# US 9,040,513 B2 · Process for preparing platinum-carbene complexes

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- Number: US 9,040,513 B2
- Document ID: US9040513B2
- Status: Granted
- Kind: B2
- Application number: 13/996,206
- Filed: 2011-12-22
- Published: 2014-02-27
- Granted: 2015-05-26
- Earliest claimed: 2010-12-23
- Assignees: Centre National De La Recherche Scientifique; Univrsite De Strasbourg
- Applicants: Stéphane Bellemin-Laponnaz; Gilles Guichard; Edith Chardon
- Inventors: Stéphane Bellemin-Laponnaz; Gilles Guichard; Edith Chardon
- Web page: https://patentgrep.com/patent/US9040513B2

## CPC

- C07F 15/0086: {Platinum compounds}
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- C07J 1/007: {the substituent being an OH group free esterified or etherified}
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07J: STEROIDS (seco-steroids C07C)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Described is a process for preparing platinum-carbene complexes.

## Claims

### Claim 1

A process for preparing platinum-carbene complexes of the following formula II:
in which:
R1 and R4 represent, independently of one another:
(i) a linear or branched C1-C12 alkyl group, optionally substituted with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
(ii) a linear or branched C2-C12alkenyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
(iii) a linear or branched C2-C12alkynyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
(iv) an aryl group having 1, 2 or 3 aromatic rings or aralkyl with a C1-C12carbon chain, the aryl or aralkyl group being optionally substituted with a C1-C12 alkyl group, or with a C1-C12alkoxy group, with a CF3 group, or with a trimethylsilyl group,
(v) a C3-C7 cycloalkyl, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to carbon atoms, with a CF3 group, or with a trimethylsilyl group, or
(vi) a polymer represented by the formula —(CH2CH2O)n—R′ or a polymer represented by the formula —(CH2CH2CH2O)n—R′, in which n=1 to 40, and R′ is a C1-C12 alkyl group,
R2 and R3 represent, independently of one another:
a hydrogen,
an aryl or aralkyl group, or
a linear or branched C2-C12 alkynyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl group,
X represents iodine, bromine or chlorine,
L2 represent:
(i) an amine of formula
in which R5, R6 and R7 represent, independently of one another:
(a) a hydrogen,
(b) a linear or branched C1-C18 alkyl, optionally substituted with an estradiol,
(c) an aryl group having 1, 2 or 3 aromatic rings, or aralkyl with a C1-C12 carbon chain, the aryl or aralkyl group being optionally substituted with a C1-C12 alkoxy group, or an alkyl group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
(d) a C3-C7 cycloalkyl, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl,
(e) a polymer represented by the formula —(CH2CH2O)n—R′ or the formula —(CH2CH2CH2O)n—R′, in which n=1 to 40, and R′ is a C1-C12 alkyl group, optionally substituted with an estradiol,
(ii) a diamine of general formula NH2—(CH2)n—NH2, n=1 to 12 carbon atoms,
(iii) a triamine of general formula NH2—(CH2)n—NH—(CH2)m—NH2, n=1 to 12 carbon atoms, m=1 to 12 carbon atoms,
(iv) a linear or branched amino alcohol with 2 to 20 carbon atoms, (v) a linear or branched amino ester with 2 to 20 carbon atoms,
(vi) a linear or branched amino amide with 2 to 20 carbon atoms,
(vii) an amino acid or esters or amides thereof,
(viii) a beta or gamma amino acid or its esters or amides,
(ix) a peptide, optionally cyclic, comprising 2 to 30 amino acids,
(x) a morpholine,
(xi) a piperazine optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl,
(xii) a piperazine N-substituted with a dansyl or dabsyl group
(xiii) a hydrazine monosubstituted with an aryl having 1, 2 or 3 aromatic rings, or a linear or branched alkyl with 1 to 12 carbon atoms,
(xiv) a glucamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms, (xv) a glucosamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms,
(xvi) a pseudopeptide of general formula H—(NH—CH(R)—CH2—X—CO)n—NHR″, with R being a side chain of one of the 20 proteinogenic amino acids; X being independently, throughout the sequence, CH2, O or NH; n=1-15; R″═H, or a short alkyl or aralkyl chain,
(xvii) a pseudopeptide of general formula Ra—CO—CH(Rb)—NH—CO—NH—CH(Rc)—CO—Rd in which Ra and Rd represent, independently of one another, H, a linear or branched C1-C6 alkyl group, a C3-C7 monocyclic cycloalkyl group, or a carboxylic acid protective group; Rb represents the side chain of lysine, the amine of said side chain being optionally substituted with a group —CO—(CH2)5—NH2; Rc represents a side chain of one of the 20 proteinogenic amino acids, optionally protected by an protective group,
(xviii) a polymer represented by the general formula NH2—(CH2(CH2)iNH)(n-1)—H, in which i=1, 2 or 3, n=1 to 1000, said polymer forming m coordination bonds with m platinum atoms, one of said coordination bonds being formed between Pt and L2 of formula (II) and m-1 coordination bonds being formed with m-1 groups of formula 1:
where R1, R2, R3, R4 and X are as defined above,
the number m being between 1 and n, the ratio m/n representing the number of platinum atoms to the number of amines of type —NH— or —NH2, said process comprising reaction of the compound of formula I:
in which:
R1, R2, R3, R4 and X have the meanings given above,
L1 representing a pyridine, or a pyridine substituted with iodine, bromine or chlorine, or disubstituted with iodine, bromine or chlorine,
with a ligand L2, or a salt of a ligand L2, said reaction being carried out optionally in the presence of a solvent.

