CA1180009A - Platinum complexes - Google Patents
Platinum complexesInfo
- Publication number
- CA1180009A CA1180009A CA000394370A CA394370A CA1180009A CA 1180009 A CA1180009 A CA 1180009A CA 000394370 A CA000394370 A CA 000394370A CA 394370 A CA394370 A CA 394370A CA 1180009 A CA1180009 A CA 1180009A
- Authority
- CA
- Canada
- Prior art keywords
- cis
- diammineplatinum
- oco
- preparation
- hoco
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Abstract
Abstract of the Disclosure Platinum complexes of the following formula useful as antitumor agents with less nephro-toxicity and higher water solubility than cisplatin:
Description
Ti-tle NO~EL PLATINUM CO~PLEXES
Back~round of the Inven-tion It has been known that various platinum compounds have antitumor activities, and for example, eisplatin (Jap.
OPI 49-7224), malonato(l,2-diaminocyelohexane)platinum(II) [Jap. OPI 53-31648], and sulfa-to(1,2-cliaminoeyelo~exane) platinum(II) [Jap. OPI 54-44620] have been reported as such eompounds.
The present inventors have investigated intensively to find the platinum eompounds which have more potent anti-tumor aetivity and less toxicity than the prior art compounds, and have aeeomplished the present invention.
,~
Brief Summary of the Iuverll;iorl The present invention relates to novel platinum complexes.
The platinulr1 compouncls in the present invention are represented by the follo~iing general formula (I).
3 Pt(II) (I) [wherein e.actl of X an-l Y is a mono-valent group represented by OCO ( Cr~l 2m m~ 1, ) O
_OCO-(Cnll2n_2JI-l) or X and Y taken together form a di-valent group reprcsented by -OCO-(C H O )-O-, m 2m m-l ~C~(cn~2n-2n-l)~~' or (wllerein m is an integer of 1 to 6, ancl n is an integer of 4 o~ 5 ) ]
The compounds of the formula (I) are obtained by the reaction of cis-diamminedinit~atoplatinum(II) of the formula: Pt(N~3)2(No3j2 witll the alkali Ine tal salts of ; hydroxycarboxyLic acicls, and may be ; adm:Lrll~tered parerlter,llly as antitllmor ~gent.C;~
~ - 2 ~
Detailed Descril:)tion In tlle formtlla (I), X and Y respectively or taken together represent a mono- or di-valent resiclue of hydro.Yy-carboYylic acicls. The hydroxycarboxylic acids are, e. g., glycolic acid, glyceri.c acid, gluconic acid, gulonic acid, glucoheptonic acid, galacturonic acid, glucuronic acid, etc., and besicles naturally occurring or synthe tically availablc! hydlo.Yycarbo.Yylic acids applicable to the above f'ornlula~ are lncluclecl in the present invention.
The typical llgarlcls rcprcserltecl by X and ~ are shown as follows.
-OCocH20l~ -OCOCH(OH)CH20H, -oco(cHoH)4c~2oH~ -OC()(CHOH)5CH20H, -OCO -OCO
HO ~ ~ o OH -OCO\
~ OH HO ~ j CH2 - OH OH
-OCO -OCO
/ CH-CH20H / CH(cHoH)3cHzoH
--O ' .' - -OCO -OCO
~CII~C~-~(J~ CII2O~ ~<L o~
L~oll o~l -oco ¦ OH
~ \J
_o \~
OH
Hydroxycarboxylic acids employed in the reaction for preparing the compounds (I) are represented by the general formula:
HOCO~(C ~l2 )-OH or HOCO (Cn 2n-2 n-l (wherein m and n have the same meanings as the above) which may be changed into the alkali metal salts pre-viously, if required. Hydroxycarboxylic acids are reacted with the objective alkali metal hydroxides to form the corresponding alkali metal salts. As the alkali metal salts, .
lithium salts, sodium salts, potassium sal-ts, etc. may be employed, and particularly the sodium salts are preferred.
For the cis-diamminedinitratoplatinum (II) an equivalent or excess amount, more preEerably 1-2 equivalents of hydroxy-carboxylic acids are employed in the reaction. More definite-ly, .it i~ aclequatq to u~e 2 equ.ivalen-ks o~ the acids in the roaction in ~rder to ob~ain ~hq complexe~ in whlch X
and Y arq ~ach a mono-va.lellt .I.icJand, and l equivcl~
lent in order to obtairl t;lle cor1lpl(?Yes .in ~hich ~ arl(l Y taken to-getller-form a ~ va:Lent Ligar]cl. The reaction may be carried ou-t under heating, preferablv at ~0 - 70C.
The compounds in the present inventiorl include not only those defined as ligands of` the formula (I), but also all of the platlnum cornple.Yes obtained by the reaction of the cis-diammine(lirlltratopLati.llum(II) ~ith the above-mentioned hyclro~ycarbo~ylic acicls ~ithin ~lle s.cope of the preserlt :inverltiorl.
The compolln-ls in tlle preserlt invetltiorl have apploxi-mately -the sarne activitv as or more potent an-titumor activity with less nephro-to~icity than cisplatin. Furthermore, they can easily be adminis-tered because of their high water solu-bility.
The compounds of -tile present invention can be administered to hwnan or animals parenterally. For e~ample, t~le compourlds (I), disso.Lved o:r suspended in proper solvents for injection (e. g., distillecl~ater for injection, physio-logical saline, 5 CO glucose aqueous solution, aqu.eous ethanol, a.queous glycerin, and aqueous propvlqne glycol), can be ad-ministered intraveneously, intramuscularLy, or subcutaneously, o:r by rnqarls o~ :i.nst:iLlat:iorl. Th~ compoLItlds (:r) can be pLaced :Ln t:Lghtly closed ampo~ s as a soLul;:Lorl or.~ a ~usp(~ i.i.orl, ~ncl morc pr~erably prescrvecl :itl a~ )ollles or vl~ls 11-l forrlls o~ crystals, ~o~d~rs, ~ crystal.s, :I.yoplli.l..izat;e, et;c , ' ~
~8~
so as to be dissolved immediately before use. Stabilizer may also be adcled.
In application for treatment of tumors, the compounds (I) may be administered paren-terally to an adult at a daily dose of 100 to 500 mg 1 to 3 times a day.
The following examples and experimen-ts will demons-trate the present inven-tion more in detail, The structural formulas shown in the examples are not definite, but o~ tentative.
Example 1 Diglucuronato-cis-diammineplatinum(II) ~ OH
NaOCO ~ OH
OH OH
cis-Pt(NH3)2(N03)2 O OH
OCO ~ ~ OH
H N / ~ \ o__~OH
OCO~ ~OE~
OH
The starting compound 1 [described in Indian J.
Chem. 8, 193 (1970)] (700 mg, 1.98 m mole) is dissolved in water ~70 ml) warmed a~ 60C, and sodium D-glucuronato mono-hydrate (936 mg, 4 m mole) is added thereto, After stirring for a short time, water is distilled o~f under reduced pressure with a rotary evaporator. The residue is washed with absolute methanol (90 ml) 5 times, and then dried under reduced pressure again. This is dissolved in a small amount of water, and methanol i9 gradually added thereto to release viscous colored substances. The supernatant is collected by decantation and evapora-ted to dryness under reduceci pres~ure. ~he residue is dissolved in water (5 ml) and khcn methanol ~80 ml) i9 added thereko to preci~itate the ~ltle oompound 2 a~ ~ colorle~s 301id. ~hi~ i~ wa3hed with methanol a~ ether ~ucce~ively, and dried under reduced pres~ure.
. . .
3~
Yield 650 ~n~ (54 ~p) mp ~ 150C (decomp.) Elemental Analysis (for Cl2H24ol4N2pt) Calcd. (%): C, 23.42; H, 3.93; N, 4.55; P-t, 31.70 Found. (~): C, 22.27; H, 4.23; N, 4.74; Pt, 31.49 IR: ~ aJl ~ 3400 (broad, -OH), rv3270(broad, -NH), 1633 (C=O), 1400, 1285, 1151, 1047, 1020, 952, 9.00, 798 cm 1.
