CA1106303A - Cyclosporin c from tolypocladium or cylindrocarbon - Google Patents

Cyclosporin c from tolypocladium or cylindrocarbon

Info

Publication number
CA1106303A
CA1106303A CA353,123A CA353123A CA1106303A CA 1106303 A CA1106303 A CA 1106303A CA 353123 A CA353123 A CA 353123A CA 1106303 A CA1106303 A CA 1106303A
Authority
CA
Canada
Prior art keywords
cyclosporin
process according
fungus species
strain
producing strain
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
Application number
CA353,123A
Other languages
French (fr)
Inventor
Maz Kuhn
Artur Ruegger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from CH1419575A external-priority patent/CH614931A5/xx
Application filed by Sandoz AG filed Critical Sandoz AG
Priority to CA353,123A priority Critical patent/CA1106303A/en
Application granted granted Critical
Publication of CA1106303A publication Critical patent/CA1106303A/en
Expired legal-status Critical Current

Links

Abstract

Abstract of the disclosure Cyclosporin C of formula I

I

useful as an intermediate in the production of isocyclo-sporin C.

Description

- ~ \

The present application, which is a divisional of our co-pending application No. 264,703, relates to the compound cyclosporin C of formula I

C~a~C~H
: ' 11 3~ ~CH3 . ~C~
7 C~ ,C,,~~~ ''~` T~3 I H2 C:H~ (.HCH~ ~¦ CH-OH C~l3 C O 1 H ~;--N--C I ~--C O--N--C H--C--~J ~ I I I ?

/C~I_CI~2~
CH3_N , . . N--Cll3 - 01 C 11 N--C O_ ~ H--r~ ---C O--C H - -- - N--C--C I l--N--C O--1 H
Ct-13 H I~HJ C ~2 C1~3 Cll CH;!
~CI~ CH3 CH3 ~1~
C~3 CHJ CH3 CH3 ~ .

.
: Cyclosporin C is a valuable intermediate useful for the production of the pharmacologically active compound dihy-drocyclosporin C. Dihydrocyclosporin C, its production from Cyclosporin C, as well as the pharmacological properties of dihydrocyclosporin C, are described in our above mentioned co-pending application No. 264, 703.
' : ' .- - : -' ' ' ' ' `

3lD3 In acldition to the foregoing the present invention also provides a process for the production of Cyclosporin C
which comprises cultivating a Cyclosporin C producing strain of the fungus species Tolypocla'dium inflatum Gams or Cylin-5. drocarpon lucidum Booth in contact witn a nutrient mediumand isolating Cyclosporin C from the resultant culture broth.

The cultivation may be effectecl in known manner, for exam-ple as described in DOS 2,455, 859 and t,he corresponding Canadian Patent No. 1,030,469 to ~arri et al. granted May 2, 1978. Preferred strains of the fungus species Toly-, pocladium inflatum Gams and Cylindrocarpon Lucidum Booth are the strains NRR~ 8044 and 5670, cultures of which have been deposited at the ~nited States Department of ~griculture (Northern Research and Development Division) Peoria, Ill., U.S.A. and are freely available. The morphological charac-teristics of both strains are fully described in the affore-mentioned Canadian Patent No. 1,030,469.

Cyclosporin C may be isolated from the obtained fermenta-tion broth by chromatography as a compound active against Aspergilius niger and having greater polarity than Cyclo-sporins A.and B (designated as S7481/F-1 and S7481/F-2 in the'above mentioned DOS and Canadian Patent).

In the following example all temperatures are in degrees : 25 centigrade.

~ ' . .

EXAMPLE

400 litres of a culture broth obtained by aerobic sub-mersion cultivation of the strain NRRL 8044 of Tolypocla-dium inflatum Gams [see Example 3 of Canadian Patent No. 1,030,469~ is extracted by stirring with 400 litres of n-butyl acetate. After separation in a "Westfalia-Separator" (trademark), the organic phase is concentrated in a vacuum and the crude extract is defatted by a three stage extraction between petroleum ether and methanol/
water (9:1). The resultant material is dissolved in chloro-form and chromatographed on 4.5 kg silicagel 60 "Merck"(diameter 0.2 to 0.5 mm), using chloroform with increasing amounts of methanol as eluant. Chloroform + 1.5% methanol elutes Cyclosporins A and B, and chloroform ~ 3~ methanol elutes Cyclosporin C. ~The Cyclosporin C may be detected using t.l.c. on silica gel foils "Polygram" using chloro-form/methanol 95:5 as eluant. Rf values - Cyclosporin A
0.44; B 0.37; C 0.26].

After combination and evaporation of the eluant fractions containing Cyclosporin C, the chromatographic purification is repeated. The Cyclosporin C containing fractions are collected and evaporated at 20 - 40~ The residue is treated with 10 times its weight of a mixture of alcohol containing 5% per weight of active charcoal.

