# US 10,308,602 B2 · Organoselenium compounds, method for producing same, and pharmaceutical uses thereof in particular as antitumor agents

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- Number: US 10,308,602 B2
- Document ID: US10308602B2
- Status: Granted
- Kind: B2
- Application number: 15/302,633
- Filed: 2015-04-07
- Published: 2017-04-27
- Granted: 2019-06-04
- Earliest claimed: 2014-04-08
- Assignees: Tetrahedron
- Applicants: Tetrahedron
- Inventors: Jean-Claude Yadan; Irene Erdelmeier; Marc Moutet; Remi Lebel
- Web page: https://patentgrep.com/patent/US10308602B2

## CPC

- C07C 391/00: Compounds containing selenium
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/223: of alpha-aminoacids
- A61K 31/23: of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K 31/231: having one or two double bonds
- A61K 31/235: having an aromatic ring attached to a carboxyl group
- A61K 31/265: of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/4453: only substituted in position 1, e.g. propipocaine, diperodon
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 213/80: in position 3
- C07D 233/90: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 295/195: Radicals derived from nitrogen analogues of carboxylic acids
- C07C 2601/02: with a three-membered ring
- C07C 2603/18: Fluorenes; Hydrogenated fluorenes
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention relates to a selenium compound. Said selenium compound has formula (I), where R1=alkyl; R2=H, R4C(=0), R4OC(=0), a-aminoacyl, CH3SeCH2CH2CH(NH2)C(=0), CH3SeCH2CH2CH(OH)C(=0); X=OH, OR3, NH2, NR4R5, α-amino acid, CH3SeCH2CH2CH(COOH)NH—, CH3SeCH2CH2CH(COOH)0-; R3=alkyl; R4=alkyl, aryl; R5=H, alkyl, aryl; R4 and R5 which can together form a 5- or 6-membered cycloalkyl radical which can comprise a heteroatom; provided that when X=NH-terbutyl, R2≠C(=0)CH3. Said compound can be used as a pharmaceutical substance, in particular as an antitumour substance.

## Claims

### Claim 1

A selenium compound having the following general formula (I):
where
R1=a radical selected from a non substituted linear, branched or cyclic saturated carbon containing radical with 1 to 26 carbon atoms, and a substituted linear, branched or cyclic saturated carbon containing radical with 1 to 26 carbon atoms which is substituted by at least one substituent selected from the group consisting of one or more fluorine atoms, one or more carbon-carbon double bonds, at least one OH group, and at least one amino group;
R2=H, R4C(═O), R4OC(═O), α-aminoacyl, CH3SeCH2CH2CH(NH2)C(═O), CH3SeCH2CH2CH(OH)C(═O);
X=OH, OR3, NH2, NR4R5, α-amino acid, CH3SeCH2CH2CH(COOH)NH—, CH3SeCH2CH2CH(COOH)O—;
R3=alkyl;
R4=alkyl, aryl;
R5=H, alkyl, aryl;
R4 and R5 being capable of forming together a 5- or 6-membered cycloalkyl radical which can comprise a heteroatom;
provided that X≠NH-tert-butyl, and any stereoisomers or the pharmaceutically accepted acid or base salts thereof.

### Claim 2 (depends on 1)

The selenium compound according to claim 1, wherein R1 represents a methyl, ethyl, or allyl group.

### Claim 3 (depends on 1)

The selenium compound according to claim 1, wherein R2 is selected from the group consisting of H, α-aminoacyls, R4(C═O), R4O(C═O), and CH3SeCH2CH2CH(OH)C(═O).

### Claim 4 (depends on 1)

The selenium compound according to claim 1, wherein X is selected from the group consisting OH, α-amino acid, CH3SeCH2CH2CH(COOH)NH—, and CH3SeCH2CH2CH(COOH)O—.

### Claim 5 (depends on 1)

The selenium compound according to claim 1, wherein R1 represents a methyl, ethyl, or allyl group; R2 represents R4(C═O), or R4O(C═O), and X represents OH or OR3.

### Claim 6 (depends on 1)

The selenium compound according to claim 1, wherein the pharmaceutically acceptable acids are selected from mineral acids comprising hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric acids, or selected from organic acids comprising formic, acetic, trifluoroacetic, propionic, tartaric, benzoic, maleic, fumaric, succinic, citric, oxalic, glyoxylic, and aspartic acids, alkanesulfonic acids comprising methanesulfonic, trifluoromethanesulfonic, and ethanesulfonic, and arylsulfonic acids comprising benzene- and paratoluenesulfonic acids.