Example 2 Glucuronato-cis-diammineplatinum(II) OH
NaOCO ~ ~ OH
> < ' cis-Pt(NH3)2(N03)2 OH OH
, >
O O
H3N > O ~ ~ OH
OH 0~
The starting compound 1 (127 mg, o.36 m mole) is dissolved in water (12 ml) warmed at 60C, and sodium D-glucuronate monohydrate ~85 m~, o,36 m mole) i5 added thereto and cli~olvecl therein, ~he mix-kur~ ls adjusted at pH 7 with a ~odium hyclroxicle ~q~eous solution, ancl wat~r is distilled o~ undor reduced pressure at 55C wit~ a rotary evaporator.
* trad~ mark The resulting colored residue is washed with absolute methanol (120 ml~ and evaporated to dryness under reduced pressure again. The residue is dissolved i~ a small amo~t of water and gradual addition of methanol yields viscous colored substances. The supernatant is collected by decantation and condensed to dryness. The residue i5 d:issolved in water (2 ml), and methanol (80 ml) is added thereto to precipitate the title compound ~ as a colorless sol:id. This is washed with methanol and ether successively, and then dried under reduced pressure.
Yield 65 mg (45 %) mp 170 - 180C (decomp.) Elemental An~lysis (for C6Xl5N207Pt) Calcd. (%): C, 17.07; H, 3.58; N, 6.63 Eound. (~): C, 16.39; H, 3.58; N, 6.15 IR: vNUJL ^_3380 (broad, -OH), ~3280 (broad, -NH), 1628 (C=O), 1406, 1148, 1105, 1046, 1015, 951, 824 cm~l, Example 3 .. . ..
Digluconato-cis-diammineplatin~n(II) NaOCO(CHOH)l~CH20H
cls-Pt(l~I3)2(N03)2 ----H3N~, " OCO ( C~IOH) ~cH2o}I
H3N f ~' OCO ( CHOH) l~CH20H
8~
The starting compo~md 1 (240 mg, o.68 m m,ole) is dissolved in water (24 ml) warmed at 60C, sodiu~ gluconate (301 mg, 1.38 m mole) is added thereto, and the mixture is stirred for a short time. The mixture is condensed to dryness at about 55C with a rotary evaporator. The residue is washed with a'bsolute methanol (80 ml) and evaporated to dryness under reduced pressure again. The residue is treated ln the same manner as ilL Example 1 to yield the title compound 4 (147 mg, yield 45 %) as a colorless solid.
mp 48 - 53C (hygroscopic and deliquescent) Elemental Analysis (for C12H28N2014Pt) Calcd. (%): C, 23.27; H, 4.56; N, 4.52 Found. ~%): C, 22.00; H, 4.53; N, 4.91 IR: ~max 3415 (broad, -OX), 3290 (broad, -NH), 1632 (C=O), 1132,- 1086, 024, 883 cm 1.
Example 4 'Gluconato-cis-diammineplatinum(II) NaOCO(CHOH)4CH20H
cis-Pt(NH3)2(N03)2 ~ >
-N / ~ O
~I3~ ' (c~IOH33cH2oH
' ' The starting compound 1 (240 m~, o.68 rn mole) i~
dissolved in water (24 ml) warmed at 60Ct and sodium gluconate (153 m~, 0.70 m mole) is added thereto and dissolved therein.
The mixture is adjusted at pH 7 with a sodium hydroxide aqueous solution and then water is distilled off under red~lced pressu~e at 55 - 60C with a rota~y evaporator. Then the residue is treated in the same manner as in Example 2 to yield th~ title compound ~ (74 mg, yield 25 ~) as a colorless hydrogroccopic solid.
m~ ^_120C (decomp.) Elemental Analysis (for C6H16N207Pt) Calcd. (~): C, 17.03; H, 3.81; N, 6.62 Found. ~%): C, 15.80; H, 3.86; N, 6.68 IR: ~NaJl ~_3400 (broad, -OH), ~3280 ~broad, -NX), 1632 (C=O), 1131, 1086, 1041, 866, 82~ cm 1.
Example 5 Digl~coheptonato-cis-diammineplatinum(II) NaOCO(CHOH)5CH20H
cis-Pt(NH3)2(N03)2 _ H3N\ / OCO~CHOH)5CH20H
H3~ / ~ 0CO(CHOH)5CH20 T~e ~tart.in~ compound 1 (LOO mg, 0.28 m molo) i~
dls~Qlved ln water (10 ml) warmed a~ 60~C, ~odlum glucohoptonatc .
-- 11 ~
dihydrate (162 mg, 0.57 m mole) is added thereto and dissolved therein. After stirring for a short time, the mixture is condensed to dryness at 55C with a rotary evaporator. The - residue is ~ashed with absolute methanol (80 ml) and evaporated to dryness under reduced pressure again. The residue is treated in the same manner as in Example 1 to yicld the title compound 6 (75 mg, yield 39 ~) as a colorless hygroscopic and deliquescent solid.
mp 78 - 85 C
Elemental Analysis (for C14H32N2016Pt) Calcd. (~: C, 24.75; H, 4.75; N, 4.12 ~ound. (~): C, 23.49; H, 4.79; N, 4.60 IR: ~ uJol 3230 ~broad, -OH, -NH), 1620 ~C=O), 1075, 1024, 884 cm 1.
Example 6 Glucohep,tonato-cis-diammineplatinum(II) cis-Pt(NH3)z(N03)2 NaOCO(CHOH)5CH20H
3--P t /
3 ( C}IOH)I~CH20H
~ .'. .
Tl~ artin~ compound 1 (1~0 m~, Q.3~ m mole) i9 dl~ol~ed ln water (12 ml) warmed at 60C; and qodium gluco-heptonat~ dihydrate (97 m~, 0.34 m mole) is added thereto and ~ 12 -dissolv~d therein. The mixture is adjusted at pH 8 ~ith a sodium~hydroxide aqueous solution, and water is distilled off under reduced pressure at 55C with a rotary evaporator.
~ The residue is ~ashed with absolute methanol (60 ml), and evaporated to dryness again. The residue is treated in the same manner as in Example 2 to yield the title compound 7 (47 m~, 30 ~) as a colorless solid.
mp 155 - 160C (decomp.) ~lernental Analysis ~for C7H13N208Pt) Calcd. (%): C, 18.55; H, 4.00; N, 6.18 Found. (~): C, 17.80; H, 4.24; N, 6.o7 IR: vmaJ 1 3425 (broad, -OH), 3285 (broad, -NH), 1612 ~C=O), 1085, 1029, 844 cm 1.
.
- 13 ~
ExE e ent 1 A;ltitumor activitY a,~ainst Sarcoma-180 ( Te s t Me thod ) 1~
~:~L8~
Sarcoma l~O tumor cells (5 x 106 cells) are in-oculated to DS mice (6 to 8 mice are employed in each test group) subcutaneously, and a predetermined an70unt of the test compounds is administered intraperitoneally for 5 days continuously from the next day of the inoculation.
(Test Compound) (A) Glucuronato-cis-diammineplatinum(I~) 0~
OCO ~ ~ OH
3 \ Pt / HO OH
H3N / \ OH
OCO ~ OH
HO OH
(produced in Example l) (B) Cisplatin (Evaluation of the Effect) On the 10th day after the inoculation of tumors, the mice are anatomized, the weight of tumors are mea~ured and comp~red wi-th that of the untrea-ted control group, and ~170 ~Pfcc~ l~ evall1ated from the effectivc do~e ~ED50) wh~ch i~iblt~ t~e ~rowt~ Or turllors by 50 ~, the 50 ~ lethal dose (LD5~), and the curatlve index (CI) .
~ 15 ~
* CI =
The larger CI is, the mo~e effective the compound is.
