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(11) | EP 2 100 605 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
| Note: Bibliography reflects the latest situation |
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Bis(thio-hydrazide amide) compounds in combination with taxol for treating cancer Bis(thiohydrazidamide) in Kombination mit Taxol für die Behandlung von Krebs Bis(thiohydrazidamide) en combinaison avec du Taxol pour le traitement du cancer |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
BACKGROUND OF THE INVENTION
[0001] Many new drugs are now available to be used by oncologists in treating patients with cancer. Often, tumors are more responsive to treatment when anti-cancer drugs are administered in combination to the patient than when the same drugs are administered individually and sequentially. One advantage of this approach is that the anti-cancer agents often act synergistically because the tumors cells are attacked simultaneously with agents having multiple modes of action. Thus, it is often possible to achieve more rapid reductions in tumor size by administering these drugs in combination. Another advantage of combination chemotherapy is that tumors are more likely to be eradicated completely and are less likely to develop resistance to the anti-cancer drugs being used to treat the patient.
[0002] One serious limitation of combination chemotherapy is that anti-cancer agents generally have severe side effects, even when administered individually. For example, the well known anti-cancer agent taxol causes neutroperia, neuropathy, mucositis, anemia, thrombocytopenia, bradycardia, diarrhea and nausea. Unfortunately, the toxicity of anti-cancer agents is generally additive when the drugs are administered in combination. As result, certain types of anti-cancel drugs are generally not combined. The combined toxic side-effects of those anti-cancer drugs that are administered simultaneously can place severe limitations on the quantities that can be used in combination. Often, it is not possible to use enough of the combination therapy to achieve the desired synergistic effects. Therefore, there is an urgent need for agents which can enhance the desirable tumor attacking properties of anti-cancer agents without further increasing their undesirable side-effects.
SUMMARY OF THE INVENTION
[0003] It has now been found that certain bis[thio-hydrazide amide] compounds significantly enhance the anti-cancer activity of taxol. For example, Compound (1) was used in combination with taxol (Paclitaxel) to treat tumors induced in nude mice from the human breast tumor cell line MDA-435. The tumor volume was about five fold less after 24 days of treatment in mice which had been administered 5 mg/kg of taxol and 25 mg/kg of Compound (1) than in mice which had only been administered 5 mg/kg of taxol or in mice which had only been administered 50 mg/kg of Compound (1) (Example 7). These results are shown graphically in Figure 1. The structure of Compound (1) is shown below:
It has also been found that these bis[thio-hydrazide amide] compounds have minimal toxic side effects. For example, the mice treated with taxol and Compound (1) showed little if any weight loss over the treatment period (see Figure 2). Based on these results, novel compounds which enhance the anti-cancer activity of taxol, pharmaceutical compositions comprising these compounds and methods of treating a subject with cancer are disclosed herein.
[0004] One embodiment of the present invention is a compound represented by the Structural Formula (I):
[0005] Y is a covalent bond, a phenylene group or a substituted or unsubstituted straight chained hydrocarbyl group. In addition, Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted aromatic group. Preferably, Y is a covalent bond or -C(R7R8)-.
[0006] R1 is an aliphatic group, a substituted aliphatic group, a non-aromatic heterocyclic group, or a substituted non-aromatic heterocyclic group.
[0007] R2-R4 are independently -H, an aliphatic group, a substituted aliphatic group, a non-aromafic heterocyclic group, a substituted non-aromatic heterocyclic group, an aryl group or a substituted aryl group, or R1 and R3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R2 and R4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring.
[0008] R5-R6 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or 2 substituted aryl group.
[0009] R7 and R8 are each independently -H, an aliphatic or substituted aliphatic group or R7 is -H and R8 is 2 substituted or unsubstituted aryl group, or, R7 and R8, taken together, are a C2-C6 substituted or unsubstituted alkylene group.
[0010] Z is = O or = S for use in the treatment of melanoma or renal cancer by administration of said compound, in the same or separate pharmaceutical composition, with paclitaxel or a paclitaxel analog.
[0011] In one embodiment R1 and R2 in the compound represented by Structural Formula (I) are not both C1-C5 alkyl (preferably not both methyl) when Y is -C(R7R8)-R3 and R4 are both phenyl and R5-R8 are all -H.
[0012] Another embodiment of the present invention is use of a compound of Structural Formula (I) for the production of a medicament for administration, in the same or separate pharmaceutical composition, with paclitaxel or a paclitaxel analog for treating melanoma or renal cancer.
[0013] The disclosed compounds increase the anti-cancer activity of taxol and taxol analogs. In addition, these compounds have minimal toxic side-effects. Consequently, it is possible to increase the effectiveness of taxol and analogs thereof when used in combination with the disclosed compounds, even when approaching the highest tolerated doses of taxol. Thus, it is expected that combination therapy with the compounds of the present invention will provide improved clinical outcomes for patients with cancers that are being treated with taxol. By coadministering the disclosed compounds with taxol, it is also possible to achieve the same therapeutic effectiveness previously achieved with higher doses of taxol, thereby reducing the side-effects and improving the quality of life for the patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014]
Figure 1 is a graph showing the average tumor volume in milliliters over time (in days) in nude mice treated with vehicle (●). Compound (1) (25 mg/kg) (◆); Paclitaxel (15 mg/kg) (■); or Compound (1) (25 mg/kg) and Paclitaxel (15 mg/kg) - (0). The tumors were generated from the human breast tumor cell line MDA-435.
Figure 2 is 2 graph showing the percent weight change over time in nude mice treated with vehicle (●); Compound (1) (25 mg/kg) (◆); Paclitaxel (15 mg/kg) (■); or Compound (1) (25 mg/kg) and Paclitaxel (15 mg/kg) (□). The mice were being treated for tumors generated from the human breast tumor cell line MDA-435.
Figure 3 is the structure of taxol (Paclitaxel)
Figures 4 is the structure of taxotere (Docetaxel)
Figures 5-25 are each the structure of taxol analog.
Figure 26 is the structure of a polymer comprising a taxol analog group pendent from the polymer backbone. The polymer is a terpolymer of the three monomer units shown.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention is directed to compounds represented by Structural Formula (I) for use as taxol enhancers in the treatment of melanoma or renal cancer. In one embodiment Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group. In addition, Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted aromatic group (preferably, a covalent bond or -C(R7R8)-); and R1 is an aliphatic group or a substituted aliphatic group, R2-R4 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R1 and R3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R2 and R4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring. The remainder of the variables in Structural Formula (I) are as described above.
[0016] In a first preferred embodiment, Y in Structural Formula (I), taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted arylene group and the compound is represented by Structural Formula (II):
[0017] R1-R6 in Structural Formula (II) are as described in Structural Formula (I). Ar is a substituted or unsubstituted arylene group. Preferably, Ar is a nitrogen-containing heteroarylene group. Examples are shown below:
Ring A is substituted or unsubstituted.
[0018] In a second preferred embodiment, Y in Structural Formula (I) is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group. R7 and R8 are as described for Structural Formula (1). Preferably, Y is a covalent bond, - C(R7R8)-, -(CH2CH2)-, trans-(CH=CH)-, cis-(CH=CH)-, -(CC)- or a 1,4-phenylene group. Even more preferably, Y is a covalent bond or -C(R7R8)-.
[0019] In a third preferred embodiment, Y in Structural Formula (I) is a covalent bond or -C(R7R8)- and the compound of the present invention is represented by Structural Formula (III):
R1-R8 are as described for Structural Formula (I). Y' is a covalent bond or -C(R7R8)-Preferably, R7 and R8 are both methyl; R7 and R8, taken together, are propylene or butylene; or R7 is -H and R8 is lower alkyl (preferably methyl), thienyl, phenyl or benzyl.
[0020] In one example of a compound represented by Structural Formula (III), at least one of R1-R2 is a substituted aliphatic group, an unsubstituted aliphatic group, a substituted non-aromatic heterocyclic group or an unsubstituted non-aromatic heterocyclic group. Preferably, R5-R8 are all -H. In another example of a compound represented by Structural Formula (III), at least one of R1-R2 is an unsubstituted cyclic aliphatic group, a substituted cyclic aliphatic group, a substituted straight chained or branched aliphatic group, a substituted non-aromatic hetereocyclic group, or an unsubstituted non-aromatic hetereocyclic group. In these two examples, R3 and R4 are preferably methyl.
[0021] In a more preferred embodiment, R5-R6 in Structural Formula (III) are -H and the compound is represented by Structural Formula (IV):
R1-R4 in Structural Formula (IV) are as described in Structural Formula (I). Y" is a covalent bond or -CH2-.
[0022] In a first example of a compound represented by Structural Formula (IV), R3 and R4 are both a substituted or unsubstituted aliphatic group, preferably both a substituted or unsubstituted lower alkyl group and more preferably both a methyl group or ethyl. When R3 and R4 in Structural Formula (IV) are both a substituted or unsubstituted aliphatic group, then: 1) R1 and R2 are preferably both a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted alkyl group and more preferably a C3-C8 substituted or unsubstituted cyclic aliphatic group such as a substituted or unsubstituted cyclopropyl group); or 2) R1 is preferably a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted cyclic aliphatic group); and R2 is preferably: i) a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group; or ii) an substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted C3-C8 cyclic aliphatic group).
