Patent Application
20080146593
The present invention relates to substituted 5-phenyl pyrimidines of the formula I,
wherein
The invention also relates to pharmaceutical compositions comprising a 5-phenyl pyrimidine of the formula I as herein defined or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Moreover the invention relates to the use of a 5-phenyl pyrimidine of the formula I as herein defined and of their pharmaceutically acceptable salts in the manufacture of a medicament for treatment of cancer and to a method for cancer treatment, which comprises administering to the subject in need thereof an effective amount of a 5-phenyl pyrimidine of the formula I as herein defined or of their pharmaceutically acceptable salts.
Despite dramatic advances in research and novel treatment options, cancer is still one of the leading cause of death. Amongst the different types of cancer such as lung, breast, prostate and colon cancer as well as colon lymphomas, are most frequently diagnosed and ovarian cancer is the 2nd most common reproductive cancer after breast cancer in women. A large number of cytotoxic compounds are known to effectively inhibit the growth of tumor cells, including taxoides like paclitaxel (Taxole), docetaxel (Taxotere), the vinka alkaloids vinorelbine, vinblastine, vindesine and vincristine. However, these compounds are natural products having a complex structure and thus are difficult to produce.
It is, therefore, an object of the present invention to provide compounds which effectively control or inhibit growth and/or progeny of tumor cells and thus are useful in the treatment of cancer. It is highly desirable that these compounds can be synthesized from simple starting compounds according to standard methods of organic chemistry.
We have found that these and further objects are achieved by the substituted 5-phenyl pyrimidines I defined at the outset. Furthermore, we have found a method for treating cancer, which comprises administering to the subject in need thereof an effective amount of a 5-phenyl pyrimidine I as herein defined or of their pharmaceutically acceptable salts.
Substituted 5-phenyl pyrimidines I have been occasionally described in the literature, e.g. in WO 02/074753, WO 03/070721, WO 03/043993 and WO 2004/103978. The compounds disclosed in these documents are active against various phytopathogenic fungi. However, these documents do not describe or suggest that these compounds may be effective in the treatment of diseases or even in the treatment of cancer.
Substituted 5-phenyl pyrimidines I can be prepared by the methods disclosed in WO 02/074753, WO 03/070721, WO 03/043993, WO 2004/103978, PCT/EP04/07258 and DE 102004034197.4 and in the literature cited therein as well as by standard methods of organic chemistry.
It is likewise possible to use physiologically tolerated salts of the 5-phenyl pyrimidines I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonic acids having from 1 to 12 carbon atoms, e.g. C1-C4-alkylsulfonic acids such as methanesulfonic acid, cycloaliphatic sulfonic acids such as S-(+)-10-camphorsulfonic acids and aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having from 2 to 10 carbon atoms such as oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lactic acid, tartaric acid, citric acid, glycolic acid and adipic acid, as well as cis- and trans-cinnamic acid, furoic acid and benzoic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in Drug Research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel and Stuttgart, 1966. The physiologically tolérated salts of 5-phenyl pyrimidines I may be present as the mono-, bis-, tris- and tetrakis-salts, that is, they may contain 1, 2, 3 or 4 of the aforementioned acid molecules per molecule of formula I. The acid molecules may be present in their acidic form or as an anion. The acid addition salts are prepared in a customary manner by mixing the free base of a 5-phenyl pyrimidine I with a corresponding acid, where appropriate in solution in water or an organic solvent as for example a lower alcohol such as methanol, ethanol, n-propanol or isopropanol, an ether such as methyl tert-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate. Solvents, wherein the acid addition salt of I is insoluble (anti-solvents), might be added to precipitate the salt. Suitable anti-solvents comprise C1-C4-alkylesters of C1-C4-aliphatic acids such as ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc., di-C1-C4-alkylethers such as methyl tert-butyl ether or diisopropyl ether.