(Result) i) In the use of 5 % glucose solution as a solvent for injection . Compound (B) ___ ED5033~4 mg/kg 5.8 mg/kg LD5093~4 mg/kg 14.2 mg/kg CI 2.8 ~.4 ii) In the use of 0.9 ~ NaCl, 0.4 % Polysorbate 80, 0.5 % CMC, and 0.5 % benzyl alcohol suspension as a solvent for injection . _ _ Compound (A) (B) __ _ 34 ~ 7.3 mg/kg LD50 113.5 mg/kg 28.3 mg/kg . .
CI 3.3 3.9 (Te~ Method) ~ 16 ~
, ~18~
Leukemia Ll210 ascites cells (105 cells) in mice are;intraperitoneaLly lnoculated to BDFl mice (4 to 10 mice are employed in each test group), and on the next day a predetermined amount of the test compounds is ad-ministered intraperitoneally. The solvent for injection consists of 0.9 ~p NaCl, 0.4 ~ Polysorbate 80, o . 5 ~ CMC,' and 0.5 % benzyl alcohol suspension.
(Test Compound) The same as in Experiment 1 (Evalu~tion of the Effect) ~ rom the average survival days (a) in the test group and those (b) of the untreated control group, the increase of lifespan (ILS) is calculated according to the following expression.
ILS (~) = (a) - (b) (b (Result) ~ Compound _ .' I ~ () .
4 (q~) 1l (0_ 5 x 1 _ 12 ` 2 10 x 1 ____ ?81 ~ ~ .~ _ . 20 ~ 1 >55 _ _26 Experlment 3 Nephro-toxicity (Test Method) - Seven weeks-old male Sprague Dawley rats are separately acco~modated in metabolic cages of stainless steel, and solid feed (Clea Japan, INC., CA-l for breeding) and water are given so that they can take them freely.
They are adapted for 3 days and then the test compounds are once administered to rats intraperitoneally a-t 10:00 a. m. The test compounds are dissolved in 5 ~ glucose injection solution to give a 10 mg/7.5 ml solution im-mediately before use, and administered at a rate of 0.75 ml/ 100 g body weight. The urine excreted during a period of 10 a. m. on the day of administration to 10 a. m. on the next day is de~ined as urine of the first day; on the urine of the 0 - 4th days the volume of urine excreted, creatinine, osmotic pressure, urinary enzyme N-acetyl-~-D-glucosaminidase (NAG), and lysozyme (LEZ) are measured, and further urinary protein and urinary sugar are examined with Lab~tl ~. In the morning on the 5th day the rats are anatomized under anesthesia with Ouropan-Soda~ (Shionogi Co., Ltd.; ~exobarbital sodium), and the blood and pa~o-lo~io specimen~ oP the kldney and the liver are collected in order to determine t~e level of pla~ma urea nitrogen and creatlnlne, and osmo-tic pre~ure.
18 ~
(Test Compound) The same a~ in Experiment l (Result) . _ _ Test Compound Item of Observation ~ (A)~.; (B) ~ _ Dose (Once, i. p.) lO mg/kg 5 mg/kg Solvent for Injectlon .
Body Weigh-t (g) + ~
Volume of Urine (ml/24hrs.) + ~ 5 Excrement of Creatinine *
(m~2~hrs./lOOgBW) Osmotic Pressure of Urine (mOsm/kg) Excrement of Solute ~
~mOsm/24hrs./lOOgBW) _ + . +
NAG ~ .
LEZ +.
Plasma Urea Nitrogen +
Plasma Crea-tinine +
Creatinine Clearance +
Plasma Osmotic Pressure i -. __ .
Kidney Weight i Liver Weight +
__ . , ,.. _ _ _ . . _~ _ . __ Urinary Prctein + ~
Urln~xy Gluco~e _ _ _ (~o-tq~ ) * : The ~olvqnt ~or ;Ln~ec~i.on i~ 5 ~ glucose in and physiologlcal ~ali~e in : increase : slight increase ~ : decrease + : no change From the abo~e results, the effect on the ~unction o~ the kidney and the action on the whole body are great in cisplatin, but the presently claimed compound has little influence on them.
' ' ' .
- 20 ~
' SUPPLEMENTA~Y DISCLOSURE
E~ample 7 Glycolato-cis-diammineplatirlum(II) NaOOCCH20H H3L~ /O
CiS-Pt(~I3)2(NO3)2 > H3~/ \J
T~e starting compound 1 (706 mg, 2.0 m mole) is dlssolved in water (30 rrll) warmed at 60C, arld sodium ~lycolic acid (196 rng, 2.0 m mole) i~ added thereto arld dissolved -thereirl. The mi.Y-ture is adjusted at pH 7 ~ith a sodiwn hydroxide aqueous solution and stirred for 3 hours.
Water is distilled off L~der reduced pressure at about 50~C, and -the rernaining solid is washed with a small amount of chilled water and dried Lmder r~duced press~lr~
to yield the title compoLmd 8 (92 rng, 15 ~p).
mp 120C -~(decomp.) Elemental Analysis (~or C2H~N203Pt) Calcd. (~o): C, 7,92; HJ 2.66; N! 9.24; Pt, 64.34 Found. ($) c, 7.77; H, 2.71; ~r, 9.34; Pt, 64.L4 IR: ~ J 3290sh, j210s, 1620s, L580s, 144~rn, 1330n~, 131jm, 1060s, 925m, 900w, 860m, 755rn cm~l.
IR: (D20 ~olutiQn, ppm ~ron~ T~lS as th~ r3~Yternal standard, ~ .5~ (~ly~oLato C~l2' J195Pt-H 33 I?~ mDle 8 Glycr-3rato-ols-di,~mrll.irleplatinLIm( lI) NaOOCC~(OH)C~20H H3N ~ / 0--~
cis-P-t(N~I3)~(N03)2 ~ Pt\
3 o ~ CH20H
l 9 In the same manner as in E~ample 2 the title compound 9;is given in 45 ~o yield.
mp 130C - (decomp.) EleLnen~al Analysis (fo~ C3Hlo~T2ol~pt) Calcd. (~): C, :L0.8L; H, 3.03; N, 8.41; Pt, 58.5 Found. (~o): C, 10.99; H, 3.42; ~, 8.47; P-t, 58.15 IR: - vNUJl 3400sh, 3130s, 1600s, 1560s, 1360m, 1330rn, 1280w, 1225w, 1105w, 1070m, lOOOm, 910w, 850~, 720m cm~l-E~N~: (D20 solution , ppm from T~S as the e~ternal sta~dard,~) 4.05 - 4.45 (m, glyceryl CH2), 4.40 - 4.~0 ~m, glyceryl CH) E mple 9 ! Diglycolato-cis-diammineplatim.~(II)
Back~round of the Inven-tion It has been known that various platinum compounds have antitumor activities, and for example, eisplatin (Jap.
OPI 49-7224), malonato(l,2-diaminocyelohexane)platinum(II) [Jap. OPI 53-31648], and sulfa-to(1,2-cliaminoeyelo~exane) platinum(II) [Jap. OPI 54-44620] have been reported as such eompounds.
The present inventors have investigated intensively to find the platinum eompounds which have more potent anti-tumor aetivity and less toxicity than the prior art compounds, and have aeeomplished the present invention.
,~
Brief Summary of the Iuverll;iorl The present invention relates to novel platinum complexes.
The platinulr1 compouncls in the present invention are represented by the follo~iing general formula (I).
3 Pt(II) (I) [wherein e.actl of X an-l Y is a mono-valent group represented by OCO ( Cr~l 2m m~ 1, ) O
_OCO-(Cnll2n_2JI-l) or X and Y taken together form a di-valent group reprcsented by -OCO-(C H O )-O-, m 2m m-l ~C~(cn~2n-2n-l)~~' or (wllerein m is an integer of 1 to 6, ancl n is an integer of 4 o~ 5 ) ]
The compounds of the formula (I) are obtained by the reaction of cis-diamminedinit~atoplatinum(II) of the formula: Pt(N~3)2(No3j2 witll the alkali Ine tal salts of ; hydroxycarboxyLic acicls, and may be ; adm:Lrll~tered parerlter,llly as antitllmor ~gent.C;~
~ - 2 ~
Detailed Descril:)tion In tlle formtlla (I), X and Y respectively or taken together represent a mono- or di-valent resiclue of hydro.Yy-carboYylic acicls. The hydroxycarboxylic acids are, e. g., glycolic acid, glyceri.c acid, gluconic acid, gulonic acid, glucoheptonic acid, galacturonic acid, glucuronic acid, etc., and besicles naturally occurring or synthe tically availablc! hydlo.Yycarbo.Yylic acids applicable to the above f'ornlula~ are lncluclecl in the present invention.