[0023] In a second example of a compound represented by Structural Formula (IV), R3 and R4 are both a substituted or unsubstituted heteroaryl group. When R3 and R4 in Structural Formula (IV) are both a substituted or unsubstituted heteroaryl group, then: 1) R1 and R2 are preferably both a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted alkyl group); or 2) R1 is preferably a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted C3-C8 cyclic aliphatic group); and R2 is preferably: i) a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group; or ii) an substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted cyclic aliphatic group).
[0024] In a third example of a compound represented by Structural Formula (IV), R3 and R4 are both a substituted or unsubstituted phenyl group (e.g., a phenyl group substituted with at least one group other than an aliphatic group). When R3 and R4 in Structural Formula (IV) are both a substituted or unsubstituted phenyl group, then: 1) R1 and R2 are preferably both a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted alkyl group and more preferably a C3-C8 substituted or unsubstituted cyclic aliphatic group such as a substituted or unsubstituted cyclopropyl group); or 2) R1 is preferably a substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted cyclic aliphatic group); and R2 is preferably: i) a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted phenyl group; or ii) an substituted or unsubstituted aliphatic group (preferably a substituted or unsubstituted cyclic aliphatic group).
[0025] In a fourth example or a compound represented by Structural Formula (IV), R1 and R2 are both a substituted or unsubstituted aliphatic group, preferably both a substituted or unsubstituted lower alkyl group, including a C3-C8 cycloalkyl group substituted with at least one lower alkyl group (e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, cyclopropyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). When R1 and R2 in Structural Formula (IV) are both an aliphatic group or a substituted aliphatic group, then R3 and R4 are preferably both:1) a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted phenyl group, or a phenyl group with at least one substituent other than an aliphatic group); or 2) a substituted or unsubtituted aliphatic group (preferably, a substituted or unsubstituted alkyl group).
[0026] In a fifth example of a compound represented by Structural Formula (IV), R1 and R2 are both a substituted or unsubstituted cyclic aliphatic group, preferably both a substituted or unsubstituted cyclopropyl alkyl group.
[0027] In a sixth example of a compound represented by Structural Formula (IV), R1 is a substituted or unsubtituted aliphatic group and R2 is a substituted or unsubstituted aryl group.
[0028] The following are specific examples of compounds represented by Structural Formula (IV): R1 and R2 are both methyl, and R3 and R4 are both p-CF3-phenyl; R1 and R2 are both methyl, and R3 and R4 are both o-CH3-phenyl; R1 and R2 are both -CH2)3COOH; and R3 and R4 are both phenyl; R1 and R2 are both represented by the following structural formula:
and R3 and R4 are both phenyl; R1 and R2 are both n-butyl and R3 and R4 are both phenyl; R1 and R2 are both n-pentyl, R3 and R4 are both phenyl; R1 and R2 are both methyl, and R3 and R4 are both 2-pyridyl; R1 and R2 are both cyclohexyl, and R3 and R4 are both phenyl; R1 and R2 are both methyl, and R3 and R4 are both 2-ethylphenyl; R1 and R2 are both methyl, and R3 and R4 are both 2,6-dichlorophenyl; R1-R4 are all methyl; R1 and R2 are both methyl, and R3 and R4 are both t-butyl, R1 and R2 are both ethyl, and R3 and R4 are both methyl; R1 and R2 are both t-butyl, and R3 and R4 are both methyl; R1 and R2 are both cyclopropyl, and R3 and R4 are both methyl; R1 and R2 are both cyclopropyl, and R3 and R4 are both ethyl; R1 and R2 are both 1-methylcyclopropyl, and R3 and R4 are both methyl; R1 and R2 are both 2-methylcyclopropyl, and R3 and R4 are both methyl; R1 and R2 are both 1-phenylcyclopropyl, and R3 and R4 are both methyl; R1 and R2 are both 2-phenylcyclopropyl, and R3 and R4 are both methyl; R1 and R2 are both cyclobutyl, and R3 and R4 are both methyl; R1 and R2 are both cyclopentyl, and R3 and R4 are both methyl; R1 is cyclopropyl, R2 is phenyl, and R3 and R4 are both methyl.
[0029] In a fourth preferred embodiment, Y in Structural Formula (I) is -C(R7R8)- and R5 and R6 are both -H. When Y is a covalent bond or -CR7R8- and R5 and R6 are both -H, the compound of the present invention is represented by Structural Formula (V):
R1-R4, R7 and R8 are as described for Structural Formula (I) and Y' is a covalent bond or -CR7R8-, R7 and R8 are the same or different. Preferably, R7 and R8 are both methyl; R7 and R8, taken together, are propylene or butylene; or R7 is -H and R8 is lower alkyl (preferably methyl), thienyl, phenyl or benzyl.
[0030] In one example of a compound represented by Structural Formule (V), R1 and R2 are both a lower alkyl group or a substituted lower alkyl group and R3 and R4 are both an aryl group or a substituted aryl group. In another example of a compound represented by Structural Formula (V), R1 and R2 are both substituted or unsubstituted aliphatic groups and R3 and R4 are both a lower alkyl group or a substituted lower alkyl group; preferably, R1 and R2 are both substituted or unsubstituted alkyl groups (more preferably substituted or unsubstituted cyclic alkyl groups), R3 and R4 are both -H, methyl or ethyl, R7 is -H and R8 is -H or methyl In yet another example of a compound represented by Structural Formula (V), R1 and R2 are both C3-C8 cyclic alkyl or substituted C3-C8 cyclic alkyl and R3 and R4 are both methyl, ethyl, phenyl, or thienyl (preferably, R7 and R8 are: 1) both methyl; 2)taken together, propylene or butylenes; or 3) R7 is -H and R8 is lower alkyl, thienyl, phenyl or benzyl). In yet another example of a compound represented by Structural Formula (V), R1 and R2 are both a lower alkyl group or a substituted lower alkyl group and R3 and R4 are both methyl, ethyl or phenyl.
[0031] The following are specific Examples of compounds represented by Structural Formula (V): R1 and R2 are both cyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both cyclopropyl; R3 and R4 are both ethyl; R7 and R8 are both -H; R1 and R2 are both cyclopropyl; R3 and R4 are both methyl; R7 is methyl; R3 is -H; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl, Y' is bond; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 is methyl and R8 is -H; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 is ethyl and R8 is -H; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 is n-propyl and R8 is -H; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both methyl; R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both ethyl; R7 and R8 are both -H; R1 and R2 are both 1-methylcyclopropyl; R3 is methyl, and R4 is ethyl; R7 and R8 are both -H; R1 and R2 are both 2-methylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both 2-phenylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both 1-phenylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both cyclobutyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both cyclopentyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both cyclohexyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both cyclohexyl; R3 and R4 are both phenyl; R7 and R8 are both -H; R1 and R2 are both methyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both methyl; R3 and R4 are both t-butyl; R7 and R8 are both -H; R1 and R2 are both methyl; R3 and R4 are both phenyl; R7 and R8 are both -H; R1 and R2 are both t-butyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are ethyl; R3 and R4 are both methyl; R7 and R8 are both -H; R1 and R2 are both n-propyl; R3 and R4 are both methyl; R7 and R8 are both -H;
[0032] In a fifth preferred embodiment, Y in Structural Formula (I) is a covalent bond or -CH2-, When Y is a covalent bond or -CH2-, the compound of the present invention is represented by Structural Formula (VI):
R1-R6 in Structural Formula (VI) arc as described for Structural Formula (I). R5 and R6 are the same or different, Y" is a covalent bond or -CH2-.
[0033] in one example, of a compound represented by Structure Formula (VI), R5 and R6 are both a lower alkyl group (preferably methyl) or a phenyl group. When R5 and R6 are both a lower alkyl group or a phenyl group, then R1 and R2 are preferably both lower alkyl or substituted lower alkyl and R3 and R4 are preferably both phenyl or substituted phenyl. Alternatively, when R5 and R6 are both a lower alkyl group or a phenyl group, R1 and R2 are both a lower alkyl group or a substituted lower alkyl group and R3 and R4 are both lower alkyl or substituted lower alkyl.
[0034] In Structural Formulas (I)-(VI), R1 and R2 are the same (e.g., R1 and R2 are both the same substituted or unsubstituted aliphatic group) or different (e.g., R1 is asubstituted or unsubstituted aliphatic group and R2 is a substituted or unsubstituted aryl group); and/or R3 and R4 are the same or different. Preferably, R1 and R2 are the same, and R3 and R4 are the same.
