WO2005065074A2 - La protection de tissus et de cellules contre les effets cytotoxique d'un rayonnement ionisant par des inhibiteurs abl - Google Patents

La protection de tissus et de cellules contre les effets cytotoxique d'un rayonnement ionisant par des inhibiteurs abl Download PDF

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WO2005065074A2
WO2005065074A2 PCT/US2004/028654 US2004028654W WO2005065074A2 WO 2005065074 A2 WO2005065074 A2 WO 2005065074A2 US 2004028654 W US2004028654 W US 2004028654W WO 2005065074 A2 WO2005065074 A2 WO 2005065074A2
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group
substituted
hydrocarbyl
methyl
alkyl
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PCT/US2004/028654
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WO2005065074A3 (fr
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E Premkumar Reddy
M. V. Ramana Reddy
Stephen C. Cosenza
Kiranmai Gumireddy
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Temple University Of The Commonwealth System Of Higher Education
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • the invention relates to the field of protecting normal cells and tissues from anticipated, planned or inadvertent exposure to ionizing radiation.
  • the invention relates to radioprotective agents administered to an individual prior to or after exposure to ionizing radiation, such as occurs during anticancer radiotherapy.
  • Ionizing radiation has an adverse effect on cells and tissues, primarily through cytotoxic effects. In humans, exposure to ionizing radiation occurs primarily through therapeutic techniques (such as anticancer radiotherapy) or through occupational and environmental exposure.
  • a major source of exposure to ionizing radiation is the administration of therapeutic radiation in the treatment of cancer or other proliferative disorders.
  • Individuals exposed to therapeutic doses of ionizing radiation typically receive between 0.1 and 2 Gy per treatment, and can receive as high as 5 Gy per treatment.
  • Therapeutic radiation is generally applied to a defined area of the individual's body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue.
  • normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of ionizing radiation throughout the course of treatment.
  • treatments that require exposure ofthe individual's entire body to the radiation, in a procedure called “total body irradiation", or "TBI.”
  • TBI total body irradiation
  • the efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors. Numerous methods have been designed to reduce normal tissue damage while still delivering effective therapeutic doses of ionizing radiation.
  • the autologous hematopoietic stem cells are returned to their body. However, if tumor cells have metastasized away from the tumor's primary site, there is a high probability that some tumor cells will contaminate the harvested hematopoietic cell population.
  • the harvested hematopoietic cell population may also contain neoplastic cells if the individual suffers from cancers ofthe bone marrow such as the various French- American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia (ALL).
  • FAB French- American-British
  • the metastasized tumor cells or resident neoplastic cells must be removed or killed prior to reintroducing the stem cells to the individual. If any living tumorigenic or neoplastic cells are re-introduced into the individual, they can lead to a relapse.
  • Prior art methods of removing tumorigenic or neoplastic cells from harvested bone marrow are based on a whole-population tumor cell separation or killing strategy, which typically does not kill or remove all of the contaminating malignant cells. Such methods include leukopheresis of mobilized peripheral blood cells, immunoaffinity-based selection or killing of tumor cells, or the use of cytotoxic or photosensitizing agents to selectively kill tumor cells.
  • the malignant cell burden may still be at 1 to 10 tumor cells for every 100,000 cells present in the initial harvest (Lazarus et al, J. Hematotherapy, 2(4):457-66, 1993).
  • a purging method designed to selectively destroy the malignant cells present in the bone marrow, while preserving the normal hematopoietic stem cells needed for hematopoietic reconstitution in the transplantation subject.
  • Exposure to ionizing radiation can also occur in the occupational setting. Occupational doses of ionizing radiation may be received by persons whose job involves exposure (or potential exposure) to radiation, for example in the nuclear power and nuclear weapons industries. There are currently 104 nuclear power plants licensed for commercial operation in the United States.
  • a radiation count of 0.84 mSv/hour (4000 times the annual limit) was detected in the immediate area.
  • Thirty-nine households (150 people) were evacuated and 200 meter radius around the site was declared off-limits.
  • the roads within a 3 kilometer radius of the site were closed and residents within 10 kilometer radius of the site were advised to stay indoors.
  • the Tokaimura "criticaliry event" is ranked as the third most serious accident - behind Three Mile Island and Chernobyl - in the history ofthe nuclear power industry.
  • Environmental exposure to ionizing radiation may also result from nuclear weapons detonations (either experimental or during wartime), discharges of actinides from nuclear waste storage and processing and reprocessing of nuclear fuel, and from naturally occurring radioactive materials such as radon gas or uranium.
  • radioactive materials such as radon gas or uranium.
  • Radiation exposure from any source can be classified as acute (a single large exposure) or chronic (a series of small low- level, or continuous low-level exposures spread over time).
  • Radiation sickness generally results from an acute exposure of a sufficient dose, and presents with a characteristic set of symptoms that appear in an orderly fashion, including hair loss, weakness, vomiting, diarrhea, skin burns and bleeding from the gastrointestinal tract and mucous membranes. Genetic defects, sterility and cancers (particularly bone marrow cancer) often develop over time. Chronic exposure is usually associated with delayed medical problems such as cancer and premature aging. An acute total body exposure of 125,000 millirem may cause radiation sickness. Localized doses such as are used in radiotherapy may not cause radiation sickness, but may result in the damage or death of exposed normal cells.
  • an acute total body radiation dose of 100,000 - 125,000 millirem (equivalent to 1 Gy) received in less than one week would result in observable physiologic effects such as skin burns or rashes, mucosal and GI bleeding, nausea, diarrhea and/or excessive fatigue.
  • Longer term cytotoxic and genetic effects such as hematopoietic and immunocompetent cell destruction, hair loss (alopecia), gastrointestinal, and oral mucosal sloughing, venoocclusive disease of the liver and chronic vascular hyperplasia of cerebral vessels, cataracts, pneumonites, skin changes, and an increased incidence of cancer may also manifest over time.
  • Acute doses of less than 10,000 millirem (equivalent to 0.1 Gy) typically will not result in immediately observable biologic or physiologic effects, although long term cytotoxic or genetic effects may occur.
  • a sufficiently large acute dose of ionizing radiation for example
  • Acute radiation poisoning a condition in which some of the Chernobyl firefighters died of acute radiation poisoning, having received acute doses in the range of 200,000 - 600,000 millirem (equivalent to 2 - 6 Gy). Acute doses below approximately 200,000 millirem do not result in death, but the exposed individual will likely suffer long-term cytotoxic or genetic effects as discussed above. Acute occupational exposures usually occur in nuclear power plant workers exposed to accidental releases of radiation, or in fire and , rescue personnel who respond to catastrophic events involving nuclear reactors or other sources of radioactive material.
  • a chronic dose is a low level (i.e., 100 - 5000 millirem) incremental or continuous radiation dose received over time.
  • Examples of chronic doses include a whole body dose of approximately 5000 millirem per year, which is the dose typically received by an adult working at a nuclear power plant.
  • the Atomic Energy Commission recommends that members of the general public should not receive more than 100 millirem per year.
  • Chronic doses may cause long-term cytotoxic and genetic effects, for example manifesting as an increased risk of a radiation-induced cancer developing later in life.
  • Recommended limits for chronic exposure to ionizing radiation are given in Table 2.
  • Table 3 sets forth the radiation doses from common sources.
  • Chronic doses of greater than 5000 millirem per year may result in long-term cytotoxic or genetic effects similar to those described for persons receiving acute doses. Some adverse cytotoxic or genetic effects may also occur at chronic doses of significantly less than 5000 millirem per year.
  • any dose above zero can increase the risk of radiation-induced cancer (i.e., that there is no threshold).
  • Epidemiological studies have found that the estimated lifetime risk of dying from cancer is greater by about 0.04% per rem of radiation dose to the whole body. While anti-radiation suits or other personal protective equipment (PPE) may be effective at reducing radiation exposure, such specialized PPE is expensive, unwieldy, and generally not available to public.
  • PPE personal protective equipment
  • radioprotective PPE will not protect normal tissue adjacent a tumor from stray radiation exposure during radiotherapy. What is needed, therefore, is a practical way to protect individuals who are scheduled to incur, or are at risk for incurring, exposure to ionizing radiation.
  • therapeutic irradiation it is desirable to enhance protection of normal cells while causing tumor cells to remain vulnerable to the detrimental effects of the radiation.
  • systemic protection from anticipated or inadvertent total body irradiation such as may occur with occupational or environmental exposures, or with certain therapeutic techniques.
  • Pharmaceutical radioprotectants offer a cost-efficient, effective and easily available alternative to radioprotective gear. However, previous attempts at radioprotection of normal cells with pharmaceutical compositions have not been entirely successful.
  • cytokines directed at mobilizing the peripheral blood progenitor cells confer a myeloprotective effect when given prior to radiation (Neta et al, Semin. Radial Oncol. 3:16-320, 1996), but do not confer systemic protection.
  • Other chemical radioprotectors administered alone or in combination with biologic response modifiers have shown minor protective effects in mice, but application of these compounds to large mammals was less successful, and it was questioned whether chemical radioprotection was of any value (Maisin, J.R., Bacq and Alexander Award Lecture. "Chemical radioprotection: past, present, and future prospects," Int. J. Radiat. Biol. 73:443- 50, 1998).
  • Pharmaceutical radiation sensitizers which are known to preferentially enhance the effects of radiation in cancerous tissues, are clearly unsuited for the general systemic protection of normal tissues from exposure to ionizing radiation.
  • ABL protein Kinase Protein kinases in general are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The phosphorylation serves as a basis for cellular signaling that regulates such fundamental cellular functions such as cellular growth, differentiation and proliferation. Accordingly, disorders associated with abnormal protein kinase activity have included many cancers and other proliferative disorders. Protein kinases are divided into tyrosine kinases and serine-threonine kinases.
  • the protein tyrosine kinases are further classified as receptor tyrosine kinases and non-receptor tyrosine kinases, which are also called cellular tyrosine kinases (CTK's).
  • Receptor tyrosine kinases include epithelial growth factor receptors (EGFR), insulin-like growth factor receptors (IGFR), platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR) and vascular endothelial growth factor receptors (VEGF).
  • Non-receptor tyrosine kinases include Abelson (ABL) tyrosine kinase as well as ten other subfamilies of CTK's.
  • ABL Abelson
  • ABL is a tyrosine kinase expressed by the c-abl proto-oncogene. Cloning ofthe c-abl gene has revealed that it spans at least 230kb, and contains at least 11 exons. Two alternative first exons exist, namely exon la and exon lb, which are spliced to the common splice acceptor site, exon 2. Exon la is 19 kb proximal to exon 2. Exon lb, which is somewhat smaller than exon la, is more than 200 kb proximal to exon 2. As a result of this configuration, at least two major c-abl messages are transcribed, differing in their 5' regions.
  • the 7-kb transcript begins with exon lb, skips the 200 kb distance to exon 2, omits exon la, and joins to exons 2 through 11.
  • both c-abl messages share a common set of 3' exons, starting from the c-abl exon 2. Consequently, the messages code for two proteins that share most of their amino acid sequence, except for the N- termini. Since the coding begins with the first exon, exonic selection will determine the protein product.
  • Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease caused by malignant transformation of stem cells as a result of fusion of the c-abl gene to the bcr gene.
  • CML CML-oncogene c-abl
  • bcr breakpoint cluster region
  • the break occurs near the end of the long arm of chromosome 9 (band 9q34) and in the upper half of chromosome 22 (band 22ql 1).
  • the 9;22 translocation in CML results in the abnormal juxtaposition of abl sequences adjacent to bcr sequences.
  • the c-abl proto-oncogene is expressed in normal cells and plays a critical role in regulating normal hematopoiesis by encoding a protein with tyrosine kinase activity. This activity is augmented in cells carrying bcr-abl hybrid genes.
  • the gene located at the breakpoint on chromosome 22 is called bcr because the break in chromosome 22 in CML occurs in a small 5.8-kilobase (kb) segment (breakpoint cluster region) ofthe gene on chromosome 22.
  • the fusion of the BCR gene with c-abl leads to an 8.5 kb chimeric mRNA consisting of 5' BCR sequences and 3' abl sequences.
  • the chimeric message is in turn translated into a larger chimeric abl protein (210 kDa) that has increased tyrosine kinase activity
  • a larger chimeric abl protein (210 kDa) that has increased tyrosine kinase activity
  • 210 kDa chimeric abl protein
  • the 210 kDa protein is considerably larger than the normal human protein of 145 kDa, and has a very high tyrosine kinase activity.
  • Oxidants are produced as part of the normal metabolism of all cells but also are an important component ofthe pathogenesis of many disease processes.
