IL35736A - Anti-arthritic compositions comprising phosphine or phosphite gold halide complexes and methods of producing them - Google Patents
Anti-arthritic compositions comprising phosphine or phosphite gold halide complexes and methods of producing themInfo
- Publication number
- IL35736A IL35736A IL35736A IL3573670A IL35736A IL 35736 A IL35736 A IL 35736A IL 35736 A IL35736 A IL 35736A IL 3573670 A IL3573670 A IL 3573670A IL 35736 A IL35736 A IL 35736A
- Authority
- IL
- Israel
- Prior art keywords
- phosphine
- lower alkyl
- pharmaceutical composition
- gold
- solution
- Prior art date
Links
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical class P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims description 18
- 238000000034 method Methods 0.000 title claims description 14
- 239000000203 mixture Substances 0.000 title claims description 13
- 230000002456 anti-arthritic effect Effects 0.000 title claims description 11
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims description 9
- -1 phosphite gold halide Chemical class 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 7
- 239000010931 gold Substances 0.000 claims description 7
- 229910052737 gold Inorganic materials 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- ZAYPNIAMEDVXRI-UHFFFAOYSA-K trichlorogold;triethylphosphane Chemical compound Cl[Au](Cl)Cl.CCP(CC)CC ZAYPNIAMEDVXRI-UHFFFAOYSA-K 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- 239000007787 solid Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 7
- 229950006389 thiodiglycol Drugs 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XYYVDQWGDNRQDA-UHFFFAOYSA-K trichlorogold;trihydrate;hydrochloride Chemical compound O.O.O.Cl.Cl[Au](Cl)Cl XYYVDQWGDNRQDA-UHFFFAOYSA-K 0.000 description 4
- 229910003771 Gold(I) chloride Inorganic materials 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- RJHLTVSLYWWTEF-UHFFFAOYSA-K gold trichloride Chemical compound Cl[Au](Cl)Cl RJHLTVSLYWWTEF-UHFFFAOYSA-K 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- XDGCJGXFGCYHEK-UHFFFAOYSA-N [Au+3].[O-]P([O-])[O-] Chemical compound [Au+3].[O-]P([O-])[O-] XDGCJGXFGCYHEK-UHFFFAOYSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940057307 dihydrate calcium sulfate Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002343 gold Chemical class 0.000 description 1
- IFPWCRBNZXUWGC-UHFFFAOYSA-M gold(1+);triphenylphosphane;chloride Chemical compound [Cl-].[Au+].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 IFPWCRBNZXUWGC-UHFFFAOYSA-M 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 208000030428 polyarticular arthritis Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- JELHWNHHIOMFRD-UHFFFAOYSA-K tribromogold;triethylphosphane Chemical compound [Br-].[Br-].[Br-].[Au+3].CCP(CC)CC JELHWNHHIOMFRD-UHFFFAOYSA-K 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- IGNTWNVBGLNYDV-UHFFFAOYSA-N triisopropylphosphine Chemical compound CC(C)P(C(C)C)C(C)C IGNTWNVBGLNYDV-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
A TI-ABTHRITIC COMPOSITIONS COMPBISING PHOSPHINB OB PHOSPHITE GOLD HA LID β COMPLEXES AND METHODS OF PBODUCING THEM This invention relates to novel pharmaceutical compositions having anti-arthritic activity and to methods of producing anti-arthritic activity by administering said compositions. More specifically the compositions of this invention comprise a phosphine or phosphite gold halide complex as the active medicament.
Gold salts have been known for many years to have anti-arthritic activity. However, their utility is limited by the requirement that they be administered only by the parenteral route and the frequent occurrence of limiting side effects. The compositions of this invention have distinct advantages in that they are active, particularly when administered by the oral route, with a reduced incidence of undesirable side effects.
The novel pharmaceutical compositions of this invention, in dosage unit form, comprise a nontoxic pharmaceutical carrier and a phosphine or phosphite gold halide complex represented generally by the following structural formula; R3P— AuX FORMULA I wherein: R represents lower alkyl, phenyl, lower alkoxy or phenoxy, with the lower alkyl and lower alkoxy moieties being straight or branched chain, of from 1 to 3 carbon atoms; and X represents chloro, bromo or iodo, preferably chloro.