[0035] A "straight chained hydrocarbyl group" is an alkylene group, i.e., -(CH2)x-, with one or more (preferably one) methylene groups optionally replaced with a linkage group. x is a positive integer (e.g., between 1 and about 10), preferably between 1 and about 6 and more preferably 1 or 2. A "linkage group," refers to a functional group which replaces a methylene in a straight chained hydrocarbyl. Examples of suitable linkage groups include a ketone (-C(O)-), alkene, alkyne, phenylene, ether (-0-), thioether (-S-), or amine [-N(Ra)]-, wherein Ra is defined below. A preferred linkage group is -C(R7R8)-, wherein R7 and R8 are defined above. Suitable substitutents for an alkylene group and a hydrocarbaryl group are those which do not substantially interfere with the reactions described herein. R7 and R8 are preferred substituents for an alkylene or hydrocarbyl group.
[0036] An aliphatic group is a straight chained, branched or cyclic non-aromatic hydrocarbon which is completely saturated or which contains one or more units of unsaturation. Typically, a straight chained or branched aliphatic group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, and a cyclic aliphatic group has from 3 to about 10 carbon atoms, preferably from 3 to about 8. An aliphatic group is preferably a straight chained or branched alkyl group, e.g, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl or octyl, or a cycloalkyl group with 3 to about 8 carbon atoms, e.g, cyclopropyl, clobutyl, cyclopentyl, cyclohexyl, or cyclooctyl. A C1-C20 straight chained or branched alkyl group or a C3-CS cyclic alkyl group is also referred to as a "lower alkyl" group.
[0037] Aromatic groups include carbocyclic aromatic groups such as phenyl, naphthyl, and anthracyl, and heteroaryl groups such as imidazolyl, thienyl, furanyl, pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrroyl, pyrazinyl, thiazole, oxazolyl, and tetrazole.
[0038] Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include benzothienyl, benzofuranyl, indolyl, quinolinyl benzothiazole, benzooxazole, benzimidazole, quinolinyl, isoquinolinyl and isoindolyl.
[0039] The term "arylene" refers to an aryl group which is connected to the remainder of the molecule by two other bonds. By way of example, the structure of a 1,4-phenylene group is shown below:
Substituents for an arylene group are as described below for an aryl group.
[0040] Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring can be five, six, seven or eight-membered. Examples include tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, and thiazolidinyl.
[0041] The terms "lower alkoxy", "lower acyl", "(lower alkoxy)methyl" and "(lower alkyl)thiomethyl" mean to -O-(lower alkyl), -C(O)-(lower alkyl), -CH2-O- (lower alkyl) and -CH2-S-(lower alkyl), respectively. The terms "substituted lower alkoxy" and "substituted lower acyl" mean -O-(substituted lower alkyl) and -C(O)-(substituted lower alkyl), respectively.
[0042] Suitable substituents on an aliphatic group, non-aromatic heterocyclic group, benzylic or aryl group (carbocyclic and heteroaryl) are those which do not substantially interfere with the ability of the disclosed compounds to enhance the anti-cancer activity of taxol and analogs thereof. A substituent substantially interferes with the ability of a disclosed compound to enhance anti-cancer activity when the enhancement is reduced by more than about 50% in a compound with the substituent compared with a compound without the substituent. Examples of suitable substituents include -OH, halogen (-Br, -Cl, -I and -F), -ORa, -O-CORa, - CORa -CN, -NO2, -COOH, -SO3H, -NH2, -NHRa, -N(RaRb), -COORa, -CHO, - CONH2, -CONHR2, -CON(RaRb), -NHCORa, -NRCORa, -NHCONH2, - NHCONRaH, -NHCON(RaRb), -NRcCONH2, -NRcCONR8H, -NRcCON(RaRb),-C(=NH)-NH2, -C(=NH)-NHRa, -C(=NH)-N(RaRb), -C(=NRc)-NH2, -C(=NRc)-NHRa, -C(=NRc)-N(RaRb), -NH-C(=NH)-NH2, -NH-C(=NH)-NHRa, -NH-C(=NH)-N(RaRb), =NH-C(=NRc)-NH2, -NH-C(=NRc)-NHRa, -NH-C(=NRc)-N(RaRb), - NRdH-C(=NH)-NH2, -NRd-C(=NH)-NHRa, -NRdC(=NH)-N(RaRb), -NRd-C(=NRc)-NH2, -NRd-C(=NRc)-NHRa, -NRd-C(=NRc)-N(RaRb), -NHNH2, -NHNHRa, - NHRaRb, -SO2NH2, -SO2NHRa, -SO2NRaRb, -CH=CHRa, -CH=CRaRb, - CRc=CRaRb,-CRc=CHRa, -CRc=CRaRb, -CCRa, -SH, -SOkRa (k is 0, 1 or 2) and - NH-C(=NH)-NH2, Ra-Rd are each independently an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group, preferably an alkyl, benzylic or aryl group. In addition, -NRaRd, taken together, can also form a substituted or unsubstituted non-aromatic heterocyclic group. A non-aromatic heterocyclic group, benzylic group or aryl group can also have an aliphatic or substituted aliphatic group as a substituent A substituted aliphatic group can also have a non-aromatic heterocyclic ring, a substituted a non-aromatic heterocyclic ring, benzyl, substituted benzyl, aryl or substituted aryl group as a substituent. A substituted aliphatic, non-aromatic heterocyclic group, substituted aryl, or substituted benzyl group can have more than one substituent.
[0043] Also included in the present invention are pharmaceutically acceptable salts of the compounds described herein. The compound of the present invention which possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylproplanate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalena-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.
[0044] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
[0045] Taxol, also referred to as "Paclitaxel", is a well-known anti-cancer drug which acts by inhibiting microtubule formation. Many analogs of taxol are known, including taxotere, the structure of which is shown in Figure 4. Taxotere is also referred to as ""Docetaxel". The structure of other taxol analogs are shown in Figures 5-25. These compounds have the basic taxane skeleton as a common structure feature and have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules. Thus, it is apparent from Figures 5-25 that a wide variety of substituents can decorate the taxane skeleton without adversely affecting biological activity. It is also apparent that zero, one or both of the cyclohexane rings of a taxol analog can have a double bond at the indicated positions. For clarity purposes, the basic taxane skelton is shown below in Structural Formula (VII):
Double bonds have been omitted from the cyclohexane rings in the taxane skeleton represented by Structural Formula (VII). It is to be understood that the basic taxane skeleton can include zero or one double bond in one or both cyclohexane rings, as indicated in Figures 5-25 and Structural Formulas (VIII) and (IX) below. A number of atoms have also omitted from Structural Formula (VII) to indicate sites in which structural variation commonly occurs among taxol analogs. For example, substitution on the taxane skeleton with simply an oxygen atom indicates that hydroxyl, acyl, alkoxy or other oxygen-bearing substituent is commonly found at the site. It is to be understood that these and other substitutions on the taxane skeleton can also be made without losing the ability to enhance and stabilize microtubule formation. Thus, the term "taxol analog" is defined herein to mean a compound which has the basic taxol skeleton and which promotes disassembly of microtubules.
[0046] Typically, the taxol analogs used herein are represented by Structural Formula (VIII) or (IX):
[0047] R10 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted phenyl group, -SR19, -NHR19 or -OR19.
[0048] R11 is a lower alkyl group, a substituted lower alkyl group, an aryl group or a substituted aryl group.
[0049] R12 is -H, -OH, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, -O-C(O)-(lower alkyl), -O-C(O)-(subsbtuted lower alkyl), -O-CH2-O-(lower alkyl) alkyl).
[0051] R14 is -H, -OH, lower alkoxy, -O-C(O)-(lower alkyl), substituted lower alkoxy, -O-C(O)-(substituted lower alkyl), -O-CH2-O-P(O)(OH)2, -O-CH2-O-(lower alkyl), -O-CH2-S-(lower alkyl) or, taken together with R20, a double bond.
[0052] R15 is -H, lower acyl, lower alkyl, substituted lower alkyl, alkoxymethyl, alkhiomethyl, -C(O)-O(lower alkyl), -C(O)-O(substituted lower alkyl), -C(O)-NH(lower alkyl) or -C(O)-NH(substituted lower alkyl).
[0054] R17 is -H, lower acyl, substituted lower acyl, lower alkyl, substituted, lower alkyl, (lower alkoxy)methyl or (lower alkyl)thiomethyl.
[0055] R18 is -H, -CH3 or, taken together with R17 and the carbon atoms to which R17 and R18 are bonded, a five or six membered a non-aromatic heterocyclic ring.
[0056] R19 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted phenyl group.
[0059] Preferably, the variables in Structural Formulas (VIII) and (IX) are defined as follows: R10 is phenyl, tert-butoxy, -S-CH2-CH-(CH3)2, -S-CH(CH3)3, -S-(CH2)3CH3, -O-CH(CH3)3, -NH-CH(CH3)3, -CH=C(CH3)2 or para-chlorophenyl; R11 is phenyl, (CH3)2CHCF2-, -2-furanyl, cyclopropyl or para-toluyl; R12 is -H, - OH, CH3CO- or -(CH2)2-N-morpholino; R13 is methyl, or, R13 and R14, taken together, are -CH2-;
[0062] R18 is -H; R20 is -H or -F; and R21, is H, -C(O)-CHBr-(CH2)13-CH3 or -C(O)-(CH2)14-CH3; -C(O)-CH2-CH(OH)-COOH, -C(O)-CH2-O-C(O)-CH2CH(NH2)-CONH2, -C(O)-CH2-O-CH2CH2OCH3 or -C(O)-O-C(O)-CH2CH3.