In the symbol definitions given in formula I above, collective terms were used which generally represent the following substituents:
With regard to their activity to inhibit growth and progeny of tumor cells preference is given to 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R1 is not hydrogen. Particularly preferred are 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R2 is hydrogen. Very particular preference is given to compounds I in which R1 is not hydrogen and R2 is hydrogen. Preference is likewise given to 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R2 is methyl or ethyl.
Particular preference is given 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R1 is C1-C6-alkyl, C2-C6-alkenyl or C1-C8-haloalkyl.
Preference is likewise given 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R1 is a group B:
in which
Z1 is hydrogen, fluorine or C1-C6-fluoroalkyl,
Z2 is hydrogen or fluorine, or
Z1 and Z2 together form a double bond;
q is 0 or 1; and
R12 is hydrogen or methyl.
Moreover, preference is given to 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R1 is C3-C6-cycloalkyl which may be substituted by C1-C4-alkyl.
If R1 and/or R2 contain haloalkyl or haloalkenyl groups having a center of chirality, the (S)-isomers are preferred for these groups. In the case of halogen-free alkyl or alkenyl groups having a center of chirality in R1 or R2, preference is given to the (R) configured isomers.
Preference is furthermore given to 5-phenyl pyrimidines I, wherein X is a radical NR1R2 in which R1 and R2 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or thiomorpholinyl ring, in particular a piperidinyl ring which is optionally substituted by one to three groups selected from halogen, C1-C4-alkyl or C1-C4-haloalkyl. Amongst these preference is given to compounds I in which R1 and R2 together with the nitrogen atom to which they are attached form a 4-methylpiperidine ring.
Preference is also given to 5-phenyl pyrimidines I, wherein the radical NR1R2 forms a pyrazole ring which is optionally substituted by one or two groups selected from halogen, C1-C4-alkyl or C1-C4-haloalkyl, in particular by 2-methyl or 3-methyl.
Preferred radicals X of the formula NR1R2 include:
NH—C2H5, NH(CH(CH3)2), NH—CH2CH2CH3, NH(CH(CH3)(C2H5), (S)—NHCH(CH3)(C2H5), NH—CH(CH3)(CH2CH2CH3), (R)—NHCH(CH3)(C(CH3)3), NH—CH(CH3)CH(CH3)2, (R)—NHCH(CH3)(CH(CH3)2), (S)—NHCH(CH3)(CH(CH3)2), NH(cyclopentyl), NHCH2CF3, NHCH(CH3)(CF3), (R)—NHCH(CH3)(CF3), (S)—NHCH(CH3)(CF3), NH—CH(CH3)CH2OCH3, NH—CH(CH3)CH2OH, NH—CH2C(CH3)═CH2, N(CH2CH3)2, N(CH3)(CH2CH═CH2), N(CH3)—CH2CH2CH═CH2, N(CH2CH═CH2)2, piperidin-1-yl, 2-methyl-piperidin-1-yl, 3-methyl-piperidin-1-yl, 4-methyl-piperidin-1-yl, 3,6-dihydro-2H-pyridin-1-yl, 2-methyl-pyrrolidin-1-yl, (S)—NHCH(CH3)(C(CH3)3), —NH-n-butyl, —NH-tert-butyl, —NH-(sec-pentyl), —NH-2-methyl-cyclopentyl, 2-methyl-oxiranyl-methyl-amino, —N(ethyl)(isopropyl), —N(ethyl)(sec-butyl), —N(sec-butyl)2, NHCH(CH3)-isobutyl NH-benzyl, —NHCH(CH3)CH2—CH(CH3)2, —NH—CH(CH3)CH2—C(O)—OH, N(CH2CH3)CH2C(CH3)═CH2, —N(n-Pr)(CH2CH═CH2), —NH—CH2CH2—CH2—OH, —N(CH3)(CH2CH2OH), —N(benzyl)(CH2CH2OH), —N(CH2CH2OH)(CH2CH═CH2)—N(CH2CH2OSiMe3)(CH2CH═CH2), —N(CN)(CH2CH═CH2), —NH—CH(CH3)CH2—OCH3, —NH—CH(CH3)CH2—C(O)—OCH3, 2-butoxycarbonyl-pyrrolidin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, 2,6-dimethyl-morpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl.