### Claim 7 (depends on 1)

The selenium compound according to claim 1, wherein the pharmaceutically acceptable bases are selected from mineral bases comprising sodium, lithium, calcium, potassium, magnesium, ammonium or zinc hydroxides, carbonates of alkali or alkaline earth metals comprising sodium, lithium, calcium, potassium, magnesium, ammonium or zinc carbonates and bicarbonates, or organic bases comprising methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, proceine, lysine, arginine, histidine, and N-methylglucamine, or else phosphonium salts comprising the alkyl-phosphonium salts, the aryl-phosphonium salts, the alkyl-aryl-phosphonium salts, and the alkenyl-aryl-phosphonium salts, or quaternary ammonium salts.

### Claim 8 (depends on 1)

The selenium compound according to claim 1, wherein said compound is selected from the group consisting of:
2-hydroxy-3-(methylseleno)propanoic acid methyl ester;
(R)-2-hydroxy-3-(methylseleno)propanoic acid methyl ester;
(S)-2-hydroxy-3-(methylseleno)propanoic acid methyl ester;
2-hydroxy-3-(methylseleno)propanoic acid ethyl ester;
(S)-(2-hydroxy-3-(methylseleno)propanoic acid benzyl ester;
3-(ethylseleno)-2-hydroxypropanoic acid methyl ester;
2-hydroxy-3-(isobutylseleno)propanoic acid methyl ester;
2-hydroxy-3-(methylseleno)propanoic acid isopropyl ester;
2-hydroxy-3-(methylseleno)propanoic acid;
(R)-2-hydroxy-3-(methylseleno)propanoic acid;
(S)-2-hydroxy-3-(methylseleno)propanoic acid;
3-ethylseleno-2-hydroxypropanoic acid;
2-hydroxy-3-(isobutylseleno)propanoic acid;
dicyclohexylammonium 2-hydroxy-3-(methylseleno)propanoate salt;
sodium 2-hydroxy-3-(methylseleno)propanoate salt;
magnesium bis(2-hydroxy-3-(methylseleno)propanoate salt;
zinc bis(2-hydroxy-3-(methylseleno)propanoate salt;
calcium bis(2-hydroxy-3-(methylseleno)propanoate salt;
2-hydroxy-3-(methylseleno)propanamide;
N-cyclopropyl-2-hydroxy-3-(methylseleno)propanamide;
N-[2-(dimethylamino)ethyl]-2-hydroxy-3-(methylseleno)propanamide;
2-hydroxy-3-(methylseleno)-1-(pyrrolidin-1-yl)propan-1-one;
2-hydroxy-3-(methylseleno)-1-(piperidin-1-yl)propan-1-one;
2-hydroxy-3-(methylseleno)-1-(morpholin-4-yl)propan-1-one;
N, N-diethyl-2-hydroxy-3-(methylseleno)propanamide;
2-hydroxy-N-(2-hydroxyethyl)-3-(methylseleno)propanamide;
[(2RS)-2-hydroxy-3-methylselenopropanoyl]-(S)-alanine;
[(2RS)-2-hydroxy-3-methylselenopropanoyl]-(S)-methionine methyl ester;
[(2RS)-2-hydroxy-3-methylselenopropanoyl]-(S)-methionine;
[(2R)-2-hydroxy-3-methylselenopropanoyl]-(S)-methionine methyl ester;
[(2R)-2-hydroxy-3-methylselenopropanoyl]-(S)-methionine;
[(2S)-2-hydroxy-3-methylselenopropanoyl]-(S)-methionine methyl ester;
[(2S)-2-hydroxy-3-methylselenopropanoyl]-(S)-methionine;
N(α)-[(2RS)-2-hydroxy-3-methylselenopropanoyl]-N(ω)-tert-butoxycarbonyl-(S)-lysine methyl ester;
N(α)-[(2RS)-2-hydroxy-3-methylselenopropanoyl]-N(ω)-fluorenylmethyloxycarbonyl-(S)-lysine methyl ester;
N(α)-[(2 RS)-2-hydroxy-3-methylselenopropanoyl]-N(ω)-benzyloxycarbonyl-(S)-lysine methyl ester;
[(2RS)-2-hydroxy-3-methylselenopropanoyl]-(S)-selenomethionine methyl ester;
[(2RS)-2-hydroxy-3-methylselenopropanoyl]-(S)-selenomethionine;
[(2R)-2-hydroxy-3-methylselenopropanoyl]-(S)-selenomethionine methyl ester;
[(2R)-2-hydroxy-3-methylselenopropanoyl]-(S)-selenomethionine;
[(2S)-2-hydroxy-3-methylselenopropanoyl]-(S)-selenomethionine methyl ester;
[(2S)-2-hydroxy-3-methylselenopropanoyl]-(S)-selenomethionine;
2-(acetyloxy)-3-(methylseleno)propanoic acid;
2-(dodecanoyloxy)-3-(methylseleno)propanoic acid;
2-(benzoyloxy)-3-(methylseleno)propanoic acid methyl ester;
2-(benzoyloxy)-3-(methylseleno)propanoic acid;
3-(methylseleno)-2-[(3′-pyridine)oxycarbonyl]propanoic acid methyl ester;
2-[(tert-butoxycarbonyl)oxy]-3-(methylseleno)propanoic acid methyl ester;
2-[(tert-butoxycarbonyl)oxy]-3-(methylseleno)propanoic acid;
(2RS)—[N-(tert-butoxycarbonyl)-S-methionyl]-3-(methylseleno)propanoic acid methyl ester;
4-methylseleno-2-(2′-acetyloxy-3′-methylselenopropanoyl)butyric acid methyl ester;
4-methylseleno-2-(2′-acetyloxy-3′-methylselenopropanoyl)butyric acid;
3-methylseleno-2-(2′-acetoxy-4′-methylselenobutanoyl)propanoic acid methyl ester;
3-methylseleno-2-(2′-hydroxy-4′-methylselenobutanoyl)propanoic acid;
2-(pentanoyloxy)-3-(methylseleno)propanoic acid;
2-(nonanoyloxy)-3-(methylseleno)propanoic acid;
2-(linoleoyloxy)-3-(methylseleno)propanoic acid;
2-(linoleoyloxy)-3-(methylseleno)propanoic acid methyl ester;
2-(pivaloyloxy)-3-(methylseleno)propanoic acid;
2-(3-chloropropanoyloxy)-3-(methylseleno)propanoic acid;
2-{(1H-imidazoyl-4-ylcarbonyl)oxy)}-3-(methylseleno)propanoic acid;
2-(pivaloyloxy)-3-(methylseleno)propanoic acid methyl ester.