The typical llgarlcls rcprcserltecl by X and ~ are shown as follows.
-OCocH20l~ -OCOCH(OH)CH20H, -oco(cHoH)4c~2oH~ -OC()(CHOH)5CH20H, -OCO -OCO
HO ~ ~ o OH -OCO\
~ OH HO ~ j CH2 - OH OH
-OCO -OCO
/ CH-CH20H / CH(cHoH)3cHzoH
--O ' .' - -OCO -OCO
~CII~C~-~(J~ CII2O~ ~<L o~
L~oll o~l -oco ¦ OH
~ \J
_o \~
OH
Hydroxycarboxylic acids employed in the reaction for preparing the compounds (I) are represented by the general formula:
HOCO~(C ~l2 )-OH or HOCO (Cn 2n-2 n-l (wherein m and n have the same meanings as the above) which may be changed into the alkali metal salts pre-viously, if required. Hydroxycarboxylic acids are reacted with the objective alkali metal hydroxides to form the corresponding alkali metal salts. As the alkali metal salts, .
lithium salts, sodium salts, potassium sal-ts, etc. may be employed, and particularly the sodium salts are preferred.
For the cis-diamminedinitratoplatinum (II) an equivalent or excess amount, more preEerably 1-2 equivalents of hydroxy-carboxylic acids are employed in the reaction. More definite-ly, .it i~ aclequatq to u~e 2 equ.ivalen-ks o~ the acids in the roaction in ~rder to ob~ain ~hq complexe~ in whlch X
and Y arq ~ach a mono-va.lellt .I.icJand, and l equivcl~
lent in order to obtairl t;lle cor1lpl(?Yes .in ~hich ~ arl(l Y taken to-getller-form a ~ va:Lent Ligar]cl. The reaction may be carried ou-t under heating, preferablv at ~0 - 70C.
The compounds in the present inventiorl include not only those defined as ligands of` the formula (I), but also all of the platlnum cornple.Yes obtained by the reaction of the cis-diammine(lirlltratopLati.llum(II) ~ith the above-mentioned hyclro~ycarbo~ylic acicls ~ithin ~lle s.cope of the preserlt :inverltiorl.
The compolln-ls in tlle preserlt invetltiorl have apploxi-mately -the sarne activitv as or more potent an-titumor activity with less nephro-to~icity than cisplatin. Furthermore, they can easily be adminis-tered because of their high water solu-bility.
The compounds of -tile present invention can be administered to hwnan or animals parenterally. For e~ample, t~le compourlds (I), disso.Lved o:r suspended in proper solvents for injection (e. g., distillecl~ater for injection, physio-logical saline, 5 CO glucose aqueous solution, aqu.eous ethanol, a.queous glycerin, and aqueous propvlqne glycol), can be ad-ministered intraveneously, intramuscularLy, or subcutaneously, o:r by rnqarls o~ :i.nst:iLlat:iorl. Th~ compoLItlds (:r) can be pLaced :Ln t:Lghtly closed ampo~ s as a soLul;:Lorl or.~ a ~usp(~ i.i.orl, ~ncl morc pr~erably prescrvecl :itl a~ )ollles or vl~ls 11-l forrlls o~ crystals, ~o~d~rs, ~ crystal.s, :I.yoplli.l..izat;e, et;c , ' ~
~8~
so as to be dissolved immediately before use. Stabilizer may also be adcled.
In application for treatment of tumors, the compounds (I) may be administered paren-terally to an adult at a daily dose of 100 to 500 mg 1 to 3 times a day.
The following examples and experimen-ts will demons-trate the present inven-tion more in detail, The structural formulas shown in the examples are not definite, but o~ tentative.
Example 1 Diglucuronato-cis-diammineplatinum(II) ~ OH
NaOCO ~ OH
OH OH
cis-Pt(NH3)2(N03)2 O OH
OCO ~ ~ OH
H N / ~ \ o__~OH
OCO~ ~OE~
OH
The starting compound 1 [described in Indian J.
Chem. 8, 193 (1970)] (700 mg, 1.98 m mole) is dissolved in water ~70 ml) warmed a~ 60C, and sodium D-glucuronato mono-hydrate (936 mg, 4 m mole) is added thereto, After stirring for a short time, water is distilled o~f under reduced pressure with a rotary evaporator. The residue is washed with absolute methanol (90 ml) 5 times, and then dried under reduced pressure again. This is dissolved in a small amount of water, and methanol i9 gradually added thereto to release viscous colored substances. The supernatant is collected by decantation and evapora-ted to dryness under reduceci pres~ure. ~he residue is dissolved in water (5 ml) and khcn methanol ~80 ml) i9 added thereko to preci~itate the ~ltle oompound 2 a~ ~ colorle~s 301id. ~hi~ i~ wa3hed with methanol a~ ether ~ucce~ively, and dried under reduced pres~ure.
. . .
3~
Yield 650 ~n~ (54 ~p) mp ~ 150C (decomp.) Elemental Analysis (for Cl2H24ol4N2pt) Calcd. (%): C, 23.42; H, 3.93; N, 4.55; P-t, 31.70 Found. (~): C, 22.27; H, 4.23; N, 4.74; Pt, 31.49 IR: ~ aJl ~ 3400 (broad, -OH), rv3270(broad, -NH), 1633 (C=O), 1400, 1285, 1151, 1047, 1020, 952, 9.00, 798 cm 1.
Example 2 Glucuronato-cis-diammineplatinum(II) OH
NaOCO ~ ~ OH
> < ' cis-Pt(NH3)2(N03)2 OH OH
, >
O O
H3N > O ~ ~ OH
OH 0~
The starting compound 1 (127 mg, o.36 m mole) is dissolved in water (12 ml) warmed at 60C, and sodium D-glucuronate monohydrate ~85 m~, o,36 m mole) i5 added thereto and cli~olvecl therein, ~he mix-kur~ ls adjusted at pH 7 with a ~odium hyclroxicle ~q~eous solution, ancl wat~r is distilled o~ undor reduced pressure at 55C wit~ a rotary evaporator.
* trad~ mark The resulting colored residue is washed with absolute methanol (120 ml~ and evaporated to dryness under reduced pressure again. The residue is dissolved i~ a small amo~t of water and gradual addition of methanol yields viscous colored substances. The supernatant is collected by decantation and condensed to dryness. The residue i5 d:issolved in water (2 ml), and methanol (80 ml) is added thereto to precipitate the title compound ~ as a colorless sol:id. This is washed with methanol and ether successively, and then dried under reduced pressure.
Yield 65 mg (45 %) mp 170 - 180C (decomp.) Elemental An~lysis (for C6Xl5N207Pt) Calcd. (%): C, 17.07; H, 3.58; N, 6.63 Eound. (~): C, 16.39; H, 3.58; N, 6.15 IR: vNUJL ^_3380 (broad, -OH), ~3280 (broad, -NH), 1628 (C=O), 1406, 1148, 1105, 1046, 1015, 951, 824 cm~l, Example 3 .. . ..