[0063] A taxol analog can also be bonded to or be pendent from a pharmaceutically acceptable polymer, such as a polyacrylamide. One example of a polymer of this type is shown in Figure 26. The term "taxol analog", as it is used herein, includes such polymers.
[0064] The disclosed compounds are enhancers of the anti-cancer activity of taxol and taxol analogs. A compound enhances the anti-cancer Activity of taxol or a taxol analog when the activity of taxol or the taxol analog is greater when administered in combination with the compound than when administered alone. The degree of the increase in activity depends upon the amount of compound administered. The compounds of the present invention can therefore be used in combination with taxol or taxol analogs to treat subjects with, melanoma, or renal cancer,
[0065] A "subject' is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
[0066] In order to achieve an enhancement of the anti-cancer activity of taxol and taxol analogs, an effective amount of a compound of the present invention and an effective amount of taxol or analog of taxol are administered to the subject. With respect to taxol or an analog of taxol, an "effective amount" is a quantity in which anti-cancer effects are normally achieved. With respect to a compound of the present invention, an "effective amount" is the quantity in which a greater anti-cancer effect is achieved when the compound is co-administered with taxol or a taxol analog compared with when taxol or the taxol analog is administered alone. The compound and taxol (or taxol analog) can be co-adminisisrsd to the subject as part of the same pharmaceutical composition or, alternatively, as separate pharmaceutical compositions. When administered as separate pharmaceutical compositions, the compound of the present invention and taxol (or taxol analog) can bs admmistered simultaneously or at different times, provided that the enhancing effect of the compound is retained.
[0067] The amount of compound and taxol (or taxol analog) administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cancer. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective dosages for taxol and taxol analog are well known and typically range from between about 1 mg/mm2 per day and about 1000 mg/mm2 per day, preferably between about 10 mg/mm2 per day and about 500 mg/mm2 per day. Effective amounts of a compound of the present invention typically range between about 1 mg/mm2 per day and about 10 grams/mm2 per day, and preferably between 10 mg/mm2 per day and about 5 grams/mm2.
[0068] The disclosed compounds are administered by any suitable route, including, for example, orally in capsules, suspensions or tablets or by parenteral administration. Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection. The compounds can also be administered orally (e.g., dietary), topically, by inhalation (e.g., intrabronchial, intranasal, oral inhalation or intranasal drops), or rectally, depending on the type of cancer to be treated. Oral or parenteral administration are preferred modes of administration. Suitable routes of administration of taxol and taxol analogs are well known in the art and include by parenteral administration, as described above for the compounds of the present invention. Suitable routes of administration for taxol and analogs thereof are well known and include inter alia parenteral and oral administration.
[0069] The disclosed compounds can be administered to the subject in conjunction with an acceptable pharmaceutical carrier as part of a pharmaceutical composition for treatment of melanoma or renal cancer. Formulation of the compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule). Suitable pharmaceutical carriers may contain inert ingredients which do not interact with the compound. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextrasn) are known in the art (Baker, et al., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986). Suitable formulations for taxol and taxol analogs are well known in the art.
[0070] The disclosed compounds can be prepared according to methods described in Examples 1-7 and also according to methods described in the co-pending US Provisional Application entitled SYNTHESIS OF TAXOL ENHANCERS, U.S. Provisional Application No. 60/304,318, filed July 10,2001.
[0071] The present invention is illustrated by the following examples, which are not intended to be limiting in any way.
EXEMPLIFICATION
Example 1.
Preparation of N-Malonyl-bis[N'-phenyl-N'-(thioacetyl)hydrazide]
[0074] A mixture of phenylhydrazine (30 mL) and ethyl malonate (in xylene (150 mL) was heated to reflux overnight The reaction was cooled to room temperature. The precipitates were collected via nitration and washed with ethanol to give N-malonyl-bis(N'-phenylhydrazide) as a white solid (14 g). The hydrazide (3.4 g) was suspended in acetic anhydride (30 mL) and cooled in an ice bath. To it was added dropwise perchloric acid (57% in water, 3 mL). The reaction mixture turned to clear solution initially and then quickly solidified. After standing at room temperature for 1 h, ether (50 mL) was added. The resulting slurry was filtered and washed with ether (2 x 00 mL) to give the perchlorate salts as a white solid (5.7 g). The salts were taken into acetone and added as a slurry over 5 min to Na2S (0.6 M in water, 90 mL) stirred at room temperature. After 30 min, the reaction was acidified with HCl(c) to afford a yellow slurry. The solid was collected via filtration and washed with water (20 mL) and ether (2x25 mL) to give N-malonyl-bis[N'-phenyl-N'-(thioacetyl)hydrazide] as an off-white solid (3.6 g). 1H NMR (DMSO-d6): δ11.5 (m, 2H); 7.5 (m, 10 H); 3.2 (m, 2H); 2.6 (s, 3H); 2.5 (s, 3H). MS calcd (400.1); Found: 423.1 (M+Na)+.
Example 2.
Preparation of Thiocyclohexanoic acid N-phenylhydrazide
[0076] Phenyl hydrazine (5.4g, 50 mmol) was dissolved in dry dichloromethane (50 mL) in a 250 mL round bottom flask. Di-tert-butyl dicarbonate (10.9 g, 50 mmol) was then added with stirring at 0 °C. The resultant solution was then stirred under reflux for 3 h. Removal of the volatile components under reduced pressure afforded a colorless solid, which was washed with hexane and dried in vacuo. 10 g (yield 96%) of the product was obtained as a colorless solid, which can be used in the next step without further purification. 2.5 g (12 mmol) of this material was dissolved in dry pyridine (5 mL). Cyclohexanecarbonyl chloride (2.0 mL, 15 mmol) was then added slowly at 0 °C. The red solution was stirred at 0 °C for half an hour and the resultant yellow suspension was stirred at rt for 3 h before pouring into ice-H2O (100 mL). The precipitate product was collected by filtration and washed thoroughly with H2O. After one recrystallization from EtOH/H2O, 3.63 g (95%) of N-phenyl-N-cyclohexyl-N'-tert-butoxycarbonylhydrazide was obtained as a white powder; mp 141-143 °C; 1H NMR (CDCl3) δ 0.9-2.3 (m, 11H), 1.4 (s, 9H), 6.9 (br, 1H), 7.4 (m, 5H) ppm.
[0077] To a solution of N-phenyl-N-cyclohexyl-N'-tert-butoxycarbonylhydrazide (1.1 g, 3.46 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (6 mL) at 0 °C. The resultant solution was stirred at 0 °C for half an hour. Volatile components were then removed under reduced pressure to afford a syrup, which was turned into a solid upon standing; this material was briefly mixed with cold 2 N NaOH (5 mL) for a few minutes at 0 °C. Solid product was then collected by filtration and recrystallized from hexane to afford cyclohexanoic acid N-phenylhydrazide (0.6 g, 80% yield) as a white powder; 1H NMR (DMSO-d6) δ 0.8-3.2 (m, 1H), 5.3 (s, 2H), 7.0-7.7 (m, 5H); ESMS calcd (C13H18N2O): 218.3; found: 241.1 (M + Na)+.
[0078] A mixture of cyclohexanoic acid N-phenylhydrazide (0.25 g, 1.15 mmol) and Lawerson's Reagent (0.16 g, 1.15 mmol) in dry toluene (20 mL) was stirred under reflux for 1 h. After being cooled to room temperature, the mixture was filtered through a short column of silica gel (5 g) which was pre-washed with benzene. Removal of benzene afforded the crude product as a solid which was purified by column chromatography on silica gel using hexane/EtOAc (4 : 1 v/v) as eluant. 0.15g (60%) of thiocyclohexanoic acid N-phenylhydrazide was obtained as an off white solid. 1H NMR (CDCl3) δ 0.8-2.4 (m, 11H), 5.65 (br, 1H), 7.1-7.6 (m, 5H); ESMS calcd (C13H18N2S): 234.1; found: 235.1 (M+H)+.
Example 3.
[0080] To a stirred solution of cyclohexanoic acid N-phenylhydrazide (0.1 g, 0.45 mmol) in dry benzene (5 mL) was added P2S5 (0.2 g, 0.45 mol). The resultant suspension was heated to reflux for 3 h. After being cooled to room temperature, the mixture was diluted with benzene (5 mL) and was filtered through a short column of silica gel (2 g), washed with benzene and 2:1 hexane/EtOAc (15 mL each). The filtrate and washings were combined and concentrated to afford a solid. Crystallized from hexane to provide the intermediate thiocyclohexanoic acid N-phenylhydrazide as an off white solid; ; 1H NMR (CDCl3) δ 0.8-2.4 (m, 11H), 5.65 (br, 1H), 7.1-7.6 (m, 5H); ESMS calcd (C13H18N2S): 234.1; found: 235.1 (M+H)+.
Example 4.
