine Hydrochloride

(24) ##STR00014##

(25) Concentrated aq HCl (0.03 mL, 1.06 mmol) was added via a syringe to a mixture of 2-chloro-6-methoxy-3-nitropyridine (0.20 g, 1.06 mmol), sodium 4-chlorobenzenesulphinate (0.32 g, 1.60 mmol), tetra-N-butylammonium chloride (0.09 g, 0.32 mmol) and DMA (3 mL) at rt. The mixture was stirred at 100 C. for 24 h. Water (8 mL) was added in one portion to the hot mixture which was allowed to cool to rt. The precipitate was collected, washed with water and dried to give the title compound (0.16 g, 40%).

(26) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.48 (d, J=8.90 Hz, 1H), 8.14-7.89 (m, 2H), 7.86-7.64 (m, 2H), 7.28 (d, J=8.89 Hz, 1H), 3.62 (s, 3H);

(27) .sup.13C NMR (151 MHz, DMSO d.sub.6) 55.40, 116.50, 129.97, 131.73, 136.67, 137.93, 139.42, 140.36, 148.29, and 163.77;

(28) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.12H.sub.10ClN.sub.2O.sub.5S, 328.9993) found, 328.9988.

Example 2: 3-Nitro-2-(phenylsulphonyl)pyridine Trifluoroacetate

(29) ##STR00015##

(30) The title compound was prepared in accordance with the procedure in Example 1 from 2-chloro-3-nitropyridine and sodium benzenesulphinate. The compound did not precipitate and instead was purified by HPLC using trifluoroacetic acid as part of the mobile phase.

(31) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.88-8.83 (m, 1H), 8.61-8.55 (m, 1H), 8.00-7.90 (m, 3H), 7.84-7.74 (m, 1H), and 7.72-7.58 (m, 2H);

(32) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.11H.sub.9N.sub.2O.sub.4S 265.0278) found, 265.0286.

Example 3: 3-Nitro-2-tosylpyridine Hydrochloride

(33) ##STR00016##

(34) The title compound was prepared in accordance with the procedure in Example 1 from 2-chloro-3-nitropyridine and sodium p-toluenesulphinate.

(35) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.84 (dd, J=1.38, and 4.69 Hz, 1H), 8.56 (dd, J=1.40, and 8.18 Hz, 1H), 7.93 (dd, J=4.67, and 8.19 Hz, 1H), 7.88-7.79 (m, 2H), 7.51-7.43 (m, 1H), and 2.40 (d, J=0.73 Hz, 3H);

(36) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.12H.sub.11N.sub.2O.sub.4S 279.0434) found, 279.0435.

Example 4: 6-Methoxy-3-nitro-2-(phenylsulphonyl)pyridine Trifluoroacetate

(37) ##STR00017##

(38) The title compound was prepared in accordance with the procedure in Example 1 from 2-chloro-6-methoxy-3-nitropyridine and sodium benzenesulphinate. The compound did not precipitate and instead was purified by HPLC using trifluoroacetic acid as part of the mobile phase.

(39) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.45 (d, J=8.90 Hz, 1H), 8.00-7.95 (m, 2H), 7.83-7.76 (m, 1H), 7.74-7.63 (m, 2H), 7.25 (d, J=8.88 Hz, 1H), and 3.58 (s, 3H);

(40) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.12H.sub.11N.sub.2O.sub.5S 295.0383) found, 295.0376.

Example 5: 2-((4-Chlorophenyl)sulphonyl)-3-nitropyridine Trifluoroacetate

(41) ##STR00018##

(42) The title compound was prepared in accordance with the procedure in Example 1 from 2-chloro-3-nitropyridine and sodium 4-chlorobenzenesulphinate. The compound did not precipitate and instead was purified by HPLC using trifluoroacetic acid as part of the mobile phase.

(43) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.94-8.77 (m, 1H), 8.67-8.48 (m, 1H), 8.07-7.87 (m, 3H), and 7.83-7.68 (m, 2H);

(44) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.11H.sub.8ClN.sub.2O.sub.4S 298.9888) found, 298.9888.

