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HK1128032A - Bis-platinum complexes with antitumor activity - Google Patents

Bis-platinum complexes with antitumor activity Download PDF

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Publication number
HK1128032A
HK1128032A HK09105552.0A HK09105552A HK1128032A HK 1128032 A HK1128032 A HK 1128032A HK 09105552 A HK09105552 A HK 09105552A HK 1128032 A HK1128032 A HK 1128032A
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HK
Hong Kong
Prior art keywords
acid
trans
platinum
bis
diamino
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HK09105552.0A
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Chinese (zh)
Inventor
Alberto Bernareggi
Mario Grugni
Giulio Mariotti
Ernesto Menta
Gianluca Pardi
Paolo Pavesi
Gabriella Pezzoni
Paola Nicoli
Sergio De Munari
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Cell Therapeutics, Inc. -Sede Secondaria
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Application filed by Cell Therapeutics, Inc. -Sede Secondaria filed Critical Cell Therapeutics, Inc. -Sede Secondaria
Publication of HK1128032A publication Critical patent/HK1128032A/en

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Description

Bis-platinum complexes with antitumor activity
The invention comprises platinum complexes having antitumor activity, processes for their preparation, pharmaceutical compositions comprising them and uses thereof, including the use for the preparation of a medicament for the treatment of tumors.
Platinum complexes are among the most effective chemotherapeutic drugs for treating solid tumors. Specifically, cisplatin [ cis-dichlorodiaminoplatinum (II); CDDP ] is one of the most widely used and effective antineoplastic agents, even though its administration is affected by severe side effects. Tumors that can be treated with the drug include testicular, ovarian, bladder, and head/neck tumors. Since its introduction into therapy, cisplatin has been the drug of choice for therapeutic treatment of germinal cell tumors and for prolongation of ovarian tumor survival treatment. Successful treatment with cisplatin is limited, primarily due to the fact that some tumor cells become resistant. Furthermore, most solid tumors (e.g., lung, colon-rectum and stomach tumors) do not respond to cisplatin or other chemotherapeutic agents (e.wong, c.m. giandomenico, the current status of Platinum-Based Antitumor Drugs (CurrentStatus of Platinum-Based Antitumor Drugs), chemical review (chem. rev.)1999, 99, 2451-2466).
Many analogues have been studied in the last decade in order to find platinum complexes with reduced toxicity, a broad spectrum of antitumor activity and no cross-resistance with cisplatin. These efforts have led to the clinical study of second generation platinum complexes with a similar profile of antitumor activity as cisplatin. Among them, carboplatin, the second platinum complex to enter the market, has a similar spectrum of antitumor activity to cisplatin, but has no toxicity of cisplatin. The third generation platinum complex that has recently entered the clinic is oxaliplatin (oxaliplatin). Other complexes being investigated are AMD0473 and satraplatin. However, it appears that none of these analogues overcome the major problem of cisplatin treatment, i.e. they do not broaden the therapeutic response to tumors, nor do they reduce the development of tumor resistance.
Finally, another problem associated with the platinum complexes currently used in therapy is: these complexes are susceptible to irreversible binding to plasma proteins by covalent bonds following intravenous administration. The kinetics of this process is dependent on the contact time, with over 90% drug binding within a few hours from administration. High irreversible binding to plasma proteins may reduce the efficacy of compounds in humans (s.s. jacobs et al, Clinical Cancer Research, vol 11, 1669-1674, 2005 and references cited therein).
Cisplatin-like fat-soluble platinum complexes are disclosed in US 5,117,022 and US 6,613,799. The compounds disclosed in US 5,117,022 can be incorporated into liposomes, whereas the complexes disclosed in US 6,613,799 have high specificity and selectivity for tumour cells when administered in contrast agents such as iodinated oil.
Bis-platinum complexes for the treatment of tumors characterized by the presence of diamino or polyamino ligands linking two platinum atoms together are disclosed in US 4,797,393, US 5,107,007, US 6,022,892 and US 6,596,889.
In particular, US 6,022,892 and US 6,596,889 disclose bis-platinum complexes characterized by the presence of polyamino ligands. These compounds are potent cytotoxic against cisplatin-resistant murine and human tumor lines such as the L1210/CDDP murine leukemia line and the A2780/CDDP human ovarian carcinoma line. The in vivo activity of these compounds in cisplatin-resistant experimental tumors is also reported.
The applicant of the present application has found that: the bis-platinum complexes disclosed in US 6,022,892 also bind irreversibly to plasma proteins in the presence of human plasma, as described above. Furthermore, it was found that the fraction of drug free in plasma water and reversibly bound to the protein rapidly and progressively degrades, resulting in pharmacologically inactive substances derived from the removal of platinum from the polyamino ligands. These substances are believed to be the result of chemical instability of the complex in plasma, probably due to the complex's interaction with endogenous molecules containing thiol nucleophiles (e.g., cysteine or glutathione residues). High binding levels of platinum compounds to human plasma proteins may facilitate this interaction. Rapid degradation in human plasma and highly irreversible binding to plasma proteins may reduce the efficacy of compounds in humans. Thus, a bis-platinum complex free of these undesirable properties is desired.
As disclosed herein, it has now surprisingly been found that: bis-platinum complexes characterized by the presence of certain carboxylate ligands in the platinum coordination sphere bind less to plasma proteins than the bis-platinum complexes described above, show good stability to deplatinization in plasma, and are capable of inhibiting tumor growth in various experimental models.
The compounds of the invention have the following general formula (I):
wherein:
r is selected from (C)1-C25) Alkyl, (C)2-C25) Alkenyl, aryl, (C)7-C10) Aralkyl group;
n and m are each independently an integer from 2 to 8;
p is 1 or 2;
a is selected from-B-, -B- (CH)2)r-B-、-B-(CH2)r-B-(CH2)z-B-, wherein r and z are integers from 2 to 8, B is-NR1-or-N (R)2)2 +1/pQ-pGroup, wherein R1Selected from hydrogen, (C)1-C4) Alkyl, (C)1-C4) Acyl, tert-butoxycarbonyl, and R2Selected from hydrogen and (C)1-C4) An alkyl group;
Q-pan anion selected from the group consisting of: chloride ions; bromide ions; iodide ions; nitrate radical; sulfate radical; hydrogen sulfate radical(ii) a Perchlorate radicals; r3COO-Wherein R is3Have the same meaning as R, and are independent of each other; and R4-O-SO3 -Wherein R is4Is (C)2-C14) An alkyl group;
provided that when Q is-pWhen selected from the group consisting of chloride, bromide, iodide, nitrate, sulfate, bisulfate, and perchlorate, R is not (C)1-C4) An alkyl group.
