IE46884B1 - Cyclosporin derivatives - Google Patents
Cyclosporin derivativesInfo
- Publication number
- IE46884B1 IE46884B1 IE1924/81A IE192481A IE46884B1 IE 46884 B1 IE46884 B1 IE 46884B1 IE 1924/81 A IE1924/81 A IE 1924/81A IE 192481 A IE192481 A IE 192481A IE 46884 B1 IE46884 B1 IE 46884B1
- Authority
- IE
- Ireland
- Prior art keywords
- cyclosporin
- formula
- compound
- substantially free
- group
- Prior art date
Links
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical class CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title description 6
- ZNVBEWJRWHNZMK-SYOLRUPNSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,2 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O ZNVBEWJRWHNZMK-SYOLRUPNSA-N 0.000 claims description 26
- 108010019594 cyclosporin D Proteins 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229930182912 cyclosporin Natural products 0.000 claims description 4
- 235000015097 nutrients Nutrition 0.000 claims description 4
- 241001149964 Tolypocladium Species 0.000 claims description 3
- 108010036941 Cyclosporins Proteins 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000000855 fermentation Methods 0.000 claims description 2
- 230000004151 fermentation Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 229930105110 Cyclosporin A Natural products 0.000 description 4
- 108010036949 Cyclosporine Proteins 0.000 description 4
- 229960001265 ciclosporin Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GEUKOOCPPICVTB-SMOCYEBVSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s)-33-[(1r,2r)-1-hydroxy-2-methylhexyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32- Chemical compound CCCC[C@@H](C)[C@@H](O)C1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O GEUKOOCPPICVTB-SMOCYEBVSA-N 0.000 description 2
- JTOKYIBTLUQVQV-QRVTZXGZSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-[(1r)-1-hydroxyethyl]-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontan Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H]([C@@H](C)O)NC1=O JTOKYIBTLUQVQV-QRVTZXGZSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JTOKYIBTLUQVQV-UHFFFAOYSA-N Cyclosporin C Natural products CC=CCC(C)C(O)C1N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C(=O)C(C(C)O)NC1=O JTOKYIBTLUQVQV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 108010019248 cyclosporin C Proteins 0.000 description 2
- 108010040781 dihydrocyclosporin D Proteins 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- UCOQITKXMNKTKF-MXGZYYNMSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28,30-decamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C)NC1=O UCOQITKXMNKTKF-MXGZYYNMSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 241000123975 Trichoderma polysporum Species 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000000287 crude extract Substances 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
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003041 laboratory chemical Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
Landscapes
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
The present invention relates to cyclosporin derivatives. More particularly, the present invention relates to the compound of formula I, CH, CH, J\CHX J I CH,X CH, CH„ 3 CH, CH, 3\ / 3 CH, CH3_N -CH— C-N—CH-A ——-C —N—CH — C I L H L II I L H H 0=C _N -CH CH '3\ » CH-CHyCH L CH, N — CH3 ! CH3- n & H 0 L 1 I! L = C _CH—N __C —CH—N —C—CH— N —C —CH—N -C — CH CH [h ch3 h ch3 ?H2 C3 C»/\h3 ch3 ch3 CH, /CHx CH, - 2 4 6 8 8 4 wherein A is a group of the formula ii, — C -1, ii II 'CH' CH3 CH — II which compound is hereinafter referred to as cyclosporin D.
The present invention also provides a process for the production of cyclosporin 0 which process comprises cultivating a cyclosporin D producing strain of the species Tolypocladium inflatuni Gams in the presence of a nutrient medium and isolating cyclosporin D.
The cultivation process may be effected in conventional manner for analogous strains, e.g. as described in Example 1 hereinafter.
A preferred cylcosporin D producing strain is the freely available strain NRRL 8044 of the species Tolypocladium inflatuni Gams, a culture of which is available from United States Department of Agriculture (Northern Research and Development Division), Peoria, ILL., U.S.A. This strain was formerly described as a strain of the species Trichoderma polysporum (Link ex Pers.) and is described in the literature, e.g. in Patent Specification No. 40549.
Alternatively cyclosporin D producing strains obtained by selection or mutation of NRRL 8044, or treatment of this strain by ultraviolet light or X-rays, or treatment of this strain with laboratory chemicals, may be used.
Cyclosporin D may be isolated in conventional manner, e.g. as described in the Example, from other natural products that may be produced in greater amounts, - 3 4 6 8 8 4 e.g. the somewhat more polar cyclosporin A (also known as S 7481/F-l), the more polar cyclosporin B (also known as S 7481/F-2) and the yet more polar cyclosporin C.
Accordingly, in a further aspect the present invention also provides cyclosporin D as defined above substantially free from other, contaminating fermentation products and, especially, substantially free from cyclosporins A, B and C.
In the following example, all temperatures are in degrees Centigrade.
All ratios are by volume unless otherwise stated.
EXAMPLE Production of Cyclosporin D ' 500 litres of a nutrient solution containing per litre, 40 g of glucose, g of sodium caseinate, 2.5 g of ammonium phosphate, 5 g of MgSO^./HgO, 2 g of KHgPO^, 3 g of NaNOg, 0.5 g of KC1, 0.01 g of FeSO^ and demineralised water to 1 litre, are inoculated with 50 litres of a pre-culture of the strain NRRL 8044 and are incubated in a steel fermenter under stirring (170 rpm) and aeration (1 litre air/minute/litre nutrient solution) for 13 days at 27° (see Patent Specification No. 40549 ).