  • Reactive oxygen species ROS
  • Oxygen free radicals also modulate the effects of nitric oxide, thereby contributing to the pathogenesis of vascular disorders, inflammatory diseases and the aging process.
  • Free radicals are molecules with one or more unpaired electrons. Free radicals act as oxidants, rapidly reacting with other molecules, and starting oxidative chain reactions. Free radicals are a normal product of metabolism. However, ionizing radiation can significantly increase the number of free radicals in the body. Certain antioxidant compounds have been shown to have cytoprotective properties. Antioxidants are believed to act by scavenging free radicals. Normal cell and organ function is maintained via a balance of oxidant and antioxidant agents. Many antioxidant compounds, e.g., the enzyme superoxide dismutases (SODs) are produced physiologically and balance the naturally occurring free radicals. Several other important antioxidant enzymes are known to exist within cells, including catalase and glutathione peroxidase.
  • SODs superoxide dismutases
  • extracellular fluids and the extracellular matrix contain only small amounts of these enzymes, other extracellular antioxidants are also known to be present, including radical scavengers and inhibitors of lipid peroxidation, such as ascorbic acid, uric acid, and ⁇ -tocopherol.
  • inhibitors of ABL provide significant and selective systemic protection of normal cells and normal tissues from radiation-induced damage in individuals exposed to ionizing radiation. It is an object of the invention to provide compositions and methods for protecting the normal cells and tissues from the cytotoxic and genetic effects of exposure to ionizing radiation, in individuals who have incurred or are at risk of incurring exposure to ionizing radiation.
  • the exposure to ionizing radiation may occur in controlled doses during the treatment of cancer and other proliferative disorders, or may occur in uncontrolled doses beyond the norm accepted for the population at large during high risk activities or environmental exposures.
  • a method for protecting an individual from cytotoxic side effects of ionizing radiation comprising administering to said individual an effective amount of at least one compound of formula I: wherein: L is selected from the group consisting of O, S, and N-R 1 ; R 1 is -H or -(C ⁇ -C 7 )hydrocarbyl, preferably -H or -(C ⁇ -Ce)alkyl, more preferably -H or -(C]-C 3 )alkyl, most preferably -H; each R 2 is independently selected from the group consisting of -(C ⁇ -C 7 )hydrocarbyl, preferably -(C ⁇ -C6)alkyl and -(C 3 -C 7 )cycloalkyl; -CO 2 H; -CO 2 (C ⁇ -C 12 )hydrocarbyl, preferably -CO 2 (C 3 -C ⁇ 2 )cycloalkyl and -CO 2 (C
  • each R 7 is independently selected from the group consisting of -H and (C ⁇ -C6)alkyl, preferably -H and (C ! -C 3 )alkyl, most preferably -H and methyl;
  • R 5 is O orN(R 7 );
  • Y is (C ⁇ -C ⁇ )alkylene;
  • e and g are independently selected from the group consisting of 0 and 1;
  • f is 0 or 1, provided that f is 0 when R 3 is formula (ii) or (v);
  • R 6 is selected from the group consisting of -H;
  • A is a radical selected from the group consisting of formula (vi),
  • a method for protecting an individual from cytotoxic side effects of ionizing radiation comprising administering to said individual an effective amount of a combination comprising at least one compound of formula I, as defined above, and at least one radioprotective ⁇ , ⁇ -unsaturated aryl or heteroaryl sulfone, sulfoxide, sulfonamide or carboxamide.
  • a method for protecting an individual from cytotoxic side effects of ionizing radiation comprising administering to said individual an effective amount of a combination comprising at least one compound of formula I, as defined above, and at least one antioxidant compound.
  • Preferred embodiments of radioprotective compounds of formula I are described as follows.
  • each R 2 is independently selected from the group consisting of -(C ⁇ -C 7 )hydrocarbyl, preferably -(C ⁇ -C ⁇ )alkyl, more preferably, -(Ci- C )alkyl, most preferably -CH 3 ; and -(C 3 -C 7 )cycloalkyl.
  • the radioprotective compound comprises a compound of formula 1(a):
  • R 2 is -(C ⁇ -C 7 )hydrocarbyl, preferably -(d-C 6 )alkyl, more • preferably, -(C ⁇ -C 4 )alkyl, most preferably -CH 3 ; or -(C 3 -C 7 )cycloalkyl;
  • a is 0 or 1;
  • b is l;
  • R 3 is a radical of formula (i): wherein: R 4 is a divalant radical of formula (iii):
  • f and g are 0;
  • R 6 is substituted aryl, preferably substituted phenyl;
  • R 7 is -H;
  • R 8 is substituted or unsubstituted heteroaryl, preferably substituted and unsubstituted pyridyl, pyrazinyl, pyrrolyl, indolyl, and imidazolyl, more preferably unsubstituted pyridyl, pyrazinyl, pyrrolyl, indolyl, and imidazolyl; most preferably unsubstituted pyridyl; and i is 0; or a pharmaceutically acceptable salt of such a compound.
  • Substituents on substituted aryl R 6 are most preferably independently selected from the group consisting of 4-methylpiperazin-l-yl(C 1 -C 6 )alkyl,
  • Preferred compounds of formula 1(a) include for example: N-(3-(4- (pyridin-3 -yl)pyrimidin-2-y lamino)-4-methylphenyl)-4-((4-methylpiperazin- 1 - yl)methyl)benzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4- ((4-methylpiperazin-l-yl)methyl)benzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)phenyl)nicotinamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methylphenyl)-4-methylbenzamide; N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)phenyl)hexanamide; N-(3-(4-(pyridin-3-y
  • More preferred compounds of formula 1(a) include for example N-(3-(4- (pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-l- yl)methyl)benzamido; and pharmaceutically acceptable salts thereof.
  • L is ⁇ R 1 ; each R 2 is independently selected from the group consisting of -(C ⁇ -C 7 )hydrocarbyl, preferably -(d-C6)alkyl and -(C 3 -C 7 )cycloalkyl; -O(C ⁇ -C 7 )hydrocarbyl, preferably -O(C 1 -C ⁇ )alkyl, more preferably -OCH 3 and -OC 2 H 5 ; -S(O) d (C ⁇ -C 7 )hydrocarbyl, preferably -S(O) d (C ⁇ - C ⁇ )alkyl, more preferably -S(O) d (C ⁇ -C )alkyl, most preferably -S(O) d CH 3 ; halogen, preferably chloro, fluoro and bromo, more preferably chloro and fluoro, most
  • Substituents on R 12 are most preferably independently selected from the group consisting of bromine, chlorine, and fluorine.
  • Preferred compounds of formula 1(b) include for example: 6-(2,6- dichlorophenyl)-2-[(4-fluoro-3-methylphenyl)amino]-8-methyl-8-hydro- pyridino[2,3-d]pyrimid ⁇ n-7-one; 6-(2,6-dichlorophenyl)-8-methyl-2-[(3-methyl- thiophenyl)amino]-8-hydropyridino[2,3-d]pyrimidin-7-one; 6-(2,6-dichloro- phenyl)-2- ⁇ [3 -(hydroxymethyl)phe ⁇ yl] amino ⁇ -8-methyl-8-hydropyridino [2,3 - d]pyrimidin-7-one; 6-(2,6-dichlorophenyl)-2-[(4-ethoxyphenyl)amino]
  • L is NR 1 ; each R 2 is independently selected from the group consisting of -(C ⁇ -C 7 )hydrocarbyl, preferably -(Ci-Q alkyl and -(C 3 -C 7 )cycloalkyl; -O(C ⁇ -C 7 )hydrocarbyl, preferably -O(d-C6)alkyl; halogen, preferably bromo, chloro and fluoro; substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; heterocyclyl(d-C6)alkylene, and heteroaryl(C ⁇ -C6)alkylene; a is 0, 1 or 2; R 3 is selected from the group consisting of -NH 2 , -NO 2 , -(Ci- Ce)haloalkoxy, and halogen; b is selected from the group consisting of -NH 2 , -NO 2 , -(Ci- Ce)halo
  • U is selected from the group consisting of O; S; arylene, preferably phenylene, more preferably 1,4-phenylene; and heteroarylene; V is (C ⁇ -C ⁇ )alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, preferably monocyclic heterocyclyl, more preferably non-aromatic monocyclic heterocyclyl; substituted and unsubstituted -NH(C ⁇ -C ⁇ )alkylenylheterocyclyl; and -NH(C 2 - C 6 )alkylene-N(d-C 6 alkyl)2.
  • Substituents on heterocyclyl W are preferably -(Ci- C 7 )hydrocarbyl, more preferably -(C ⁇ -C ⁇ )alkyl, most preferably -CH 3 .
  • U is O; V is -CH 2 CH 2 CH 2 -; and W is 4- methylpiperazin-1-yl.
  • each R 2 is independently selected from the group consisting of -(C ⁇ -C 7 )hydrocarbyl, preferably -(C ⁇ -C ⁇ )alkyl and -(C 3 -C 7 )cycloalkyl; -O(d-C 7 )hydrocarbyl, preferably -O(Ci-Ce)alkyl; and halogen, preferably bromo, chloro and fluoro; a and b are independently selected from the group consisting of 1 and 2; and each R 3 is independently selected from the group consisting of -NH 2 , -NO 2 , -(C ⁇ -C 6 )haloalkoxy, and halogen.
  • a preferred compound of formula 1(c) is 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazinyl)- pro ⁇ oxy]quinoline-3-carbonitrile; and pharmaceutically acceptable salts thereof.
  • each R 13 is independently selected from the group consisting of -OH, -(C ⁇ -C ⁇ )alkyl, -O(d-C 6 )alkyl, halogen, -NH 2 , -NO 2 , -CN, -SH and -S(O) j (d-C 6 )alkyl; j is 0, 1 or 2; and k is 1, 2 or 3.
  • the radioprotective compound comprises a compound of formula 1(d):
  • R 2 is selected from the group consisting of -CO 2 H, -CONH 2 , -CO 2 (C ⁇ -C 6 )alkyl, -CO 2 (C 3 -C ⁇ 2 )cycloalkyl, and substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; a is 1; and b is O.
  • Preferred compounds according to formula 1(d) include: methyl 4- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ benzoate; 3- ⁇ [(2,5-dihydroxyphenyl)- methyl]amino ⁇ benzoic acid; 2-[(2,5-dihydroxyphenyl)methylthio]benzoic acid; 2- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ benzamide; 2- ⁇ [(2,5-dihydroxy- phenyl)methyl] amino ⁇ benzoic acid; 4- ⁇ [(2,5-dihydroxyphenyl)methyl]- amino ⁇ benzamide; methyl 2- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ benzoate; and pharmaceutically acceptable salts thereof.
  • L is R 1 ; each R 2 is independently selected from the group consisting of -(C ⁇ -C 7 )hydrocarbyl, preferably -(C ⁇ -C ⁇ )alkyl and -(C 3 -C 7 )cycloalkyl; -O(Ci-C 7 )hydrocarbyl, preferably -O(C ⁇ -C ⁇ )alkyl; halogen, preferably bromo, chloro and fluoro; substituted and unsubstituted heterocyclyl, preferably substituted and unsubstituted monocyclic heterocyclyl; heterocyclyl(C ⁇ -C ⁇ )alkylene, and heteroaryl(C]-C ⁇ )alkylene; a is 1 or 2; b is 0; A is a radical of formula (vii):
  • X is N;
  • R 10 is -H or -O(C ⁇ -C 7 )hydrocarbyl, preferably -O(d-C 6 )alkyl, more preferably -O(C ⁇ -C 4 )alkyl, most preferably -OCH 3 ;
  • U is selected from the group consisting of N(H); N -C ⁇ alkyl), preferably N(CH 3 ); O; S; arylene, preferably phenylene, more preferably 1,4-phenylene;.
  • the radioprotective compound comprises a compound of formula 1(e):
  • U is selected from the group consisting of O; S; arylene, preferably phenylene, more preferably 1,4-phenylene; and heteroarylene; V is (C ⁇ -C ⁇ )alkylene; and W is selected from the group consisting of substituted and unsubstituted heterocyclyl, substituted and unsubstituted -NH(d- C 6 )alkylenylheterocyclyl, and -NH(C 2 -C6)alkylene-N(Ci-C6alkyl) 2 .
  • Substituents on heterocyclyl W are preferably -(C ⁇ -C 7 )hydrocarbyl, more preferably -(C ⁇ -C ⁇ )alkyl, most preferably -CH 3 .
  • Preferred compounds according to formula 1(e) include (3-chloro-4- fluorophenyl)[7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amine; and pharmaceutically acceptable salts thereof.
  • the radioprotective compound or combination of compounds is administered before exposure to the ionizing radiation.
  • the radioprotective compound or combination of compounds is administered after exposure to ionizing radiation.