Amongst 5-phenyl pyrimidines I, wherein X is a radical OR1a or SR1a, preference is given to those wherein X is OR1a. The radical R1a is preferably selected from C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkinyl or C3-C6-cycloalkyl. In particular R1a is selected from C1-C6-alkyl, C2-C6-alkenyl or C1-C6-haloalkyl which are branched in α-position. Likewise preferred are compounds I wherein R1a is C1-C4-haloalkyl. Amongst these 5-phenyl pyrimidines I are especially preferred, wherein R1a is ethyl, propyl, i-propyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, 1-methyl-2,2,2-trifluoroethyl or 2,2,2-trifluoroethyl.
Preference is given to 5-phenyl pyrimidines I, wherein Y is halogen, C1-C4-alkyl, cyano or C1-C4-alkoxy, such as chlorine, bromine, methyl, cyano, methoxy or ethoxy, especially chlorine, bromine or methyl, in particular chlorine.
The phenyl ring in the 5-phenyl pyrimidines I may be unsubstituted or preferably carries 1, 2, 3, 4 or 5, in particular 1, 2 or 3 substituents L which are different from hydrogen. Suitable radicals L usually comprises from 1 to 10 atoms that are different from hydrogen and which are selected from carbon, halogen, nitrogen, oxygen and sulfur, the number of carbon atoms are usually from 0 to 10, the number of halogen atoms are usually from 0 to 5 and the number of heteroatoms that are different from halogen are generally being from 0 to 4. Examples of suitable radicals L comprise:
halogen, cyano, cyanato (OCN), C1-C8-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C1-C6-alkoxy, —C(═O)-A1, —C(═O)—O-A1, —C(═O)—N(A2)A1, C(A2)(═N-OA1), N(A2)A1, N(A2)-C(═O)-A1, N(A3)-C(═O)—N(A2)A1, S(═O)p-A1, S(═O)p—O-A1 or S(═O)p—N(A2)A1, wherein
In particular L is selected from the group of the radicals La, Lb, Lc, Ld and Le as described hereinafter.
Preferably the radicals L are selected from the group consisting of halogen, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylsulfonyl, CO—NH2, alkylaminocarbonyl, di-C1-C4-alkylaminocarbonyl, C1-C4-alkylcarbonylamino, N—C1-C4-alkylcarbonyl-N—C1-C4-alkylamino and C1-C4-alkoxycarbonyl, in particular fluorine, chlorine, bromine, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkoxycarbonyl, especially preferably fluorine, chlorine, C1-C2-alkyl, such as methyl or ethyl, C1-C2-fluoroalkyl, such as trifluoromethyl, C1-C2-alkoxy, such as methoxy, or C1-C2-alkoxycarbonyl, such as methoxycarbonyl, SCH3, SO2CH3, CO—NH2, CO—NHCH3, CO—NHC2H5, CO—N(CH3)2, NH—C(═O)CH3, N(CH3)—C(═O)CH3 or COOCH3
More preferably the radicals L are selected from the group consisting of halogen, cyano, nitro, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-alkoxy and C1-C4-alkoxycarbonyl, in particular fluorine, chlorine, bromine, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C1-C4-alkoxycarbonyl, especially preferably fluorine, chlorine, C1-C2-alkyl, such as methyl or ethyl, C1-C2-fluoroalkyl, such as trifluoromethyl, C1-C2-alkoxy, such as methoxy, or C1-C2-alkoxycarbonyl, such as methoxycarbonyl.
Preference is given to 5-phenyl pyrimidines I, wherein one or two radical(s) L is (are) attached to one (or two) of the ortho-position(s) of the phenyl ring.