[0081]
Cyclopropyl bromide (4.8g, 40 mmol) was added into 50 ml anhydrous THF solution containing magnesium powder (1.1g, 45 mmol), stirred for 30 min, and refluxed for another 30 min. After it was cooled, the clear reaction solution was added into carbon disulfide (4 ml, 67 mmol) at 0 °C, and stirred for 30 min at rt. The resulting mixture was then added into methylhydrazine (8 ml, 150 mmol) at 0 °C, and stirred for another 2 hours. To this solution was added water (40 ml) and extracted with EtOAc (60 ml x 3). The organic solution was concentrated to minimum volume, and subjected to silica gel column chromatography (1:1 ethyl acetate: hexanes; ethyl acetate) to give thiocyclopropyl carboxylic acid N1-methyl hydrazide (2.8 g, 55 %). 1H NMR (300MHz, CDCl3): δ 5.21 (br., 2H), 3.62 (s, 3h), 1.91 (m, 1H), 1.25 (m, 2H), 0.98 (m, 2H). ESMS cacld (C5H10N2S): 130.1; found: 131.1 (M+H)+. To the hydrazide EtOAc solution (2.8 g, 22 mmol, 40ml) containing TEA (2.2g, 22mmol) was added malonyl chloride EtOAc solution (1.6g, 11 mmol, 4ml) at 0 °C, and the reaction mixture was stirred at rt for 20 min. 20 ml water was added to quench the reaction, and the EtOAc layer was continuously washed twice with water (20 ml x 2). The EtOAc solution was concentrated to minimum volume, and subjected to silica gel column chromatography (eluant: 1:1-12 hexanes : ethyl acetate) to give SBR-11-5685 (2.1 g, yield: 60%). (2.1 g, yield: 60%). 1H NMR (300MHz, CDCl3): δ 10.01-8.95 (m, 2H), 3.78-3.41(m, 6H), 2.34-0.82 (m, 10H). ESMS cacld(C13H20N4O2S2): 328.1; found: 327 (M-H)+.
Example 5 - Preparation of 2-Methylmalonyl-bis(2-Amino-2,3-dihydro-isoindole-1-thione)
[0083] 2-carboxybenzaldehyde (150 mg, 1 mmol) and carbazic acid (132 mg, 1 mmol) in 40 ml methanol was stirred at room temperature for 4 h. To this solution was added Pd/C (60 mg, containing 50 % H2O), the reaction was under H2 atmosphere for 3 h. The reaction mixture was filtered, and the solvent was evaporated. The resulting residue was subjected to silica gel column chromatography. (eluent: 20% to 50 %, EtOAc in hexanes) to obtain 50 mg of product. 1H NMR (300MHz, CDCl3): δ 8.71-7.45 (m, 4H), 4.78 (s, 2H), 1.61(s, 9H). The resulting product was dissolved in CF3COOH (5ml), stirred for 30 min. The CF3COOH was evaporated, and the residue was subjected to silica gel column chromatography (eluent: 50% to 0%, hexanes in EtOAc) to give 2-amino-2,3-dihydroisoindol-1-one (26mg) as a white solid. 1H NMR (300MHz, CDCl3): δ 7.85-7.39 (m, 4H), 4.54 (s, 2H). MS: 149 (M+H). Subsequent Lawesson's thiolation and DCC coupling with 2-methylmaloic acid under conditions described above afforded 2-methylmalonyl-bis(2-amino-2,3-dibydro-isoindole-1-thione) as a yellow powder. 1H NMR (CDCl3) δ 10.35 (s, 2H), 8.21-7.51(m, 8H), 5.15(s, 4H), 1.62 (s, 3H); ESMS cacld (C20H18N4O2S2): 410.09; found: 411.1 (M+H).
Example 6. The following compounds shown below were prepared by the procedures described above. Analytical data is provided for these compounds.
[0085] 1H NMR (DMSO-d6) δ 0.9-1.8m, 22H), 3.1-3.5 (m, 2H), 7.2-7.6 (m, 10H), 11.1 - 11.7 (ms, 2H) ppm; ESMS calcd (C29H36N4O2S2):536.3; found: 537.3(M-H)+.
[0086] 1H NMR (CDCl3): δ 3.6-3.4 (m, 8H), 2.7-2.5 (m, 6H); ESMS cacld for C9H16N4O2S2: 276.1; Found: 274.9 (M-H)+.
[0087] 1H NMR (CDCl3): δ 2.63 (s, 2H); 2.18 (s, 6H); 1.25 (s, 18H). MS calcd for C15H28N4O2S2: 360.2; Found: 383.1 (M+Na)+.
[0088] 1H NMR (CDCl3): δ 7.3 (m, 10H); 3.2 (m, 2H); 2.45 (t, J=7.4 Hz, 4H); 2.21 (t, J=7.4 Hz, 4H); 1.90 (m, 8H). MS calcd for C25H28N4O6S2: 544.15; Found: 567.2 (M+Na)+.
[0089] 1H NMR (CDCl3): δ 7.8.7.4 (br s, 8H), 3.75-3.5 (m, 2H), 3.95-3.8(m, 4H), 2.58 (s, 6H), 1.4 (m, 6H). ESMS cacld for C23H28N4O2S2: 456.2; Found: 479.2 (M+Na).
[0090] 1H NMR (CDCl3): δ 8.3-8.05 (m, 4H), 7.75 (t, J=8.0 Hz, 2H), 7.1 (br s, 2H), 3.74 (s, 2H), 2.38 (s, 6H). ESMS cacld for C17H18N6O2S2: 402.1. Found: 403.1 (M+H)+.
[0091] 1H NMR (CDCl3): δ 7.38 (m, 10 H), 2.40 (s, 6H), 1.5-1.6 (6H); ESMS cacld for C21H24N4O2S2: 564.1; Found: 565.2 (M+H)+.
[0092] The method was the same as one used in synthesis of 4783, oxalyl chloride was used instead of malonyl dichloride. 1N MMR (300MHz, DMSO): δ 11.95 (s, 2H), 7.48-7.07(m, 10H), 3.52(s, 6H). ESMS cacld(C18H18N4O2S2):386.09; found: 387 (M+H)+.
[0093] 1H NMR (300MHz, CDCl3): δ 9.66-8.83 (m, 2H), 3.73-3.23(m, 6H), 2.10-1.20 (m, 20H). ESMS cacld(C15H28N4O2S2):360.17; found: 359 (M-H)+.
[0094] 1H NMR (300MHz, CDCl3): δ 3.66-3.42(m, 6H), 2.84-2.58(m, 4H), 1.40-1.19(m, 6H). ESMS cacld(C11H20N4O2S2):304.10; found: 303 (M-H)+.
[0095] 1H NMR (300MHz, CDCl3): δ 4.15-3.40(m, 6H), 2.00-1.01(m, 14H). ESMS cacld(C14H22N4O2S2):342.12; found: 341 (M-H)+.
[0096] 1H NMR (300MHz, CDCl3): δ 3.90-3.18(m, 6H), 2.11-0.91(m, 10H). ESMS cacld(C12H18N4O2S2):314.09; found: 313 (M-H)+.
[0097] 1H NMR (300MHz, CDCl3): δ 10.08-9.01(m, 2H), 3.68-3.20(m, 6H), 2.59-1.12(m, 16H). ESMS cacld(C15H24N4O2S2):356.13; found: 355 (M-H)+.
[0098] 1HNMR (300MHz, CDCl3): δ 10.22-9.41(m, 2H), 7.48-7.20(m, 5H), 3.82-3.02(m, 6H), 2.38-0.82(m, 7H). ESMS cacld (C16H20N4O2S2): 364.10; found: 363 (M-H)+.
[0099] 1H NMR (300MHz, CDCl3): δ 10.03-9.02(m, 2H), 3.71-3.42(m, 6H), 2.80-0.81(m, 16H). ESMS cacld(C13H24N4O2S2): 332.13; found: 331 (M-H)+.
[0100] 1H NMR (300MHz, CDCl3): δ 3.78-3.08(m, 5H), 1.90-0.81 (m, 18H). ESMS cacld(C15H24N4O2S2): 356.13; found: 355 (M-H)+.
[0101] 1HNMR (300MHz, CDCl3): δ 10.00-8.79(m, 2H), 3.65-3.07(m, 6H), 2.79-1.08(m, 24H). ESMS cacld(C19H32N4O2S2): 412.20; found: 411 (M-H)+.
[0102] 1H NMR (300MHz, CDCl3): δ 9.79(br, 2H), 3.79-3.41(m, 6H), 1.60-0.75(m, 18H). ESMS cacld(C15H24N4O2S2): 356.13; found: 355 (M-H)+.
[0103] 1H NMR (300MHz, CDCl3): δ 10.03-9.14(m, 2H), 421-3.39(m, 4H), 2.20-0.76(m, 18H). ESMS cacld(C15H24N4O2S2): 356.13; found: 355 (M-H)+.
[0104] 1H NMR (300MHz, CDCl3): δ 7.57(br, 2H), 3.72(s, 6H), 2.95(m, 6H), 1.96-0.81(m, 10H). ESMS cacld(C21H36N4O2S2):440.13; found: 439 (M-H)+.