The compounds of formula I above are either known or are prepared by methods known in the literature. For example, a solution of thiodiglycol in a nonreactive organic solvent is mixed with an aqueous solution of gold acid chloride trihydrate, cooled to a temperature of from -10° to -5°C. and then the solution is reacted with an appropriate phosphine or phosphite to give the corresponding phosphine or phosphite gold chlorides. Reference may be made also to J . Chem. Soc. , 1828 (1937) and 1235 (1940) Australian J. Chem. ,19, 547 (1966).
The anti-arthritic activity of the compositions of this invention is measured by the ability of the active medicament to inhibit adjuvant-induced polyarthritis in rats. The active medicaments of formula I produce marked inhibition of the development of adjuvant arthritis in rats at daily oral doses of 1.5 mg. to 10 mg. (calculated on gold content) per kilogram of body weight. Adjuvant arthritis in rats is produced by a single injection of 0.75 mg. of Mycobacterium butyrieum suspended in white paraffin (N.F.) into a hindpaw (left footpad). The. injected paw becomes inflamed and reaches a maximum volume in 3-5 days (primary lesion) . The animals exhibit a decrease in body weight gain during this initial period. Adjuvant arthritis (secondary phase) occurs after a delay of approximately 10 days and is characterized by inflammation of the non-injected sites (right hind leg), decrease in body weight gain and further increases in the volume of the injected hind leg. The compounds of formula I administered in the doses described above beginning on the day of adjuvant injection and continuing for 17 days, thereafter, exclusive of days 4, 5, 11 and 12 protect the animals against development of both primary and secondary lesions of adjuvant arthritis.
The pharmaceutical compositions of this invention are prepared in conventional dosage unit forms by incorpora- ting an amount of a compound of formula I sufficient to produce anti-arthritic activity, without limiting side effects , with a nontoxic pharmaceutical carrier according to accepted procedures. Preferably the compositions will contain a phosphine or phosphite gold halide complex of formula I in an amount of from about 1 mg. to about 5 mg., calculated on gold content, per dosage unit.
The pharmaceutical carrier employed may be, for example , either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the. preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
The pharmaceutical dosage unit forms described hereinabove exclude simple non-sterile solutions of the active medicament in water or in common organic solvents and exclude simple aqueous suspensions of the active medicament -in the absence of a suspending agent. of treating arthritis The method ¾p.jac oxd rice.J±£ ihrL&- Aw&nti&n- com- 0 prises administering internally to an animal organism phos-phine or phosphite gold halide complex of formula I above, usually combined with a pharmaceutical carrier, in an amount sufficient to produce anti-arthritic activity without limiting side effects. The active medicament will be administered in a dosage unit, preferably in an amount of from about 1 mg. to about 5 mg., calculated on gold content. The route of administration may be orally or parenterally , the oral route being preferred. Advantageously equal doses will be administered one or two times daily with the daily dosage regimen being from about 1 mg. to about 10 mg., calculated on gold content. When the method described above is carried out anti-arthritic activity is produced with a minimum of side effects.
The pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.
The following examples illustrate the preparation of compounds of formula I and their incorporation into pharmaceutical compositions of this invention, and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
EXAMPLE 1 A solution of 10.0 g. (0.08 mole) of thiodiglycol in 25 ml. of ethanol is mixed with a solution of 15.76 g. (0.04 mole) of gold acid chloride trihydrate in 75 ml. of distilled water. When the bright ofange~yellow solution is almost colorless , it is cooled to below -5°C. and an equally cold solution of 5.0 g. (0.0425 mole) of triethylphosphine in 25 ml. of ethanol is added dropwise to the stirred solution. After the addition is complete, the cooled mixture is stirred for 1/2 hour. Solid that separates is removed and the filtrate is concentrated to about 30 ml. to yield a second crop. The combined solid is washed with aqueous-ethanol (2:1) and recrystallized from ethanol by adding water to the cloud point. The product is obtained as white needles, m.p. 85-86°C.
EXAMPLE 2 Triisopropylphpsphinegold chloride A mixture of 11.82 g. (0.03 mole) of gold acid chloride trihydrate and 7.9 g. (0.065 mole) of thiodiglycol in 100 ml. of aqueous ethanol (3; 2) is stirred until the color of auric gold disappears. The almost colorless solution is cooled below ~5°C. and an equally cold solution of 5.6 g. (0.035 mole) of triisopropylphosphine in 20 ml. of ethanol is added dropwise. The volume of the final reaction mixture is increased to 250 ml. with aqueous ethanol (1:1) in order to maintain a fluid mixture. After the addition is complete, the mixture is stirred in the cold for 45 minutes. The solid is removed by filtration, washed first with alcohol-water (1-2) then with water and dried. It is redissolved by suspending in ethanol and adding sufficient methylene chloride for solution. The cloudy solution is filtered from suspended gold and the filtrate concentrated until crystallization.