In a particular preferred embodiment of the invention the phenyl ring of the 5-phenyl pyrimidines I is of the formula C
in which # is the point of attachment to the pyrimidine ring and
L1 is hydrogen, fluorine, chlorine, CH3 or CF3;
L2, L4 independently of one another are hydrogen or fluorine, in particular hydrogen;
L3 is hydrogen, fluorine, chlorine, cyano, CH3, OCH3 or COOCH3; and
L5 is hydrogen, fluorine or CH3,
where at least one of the radicals L1 to L5 and in particular 1, 2 or 3 of the radicals L1 to L5 are different from hydrogen.
The substituted 5-phenyl pyrimidines also carry a radical R4 in the 2-position, which is different from hydrogen. This radical R4 comprises from 1 to 15, in particular 2 to 15 atoms that are different from hydrogen and which are selected from carbon, halogen, nitrogen, oxygen and sulfur, the number of carbon atoms are usually from 0 to 10, the number of halogen atoms are usually from 0 to 5 and the number of heteroatoms that are different from halogen are generally being from 1 to 4. Preferred substituents in the 2-position are the radicals R4a, R4b, R4c and R4d as described hereinafter.
In a first embodiment of the invention the substituted 5-phenylpyrimidine compounds I carry a radical R4a in the 2-position of the pyrimidine ring, wherein
Preferably R4a is selected from cyano, N3, C2-C8-alkinyl, C1-C6-haloalkyl, C3-C8-alkenyloxy, C3-C8-alkinyloxy, C1-C6-haloalkoxy, C3-C8-alkenylthio, C3-C8-alkinylthio, C1-C6-haloalkylthio, or a radical of the formulae —ON═CRaRb, —CRc═NORa, —NRcN═CRaRb, —NRcNRaRb, —NORa; —NRcC(═NRd)—NRaRb, —NRcC(═O)—NRaRb, —NRaC(═O)Rc, —NRaC(═NORc)—Rd, —O(C═O)Rc, —C(═O)—ORa, —C(═O)—NRaRb, —C(═NORc)—NRaRb, —CRc(═NNRaRb), wherein
Ra, Rb, Rc, Rd independently of each other denote hydrogen, C1-C6-alkyl, C2-C8-alkenyl, C2-C8-alkinyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, Ra may also be C1-C6-alkylcarbonyl, or Ra and Rb together form a C2-C4-alkylene group which may be interrupted by an oxygen atom and/or comprise a double bond or Ra and Rc together form a C2-C4-alkylene group which may be interrupted by an oxygen atom and/or comprise a double bond;
More preferably R4a is selected from halogen, cyano or a radical of the formulae —ON═CRaRb, CRc═NORa, —NRcN═CRaRb, —NRcNRaRb, —NRcC(═O)NRaRbNRaC(═O)Rc, —NRaC(═NORc)—Rd, —C(═O)—NRaRb, —C(═NORc)—NRaRb, —CRc(═NNRaRb), wherein Ra, Rb, Rc and Rd are as defined above.
In particular Ra is H or C1-C6-alkyl, Rb is H or C1-C6-alkyl, Rc is H, C1-C6-alkyl or C1-C4-haloalkyl and Rd is H or C1-C6-alkyl, or Ra and Rb or Ra and Rc together form a C2-C4-alkylene group which may comprise a double bond.
Examples of preferred radicals R4a include:
2-oxo-pyrrolidin-1-yl, —C(CH3)═NOH, —C(NH2)═NOH, —C(NH2)═NOCH3, —C(NH2)═NOC2H5, —C(NH2)═NOCHF2, —C(O)NH2, —C(O)NH(CH3), —C(O)NHC(O)CH3, —CN, —N(CH3)NH2, —NHN═CH(CH(CH3)C(═O)OC2H5) and —ON═C(CH3)2.