The invention also includes enantiomers and diastereomers of the compounds of formula (I).
Term (C)1-C25) Alkyl refers to a straight or branched chain alkyl residue of 1 to 25 carbon atoms, optionally substituted with 1 to 5 of the following groups: a hydroxyl group; (C)1-C4) An alkoxy group; (C)1-C4) An acyloxy group; (C)1-C4) An alkoxycarbonyl group; halogen; (C)1-C4) aminocarbonyl-CONRaRbWherein R isaAnd RbIndependently H, (C)1-C4) Alkyl and aryl groups; (C)1-C4) An alkylcarbonylamino group; -NRaCORb、-OCONRaRbWherein R isaAnd RbAs defined above; -NRaCOORcWherein R isaAs defined above and RcIs C1-C4Alkyl, aryl; the alkyl chains are optionally interrupted by 1 to 12 oxygen atoms, with the proviso that when the number of oxygen atoms is greater than 2 they are separated by at least 2 carbon atoms.
Term (C)2-C25) Alkenyl refers to a straight or branched chain alkenyl residue containing 2 to 25 carbon atoms and 1 to 8 double bonds, each double bond independently in cis or trans configuration, said residue being alkenyl optionally substituted with 1 to 5 of the following groups: a hydroxyl group; (C)1-C4) An alkoxy group; (C)1-C4) An acyloxy group; (C)1-C4) An alkoxycarbonyl group; halogen; -CONRaRbWherein R isaAnd RbIndependently H, (C)1-C4) Alkyl and aryl groups; -NRaCORb、-OCONRaRbWherein R isaAnd RbAs defined above; -NRaCOORcWherein R isaAs defined above, and RcIs (C)1-C4) Alkyl, aryl; with the proviso that the hydroxy, alkoxy, acyloxy, alkylcarbonylamino, alkylaminocarbonyloxy and alkoxycarbonylamino groups are not attached to a carbon atom forming a carbon-carbon double bond.
Aryl preferably means a phenyl, diphenyl or naphthyl group which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, nitro groups, cyano, hydroxy, (C)1-C4) Alkoxy group, (C)1-C4) Acyloxy, (C)1-C3) Haloalkoxy, (C)1-C4) Alkoxycarbonyl, carboxyl, (C)2-C4) An acyl group. The aryl group is preferably an unsubstituted phenyl group or a substituted phenyl group as described above.
Preferably, the R group together with the carboxylate group to which it is bonded is a saturated, mono-unsaturated or polyunsaturated fatty acid residue. The preferred embodiments are: saturated fatty acids having 10 to 24 carbon atoms, such as capric acid (capric acid), neodecanoic acid, lauric acid (lauric acid), myristic acid (myristic acid), palmitic acid (palmitic acid), stearic acid (stearic acid), arachidic acid (arachidic acid), behenic acid (behenic acid), lignoceric acid (lignoceric acid), 15-hydroxypentadecanoic acid, 16-hydroxypalmitic acid (16-hydroxyhexadecanoic acid; juniperic acid), 6-hydroxypalmitic acid, (R) -7-hydroxyhexadecanoic acid, 17-hydroxyheptadecanoic acid, (S) -9-hydroxyoctadecanoic acid, (S) -13-hydroxyoctadecanoic acid, 12-hydroxystearic acid (12-hydroxyoctadecanoic acid), erythro-6, 7-dihydroxyoctadecanoic acid, threo-9, 10-dihydroxystearic acid, erythro-9, 10-dihydroxystearic acid, erythro-12, 13-dihydroxyoctadecanoic acid, erythro-15, 16-dihydroxyoctadecanoic acid; monounsaturated fatty acids having 16 to 22 carbon atoms, such as oleic acid (cis-9-octadecenoic acid), ricinoleic acid ((R) -12-hydroxy-cis-9-octadecenoic acid; 12-hydroxyoleic acid), erucic acid (cis-13-docosenoic acid); polyunsaturated fatty acids, for example linoleic acid (cis, cis-6, 9-octadecadienoic acid), elaidic acid (trans, trans-9, 12-octadecadienoic acid), linolenic acid (cis, cis-9, 12, 15-octadecatrienoic acid), gamma-linolenic acid (cis, cis-6, 9, 12-octadecatrienoic acid), elaidic acid (trans, trans-9, 12, 15-octadecatrienoic acid), arachidonic acid (cis, cis-5, 8, 11, 14-eicosatetraenoic acid), cis-5, 8, 11, 14, 17-eicosapentaenoic acid (EPA), cis-4, 7, 10, 13, 16, 19-docosahexaenoic acid (DHA), 4(E), 7(Z), 10(Z), 13(Z), 16(Z), 19(Z) -docosahexaenoic acid.
Preferred R4-O-SO3 -The radical is n-hexyl sulfate, 2-ethylhexyl sulfate, n-octyl sulfate, n-decyl sulfate, n-dodecyl sulfate; dodecyl sulfate is particularly preferred.
Particularly preferred compounds are those in which H2N-(CH2)n-A-(CH2)m-NH2A compound in which the group is one of the following residues:
H2N-(CH2)3-NH2 +-(CH2)4-NH2
H2N-(CH2)3-NH2 +-(CH2)4-NH2 +-(CH2)3-NH2
H2N-(CH2)6-NH2 +-(CH2)2-NH2 +-(CH2)6-NH2
H2N-(CH2)5-NH2 +-(CH2)4-NH2 +-(CH2)5-NH2。
in the present specification, the expression "residue" refers to a group that is not completely covalently bonded.