### Claim 2 (depends on 1)

The process according to claim 1, wherein said reaction is carried out in the presence of a solvent selected from the group consisting of ethanol, methanol, dichloromethane, tetrahydrofuran, toluene, and ethyl acetate.

### Claim 3 (depends on 1)

The process according to claim 1, wherein said reaction is carried out in the absence of solvent, L2 being liquid at the reaction temperature and performing the role of solvent.

### Claim 4 (depends on 1)

The process according to claim 1, comprising adding a base selected from a tertiary amine, when the ligand L2 is in the form of salt.

### Claim 5 (depends on 1)

The process according to claim 1, wherein said compound of formula I is reacted with a salt of a ligand L2, said salt being in the form of ammonium salt, to obtain a compound of formula (II), wherein L2 is an amine.

### Claim 6 (depends on 1)

The process according to claim 1, wherein the temperature of the reaction is from 10° C. to 65° C.

### Claim 7 (depends on 1)

The process according to claim 1, wherein the reaction between the compound of formula I and the ligand L2 is carried out in the presence of ethanol as solvent, at a temperature from 45° C. to 65° C.

### Claim 8 (depends on 1)

The process according to claim 1, wherein the reaction between the compound of formula I and the ligand L2 is carried out in the presence of dichloromethane as solvent, at a temperature from 10° C. to 35° C.

### Claim 9 (depends on 1)

The process for preparing the platinum-carbene complexes of formula II according to claim 1, in which the compound of formula I is obtained by reacting
(i) a compound of formula III:
in which:
(a) R1, R2, R3, R4 have the meanings given above,
(b) Xa represents iodine, bromine or chlorine, or a counter-anion,
with the following molecules:
(ii) Pt(Xb)2, in which Xb represents iodine, bromine or chlorine, and
(iii) a ligand L1, L1 representing a pyridine, a pyridine substituted with iodine, bromine or chlorine, or disubstituted with iodine, bromine or chlorine, and
(iv) optionally NaXc in excess relative to Xa or to Xb, Xc representing iodine, bromine or chlorine,
said reaction being carried out optionally in the presence of a solvent.