There is obtained white crystals, m.p. 184-6°C.
EXAMPLE 3 Trimethylphosphinegold chloride A solution of 2.44 g. (0.02 mole) of thiodiglycol in 15 ml. of methanol is mixed with a solution of 3.98 g. . distilled water. When the orange-yellow solution becomes almost colorless, it is cooled to -15°C. and an equally cold solution of 760 mg. (0.01 mole) of trimethylphosphine in ml. of methanol is added dropwise to the stirred solution. After the addition, the cooled mixture is stirred for one-half hour. The product is filtered off and. the filtrate concentrated under reduced pressure to yield a second crop. The combined product is washed with cold aqueous methanol (2:1) and water, m.p. 228-229°C, EXAMPLE 4 By following procedures outlined in J. Chem. Soc. 1828 (1937) trialkylphosphinegold iodide complexes are prepared, for example triethylphosphinegold iodide. Similarly, by following procedures outlined in J. Chem. Soc, 1235 (1940) trialkylphosphinegold bromides are prepared, for example triethylphosphinegold bromide and trimethylphosphinegold bromide.
EXAMPLE 5 Mg. /Tablet Triethylphosphinegold chloride 5 Calcium sulfate, dihydrate 150 Sucrose 25 Starch 15 Talc 5 Stearic acid 3 The sucrose, calcium sulfate and triethylphosphinegold chloride are thoroughly mixed and granulated with hot 10% gelatin solution. The wetted mass is passed through a #6 mesh screen directly onto drying trays. The granules are dried at 120°F. and passed through a #20 mesh screen, mixed with the starch, talc and stearic acid, and compressed into tablets.
EXAMPLE 6 Ingredients Mg. /Capsule Triethylphosphinegold chloride 1 Magnesium stearate 5 Lactose 400 The above ingredients are screened through a #40 mesh screen, mixed and filled into #0 hard gelatin capsules.
EXAMPLE 7 Trimethylphosphltegold chloride Gold acid chloride trihydrate (4.0. g. ) is reduced to aurous chloride with 2.44 g. of thiodiglycol In aqueous -methanol (1:2) solution. The resulting solution is cooled to below -5°C. and an equally cold solution of 1.5 g. of trimethylphosphite in 10 ml. of methanol is added dropwise, with stirring under nitrogen. The reaction mixture is stirred for 30 minutes, filtered and the solid is washed with cold aqueous methanol and dried. The product is dissolved in 5 ml. of chloroform, diluted with 10 ml. of methanol and filtered through charcoal. The filtrate is concentrated under reduced pressure, cooled and diluted with ice-water to precipitate the product, m.p. 99-100°C.
EXAMPLE 8 Triethylphosphitegold chloride Gold acid chloride trihydrate (5. 9 g., 0.015 m.) is reduced to aurous chloride with thiodiglycol (3.7 g. , 0.03 m.) in aqueous ethanol (1:2) solution. The solution is cooled to -10°C. and an equally cold solution of 3.72 g. (0.02 m.) of triethylphosphite in 20 ml. of ethanol is added, dropwise with stirring. The temperature is maintained at -10°C. and stirring is continued for 30 minutes. The ethanol is removed from the reaction mixture under reduced pressure without heating. The aqueous residue is extracted with methylene chloride and the dried extract is evaporated under reduced pressure. The crude product is purified by chromatography over a silica column to give an oil.
EXAMPLE 9 Triphenylphosphinegold chloride Gold acid chloride trihydrate (4.0 g. , 0.01 m.) is reduced to aurous chloride with thiodiglycol in 1:2 aqueous ethanol. After cooling this solution in an ice-bath a cold solution of 2.62 g. (0.01 m.) of triphenylphosphine in a minimum amount of ethanol is added with stirring. The reaction mixture is stirred for about 30 minutes, filtered and the product washed with cold aqueous alcohol, then ice-water and dried, m.p0 242-243°C.