Digluconato-cis-diammineplatin~n(II) NaOCO(CHOH)l~CH20H
cls-Pt(l~I3)2(N03)2 ----H3N~, " OCO ( C~IOH) ~cH2o}I
H3N f ~' OCO ( CHOH) l~CH20H
8~
The starting compo~md 1 (240 mg, o.68 m m,ole) is dissolved in water (24 ml) warmed at 60C, sodiu~ gluconate (301 mg, 1.38 m mole) is added thereto, and the mixture is stirred for a short time. The mixture is condensed to dryness at about 55C with a rotary evaporator. The residue is washed with a'bsolute methanol (80 ml) and evaporated to dryness under reduced pressure again. The residue is treated ln the same manner as ilL Example 1 to yield the title compound 4 (147 mg, yield 45 %) as a colorless solid.
mp 48 - 53C (hygroscopic and deliquescent) Elemental Analysis (for C12H28N2014Pt) Calcd. (%): C, 23.27; H, 4.56; N, 4.52 Found. ~%): C, 22.00; H, 4.53; N, 4.91 IR: ~max 3415 (broad, -OX), 3290 (broad, -NH), 1632 (C=O), 1132,- 1086, 024, 883 cm 1.
Example 4 'Gluconato-cis-diammineplatinum(II) NaOCO(CHOH)4CH20H
cis-Pt(NH3)2(N03)2 ~ >
-N / ~ O
~I3~ ' (c~IOH33cH2oH
' ' The starting compound 1 (240 m~, o.68 rn mole) i~
dissolved in water (24 ml) warmed at 60Ct and sodium gluconate (153 m~, 0.70 m mole) is added thereto and dissolved therein.
The mixture is adjusted at pH 7 with a sodium hydroxide aqueous solution and then water is distilled off under red~lced pressu~e at 55 - 60C with a rota~y evaporator. Then the residue is treated in the same manner as in Example 2 to yield th~ title compound ~ (74 mg, yield 25 ~) as a colorless hydrogroccopic solid.
m~ ^_120C (decomp.) Elemental Analysis (for C6H16N207Pt) Calcd. (~): C, 17.03; H, 3.81; N, 6.62 Found. ~%): C, 15.80; H, 3.86; N, 6.68 IR: ~NaJl ~_3400 (broad, -OH), ~3280 ~broad, -NX), 1632 (C=O), 1131, 1086, 1041, 866, 82~ cm 1.
Example 5 Digl~coheptonato-cis-diammineplatinum(II) NaOCO(CHOH)5CH20H
cis-Pt(NH3)2(N03)2 _ H3N\ / OCO~CHOH)5CH20H
H3~ / ~ 0CO(CHOH)5CH20 T~e ~tart.in~ compound 1 (LOO mg, 0.28 m molo) i~
dls~Qlved ln water (10 ml) warmed a~ 60~C, ~odlum glucohoptonatc .
-- 11 ~
dihydrate (162 mg, 0.57 m mole) is added thereto and dissolved therein. After stirring for a short time, the mixture is condensed to dryness at 55C with a rotary evaporator. The - residue is ~ashed with absolute methanol (80 ml) and evaporated to dryness under reduced pressure again. The residue is treated in the same manner as in Example 1 to yicld the title compound 6 (75 mg, yield 39 ~) as a colorless hygroscopic and deliquescent solid.
mp 78 - 85 C
Elemental Analysis (for C14H32N2016Pt) Calcd. (~: C, 24.75; H, 4.75; N, 4.12 ~ound. (~): C, 23.49; H, 4.79; N, 4.60 IR: ~ uJol 3230 ~broad, -OH, -NH), 1620 ~C=O), 1075, 1024, 884 cm 1.
Example 6 Glucohep,tonato-cis-diammineplatinum(II) cis-Pt(NH3)z(N03)2 NaOCO(CHOH)5CH20H
3--P t /
3 ( C}IOH)I~CH20H
~ .'. .
Tl~ artin~ compound 1 (1~0 m~, Q.3~ m mole) i9 dl~ol~ed ln water (12 ml) warmed at 60C; and qodium gluco-heptonat~ dihydrate (97 m~, 0.34 m mole) is added thereto and ~ 12 -dissolv~d therein. The mixture is adjusted at pH 8 ~ith a sodium~hydroxide aqueous solution, and water is distilled off under reduced pressure at 55C with a rotary evaporator.
~ The residue is ~ashed with absolute methanol (60 ml), and evaporated to dryness again. The residue is treated in the same manner as in Example 2 to yield the title compound 7 (47 m~, 30 ~) as a colorless solid.
mp 155 - 160C (decomp.) ~lernental Analysis ~for C7H13N208Pt) Calcd. (%): C, 18.55; H, 4.00; N, 6.18 Found. (~): C, 17.80; H, 4.24; N, 6.o7 IR: vmaJ 1 3425 (broad, -OH), 3285 (broad, -NH), 1612 ~C=O), 1085, 1029, 844 cm 1.
.
- 13 ~
ExE e ent 1 A;ltitumor activitY a,~ainst Sarcoma-180 ( Te s t Me thod ) 1~
~:~L8~
Sarcoma l~O tumor cells (5 x 106 cells) are in-oculated to DS mice (6 to 8 mice are employed in each test group) subcutaneously, and a predetermined an70unt of the test compounds is administered intraperitoneally for 5 days continuously from the next day of the inoculation.
(Test Compound) (A) Glucuronato-cis-diammineplatinum(I~) 0~
OCO ~ ~ OH
3 \ Pt / HO OH
H3N / \ OH
OCO ~ OH
HO OH
(produced in Example l) (B) Cisplatin (Evaluation of the Effect) On the 10th day after the inoculation of tumors, the mice are anatomized, the weight of tumors are mea~ured and comp~red wi-th that of the untrea-ted control group, and ~170 ~Pfcc~ l~ evall1ated from the effectivc do~e ~ED50) wh~ch i~iblt~ t~e ~rowt~ Or turllors by 50 ~, the 50 ~ lethal dose (LD5~), and the curatlve index (CI) .
~ 15 ~
* CI =
The larger CI is, the mo~e effective the compound is.
(Result) i) In the use of 5 % glucose solution as a solvent for injection . Compound (B) ___ ED5033~4 mg/kg 5.8 mg/kg LD5093~4 mg/kg 14.2 mg/kg CI 2.8 ~.4 ii) In the use of 0.9 ~ NaCl, 0.4 % Polysorbate 80, 0.5 % CMC, and 0.5 % benzyl alcohol suspension as a solvent for injection . _ _ Compound (A) (B) __ _ 34 ~ 7.3 mg/kg LD50 113.5 mg/kg 28.3 mg/kg . .
CI 3.3 3.9 (Te~ Method) ~ 16 ~
, ~18~
Leukemia Ll210 ascites cells (105 cells) in mice are;intraperitoneaLly lnoculated to BDFl mice (4 to 10 mice are employed in each test group), and on the next day a predetermined amount of the test compounds is ad-ministered intraperitoneally. The solvent for injection consists of 0.9 ~p NaCl, 0.4 ~ Polysorbate 80, o . 5 ~ CMC,' and 0.5 % benzyl alcohol suspension.
(Test Compound) The same as in Experiment 1 (Evalu~tion of the Effect) ~ rom the average survival days (a) in the test group and those (b) of the untreated control group, the increase of lifespan (ILS) is calculated according to the following expression.
ILS (~) = (a) - (b) (b (Result) ~ Compound _ .' I ~ () .
4 (q~) 1l (0_ 5 x 1 _ 12 ` 2 10 x 1 ____ ?81 ~ ~ .~ _ . 20 ~ 1 >55 _ _26 Experlment 3 Nephro-toxicity (Test Method) - Seven weeks-old male Sprague Dawley rats are separately acco~modated in metabolic cages of stainless steel, and solid feed (Clea Japan, INC., CA-l for breeding) and water are given so that they can take them freely.