### Claim 10 (depends on 9)

The process according to claim 9, wherein said reaction is carried out without solvent, the ligand L1 being liquid at the reaction temperature.

### Claim 11 (depends on 9)

The process according to claim 9, wherein the process is carried out with NaXc in excess with respect to Xa and Xb, when Xa is different from Xb.

### Claim 12 (depends on 9)

The process according to claim 9, wherein the process is optionally without the addition of NaXc, when Xa and Xb are identical.

### Claim 13 (depends on 9)

The process according to claim 9, wherein the reaction between the compound of formula III and the ligand L1 is carried out in the presence of a base.

### Claim 14 (depends on 1)

A process according to claim 1, for preparing platinum-carbene complexes of the following formula II:
in which:
R1 and R4 represent, independently of one another:
(i) a linear or branched C1-C8 alkyl group, optionally substituted with an alkoxy group with 1 to 8 carbon atoms, with a CF3 group or with a trimethylsilyl group,
(ii) a linear or branched C2-C8 alkenyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 8 carbon atoms, with a CF3 group, or with a trimethylsilyl group,
(iii) a linear or branched C2-C8 alkynyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 8 carbon atoms, with a CF3 group, or with a trimethylsilyl group,
(iv) a phenyl or aralkyl with a C1-C8 carbon chain, the phenyl or aralkyl group being optionally substituted with a C1-C8 alkyl group, or with a methoxy, with a CF3 group or with a trimethylsilyl group,
(v) a C3-C7 cycloalkyl, optionally substituted with an alkyl group with 1 to 8 carbon atoms, with an alkoxy group with 1 to 8 carbon atoms, with a CF3 group, or with a trimethylsilyl group, or
(vi) a polymer represented by the formula —(CH2CH2O)n—R′ or a polymer represented by the formula —(CH2CH2CH2O)n—R′, in which n=1 to 20, and R′ is a C1-C8 alkyl group,
R2 and R3 represent, independently of one another:
a hydrogen,
a phenyl or benzyl group, or
a linear or branched C2-C8 alkynyl group, optionally substituted with an alkyl group with 1 to 8 carbon atoms, with an alkoxy group with 1 to 8 carbon atoms, with a CF3 group, or with a trimethylsilyl group,
X represents iodine, bromine or chlorine,
L2 represent:
(i) an amine of formula
in which R5, R6 and R7 represent, independently of one another:
(a) a hydrogen,
(b) a linear or branched C1-C18 alkyl, optionally substituted with an estradiol,
(c) a phenyl, or aralkyl with a C1-C8 carbon chain, the phenyl, aralkyl group being optionally substituted with a methoxy, or an alkyl group with 1 to 8 carbon atoms, with a CF3 group or with a trimethylsilyl group,
(d) a C3-C7 cycloalkyl, optionally substituted with an alkyl group with 1 to 8 carbon atoms, with an alkoxy group with 1 to 8 carbon atoms, with a CF3 group, or with a trimethylsilyl,
(e) a polymer represented by the formula —(CH2CH2O)n—R′ or by the formula —(CH2CH2CH2O)n—R′, in which n=1 to 20, and R′ is a C1-C8 alkyl group, optionally substituted with an estradiol,