  • a method for protecting an individual from cytotoxic side effects of ionizing radiation comprising administering to the individual an effective amount of at least one compound of formula I, and an effective amount of at least one compound of formula II: wherein: Q 1 and Q 2 are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably substituted or unsubstituted phenyl; more preferably substituted phenyl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below:
  • Q 1 is phenyl.
  • Q 2 is phenyl.
  • both Q 1 and Q 2 are phenyl.
  • X is selected from the group consisting of (i), (ii) and (iii).
  • X is selected from the group consisting of (i) and (ii). According to yet another sub-embodiment of the compounds according to formula II, X is (i). According to some embodiments of compounds according to formula II, the aryl and heteroaryl groups comprising Q 1 and Q 2 are mono-, di- or tri- substituted. According to other embodiments of compounds according to formula II, the aryl and heteroaryl groups comprising Q 1 and Q 2 are substituted at all substitutable positions.
  • Substituted phenyl R z is preferably mono- di- or tri-substituted, more preferably mono or di substituted, most preferably mono-substituted by substituents independently selected from the group consisting of -R x , -NR x 2 , -NO 2 , -OR x , -CN, -CO 2 R x , halogen, -SR X and SO 2 R x .
  • Substituents on substituted phenyl R z are more preferably independently selected from the group consisting of -(C ⁇ -C ⁇ )alkyl, -NH 2 , NH(d-C ⁇ )alkyl, -NO 2 , -O(d-C 6 )alkyl, -OH, -CN, -CO 2 (C ⁇ -C 6 )alkyl, CO 2 H, , halogen, -S(d- C 6 )alkyl, -SH, and SO 2 (C 1 -C 6 )alkyl.
  • Substituents on substituted phenyl R z are most preferably independently selected from the group consisting of methyl, ethyl, -NH 2 , NHCH 3 , -NO 2 , -OCH 3 , -OH, -CN, -CO 2 CH3, CO2Et, CO 2 H, , halogen, -SCH 3 , -SH, and SO 2 CH 3 .
  • R x is most preferably -H or -(C ⁇ -C 6 )alkyl.
  • R y is preferably selected from -H, -(d-C ⁇ hydrocarbyl, -O(C ⁇ - C 8 )hydrocarbyl, substituted phenyl, -NHR X , -(d-C 6 )haloalkyl, -(Ci- C 3 )alkyleneNH 2 , -(C ⁇ -C 3 )alkyleneN(CH 3 ) 2 , -(C ⁇ -C 3 )alkylene-OR 1 , -(Ci- C 4 )alkylene-CO 2 R 1 , and -(Ci-C ⁇ perfluoroalkylene-CO ⁇ R 1 .
  • R y is more preferably selected from -H, -(C ⁇ -C 8 )hydrocarbyl, -O(C ⁇ -
  • R z is' preferably selected from the group consisting of-H, -(C ⁇ -C 6 )alkyl, and phenyl.
  • Preferred compounds according to formula II include, for example: 4-
  • More preferred compounds according to formula II include, for example: 4-((lR)-2- ⁇ [(4-fluorophenyl)methyl]sulfonyl ⁇ vinyl)benzoic acid; 4-((lE)-2- ⁇ [(4-iodo ⁇ henyl)methyl]sulfonyl ⁇ vinyl)benzoic acid; 4-((lE)-2- ⁇ [(4-chloro- phenyl)-methyl]sulfonyl ⁇ vinyl)benzoic acid; l-[5-((lR)-2- ⁇ [(4-chlorophenyl)- methy 1] -sulfonyl ⁇ vinyl)-2-fluorophenyl] -2-(dimethylamino)ethan- 1 -one; (IE)- 2-(2,4-difluorophenyl)- 1 - ⁇ [(4-bromophenyl)methyl] sulfonyl ⁇ ethene; (
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one compound according to formula I as defined above, and at least one compound according to formula II as defined above.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one compound according to formula I as defined above, and at least one antioxidant compound.
  • a method of treating an individual with a proliferative disorder comprising: (a) administering to the individual an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound; and (b) administering an effective amount of therapeutic ionizing radiation.
  • the proliferative disorder is cancer.
  • a method of safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders comprising administering to the individual an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound.
  • the radioprotective compound or combination of compounds is administered prior to administration ofthe therapeutic ionizing radiation.
  • the radioprotective compound or combination of compounds induces a temporary radioresistant phenotype in the normal tissue ofthe individual.
  • a method for treating an individual who has incurred, or is at risk for incurring, remediable radiation damage from exposure to ionizing radiation comprising administering to the individual an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound
  • the compound or compounds may be administered before or after incurring remediable radiation damage from exposure to ionizing radiation.
  • a method is provided of reducing the number of malignant cells in bone marrow of an individual, comprising: (1) removing a portion ofthe individual's bone marrow; (2) administering to the removed bone marrow an effective amount of either: (i) at least one radioprotective compound according to formula I; or (ii) at least one radioprotective compound according to formula I, and an effective amount of either at least one compound according to formula II as defined above, or at least one antioxidant compound; and (3) irradiating the bone marrow with an effective amount of ionizing radiation.
  • the bone marrow is reimplanted into the individual.
  • the individual receives therapeutic ionizing radiation prior to reimplantation ofthe bone marrow.
  • the individual receives therapeutic ionizing radiation prior to reimplantation of the bone marrow, and is administered a radioprotective compound or combination of compounds as defined above prior to receiving the therapeutic ionizing radiation.
  • a compound of formula I, or a pharmaceutically acceptable salt thereof is used in the manufacture of a medicament for protecting an individual from cytotoxic side effects of ionizing radiation.
  • a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound of formula II are used in the manufacture of a medicament for protecting an individual from cytotoxic side effects of ionizing radiation.
  • a compound of formula I, or a pharmaceutically acceptable salt thereof, and an antioxidant compound are used in the manufacture of a medicament for protecting an individual from cytotoxic side effects of ionizing radiation.
  • the compounds are for administration before exposure to ionizing radiation.
  • the compounds are for administration after exposure to ionizing radiation.
  • the formula I compounds are for administration before or after administration of therapeutic ionizing radiation, for treatment of a proliferative disorder.
  • the compounds are for treating an individual who has incurred or is at risk of incurring remediable radiation damage from exposure to ionizing radiation.
  • the compounds are used for the preparation of a medicament for treating bone marrow prior to irradiating the bone marrow with an effective amount of ionizing radiation.
  • the compounds are used for the preparation of a medicament for safely increasing the dosage of therapeutic ionizing radiation used in the treatment of cancer or other proliferative disorders.
  • the term "individual" includes human beings and non-human animals and, as used herein, refers to an organism which is scheduled to incur, is at risk of incurring, or has incurred, exposure to ionizing radiation.
  • ionizing radiation is radiation of sufficient energy that, when absorbed by cells and tissues, induces formation of reactive oxygen species and DNA damage.
  • This type of radiation includes X-Rays, gamma rays, and particle bombardment (e.g., neutron beam, electron beam, protons, mesons and others), and is used for medical testing and treatment, scientific purposes, industrial testing, manufacturing and sterilization, weapons and weapons development, and many other uses.
  • the Sv is the Gy dosage multiplied by a factor that includes tissue damage done.
  • penetrating ionizing radiation e.g., gamma and beta radiation
  • have a factor of about 1 Sv ⁇ 1 Gy.
  • effective amount of ionizing radiation is meant an amount of ionizing radiation effective in killing, or in reducing the proliferation, of abnormally proliferating cells in an individual.
  • effective amount of ionizing radiation means an amount of ionizing radiation effective in killing, or in reducing the proliferation, of malignant cells in a bone marrow sample removed from an individual.
  • acute exposure to ionizing radiation or “acute dose of ionizing radiation” is meant a dose of ionizing radiation absorbed by an individual in less than 24 hours.
  • the acute dose may be localized, as in radiotherapy techniques, or may be absorbed by the individual's entire body. Acute doses are typically above 10,000 millirem (0.1 Gy), but may be lower.
  • chronic exposure to ionizing radiation or “chronic dose of ionizing radiation” is meant a dose of ionizing radiation absorbed by an individual over a period greater than 24 hours. The dose may be intermittent or continuous, and may be localized or absorbed by the individual's entire body. Chronic doses are typically less than 10,000 millirem (0.1 Gy), but may be higher.
  • ⁇ , ⁇ -unsaturated (aryl or heteroaryl) sulfone, sulfonamide or carboxamide is meant a compound ofthe formula II:
  • Q 1 X — CH CH— Q 2 II wherein, Q 1 and Q 2 are, same or different, are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably substituted or unsubstituted phenyl; and X is selected from the group consisting of (i), (ii), (iii) and (iv) below: (i) ( ⁇ )
  • antioxidant is meant a pharmaceutically acceptable chemical compound that prevents or slows the breakdown of another substance by oxygen.
  • antioxidants useful in the methods of the present invention are small molecule organic compounds.
  • effective amount in the context of an amount of radioprotective compound is meant an amount, alone, or in combination with either another radioprotective compound or an antioxidant compound, which is effective to reduce or eliminate the toxicity associated with radiation in normal cells ofthe individual.
  • an effective amount of a radioprotective compound means an amount of the compound effective to reduce or eliminate the toxicity associated with radiation in bone marrow removed from an individual.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight, branched or cyclic chain saturated hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated in an expression such as (C x -C y )alkyl.
  • (C x -C y )alkyl wherein x ⁇ y, represents an alkyl chain containing a minimum of x carbon atoms and a maximum of y carbon atoms.
  • Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclohexyl and cyclopropylmethyl.
  • Preferred is (d-C 3 )alkyl, particularly ethyl, methyl and isopropyl.
  • cycloalkyl refers to alkyl groups that contain at least one cyclic structure. Examples include cyclohexyl, cyclopentyl, norbornyl, adamantyl and cyclopropylmethyl.
  • alkylene refers to a divalent alkyl radical having the number of carbon atoms designated (i.e.
  • (d-C ⁇ ) means -CH 2 -; -CH 2 CH 2 -; -CH2CH2CH2-; -CH 2 CH 2 CH 2 CH 2 -; -CH 2 CH 2 CH2CH 2 CH2-; and -CH2CH2CH2CH2CH2-, and also includes branched divalent structures such as, for example, -CH 2 CH(CH 3 )CH 2 CH 2 - and -CH(CH 3 )CH(CH 3 )-, and divalant cyclic structures such as, for example 1,3-cyclopentyl.
  • arylene by itself or as part of another substituent means, unless otherwise stated, a divalent aryl radical.
  • divalent phenyl radicals or "phenylene” groups, particularly 1 ,4-divalent phenyl radicals.
  • heteroarylene by itself or as part of another substituent means, unless otherwise stated, a divalent heteroaryl radical.
  • Preferred are five- or six-membered monocyclic heteroarylene.
  • heteroarylene moieties comprising divalent heteroaryl rings selected from the group consisting of pyridine, piperazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, thiazole, imidazole and oxazole, such as, for example 2,5-divalent pyrrole, thiophene, furan, thiazole, oxazole, and imidazole.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred are (Ci- C 6 )alkoxy, particularly ethoxy and methoxy.
  • the carbon chains in the alkyl and alkoxy groups which may occur in the compounds of the invention may be cyclic, straight or branched, with straight chain being preferred.
  • (C ⁇ -C ⁇ )alkyl thus extends to alkyl groups containing one, two, three, four, five or six carbons.
  • (C]-C ⁇ )alkoxy thus extends to alkoxy groups containing one, two, three, four, five or six carbons.
  • hydrocarbyl refers to any moiety comprising only hydrogen and carbon atoms. The term includes, for example, alkyl, alkenyi, alkynyl, aryl and benzyl groups. Preferred are (C ⁇ -C 7 )hydrocarbyl. More preferred are (Ci- C ⁇ )alkyl and (C 3 -Ci2)cycloalkyl.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH- OCH 3 , or-CH 2 -CH 2 -S-S-CH 3 .
  • the terms "halo" or "halogen" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (4n + 2) delocalized ⁇ (pi) electrons).
  • aromatic is intended to include not only ring systems containing only carbon ring atoms but also systems containing one or more non- carbon atoms as ring atoms. Systems containing one or more non-carbon atoms may be known as “heteroaryl” or “heteroaromatic” systems. The term “aromatic” thus is deemed to include “aryl” and “heteroaryl” ring systems.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl; anthracyl; and naphthyl which may be substituted or unsubstituted. The aforementioned listing of aryl moieties is intended to be representative, not limiting.
  • heterocycle or “heterocyclyl” or “heterocyclic” by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, monocyclic or polycyclic heterocyclic ring system which consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a stable structure.