They are adapted for 3 days and then the test compounds are once administered to rats intraperitoneally a-t 10:00 a. m. The test compounds are dissolved in 5 ~ glucose injection solution to give a 10 mg/7.5 ml solution im-mediately before use, and administered at a rate of 0.75 ml/ 100 g body weight. The urine excreted during a period of 10 a. m. on the day of administration to 10 a. m. on the next day is de~ined as urine of the first day; on the urine of the 0 - 4th days the volume of urine excreted, creatinine, osmotic pressure, urinary enzyme N-acetyl-~-D-glucosaminidase (NAG), and lysozyme (LEZ) are measured, and further urinary protein and urinary sugar are examined with Lab~tl ~. In the morning on the 5th day the rats are anatomized under anesthesia with Ouropan-Soda~ (Shionogi Co., Ltd.; ~exobarbital sodium), and the blood and pa~o-lo~io specimen~ oP the kldney and the liver are collected in order to determine t~e level of pla~ma urea nitrogen and creatlnlne, and osmo-tic pre~ure.
18 ~
(Test Compound) The same a~ in Experiment l (Result) . _ _ Test Compound Item of Observation ~ (A)~.; (B) ~ _ Dose (Once, i. p.) lO mg/kg 5 mg/kg Solvent for Injectlon .
Body Weigh-t (g) + ~
Volume of Urine (ml/24hrs.) + ~ 5 Excrement of Creatinine *
(m~2~hrs./lOOgBW) Osmotic Pressure of Urine (mOsm/kg) Excrement of Solute ~
~mOsm/24hrs./lOOgBW) _ + . +
NAG ~ .
LEZ +.
Plasma Urea Nitrogen +
Plasma Crea-tinine +
Creatinine Clearance +
Plasma Osmotic Pressure i -. __ .
Kidney Weight i Liver Weight +
__ . , ,.. _ _ _ . . _~ _ . __ Urinary Prctein + ~
Urln~xy Gluco~e _ _ _ (~o-tq~ ) * : The ~olvqnt ~or ;Ln~ec~i.on i~ 5 ~ glucose in and physiologlcal ~ali~e in : increase : slight increase ~ : decrease + : no change From the abo~e results, the effect on the ~unction o~ the kidney and the action on the whole body are great in cisplatin, but the presently claimed compound has little influence on them.
' ' ' .
- 20 ~
' SUPPLEMENTA~Y DISCLOSURE
E~ample 7 Glycolato-cis-diammineplatirlum(II) NaOOCCH20H H3L~ /O
CiS-Pt(~I3)2(NO3)2 > H3~/ \J
T~e starting compound 1 (706 mg, 2.0 m mole) is dlssolved in water (30 rrll) warmed at 60C, arld sodium ~lycolic acid (196 rng, 2.0 m mole) i~ added thereto arld dissolved -thereirl. The mi.Y-ture is adjusted at pH 7 ~ith a sodiwn hydroxide aqueous solution and stirred for 3 hours.
Water is distilled off L~der reduced pressure at about 50~C, and -the rernaining solid is washed with a small amount of chilled water and dried Lmder r~duced press~lr~
to yield the title compoLmd 8 (92 rng, 15 ~p).
mp 120C -~(decomp.) Elemental Analysis (~or C2H~N203Pt) Calcd. (~o): C, 7,92; HJ 2.66; N! 9.24; Pt, 64.34 Found. ($) c, 7.77; H, 2.71; ~r, 9.34; Pt, 64.L4 IR: ~ J 3290sh, j210s, 1620s, L580s, 144~rn, 1330n~, 131jm, 1060s, 925m, 900w, 860m, 755rn cm~l.
IR: (D20 ~olutiQn, ppm ~ron~ T~lS as th~ r3~Yternal standard, ~ .5~ (~ly~oLato C~l2' J195Pt-H 33 I?~ mDle 8 Glycr-3rato-ols-di,~mrll.irleplatinLIm( lI) NaOOCC~(OH)C~20H H3N ~ / 0--~
cis-P-t(N~I3)~(N03)2 ~ Pt\
3 o ~ CH20H
l 9 In the same manner as in E~ample 2 the title compound 9;is given in 45 ~o yield.
mp 130C - (decomp.) EleLnen~al Analysis (fo~ C3Hlo~T2ol~pt) Calcd. (~): C, :L0.8L; H, 3.03; N, 8.41; Pt, 58.5 Found. (~o): C, 10.99; H, 3.42; ~, 8.47; P-t, 58.15 IR: - vNUJl 3400sh, 3130s, 1600s, 1560s, 1360m, 1330rn, 1280w, 1225w, 1105w, 1070m, lOOOm, 910w, 850~, 720m cm~l-E~N~: (D20 solution , ppm from T~S as the e~ternal sta~dard,~) 4.05 - 4.45 (m, glyceryl CH2), 4.40 - 4.~0 ~m, glyceryl CH) E mple 9 ! Diglycolato-cis-diammineplatim.~(II)
2~TaOO~CH20H H3~T~ ~ ococH2oH
cis-Pt(N~I3)2(N03)2 ~ H3`T/ ~ ococH2oH
ln the 5ame marLner a~, in E~Yarnple l the title c ~mpQL~nd lO is given ln 79 ~q y-Le Ld .
mp 13(~qC ~ (ClqCOrllp~ ) Elenlentsll Analysi~
~ j 2~ -Calcd, (~p): C, 12,67; ~I, 3.19; ~, 7.39; Pt, 51,44 Follnd. (~o): C, 12.38; H, 3,29; N, 7.43; P-t, 50.97 IR: yNljOl 3250sh, 3200s, 1620s, 1580s, l440m, L330m, max 1320m, 1060s, 930m, 900w, 860~, 760w, 720w cm : (D20 sol-ltion. pp~ from T~IS as the e.Yternal standard, ~ ,51 (glycc~:lato CH2), 3-5 - 5~5 (~I3) Exa~_e 10 Diglycerato-cis-diaounineplatin~n(II) ; . 2NaOOCCH(OH)CH20H H ~ / OcOcH(OH)cH OH
cis-Pt(lYH3)2(N3)2 ~ 3 Pt 2 H3~/ ~ OCOCH(OH)CH20H
In -the same ma~ner as in Example 1 the ti~le compound li is given in 86 ~p yield, mp 70 - 80C
Elemental Analysis (for C6H16N208Pt) Calcd, (~o): C, 16 40; H, 3,67; N, 6,38; Pt, 44,40 FoLlnd. (~o): C, 15-73; H. 3.84; N, 6,97; Pt, 45.86 IR: v n~Y 3350sh, 3240s, 1620s, lllOm. 1060m, lOOOm, 870w, 820w. 770w, 720w cm 1, (D20 .~olLIt:ion~ ppm fro((l TI~IS a5 the qYt~tn,ll ~tanch~rcl, ~) 4.13 ~ l (m. ~lycqrato CH2), 4.57 _ 4~75 (m~
~lycqrato CH), 3~0 ~ 5,l~o ~N~13) ~8~
Experiment 4 Antitumor activit-y a~alnst Sarcoma-18_ (Test Method) The test was carried out in the same ma~ner as in Experiment 1, wherein the test co~lpounds were administered i~.tra~enously for 5 days.
(Test Compollnd) (A) Glucuronato-cis-diarrlm:ineplatinum(II) (B) Cisplatin (C) Glycolato-cis-diammineplatinurn(II) H3N pt/ O
(produced in Eample 7) (D) DigLycolato-sis-diammineplatinum(II) H N / ococH2oH
cis-Pt(N~I3)2(N03)2 ~ H3`T/ ~ ococH2oH
ln the 5ame marLner a~, in E~Yarnple l the title c ~mpQL~nd lO is given ln 79 ~q y-Le Ld .