Example 6: 6-Methoxy-3-nitro-2-tosylpyridine

(45) ##STR00019##

(a) 6-Methoxy-3-nitro-2-(p-tolylthio)pyridine

(46) A mixture of 2-chloro-6-methoxy-3-nitropyridine (0.25 g, 1.33 mmol), 4-methylthiophenol (0.16 g, 1.33 mmol), K.sub.2CO.sub.3 (0.22 g, 1.62 mmol) and DMF (1 mL) was stirred at rt for 0.5 h. The mixture was poured into water and filtered to give the sub-title compound (0.36 g, 98%).

(b) 6-Methoxy-3-nitro-2-tosylpyridine

(47) NaOCl (aq, 10%, 1.71 mL, 2.86 mmol) was added dropwise to a stirred mixture of 6-methoxy-3-nitro-2-(p-tolylthio)pyridine (0.36 g, 1.30 mmol), glacial acetic acid (0.10 mL, 1.67 mmol) and DMF (2 mL) at 40 C. The mixture was stirred at 40 C. for 12 h and poured into water. The pH was adjusted to 9 with aq NaOH (20% (w/v). After stirring for 30 min the precipitate was collected and washed with water. The solid was recrystallized from H.sub.2O/EtOH (3:2) to give the title compound (0.19 g, 48%).

(48) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07-8.04 (1H, m), 7.97-7.94 (2H, m), 7.40-7.36 (2H, m), 6.94-6.90 (1H, m), 3.72 (3H, s), 2.46 (3H, s);

(49) .sup.13C NMR (100 MHz, CDCl.sub.3) 163.8, 150.2, 145.6, 136.2, 135.2, 130.1, 130.0, 129.7, 115.1, 55.2, 21.9; ESI-MS: 309 [M+H].sup.+.

Example 7: 6-Methoxy-2-((4-methoxyphenyl)sulfonyl)-3-nitropyridine

(50) ##STR00020##

(51) The title compound was prepared in accordance with the procedure in Example 6 from 2-chloro-6-methoxy-3-nitropyridine and 4-methoxythiophenol. The compound did not precipitate and was purified by reverse phase chromatography.

(52) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.05-8.02 (1H, m), 8.02-7.99 (2H, m), 7.06-7.02 (2H, m), 6.93-6.90 (1H, m), 3.89 (3H, s), 3.75 (3H, s);

(53) .sup.13C NMR (100 MHz, CDCl.sub.3) 164.5, 163.8, 150.4, 136.1, 132.3, 129.3, 115.0, 114.3, 55.9, 55.2; ESI-MS: 325 [M+H].sup.+.

Example 8: 6-Chloro-2-((4-chlorophenyl)sulfonyl)-3-nitropyridine

(54) ##STR00021##

(a) 6-Chloro-5-nitropyridin-2-amine

(55) ##STR00022##

(56) Conc. HNO.sub.3 (2.39 mL, 35.00 mmol) was added dropwise to a mixture of conc H.sub.2SO.sub.4 (56 mL, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34 mmol) at 0 C. The mixture was stirred at 0 C. for 4 h and poured into ice-water. The mixture was extracted with EtOAc (3100 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.38 g, 34%).

(b) 6-((4-Chlorophenyl)thio)-5-nitropyridin-2-amine

(57) ##STR00023##

(58) A mixture of 6-chloro-5-nitropyridin-2-amine (0.18 g, 1.06 mmol), 4-chlorothiophenol (0.17 g, 1.17 mmol), K.sub.2CO.sub.3 (0.18 g, 1.29 mmol) and DMF (1.5 mL) was stirred at rt for 3.5 h. The mixture was poured into water and extracted with CH.sub.2OCl.sub.2 (315 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was dissolved in CH.sub.2OCl.sub.2, and the product was precipitated by addition of hexane to give the sub-title compound (0.25 g, 82%).