  • Heterocyclyl groups are inclusive of monocyclic and polycyclic heteroaryl groups and monocyclic and polycyclic groups that are not aromatic, such as saturated and partially saturated and monocyclic and polycyclic partially saturated monocyclic and polycyclic groups.
  • the term "heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character, and includes both monocyclic heteroaryl groups and polycyclic heteroaryl groups.
  • a polycyclic heteroaryl group may include one or more rings which are partially saturated.
  • Examples of monocyclic heteroaryl groups include: Pyridyl; pyrazinyl; pyrimidinyl, particularly 2- and 5-pyrimidyl; pyridazinyl; thienyl; furyl; pyrrolyl, particularly 2-pyrrolyl and l-alkyl-2-pyrrolyl; imidazolyl, particularly 2-imidazolyl; thiazolyl, particularly 2-thiazolyl; oxazolyl, particularly 2- oxazolyl; pyrazolyl, particularly 3- and 5-pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl; and 1,3,4-oxadiazolyl.
  • monocyclic heterocycles that are not aromatic include saturated monocyclic groups such as: Aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, 1,4-dioxane, 1,3-dioxane, sulfolane, tetrahydrofuran, thiophane, piperazine, morpholine, thiomorpholine, tetrahydropyran, homopiperazine, homopiperidine, 1,3-dioxepane, hexamethyleneoxide and piperidine; and partially saturated monocyclic groups such as: 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, 2,3-dihydrofuran, 2,5-dihydrofuran , 2,3-dihydropyran, 1,2-dihydro
  • polycyclic heteroaryl groups include: Indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl, quinolyl, isoquinolyl, particularly 1- and 5- isoquinolyl, cinnolinyl, quinoxalinyl, particularly 2- and 5-quinoxalinyl, quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, benzofuryl, particularly 3-, 4-, 1,5-naphthyridinyl, 5-, 6- and 7-benzofuryl, 1,2- benzisoxazolyl, benzothienyl, particularly 3-, 4-, 5-, 6-, and 7-benzothienyl, benzoxazolyl, benzthiazolyl, particularly 2-benzothiazolyl and 5-benzothiazolyl, purinyl, benzimidazolyl, particularly 2-benzimidazolyl, benztriazolyl,
  • non-aromatic polycyclic heterocycles include: pyrrolizidinyl and quinolizidinyl.
  • the aforementioned listing of non-aromatic heterocyclic moieties and heteroaryl moieties is intended to be representative, not limiting.
  • Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; pyrazinyl; 2- and 5- pyrimidinyl; 3-pyridazinyl; 2- and 3-thienyl; 2- and 3-furyl; pyrrolyl; particularly N-methylpyrrol-2-yl; 2-imidazolyl; 2-thiazolyl; 2-oxazolyl; pyrazolyl; particularly 3- and 5-pyrazolyl; isothiazolyl; 1,2,3-triazolyl; 1,2,4- triazolyl; 1,3,4-triazolyl; tetrazolyl, 1,2,3-thiadiazolyl; 1,2,3-oxadiazolyl; 1,3,4- thiadiazolyl and 1,3,4-oxadiazolyl; indolyl, particularly 2-, 3-, 4-, 5-, 6- and 7- indolyl; cinnolinyl; quinoxalinyl, particularly 2- and 5-quinoxalinyl; quinazolinyl
  • heteroaryl groups are 2, 3- and 4-pyridyl; 2- and 3- thienyl; 2- and 3 -furyl; 2-pyrrolyl; 2-imidazolyl; 2-thiazolyl; 2-oxazolyl; 2- and 3-indolyl; 2-, and 3-benzofuryl; 3-(l,2-benzisoxazolyl); 2-, and 3-benzothienyl; 2-benzoxazolyl; 1- and 2-benzimidazolyl, 2-, 3- and 4-quinolyl; and 2- and 5- benzthiazolyl.
  • Most preferred heteroaryl groups are 2- and 3-indolyl; 2- and 3- pyrrolyl, 2-, and 3-benzofuryl; and 2-, and 3-benzothienyl.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • substituted refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • substituted and unsubstituted -NH(C ⁇ - C ⁇ )alkylenylheterocyclyl refers to a monovalent substituent that is a substituted or unsubstituted heterocyclyl ring bonded to an alkylene group, which alkylene group is bonded through a divalent nitrogen to the molecule on which it is a substituent.
  • alkylene group which alkylene group is bonded through a divalent nitrogen to the molecule on which it is a substituent.
  • Examples include sub-structures such as those shown below:
  • Radioprotective small molecule inhibitors of ABL kinase and all of the ⁇ , ⁇ -unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides are characterized by isomerism resulting from the presence of a double bond.
  • This isomerism is commonly referred to as cis-trans isomerism, but the more comprehensive naming convention employs E and Z designations.
  • the compounds are named according to the Cahn-Ingold-Prelog system, the IUPAC 1974 Recommendations, Section E: Stereochemistry, in Nomenclature of Organic Chemistry, John Wiley & Sons, Inc., New York, NY, 4 th ed., 1992, p. 127-138.
  • ⁇ , ⁇ -unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides Some ofthe radioprotective small molecule inhibitors of ABL kinase and some of the ⁇ , ⁇ -unsaturated (aryl or heteroaryl) sulfones, sulfonamides and carboxamides may be characterized by isomerism resulting from the presence of a chiral center. The isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system. See March, Advanced Organic Chemistry, 4 th Ed., (1992), p. 109.
  • the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order ofthe other groups proceeds clockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated (S).
  • the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.
  • FIG. 1 shows a fixed polyacrylamide gel showing qualitatively the inhibition of ABL kinase activity by N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylphenyl)-4-((4-methylpiperazin- 1 -y ⁇ )methyl)benzamide (a compound of formula I), by 4-((lE)-2- ⁇ [(4-chlorophenyl)- methyl]sulfonyl ⁇ vinyl)benzoic acid (a compound of formula II) and by a combination ofthe two compounds, all as a function of dose.
  • FIG. 1 shows a fixed polyacrylamide gel showing qualitatively the inhibition of ABL kinase activity by N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methylphenyl)-4-((4-methylpiperazin- 1 -y ⁇ )methyl)benzamide (a compound of formula I), by 4-((lE)-2-
  • FIG. 2 shows quantitatively the inhibition of ABL kinase activity by N- (3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methyl- piperazin-l-yl)methyl)benzamide plotted as percent of solvent treated control.
  • FIG. 3 shows the radioprotective effect of N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-l-yl)methyl)- benzamide (Compound of Formula I) on human fibroblasts HFL-1 exposed to 10 Gy of ionizing radiation.
  • FIG. 1 shows the radioprotective effect of N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-l-yl)methyl)- benzamide
  • FIG. 5 shows quantitatively the inhibition of ABL kinase activity by compounds 1 ( ⁇ ), 2 ( ⁇ ), 3 (V), 4 (0), 5 (•) and 6 (o) plotted as percent of solvent treated control.
  • FIG. 6 shows quantitatively the inhibition of ABL kinase activity by compounds 7 ( ⁇ ), 8 ( ⁇ ), 9 (V), 10 (0), 11 (•) and 12 (a), plotted as percent of solvent treated control.
  • FIG. 7 shows quantitatively the inhibition of ABL kinase activity by compounds 13 ( ⁇ ), 14 ( ⁇ ), 15 (repeated three times as V, •, and G), and 16 (0), plotted as percent of solvent treated control.
  • FIG. 8 shows quantitatively the inhibition of ABL kinase activity by compounds 17 ( ⁇ ), 18 ( ⁇ ), and 19 (V) plotted as percent of solvent treated control.
  • FIG. 9 shows quantitatively the inhibition of ABL kinase activity by compounds 20 ( ⁇ ), 21 ( ⁇ ), and 22 (V) plotted as percent of solvent treated control.
  • small molecule inhibitors of ABL activity are also capable of protecting cells, tissues and individuals from the cytotoxic effects of ionizing radiation.
  • the radioprotective compounds protect normal cells and tissues from the effects of acute and chronic exposure to ionizing radiation.
  • compositions comprising a small molecule inhibitor of ABL activity, in combination with either an antioxidant compound or an ⁇ , ⁇ - unsaturated (aryl or heteroaryl) sulfone, sulfonamide or carboxamide, are capable of protecting cells, tissues and individuals from the cytotoxic effects of ionizing radiation.
  • Preferred antioxidant compounds useful in combination small molecule inhibitors of ABL activity include, for example, carotenoids, catechins, isoflavones, flavanones, flavanols, flavanoid chalcones, vitamin E compounds, (3-aminopropyl)[2-(phosphonothio)ethyl]amine, ascorbic acid, cysteine, glutathione, probucol, ⁇ -mercaptoethanol dithiothreitol, pyrrolidine dithiocarbamate, N-acetyl-L-cysteine, ubiquinone, and porphyrin compounds such as those disclosed in EP 1,045,851, the entire contents of which is incorporated herein by reference.
  • Preferred carotenoids include ⁇ -carotene, ⁇ - carotene, lutein. lycopene.
  • Preferred catechins include gallic acid, propyl gallate, (+)-catechin, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)- epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), (-)-catechin gallate (CG), and (-)-gallocatechin gallate.
  • Preferred isoflavones include genistein and daidzein.
  • Preferred flavanols include hesperitin, hesperidin, and quercetin, kaempferol, myricetin.
  • Preferred flavanoid chalcones include xanthohumol and isoxanthohumol.
  • Preferred vitamin E compounds include tocopherols and tocotrienols.
  • Antioxidant compounds more preferably include, for example, ⁇ - carotene, ⁇ -carotene, lutein, lycopene, gallic acid, propyl gallate, (+)-catechin, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), (-)-catechin gallate (CG), (-)-gallocatechin gallate, genistein, hesperitin, hesperidin, quercetin, kaempferol, myricetin, xanthohumol, isoxanthohumol, tocopherols, tocotrienol, (3-amin
  • a metal selected from the group consisting of iron, copper, cobalt, nickel and zinc.
  • Such disorders include cancerous and non-cancer proliferative disorders.
  • the present compounds and pharmaceutical compositions are believed effective in protecting normal cells during therapeutic irradiation of a broad range of tumor types, including but not limited to the following: breast- prostate, ovarian, lung, colorectal, brain (i.e., glioma) and renal.
  • the compounds and compositions are also effective in protecting normal cells during therapeutic irradiation of leukemic cells.
  • the compounds are also believed useful in protecting normal cells during therapeutic irradiation of abnormal tissues in non-cancer proliferative disorders, including but not limited to the following: hemangiomatosis in newborn, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganglioneuromatosis, keloid formation, Paget's Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis.
  • the radioprotective ABL inhibitors of formula I useful in the method of the invention may be prepared by organic synthesis using techniques that are known in the art or readily adapted from techniques known in the art. The following general synthesis methods are representative of methods whereby the compounds useful in the claimed method may be prepared.
  • the compounds of formula 1(a) comprise anilinopyrimidines which may be prepared according to the method of Zimmermann et al, Bioorg. & Med. Chem. Lett., Vol. 7, No. 2, pp. 187-192 and Zimmermann et al, US Patent
  • ketone 1 is reacted with dimethylacetamide dimethylacetal to form the enamine 2 by heating the reagents together in a suitable inert solvent.
  • suitable inert solvents include, for example, alkyl alcohols, such as methanol, ethanol, and isopropanol; esters such as methyl acetate or ethyl acetate; halogenated solvents, such as methylene chloride, chloroform or carbon tetrachloride; ethers such as tetrahydrofuran, 1,4-dioxane or tert-butylethylether; and aromatic solvents such as toluene.
  • the reaction may be conveniently carried out at a temperature in the range, for example, from about 25°C to about 150°C, preferably in the range from about 25°C to about 80° C, most preferably at the reflux temperature ofthe reaction mixture.
  • the desired enamine intermediate 2 may be isolated from the reaction mixture by, for example, removing the volatile components of the reaction mixture under vacuum and purifying the residue by chromatographic separation.
  • B. The enamine 2 is reacted with a suitably substituted phenyl guanidine 3 in a suitable solvent as defined above, preferably a polar solvent, to generate the anilinopyrimidine 4.
  • the polar solvent may comprise an alkyl alcohol such as, for example, isopropanol.
  • the reaction of 2 with 3 may be carried out at an elevated temperature of from about 30°C to about 150°C, conveniently at the boiling point ofthe solvent in which the reaction is performed.