Examples of compounds of the invention are:
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (undecanoate-O) platinum (II)]Tetra (undecanoate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (palmitate-O) platinum (II)]Tetrapalmitate salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino(oleate-O) platinum (II)]Tetra oleate
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (linoleate-O) platinum (II)]Quarternary tetralinoleate
{ mu- (1, 8, 11, 18-Tetraazaoctadecane N1，N18) Bis [ trans-diamino (linolenate-O) platinum (II)]Tetra-linolenic acid salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (cis-4, 7, 10, 13, 16, 19-docosahexaenoate-O) platinum (II)]Tetrakis (cis-4, 7, 10, 13, 16, 19-docosahexaenoate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (cis-5, 8, 11, 14, 17-eicosapentaenoic acid radical-O) platinum (II)]Tetrakis (cis-5, 8, 11, 14, 17-eicosapentaenoic acid salt)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (ricinoleate-O) platinum (II)]Quarternary tetraricinoleate
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (16-hydroxyhexadecanoate-O) platinum (II)]Tetra (16-hydroxyhexadecanoate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (12(R, S) -hydroxyoctadecanoate-O) platinum (II)]Tetrakis (12(R, S) -hydroxyoctadecanoate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans ]Diamino (decanoate-O) platinum (II)]Tetradecanoate salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (undecanoate-O) platinum (II)]Tetra (undecanoate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (palmitate-O) platinum (II)]Tetrapalmitate salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (oleate-O) platinum (II)]Tetra oleate
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (linoleate-O) platinum (II)]Quarternary tetralinoleate
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (linolenate-O) platinum (II)]Tetra-linolenic acid salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (cis-4, 7, 10, 13, 16, 19-docosahexaenoate-O) platinum (II)]Tetrakis (cis-4, 7, 10, 13, 16, 19-docosahexaenoate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (cis-5, 8, 11, 14, 17-eicosapentaenoic acid radical-O) platinum (II)]Tetrakis (cis-5, 8, 11, 14, 17-eicosapentaenoic acid salt)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (ricinoleate-O) platinum (II)]Quarternary tetraricinoleate
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (16-hydroxyhexadecanoate-O) platinum (II)]Tetra (16-hydroxyhexadecanoate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (12(R, S) -hydroxyoctadecanoate-O) platinum (II)]Tetrakis (12(R, S) -hydroxyoctadecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (undecanoate-O) platinum (II)]Tetra (undecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane)alkane-N1，N14) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (palmitate-O) platinum (II)]Tetrapalmitate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (oleate-O) platinum (II)]Tetra oleate
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (linoleate-O) platinum (II)]Quarternary tetralinoleate
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (linolenate-O) platinum (II)]Tetra-linolenic acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (cis-4, 7, 10, 13, 16, 19-docosahexaenoate-O) platinum (II)]Tetrakis (cis-4, 7, 10, 13, 16, 19-docosahexaenoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (cis-5, 8, 11, 14, 17-eicosapentaenoic acid radical-O) platinum (II)]Tetrakis (cis-5, 8, 11, 14, 17-eicosapentaenoic acid salt)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (ricinoleate-O) platinum (II)]Quarternary tetraricinoleate
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (16-hydroxyhexadecanoate-O) platinum (II)]Tetra (16-hydroxyhexadecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (12(R, S) -hydroxyoctadecanoate-O) platinum (II)]Tetrakis (12(R, S) -hydroxyoctadecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (undecanoate-O) platinum (II)]Tetra (undecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (palmitate-O) platinum (II)]Tetrapalmitate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (oleate-O) platinum (II)]Tetra oleate
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (linoleate radical)-O) platinum (II)]Quarternary tetralinoleate
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (linolenate-O) platinum (II)]Tetra-linolenic acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (cis-4, 7, 10, 13, 16, 19-docosahexaenoate-O) platinum (II)]Tetrakis (cis-4, 7, 10, 13, 16, 19-docosahexaenoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (cis-5, 8, 11, 14, 17-eicosapentaenoic acid radical-O) platinum (II)]Tetrakis (cis-5, 8, 11, 14, 17-eicosapentaenoic acid salt)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (ricinoleate-O) platinum (II)]Quarternary tetraricinoleate
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (16-hydroxyhexadecanoate-O) platinum (II)]Tetra (16-hydroxyhexadecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (12(R, S) -hydroxyoctadecanoate-O) platinum (II)]Tetrakis (12(R, S) -hydroxyoctadecanoate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino(Butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
The compounds of formula (I) may be prepared as follows: reacting a compound of formula (II)
Wherein A has the same meaning as in the compound of formula (I), wherein p is 1 and Q-pIs a nitrate anion, is reacted with at least two equivalents of silver nitrate to give an intermediate, which is then reacted with at least two equivalents of a compound of formula (III)
RCOOM
(III)
Wherein R has the same meaning as in the compound of formula (I) and M is an alkali metal, alkaline earth metal or quaternary ammonium salt (e.g. tetramethylammonium, tetrabutylammonium) cation, to give a compound wherein Q-pIs nitrate radical (NO)3 -) Or carboxylate Radical (RCOO)-) An anion, wherein p is 1 and R is a compound of formula (I) as defined in formula (I).
The reaction of the compound of formula (II) with silver nitrate and subsequently with the compound of formula (III) is generally carried out in a solvent such as water, dimethylformamide or a mixture thereof at a temperature of 10-60 ℃ for a reaction time of 15 hours to 3 weeks. Preferably, 2 equivalents of the compound of formula III are used per equivalent of the compound of formula II and the reaction is generally complete within 2 days.
Wherein Q-pCompounds of formula (I) which are nitrate anions may be prepared by reacting a compound of formula (II)II with at least 2 equivalents of silver carboxylate of the formula (III'),
RCOOAg
(III′)
the reaction is usually carried out in a solvent such as water, dimethylformamide or a mixture thereof at a temperature of 10 to 60 ℃ for a reaction time of 15 hours to 3 weeks. Preferably, the reaction is generally completed within 2 days using a molar excess (2 equivalents) of the compound of formula III'.
Wherein Q-pIs RCOO-The compounds of formula (I) can be prepared by reacting a compound of formula (II
Wherein A is as defined for formula I, wherein p is 1 and Q-pIs a chloride ion, is obtained by reaction with a silver carboxylate of formula (III').
The reaction is generally carried out in a solvent such as water, dimethylformamide or mixtures thereof at a temperature of 10-60 ℃ for a period of 15 hours to 3 weeks, preferably using a 6 equivalent molar excess of the compound of formula III'; the reaction is usually complete within 2 days.
Wherein Q-pIs R3-O-SO3 -The compounds of formula (I) can be obtained as follows: reacting a compound of formula (II) with at least 2 equivalents of silver nitrate to produce an intermediate, then reacting the intermediate with a compound of formula (III), followed by treatment with an alkyl sulfate of formula IV
R3-O-SO3M
(IV)
Wherein R is3And M is as defined above.
The reaction is generally carried out in a solvent such as water, dimethylformamide, methanol or mixtures thereof at a temperature of 10-60 ℃ for a period of 15 hours to 3 weeks, preferably using a molar excess (6 equivalents) of the compound of formula (III) and a stoichiometric or slight excess of the compound of formula (IV).
Processes for preparing compounds of formula (II) and formula (II') are disclosed in US 6,022,892 and US 6,596,889.
The compounds of formula (III) are commercially available (e.g.from Sigma-Aldrich, St. Louis (MO), USA) or can be prepared in a known manner from the corresponding carboxylic acids of formula (V)
RCOOH
(V)
Wherein R is as defined for formula (I). The compound of formula (III') may be prepared according to US 5,117,022.
The alkyl sulfates of formula (IV) and carboxylic acids of formula (V) are commercially available (e.g., from Sigma-Aldrich, st. louis (MO), USA) or can be prepared according to known methods.