(59) ##STR00024##

(60) Isoamylnitrite (0.19 mL, 1.44 mmol) was added to a stirred mixture of 6-((4-chlorophenyl)thio)-5-nitropyridin-2-amine (0.20 g, 0.72 mmol), CuCl.sub.2 (0.19 g, 1.44 mmol) and MeCN (5 mL) at rt. The mixture was stirred at 60 C. for 2.5 h, poured into water and extracted with EtOAc (315 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (0.08 g, 38%).

(d) 6-Chloro-2-((4-chlorophenyl)sulfonyl)-3-nitropyridine

(61) mCPBA (0.15 g, 0.61 mmol) was added in portions to a stirred mixture of 6-chloro-2-((4-chlorophenyl)thio)-3-nitropyridine (0.08 g, 0.28 mmol) and CH.sub.2Cl.sub.2 (7 mL) at 0 C. The mixture was stirred at 0 C. for 12 h and poured into water. The phases were separated and the aq layer extracted with CH.sub.2Cl.sub.2. The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude mixture was purified by chromatography to give the title compound (0.07 g, 71%).

(62) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.69-8.67 (m, 1H), 8.14-8.12 (m, 1H), 8.06-7.92 (m, 2H), 7.89-7.73 (m, 2H);

(63) .sup.13C NMR (100 MHz, DMSO-d.sub.6) 151.8, 148.2, 144.1, 140.5, 137.5, 135.6, 131.1, 130.8, 129.9;

(64) ESI-MS: 333 and 335[M+H]+.

Example 9: 6-Chloro-2-((4-methoxyphenyl)sulfonyl)-3-nitropyridine

(65) ##STR00025##

(66) The title compound was prepared according to the procedure in Example 8, Steps (a) to (d) from 6-chloropyridin-2-amine and 4-methoxythiophenol.

(67) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.63 (d, J=8.5 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.96-7.86 (m, 2H), 7.29-7.19 (m, 2H), 3.88 (s, 3H);

(68) .sup.13C NMR (100 MHz, DMSO-d.sub.6) 164.5, 151.6, 148.8, 144.0, 137.2, 131.7, 130.4, 127.7, 115.1, 56.0;

(69) ESI-MS: 329 and 331 [M+H].sup.+.

Example 10: 6-Chloro-3-nitro-2-(phenylsulfonyl)pyridine

(70) ##STR00026##

(71) The title compound was prepared according to the procedure in Example 8, Steps (a) to (d) from 6-chloropyridin-2-amine and thiophenol.

(72) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12-8.11 (m, 1H), 8.10-8.09 (m, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.74-7.70 (m, 1H), 7.64-7.58 (m, 3H);

(73) .sup.13C NMR (100 MHz, CDCl.sub.3) 153.2, 150.8, 137.3, 135.4, 135.0, 130.0, 129.4, 129.0;

(74) ESI-MS: 299 [M+H].sup.+.

Example 11: 6-Chloro-3-nitro-2-tosylpyridine

(75) ##STR00027##

(76) The title compound was prepared according to the procedure in Example 8, Steps (a) to (d) from 6-chloropyridin-2-amine and 4-methylthiophenol.

(77) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00-7.97 (m, 3H), 7.61 (d, J=8.4 Hz, 1H), 7.42-7.38 (m, 2H), 2.47 (s, 3H);

(78) .sup.13C NMR (100 MHz, CDCl.sub.3) 153.2, 151.0, 146.4, 144.3, 135.3, 134.2, 130.3, 130.1, 128.9, 22.0;

(79) ESI-MS: 313 [M+H].sup.+.

Example 12: 6-((4-Methoxyphenyl)sulfonyl)-N,N-dimethyl-5-nitropyridin-2-amine

(80) ##STR00028##

(a) 6-Chloro-N,N-dimethylpyridin-2-amine

(81) A mixture of 2,6-dichloropyridine (2.20 g, 14.9 mmol) and DMF (11.5 mL, 148.7 mmol) was heated under microwave irradiation at 180 C. for 1 h. The mixture was poured into water and extracted with EtOAc (330 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (2.12 g, 91%).