Amongst the 5-phenyl pyrimidines I, which carry a radical R4a in the 2-position of the pyrimidine moiety, compounds formula Ia
are preferred, in which R1, R2 and R4a have the meanings given above,
In a second embodiment of the invention the substituted 5-phenylpyrimidine compounds I carry a radical R4b in the 2-position of the pyrimidine ring, wherein R4b denotes a five- to ten-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle comprising one to four hetero atoms selected from the group consisting of O, N or S, it being possible for R4b to be substituted by one to three identical or different groups R44, wherein
Preferably the radical R4b is selected from an aromatic heterocyclic radical which comprises 1, 2 or 3 nitrogen atoms as ring members or 1 or 2 nitrogen atoms and 1 oxygen atom or 1 sulfur atom as ring members, in particular pyrazol, in particular pyrazol-1-yl, thiazol, in particular thiazol-2-yl or thiazol-4-yl, 1,2,3-triazol, in particular 1,2,3-triazol-1-yl or 1,2,3-triazol-2-yl, 1,2,4-triazol, in particular 1,2,4-triazol-1-yl, pyridyl, in particular pyridin-2-yl, pyrazin, in particular pyrazin-2-yl, and pyridazin, in particular pyridazin-3-yl. The aforementioned aromatic heterocyclic radicals may carry 1, 2 or 3 identical or different groups R44 as defined above, in particular a radical R44 which is selected from halogen, cyano, nitro, amino, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkylcarbonyloxy, C1-C4-haloalkyl, C1-4-haloalkoxy, C1-C4-alkylthio, C1-C4-alkylsulfonyl, —S—CH2—C6H5 (benzylthio), phenyl or furyl.
Examples of preferred radicals R4b include:
pyrazol-1-yl, 3-amino-pyrazol-1-yl, 3-(i-propyl)pyrazol-1-yl, 3-bromo-pyrazol-1-yl, 3-CH3-pyrazol-1-yl, 3-CF3-pyrazol-1-yl, 3-phenylpyrazol-1-yl, 4-bromo-pyrazol-1-yl, 4-chloro-pyrazol-1-yl, 4-iodo-pyrazol-1-yl, 4-CH3-pyrazol-1-yl, 4-cyano-pyrazol-1-yl, 5-nitropyrazol-1-yl, 3-amino-4-cyano-pyrazol-1-yl, 3-(furan-2-yl)-4-methyl-pyrazol-1-yl, 4-methyl-5-oxo-2,5-dihydro-pyrazol-1-yl, 5-chloro-4-methyl-pyrazol-1-yl, 5-ethoxycarbonyl-3-methyl-pyrazol-1-yl, 5-methoxy-4-methyl-pyrazol-1-yl, 3,5-dimethylpyrazol-1-yl, 3,5-dimethyl-4-chloropyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, 3-amino-1,2,4-triazol-1-yl, 3-benzylsulfanyl-1,2,4-triazol-1-yl, 3-nitro-1,2,4-triazol-1-yl, 3,5-dimethyl-1,2,4-triazol-1-yl, thiazol-2-yl, 2-methyl-thiazol-4-yl, 4-methyl-thiazol-2-yl, 2-pyridyl, 4-CH3-pyrid-2-yl, 6-CH3-pyrid-2-yl, pyrazin-2-yl and pyridazin-3-yl.
Amongst the 5-phenyl pyrimidines I, which carry a radical R4b in the 2-position of the pyrimidine moiety, compounds formula Ib
are preferred in which R1, R2 and R4b are as define above,
In a third embodiment of the invention the substituted 5-phenylpyrimidine compounds I carry a radical R4c in the 2-position of the pyrimidine ring, wherein
R4c corresponds to one of the formulae:
Rh, Rk have the same meanings as Re and may additionally be halogen or cyano;
Rh together with the carbon to which it is attached may be a carbonyl group;
Preferably, the radical R4c corresponds one of the following formulae:
wherein Re#, Rg and Rh are as defined above. In these formulae Re#, Rg and Rh are preferably independently of one another hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C3-C6-cycloalkyl, in particular are hydrogen, methyl or ethyl. Amongst these preference is given to radicals R4c of the formulae:
wherein Re#, Rg and Rh are as defined above. Examples for these radicals include radicals of the following formulae:
Likewise, preference is given to 5-phenyl pyrimidines I, wherein the radical R4c in the 2-position is of the formula:
wherein Z, Re, Rf and Rg are as defined above. Preferably Z is oxygen. Preferably Re, Rf and Rg are independently of one another hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or C3-C6-cycloalkyl, in particular hydrogen, methyl or ethyl or Rf and Rg together with the nitrogen are a radical Re-Z-C(Rh)═N, wherein Z, Re and Rh are as defined above. In particular Z is oxygen and Re and Rh are H or C1-C6-alkyl. Examples of this type of radical R4c include:
Amongst the 5-phenyl pyrimidines I, which carry a radical R4c in the 2-position of the pyrimidine moiety, compounds formula Ic
in which R1, R2 and R4c have the meanings given above,
Particular preference is also given to compounds Ic in which Yc is C1-C4-alkyl which may be substituted by halogen. Moreover, particular preference is given to compounds Ic in which Yc is halogen, cyano, C1-C4-alkyl or C1-C4-alkoxy. Especially preferred are compounds I in which Yc is methyl, ethyl, cyano, bromine or in particular chlorine.