The platinum complexes of the present invention show lower binding activity and better stability when incubated in the presence of human plasma than the platinum complexes disclosed in US 6,022,892.
When measured in per m2The compounds of the invention induce tumor regression when administered to a human or animal bearing cisplatin-treatable or cisplatin-resistant tumors at a dose of 0.1mg to 1.2g of body area.
In general, the compounds of the invention can be used for the treatment of pathological conditions treatable with cisplatin, i.e. for the treatment of tumors and for increasing the sensitivity of tumors to radiotherapy [ Douple et al, Cis-platinum Current Status and Developments, and A.W.Prestayk et al, Academic Press, 125 (1980); double et al, platinum Metals Res., 29; 118(1985) and for the treatment of parasitic diseases such as african trypanosomiasis [ Farrell et al, biochemistry and pharmacology (biochem. pharmacol.), 33, 961(1984) ]. Accordingly, the present invention also includes a method of treating a tumor in a subject in need thereof, comprising administering to the subject an effective tumor treating amount of a compound of formula (I). As used herein, the term "treating" may include one or more of the following: preventing tumor growth, killing tumor cells, preventing tumor cells, or prolonging survival.
Another embodiment of the present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) together with conventional carriers and excipients.
Effective dosages of the compounds of the present invention can be determined by the skilled practitioner according to routine methods. Relationship between dose and size for animals of different species and relationship between dose and size for humans (in mg/m)2Body area calculation) described in Freirech et al, Quantitative comparisons of Toxicity of Anticancer Agents in mice, rats, hamsters, dogs, monkeys and humans (Quantitative company of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkeyand Man), Cancer Chemotherer Rep., 50, N.4, 219-244 (1986). However, patients will generally receive a dosage of 0.1-200mg/kg body weight of the above-described complex, and the dosage regimen will vary according to a variety of factors well known to the skilled practitioner.
The treatment protocol may be suitably adapted, as is well known to the expert, according to the tumor to be treated and the condition of the patient.
The compounds of the invention may be administered by parenteral or oral routes.
Pharmaceutical compositions for parenteral use include sterile saline solutions as defined above, or sterile powders for the extemporaneous preparation of solutions, and oily preparations for intramuscular (im) or intraperitoneal (ip) administration.
The compounds of the invention are preferably administered as sterile aqueous solutions containing an appropriate concentration (0.1-0.9mg/ml) of sodium chloride. The solutions are preferably administered by the intravenous (iv) or intra-arterial (ia) route, although other forms of administration may be employed in particular cases.
Pharmaceutical compositions for oral administration include, for example, syrups or similar liquid forms, as well as solid forms such as tablets, capsules and the like.
The Pharmaceutical compositions according to the invention may be prepared according to conventional methods such as those reported in Remington's handbook of Pharmaceutical sciences (Remington's Pharmaceutical sciences handbook), XVII ed.
It is sometimes advantageous to administer the platinum complexes of the present invention in combination with one or more agents that increase antitumor activity or reduce undesirable side effects and that can be used in combination therapy with the platinum complexes. For example, the platinum complexes of the invention may be administered with reduced glutathione as described in GB 2.174.905 and u.s.4.871.528.
Furthermore, it may be advantageous to administer the platinum complexes of the invention in combination with other antitumor platinum complexes.
Accordingly, another embodiment of the present invention encompasses pharmaceutical compositions comprising at least one compound of formula (I) and a platinum complex having antitumor activity.
Another embodiment of the present invention encompasses the use of a compound of formula (I) for the manufacture of a medicament for treating a mammal afflicted with a cisplatin-treatable or cisplatin-resistant tumor.
The invention is further illustrated in the following examples.
Examples
Preparation 1: tetrabutylammonium octanoate
Under stirring, 0.4M aqueous tetrabutylammonium hydroxide solution(15.3mL, 6.12mmol) was added dropwise to H in octanoic acid (n-octanoic acid) (1mL, 6.184mmol)2O (20mL) dispersion. The resulting solution was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure, and water was removed with toluene. The residue was dried under vacuum at 35 ℃ to give 2.416g (> 99% yield) of a clear oil.
1H NMR(DMSO-d6)：δ3.18(8H，t，J＝8.34Hz)；1.73(2H，t，J＝7.39)；1.58(8H，m)；1.32(10H，m)；1.22(8H，m)；0.94(12H，t，J＝7.32)；0.86(3H，t，J＝6.87).
Preparation 2: tetrabutylammonium dodecanoate
0.4M aqueous tetrabutylammonium hydroxide solution (1mL, 0.4mmol) was added dropwise to dodecanoic acid (0.12g, 0.6mmol) in MilliQ H under stirring2O (12mL) suspension. The resulting suspension was stirred at room temperature for 1 hour. The solid was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure, with water being removed with EtOH. 0.17g (96% yield) of a yellow oil is obtained.
1H NMR(D2O)：δ3.20(8H，m)；2.18(2H，t，J＝7.35Hz)；1.66(8H，m)；1.37(8H，m)；1.29(18H，m)；0.96(12H，t，J＝7.38)；0.87(3H，m).
The following compounds were prepared in a similar manner to preparations 1 and 2:
tetrabutylammonium hexanoate
Tetrabutylammonium dodecanoate
Tetrabutylammonium tridecanoate
Tetrabutylammonium myristate
Tetrabutylammonium stearate
Example 1: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
Hexanoic acid (0.16mL, 1.277mmol) in MilliQ H was added under stirring2The O (2mL) dispersion was added dropwise to a 0.4M aqueous solution of tetrabutylammonium hydroxide (2.89mL, 1.156 mmol). The resulting solution was stirred at room temperature for 1 hour and then used without further treatment.
The reaction was carried out under nitrogen atmosphere in MilliQ H2And performing O neutralization under the condition of keeping out light. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (12mL) solution, and the resulting suspension was stirred at room temperature for 24 hours. The mixture was filtered twice through a double microfiber (double microfiber) filter to remove solids; the filter was washed with 1mL of H2O wash and combine it with the filtrate. Tetrabutylammonium hexanoate (0.414g, 1.158mmol) in H was stirred2O (5mL) solution was added dropwise to the filtrate; the resulting solution was stirred at room temperature overnight. The solution was evaporated to dryness under reduced pressure (35 ℃), and the oily residue was then solidified by treatment with anhydrous EtOH (2 mL). Suspend the solid in Et2O (8mL) and stirred overnight, then collected and suspended in CH2Cl2(6mL) and the mixture was stirred overnight. The solid was collected on a Buchner filter using CH2Cl2Washed and dried under vacuum at 40 ℃ to give 0.055g (24% yield) of a white powder.