., *

Trademark ;

' 6~3 After filtration the mixture is evaporated at 20 to 40 in a vacuum and then dried in a hiqh vacuum at 55C.

Final purification comprises dissolving the resultant resi-du~ in a 5 times amount of ether and by the slow addition of a 30 times amount of hexane. On shaking, a solid sub-stance precipitates and is co:Llected after cooling of the mixture at 0 to 5. This is washed with cold hexane and dr.ied at 55 in a high vacuum. From a 2.5 times amount of acetone the residue affords at -15 colourless, pris-matic needles of crystalline Cyclosporin C.
M.Pt. = 152 - 155 [a]D= -255 (c = 0.5; CHC13) [~]20= -182 (c = 0.5; CH30H)o

Claims (7)

The embodiments of the invention in which an exclusive property or privelege is claimed are defined as follows:
1. A process for the production of Cyclosporin C of formula I
which process comprises cultivating a Cyclosporin C
producing strain of the fungus species Tolypocladium inflatum Gams or Cylindrocarpon lucidum Booth in con-tact with a nutrient medium and isolating Cyclosporin C
from the resultant culture broth.
2. Process according to claim 1 wherein the Cyclosporin C
producing strain is the strain NRRL 8044 of the fungus species Tolypocladium inflatum Gams.
3, Process according to claim 1 wherein the Cyclosporin C
producing strain is the strain NRRL 5760 of the fungus species Cylindrocarpon lucidum Booth.
4. Process according to claim 1 wherein the Cyclosporin C
is isolated in a form substantially free from Cyclo-sporin A and Cyclosporin B.
5. Process according to claim 4 wherein the Cyclosporin C
is isolated in crystalline form.
6. Cyclosporin C whenever prepared by a process as claimed in any one of claims 1 to 3.
7. Cyclosporin C whenever prepared by a process as claimed in claim 4 or 5.
CA353,123A 1975-11-04 1980-05-30 Cyclosporin c from tolypocladium or cylindrocarbon Expired CA1106303A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA353,123A CA1106303A (en) 1975-11-04 1980-05-30 Cyclosporin c from tolypocladium or cylindrocarbon

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH1419575A CH614931A5 (en) 1975-11-04 1975-11-04
CH14195/75 1975-11-04
CA264,703A CA1087609A (en) 1975-11-04 1976-11-02 Dihydrocyclosporin c
CA353,123A CA1106303A (en) 1975-11-04 1980-05-30 Cyclosporin c from tolypocladium or cylindrocarbon

Publications (1)

Publication Number Publication Date
CA1106303A true CA1106303A (en) 1981-08-04

Family

ID=27164735

Family Applications (1)

Application Number Title Priority Date Filing Date
CA353,123A Expired CA1106303A (en) 1975-11-04 1980-05-30 Cyclosporin c from tolypocladium or cylindrocarbon

Country Status (1)

Country Link
CA (1) CA1106303A (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727018A (en) * 1984-05-18 1988-02-23 Eichner Ronald D Immunoregulation of transplantable tissue
US7361636B2 (en) 2004-10-06 2008-04-22 Amr Technology, Inc. Cyclosporin alkynes and their utility as pharmaceutical agents
US7378391B2 (en) 2004-09-29 2008-05-27 Amr Technology, Inc. Cyclosporin alkyne analogues and their pharmaceutical uses
US7511013B2 (en) 2004-09-29 2009-03-31 Amr Technology, Inc. Cyclosporin analogues and their pharmaceutical uses
US7538084B2 (en) 2003-03-17 2009-05-26 Amr Technology, Inc. Cyclosporins
US7696166B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
US7696165B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727018A (en) * 1984-05-18 1988-02-23 Eichner Ronald D Immunoregulation of transplantable tissue
US7538084B2 (en) 2003-03-17 2009-05-26 Amr Technology, Inc. Cyclosporins
US7378391B2 (en) 2004-09-29 2008-05-27 Amr Technology, Inc. Cyclosporin alkyne analogues and their pharmaceutical uses
US7511013B2 (en) 2004-09-29 2009-03-31 Amr Technology, Inc. Cyclosporin analogues and their pharmaceutical uses
US7361636B2 (en) 2004-10-06 2008-04-22 Amr Technology, Inc. Cyclosporin alkynes and their utility as pharmaceutical agents
US7632807B2 (en) 2004-10-06 2009-12-15 Albany Molecular Research, Inc. Cyclosporin alkynes and their utility as pharmaceutical agents
US7696166B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne/alkene analogues for preventing or treating viral-induced disorders
US7696165B2 (en) 2006-03-28 2010-04-13 Albany Molecular Research, Inc. Use of cyclosporin alkyne analogues for preventing or treating viral-induced disorders

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