(ii) a diamine of general formula NH2—(CH2)n—NH2, n=1 to 12 carbon atoms,
(iii) a triamine of general formula NH2—(CH2)n—NH—(CH2)m—NH2, n=1 to 12 carbon atoms, m=1 to 12 carbon atoms,
(iv) prolinol,
(v) a linear or branched amino ester with 2 to 10 carbon atoms,
(vi) prolinamide,
(vii) an amino acid selected from the 20 proteinogenic α-amino acids or their esters or amides, (viii) a beta or gamma amino acid or its esters or amides,
(ix) a peptide, optionally cyclic, comprising 2 to 10 amino acids,
(x) a morpholine,
(xi) a piperazine optionally substituted with an alkyl group with 1 to 8 carbon atoms, with an alkoxy group with 1 1 to 8 carbon atoms, with a CF3 group, or with a trimethylsilyl group,
(xii) a piperazine N-substituted with a dansyl or dabsyl group,
(xiii) a hydrazine monosubstituted with a phenyl, or a linear or branched alkyl with 1 to 12 carbon atoms,
(xiv) N-methylglucamine, N-ethylglucamine or N-dodecylglucamine,
(xv) a glucosamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms, or
(xvi) a pseudopeptide of general formula H—(NH—CH(R)—CH2—X—CO)n—NHR″, with R being a side chain of one of the 20 proteinogenic amino acids; X being independently, throughout the sequence, CH2, O or NH; n=1-15; R″═H, or a short alkyl or aralkyl chain,
(xvii) a pseudopeptide of general formula Ra—CO—CH(Rb)—NH—CO—NH—CH(Rc)—CO—Rd in which Ra and Rd represent, independently of one another, H, a linear or branched C1-C6 alkyl group, a C3-C7 monocyclic cycloalkyl group, or a carboxylic acid protective group; Rb represents the side chain of lysine, the amine of said side chain being optionally substituted with a group —CO—(CH2)5—NH2; Rc represents a side chain of one of the 20 proteinogenic amino acids, optionally protected by an ad hoc protective group,
(xviii) a polymer represented by the general formula NH2—(CH2(CH2)iNH)(n-1)—H, in which i=1, 2 or 3, n=1 to 500, said polymer forming m coordination bonds with m platinum atoms, one of said coordination bonds being formed between Pt and L2 of formula (II) and m-1 coordination bonds being formed with m-1 groups of formula 1:
where R1, R2, R3, R4 and X are as defined above,
the number m being between 1 and n, the ratio m/n representing the number of platinum atoms to the number of amines of type —NH— or —NH2,
said process comprising:
(i) reacting a compound of the following formula III:
in which:
(a) R1, R2, R3, R4 have the meanings given above,
(b) Xa represents iodine, bromine or chlorine,
with Pt(Xb)2, and a ligand L1 and optionally NaXc in excess, to obtain a compound of the following formula I
in which
R1, R2, R3, R4 and X have the meanings given above,
L1 representing 3-bromopyridine, or 3-chloropyridine, or 3,5-dibromopyridine,
and
(ii) reacting the compound of formula I above with a ligand L2, carried out optionally in the presence of a solvent, to obtain a platinum-carbene complex of formula II above.