Elemental analysis calcd C26.09% H5.89% N14.04% Pt 32.59%
Found C24.88% H5.73% N13.24% Pt 31.58%
MS：1159.1，[MH+C3F7COOH-4HNO3]+
1H NMR(D2O)：δ(3.31(4H，s)；3.03(4H，t，J＝7.68Hz)；2.62(4H，m)；2.26(4H，t，J＝7.53)；1.67(8H，m)；1.52(4H，m)；1.39(8H，m)；1.26(8H，m)；0.86(6H，t，J＝7.03).
The following compounds were prepared in a similar manner
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra nitrate salt
Example 2: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
The reaction is carried out in MilliQ H2And performing O neutralization under the condition of keeping out light. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O is washed, andwater was combined with the filtrate. Tetrabutylammonium octanoate (0.462g, 1.198mmol) of preparation 1 in H2O (18mL) solution was added dropwise to the filtrate; the resulting suspension was stirred at room temperature for 23 hours. The viscous material was removed from the suspension and the filtrate was concentrated to a small volume under reduced pressure at 35 ℃. The white precipitate was collected, dried under vacuum at 35 ℃ and suspended in CHCl3(5 mL); the mixture was stirred for 1 hour and the solid was collected on a Buchner funnel and washed with hexane to give 0.025g (10% yield) of a clear powder.
Elemental analysis calcd for C28.75% H6.27% N13.41% Pt 31.13%
Found C27.72% H6.06% N12.79% Pt 29.631%
MS：1215.2，[MH+C3F7COOH-4HNO3]+
1H NMR(D2O)：δ(3.24(4H，s)；2.99(4H，m)；2.62(4H，t，J＝7.64Hz)；2.26(4H，t，J＝7.53)；1.66(8H，m)；1.52(4H，m)；1.39(8H，m)；1.27(16H，m)；0.87(6H，t，J＝6.82).
The following compounds were prepared in a similar manner
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetra nitrate salt
Example 3: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoic acid salt))
The reaction was carried out under nitrogen atmosphere in MilliQ H2And performing O neutralization under the condition of keeping out light. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (10mL) solution, and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 4mL of H2O wash and combine water with the filtrate. Tetrabutylammonium dodecanoate (0.511g, 1.158mmol) H of preparation 2 was added under stirring2O (6mL) solution was added dropwise to the filtrate; the resulting solution was stirred at room temperature overnight. The separated viscous material was collected and suspended in acetone (4 mL); the suspension was stirred for 2 hours and the solid was collected on a Buchner funnel and dried under vacuum at 40 ℃ to give 0.145g (39% yield) of a clear powder.
MS：1327.3，[MH+C3F7COOH-4C11H23COOH]+
1H NMR(CDCl3/CD3OD 75/1)：δ8.47(2H，s)；2.76(4H，s)；2.60(4H，t，J＝6.71Hz)；2.51(4H，m)；2.16(8H，t，J＝7.60)；2.06(4H，t，J＝7.72)；1.44(22H，m)；1.17(102H，m)；0.79(18H，t，J＝6.67).
The following compounds were prepared in a similar manner
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (dodecanoate-O)Platinum (II)]Tetra (dodecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (dodecanoate-O) platinum (II)]Tetra (dodecanoate)
Example 4: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
0.4M aqueous tetrabutylammonium hydroxide solution (2.89mL, 1.156mmol) was added dropwise to tridecanoic acid (0.278g, 1.277mmol) in MilliQ H under stirring2O (20mL) suspension. The resulting suspension was stirred at room temperature for 1 hour, filtered to remove solids, and the filtrate was used without further treatment.
The reaction was carried out under nitrogen atmosphere in MilliQ H2And performing O neutralization under the condition of keeping out light. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (23mL) solution, and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. The tetrabutylammonium tridecanoate solution prepared above was added dropwise to the filtrate under stirring; the resulting solution was stirred at room temperature overnight. Collecting the separated viscous material with H2O wash, dried under vacuum at 30 ℃ and then suspended in hexane (12 mL); and the mixture was stirred overnight, the resulting solid was collected on a Buchner funnel, washed with hexane and dried under vacuum at 30 ℃ to give 0.098g (25% yield) of a clear powder.
Elemental analysis calcd for C55.28% H9.99% N5.61% Pt 19.52%
Found C54.42% H9.82% N5.45% Pt 19.06%
MS：1355.3，[MH+C3F7COOH-4C12H25COOH]+
1H NMR(CD3OD)：δ2.89(4H，s)；2.73(4H，t，J＝7.59Hz)；2.61(4H，t，J＝7.70)；2.19(12H，m)；1.60(20H，m)；1.41(8H，m)；1.29(108H，m)；0.90(18H，t，J＝6.83).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (tridecanoate-O) platinum (II)]Tetra (tridecanoate)
Example 5: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
Method A
0.4M aqueous tetrabutylammonium hydroxide solution (2.9mL, 1.16mmol) was added dropwise to myristic acid (0.53g, 2.32mmol) in MilliQ H with stirring2O (18mL) in suspension. Will be provided withThe resulting suspension was stirred at room temperature for 1 hour, filtered to remove solids, and the filtrate was used without further treatment.
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. The filtrate was added dropwise to tetrabutylammonium myristate (1.16mmol) in H with stirring2O (18mL) solution; the resulting suspension was stirred at room temperature for 23 hours, the solid was collected and suspended in H2O (20 mL). And the mixture was stirred for 1 hour, then the solid was collected with H2O washing and washing in CHCl3(15mL) and H2Partition between O (15 mL). The two-phase system was stirred for 1 hour 30 minutes; the organic phase is separated from the aqueous phase and evaporated to dryness under reduced pressure (35 ℃). The viscous residue was suspended in hexane (40mL) and the mixture was stirred for 22 hours, the solid was collected on a Buchner funnel and washed with hexane to give 0.082g (20% yield) of a brown powder.
Method B
Step a) tetrabutylammonium myristate
0.4M aqueous tetrabutylammonium hydroxide solution (10mL, 4mmol) was added dropwise to myristic acid (1.370g, 6mmol) in MilliQ H with stirring2O (50mL) suspension. The resulting suspension was stirred at room temperature for 1 hour. The solid was removed by filtration, then evaporated to dryness under reduced pressure, and the dry residue was removed with toluene. In vacuum, 3After drying at 5 ℃ 1.612g (86% yield) of a brown oil are obtained.
1H NMR(CDCl3)：δ3.48(8H，m)；2.29(2H，t，J＝7.7Hz)；1.65(8H，m)；1.45(8H，m)；1.3(22H，m)；1.01(12H，t，J＝7.5)；0.88(3H，t，J＝6.6).