  • Synthesis of Formula Kb) Compounds
  • the compounds of formula 1(b) comprise pyridopyrimidines which may be prepared according to the method of Boschelli etal, J. Med. Chem. 1998, 41, pp. 4865-4377, the entire disclosure of which is incorporated herein by reference. The method is described in Scheme 4:
  • starting material 5 is reacted with an aryl or heteroaryl acetonitrile in a suitable inert solvent in the presence of a suitable base under basic conditions to effect annulation of the pyridine ring to yield an intermediate 6-aryl and heteroaryl pyridopyrimidine-2-thiomethyl-5-imino derivative, 6.
  • Suitable inert solvents include, for example alkyl alcohols, such as methanol, ethanol, isopropanol; esters such as methyl acetate or ethyl acetate; halogenated solvents, such as methylene chloride, chloroform or Carbon tetrachloride; ethers such as tetrahydrofuran, 1,4-dioxane or tert-butylethylether; aromatic solvents such as toluene; and polar aprotic solvents such as, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or N- methylpyrrolidinone (NMP).
  • alkyl alcohols such as methanol, ethanol, isopropanol
  • esters such as methyl acetate or ethyl acetate
  • halogenated solvents such as methylene chloride, chloroform or Carbon tetrachloride
  • ethers such as t
  • Suitable bases include, for example, organic amine bases such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or l,8-diazabicyclo[5.4.0]undecane; and alkali or alkaline earth metal carbonates or hydroxides, for example, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide; alkali metals or alkaline earth metal amides, for example sodium amide or sodium bis(trimethylsilyl)amide.
  • Suitable bases may also include a reagent that is immobilized on a solid phase support.
  • solid phase amine bases include diisopropylethylamine bound to polystyrene.
  • the reaction may be conveniently carried out at a temperature in the ⁇ range, for example, from about 25° C. to about 150° C, preferably in the range from about 25° C to about 100° C.
  • the amidino group of 6 is then converted from the amidine to the corresponding lactam by first acylating the imino nitrogen of 6 with a suitable acylating agent such as, for example, acetic anhydride.
  • the acylated amidine is then subjected to hydrolytic conditions such as, for example, concentrated aqueous HCl to form lactam intermediate 7.
  • hydrolytic conditions such as, for example, concentrated aqueous HCl to form lactam intermediate 7.
  • the thioether group of intermediate 7 is then oxidized to the sulfone to provide a leaving group at the 2-position.
  • the oxidation may be done in a suitable inert solvent by reaction with any suitable oxidizing agent to form the corresponding 2-methylsulfonyl-6-aryl intermediate 8.
  • suitable oxidizing agents are those capable of selectively oxidizing a sulfide to a sulfone, for example meta-chloroperoxybenzoic acid (mCPBA).
  • mCPBA meta-chloroperoxybenzoic acid
  • a suitable inert solvent for the oxidation reaction is a solvent that is not oxidized under the reaction conditions.
  • Preferred solvents include halogenated solvents such as, for example, chloroform, methylene chloride and carbon tetrachloride; and aromatic solvents such as toluene.
  • D. Reaction of the 2-methylsulfonyl-6-aryl intermediate 8 with a suitably substituted aniline, with or without an additional solvent at an elevated temperature, for example, from about 100° C to about 200° C, yields the pyridopyrimidines of Formula 1(b).
  • Additional solvents suitable for the reaction of intermediate 8 with a substituted aniline include, for example, aromatic solvents such as xylene or mesitylene.
  • the 3-cyanoquinoline intermediate 10 comprises a leaving group at the 4-position.
  • the leaving group may be a halogen, or a sulfonate group such as a triflate, mesylate, nosylate or tosylate.
  • Intermediate 10 is reacted with a suitably substituted aniline with or without an additional solvent to yield the 4-anilino-3- quinolinecarbonitriles of formula 1(c).
  • Additional solvents suitable for the reaction of intermediate 10 with a substituted aniline include, for example, aromatic solvents such as xylene or mesitylene.
  • the reaction is preferably performed at a temperature of from about 100°C to about 200°C, preferably about 150°C.
  • Compounds of formula 1(d) are prepared from an intermediate 11 which comprises a nucleophilic group L*.
  • Group L* corresponds to the divalent group L in formula 1(d).
  • the group L* may thus represent -OH, -SH or a primary or secondary amino group.
  • Intermediate 12 comprises a suitable leaving group such as, for example, a halogen or a sulfonate such as a tosylate, nosylate, mesylate or triflate group.
  • Intermediates 11 and 12 are reacted together under suitable conditions such that the nucleophilic group L* on intermediate 11, effects an SN2 displacement of the leaving group of intermediate 12, thereby generating a compound of formula 1(d) as defined herein.
  • Suitable conditions for the reaction of intermediates 11 and 12 include reaction in a suitable solvent, preferably in the presence of an acid scavenging reagent.
  • suitable solvents include, for example halogenated solvents, such as methylene chloride, chloroform or carbon tetrachloride; alkyl nitriles such as acetonitrile; ethers such as tetrahydrofuran, 1,4-dioxane or tert-butylethylether; aromatic solvents such as toluene; and polar aprotic solvents such as, for example, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or N- methylpyrrolidinone (NMP).
  • DMSO dimethyl sulfoxide
  • DMF dimethylformamide
  • NMP N- methylpyrrolidinone
  • the acid scavenger may be a soluble base that is otherwise unreactive under the reaction conditions, such as, for example a tertiary amine such as triethylamine, 2,6-lutidine or l,8-diazabicyclo[5.4.0]undecane.
  • the acid scavenger may be an inorganic base that is insoluble or has limited solubility in the organic solvent, such as potassium carbonate.
  • the acid scavenger may also be a reagent that is immobilized on a solid phase support. Examples of solid phase acid scavengers include diisopropylethylamine bound to polystyrene.
  • the product of formula 1(d) may be isolated from the reaction mixture, for example by concentrating the reaction mixture under vacuum and subjecting the residue to chromatographic separation.
  • quinazoline 13 comprising a suitable leaving group at the 4-position, is reacted with aniline intermediate 14, preferably in the presence of a suitable base, to yield a compound of formula 1(e).
  • Suitable leaving groups on quinazoline 14 include, for example, halogen, such as chloro, bromo and iodo; alkoxy, such as methoxy or ethoxy; aryloxy, such as phenoxy; and sulphonyloxy groups, such as methanesulphonyloxy
  • Suitable bases for the reaction include, for example, amine bases such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine and 1,8- diazabicyclo[5.4.0]undecane; alkali or alkaline earth metal carbonates or hydroxides, for example sodium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide; alkali metal or alkaline earth metal amides, for example sodium amide or sodium bis(trimethylsilyl)amide; and reagents that are immobilized on a solid phase support, such as solid phase amine bases, e.g., diisopropylethylamine bound to polystyrene.
  • amine bases such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine and 1,8-
  • the reaction may be preferably carried out in the presence of a suitable inert solvent or diluent, for example an alkyl alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate; a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride; an ether such as tetrahydrofuran or 1,4-dioxane; an aromatic solvent such as toluene; or a polar aprotic solvent such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N- methylpyrrolidin-2-one ( ⁇ MP) or dimethylsulphoxide (DMSO).
  • a suitable inert solvent or diluent for example an alkyl alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate; a halogenated solvent such as methylene chloride, chloroform
  • the reaction may be conveniently carried out at a temperature in the range of from about 10° C. to about 150° C, preferably in the range from about 20° C to about 80° C.
  • the intermediate quinazoline 13 may be prepared according to Scheme 8 from a corresponding quinazoline 13a that is substituted at the 6-position with a hydroxyl group .
  • Scheme 8 The 6-hydroxyl group of quinazoline intermediate 13a may be conveniently alkylated in the presence of a suitable base.
  • Suitable alkylating agents include any agent known in the art for the alkylation of a hydroxy group to produce an amino-substituted alkoxy group.
  • alkylating agents include amino-substituted alkyl halides, such as amino-substituted alkyl chlorides, bromides or iodides.
  • the alkyl halide may be substituted with a functional group that is a precursor to an amine.
  • precursors include nitro groups; aldehydes, ketones and ketals; and amines protected by protecting groups such as, for example, tert-butoxycarbonyl (t- BOC) and carbobenzyloxy (CBZ).
  • t- BOC tert-butoxycarbonyl
  • CBZ carbobenzyloxy
  • the alkylation reaction is preferably performed at a temperature in the range of from about 10° C to about 140° C, conveniently at or near about 80° C.
  • the intermediate quinazoline 13 may be prepared according to Scheme 8 from a corresponding quinazoline 13b that is substituted at the 6-position with a hydroxyalkyl group, or a reactive derivative thereof, which group may be conveniently aminated with an appropriate amine in the presence of a suitable base as defined above in the synthesis of formula 1(e) compounds.
  • a suitable reactive derivative of a hydroxy(C 1 -C ⁇ )alkoxy group is, for example, a derivative comprising a leaving group as described above in the quinazoline synthesis method.
  • the amination reaction of Scheme 8 is preferably carried out in the presence of a suitable inert solvent as defined hereinbefore in the quinazoline synthesis method, and at a temperature in the range of from about 10° C to about 150° C, conveniently at or near about 50° C.
  • the reaction mixture (0.1 mol) is added portionwise and the reaction mixture may be reftuxed for 2-3 hours, then cooled to ambient temperature. The cooled reaction mixture is poured onto crushed ice and neutralized with dilute hydrochloric acid (200 mL).
  • the resulting thioacetic acid 16 (0.1 mol) may be oxidized to the corresponding sulfonyl acetic acid 17b by use of any reagent capable of oxidizing a sulfide to a sulfone.
  • the thioacetic acid 16 may alternately be oxidized to the sulfinyl acetic acid 17a by treatment with any reagent capable of selectively oxidizing a sulfide to a sulfoxide.
  • Suitable oxidizing reagents for both oxidation reactions include peroxides such as hydrogen peroxide, peracids such as meta-chloroperoxybenzoic acid (MCPBA) or persulfates such as OXONE® (potassium peroxymonosulfate).
  • MCPBA meta-chloroperoxybenzoic acid
  • OXONE® potential peroxymonosulfate
  • the reaction is preferably carried out in the presence of a suitable solvent.
  • Suitable solvents include, for example, water, acetic acid or non-polar solvents such as dichloromethane (DCM).
  • Reaction to selectively form the sulfinyl acetic acid 17a is preferably performed at low temperature, more preferably from about -10 to about 20°C.
  • a reaction to form the sulfinyl acetic acid 17a is preferably monitored so as to terminate the reaction prior to appreciable oxidation to the sulfonyl acetic acid 17b.
  • the reaction mixture may be poured onto crushed ice.
  • a solid precipitate may be collected by filtration and recrystallized from hot water to yield the purified sulfinyl acetic acid 17a.
  • Reaction to form the sulfonyl acetic acid 17 b may be performed at higher temperature, for example, from about 30 to about 100°C with 30% hydrogen peroxide (0.12 mol) in glacial acetic acid (25 mL) by refluxing for 1-2 hours.
  • the reaction mixture may be cooled to ambient temperature and poured onto crushed ice. A solid precipitate may be collected by filtration and recrystallized from hot water to yield the purified sulfonyl acetic acid 17b.
  • the , ⁇ -unsaturated sulfone 19b may be prepared by mixing the sulfonyl acetic acid 17b (0.001 mol), an aromatic aldehyde 18 (0.001 mol) and benzylamine (1 mL) in glacial acetic acid (15 mL) and heating the mixture at reflux temperature for 2-3 hours.
  • the , ⁇ -unsaturated sulfoxide 19a may be prepared by mixing the sulfinyl acetic acid 17a (0.001 mol), an aromatic aldehyde 18 (0.001 mol) and benzylamine (1 mL) in glacial acetic acid (15 mL) and heating the mixture at reflux temperature for 2-3 hours.
  • the reaction mixture may be cooled to ambient temperature and treated with dry ether (50 mL). Any precipitated product may be collected by filtration.
  • the filtrate may be diluted with more ether and washed successively with a saturated solution of sodium bicarbonate (20 mL), sodium bisulfite (20 mL), dilute hydrochloric acid (20 mL) and finally with water (35 mL). Evaporation of the dried ether layer yields a solid compound of formula II in many cases. However, in some cases a syrupy material separates and may be solidified on treatment with 2-propanol. The purity of the product may be checked by TLC (silica gel, hexane/ethyl acetate 3:1).
  • an aromatic mercaptan may be converted to the corresponding sodium thiolate 21.
  • an alkyl alcohol is added an aryl acetylene 20.
  • the reaction is preferably performed at elevated temperature, more preferably at the reflux temperature of the reaction mixture.
  • the reaction mixture may be poured onto water ice.
  • the crude product may be collected by filtration and purified, preferably by recrystallization from a suitable solvent, to yield a pure (Z)- ⁇ , ⁇ -unsaturated (aryl or heteroaryl)sulfide 22.