### Claim 15 (depends on 1)

The process according to claim 1, wherein,
(A) L2 represents:
(i) an amine of formula
in which R5, R6 and R7 represent, independently of one another:
(b) a linear or branched, non-cyclized C1-C18 alkyl, optionally substituted with an estradiol,
(c) an aryl having 1 or 2 or 3 aromatic rings, optionally substituted with a C1-C12 alkoxy group, or with an alkyl group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl,
(d) a polymer represented by the formula —(CH2CH2O)n—R′ or the formula —(CH2CH2CH2O)n—R′, in which n=1 to 40, and R′ is a C1-C12 C1-C8 alkyl group, optionally substituted with an estradiol,
provided that at least one of the R5, R6 and R7 radicals is different from hydrogen,
(ii) a diamine of general formula NH2—(CH2)n—NH2, n=1 to 12 carbon atoms,
(iii) a triamine of general formula NH2—(CH2)n—NH—(CH2)m—NH2, n=1 to 12 carbon atoms, m=1 to 12 carbon atoms,
(iv) a linear or branched amino alcohol with 2 to 20 carbon atoms,
(v) a linear or branched amino ester with 2 to 20 carbon atoms,
(vi) a linear or branched amino amide with 2 to 20 carbon atoms,
(vii) an amino acid or esters or amides thereof,
(viii) a beta or gamma amino acid or its esters or amides,
(ix) a peptide, optionally cyclic, comprising 2 to 30 amino acids,
(x) a hydrazine monosubstituted with an aryl having 1, 2 or 3 aromatic rings, or a linear or branched alkyl with 1 to 12 carbon atoms,
(xi) a glucamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms, (xii) a glucosamine optionally N-substituted with an alkyl group with 1 to 20 carbon atoms,
(xiii) a pseudopeptide of general formula H—(NH—CH(R)—CH2—X—CO)n—NHR″, with R being a side chain of one of the 20 proteinogenic amino acids; X being independently, throughout the sequence, CH2, O or NH; n=1-15; R″═H, or a short alkyl or aralkyl chain,
(xiv) a pseudopeptide of general formula Ra—CO—CH(Rb)—NH—CO—NH—CH(Rc)—CO—Rd in which Ra and Rd represent, independently of one another, H, a linear or branched C1-C6 alkyl group, a C3-C7 monocyclic cycloalkyl group, or a carboxylic acid protective group; Rb represents the side chain of lysine, the amine of said side chain being optionally substituted with a group —CO—(CH2)5—NH2; Rc represents a side chain of one of the 20 proteinogenic amino acids, optionally protected by an ad hoc protective group, or
(xv) a polymer represented by the general formula NH2—(CH2(CH2)iNH)(n-1)—H, in which i=1, 2 or 3, n=1 to 1000, said polymer forming m coordination bonds with m platinum atoms, one of said coordination bonds being formed between Pt and L2 of formula (II) and m-1 coordination bonds being formed with m-1 groups of formula 1:
where R1, R2, R3, R4 and X are as defined above,
the number m being between 1 and n, the ratio m/n representing the number of platinum atoms to the number of amines of type —NH— or —NH2,
and X represents iodine, bromine or chlorine;
(B) R1 or R4 represents:
a linear or branched C1-C6 alkyl group, substituted with a trimethylsilyl group, or a linear or branched, non-cyclized C7-C12 alkyl group, optionally substituted with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
a linear or branched C2-C12 alkenyl group, substituted with a trimethylsilyl group,
a linear or branched C2-C12 alkynyl group, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group or with a trimethylsilyl group,
a polymer represented by the formula —(CH2CH2O)n—R′ or a polymer represented by the formula —(CH2CH2CH2O)n—R′, in which n=1 to 40, and R′ is a C1-C12 alkyl group, or
(C) R2 or R3 represents:
an aralkyl group with a C1-C12carbon chain, the aralkyl group being optionally substituted with a C1-C12 alkyl group, or with a C1-C12alkoxy group, with a CF3 group, or with a trimethylsilyl group, or
a linear or branched C2-C12 alkynyl, optionally substituted with an alkyl group with 1 to 12 carbon atoms, with an alkoxy group with 1 to 12 carbon atoms, with a CF3 group, or with a trimethylsilyl group.

### Claim 16 (depends on 2)

The process according to claim 2, comprising adding a base selected from triethylamine, or diisopropylethylamine, when the ligand L2 is in the form of salt.

### Claim 17 (depends on 3)

The process according to claim 3, comprising adding a base selected from triethylamine, or diisopropylethylamine, when the ligand L2 is in the form of salt.

### Claim 18 (depends on 2)

The process according to claim 2, wherein said compound of formula I is reacted with a salt of a ligand L2, said salt being in the form of ammonium hydrochloride or ammonium trifluoroacetate.

### Claim 19 (depends on 3)

The process according to claim 3, wherein said compound of formula I is reacted with a salt of a ligand L2, said salt being in the form of ammonium hydrochloride or ammonium trifluoroacetate, to obtain a compound of formula (II) wherein L2 is an amine.

### Claim 20 (depends on 4)

The process according to claim 4, wherein said compound of formula I is reacted with a salt of a ligand L2, said salt being in the form of ammonium hydrochloride or ammonium trifluoroacetate, to obtain a compound of formula (II) wherein L2 is an amine.