### Claim 9 (depends on 1)

A method for preparing the selenium compounds of general formula (I), defined in claim 1, wherein it includes the following steps:
a) the reaction of a racemic (DL) oxirane-2-carboxylic acid ester or of one of the enantiomers thereof (D or L) which are commercially available, with:
either an alkylselenol R1SeH, which is itself prepared in situ from an alkali metal salt of alkylselenolate of formula R1—Se-M1 which is itself obtained by reduction of dialkyl diselenide where M1 represents an alkali metal atom), which is reacted with ammonium chloride;
or a dialkylaluminum alkylselenolate derivative of formula Al(R1)2SeR1, which is itself generated in situ from the corresponding trialkylaluminum Al(R1)3 and elemental selenium Se(0),
b) if applicable, one or more of the following reactions or series of reactions:
hydrolysis of the ester function, then
acidification of the reaction medium in order to obtain the corresponding acids of formula (I) where X=OH; then
esterification of the acids of formula (I) or of the alkali metal salts thereof with an alcohol or an alkyl halide in order to obtain the corresponding esters of general formula (I) where X=OR3, with R3 as defined above;
amidification of the acids of formula (I) with an appropriate amine of formula R4R5NH or NH3 where R5 is as defined above, in order to obtain the compound of general formula (I) where X=NH2, NR4R5 or α-amino acid, CH3SeCH2CH2CH(COOH)NH—,
esterification, when R2=H, of the hydroxyl function by an appropriate acid in order to obtain the compound of general formula (I) where OR2 is different from the OH group;
salification by an acid or by a base.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the selenium reagent is:
either a dialkylaluminum alkylselenolate, in an aprotic polar solvent;
or an alkylselenol, generated in situ from metal selenium Se(0) and alkyl lithium, in an aprotic polar solvent, and then put in the presence of ammonium chloride.

### Claim 11 (depends on 9)

The method according to claim 9, wherein reaction 1) takes place in an aprotic polar solvent, and in that the subsequent reactions leading to the different compounds of formula (I) include at least one acidification, or esterification, or amidification and salification.

### Claim 12 (depends on 1)

A method of carrying out treatment of tumors or cancers comprising:
providing at least one selenium compound of formula (I) as defined in claim 1 as a pharmaceutical agent alone or combined with at least one other agent selected from at least one other pharmaceutical agent and at least one other antitumor agent, and
carrying out a treatment of the tumors or cancers using the pharmaceutical agent alone or combined with at least one other agent selected from at least one other pharmaceutical agent and at least one other antitumor agent.

### Claim 13 (depends on 1)

A pharmaceutical composition, wherein it includes at least one pharmaceutically active ingredient including at least one selenium compound of general formula (I) as defined in claim 1, alone or combined with at least one other pharmaceutically active ingredient.

### Claim 14 (depends on 13)

The pharmaceutical composition according to claim 13, wherein the selenium compound of general formula (I) constitutes a pharmaceutically active ingredient for carrying out the treatment of tumors or cancers selected from the group consisting of tumors or cancers of the prostate, of the liver, of the pancreas, of the breast, and of the colon, either alone or in combination with one or more other known anticancer or cytotoxic agents, either by pre-administration or by co-administration.