  • Preferable recrystallization solvents include water miscible alcohols and aqueous mixtures of water-miscible alcohols.
  • the (Z)- ⁇ , ⁇ -unsaturated (aryl or heteroaryl)sulfide 22 may be oxidized to the corresponding sulfone by use of any reagent capable of oxidizing a sulfide to a sulfone.
  • the (Z)- ⁇ , ⁇ -unsaturated (aryl or heteroaryl)sulfide 22 may be oxidized to the corresponding sulfoxide by use of any reagent capable of oxidizing a sulfide to a sulfoxide.
  • Suitable reagents and conditions for oxidation to a sulfone or sulfoxide are the same as the conditions for preparation of sulfonyl acetic acid 17b and sulfinyl acetic acid 17a.
  • the purity ofthe (Z)- ⁇ , ⁇ - unsaturated (aryl or heteroaryl)sulfone or sulfoxide may be ascertained by thin layer chromatography and geometrical configuration may be assigned by analysis of infrared and nuclear magnetic resonance spectral data.
  • the sodium sulfoacetate intermediate is then reacted with a chlorinating agent, preferably PC1 5 , to form the methyl (or ethyl) ⁇ -chlorosulfonylacetate intermediate 24.
  • a chlorinating agent preferably PC1 5
  • Reaction of intermediate 24 with the aromatic amine 25 yields the arylaminosulfonylacetate intermediate 26.
  • the latter reaction may be conducted in a nonprotic solvent in the presence of a base.
  • the same compound may serve as both the nonprotic solvent and the base.
  • dual-function solvents include, for example, pyridine, substituted pyridines, trimethylamine and triethylamine.
  • the arylaminosulfonylacetate 26 is then converted to the corresponding arylaminosulfonylacetic acid compound 27 by any base capable of hydrolyzing the ester function of 26 to an acid.
  • bases include, for example, KOH and NaOH.
  • the arylaminosulfonylacetic acid compound is condensed with arylaldehyde 18 in the presence of a basic catalyst via a Rnoevenagel reaction and decarboxylation of an intermediate.
  • Basic catalysts include, for example, pyridine and benzylamine. The reaction yields the desired N-(aryl)-2-arylethenesulfonamide of formula II.
  • reaction mixture is cooled and poured into ice water (IL) and concentrated hydrochloric acid (100 mL) is added.
  • IL ice water
  • hydrochloric acid 100 mL
  • the precipitated product may be separated by filtration and crystallized to yield a pure E- or Z-N-(aryl or heteroaryl)-3-(aryl or heteroaryl)-2- propenamide of formula II.
  • therapeutic ionizing radiation may be administered to an individual on any schedule and in any dose consistent with the prescribed course of treatment.
  • the radioprotective compound is administered prior to the therapeutic ionizing radiation.
  • the course of treatment differs from individual to individual, and those of ordinary skill in the art can readily determine the appropriate dose and schedule of therapeutic radiation in a given clinical situation.
  • reference to administration of radioprotective compound shall mean administration of a radioprotective compound according to formula I alone, or in combination with either a radioprotective compound of formula II, or an antioxidant compound.
  • the formula II compound or antioxidant compound may be administered simultaneously with the formula I compound, or may be administered separately.
  • the compounds may be administered by the same or by different routes.
  • the administration times are preferably optimized to obtain the radioprotective benefit of the combination based on the pharmacokinetic profiles of the compounds administered.
  • the administration may be by the same or by different routes.
  • simultaneous administration is done by administering the compounds as part of the same pharmaceutical composition.
  • the radioprotective compound should be administered far enough in advance ofthe therapeutic radiation such that the compound is able to reach the normal cells of the individual in sufficient concentration to exert a radioprotective effect on the normal cells.
  • the radioprotective compound may be administered as much as about 24 hours, preferably no more than about 18 hours, prior to administration of the radiation.
  • the radioprotective compound is administered at least about 6-12 hours before administration ofthe therapeutic radiation.
  • the radioprotective compound is administered once at about 18 hours and again at about 6 hours before the radiation exposure.
  • One or more radioprotective compounds may be administered simultaneously, or different radioprotective compounds may be administered at different times during the treatment.
  • the therapeutic radiation is administered in serial fashion, it is preferable to intercalate administration of one or more radioprotective compounds within the schedule of radiation treatments.
  • different radioprotective compounds may be administered either simultaneously or at different times during the treatment.
  • an about 24 hour period separates administration of a radioprotective compound and the therapeutic radiation.
  • the administration of a radioprotective compound and the therapeutic radiation is separated by about 6 to 18 hours.
  • This strategy will yield significant reduction in radiation-induced side effects without affecting the anticancer activity ofthe therapeutic radiation.
  • therapeutic radiation at a dose of 0.1 Gy may be given daily for five consecutive days, with a two-day rest, for a total period of 6-8 weeks.
  • One or more compounds according to the invention may be administered to the individual 18 hours previous to each round of radiation.
  • more aggressive treatment schedules i.e., delivery of a higher dosage, is contemplated according to the present invention due to the protection of the normal cells afforded by the radioprotective compounds.
  • the radioprotective effect of the radioprotective compound increases the therapeutic index of the therapeutic radiation, and may permit the physician to safely increase the dosage of therapeutic radiation above presently recommended levels without risking increased damage to the surrounding normal cells and tissues.
  • the radioprotective compounds of the invention are further useful in protecting normal bone marrow cells from radiological treatments designed to destroy hematological neoplastic cells or tumor cells which have metastasized into the bone marrow.
  • Such cells include, for example, myeloid leukemia cells.
  • the appearance of these cells in the bone marrow and elsewhere in the body is associated with various disease conditions, such as the French-American-British (FAB) subtypes of acute myelogenous leukemias (AML), chronic myeloid leukemia (CML), and acute lymphocytic leukemia (ALL).
  • FAB French-American-British subtypes of acute myelogenous leukemias
  • CML chronic myeloid leukemia
  • ALL acute lymphocytic leukemia
  • CML in particular, is characterized by abnormal proliferation of immature granulocytes (e.g., neutrophils, eosinophils, and basophils) in the blood, bone marrow, spleen, liver, and other tissues and accumulation of granulocytic precursors in these tissues.
  • immature granulocytes e.g., neutrophils, eosinophils, and basophils
  • the individual who presents with such symptoms will typically have more than 20,000 white blood cells per microliter of blood, and the count may exceed 400,000.
  • Virtually all CML patients will develop "blast crisis", the terminal stage of the disease during which immature blast cells rapidly proliferate, leading to death.
  • Other individuals suffer from metastatic tumors, and require treatment with total body irradiation (TBI).
  • TBI total body irradiation
  • TBI will also kill the individual's hematopoietic cells
  • a portion ofthe individual's bone marrow is removed prior to irradiation for subsequent reimplantation.
  • metastatic tumor cells are likely present in the bone marrow, and reimplantation often results in a relapse of the cancer within a short time.
  • Individuals presenting with neoplastic diseases of the bone marrow or metastatic tumors may be treated by removing a portion of the bone marrow (also called “harvesting"), purging the harvested bone marrow of malignant stem cells, and reimplanting the purged bone marrow.
  • the individual is simultaneously treated with radiation or some other anti-cancer therapy.
  • the invention provides a method of reducing the number of malignant cells in bone marrow, comprising the steps of removing a portion of the individual's bone marrow, administering an effective amount of at least one radioprotective compound of formula I and irradiating the treated bone marrow with a sufficient dose of ionizing radiation such that neoplastic or tumor cells in the bone marrow are killed.
  • malignant cell means any uncontrollably proliferating cell, such a tumor cell or neoplastic cell.
  • the radioprotective compound protects the normal hematopoietic cells present in the bone marrow from the deleterious effects ofthe ionizing radiation.
  • each radioprotective compound is administered in a concentration from about 0.25 to about 100 micromolar; more preferably, from about 1.0 to about 50 micromolar; in particular from about 2.0 to about 25 micromolar. Particularly preferred concentrations are 0.5, 1.0 and 2.5 micromolar and 5, 10 and 20 micromolar. Higher or lower concentrations may also be used.
  • the radioprotective compound may be added directly to the harvested bone marrow, but are preferably dissolved in an organic solvent such as dimethylsulfoxide (DMSO). Pharmaceutical formulations of radioprotective compounds such as are described in more detail below may also be used.
  • the radioprotective compound is added to the harvested bone marrow about 20 hours prior to radiation exposure, preferably no more than about 24 hours prior to radiation exposure. In one embodiment, the radioprotective compound is administered to the harvested bone marrow at least about 6 hours before radiation exposure.
  • One or more radioprotective compounds of formula I may be administered simultaneously, or different radioprotective compounds may be administered at different times. Other dosage regimens may also be used. If the individual is to be treated with ionizing radiation prior to reimplantation of the purged bone marrow, the individual may be treated with one or more radioprotective compounds of formula I prior to receiving the ionizing radiation dose, as described above.
  • An individual may also be exposed to ionizing radiation from occupational or environmental sources, as discussed in the background section.
  • the source of the radiation is not as important as the type (i.e., acute or chronic) and dose level absorbed by the individual. It is understood that the following discussion encompasses ionizing radiation exposures from both occupational and environmental sources. Individuals suffering from effects of acute or chronic exposure to ionizing radiation that are not immediately fatal are said to have remediable radiation damage. Such remediable radiation damage can be reduced or eliminated by the compounds and methods ofthe present invention.
  • An acute dose of ionizing radiation which may cause remediable radiation damage includes a localized or whole body dose, for example, between about 10,000 millirem (0.1 Gy) and about 1,000,000 millirem (10 Gy) in 24 hours or less, preferably between about 25,000 millirem (0.25 Gy) and about 200,000 (2 Gy) in 24 hours or less, arid more preferably between about 100,000 millirem (1 Gy) and about 150,000 millirem (1.5 Gy) in 24 hours or less.
  • a chronic dose of ionizing radiation which may cause remediable radiation damage includes a whole body dose of about 100 millirem (.001 Gy) to about 10,000 millirem (0.1 Gy), preferably a dose between about 1000 millirem (.01 Gy) and about 5000 millirem (.05 Gy) over a period greater than 24 hours, or a localized dose of 15,000 millirem (0.15 Gy) to 50,000 millirem (0.5 Gy) over a period greater than 24 hours.
  • the invention therefore provides a method for treating individuals who have incurred remediable radiation damage from acute or chronic exposure to ionizing radiation, comprising reducing or eliminating the cytotoxic effects of radiation exposure on normal cells and tissues by administering an effective amount of at least one radioprotective compound of formula I.
  • the compound is preferably administered in as short a time as possible following radiation exposure, for example between 0 - 6 hours following exposure.
  • Remediable radiation damage may take the form of cytotoxic and genotoxic (i.e., adverse genetic) effects in the individual.
  • a method of reducing or eliminating the cytotoxic and genotoxic effects of radiation exposure on normal cells and tissues comprising administering an effective amount of at least one radioprotective compound prior to acute or chronic radiation exposure.
  • the compound may be administered, for example about 24 hours prior to radiation exposure, preferably no more than about 18 hours prior to radiation exposure.
  • the compound is administered at least about 6 hours before radiation exposure. Most preferably, the compound is administered at about 18 and again at about 6 hours before the radiation exposure.
  • One or more radioprotective compounds of formula I may be administered simultaneously, or different compounds may be administered at different times.
  • the administration times are preferably optimized to obtain the radioprotective benefit of the combination based on the pharmacokinetics ofthe compounds administered.
  • the administration may be by the same or by different routes.
  • simultaneous administration of more than one compound of formula I is done by administering the compounds as part of the same pharmaceutical composition.
  • the radioprotective compound may be administered multiple times. For example, if fire or rescue personnel must enter contaminated areas multiple times, the radioprotective compound may be administered prior to each exposure.
  • an about 24-hour period separates administration of radioprotective compound and the radiation exposure. More preferably, the administration of a radioprotective compound and the radiation exposure is separated by about 6 to 18 hours. It is also contemplated that a worker in a nuclear power plant may be administered an effective amount of radioprotective compound prior to beginning each shift, to reduce or eliminate the effects of exposure to ionizing radiation. If an individual anticipates chronic exposure to ionizing radiation, the radioprotective compound may be administered periodically throughout the duration of anticipated exposure. For example, a nuclear power plant worker or a soldier operating in a forward area contaminated with radioactive fallout may be given a radioprotective compound of formula I every 24 hours, preferably every 6-18 hours, in order to mitigate the effects of radiation damage. Likewise, the radioprotective compound may be periodically administered to civilians living in areas contaminated by radioactive fallout until the area is decontaminated or the civilians are removed to a safer environment.