The culture liquor is stirred with the same amount of n-butyl acetate, concentration by evaporation in a vacuum after separation of the organic phase and the crude extract is de-fatted by a 3-stage partition between methanol/water (9:1) and ’ petroleum ether. The methanolic phase is separated, concentrated by evaporation in vacuum and the crude product is precipitated by the addition of water. The material obtained upon filtration is chromatographed on silica gel with n-hexane/ acetone (2:1) as eluant. The initially eluted fractions contain predominantly cyclosporin A and cyclosporin D and the later eluted fractions contain predominantly cyclosporin C. For further purification the cyclosporin A- and D-containing fractions are crystallised from a 2- to 2.5-fold amount of acetone at -15°. The crystallate is further chromatographed twice on silica gel, the fractions initially eluted with water-saturated ethyl acetate, containing cyclosporin D in greatly enriched form. These are dissolved in twice the amount of acetone and are allowed - 4 to crystallise at -15°. The resulting crude crystalline product of cyclosporin D is dissolved for further purification in a 10-fold amount of acetone, 2% by weight of active charcoal are added and heating is effected for 5 minutes to 60°. The clear and almost colourless filtrate obtained upon filtration over talc is concentrated by evaporation to a third of its volume and is allowed to cool down at room temperature, whereupon cyclosporin D crystallises spontaneously. The crystallisation is completed by allowing to stand at -17°. The crystals obtained by filtration are washed with a small amount of ice-cold acetone and are subsequently dried in a high vacuum at 80° for 2 hours.
Characterisation of Cyclosporin D: /ex 7 20 = -245° (c = 0,52 in chloroform) D 7 ~ ~ D Cyclosporin D exhibits pharmacological activity. In particular, it exhibits anti-inflammatory activity and anti-arthritic activity as indicated in standard tests with animals, for example by an inhibition of swellings in the Freunds adjuvant arthritis test in rats on p.o. administration of 3 to 100 mg/kg of the compounds.
Cyclosporin D is therefore indicated for the treatment and prophylaxis of chronic inflammations e.g. arthritis and rheumatic disorders. For this use an indicated daily dose is from 50 to 900 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 15 to 450 mg, or in sustained release form.
The present invention also provides a pharmaceutical composition comprising cyclosporin D in association with a pharmaceutical carrier or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
Cyclosporin D is also useful as an intermediate for the production of derivatives thereof, particularly the compounds known as dihydrocyclosporin D and isocyclosporin D. The said derivatives dihydrocyclosporin D and isocyclosporin D, - 5 46884 as well as their production from cyclosporin D, are the subject of our Patent Specification No. 46883.
Claims (8)
1. A process for the production of a compound of formula I, CH CH, CH, CH, \CH/ J CH ? CH 3\ C() / Ct, 3 C f 3 , CH CH, 3\ / 3 CH CH CH 3 .. N -CH.....C - N — CH-----A-----C —N — CH - C ____N _____CH I L II L 0=C 3\ I CH-CHa-CH L CH 3 , OHO 0 Ιο II l I ii l i 0 = C —CH „N _C_CH— N —C—CH— N —C Il I II CH L / \ • CH —N CH 3 ( I} ch 3 h CH, CH, / Cl \ ' 2 3 CH 3 CH 3 CH, CH, CH, CH I i 2 / c x CH, wherein A is a group of formula II, - 6 4 6 8 8 4 CH Η II / c \ H CH 2 HO CH \ R Z\ -N ~ CH II which compound is hereinafter referred to as cyclosporin D, which process comprises cultivating a cyclosporin D producing strain of the species Tolypocladium inf 1atum Gams in a nutrient medium and isolating cyclosporin D. g
2. A process as claimed in Claim 1, substantially as hereinbefore described in the accompanying Example.
3. Cyclosporin D, whenever prepared by a process as claimed in Claim 1 or Claim 2.
4. Cyclosporin D of formula I as i llustrated in Claim 1, wherein A is a 10 group of formula II as illustrated in Claim 1.
5. Cyclosporin D as claimed in Claim 4, substantially free from other , contaminating fermentation products.
6. Cyclosporin D as claimed in Claim 5, substantially free from cyclosporins A, B and C. 15
7. Cyclosporin D as claimed in Claim 4, in crystalline form.
8. A pharmaceutical composition comprising cyclosporin D as claimed in any one of Claims 4 to 7 in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH582377A CH628023A5 (en) | 1977-05-10 | 1977-05-10 | Process for the preparation of an antibiotic derivative |
| CH582277A CH628022A5 (en) | 1977-05-10 | 1977-05-10 | Process for the preparation of an antibiotic derivative |
| CH745777A CH632010A5 (en) | 1977-06-17 | 1977-06-17 | Process for the preparation of a novel antibiotic |
| IE932/78A IE46883B1 (en) | 1977-05-10 | 1978-05-08 | Cyclosporin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE811924L IE811924L (en) | 1978-11-10 |
| IE46884B1 true IE46884B1 (en) | 1983-10-19 |
Family
ID=27428942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1924/81A IE46884B1 (en) | 1977-05-10 | 1978-05-08 | Cyclosporin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE46884B1 (en) |
-
1978
- 1978-05-08 IE IE1924/81A patent/IE46884B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE811924L (en) | 1978-11-10 |
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