(b) 6-Chloro-N,N-dimethyl-5-nitropyridin-2-amine

(82) Conc HNO.sub.3 (0.9 mL, 13.52 mmol) was added dropwise to a mixture of conc H.sub.2SO.sub.4 (32.4 mL, 608.6 mmol) and 6-chloro-N,N-dimethylpyridin-2-amine (2.12 g, 13.5 mmol) at 0 C. The mixture was stirred at 0 C. for 1.5 h and poured into ice-water. The mixture was extracted with CH.sub.2Cl.sub.2 (3100 mL). The combined organic layers were washed with saturated aq Na.sub.2CO.sub.3, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by chromatography to give the sub-title compound (0.89 g, 33%).

(83) A mixture of 6-chloro-N,N-dimethyl-5-nitropyridin-2-amine (0.20 g, 1.00 mmol), 4-methoxythiophenol (0.13 mL, 1.09 mmol), K.sub.2CO.sub.3 (0.17 g, 1.21 mmol) and DMF (1 mL) was stirred at 80 C. for 1 h. The mixture was poured into water, the precipitate was collected, washed with water and dried to give the sub-title compound (0.30 g, 97%).

(d) 6-((4-Methoxyphenyl)sulfonyl)-N,N-dimethyl-5-nitropyridin-2-amine

(84) mCPBA (0.26 g, 1.07 mmol) was added in portions to a stirred mixture of 6-((4-methoxy-phenyl)thio)-N,N-dimethyl-5-nitropyridin-2-amine (0.15 g, 0.48 mmol) and CH.sub.2Cl.sub.2 (8 mL) at 0 C. The mixture was stirred at rt for 5 h and poured into water. The phases were separated and the aq layer extracted with CH.sub.2Cl.sub.2. The combined organic phases were washed with saturated aq Na.sub.2S.sub.2O.sub.5 and NaHSO.sub.3 mixture, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was recrystallized from H.sub.2O/EtOH (9:1) to give the title compound (0.11 g, 69%).

(85) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11-8.07 (1H, m), 7.95-7.90 (2H, m), 7.04-6.99 (2H, m), 6.50-6.46 (1H, m), 3.88 (3H, s), 2.89 (6H, br s);

(86) .sup.13C NMR (100 MHz, CDCl.sub.3) 163.9, 157.7, 153.3, 135.8, 132.3, 130.3, 113.9, 106.8, 55.9, 38.2;

(87) ESI-MS: 338 [M+H].sup.+.

Example 13: 6-((4-Chlorophenyl)sulfonyl)-N,N-dimethyl-5-nitropyridin-2-amine XXX

(88) ##STR00029##

(89) The title compound was prepared according to the procedure in Example 12, Steps (c) to (d) from 6-chloro-N,N-dimethyl-5-nitropyridin-2-amine and 4-chlorothiophenol.

(90) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.18-8.14 (1H, m), 7.97-7.92 (2H, m), 7.55-7.51 (2H, m), 6.53-6.49 (1H, m), 2.87 (6H, br s);

(91) .sup.13C NMR (100 MHz, CDCl.sub.3) 157.7, 152.9, 140.3, 137.8, 136.0, 131.5, 131.5, 128.9, 107.1, 38.2;

(92) ESI-MS: 342 [M+H].sup.+.

Example 14: N,N-dimethyl-5-nitro-6-(phenylsulfonyl)pyridin-2-amine

(93) ##STR00030##

(94) The title compound was prepared according to the procedure in Example 12, Steps (c) to (d) from 6-chloro-N,N-dimethyl-5-nitropyridin-2-amine and thiophenol.

(95) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.15 (1H, d, J=9.2 Hz), 8.02-7.98 (2H, m), 7.66-7.61 (1H, m), 7.58-7.52 (2H, m), 6.49 (1H, d, J=9.3 Hz), 2.81 (6H, br s);

(96) .sup.13C NMR (100 MHz, CDCl.sub.3) 157.7, 153.2, 139.1, 135.9, 133.5, 130.0, 130.0, 128.7, 106.9, 38.1;

(97) ESI-MS: 308 [M+H].sup.+.