  • administered means the act of making the radioprotective compounds of formula I (alone, or in combination with a compound of formula II or an antioxidant) available to the individual such that a pharmacological effect of radioprotection is realized.
  • This pharmacological effect may manifest as the absence of expected physiologic or clinical symptoms at a certain level of radiation exposure.
  • One skilled in the art may readily determine the presence or absence of radiation-induced effects, by well- known laboratory and clinical methods.
  • the radioprotective compound may thus be administered by any route which is sufficient to bring about the desired radioprotective effect in the patient.
  • Routes of administration include, for example enteral (e.g., oral, rectal, intranasal, etc.) and parenteral administration.
  • Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intravaginal, intravesical (e.g., into the bladder), intradermal, topical or subcutaneous administration.
  • parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intravaginal, intravesical (e.g., into the bladder), intradermal, topical or subcutaneous administration.
  • a depot of a radioprotective compounds of formula I may be administered to the patient more than 24 hours before the administration of radiation.
  • at least a portion of the compound is retained in the depot and not released until an about 6-18 hour window prior to the radiation exposure.
  • the radioprotective compound may be administered in the form of a pharmaceutical composition comprising one or more compounds of formula I in combination with a pharmaceutically acceptable carrier.
  • the active compound in such formulations may comprise from 0.1 to 99.99 weight percent.
  • pharmaceutically acceptable carrier is meant any carrier, diluent or excipient, which is compatible with the other ingredients of the formulation and is not deleterious to the individual. It is within the skill in the art to formulate appropriate pharmaceutical compositions with radioprotective compounds.
  • the radioprotective compound may be formulated into pharmaceutical compositions according to standard practices in the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, PA.
  • Suitable pharmaceutical compositions include, for example, tablets, capsules, solutions (especially parenteral solutions), troches, suppositories, or suspensions.
  • the radioprotective compound may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, cyclodextrans or a glycol such as propylene glycol or polyethylene glycol.
  • Solutions for parenteral administration preferably contain a pharmaceutically acceptable, water-soluble salt of the radioprotective compound. Stabilizing agents, antioxidizing agents and preservatives may also be added.
  • Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
  • the radioprotective compound may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, or other suitable oral dosage forms.
  • the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods.
  • the specific dose and schedule of radioprotective compound to obtain the radioprotective benefit will, of course, be determined by the particular circumstances of the individual patient including, the size, weight, age and sex of the patient, the nature and stage of the disease being treated, the aggressiveness of the disease, and the route of administration, and the specific toxicity of the radiation.
  • a daily dosage of from about 0.01 to about 150 mg/kg/day may be utilized, more preferably from about 0.05 to about 50 mg/kg/day.
  • the dose may be given over multiple administrations, for example, two administrations of 3.5 mg/kg. Higher or lower doses are also contemplated.
  • the radioprotective compounds may take the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric, galactaric
  • Suitable pharmaceutically acceptable base addition salts include metallic salts made from calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N.N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding radioprotective compound by reacting, for example, the appropriate acid or base with the free acid or free base ofthe compound.
  • the compositions useful in the method ofthe present invention may also be formulated so as to provide slow or controlled-release ofthe active ingredient therein.
  • a controlled-release preparation is a composition capable of releasing the active ingredient at the required rate to maintain constant pharmacological activity for a desirable period of time.
  • dosage forms may provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than other non-controlled formulations.
  • U.S. Patent No. 5,674,533 discloses controlled-release compositions in liquid dosage forms for the administration of moguisteine, a potent peripheral antitussive.
  • U.S. Patent No. 5,059,595 describes the controlled-release of active agents by the use of a gastro-resistant tablet for the therapy of organic mental disturbances.
  • U.S. Patent No. 5,120,548 discloses a controlled-release drug delivery device comprised of swellable polymers.
  • U.S. Patent No. 5,073,543 discloses controlled-release formulations containing a trophic factor entrapped by a ganglioside-liposome vehicle.
  • U.S. Patent No. 5,639,476 discloses a stable solid controlled-release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer. The patents cited above are incorporated herein by reference.
  • Biodegradable microparticles may be used in controlled-release formulations useful in the method of this invention.
  • U.S. Patent No. 5,354,566 discloses a controlled-release powder that contains the active ingredient.
  • U.S. Patent No. 5,733,566 describes the use of polymeric microparticles that release antiparasitic compositions. These patents are incorporated herein by reference.
  • the controlled-release of the active ingredient may be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the controlled-release component can swell and form porous openings large enough to release the active ingredient after administration to a patient.
  • controlled-release component in the context of the present invention is defined herein as a compound or compounds, such as polymers, polymer matrices, gels, permeable membranes, liposomes and/or microspheres, that facilitate the controlled-release of the radioprotective compound of formula I in a pharmaceutical composition.
  • the controlled-release component may be biodegradable, induced by exposure to the aqueous environment, pH, temperature, or enzymes in the body.
  • sol-gels may be used, wherein the active ingredient is incorporated into a sol-gel matrix that is a solid at room temperature.
  • This * matrix is implanted into a patient, preferably a mammal, having a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing the active ingredient into the patient.
  • a patient preferably a mammal, having a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing the active ingredient into the patient.
  • the practice ofthe invention is illustrated by the following non-limiting examples. Examples
  • Example 1 Synthesis of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4- methyl-phenyl)-4-((4-methylpiperazin-l-yI)methyl)benzamide.
  • the compound of Example 1, an anilinopyrimidine of formula 1(a), is synthesized according to Scheme 14.
  • the product 1(a), (2E)- 3-(dimethylamino)-l-(3-pyridyl)prop-2-en-l-one is isolated by removing the volatiles under vacuum and purifying the residue by high throughput preparative HPLC.
  • reaction is monitored by HPLC for disappearance of the starting pyrimidine aldehyde 2(b).
  • the mixture is cooled to ambient temperature, diluted with water and extracted with ether.
  • the ether extract is concentrated and the residue is purified the residue by preparative HPLC to yield the product 2(c), 6-(2,6- dichlorophenyl)-8-methyl-2-methylthio-8-hydropyridino[2,3-d]pyrimidin-7- imine.
  • 6-(2,6-dichlorophenyl)-8-methyl-2-methylthio-8-hvdropyridinor2 - d]pyrimidin-7-one.2(d) A mixture of 2(c) (6 mmol, 2.1 g) and acetic anhydride (16 mL) is heated to reflux for 30 minutes. The reaction mixture is then cooled to ambient temperature, diluted with ether and concentrated under vacuum. The resulting residue is triturated in ether to yield 2(d), 6-(2,6-dichlorophenyl)-8-methyl-2- methylthio-8-hydropyridino[2,3-d]pyrimidin-7-one.
  • Example 2 compound 6-(2,6-dichlorophenyl)-8-methyl-2-[(3-methylthio- phenyl)amino]-8-hydro-pyridino-[2,3-d]pyrimidin-7-one.
  • Example 3 Synthesis of 4-[(2,4-dichIoro-5-methoxyphenyI)amino]-6- methoxy-7-[3-(4-methyIpiperazinyl)-propoxy]quinoIine-3-carbonitrile
  • the title compound of Example 3, an anilino-3 ⁇ quinolinecarbonitriles of formula 1(c) is synthesized according to Scheme 16.
  • reaction mixture is cooled to ambient temperature and filtered and extracted with methylene chloride.
  • methylene chloride extract is dried and concentrated.
  • the resulting residue is purified by trituration with ether hexane (1:10) to yield intermediate 3(c), methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate.
  • the mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated under vacuum to yield the 4-anilinoquinoline.
  • This intermediate is used without further purification in the next step.
  • the intermediate, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(3- chloropropoxy)-6-methoxyquinoline-3-carbonitrile is added to N- methylpiperazine (2 mL) along with a catalytic amount of sodium iodide. The mixture is heated to 90° C for 17 hours.
  • Example 5 Synthesis of (3-chloro-4-fluorophenyl)[7-methoxy-6-(3- morpholin-4-ylpropoxy)quinazolin-4-yl]amine The title compound of Example 5, a quinazoline of formula 1(e). is synthesized according to Scheme 18.
  • 6-Acetoxy-4-chloro-7-methoxyquinazoline 5(d).
  • a mixture of 5(c) 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (15 g), thionyl chloride (215 mL) and DMF (4.3 mL) is stirred and heated to 90° C for 4 hours.
  • the mixture is cooled to ambient temperature and concentrated under vacuum to yield 5(d), 6-acetoxy-4-chloro-7-methoxyquinazoline, hydrochloride salt, which intermediate is used without further purification.
  • Example 5 compound 4-(3 '-chloro-4'-fluoroanilino)-7-methoxy-6-(3 -morpholinopropoxy)- quinazoline.
  • Example 6 Inhibition of ABL Tyrosine Kinase by N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)- methyl)benzamide: Method A The inhibition of ABL activity by compounds of formula I was demonstrated as follows.
  • recombinant human c-abl (Abll, Histidine tagged, Panvera, CA) was incubated with various concentrations of N- (3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methyl- piperazin-l-yl)methyl)benzamide (Abl inhibitor) for 30 minutes in kinase buffer (50 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), 0.1% ⁇ P-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl 2 , pH 7.5) at room temperature in a total volume of 15 ⁇ l.
  • kinase buffer 50 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid), 0.1% ⁇ P-40, 300 mM, 2.0 mM DTT,
  • kinase reactions were performed by adding cold ATP and ⁇ -32P-ATP in the presence of 6 ⁇ g of ABL kinase substrate (recombinant murine Crk) for 20 minutes at 30°C.
  • the reactions were stopped by the addition of 20 ⁇ l of 2x SDS sample buffer.
  • the samples were boiled and resolved on a 10 % SDS-polyacrylamide gel.
  • the gel was fixed, and exposed to X-ray film. The exposed gel is reproduced in Figure 1, wherein the darker spots on the film indicate less enzyme inhibition.
  • Quantitation of Crk phosphorylation may also be determined using a phosphoimager system (Fuji).
  • Example 7 Inhibition of ABL Tyrosine Kinase by N-(3-(4-(pyridin-3- yI)pyrimidin-2-ylamino)-4-methyl-phenyI)-4-((4-methyIpiperazin-l- yl)methyl)benzamide: Method B - Quantitation using filter assay.
  • recombinant human c-abl (Abll, Histidine tagged, Panvera, CA) was incubated with various concentrations of N-(3-(4-(pyridin-3- yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)- benzamide for 30 minutes in kinase buffer (50 mM HEPES, 0.1% ⁇ P-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl 2 , pH 7.5) at room temperature in a total volume of 15 ⁇ l.
  • kinase buffer 50 mM HEPES, 0.1% ⁇ P-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl 2 , pH 7.5
  • kinase reactions were perfonned by adding cold ATP and ⁇ -32P-ATP in the presence of Crk (6 ⁇ g) for 20 minutes at 30° C. After incubation, 10 ⁇ l aliquots were spotted onto 2 cm x 2 cm P81 phosphocellulose paper. The paper was air dried and then washed 3x with 0.75% phosphoric acid, and fixed with acetone for 5 minutes. The wet filters were then placed into scintillation vials containing scintillation fluid (Ecolume) and counted for 32P using a scintillation counter. The counts per minute (CPM) of each treated sample were compared to the amount of radioactivity resulting from control reactions in the presence of DMSO. The reactions were performed in triplicates, and the average CPM +/- SD for each were plotted as percent of solvent treated control. The dose response data are listed in Table 4 and plotted in Figure 2. Table 4:
  • Example 8 Inhibition of ABL Tyrosine Kinase by Compounds according to Formula II: Method B - Quantitation using filter assay.
  • Purified (5-10 ng) recombinant human c-abl (Abll, Histidine tagged, Panvera, CA) was incubated with various concentrations of each compound of Formula II listed in Table 5 for 30 minutes in kinase buffer (50 mM HEPES, 0.1% NP-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl 2 , pH 7.5) at room temperature in a total volume of 15 ⁇ l.
  • kinase buffer 50 mM HEPES, 0.1% NP-40, 300 mM, 2.0 mM DTT, 1.0 mM EDTA, 10 mM MgCl 2 , pH 7.5
  • kinase reactions were performed by adding cold ATP and ⁇ -32P-ATP in the presence of Crk (6 ⁇ g) for 20 minutes at 30° C. After incubation, 10 ⁇ l aliquots were spotted onto 2 cm x 2 cm P81 phosphocellulose paper. The paper was air dried and then washed 3x with 0.75% phosphoric acid, and fixed with acetone for 5 minutes. The wet filters were then placed into scintillation vials containing scintillation fluid (Ecolume) and counted for 32P using a scintillation counter. The counts per minute (CPM) of each treated sample were compared to the amount of radioactivity resulting from control reactions in the presence of DMSO.
