FI63561C - FRAMEWORK FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC DIHYDROCYCLOSPORIN D - Google Patents

Description

.-... ANNOUNCEMENT, u ,, W (11) utlAggningsskkift 6 3 5 61 C Patent granted 11 07 19C3 (45> Patent meddelat ^ ^ (51) K ».ik? /Iot.a.3 C 07 C 103 / 52 FINLAND —FINLAND (21) hwntayomui-Utumiiiekmm 801681 (22) Hakemtaptlvt — Amölmlngadt · 26. 05.80 (23) Aikuptivt — GIMgh «Ud« c 02.05.78 (41) Tulluc lulklMkal - Mhrtt off «ttN | 26. 05.80 r> twitu- i> r * klft * Hhallitut (44) NlhttvUulpanon I »kii« iL | ulkalMn datm

Mutt · och r * gist * rttyr * lMn '' AiNtkan uttajd odi utUkrlfem pubttcand 31. 03.83 (32) (33) (31) requested * Welk # i «- * HW piMt * 10.05.77 10.05.77, 17.06.77 Swiss-Swiss (CH) 5822/77, 5823/77, 7 ^ 57/77 (71) Sandoz AG, Basel, Swiss-Swiss (CH) (72) Ren§ P. Traber, Basel, Max Kuhn, Basel, Hans Hoftaann, Ettingen,

Eugen Harri, Thervil, Switzerland-Switzerland (CH) (7 * 0 Oy Kolster Ab

(5I +) Process for the preparation of therapeutically useful dihydrocyclosporin D - For the preparation of dihydrocyclosporin D for therapeutic use

(62) Divided by division 7813I + 8 (patent 598lU) -Avdelad fr & n trap 7813 ^ + 8 (patent 598lU)

The invention relates to a process for the preparation of a therapeutically useful dihydrocyclosporin D of formula I

CHjn iH * mac t: m? CHj /.CMJ 1 / SCH |] ϋ | *, c M Cl, 3 / C "j

I CHj \ / = »1 crf '' CM, XCH

CHj CHj Cu CH- »I CH» I. I 1 I I 1 CH 2 -N-CU-C 6 -g (.M-c - H ----- CU-CO-H-CM-C-N-CM,

1 L il 1 I I II

CO ° H 0

cm’n I CO

CH-CH 2 -CH 1 I

CH3 ^ I I

CMj-N N-CHj I

I V OM

I 0 <-1 i li «. I v

OC-CM tJ CO-Cu - N CO CH-N —— c CM —- N - CO —- CH

I I I III I

CM3 H CHj CHj CHj cm CM)

CH) CH) I

CU CM

//

Cu-, ΓΗ) CH CH 2 2,63561

The process for the preparation of dihydrocyclosporin D according to the invention is characterized by the hydrogenation of cyclosporin D of formula II

CV <3 \ / H c

II

H XHj CH3 \ / CM3 Ir CU, / CH, 1.0 ^ VC'V \ / 3 I Ch3 ^ / C ") cm CH3 cir CHJ CM, CM CHi | I CM 3 iiii I li CM, -N-CH -CO-H-C1I-CM-CM-CO-H-CH-CN-CHj

5 I I l II I II 11 I

, 1 o HO

co I

cn3 \ I

CH-CH5-Ch i

/ | I

CM3 I N-CHj II

CM, -N

3 I H OM

I O l | l II L I C

oc- CM-N-CO-CH - N-CO - CH-H-C-CM-N-CO-CM

III III I

CHi H CHj CH, CHj CM CM *

I - s' V. I

I C Mj CHj I

CM .CH

/ \ X S

CM3 CM3 CHj CM3

The process according to the invention can be carried out in a manner known per se, for example by catalytic hydrogenation.

As the solvent, a lower aliphatic alcohol such as methanol, ethanol, isopropanol, or ethyl acetate is preferably used. The hydrogenation is conveniently carried out at neutral pH in the temperature range from 20 to 30 ° C at normal pressure or at slightly elevated pressure. Palladium, for example a Pd / C catalyst, is preferably used as the catalyst.

Dihydrocyclosporin D has interesting chemotherapeutic and pharmacological properties. It has use in the treatment of self-immune diseases, in particular dihydrocyclosporin D has use in the treatment of arthritis.

Dihydrocyclosporin D can be formulated into a pharmaceutical form together with non-pharmacologically active excipients.