Step b) { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. Tetrabutylammonium myristate (1.16mmol) in H2O (18mL) solution was added dropwise to the filtrate; the resulting suspension was stirred at room temperature for 24 hours, and the solid was collected with H2O washing and washing in CHCl3(15mL) and H2Partition between O (15 mL). The two-phase system was stirred for 1 hour 30 minutes; the organic phase is separated from the aqueous phase and evaporated to dryness under reduced pressure (35 ℃). By using Et2O treatment, solidification of the viscous residue, followed by evaporation under reduced pressure at 35 ℃. The solid was collected on a Buchner funnel and dried under vacuum at 35 ℃ to give 0.278g (68% yield) of a clear powder.
Elemental analysis calculated C56.51% H10.16% N5.38% Pt 18.73
Found C58.91% H10.38% N4.25% Pt 16.12
MS：1383.4，[MH+C3F7COOH-4C13H27COOH]+
1H NMR(CDCl3/CD3OD 75/1)：δ2.80(4H，s)；2.63(4H，t，J＝6.24Hz)；2.56(4H，t，J＝6.38)；2.15(8H，t，J＝7.54)；2.08(4H，t，J＝7.60)；1.50(18H，m)；1.20(130H，m)；0.82(18H，t，J＝6.05).
195Pt NMR(CDCl3)：δ-2095.81.
The following compounds were prepared in a similar manner
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (myristate-O) platinum (II)]Tetramyristate acid salt
Example 6: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
0.4M aqueous tetrabutylammonium hydroxide solution (2.9mL, 1.16mmol) was added dropwise to stearic acid (0.7g, 2.461mmol) in MilliQ H with stirring2O (20mL) suspension. The resulting suspension was stirred at room temperature for 1 hour, and the solid was removed by filtrationThe filtrate is then used without further treatment.
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. Tetrabutylammonium stearate (1.16mmol) in H was stirred2An O (20mL) solution was added dropwise to the filtrate, and the resulting suspension was stirred at room temperature for 23 hours. The solid was collected and suspended in H2To O (20mL), the mixture was stirred for 1 hour. The solid was collected on a Buchner funnel and washed with H2O washed and dried under vacuum at 30 ℃ to give 0.349g (75% yield) of a clear powder.
Elemental analysis calcd for C60.56% H10.75% N4.63% Pt 16.125
Found C60.15% H10.68% N4.20% Pt 14.86
MS：1495.4，[MH+C3F7COOH-4C17H35COOH]+
1H NMR(CDCl3)：δ6.25(4H，s)；4.46(12H，s)；2.93(4H，s)；2.71(8H，m)；2.22(8H，t，J＝7.65Hz)；2.15(4H，t，J＝7.79)；1.53(20H，m)；1.28(176H，m)；0.90(18H，t，J＝6.81).
195Pt NMR (CDCl3)：δ-2096.19.
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino(stearate-O) platinum (II)]Tetra stearate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (stearate-O) platinum (II)]Tetra stearate salt
Example 7: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. The filtrate was added dropwise to sodium caprate (0.225g, 1.158mmol) in H with stirring2To a solution of O (30mL), the resulting mixture was stirred at room temperature for 6 days. After decanting the solvent, the viscous material was taken up in CHCl3(20mL) and H2Partition between O (20mL) and filter to remove insoluble solids from the biphasic system. The organic phase is separated from the aqueous phase and evaporated to dryness under reduced pressure (35 ℃); by suspending in Et2In O, the viscous residue is solidified, followed by Et under reduced pressure2O was evaporated (35 ℃). The resulting solid was collected and dried under vacuum at 35 ℃ to give 0.064g (19% yield) of a brown powder.
Elemental analysis calcd C50.90% H9.35% N6.42%
Found C48.88% H9.66% N6.61%
MS：1171.4，[MH+CF3COOH-4C9H19COOH]+
1H NMR(CDCl3)：δ6.25(4H，s)；4.45(12H，s)；2.90(4H，s)；2.70(8H，m)；2.15(12H，m)；1.54(20H，m)；1.26(80H，m)；0.87(18H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (decanoate-O) platinum (II)]Tetradecanoate salt
Example 8: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
0.4M aqueous tetrabutylammonium hydroxide solution (2.9mL, 1.16mmol) was added dropwise to 16-hydroxypalmitic acid (0.645g, 2.3mmol) in MilliQ H under stirring2O (18mL) in suspension. The resulting suspension was stirred at room temperature for 1 hour, filtered to remove solids, and the filtrate was used without further treatment.
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.072g, 0.424mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. Stirring a solution of tetrabutylammonium 16-hydroxypalmitate (1.16mmol) in H2O (18mL) solution was added dropwise to the filtrate; the resulting suspension was stirred at room temperature for 24 hours and the precipitated solid was collected with H2O washed and dried under vacuum at 35 ℃. Et of the solid2O (30mL) suspension was stirred at room temperature for 1 hour, then the solid was collected on a Buchner funnel and Et2O wash to give 0.428g (95% yield) of the title product.
Elemental analysis calcd C56.29% H10.05% N4.77% Pt 16.62%
Found C55.53% H9.97% N4.33% Pt 15.14%
MS：1471.4，[MH+C3F7COOH-4HOC15H30COOH]+
1H NMR(CD3OD)：δ3.54(12H，t)；2.89(4H，s)；2.73(4H，m)；2.61(4H，m)；2.20(12H，m)；1.60(30H，m)；1.40(6H，m)；1.35(136H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxy brown)Palmitate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (16-hydroxypalmitate-O) platinum (II)]Tetra (16-hydroxypalmitate)
Example 9: { mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 7, 12, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 48 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. Sodium butyrate (0.127g, 1.154mmol) was added to the filtrate, and the solution was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure at 35 ℃ and the solid residue was dried under vacuum at 35 ℃. The solid was then suspended in i-PrOH (20mL) and the suspension was stirred at room temperature for 1 hour. Insoluble material was removed by filtration and the filtrate was evaporated in vacuo (35 ℃ C.) at room temperature. The solid residue was collected on a Buchner funnel and used for Et2O washes and dries at 35 ℃ under vacuum to give 0.149g (62% yield) of the title product as a white solid.