  • CPM counts per minute
  • Example 9 Inhibition of ABL Tyrosine Kinase by a Composition Comprising N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)- 4-((4-methylpiperazin-l-yl)methyl)benzamide and 4-((lE)-2- ⁇ [(4- chIorophenyl)methyl]sulfonyl ⁇ vinyl)benzoic acid: Method A Ten ng of recombinant c-Abl-1 protein (Panvera) was incubated with different concentrations of a mixture of N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide and 4-((lE)-2- ⁇ [(4-chlorophenyl)methyl]-sulfonyl ⁇ vinyl)benzoic acid (Com
  • the data show that, for a composition containing 10 nM N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl- phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide and 1 nM of 4-((lE)-2- ⁇ [(4-chlorophenyl)methyl]sulfonyl ⁇ vinyl)benzoic acid, the kinase activity of C- abl was completely blocked. The concentration of either agent individually required to completely block c-abl kinase activity was 1 ⁇ M.
  • Example 10 Radioprotective Effect of N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide on Cultured Normal Cells: The radioprotective effect of N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide on cultured normal cells was evaluated as follows.
  • HFL-1 cells which are normal diploid lung fibroblasts, were plated into 24 well dishes at a cell density of 3000 cells per 10 mm 2 in DMEM completed with 10% fetal bovine serum and antibiotics. N-(3-(4-(pyridin-3-yl)pyrimidin- 2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide was added to the cells 24 hours later at concentrations 0.25, 0.5, 1.0 and 2.0 micromolar, using DMSO as a solvent. Control cells were treated with DMSO alone. The cells were exposed to the test compound or DMSO for 24 hrs.
  • the cells were then irradiated with either 10 Gy or 15 Gy of ionizing radiation (IR) using a J.L. Shepherd Mark I, Model 30-1 Irradiator equipped with 137 cesium as a source. After irradiation, the medium on the test and control cells was removed and replaced with fresh growth medium without the test compounds or DMSO. The irradiated cells were incubated for 96 hours and duplicate wells were trypsinized and replated onto 100 mm 2 tissue culture dishes. The replated cells were grown under normal conditions with one change of fresh medium for 3 weeks. The number of colonies from each 100 mm 2 culture dish, which represents the number of surviving cells, was determined by staining the dishes as described below.
  • IR ionizing radiation
  • radioprotective activity of N-(3- (4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin- l-yl)methyl)benzamide is substantial, demonstrating a greater than 90% increase in the number of cells surviving irradiation when treated at 1.0 micromolar concentration.
  • Example 11 Radioprotective Effect of a Composition Comprising a Mixture of iV-(3-(4-(pyridin-3-yl)pyrimidin-2-yIamino)-4-methyl-phenyl)-4- ((4-methyIpiperazin-l-yl)methyl)benzamide and a Compound of Formula II or an Antioxidant Compound on Cultured Normal Cells:
  • the radioprotective effect of a composition comprising N-(3-(4-(pyridin- 3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methylpiperazin-l- yl)methyl)benzamide in combination with either a compound of formula II (e.g., 4-((lE)-2- ⁇ [(4-chlorophenyl)methyl]sulfonyl ⁇ vinyl)benzoic acid (compound 23 of Table 5)) or an antioxidant compound on cultured normal cells is evaluated as follows.
  • HFL-1 cells which are normal diploid lung fibroblasts, are plated into 24 well dishes at a cell density of 3000 cells per 10 mm 2 in DMEM completed with 10% fetal bovine serum and antibiotics.
  • N-(3-(4-(pyridin-3-yl)pyrimidin- 2-y lamino)-4-methyl-phenyl)-4-((4-methy lpiperazin- 1 -yl)methy l)benzamide is added to the cells 24 hours later at concentrations 0.25, 0.5, 1.0 and 2.0 micromolar, alone or in combination with either an antioxidant compound or a compound of formula II (e.g., compound 23) using DMSO as a solvent. Control cells are treated with DMSO alone.
  • the cells are exposed to the test compound (or combination of compounds) or DMSO for 24 hrs.
  • the cells are then irradiated with either 10 Gy or 15 Gy of ionizing radiation (IR) using a J.L. Shepherd Mark I, Model 30-1 Irradiator equipped with 137 cesium as a source.
  • IR ionizing radiation
  • the medium on the test and control cells is removed and replaced with fresh growth medium without the test compounds or DMSO.
  • the irradiated cells are incubated for 96 hours and duplicate wells are trypsinized and replated onto 100 mm 2 tissue culture dishes. The replated cells are grown under normal conditions with one change of fresh medium for 3 weeks.
  • the number of colonies from each 100 mm 2 culture dish which represents the number of surviving cells, is determined by staining the dishes as described below.
  • the medium is removed and the plates are washed one time with ambient temperature phosphate buffered saline.
  • the cells are stained with a 1:10 diluted Modified Giemsa staining solution (Sigma) for 20 minutes. The stain is removed, and the plates are washed with tap water. The plates are air-dried, the number of colonies from each plate is counted and the average from duplicate plates is determined.
  • Example 12 Treatment of bcr-abl Transformed Leukemic Cells by a Composition Comprising N-(3-(4-(pyridin-3-yI)pyrimidin-2-ylamino)-4- methyl-phenyl)-4-((4-methylpiperazin-l-yl)methyl)benzamide (A Compound of Formula T) and (lE)-2-(2,4-difluorophenyI)-l- ⁇ [(4- bromophenyl)methyl]sulfonyl ⁇ ethene (A Compound of Formula IT): K562 cells, a cell line isolated from a 35 year old patient with chronic myelogenous leukemia (CML), transformed due to the Philadelphia chromosome translocation resulting in the expression of bcr-abl kinase was used as the target cell line.
  • CML chronic myelogenous leukemia
  • K562 cells were plated at a cell density of 1.0 x 10 5 cells/mL in 12 well dishes and treated with a constant concentration (0.2 ⁇ M) of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4-methyl- piperazin-l-yl)methyl)benzamide (a concentration that would reduce the growth of K562 cells by no more than 20% based upon previous dose response assays).
  • the cells were further treated with a series of concentrations of the compound ( 1 E)-2-(2,4-difluorophenyl)- 1 - ⁇ [(4-bromophenyl)-methyl] sulfonyl ⁇ ethene. Following an incubation period of 96 hours at 37°C under 5% CO 2 , the number of viable cells remaining in each well was determined by counting using a hemacytometer and trypan blue staining. The total number of viable cells remaining was calculated and plotted as the percent of vehicle treated control cells. The results are depicted in Figure 4.
  • Example 13 Effect of Exposure to Ionizing Radiation on Normal and Malignant Hematopoietic Progenitor Cell Growth After Pretreatment with N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4-((4- methylpiperazin-l-yl)methyl)benzamide.
  • the effect of ionizing radiation on normal and malignant hematopoietic progenitor cells which are pretreated with N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-phenyl)-4-((4-methylpi ⁇ erazin- 1 -yl)methyl)benzamide is determined by assessing cloning efficiency and development of the pretreated cells after irradiation.
  • human bone marrow cells (BMC) or peripheral blood cells (PB) are obtained from normal healthy, or acute or chronic myelogenous leukemia (AML, CML), volunteers by Ficoll- Hypaque density gradient centrifugation, and are partially enriched for hematopoietic progenitor cells by positively selecting CD34 + cells with immunomagnetic beads (Dynal A.S., Oslo, Norway).
  • the CD34 + cells are suspended in supplemented alpha medium and incubated with mouse anti- HPCA-I antibody in 1 :20 dilution, 45 minutes, at 4°C with gentle inverting of tubes.
  • Cells are washed x 3 in supplemented alpha medium, and then incubated with beads coated with the Fc fragment of goat anti-mouse IgGi (75 ⁇ l of immunobeads/107 CD34 + cells). After 45 minutes of incubation (4°C), cells adherent to the beads are positively selected using a magnetic particle concentrator as directed by the manufacturer.
  • ' 2 x 10 4 CD34 + cells are incubated in 5 mL polypropylene tubes (Fisher Scientific, Pittsburgh, PA) in a total volume of 0.4 mL of Iscove's modified Dulbecco's medium (IMDM) containing 2% human AB serum and 10 mM Hepes buffer.
  • IMDM Iscove's modified Dulbecco's medium
  • N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methyl-phenyl)-4- ((4-methylpiperazin-l-yl)methyl)benzamide is added to the cells; in four different concentrations (0.25 ⁇ M, 0.5 ⁇ M, 1.0 ⁇ M and 2.0 ⁇ M) is added separately to the cells.
  • Control cells receive DMSO alone. The cells are incubated for 20-24 hours and irradiated with 5 Gy or 10 Gy of ionizing radiation. Immediately after irradiation, the medium is removed and replaced with fresh medium without the test compound or DMSO.
  • the treatment and control cells are prepared for plating in plasma clot or methylcellulose cultures.
  • Cells (1 x 1Q 4 CD34 + cells per dish) are not washed before plating.
  • Assessment of the cloning efficiency and development of the treated hematopoietic progenitor cells are carried out essentially as reported in Gewirtz et al, Science 242, 1303-1306 (1988), the disclosure of which is incorporated herein by reference.
  • Example 14 Bone Marrow Purging with Ionizing Radiation After Pretreatment with N-(3-(4-(pyridin-3-yl)pyrimidin-2-yIamino)-4-methyI- phenyl)-4-((4-methylpiperazin-l-yl)methyI)benzamide.
  • Bone marrow is harvested from the iliac bones of an individual under general anesthesia in an operating room using standard techniques. Multiple aspirations are taken into heparinized syringes. Sufficient marrow is wididrawn so that the individual will be able to receive about 4 x 10 8 to about 8 x 10 8 processed marrow cells per kg of body weight.
  • marrow about 750 to 1000 mL of marrow is withdrawn.
  • the aspirated marrow is transferred immediately into a transport medium (TC-199, Gibco, Grand Island, New York) containing 10,000 units of preservative-free heparin per 100 mL of medium.
  • the aspirated marrow is filtered through three progressively finer meshes to obtain a cell suspension devoid of cellular aggregates, debris and bone particles.
  • the filtered marrow is then processed further into an automated cell separator (e.g., Cobe 2991 Cell Processor) which prepares a "buffy coat" product, (i.e., leukocytes devoid of red cells and platelets).
  • the buffy coat preparation is then placed in a transfer pack for further processing and storage.
  • purging may be carried out immediately, then the purged marrow may be stored frozen in liquid nitrogen until it is ready for transplantation.
  • the purging procedure is carried out as follows. Cells in the buffy coat preparation are adjusted to a cell concentration of about 2 x 10 7 /mL in TC-199 containing about 20% autologous plasma.
  • N-(3-(4-(pyridin-3-yl)pyrimidin-2- ylamino)-4-methyl-pheny l)-4-((4-methylpiperazin- 1 -yl)methyl)benzamide for example, at a concentration of from 0.25 ⁇ M to 2.0 ⁇ M is added to the transfer packs containing the cell suspension and incubated in a 37°C waterbath for 20- 24 hours with gentle shaking. The transfer packs are then exposed to 5-10 Gy ionizing radiation.
  • Recombinant human hematopoietic growth factors e.g., rH IL-3 or rH GM-CSF
  • rH IL-3 or rH GM-CSF may be added to the suspension to stimulate growth of hematopoietic neoplasms and thereby increase their sensitivity to ionizing radiation.
  • the cells may then either be frozen in liquid nitrogen or washed once at

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Abstract

L'invention concerne un pré-traitement à l'aide d'un ou de plusieurs composés représentés par la formule (I), telle que décrite ici, destiné à protéger les cellules normales des effets secondaires toxiques d'un rayonnement ionisant. L'administration d'un ou de plusieurs composés radioprotecteurs, représentés par la formule (I), à un patient avant une radiothérapie anticancéreuse permet de réduire les effets secondaires cytotoxiques du rayonnement sur les cellules normales. L'effet radioprotecteur d'un ou de plusieurs composés représentés par la formule (I) permet d'augmenter en toute sécurité le dosage des rayonnements anticancéreux. L'augmentation de la toxicité suite à une exposition aux rayonnements par inadvertance peut également être réduite grâce à l'administration d'un ou de plusieurs composés représentés par la formule (I).
PCT/US2004/028654 2003-09-09 2004-09-02 La protection de tissus et de cellules contre les effets cytotoxique d'un rayonnement ionisant par des inhibiteurs abl WO2005065074A2 (fr)

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US7767678B2 (en) * 2005-07-01 2010-08-03 Wyeth Llc Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile and methods of preparing the same
US20100048597A1 (en) * 2006-12-22 2010-02-25 Novartis Ag Organic Compounds and Their Uses
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