[0105] 1H NMR (300MHz, CDCl3): δ 10.09-8.95(m, 2H), 3.78-3.05(m, 6H), 2.04-1.22(m, 20H). ESMS cacld(C17H28N4O2S2):384.17; found: 383 (M-H)+.
[0106] 1H NMR (300MHz, CDCl3); δ 10.09-8.51 (m, 2H), 7.41-7.01 (m, 10H), 3.62-3.02(m, 6H), 1.78-1.03(m, 10H). ESMS cacld(C25H28N4O2S2): 480.17; found: 479 (M-H)+.
[0107] 1H NMR (300MHz, CDCl3): δ 10.09-8.81(m, 2H), 7.51-7.11(m, 10H), 3.80-3.06(m, 6H), 2.92-1.53(m, 10H). ESMS cacld(C25H28N4O2S2): 480.17; found: 479 (M-H)+.
Example 7
Compound (1) Enhances the Anti-Cancer Activity of Paclitaxel in vivo (Human xenograft model: Human Breast Carcinoma MDA-435 in nude mice)
General Procedure of in vivo Anti-Tumor Study
[0108] The in vivo anti-cancer enhancing effect of novel compounds was assessed in tumor bearing mice using the tumor growth inhibition assay. Tumor cells were implanted by injector of a tumor cell suspension subcutaneously in the flank of a mouse. Treatment of the tumor with an experimental compound and Paclitaxel began after the tumor had been established (volume was about 150 mm3). Animal then begun a multiple injection schedule where the compound and Paclitaxel were given by IV route of administration. Tumors were measured two times a week. During the course of this assay, animals were monitored daily for signs of toxicity including body weight loss.
Detailed Procedure of MDA-435 (Human Breast Carcinoma) Anti-Tumor Study
[0109] A supplemented media was prepared from 50% DMEM/DuIbecco Modified Eagle Medium (High Glucose), 50% RPMI 1640, 10% FBS/Fetal Bovine Serum (Hybridoma Tested; Sterile Filtered), 1% L-Glutamine, 1% Penicillin-Streptomycin, 1% MEM Sodium Pyruvate and 1% MEM Non-Essential Amino Acids. FBS was obtained from Sigma Chemical Co. and other ingredients were obtained from Invitrogen Life Technologies, USA). The supplemental media was warmed to 37° C and 50 ml of media was added to a 175 cm2 tissue culture flask
[0110] The cells used in the assay were MDA-435 (Human Breast Carcinoma from the American Type Culture Collection. 1 vial of MDA-435 cells from the liquid nitrogen frozen cell stock was removed. The frozen vial of cells was immediately placed into a 37° C water bath and gently swirled until thawed. The freeze-vial was wiped with 70% ethanol and cells were immediately pipetted into the 175 cm2 tissue culture flask containing supplemented media. The cells were incubated overnight and the media was removed and replaced with fresh supplemented media the next day. The flask was incubated until flask became about 90% confluent. This took anywhere from 5-7 days.
[0111] The flask was washed with 10 ml of sterile room temperature phosphate buffered saline (PBS). The cells were trypsinized by adding 5 ml of warmed Trypsin-EDTA (Invitrogen) to the flask of cells. The cells were then incubated for 2-3 minutes at 37° C until cells begun to detach from the surface of the flask. An equal volume of supplemented media (5 ml) was added to the flask. All the cells were collected into 50 ml tube, and centrifuged at 1000 RPM for 5 minutes at 20° C. The supernatant was aspirated and the cell pellet was resuspended in 10 ml of supplemented media and the cells were counted. 1-3 million cells/flask were seeded into 5-7 tissue culture flasks (175 cm2). Each flask contained 50 ml of supplemented media. The flasks were incubated until about 90% confluent. The passaging of the cells was repeated until enough cells have been grown for tumor implantation.
[0112] The above procedure for trypsinizing and centrifuging the cells were followed. The supernatant was aspirated and the cell pellet was resuspended in 10 ml of sterile PBS and the cells were counted. The cells were centrifuged and then resuspended with appropriate volume of sterile PBS for injection of correct number of cells needed for tumor implantation. In the case of MDA-435, 100 million cells were suspended with 2.0 ml of sterile PBS to a final concentration of 50 million cells/ml in order to inject 5 million cells in 0.1 ml/mouse.
[0113] Mice (CD-1 nu/nu) were obtained from Charles River Laboratories: nomenclature: Crl:CD-1-nuBR, Age: 6-8 weeks. The mice were allowed to acclimate for 1 week prior to their being used in an experimental procedure.
[0114] Implantation of the MDA-435 tumor cell suspension took place into the corpus adiposum of the female CD-1 nu/nu mouse. This fat body is located in the ventral abdominal viscera of the mouse. Tumor cells were implanted subcutaneously into the fat body located in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur). 5 million MDA-435 cells in 0.1 ml of sterile PBS were injected using 27 G (1/2 inch) needle. MDA-435 tumors developed 2-3 weeks after implantation.
[0115] Compound stock solutions were prepared by dissolving the compound in a 50: 50 mixture of EtOH and Cremophor EL (Polyoxyl 35 Castor Oil, BASF, Germany). This stock solution in 50%.BtOH / 50%CrEL was sonicated in an ultrasonic water bath until all the powder dissolved.
[0116] Preparation of Dosing Solution for Compound Administration: The compound stock solution was diluted 1:10 with D5W (5% Dextrose in Water, Abbott Laboratories USA). : 1) 2.0 ml of 2.5 mg/ml dosing solution of Compound (1) was prepared by diluting 0.2 ml of a 25 mg/ml Compound Stock solution with 1.8 ml of 100% D5W; and 2) a dosing solution comprising of 1.5 mg/ml of Paclitaxel (obtained from Sigma Chemical Co.) and 2.5 mg/ml of Compound (1) was obtained by mixing 0.2 ml of a 50%EtOH/ 50% CrEL stock solution containing 25 mg/ml of Compound (1) and 15 mg/ml of Paclitaxel with 1.8 ml of a 100% D5W solution. The final formulation for the dosing solution was 5% EtOH, 5% CrEL, 4.5 % Dextrose, and 85.5% water.
[0117] The Dosing Solution (Dosing Volume: 0.01 ml/gram = 10 mL/ kg) was injected intravenously into the mice bearing MDA-435 human breast tumor.
PROTOCOL
[0118]
Mice: CD-1 nu/nu female (n=5/group)
Tumor: MDA-435 (Human breast carcinoma)
Implantation: 5x106 cells/mouse
Formulation: 5% Cremophor EL, 5% ethanol, and 4.5 % glucose water solution
Administration route: intravenous bolus injection
Dosing schedule: weekly x 4
| Group | Drug Treatment (Dose) |
| 1 | Vechicle Only |
| 2 | Paclitaxel (15 mg/kg) |
| 3 | Compound (1) (25 mg/kg) |
| 4 | Paclitaxel (15 mg/kg) + Compound (1) (25 mg/kg) |
RESULTS
[0119] Figure 1 shows the effects of Compound (1) on enhancing anti-tumor activity of Paclitaxel (Taxol). As can be seen from Figure 1, Compound (1) significantly enhanced anti-tumor activity of Paclitaxel on human breast tumor MDA-435 in nude mice. Figure 2 shows the effects of Compound (1) and Paclitaxel on the body weight of nude mice bearing MDA-435 human breast tumor. As can be seen from Figure 2, Compound (I) significantly enhanced anti-tumor activity of Paclitaxel without increasing toxicity.
or a pharmaceutically acceptable salt thereof, wherein:
Y is a covalent bond, a phenylene group or a substituted or unsubstituted straight chained hydrocarbyl group, or, Y, taken together with both >C=Z groups to which it is bonded, is a substituted or unsubstituted aromatic group;
R1 is an aliphatic group, a substituted aliphatic group, a non-aromatic heterocyclic group, or a substituted non-aromatic heterocyclic group;
R2-R4 are independently -H, an aliphatic group, a substituted aliphatic group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, an aryl group or a substituted aryl group, or R1 and R3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R2 and R4 taken together with the carbon and nitrogen atoms to which they are bonded, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring;
R5-R6 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group;
and Z is =O or =S,
for use in the treatment of melanoma or renal cancer by administration of said compound, in the same or separate pharmaceutical composition, with paclitaxel or a paclitaxel analog.or
wherein:
R10 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted phenyl group, -SR19, -NHR19 or -OR19;
R11 is a lower alkyl group, a substituted lower alkyl group, an aryl group or a substituted aryl group;
R12 is -H, -OH, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, -O-C(O)-(lower alkyl), -O-C(O)-(substituted lower alkyl), -O-CH2-O-(lower alkyl) -S-CH2-O-(lower alkyl);
R13 is -H, -CH3, or, taken together with R14, -CH2-;
R14 is -H, -OH, lower alkoxy, -O-C(O)-(lower alkyl), substituted lower alkoxy, - O-C(O)-(substituted lower alkyl), -O-CH2-O-P(O)(OH)2, -O-CH2-O-(lower alkyl), -O-CH2-S-(lower alkyl) or, taken together with R20, a double bond;
R15 -H, lower acyl, lower alkyl, substituted lower alkyl, alkoxymethyl, alkthiomethyl, -C(O)-O(lower alkyl), -C(O)-O(substituted lower alkyl), -C(O)-NH(lower alkyl) or -C(O)-NH(substituted lower alkyl);
R16 is phenyl or substituted phenyl;
R17 is -H, lower acyl, substituted lower acyl, lower alkyl, substituted, lower alkyl, (lower alkoxy)methyl or (lower alkyl)thiomethyl;
R18 -H, -CH3 or, taken together with R17 and the carbon atoms to which R17 and R18 are bonded, a five or six membered a non-aromatic heterocyclic ring;
R19 is a lower alkyl group, a substituted lower alkyl group, a phenyl group, a substituted phenyl group;
R20 is -H or a halogen; and
R21 is -H, lower alkyl, substituted lower alkyl, lower acyl or substituted lower acyl,
wherein the term lower alkyl refers to a C1-C20 straight chained or branched alkyl group or a C3-C8 cyclic alkyl group.or docetaxel.