Elemental analysis calcd C36.77% H7.31% N9.03% Pt 31.43%
Found C33.59% H6.69% N9.18% Pt 31.78%
MS：1103.0，[MH+C3F7COOH-4C3H7COOH]+
1H NMR(D2O)：δ3.04(8H，m)；2.63(4H，t，J＝7.5Hz)；2.24(4H，t，J＝7.3)；2.16(8H，t，J＝7.3)；1.72(12H，m)；1.56(12H，m)；1.43(4H，m)；0.88(18H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane N1，N18) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra-butyric acid salt
Example 10: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.0655g, 0.386mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 48 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and add this water to the filtrate. The filtrate was added dropwise to a solution of sodium octanoate (0.192g, 1.155mmol) in MeOH (19mL) with stirring, and the resulting solution was stirred at room temperature for 24 hours. The filtrate was subjected to reduced pressureConcentrate to half volume (35 deg.C) and add the separated oil to CHCl3(18mL) was dissolved. After stirring at room temperature for 10 minutes, the organic phase is separated from the aqueous phase and evaporated to dryness under reduced pressure (35 ℃). Et was added2O solidified the oily residue, which was then evaporated under reduced pressure (35 ℃). The solid was collected on a Buchner funnel and dried under vacuum at 35 ℃ to give 0.217g (71% yield) of the title product as a white solid.
Elemental analysis calcd for C47.19% H8.82% N7.10% Pt 24.72%
Found C46.89% H8.70% N7.03% Pt 24.25%
MS：1215.1，[MH+C3F7COOH-4C7H15COOH]+
1H NMR(CDCl3)：δ6.20(4H，s)；4.40(12H，s)；2.93(4H，s)；2.73(8H，m)；2.21(8H，t，J＝7.5Hz)；2.15(4H，t，J＝7.5)；1.54(20H，m)；1.30(56H，m)；0.90(18H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (octanoate-O) platinum (II)]Tetraoctanoic acid salt
Example 11: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
The reaction was carried out under exclusion of light and MilliQ H2In O. Capric acid (0.286g, 1.472mmol) in H was added under stirring2O (5mL) solution was added dropwise to { mu- (1, 8, 11, 18-tetraazaoctadecane-N) of example 11，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]H of tetranitrate (0.441g, 0.368mmoli)2O (25mL) solution; and the resulting mixture was stirred at room temperature for 15 minutes. Adding CHCl into the gel-like material separated from the mixture3(25mL) was dissolved. After stirring at room temperature for 15 minutes, the organic phase is separated from the aqueous phase and evaporated to dryness under reduced pressure at 35 ℃. Et was added2O solidified the oily residue, which was then evaporated under reduced pressure at 35 ℃. The solid was collected on a Buchner funnel and dried under vacuum at 35 ℃ to give 0.387g (64% yield) of the title product.
Elemental analysis calcd for C48.51% H9.01% N6.86% Pt 23.88%
Found C48.09% H8.99% N6.62% Pt 23.31%
MS：1159.0，[MH+C3F7COOH-4C9H19COOH]+
1H NMR(CD3OD)：δ2.88(4H，s)；2.73(4H，t)；2.61(4H，m)；2.19(12H，m)；1.6(18H，m)；1.41(8H，m)；1.3(58H，m)；0.9(18H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetraammine hydrochloride of sheep
Example 12: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.072g, 0.424mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. The mixture was filtered twice through a double microfiber filter to remove solids, which was filtered with 1mL H2O wash and combine this water with the filtrate. A solution of hydrated sodium pivalate (0.144g, 1.16mmol) in MeOH (19mL) was added dropwise to the filtrate with stirring; and the resulting solution was stirred at room temperature for 24 hours. Then concentrated under reduced pressure (35 ℃ C.) to half volume and sodium lauryl sulfate (0.222g, 0.77mmol) in H is added dropwise with stirring2O (15mL) solution. After stirring at room temperature for 15 minutes, the precipitated solid was collected on a Buchner funnel and dried under vacuum at 35 ℃ to give 0.262g (68% yield) of the title product.
Elemental analysis calcd for C43.62% H8.44% N5.65% Pt 19.68% S6.47%
Found C43.48% H8.27% N5.77% Pt 19.69% S6.03%
MS：1131.1，[MH+C3F7COOH-4C12H25OSO3H]+
1H NMR(CD3OD)：δ4.17(12H，bs)；4.00(8H，t，J＝6.77Hz)；3.19(4H，s)；2.97(4H，m)；2.65(4H，m)；1.67(16H，m)；1.52-1.24(80H，m)；1.10(18H，s)；0.90(12H，t，J＝7.14).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (pivalate-O) platinum (II)]Tetra (dodecyl sulfate)
Example 13: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.072g, 0.424mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and combine this water with the filtrate. Under the condition of stirring, the mixture is stirred,a solution of sodium caproate (0.16g, 1.158mmol) in MeOH (19mL) was added dropwise to the filtrate; and the resulting solution was stirred at room temperature for 24 hours, then concentrated under reduced pressure (35 ℃) to half volume and sodium dodecyl sulfate (0.222g, 0.77mmol) in H was added dropwise with stirring2O (15mL) solution. After stirring for 15 minutes at room temperature, the precipitated solid was collected on a Buchner funnel, washed with a few ml of water and dried under vacuum at 35 ℃ to give 0.301g (78% yield) of the title product.
Elemental analysis calcd C44.21% H8.52% N5.57% Pt 19.40% S6.38%
Found C43.53% H8.42% N5.45% Pt 19.02% S6.80%
1H NMR(CD3OD)：δ4.17(12H，bs)；4.00(8H，t，J＝6.58Hz)；3.20(4H，s)；2.98(4H，t，J＝7.5)；2.65(4H，m)；2.18(4H，t，J＝8.24)；1.76-1.21(108H，m)；0.90(18H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (hexanoate-O) platinum (II)]Tetra (dodecyl sulfate)
Example 14: { mu- (1, 8, 11, 18-Tetraazaoctadecane-N1，N18) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
The reaction was carried out under exclusion of light and MilliQ H2In O. Mixing AgNO3(0.072g, 0.424mmol) was added to { mu- (1, 8, 11, 18-tetraazaoctadecane-N)1，N18) Bis [ trans-diamino (dichloro) platinum (II)]Tetranitrate (0.2g, 0.193mmol) in H2O (18mL) solution and the resulting suspension was stirred at room temperature for 24 hours. Filtering the mixture twice through a double microfiber filter to remove solids; the filter was washed with 1mL of H2O wash and add this water to the filtrate. Sodium butyrate (0.127g, 1.154mmol) was added to the filtrate, and the resulting solution was stirred at room temperature for 24 hours, then sodium lauryl sulfate (0.222g, 0.77mmol) in H was added dropwise with stirring2O (10mL) solution. After stirring for 15 minutes at room temperature, the precipitated solid was collected on a Buchner funnel with a few milliliters of H2O washes and dries at 35 deg.C under vacuum to yield 0.28g (74% yield) of the title product.
Elemental analysis calcd C43.02% H8.35% N5.73% Pt 19.96% S6.56%
Found C42.72% H8.46% N5.62% Pt 19.66% S6.69%
MS：1103.0，[MH+C3F7COOH-4C12H25OSO3H]+
1H NMR(CD3OD)：δ4.17(12H，bs)；4.01(8H，t，J＝6.58Hz)；3.37(4H，s)；3.10(4H，t，J＝6.95)；2.66(4H，m)；2.17(4H，t，J＝7.68)；1.80-1.22(100H，m)；0.90(18H，m).