Moreover, particular preference is given to compounds Ic in which the index o and the substituents Lc are as defined below:
Especially preferred are compounds Ic, where the substituent Lc is as defined below:
Ru is preferably halogen, cyano, C1-C8-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C1-C6-alkoxy, C2-C10-alkenyloxy, C2-C10-alkynyloxy, C3-C6-cycloalkyl, C5-C6-cycloalkenyl, —C(═O)—O-A1, —C(═O)—N(A2)A1, C(A2)(═N-OA1), where the aliphatic or alicyclic groups for their part may be partially or fully halogenated or may carry one to three groups Rv, Rv having the same meaning as Ru. Ru is in particular halogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C2-C6-alkenyloxy, C2-C6-alkynyloxy, C3-C6-cycloalkyl, C5-C6-cycloalkenyl.
Amongst compounds Ic preference is given to compounds Ic′
wherein R1, R2, R4c and Yc are as defined above and wherein
In a fourth embodiment of the invention the substituted 5-phenyl pyrimidine compounds I carry a radical R4d in the 2-position of the pyrimidine ring, wherein
R4d corresponds to one of the formulae
where
Preferred radicals R4d are of the following formulae
wherein W and Rq# are as defined above.
Finally, R4d may preferably have the following meanings, which may also be understood as prodrug radical definitions (see Medicinal Research Reviews 2003, 23, 763-793, or J. of Pharmaceutical Sciences 1997, 86, 765-767):
In the ten aforementioned radicals the index n in the alkenyl radicals of the above formulae is an integer from 1, 2 or 3. The substituent Rz is preferably hydrogen, methyl, allyl or propargyl and particularly preferably hydrogen. The substituent Rq is preferably hydrogen, C1-C6-alkyl or C2-C6-alkenyl and with particular preference methyl, allyl or propargyl.
Amongst the 5-phenyl pyrimidines I, which carry a radical R4d in the 2-position of the pyrimidine moiety, compounds formula Id
are preferred, in which R1, R2 and R4d have the meanings given in claim 1,
Particular preference is also given to compounds Id in which Yd is C1-C4-alkyl which may be substituted by halogen. Moreover, particular preference is given to compounds Ic in which Yd is halogen, cyano, C1-C4-alkyl or C1-C4-alkoxy. Especially preferred are compounds I in which Yd is methyl, ethyl, cyano, bromine or in particular chlorine.
Amongst compounds Id preference is given to compounds Id′
wherein R1, R2, R4d and Yd are as defined above and wherein
In another embodiment of the invention, the substituted 5-phenyl pyrimidines I are of formula Ie
in which R1a is as defined in claim 1,
Ye is in particular halogen, C1-C4-alkyl, cyano or C1-C4-alkoxy, such as chlorine, bromine, methyl, cyano, methoxy or ethoxy, especially chlorine, bromine or methyl, most preferably chlorine.