Example 15: N,N-dimethyl-5-nitro-6-tosylpyridin-2-amine

(98) ##STR00031##

(99) The title compound was prepared according to the procedure in Example 12, Steps (c) to (d) from 6-chloro-N,N-dimethyl-5-nitropyridin-2-amine and 4-methylthiophenol.

(100) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.10 (1H, d, J=9.3 Hz), 7.90-7.95 (2H, m), 7.36-7.32 (2H, m), 6.48 (1H, d, J=9.3 Hz), 2.85 (6H, br s), 2.44 (3H, s);

(101) .sup.13C NMR (100 MHz, CDCl.sub.3) 157.7, 153.2, 144.6, 136.0, 135.8, 130.1, 129.3, 106.8, 38.1, 21.8;

(102) ESI-MS: 322 [M+H].sup.+.

Biological Examples

Biological Example 1: Inhibition of Recombinant TrxR1 and GR

(103) Small molecule inhibition of recombinant thioredoxin reductase 1 (TrxR1) and gluthathione reductase (GR) was examined in 96-well plate format. 15 nM TrxR1 was incubated in the presence of 250 M NADPH, 0.1 mg/ml BSA, and various concentrations of the compound of Example 1 (1% DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA buffer for 15 minutes. Following the incubation period, 2.5 mM DTNB was added to each well and the change in O.D. at 412 nm was followed. Percent activity was determined using DMSO vehicle and no TrxR1 (blank) controls. 2 nM GR was incubated in the presence of 250 M NADPH, 0.1 mg/ml BSA, and various concentrations of compounds (1% DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA buffer for 15 minutes. Following the incubation period, 1 mM GSSG was added to each well and the change in O.D. at 340 nm was followed. Percent activity was determined using DMSO vehicle and no GR (blank) controls.

(104) Using the assays described in Biological Example 1, the following IC.sub.50 values were obtained. Results obtained for the compound of Example 1 are also represented in FIG. 1.

(105) TABLE-US-00001 TrxR inhibition GR inhibition Example (nM) (M) 1 12 >100 2 155 >100 3 282 >100 4 24 25.2 5 98 47.9

Biological Example 2: Cell Culture

(106) Cell lines were plated 2000 cells/well in 96-well black optical plates in the presence of 10% FBS media containing 25 nM selenite. The following day cells were treated with various concentrations of the compound of Example 1 (0.1% DMSO final) and incubated for 72 hrs. After the incubation Cell-Quanti Blue reagent was added to each well and incubated for additional 3 hrs. Fluorescence was read ex:530 nm/em:590 nm, and percent of viability was determined using DMSO vehicle and no cell (blank) controls.

(107) Various results obtained are shown in FIG. 2 herein, wherein data for the following cell lines is presented.

(108) TABLE-US-00002 Cell line Cell type FaDu pharyngeal squamous cell carcinoma HCT116 colorectal carcinoma HCT116 p53 colorectal carcinoma HCT116 ++ BLC2 colorectal carcinoma A431 epidermoid (skin) carcinoma KPC-Luc pancreatic ductal carcinoma MDA-MB-231 metastatic mammary adenocarcinoma A549 lung carcinoma THP-1 acute monocytic leukemia

(109) Further results obtained in similar experiments were as indicated below (GI50 refers to concentration of compound yielding 50% growth inhibition; E denotes an exponent to the base 10).

