1. Compound of following formula (I):
wherein:
R1 and R2 each independently represent a methoxy group optionally substituted with one or more fluorine atoms,
R2 and R4 each independently represent a hydrogen atom or a methoxy group optionally substituted with one or more fluorine atoms,
A is a cycle chosen from the group comprising aryl and heteroaryl groups, said heteroaryls being chosen from among quinolyl, isoquinolyl, imidazolyl, indolyl, benzothiophenyl, benzofuranyl, benzoimidazolyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl and thiophenyl groups, said cycle possibly being:
either adjoined to a 6-membered heterocycle, optionally comprising one or more unsaturations and optionally substituted with one or more C1 to C4 alkyl groups andor with an oxo group,
or substituted with one or more groups chosen from among halogen atoms, the groups \u2014B(OH)2, C1 to C6 alkyl optionally substituted with OH, C2 to C4 alkenyl, C2 to C4 alkynyl, aryl, heteroaryl, aryloxy, aryl-(C1 to C4 alkyl), \u2014COOH, \u2014NO2, \u2014NR7R8, \u2014NHCOR7, \u2014CONR7R8, \u2014NHCOOR9, \u2014OSi(C1-C4 alkyl)3, \u2014NHSO2R9, C1 to C4 alcoxy optionally substituted with one or more fluorine atoms, \u2014OCONR7R8, \u2014OSO2CF3, \u2014OSO2R9, \u2014SO2R9, \u2014SO3R9, \u2014OSO3H, \u2014OPO(OR10)2, \u2014ONR7R8, \u2014OR11, \u2014SO2NR12R13, \u2014SO2NHCOR14, \u2014OCOR15, \u2014OCOOR16, \u2014SR17 and a residue of a molecule with anti-tumour activity bound via an ester or amide bond, the aryl rings of said groups optionally being substituted with one or more OH, C1 to C4 alkoxy, NR7R8 groups,
X represents a nitrogen atom or a CH group and advantageously represents a CH group,
Z1 represents a hydrogen atom or a fluorine atom, and
Z2 represents a hydrogen atom, a fluorine atom, a C1 to C4 alkyl, \u2014CN, \u2014SO3R9, \u2014COOR15 or \u2014COR15 group,
wherein
R7 and R8 each independently represent a hydrogen atom or a C1 to C4 alkyl, aryl or heteroaryl group, and advantageously represent a hydrogen atom or C1 to C4 alkyl group,
R9 represents a C1 to C4 alkyl, aryl or heteroaryl group, and advantageously represents a C1 to C4 alkyl group,
R10 represents a hydrogen atom or a C1 to C4 alkyl group or a benzyl group,
R11 represents a hydrogen atom, an O-protecting group, a sugar, an amino-sugar, or amino acid, the free OH and NH2 groups of sugars, amino-sugars and amino acids possibly being substituted with an O-protecting and N-protecting group respectively,
R12 and R13 each independently represent a hydrogen atom or a C1 to C4 alkyl, aryl or heteroaryl group,
R14 represents a \u2014CO\u2014(C1 to C4 alkyl) group or the residue of an amino acid molecule attached to the \u2014SO2NH\u2014 group via its carboxylic acid function,
R15 represents a hydrogen atom, a C1 to C4 alkyl, aryl or heteroaryl group, or a \u2014(CH2)mCO2H or \u2014(CH2)mNR7R8 group where m represents an integer of between 1 and 3,
R16 represents a C1 to C4 alkyl, aryl or heteroaryl group, or a \u2014(CH2)mCO2H or \u2014(CH2)mNR7R8 group where m represents an integer of between 1 and 3, and
R17 represents a hydrogen atom or a C1 to C4 alkyl or aryl group, and the pharmaceutically acceptable salts thereof and isomers thereof including the enantiomers and mixtures of isomers in any proportion,
with the exception of the following compounds:
2. The compound according to claim 1, characterized in that R4 represents a hydrogen atom and R1, R2 and R3 each independently represent a methoxy group optionally substituted with one or more fluorine atoms, and advantageously a methoxy group.
3. The compound according to either of claims 1 and 2, characterized in that the anti-vascular molecule is chosen from among 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestan, aminoglutethimide, anastrazole, letrozole, tamoxifene, octreotide, lanroetide, (Z)-3-2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl-propionic acid, 4-((9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidol(5,4-d)(2)benzazepin-2-yl)amino)benzoic acid, 5,6-dimethylxanthenone-4-acetic acid or even 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid.