The following compounds were prepared in a similar manner:
{ mu- (1, 7, 12, 18-Tetraazaoctadecane N1，N18) Double is[ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5,10, 14-Tetraazatetradecane-N1，N14) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
{ mu- (1, 5, 10-triazadecane-N1，N10) Bis [ trans-diamino (butyrate-O) platinum (II)]Tetra (dodecyl sulfate)
Example 15: pharmacological evaluation of the Compounds of the invention
Representative compounds of the invention were tested for their cytotoxic effect in vitro on various tumor cell lines, murine leukemia L1210, human ovarian carcinoma A2780 or respective cisplatin-resistant sublines L1210/CDDP and A2780/CDDP. Representative compounds of the invention have cytotoxic effects and they are able to overcome resistance mechanisms that limit the use of cisplatin.
In addition, representative compounds of the invention were tested in vivo experiments in which human tumor cell lines such as A2780 (human ovary), A2780/CDDP (cisplatin-resistant human ovary), or LoVo (human colon) were subcutaneously inoculated into immunosuppressed nude mice. After tumor inoculation, the compounds are administered intravenously every four or seven days for three cycles. In these experimental models, the compounds of the invention demonstrate high antitumor efficacy at tolerated doses.

Claims (12)

1. A compound of formula (I):
wherein:
r is selected from (C)1-C25) Alkyl, (C)2-C25) Alkenyl, aryl, (C)7-C10) Aralkyl group;
n and m are each independently an integer from 2 to 8;
p is 1 or 2;
a is selected from-B-, -B- (CH)2)r-B-、-B-(CH2)r-B-(CH2)z-B-, wherein r and z are integers from 2 to 8, B is-NR1-or-N (R)2)2 +1/pQ-pGroup, wherein R1Selected from hydrogen, (C)1-C4) Alkyl, (C)1-C4) Acyl, tert-butoxycarbonyl, and R2Selected from hydrogen and (C)1-C4) An alkyl group;
Q-pan anion selected from the group consisting of: chloride ions; bromide ions; iodide ions; nitrate radical; sulfate radical; hydrogen sulfate radical; perchlorate radicals; r3COO-Wherein R is3Have the same meaning as R, and are independent of each other; and R4-O-SO3 -Wherein R is4Is (C)2-C14) An alkyl group;
provided that when Q is-pWhen selected from the group consisting of chloride, bromide, iodide, nitrate, sulfate, bisulfate, and perchlorate, R is not (C)1-C4) An alkyl group.
2. A compound according to claim 1, wherein the R group together with the carboxylate group to which it is bonded is the residue of a saturated, mono-unsaturated or polyunsaturated fatty acid.
3. A compound according to claim 2, wherein the R group together with the carboxylate group to which it is bonded is the residue of a saturated fatty acid containing 10 to 24 atoms.
4. The compound according to claim 2, wherein the saturated fatty acid is selected from capric acid (capric acid), neodecanoic acid, lauric acid (dodecanoic acid), myristic acid (tetradecanoic acid), palmitic acid (hexadecanoic acid), stearic acid (octadecanoic acid), arachidic acid (eicosanoic acid), behenic acid (docosanoic acid), lignoceric acid (tetracosanoic acid), 15-hydroxypentadecanoic acid, 16-hydroxypalmitic acid (16-hydroxyhexadecanoic acid; juniperic acid), 6-hydroxypalmitic acid, (R) -7-hydroxyhexadecanoic acid, 17-hydroxyheptadecanoic acid, (S) -9-hydroxyoctadecanoic acid, (S) -13-hydroxyoctadecanoic acid, 12-hydroxystearic acid (12-hydroxyoctadecanoic acid), erythro-6, 7-dihydroxyoctadecanoic acid, threo-9, 10-dihydroxystearic acid, erythro-9, 10-dihydroxystearic acid, erythro-12, 13-dihydroxyoctadecanoic acid and erythro-15, 16-dihydroxyoctadecanoic acid.
5. A compound according to claim 2, wherein the R group together with the carboxylate group to which it is bonded is the residue of an unsaturated fatty acid containing from 16 to 22 carbon atoms.
6. A compound according to claim 5, wherein the unsaturated fatty acid is selected from the group consisting of oleic acid (cis-9-octadecenoic acid), ricinoleic acid ((R) -12-hydroxy-cis-9-octadecenoic acid; 12-hydroxyoleic acid), erucic acid (cis-13-docosenoic acid); linoleic acid (cis, cis-6, 9-octadecadienoic acid), elaidic acid (trans, trans-9, 12-octadecadienoic acid), linolenic acid (cis, cis-9, 12, 15-octadecatrienoic acid), gamma-linolenic acid (cis, cis-6, 9, 12-octadecatrienoic acid), elaidic acid (trans, trans-9, 12, 15-octadecatrienoic acid), arachidonic acid (cis, cis-5, 8, 11, 14-eicosatetraenoic acid), cis-5, 8, 11, 14, 17-eicosapentaenoic acid (EPA), cis, 4,7, 10, 13, 16, 19-docosahexaenoic acid (DHA) and 4(E), 7(Z), 10(Z), 13(Z), 16(Z), 19(Z) -docosahexaenoic acid.
7. The compound according to any one of claims 1-6, wherein H2N-(CH2)n-A-(CH2)m-NH2The group is one of the following residues:
H2N-(CH2)3-NH2 +-(CH2)4-NH2
H2N-(CH2)3-NH2 +-(CH2)4-NH2 +-(CH2)3-NH2
H2N-(CH2)6-NH2 +-(CH2)2-NH2 +-(CH2)6-NH2
H2N-(CH2)5-NH2 +-(CH2)4-NH2 +-(CH2)5-NH2。
8. the compound according to any one of claims 1 to 7, wherein Q-pIs R selected from the group consisting of n-hexyl sulfate, 2-ethylhexyl sulfate, n-octyl sulfate, n-decyl sulfate and n-dodecyl sulfate4OSO3-A group.
9. A compound according to claim 8, wherein R4-O-SO3 -Is n-dodecyl sulfate.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 together with a suitable carrier or excipient.
11. Use of a compound according to claims 1-9 for the preparation of a medicament with anti-tumor activity.
12. A method of treating a tumor in a subject in need thereof, the method comprising administering to the subject a tumor treating effective amount of a compound according to any one of claims 1-9.
HK09105552.0A 2005-12-22 2006-12-21 Bis-platinum complexes with antitumor activity HK1128032A (en)

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