(110) TABLE-US-00003 Panel/Cell Line GI50 (M) Leukemia CCRF-CEM 2.93E6 HL-60(TB) 6.81E6 K-562 3.02E6 MOLT-4 3.59E6 RPMI-8226 3.38E6 SR 2.99E6 Non-Small Cell Lung Cancer A549/ATCC 1.85E5 HOP-62 1.66E5 HOP-92 2.00E6 NCI-H226 1.02E5 NCI-H23 4.58E6 NCI-H322M 2.04E5 NCI-H460 1.46E5 NCI-H522 1.86E6 Colon Cancer COLO 205 1.96E6 HCC-2998 8.38E6 HCT-116 2.90E6 HCT-15 2.05E6 HT29 3.34E6 KM12 1.40E5 SW-620 2.06E6 CNS Cancer SF-268 4.57E6 SF-295 1.31E5 SF-539 3.39E6 SNB-19 1.30E5 SNB-75 1.10E5 U251 8.69E6 Melanoma LOX IMVI 1.98E6 MALME-3M 2.00E6 M14 3.05E6 MDA-MB-435 1.75E6 SK-MEL-2 1.14E5 SK-MEL-28 3.57E6 SK-MEL-5 1.20E5 UACC-257 1.13E5 UACC-62 3.56E6 Ovarian Cancer IGROV1 1.22E5 OVCAR-3 2.33E6 OVCAR-4 2.32E6 OVCAR-5 3.13E6 OVCAR-8 3.67E6 NCI/ADR-RES 4.93E6 SK-OV-3 1.51E5 Renal Cancer 786-0 2.51E6 ACHN 2.08E6 CAKI-1 1.61E6 RXF 393 4.45E6 SN12C 3.82E6 TK-10 3.57E6 UO-31 2.97E6 Prostate Cancer PC-3 1.73E5 DU-145 9.63E6 Breast Cancer MCF7 2.24E6 MDA-MB-231/ATCC 2.83E6 HS 578T 1.30E5 BT-549 2.75E6 T-47D 2.12E6 MDA-MB-468 1.93E6

Biological Example 3: Mouse Model

(111) Fox Chase male severe combined immunodeficiency (SCID, Charles River, #250) mice were inoculated with 110.sup.6 FaDu cells in PBS at a pre-shaved region located at the anterior lateral thoracic wall. After 13 days of growth, tumors were caliper measured and treatments were initiated. Mice were injected with 10 mg/kg of the compound of Example 1, or vehicle a total of nine times in a five-day span via iv. tail injection. Upon the final dose, injections were performed subcutaneously (s.c.) due to pronounced hematomas at the tail injection site. Mouse health status was monitored daily, weight was measured, and tumor volume was recorded from caliper measurements. The mice displayed no overt signs of general or systemic toxic effects in normal cells or tissues. Tumor growth was normalized to day 0 caliper measurements, and treatment with the compound of Example 1 (N=6, p<0.01) was compared to vehicle (N=4) using a repeated measures ANOVA with a Dunnett's multiple comparison post test.

(112) The results obtained are provided in FIG. 3 herein.

Biological Example 4: Inhibition of Recombinant TrxR1 and GR, and Cell Culture Assay

(113) Using the assays described in Biological Example 1 to assess inhibition of recombinant TrxR1 and GR, the following IC.sub.50 values were obtained for the examples described herein. Further, following the protocol described in Biological Example 2, the following IC.sub.50 values were obtained for inhibition of cell viability using the FaDu cell line.

(114) TABLE-US-00004 Cell viability TrxR inhibition GR inhibition inhibition in Example (nM) (M) FaDu cell line (M) 1 21 >100 2.99 2 289 >100 1.42 3 221 >100 2.55 4 24 30.82 3.26 5 151 93.05 1.84 6 103 >100 1.38 7 228 >100 2.75 8 16 3.57 0.84 9 70 41.65 0.51 10 56 14.46 0.25 11 40 23.68 0.39 12 513 >100 7.89 13 176 >100 12.90 14 345 >100 5.32 15 438 >100 5.91

Pyridines and their use in the treatment of cancer

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Cpc classification

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A61P35/02

HUMAN NECESSITIES

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A61K45/06

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C07D213/71

CHEMISTRY; METALLURGY

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A61P35/00

HUMAN NECESSITIES

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A61P43/00

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International classification

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C07D213/71

CHEMISTRY; METALLURGY

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A61K45/06

HUMAN NECESSITIES

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A61P35/00

HUMAN NECESSITIES

Abstract

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