4. The compound according to any of claims 1 to 3, characterized in that A is a cycle chosen from the group comprising the groups phenyl, naphtyl, quinolyl, isoquinolyl, imidazolyl, indolyl, benzothiophenyl, benzofuranyl, benzoimidazolyl, purinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl and thiophenyl, and in particular the phenyl, naphtyl, purinyl, benzofuranyl, pyridinyl, quinolyl and indolyl groups,
said cycle possibly being substituted with one or more groups chosen from among -Me, -Bn, \u2014C6H4\u2014OMe, \u2014CH2\u2014C6H4\u2014OMe, \u2014(CH2)2\u2014C6H4\u2014OMe, \u2014(CH2)2\u2014C6H2\u2014(OMe)3, \u2014OH, \u2014OMe, \u2014OBn \u2014OCOMe, \u2014C6H4NH2, \u2014OC6H4NH2, \u2014NH2, \u2014OCONEt2, \u2014(CH2)x\u2014OH where x=3, 4, 5 or 6, \u2014OCOCH2NMe2, \u2014OPO3H2, \u2014F and
or possibly being fused to a heterocycle of formula
the dotted line representing the common bond between the heterocycle and said cycle.
5. The compound according to any of claims 1 to 4, characterized in that it meets the following formula (Ia):
or a pharmaceutically acceptable salt or isomer thereof,
wherein:
R1, R2, R3, R4, X, Z1 and Z2 are such as defined in claim 1,
Ra represents a hydrogen or halogen atom, or a group \u2014B(OH)2, C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, aryl, heteroaryl, \u2014COOH, \u2014NO7, \u2014NR7R8, \u2014NHCOR7, \u2014CONR7R8, \u2014NHCOOR9, \u2014OSi(C1 to C4 alkyl)3, \u2014NHSO2R9, C1 to C4 alcoxy optionally substituted with one or more fluorine atoms, \u2014OCONR7R8, \u2014OSO2CF3, \u2014OSO2R9, \u2014SO2R9, \u2014SO3R9, \u2014OSO3H, \u2014OPO(OR10)2, \u2014ONR7R8, \u2014OR11, \u2014SO2NR12R13, \u2014SO2NHCOR14, \u2014OCOR15, \u2014OCOOR16 or \u2014SR17, and advantageously represents a hydrogen atom, and
Rb represents a halogen atom, and preferably a fluorine atom, a group aryloxy \u2014OR11, \u2014OCOR15, \u2014OCOOR15, \u2014OCONR7R8, \u2014OSO2R9, \u2014OSO2CF3, \u2014OSO3H, \u2014OPO(OR10)2, \u2014ONR7R8, \u2014NR7R8, \u2014NHCOR7, \u2014NHCOOR9, \u2014NHSO2R9 or a residue of an anti-vascular molecule bound via an ester or amide bond,
the aryl nuclringsei of said Ra and Rb groups optionally being substituted with one or more OH, C1 to C4 alcoxy, NR7R8 groups,
R7, R8, R9, R10, R11, R12, R13, R14 and R15 being such as defined in claim 1.
6. The compound according to any of claims 1 to 5 characterized in that it is chosen from among:
7. Method for preparing a compound of formula (I) such as defined in claim 1, wherein X represents a CH group characterized in that it comprises the following successive steps:
hydrogenation of a compound of following formula (II):
wherein R1, R2, R3, R4, A, Z1 and Z2 are such as defined in claim 1, and
separation of the compound (I) formed at the preceding step from the reaction medium.
8. The method for preparing a compound of formula (I) such as defined in claim 1, wherein X represents a nitrogen atom, characterized in that it comprises the following successive steps:
reacting a compound of following formula (IX):
wherein R1, R2, R3 and R4 are such as defined in claim 1,
with a compound of formula A-Hal, wherein A is such as defined in claim 1 and Hal represents a halogen atom, preferably a bromine, in the presence of a catalyst and a base,
to give a compound of following formula (X):
wherein R1, R2, R3, R4 and A are such as defined in claim 1,
reacting the compound of formula (X) obtained at the preceding step with a compound of formula Z1Z2CH\u2014X1, wherein Z1 and Z2 are such as defined in claims 1 and X1 represents a halogen atom, in the presence of a base to form a compound of formula (I), and
separation of the compound (I) formed at the preceding step from the reaction medium.