3,63561

When dihydrocyclosporin D prepared by the process of the invention is compared with known cyclosporins such as cyclosporin A (FI patent 54 606) and dihydrocyclosporin C (FI patent 60 701), it is found that dihydrocyclosporin D: The effect of n differs from that of cyclosporin A and dihydrocyclosporin C in both the subject of the effect and the potency of the effect. In most experiments investigating resistance to rejection, it was found that dihydrocyclosporin D has little or no effect, in particular, it does not inhibit antibody formation in vivo and does not prolong the duration of rejection in organ transplants. In contrast, dihydrocyclosporin D is very active in the treatment of self-immune diseases: it prevents the development or onset of Freund's adjuvant-induced arthritis and prevents or ameliorates experimental allergic cerebrospinal inflammation in rats and rhesus monkeys; in the latter case, it was found that when dihydrocyclosporin D was used in particular, unlike when cyclosporin A was used, most rats no longer showed paralysis after treatment.

The cyclosporin D used as a starting material in the process is prepared by culturing the fungal species Tolypocladium inflatum Gams Strain NRRL 8044 in the culture medium and isolating the cyclosporin D from the culture medium according to FI patent publication 59,814.

In the following example, all temperatures are in degrees Celsius.

Example: Dihydrocyclosporin D

400 mg of Pd / C catalyst (10% palladium) are prehydrated for 20 minutes in 15 ml of ethanol. A solution of cyclosporin D (33.66 g) in 30 ml of ethanol is added to the suspension of Pd / C catalyst, and the mixture is hydrogenated at 24 ° under a pressure of 736 mmHg until hydrogen binding ceases. The catalyst is filtered off and the filtrate is evaporated in vacuo at 20-40 °. Thin layer chromatography gives dihydrocyclosporin D as a colorless amorphous powder. It is dried under high vacuum at 70 ° for 4 hours.

Properties of dihydrocyclosporin D f oi J2 ° = -237 ° (c = 0.56, CHCl3) = -196 ° (c = 0.58, CH3OH) m.p. 153-156 °.

Claims (1)

* 63561 Claim. Process for the preparation of a therapeutically useful dihydrocyclosporin D of formula IT "1 CH3 \ / CM3 111. CH, yCH, CM HO 3/3} c" \ / CM 'CM Ch3 Crl CHj CM, CM CM, II CMj ii I i I li CIC-tf-CM-CO-N-CM-c - n --- CM-CO-M-CM-cU-CMj Il t II III II I o MO co c ,, \ I co CM-CMj-CM L CHj ^ | Ιί-CHj I CM, —N J I M O »· I o i | t || i I i OC-CM-f. '- CO-CM - n CO CM-M C cm - »- CO - CM III III ICM j H CM3 CM j CM3 CM CM} I CM3 ^ CHJ l CM CM / \ / s. CM3 CM3 CH3 CM3 5 63561 characterized in that the cyclosporin D of the formula II D, K c II M CHav »/ CM3„ Ip »cm, yC \ i, is hydrogenated. CM CM \ / 3, I Cl <3 ^ ^ C '' 3 CM CMJ CU C mj C Mj CM CM j I j CMj iiii I li CM.-li-CM-CO-N - CM - c: - m ---- CM-C C —-CM-CnC MJ Il I II «II II I o MO co CMj I CO \ I CM-CMj-CM l CM J n-ch, II IM OH I ol | l | ll I l OC-CM - u— CO-cm —li CO - CM II C — CM —f; -CO — CM lii lii ICM j MCM 3 CMj CM j CM CMj I CM3 CMj I CM .CH / \ / CMJ CMJ C Mj CM3 63561 6 Patentkrav. For the preparation of a therapeutically active dihydrocyclosporin D with the formula I c ,, 3 \ uiC cm2 CM3 \ / CM3 In CU, .CU CM 3 \ / 2 and CM Nchj CM CU; CM, CM CM, II CHi iiii I li CH, -N-CM-CO-N-CM-c - M ----- CM-CO-U-CM-CN-CM, Il l II II l II | O MO, CO cm, I co \ I CM-Cllj-CM L CMj I N-CHj I CM, -N I M OM I O L I L II L | l OC-CM-K —- CO-οι - II CO - CM-- '1 c CM - tl -CO - CM III III I CM, M CM, CM, CM, CM CM, I / \ II CM3 CM, I CM CM / \ /. . CM3 CM3 CM3 CMj