Claims (10)
1. A pharmaceutical composition having anti-arthritic activity, in dosage unit form, comprising a pharmaceutical carrier and an effective, nontoxic amount of a phosphine or phosphite gold halide complex of the formula: R3P→AuX in which: R is lower alkyl, phenyl, lower alkoxy or phenoxy, said* lower alkyl and lower alkoxy being straight or branched chain of from 1 to 3 carbon atoms; and X is chloro, bromo or iodo.
2. A pharmaceutical composition according to claim 1 in which X is chloro.
3. A pharmaceutical composition according to claim 2 in which R is lower alkyl.
4. A pharmaceutical composition according to claim 3 in which R is ethyl.
5. A pharmaceutical composition according to claim 4 in which the amount of the active medicament is from about 1 mg. to about 5 mg. , calculated on gold content.
6. A process for the preparation of a pharmaceutical composition, in dosage unit form, having anti-arthritic activity which comprises the association of a phosphine or phosphite gold halide complex of the formula: R3P-^AuX in which: R is lower alkyl, phenyl, lower alkoxy or phenoxy, said lower alkyl and lower alkoxy being straight or branched chain of from 1 to 3 carbon atoms; and X is chloro, bromo or iodo, with a pharmaceutical carrier .
7. A process according to claim 6 in which X is chloro.
8. A process according to claim 7 in which R is lower alkyl.
9. A process for the preparation of a pharmaceu- according to any of claims 1 to 5 tical composition/ in dosage unit form, having anti-arthritic activity which comprises the association of triethylphosphine gold chloride with a pharmaceutical carrier.
10. A process according to claim 9 in which the dosage unit form is a tablet or capsule.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US88470969A | 1969-12-12 | 1969-12-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
IL35736A0 IL35736A0 (en) | 1971-01-28 |
IL35736A true IL35736A (en) | 1973-06-29 |
Family
ID=25385205
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL35736A IL35736A (en) | 1969-12-12 | 1970-11-26 | Anti-arthritic compositions comprising phosphine or phosphite gold halide complexes and methods of producing them |
Country Status (9)
Country | Link |
---|---|
BE (1) | BE760073A (en) |
CA (1) | CA974881A (en) |
DE (1) | DE2061181C3 (en) |
FR (1) | FR2081345B1 (en) |
GB (1) | GB1271906A (en) |
IE (1) | IE34764B1 (en) |
IL (1) | IL35736A (en) |
NL (1) | NL160165C (en) |
ZA (1) | ZA707816B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4171360A (en) * | 1978-02-21 | 1979-10-16 | Smithkline Corporation | Phosphinegold (I) salts having antiarthritic activity |
CZ303649B6 (en) * | 2011-07-11 | 2013-01-23 | Univerzita Palackého | Complexes of gold with derivatives of N6-benzyladenine and phosphane derivatives, process of their preparation and use of such complexes as medicaments in antiphlogistic therapy |
-
1970
- 1970-11-18 CA CA098,455A patent/CA974881A/en not_active Expired
- 1970-11-19 ZA ZA707816A patent/ZA707816B/en unknown
- 1970-11-26 IE IE1517/70A patent/IE34764B1/en unknown
- 1970-11-26 IL IL35736A patent/IL35736A/en unknown
- 1970-12-09 BE BE760073D patent/BE760073A/en not_active IP Right Cessation
- 1970-12-10 FR FR7044555A patent/FR2081345B1/fr not_active Expired
- 1970-12-11 DE DE2061181A patent/DE2061181C3/en not_active Expired
- 1970-12-11 NL NL7018126.A patent/NL160165C/en not_active IP Right Cessation
- 1970-12-11 GB GB58979/70A patent/GB1271906A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
NL160165C (en) | 1979-10-15 |
DE2061181B2 (en) | 1980-10-23 |
IE34764L (en) | 1971-06-12 |
CA974881A (en) | 1975-09-23 |
IE34764B1 (en) | 1975-08-06 |
FR2081345A1 (en) | 1971-12-03 |
GB1271906A (en) | 1972-04-26 |
DE2061181A1 (en) | 1971-06-16 |
NL7018126A (en) | 1971-06-15 |
NL160165B (en) | 1979-05-15 |
BE760073A (en) | 1971-06-09 |
ZA707816B (en) | 1971-08-25 |
IL35736A0 (en) | 1971-01-28 |
DE2061181C3 (en) | 1981-05-27 |
FR2081345B1 (en) | 1975-01-10 |
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