9. The compound of formula (I) according to any of claims 1 to 6, including a compound of formula:
for use thereof as medicament, notably as inhibitor of tubulin polymerization.
10. The compound according to claim 9, for use thereof as medicament intended to treat or prevent proliferative diseases such as cancer, psoriasis or fibrosis.
11. Pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 6, including a compound of formula:
combined with one or more pharmaceutically acceptable excipients.
12. The pharmaceutical composition according to claim 11, characterized in that it comprises at least one other active ingredient, advantageously chosen from among 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestan, aminoglutethimide, anastrazole, letrozole, tamoxifene, octreotide and lanroetide.
13. Pharmaceutical composition comprising:
(i) at least one compound of formula (I) according to any of claims 1 to 6, including a compound of formula:
and
(ii) at least one other active ingredient, as combination products for simultaneous, separate or sequential use.
14. The composition according to claim 13, characterized in that the active principle(s) are chosen from among 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestan, aminoglutethimide, anastrazole, letrozole, tamoxifene, octreotide and lanroetide.
15. The composition according to any of claims 11 to 14 for use thereof as medicament, notably intended to treat or prevent proliferative diseases such as cancer, psoriasis or fibrosis.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A system for delivering audio content correlated to the time andor date of a calendar comprising:
a compact disk drive coupled to multiple processors, wherein said multiple processors implement enhanced CD functionality and reside on a printed circuit board, and wherein said multiple processors control clock and display functions, and to transfer control, command and digital audio data to and from said compact disk drive and wherein said multiple processors determine whether a compact disk inserted into said compact disk drive is a particular format for accessing and playing a track, having a date and time of day indicator, when said track date and time match with a current date and time of day in said calendar and clock; and
a user display coupled to said printed circuit board;
an input device coupled to said printed circuit board;
a radio module coupled to said printed circuit board; and
an audio output device operable to select an audio signal from said radio module or said compact disk drive.
2. The system of claim 1, wherein said user display comprises a liquid crystal display.
3. The system of claim 1, wherein said input device comprises a keyboard and or volume and function selector controls.
4. The system of claim 1, wherein said audio output device comprises at least one speaker.
5. The system of claim 1, wherein said compact disk drive interfaces to said printed circuit board via an Advanced Technology Attachment Packet Interface.
6. The system of claim 1, wherein said multiple processors comprise:
a first processor tasked with clock and display functions; and
a second processor tasked with transfer control, command and digital audio data to and from said compact disk drive, and wherein said first and second processor pass data communicate with each other via an internal bi-directional digital data bus.
7. The system of claim 1 wherein said audio output device comprises an audio multiplexer, audio amplifier and the operator controls.
8. The system of claim 1, wherein said enhanced CD functionality is implemented by code executed by said multiple processors, wherein said code detects enhanced compact disks.
9. The system of claim 7, wherein said enhanced compact disks comprise either timedate enhanced CD format or the sequential enhanced CD format.
10. The system of claim 8, wherein said multiple processors communicate data such as time, date, track information, play and stop commands.
11. The system of claim 1, wherein said audio output device comprises two single channel audio amplifiers that condition and amplify signals received from the compact disk drive or said radio module for output to at least one speaker.
12. The system of claim 3, wherein said keyboard comprises a 12 key matrix design to enter the parameters and data.
13. The system of claim 3, wherein said radio can be digitally tuned based on keyboard input.
14. The system of claim 13, wherein said multiple processors receive an input for and decode a key code on said compact disk indicating said particular format, and treat said compact disk as a conventional compact disk when said key code is not detected.
15. The system of claim 13, wherein a desired play mode from among a plurality of possible play modes.
16. The system of claim 14, wherein said plurality of possible play modes comprises SLEEP, SNOOZE, REPEAT, REVIEW and PREVIEW.
17. The system of claim 13, wherein a particular compact disk format comprises an encrypted header key for use in decrypting compact disk track data.
18. The system of claim, 16, wherein said header additionally comprises a function control segment having compact disk specific rules for use.
19. The system of claim 17, further comprising search and function control segment for a compact disk specific mode when said play mode is PREVIEW or REVIEW.