or a pharmaceutically acceptable salt thereof, wherein:
Y' is a covalent bond or -CR7R8-; and
R7 and R8 are each independently -H, an aliphatic or substituted aliphatic group, or R7 is -H and R8 is a substituted or unsubstituted aryl group, or, R7 and R8, taken together, are a C2-C6 substituted or unsubstituted alkylene group; and
R1-R4 are as defined in Claim 1.
or a pharmaceutically acceptable salt thereof, wherein:
Y' is a covalent bond or -CR7R8-;
R1 and R2 are both a substituted or unsubstituted aliphatic group;
R3 and R4 are both -H, methyl or ethyl; and
R7 is -H and R8 is -H or methyl.
or a pharmaceutically acceptable salt thereof, wherein Y' is a covalent bond or -CR7R8-: and wherein
a) R1 and R2 are both cyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H;
b) R1 and R2 are both cyclopropyl; R3 and R4 are both ethyl; R7 and R8 are both H;
c) R1 and R2 are both cyclopropyl; R3 and R4 are both methyl; R7 is methyl; R8 is - H;
d) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; Y' is bond;
e) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H;
f) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 is methyl and R8 is -H;
g) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 is ethyl and R8 is -H;
h) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 is n-propyl and R8 is -H;
i) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both methyl;
j) R1 and R2 are both 1-methylcyclopropyl; R3 and R4 are both ethyl; R7 and R8 are both -H;
k) R1 and R2 are both 1-methylcyclopropyl; R3 is methyl, and R4 is ethyl; R7 and R8 are both -H;
l) R1 and R2 are both 2-methylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H;
m) R1 and R2 are both 2-phenylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H;
n) R1 and R2 are both 1-phenylcyclopropyl; R3 and R4 are both methyl; R7 and R8 are both -H;
o) R1 and R2 are both cyclobutyl; R3 and R4 are both methyl; R7 and R8 are both -H;
p) R1 and R2 are both cyclopentyl; R3 and R4 are both methyl; R7 and R8 are both -H;
q) R1 and R2 are both cyclohexyl; R3 and R4 are both methyl; R7 and R6 are both - H;
r) R1 and R2 are both cyclohexyl; R3 and R4 are both phenyl; R7 and R8 are both - H;
s) R1 and R2 are both methyl; R3 and R4 are both methyl; R7 and R8 are both -H;
t) R1 and R2 are both methyl; R3 and R4 are both t-butyl; R7 and R8 are both -H;
u) R1 and R2 are both methyl; R3 and R4 are both phenyl; R7 and R8 are both -H;
v) R1 and R2 are both t-butyl; R3 and R4 are both methyl; R7 and R8 are both -H;
w) R1 and R2 are ethyl; R3 and R4 are both methyl; R7 and R8 are both -H; or
x) R1 and R2 are both n-propyl; R3 and R4 are both methyl; R7 and R8 are both -H.
or
or a pharmaceutically acceptable salt thereof.
oder ein pharmazeutisch akzeptables Salz hiervon, wobei:
Y für eine kovalente Bindung, eine Phenylengruppe oder eine substituierte oder unsubstituierte geradkettige Hydrocarbylgruppe steht oder Y zusammengenommen mit beiden >C=Z-Gruppen, an die es gebunden ist, für eine substituierte oder unsubstituierte aromatische Gruppe steht;
R1 für eine aliphatische Gruppe, eine substituierte aliphatische Gruppe, eine nichtaromatische heterocyclische Gruppe oder eine substituierte nichtaromatische heterocyclische Gruppe steht;
R2-R4 unabhängig voneinander für -H, eine aliphatische Gruppe, eine substituierte aliphatische Gruppe, eine nichtaromatische heterocyclische Gruppe, eine substituierte nichtaromatische heterocyclische Gruppe, eine Arylgruppe oder eine substituierte Arylgruppe stehen oder R1 und R3 zusammengenommen mit den Kohlenstoff- und Stickstoffatomen, an die sie gebunden sind, und/oder R2 und R4 zusammengenommen mit den Kohlenstoff- und Stickstoffatomen, an die sie gebunden sind, einen nichtaromatischen heterocyclischen Ring, der optional an einen aromatischen Ring kondensiert ist, bilden;
R5-R6 unabhängig voneinander für -H, eine aliphatische Gruppe, eine substituierte aliphatische Gruppe, eine Arylgruppe oder eine substituierte Arylgruppe stehen;
und Z für =O oder =S steht,
zur Verwendung bei der Behandlung von einem Melanom oder Nierenkrebs durch Verabreichung der Verbindung in der gleichen oder einer getrennten pharmazeutischen Zusammensetzung mit Paclitaxel oder einem Paclitaxel-Analogon.
oder
ausgewählt ist, wobei:
R10 für eine Niederalkylgruppe, eine substituierte Niederalkylgruppe, eine Phenylgruppe, eine substituierte Phenylgruppe, -SR19, -NHR19 oder -OR19 steht;
R11 für eine Niederalkylgruppe, eine substituierte Niederalkylgruppe, eine Arylgruppe oder eine substituierte Arylgruppe steht;
R12 für -H, -OH, Niederalkyl, substituiertes Niederalkyl, Niederalkoxy, substituiertes Niederalkoxy, -O-C(O)-(Niederalkyl), -O-C(O)-(substituiertes Niederalkyl), -O-CH2-O-(Niederalkyl), -S-CH2-O-(Niederalkyl) steht;
R13 für -H, -CH3 steht oder zusammengenommen mit R14 für -CH2- steht;
R14 für -H, -OH, Niederalkoxy, -O-C(O)-(Niederalkyl), substituiertes Niederalkoxy, -O-C(O)-(substituiertes Niederalkyl), -O-CH2-O-P(O)(OH)2, -O-CH2-O-(Niederalkyl), -O-CH2-S-(Niederalkyl) steht oder zusammengenommen mit R20 für eine Doppelbindung steht;
R15 für -H, Niederacyl, Niederalkyl, substituiertes Niederalkyl, Alkoxymethyl, Alkthiomethyl, -C(O)-O(Niederalkyl), -C(O)-O(substituiertes Niederalkyl), -C(O)-NH(Niederalkyl) oder -C(O)-NH(substituiertes Niederalkyl) steht;
R16 für Phenyl oder substituiertes Phenyl steht;
R17 für -H, Niederacyl, substituiertes Niederacyl, Niederalkyl, substituiertes Niederalkyl, (Niederalkoxy)methyl oder (Niederalkyl)thiomethyl steht; R18 für -H, -CH3 steht oder zusammengenommen mit R17 und den Kohlenstoffatomen, an die R17 und R18 gebunden sind, für einen 5- oder 6-gliedrigen nichtaromatischen heterocyclischen Ring steht;
R19 für eine Niederalkylgruppe, eine substituierte Niederalkylgruppe, eine Phenylgruppe, eine substituierte Phenylgruppe steht;
R20 für -H oder ein Halogen steht; und
R21 für -H, Niederalkyl, substituiertes Niederalkyl, Niederacyl oder substituiertes Niederacyl steht,
wobei der Ausdruck Niederalkyl eine geradkettige oder verzweigte C1-C20-Alkylgruppe oder eine cyclische C3-C8-Alkylgruppe bezeichnet.oder Docetaxel.
oder ein pharmazeutisch akzeptables Salz hiervon, wobei:
Y' für eine kovalente Bindung oder -CR7R8- steht; und
R7 und R8 jeweils unabhängig voneinander für -H, eine aliphatische oder substituierte aliphatische Gruppe stehen oder R7 für -H steht und R8 für eine substituierte oder unsubstituierte Arylgruppe steht oder R7 und R8 zusammengenommen für eine substituierte oder unsubstituierte C2-C6-Alkylengruppe stehen, und
R1-R4 wie in Anspruch 1 definiert sind.
oder ein pharmazeutisch akzeptables Salz hiervon, wobei:
Y' für eine kovalente Bindung oder -CR7R8- steht;
R1 und R2 beide für eine substituierte oder unsubstituierte aliphatische Gruppe stehen;
R3 und R4 beide für -H, Methyl oder Ethyl stehen; und
R7 für -H steht und R8 für -H oder Methyl steht.