mp 13(~qC ~ (ClqCOrllp~ ) Elenlentsll Analysi~
~ j 2~ -Calcd, (~p): C, 12,67; ~I, 3.19; ~, 7.39; Pt, 51,44 Follnd. (~o): C, 12.38; H, 3,29; N, 7.43; P-t, 50.97 IR: yNljOl 3250sh, 3200s, 1620s, 1580s, l440m, L330m, max 1320m, 1060s, 930m, 900w, 860~, 760w, 720w cm : (D20 sol-ltion. pp~ from T~IS as the e.Yternal standard, ~ ,51 (glycc~:lato CH2), 3-5 - 5~5 (~I3) Exa~_e 10 Diglycerato-cis-diaounineplatin~n(II) ; . 2NaOOCCH(OH)CH20H H ~ / OcOcH(OH)cH OH
cis-Pt(lYH3)2(N3)2 ~ 3 Pt 2 H3~/ ~ OCOCH(OH)CH20H
In -the same ma~ner as in Example 1 the ti~le compound li is given in 86 ~p yield, mp 70 - 80C
Elemental Analysis (for C6H16N208Pt) Calcd, (~o): C, 16 40; H, 3,67; N, 6,38; Pt, 44,40 FoLlnd. (~o): C, 15-73; H. 3.84; N, 6,97; Pt, 45.86 IR: v n~Y 3350sh, 3240s, 1620s, lllOm. 1060m, lOOOm, 870w, 820w. 770w, 720w cm 1, (D20 .~olLIt:ion~ ppm fro((l TI~IS a5 the qYt~tn,ll ~tanch~rcl, ~) 4.13 ~ l (m. ~lycqrato CH2), 4.57 _ 4~75 (m~
~lycqrato CH), 3~0 ~ 5,l~o ~N~13) ~8~
Experiment 4 Antitumor activit-y a~alnst Sarcoma-18_ (Test Method) The test was carried out in the same ma~ner as in Experiment 1, wherein the test co~lpounds were administered i~.tra~enously for 5 days.
(Test Compollnd) (A) Glucuronato-cis-diarrlm:ineplatinum(II) (B) Cisplatin (C) Glycolato-cis-diammineplatinurn(II) H3N pt/ O
(produced in Eample 7) (D) DigLycolato-sis-diammineplatinum(II) H N / ococH2oH
3 ocOCH20H
(produced in Example 9) (E) Glycerato-cis-dian-mlneplatinum(II) 3 Pt H3N / ~ CH~OH
(yroducq~l in E~ampLf~ 8) ~valuation o~ th~7 ~e~t) ~`~e ~valLIc~Ltion ~as mad~ in the sam~ marLn~r as in E~pe ~imq n t 1 .
~ 2 ( Re s ul t ) Compound ¦ ~ ¦ B ¦ C ~ D ¦ E
l _ ED50 (rng/kg) 63-4 ¦4.5 18 7 24.1 L~4 _ _ _ LD50 ( mg/ g) 18614 . 2 86 . 6 80 . 0 186 . 6 l l _ C I ¦2 - 93 - 2 ¦ 4 - 63 34 . 2 ~* Administered as 5 ~ glllcose solutiorl.
25 ~
(produced in Example 9) (E) Glycerato-cis-dian-mlneplatinum(II) 3 Pt H3N / ~ CH~OH
(yroducq~l in E~ampLf~ 8) ~valuation o~ th~7 ~e~t) ~`~e ~valLIc~Ltion ~as mad~ in the sam~ marLn~r as in E~pe ~imq n t 1 .
~ 2 ( Re s ul t ) Compound ¦ ~ ¦ B ¦ C ~ D ¦ E
l _ ED50 (rng/kg) 63-4 ¦4.5 18 7 24.1 L~4 _ _ _ LD50 ( mg/ g) 18614 . 2 86 . 6 80 . 0 186 . 6 l l _ C I ¦2 - 93 - 2 ¦ 4 - 63 34 . 2 ~* Administered as 5 ~ glllcose solutiorl.
25 ~
Claims (24)
1. A process for preparing a platinum complex of the formula:
wherein each of X and Y is a mono-valent group of -OCO-(CmH2mOm-1)-OH or -OCO-(CnH2n-2On-1)-OH
or X and Y taken together form a divalent group of -OCO-(CmH2mOm-1)-O- or -OCO-(CnH2n-2On-1)-O-wherein m is an integer of 1 to 6, and n is an integer of 4 or 5, comprising reacting cis-diamminedinitratoplatinum (II) with a hydroxycarboxylic acid of the formula:
HOCO-(CmH2mOm-1)-OH or HOCO-(CnH2n-2On-1)-OH
wherein m and n each has the same significances as mentioned above.
wherein each of X and Y is a mono-valent group of -OCO-(CmH2mOm-1)-OH or -OCO-(CnH2n-2On-1)-OH
or X and Y taken together form a divalent group of -OCO-(CmH2mOm-1)-O- or -OCO-(CnH2n-2On-1)-O-wherein m is an integer of 1 to 6, and n is an integer of 4 or 5, comprising reacting cis-diamminedinitratoplatinum (II) with a hydroxycarboxylic acid of the formula:
HOCO-(CmH2mOm-1)-OH or HOCO-(CnH2n-2On-1)-OH
wherein m and n each has the same significances as mentioned above.
2. The process of claim 1 wherein m is an integer of 5 or 6 and n is an integer of 5.
3. The process of claim 1 for the preparation of diglucuronato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOCO-(C5H8O4)-OH.
4. The process of claim 1 for the preparation of glucuronato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOCO-(C5H8O4)-OH.
5. The process of claim 1 for the preparation of digluconato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOCO-(C5H10O4)-OH.
6. The process of claim 1 for the preparation of gluconato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOCO-(C5H10O4)-OH.
7. The process of claim 1 for the preparation of diglucoheptonato-cis-diammineplatinum (II), wherein the hydroxycarboxylic acid is HOCO-(C6H12O5)-OH.
8. The process of claim 1 for the preparation of glucoheptonato-cis-diammineplatinum (II), wherein the hydroxycarboxylic acid is HOCO-(C6H12O5)-OH.
9. Platinum complexes of the formula:
wherein each of X and Y is a mono-valent group of -OCO-(CmH2mOm-1)-OH or -OCO-(CH2n-2On-1)-OH
or X and Y taken together form a di-valent group of -OCO-(CmH2mOm-1)-O-, or -OCO-(CnH2n-2On-1)-O-(wherein m is an integer of 1 to 6, and n is an integer of 4 or 5) when prepared by the process of claim 1.
wherein each of X and Y is a mono-valent group of -OCO-(CmH2mOm-1)-OH or -OCO-(CH2n-2On-1)-OH
or X and Y taken together form a di-valent group of -OCO-(CmH2mOm-1)-O-, or -OCO-(CnH2n-2On-1)-O-(wherein m is an integer of 1 to 6, and n is an integer of 4 or 5) when prepared by the process of claim 1.
10. Platinum complexes as claimed in claim 9, wherein m is an integer of 5 or 6 and n is an integer of 5 when prepared by the process of claim 2.
11. Diglucuronato-cis-diammineplatinum (II) when pre-pared by the process of claim 3.
12. Glucuronato-cis-diammineplatinum (II) when pre-pared by the process of claim 4.
13. Digluconato-cis-diammmineplatinum (II) when pre-pared by the process of claim 5.
14. Gluconato-cis-diammineplatinum (II) when prepared by the process of claim 6.
15. Diglucoheptonato-cis-diammineplatinum (II) when prepared by the process of claim 7.
16. Glucoheptonato-cis-diammineplatinum (II) when pre-pared by the process of claim 8.
CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
17. The process of claim 1 for the preparation of glycolato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOOCCH2OH.
18. The process of claim 1 for the preparation of glycerato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOOCCH(OH)CH2OH.
19. The process of claim 1 for the preparation of diglycolato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOOCCH2OH.
20. The process of claim 1 for the preparation of diglycerato-cis-diammineplatinum (II), wherein the hydroxy-carboxylic acid is HOOCCH(OH)CH2OH.