### Claim 15 (depends on 13)

The pharmaceutical composition according to claim 13, wherein at least one of the other anticancer agents is selected from the following compounds:
aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, matrix metalloproteinase inhibitors; VEGF inhibitors selected from the group comprising anti-VEGF antibodies (Avastin (R)) and the small molecules selected from the group comprising ZD6474 and SU6668, vatalanib, BAY-43-9006, SU11248, CP-547632 and CEP-7055, the SA-1 and SA-2 inhibitors selected from the group comprising the anti-HER2 antibodies (Herceptin), EGFR inhibitors selected from the group comprising gefitinib, erlotinib, ABX-EGF, EMD72000, 11F8, and cetuximab, Eg5 inhibitors selected from the group comprising SB-715992, SB-743921, and MKI-833; PAN inhibitors selected from the group comprising canertinib, EKB-569, CI-1033, AEE-788, and XL-647; kinase inhibitors selected from the group comprising 2C4, and GW-572016, dasatinib, bicalutamide, tamoxifen, MAPK kinase inhibitors, PI3 kinase inhibitors, PDGF inhibitors selected from the group comprising imatinib, anti-angiogenic agents and the antivascular agents, receptor and non-receptor tyrosine kinase inhibitors, inhibitors of integrin signaling; tubulin, anticancer agents selected from the group comprising vinblastine, vincristine, vinorelbine, vinflunine, paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel, 4-deacetyl-4-methylcarbonatepaclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, deoxyepothilone A, deoxyepothilone B, oxabicyclo[14.1.0]-heptadecane-5-9-dione (ixabepilone), leucovorin, tegafur, CDK inhibitors, antiproliferative cell cycle inhibitors, epidophyllotoxin, etoposide, VM-26; anti-neoplastic enzymes, topoisomerase I or II inhibitors selected from the group comprising camptothecin, topotecan, SN-38, procarbazine, mitoxantrone; platinum coordination complexes selected from the group comprising cisplatin, carboplatin and oxaliplatin, purine antagonists selected from the group comprising 6-thioguanine and 6-mercaptopurine, and glutamine antagonists.

### Claim 16 (depends on 13)

The pharmaceutical composition according to claim 13, wherein at least one of the other cytotoxic agents is selected from at least one compound that follows: cyclophosphamide, doxorubicin, daunorubicin, mitoxantrone, melphalan, hexamethyl melamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, bicalutamide, leuprolide, pyridobenzoindole derivatives, the interferons, the interleukins.

### Claim 17 (depends on 13)

The pharmaceutical composition according to claim 13, wherein it includes at least one selenium compound of formula (I) at a concentration between 0.02% and 0.15% by weight in selenium equivalent.

### Claim 18 (depends on 1, 13)

The pharmaceutical composition according to claim 13, wherein it includes at least one pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the selenium compounds selected from the group consisting of a selenium compound as defined in claim 1, of a stereoisomer thereof, of a tautomer thereof, and of a pharmaceutically acceptable salt thereof, said carrier consisting essentially of:
an injectable or drinkable solution,
a solid medium composed of one or more excipients which are selected from the group consisting of vitamins, natural antioxidants, L-ergothioneine, mineral salts, mono-, di- or polysaccharides, folic acid, vitamins B6, vitamin E, vitamin C, lactose, starch.

### Claim 19 (depends on 13)

The pharmaceutical composition according to claim 13, wherein it is formulated for a route of administration selected from the oral route, intravenous route, parenteral route, topical route selected from a transdermal route, a nasal route, an ocular route, and inhalation.

### Claim 20 (depends on 13)

The pharmaceutical composition according to claim 13, wherein said at least one selenium compound of formula (I) is selected from the group consisting of

### Claim 21 (depends on 20)

The pharmaceutical composition according to claim 20, wherein said at least one selenium compound of formula (I) is incorporated in an effective amount to treat a tumor or cancer selected from the group consisting of a tumor or cancer of the prostate, a tumor or cancer of the liver, a tumor or cancer of the pancreas, a tumor or cancer of the breast, and a tumor or cancer of the colon.

### Claim 22 (depends on 12)

The method of claim 12, wherein said at least one selenium compound of formula (I) is selected from the group consisting of

### Claim 23 (depends on 22)

The method according to claim 22, wherein said at least one selenium compound of formula (I) is incorporated in an effective amount to treat a tumor or cancer selected from the group consisting of a tumor or cancer of the prostate, a tumor or cancer of the liver, a tumor or cancer of the pancreas, a tumor or cancer of the breast, and a tumor or cancer of the colon.