oder ein pharmazeutisch akzeptables Salz hiervon, wobei: Y' für eine kovalente Bindung oder -CR7R8- steht; und wobei
a) R1 und R2 beide für Cyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
b) R1 und R2 beide für Cyclopropyl stehen; R3 und R4 beide für Ethyl stehen; R7 und R8 beide für -H stehen;
c) R1 und R2 beide für Cyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 für Methyl steht; R8 für -H steht;
d) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; Y' für eine Bindung steht;
e) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen
f) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 für Methyl steht und R8 für -H steht;
g) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 für Ethyl steht und R8 für -H steht;
h) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 für n-Propyl steht und R8 für -H steht;
i) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für Methyl stehen;
j) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 und R4 beide für Ethyl stehen; R7 und R8 beide für -H stehen;
k) R1 und R2 beide für 1-Methylcyclopropyl stehen; R3 für Methyl steht und R4 für Ethyl steht; R7 und R8 beide für -H stehen;
l) R1 und R2 beide für 2-Methylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
m) R1 und R2 beide für 2-Phenylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
n) R1 und R2 beide für 1-Phenylcyclopropyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
o) R1 und R2 beide für Cyclobutyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
p) R1 und R2 beide für Cyclopentyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
q) R1 und R2 beide für Cyclohexyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen
r) R1 und R2 beide für Cyclohexyl stehen; R3 und R4 beide für Phenyl stehen; R7 und R8 beide für -H stehen;
s) R1 und R2 beide für Methyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
t) R1 und R2 beide für Methyl stehen; R3 und R4 beide für tert-Butyl stehen; R7 und R8 beide für -H stehen;
u) R1 und R2 beide für Methyl stehen; R3 und R4 beide für Phenyl stehen; R7 und R8 beide für -H stehen;
v) R1 und R2 beide für tert-Butyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen;
w) R1 und R2 beide für Ethyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen; oder
x) R1 und R2 beide für n-Propyl stehen; R3 und R4 beide für Methyl stehen; R7 und R8 beide für -H stehen.
oder
oder ein pharmazeutisch akzeptables Salz hiervon.
ou un sel pharmaceutiquement acceptable de celui-ci, dans lequel :
Y est une liaison covalente, un groupe phénylène ou un groupe hydrocarbyle à chaîne linéaire substitué ou non substitué, ou Y, conjointement avec les deux groupes >C=Z auxquels il est lié, est un groupe aromatique substitué ou non substitué ;
R1 est un groupe aliphatique, un groupe aliphatique substitué, un groupe hétérocyclique non aromatique, ou un groupe hétérocyclique non aromatique substitué ;
R2 - R4 sont indépendamment -H, un groupe aliphatique, un groupe aliphatique substitué, un groupe hétérocyclique non aromatique, un groupe hétérocyclique non aromatique substitué, un groupe aryle ou un groupe aryle substitué, ou R1 et R3 conjointement avec les atomes de carbone et d'azote auxquels ils sont liés, et/ou R2 et R4 conjointement avec les atomes de carbone et d'azote auxquels ils sont liés forment un cycle hétérocyclique non aromatique facultativement condensé avec un cycle aromatique ;
R5 - R6 sont indépendamment -H, un groupe aliphatique, un groupe aliphatique substitué, un groupe aryle ou un groupe aryle substitué ;
et Z est =O ou =S ;
pour l'utilisation dans le traitement d'un mélanome ou d'un cancer rénal par administration dudit composé, dans une composition pharmaceutique commune ou séparée, avec du paclitaxel ou un analogue du paclitaxel.ou
où :
R10 est un groupe alkyle inférieur, un groupe alkyle inférieur substitué, un groupe phényle, un groupe phényle substitué, -SR19, -NHR19 ou -OR19 ;
R11 est un groupe alkyle inférieur, un groupe alkyle inférieur substitué, un groupe aryle ou un groupe aryle substitué ;
R12 est -H, -OH, un alkyle inférieur, un alkyle inférieur substitué, un alcoxy inférieur, un alcoxy inférieur substitué, -O-C(O)-(alkyle inférieur), -O-C(O)-(alkyle inférieur substitué), -O-CH2-O-(alkyle inférieur), -S-CH2-O-(alkyle inférieur) ;
R13 est -H, -CH3, ou, conjointement avec R14, -CH2- ;
R14 est -H, -OH, alcoxy inférieur, -O-C(O)-(alkyle inférieur), un alcoxy inférieur substitué, -O-C(O)-(alkyle inférieur substitué), -O-CH2-O-P(O) (OH)2, -O-CH2-O-(alkyle inférieur), -O-CH2-S-(alkyle inférieur) ou, conjointement avec R20, une double liaison ;
R15 est -H, un acyle inférieur, un alkyle inférieur, un alkyle inférieur substitué, un alcoxyméthyle, un alkylthiométhyle, -C(O)-O-(alkyle inférieur), -C(O)-O-(alkyle inférieur substitué), -C(O)-NH-(alkyle inférieur) ou -C(O)-NH-(alkyle inférieur substitué) ;
R16 est un phényle ou un phényle substitué ;
R17 est -H, un acyle inférieur, un acyle inférieur substitué, un alkyle inférieur, un alkyle inférieur substitué, un (alcoxy inférieur)méthyle ou un (alkyle inférieur)thiométhyle ;
R18 est -H, -CH3 ou, conjointement avec R17 et les atomes de carbone auxquels R17 et R18 sont liés, un cycle hétérocyclique non aromatique de cinq ou six chaînons ;
R19 est un groupe alkyle inférieur, un groupe alkyle inférieur substitué, un groupe phényle, un groupe phényle substitué ;
R20 est -H ou un halogène ; et
R21 est -H, un alkyle inférieur, un alkyle inférieur substitué, un acyle inférieur ou un acyle inférieur substitué ;
où le terme alkyle inférieur désigne un groupe alkyle à chaîne linéaire ou ramifié en C1-C20 ou un groupe alkyle cyclique en C3-C8.ou le docétaxel.
ou un sel pharmaceutiquement acceptable de celui-ci, dans lequel :
Y' est une liaison covalente ou -CR7R8- ; et
R7 et R8 sont chacun indépendamment -H, un groupe aliphatique ou un groupe aliphatique substitué, ou R7 est -H et R8 est un groupe aryle substitué ou non substitué, ou, R7 et R8, sont conjointement un groupe alkylène substitué ou non substitué en C2-C6 ; et
R1 - R4 sont tels que définis dans la revendication 1.
ou un sel pharmaceutiquement acceptable de celui-ci, dans lequel :
Y' est une liaison covalente ou -CR7R8- ; et
R1 et R2 sont tous deux un groupe aliphatique substitué ou non substitué ;
R3 et R4 sont tous deux -H, un méthyle ou un éthyle ; et
R7 est -H et R8 est -H ou un méthyle.
ou un sel pharmaceutiquement acceptable de celui-ci, dans lequel Y' est une liaison covalente ou -CR7R8- ; et où
a) R1 et R2 sont tous deux un cyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
b) R1 et R2 sont tous deux un cyclopropyle ; R3 et R4 sont tous deux un éthyle ; R7 et R8 sont tous deux -H ;
c) R1 et R2 sont tous deux un cyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 est un méthyle ; R8 est -H ;
d) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; Y' est une liaison ;
e) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
f) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 est un méthyle et R8 est -H ;
g) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 est un éthyle et R8 est -H ;
h) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 est un n-propyle et R8 est -H ;
i) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux un méthyle ;
j) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 et R4 sont tous deux un éthyle ; R7 et R8 sont tous deux -H ;
k) R1 et R2 sont tous deux un 1-méthylcyclopropyle ; R3 est un méthyle, et R4 est un éthyle ; R7 et R8 sont tous deux -H ;
l) R1 et R2 sont tous deux un 2-méthylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
m) R1 et R2 sont tous deux un 2-phénylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
n) R1 et R2 sont tous deux un 1-phénylcyclopropyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
o) R1 et R2 sont tous deux un cyclobutyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
p) R1 et R2 sont tous deux un cyclopentyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
q) R1 et R2 sont tous deux un cyclohexyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
r) R1 et R2 sont tous deux un cyclohexyle ; R3 et R4 sont tous deux un phényle ; R7 et R8 sont tous deux -H ;
s) R1 et R2 sont tous deux un méthyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
t) R1 et R2 sont tous deux un méthyle ; R3 et R4 sont tous deux un t-butyle ; R7 et R8 sont tous deux -H ;
u) R1 et R2 sont tous deux un méthyle ; R3 et R4 sont tous deux un phényle ; R7 et R8 sont tous deux -H ;
v) R1 et R2 sont tous deux un t-butyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ;
w) R1 et R2 sont un éthyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H ; ou
x) R1 et R2 sont tous deux un n-propyle ; R3 et R4 sont tous deux un méthyle ; R7 et R8 sont tous deux -H.
ou
ou un sel pharmaceutiquement acceptable de celui-ci.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description
Non-patent literature cited in the description
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