21. Glycolato-cis-diammineplatinum (II) when prepared by the process of claim 17.
22. Glycerato-cis-diammineplatinum (II) when prepared by the process of claim 18.
23. Diglycolato-cis-diammineplatinum (II) when prepared by the process of claim 19.
24. Diylycerato-cis-diammineplatinum (II) when prepared by the process of claim 20.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9463/1981 | 1981-01-23 | ||
JP56009463A JPS57123198A (en) | 1981-01-23 | 1981-01-23 | Novel platinum complex |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1180009A true CA1180009A (en) | 1984-12-27 |
Family
ID=11720966
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000394370A Expired CA1180009A (en) | 1981-01-23 | 1982-01-18 | Platinum complexes |
Country Status (7)
Country | Link |
---|---|
US (1) | US4575550A (en) |
EP (1) | EP0057023B1 (en) |
JP (1) | JPS57123198A (en) |
AU (1) | AU557336B2 (en) |
CA (1) | CA1180009A (en) |
DE (1) | DE3260164D1 (en) |
GB (1) | GB2091731B (en) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5921697A (en) * | 1982-06-24 | 1984-02-03 | Yoshinori Kitani | Novel platinum complex |
JPS59222498A (en) * | 1983-06-01 | 1984-12-14 | Shionogi & Co Ltd | Novel glycolic acid platinum complex and antineoplastic agent |
US4562275A (en) * | 1984-03-23 | 1985-12-31 | Bristol-Myers Co. | Antitumor platinum complexes |
JPS617283A (en) * | 1984-06-20 | 1986-01-13 | Shionogi & Co Ltd | Novel platinum complex and anti-malignant tumor agent |
IL76889A0 (en) * | 1984-11-02 | 1986-02-28 | Johnson Matthey Plc | Solubilised platinum compound,method for the production thereof and pharmaceutical compositions containing the same |
NZ214504A (en) * | 1984-12-17 | 1988-07-28 | American Cyanamid Co | Platinum/saccharide complexes and pharmaceutical compositions |
JPS6296A (en) * | 1985-03-06 | 1987-01-06 | Sumitomo Pharmaceut Co Ltd | Fat-soluble platinum(ii) complex and production thereof |
JPH0665648B2 (en) * | 1985-09-25 | 1994-08-24 | 塩野義製薬株式会社 | Stable freeze-drying formulation of platinum anticancer substance |
WO1987007142A1 (en) * | 1986-05-21 | 1987-12-03 | Kuraray Co., Ltd. | Novel complexes, process for their preparation, and medicinal use of them |
US5011959A (en) * | 1986-11-17 | 1991-04-30 | The Board Of Regents, The University Of Texas System | 1,2-diaminocyclohexane-platinum complexes with antitumor activity |
KR900003457B1 (en) * | 1986-12-18 | 1990-05-19 | 시오노기세이야꾸 가부시끼가이샤 | Ammine-alicyclic amine platinum complex and antitumor agent |
US4895935A (en) * | 1987-07-17 | 1990-01-23 | Georgetown University | Platinum pharmaceuticals |
US4956459A (en) * | 1987-07-17 | 1990-09-11 | Georgetown University | Platinum compounds suitable for use as pharmaceuticals |
DE3879709T2 (en) * | 1987-07-17 | 1993-10-07 | Georgetown University Washingt | PLATINUM MEDICINAL PRODUCTS. |
US4895936A (en) * | 1987-07-17 | 1990-01-23 | Georgetown University | Platinum pharmaceuticals |
JPH01294683A (en) * | 1988-02-04 | 1989-11-28 | Kanebo Ltd | Novel platinum complex, antitumor agent containing said complex as active ingredient and intermediate for preparing the same compound |
WO1990003402A1 (en) * | 1988-09-27 | 1990-04-05 | Kuraray Co., Ltd. | Novel composite, process for its preparation and medicinal use thereof |
US5393909A (en) * | 1988-11-22 | 1995-02-28 | Board Of Regents, The University Of Texas System | Diamine platinum complexes as antitumor agents |
US4946954A (en) * | 1989-01-17 | 1990-08-07 | Georgetown University | Platinum pharmaceutical agents |
US5130450A (en) * | 1990-04-25 | 1992-07-14 | Nippon Kayaku Kabushiki Kaisha | Platinum complexes |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
JP5364381B2 (en) * | 2006-12-08 | 2013-12-11 | 片山化学工業株式会社 | Liposome encapsulating ammine platinum complex at high concentration and method for producing the same |
CN100500682C (en) * | 2007-02-14 | 2009-06-17 | 江苏奥赛康药业有限公司 | Method of purifying medaplatin |
CN101402655B (en) * | 2008-11-07 | 2011-06-15 | 江苏奥赛康药业有限公司 | Process for producing platinum |
CN102417522B (en) * | 2011-10-20 | 2014-11-26 | 南京工业大学 | Preparation method of nedaplatin |
CN105399777A (en) * | 2015-11-23 | 2016-03-16 | 南京先声东元制药有限公司 | Nedaplatin analogue and preparation method thereof |
CN105622673B (en) * | 2016-01-25 | 2018-11-06 | 南开大学 | Glycosylation tetravalence platinum-like compounds with active anticancer, preparation method and application |
CN112225757B (en) * | 2020-09-17 | 2023-07-21 | 昆明贵研药业有限公司 | Preparation method of lobaplatin trihydrate |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH605550A5 (en) * | 1972-06-08 | 1978-09-29 | Research Corp | |
US4115418A (en) * | 1976-09-02 | 1978-09-19 | Government Of The United States Of America | 1,2-diaminocyclohexane platinum (ii) complexes having antineoplastic activity |
JPS5829957B2 (en) * | 1977-09-12 | 1983-06-25 | 喜徳 喜谷 | Novel platinum complex |
DE2845371A1 (en) * | 1977-10-19 | 1979-04-26 | Johnson Matthey Co Ltd | PLATINUM COMPLEX COMPOSITION, PHARMACEUTICAL COMPOSITION WITH SUCH COMPLEX AND THEIR APPLICATION |
SE447902B (en) * | 1977-10-19 | 1986-12-22 | Johnson Matthey Co Ltd | CIS COORDINATION ASSOCIATION OF PLATINUM AND COMPOSITION CONTAINING ASSOCIATION |
US4234500A (en) * | 1979-03-07 | 1980-11-18 | Engelhard Minerals & Chemicals Corporation | Ethylenediamine platinum(II) and 1,2-diamino-cyclohexane platinum(II) pyrophosphate complexes |
US4291023A (en) * | 1979-03-07 | 1981-09-22 | Engelhard Minerals & Chemicals Corp. | Method for treating tumors using cis-diammineplatinum (II) organophosphate complexes |
US4248840A (en) * | 1979-03-07 | 1981-02-03 | Engelhard Minerals And Chemicals Corporation | Cis-diammineplatinum(II) orthophosphate complexes |
US4234499A (en) * | 1979-03-07 | 1980-11-18 | Engelhard Minerals & Chemicals Corporation | Cis-diammireplatinum(II) organophosphate complexes |
US4271085A (en) * | 1979-06-20 | 1981-06-02 | Engelhard Minerals & Chemicals Corporation | Cis-platinum (II) amine lactate complexes |
US4322362A (en) * | 1980-07-28 | 1982-03-30 | Bristol-Myers Company | Salts of 2-hydroxymalonate platinum complexes |
-
1981
- 1981-01-23 JP JP56009463A patent/JPS57123198A/en active Granted
-
1982
- 1982-01-07 EP EP82200020A patent/EP0057023B1/en not_active Expired
- 1982-01-07 DE DE8282200020T patent/DE3260164D1/en not_active Expired
- 1982-01-18 CA CA000394370A patent/CA1180009A/en not_active Expired
- 1982-01-20 GB GB8201616A patent/GB2091731B/en not_active Expired
- 1982-01-22 AU AU79765/82A patent/AU557336B2/en not_active Expired
-
1983
- 1983-04-14 US US06/485,584 patent/US4575550A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
AU557336B2 (en) | 1986-12-18 |
US4575550A (en) | 1986-03-11 |
JPS57123198A (en) | 1982-07-31 |
GB2091731B (en) | 1985-01-30 |
JPS637194B2 (en) | 1988-02-15 |
GB2091731A (en) | 1982-08-04 |
AU7976582A (en) | 1982-07-29 |
EP0057023B1 (en) | 1984-05-23 |
EP0057023A1 (en) | 1982-08-04 |
DE3260164D1 (en) | 1984-06-28 |
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