Amongst compounds Ie preference is given to compounds Ie′
wherein R1, R2, R4e and Ye are as defined above and wherein
The substituted 5-phenyl pyrimidines I, in particular the compounds of the formulae Ia, Ib, Ic, Id and Ie effectively inhibit growth and/or progeny of tumor cells as can be shown by standard tests on tumor cell lines such as HeLa, MCF-7 and COLO 205. In particular, 5-phenyl pyrimidines I show in general IC50 values <10−6 mol/l (i.e. <1 μM), preferably IC50 values <10−7 mol/l (i.e. <100 nM) for cell cycle inhibition in HeLa cells as determined by the test procedure outlined below.
Based on the results of these standard pharmacological test procedures, substituted 5-phenyl pyrimidines are useful as agents for treating, inhibiting or controlling the growth and/or progeny of cancerous tumor cells and associated diseases in a subject in need thereof. Therefore these compounds are useful in therapy of cancer in warm blooded vertebrates, i.e. mammals and birds, in particular human beings but also in other mammals of economic and/or social importance e.g. carnivores such as cats and dogs, swine (pigs, hogs and wild boars), ruminats (e.g. cattle, oxen, sheep, deer, goats, bison) and horses, or bird in particular poultry such as turkeys, chickens, ducks, geese, guinea fowl and the like.
In particular 5-phenyl pyrimidines I are useful in therapy of cancer or cancerous disease including cancer of breast, lung, colon, prostate, melanoma, epidermal, kidney bladder, mouth, larynx, esophagus, stomach, ovary, pancreas, liver, skin and brain.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and severity of the condition being treated. However, in general satisfactory results are obtained when the compounds of the invention are administered in amounts ranging from about 0.10 to about 100 mg/kg of body weight per day. A preferred regimen for optimum results would be from about 1 mg to about 20 mg/kg of body weight per day and such dosage units are employed that a total of from about 70 mg to about 1400 mg of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.
The dosage regimen for treating mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decidedly practical advantage is that these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes. The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatine capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 1000 mg of active compound.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth or microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.
The following examples 1 to 221 given in table 1 are representative compounds of this invention which are useful as anticancer agents. In table 1 the compounds are defined by formula I-A, wherein for the respective example R1, R2, R4, Y, (L)m are given in the rows of table 1.
HeLa B cells are grown in DMEM (Life Technologies Cat No 21969-035) supplemented with 10% Fetal Calf Serum (FCS, Life Technologies Cat No 10270-106) in 180 cm2 Flasks at 37° C., 92% humidity and 7% CO2.
Cells are seeded at 5×104 cells per well in a 24-well plate. Twenty hours later the compounds are added such that the final concentration is 1×10−6, 3.3×10−7, 1.1×10−7, 3.7×10−8, 1.2×10−8 and 1×10−9 M in a final volume of 500 μl. DMSO alone is added to 6 wells as a control. Cells are incubated with the compounds as above for 20 h. Then cells are observed under the microscope to check for cell death, and the 24-well plate is then centrifuged at 1200 rpm for 5 min at 20° C., acceleration position 7 and break position 5 (Eppendorf centrifuge 5804R).
The supernatant is removed and the cells lysed with 0.5 ml RNase Buffer (10 mM NaCitrate, 0.1% Nonidet NP40, 50 μg/ml RNase, 10 μg/ml Propidium iodide) per well. The plates are then incubated for at least 30 min in the dark at RT and the samples then transferred to FACS tubes. Samples are measured in a FACS machine (Beckton Dickinson) at the following settings:
The ratio of cells in G0/G1-phase to G2/M phase is calculated and compared to the value for the controls (DMSO) only. Results are given in table 2 as the IC50 value calculated from the concentration curve plotted against the cell cycle ratio and indicate the compound concentration at which 50% of cells are in cell cycle arrest after treatment with the compound.
Test on other cell lines (MCF-7 and COLO 205) were done in the same way except that they were incubated with the growth medium recommended by the American Tissue Culture collection for that cell type.
| Number | Date | Country | Kind |
|---|---|---|---|
| 05001955.3 | Jan 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP06/00774 | 1/30/2006 | WO | 00 | 7/30/2007 |
