Cyclosporins

Details Cyclosporins Cyclosporins

2001-01-08

2003-06-24

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S327000, C530S345000, C514S002600, C514S011400, C514S015800

Reexamination Certificate

active

06583265

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel cyclosporins, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them. Furthermore, this invention discloses a novel general method for the exchange of substituents at the sarcosine residue of the cyclosporin macrocycle.
2. Description of the Related Art
Cyclosporin A is well known for its immunosuppressive and antiinflammatory properties but many biological properties have been described in addition. EP 0 194 972 describes cyclosporin derivatives with substituents on the sarcosine in position 3 of the macrocycle, the introduction of such substituents, as well as the immunosuppressive, antiinflammatory and antiparasitic activity of these cyclosporin derivatives. EP 0 484 281 describes cyclosporin derivatives with reduced immuno-suppressive potency and activity against HIV.
The present invention discloses novel cyclosporins which can be used for the treatment of infectious diseases, of chronic inflammatory and autoimmune diseases, to prevent cardiac hypertrophy, to treat and prevent ischemia and reperfusion injury, to treat neurodegenerative diseases, and to induce processes of tissue regeneration.
SUMMARY OF THE INVENTION
A second embodiment of the present invention is a novel method to prepare cyclosporins with substituents at the sarcosine in position 3 of the macrocycle. EP 0 194 972 describes the introduction of certain substituents at the sarcosine. The method described in EP 0 194 972 involves treatment of a cyclosporin with strong base to generate a polyanion and subsequent reaction of this polyanion with electrophiles, such as disulfides, alkyl halides or other suitable alkylating agents. Halogens or sources of positive halogen can also be used, as well as aldehydes. There is no example in the prior art which describes the exchange of such a substituent by another. The present invention discloses such a method. In this novel method, a suitable substituent is first introduced into a cyclosporin polyanion and the resulting product is isolated. The substituent is subsequently activated to become a leaving group and replaced by the desired novel substituent. This novel method allows the introduction of a wide variety of substituents into the sarcosine residue of the cyclosporin macrocycle.
The cyclosporin nomenclature and numbering systems used hereafter are those used by J. Kallen et al., “Cyclosporins: Recent Developments in Biosynthesis, Pharmacology and Biology, and Clinical Applications”, Biotechnology, second edition, H.-J. Rehm and G. Reed, ed., 1997, p535-591 and are shown below:
Position
Letter in
numbering
Formula
Amino acid in cyclosporin A
1
A
N-Methyl-butenyl-threonine (MeBmt)
2
B
&agr;-aminobutyric acid (Abu)
3
C
Sarcosine (Sar)
4
D
N-Methyl-leucine (MeLeu)
5
E
Valine (Val)
6
F
N-Methyl-leucine (MeLeu)
7
G
Alanine (Ala)
8
H
(D)-Alanine ((D)-Ala)
9
I
N-Methyl-leucine (MeLeu)
10
K
N-Methyl-leucine (MeLeu)
11
L
N-Methylvaline (MeVal)
Objects of the present invention are therefore compounds of the formula I
and their pharmaceutically acceptable salts wherein the letters A to L represent residues of the following amino acids:
A (L)-alpha-N-methylamino-beta-hydroxy acid of the formula II,
 wherein R1 is (E)-2-butenyl-1,
B alpha-amino-butyric acid, alpha-amino-valerianic acid (norvaline), threonine, or valine,
C substituted sarcosine of the formula III
 in which x is
S—(O)
n
—R2, in which n has the value zero, one or two, and R2 is hydrogen, unsubstituted or substituted, unbranched or branched, acyclic, monocyclic or polycyclic, saturated or unsaturated lower alkyl, substituted or unsubstituted aryl or heteroaryl, or
X is O—R3, in which R3 is hydrogen, unsubstituted or substituted, unbranched or branched, saturated or unsaturated, acyclic, monocyclic or polycyclic lower alkyl, or acyl, or
X is sulfonium groups of the formula IV,
 in which R4 and R5 are independently selected from lower alkyl, aryl, or heteroaryl and Y
−
is an anion, or
X is a group of the formula V,
 in which R6 and R7 are independently selected from lower alkyl or aryl or form together a ring and R8 is hydrogen or substituted or unsubstituted lower alkyl and Y
−
is an anion, or
C is a residue of the formula VI and Y
−
is an anion,
[H—N
+
(CH
3
)═CH—CO—OH]Y
−
  Formula VI
D N-methyl-leucine, gamma-hydroxy-N-methyl-leucine, N-methyl-valine, or N-methyl-isoleucine,
E valine,
F N-methyl-leucine,
G alanine,
H glycine, (D)-alanine, (D)-serine, O-hydroxyethyl-(D)-serine,
I,K N-methyl-leucine, and
L N-methyl-valine.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The (E)-2-butenyl-1 rest in A has preferrably the trans configuration.
Examples for lower alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl and its isomers.
Examples for monocyclic lower alkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Examples for polycyclic lower alkyl groups are bicylo[2.1.1]hexyl, norbornyl, bicyclo[2.2.2]octyl.
Examples for unsaturated lower alkyl are vinyl, allyl, butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl.
Examples for substituents in these radicals are hydroxy, methoxy, ethoxy, propoxy, isopropoxy, amino, monoalkylamino, dialkylamino, acylamino, halogen, acyl, carboxy, carbamido.
Examples for monoalkylamino are methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, isopentylamino, tert-pentylamino, neopentylamino, hexylamino and its isomers.
Examples for dialkylamino are N,N-dimethylamino, N-methyl-N-ethylamino, N,N-diethylamino, N-propyl-N-methylamino, N-methyl-N-isopropylamino, dipropylamino, diisopropylamino, N-butyl-N-methylamino and its isomers, N-butyl-N-ethylamino and its isomers, N-butyl-N-propylamino and its isomers, N,N-dibutylamino and its isomers.
The alkyl groups of dialkylamino may also form a ring together. Examples are azetidine, pyrrolidine, piperidine, morpholine, piperazine, N′-alkylpiperazine, azabicylo[2.1.1]hexane, azanorbornane, azabicyclo[2.2.2]octane.
Examples for acyl are formyl, acetyl, propionyl, butyryl, pivaloyl, benzoyl, alkoxycarbonyl.
Examples for acylamino are N-formylamino, N-acetylamino, N-tert-butoxycarbonyl-amino, N-benzyloxycarbonyl-amino, N-benzoyl-amino, N-phthaloyl.
Examples for substituted aryl are tolyl, chlorphenyl, methoxyphenyl, aminophenyl, dimethylaminophenyl, 1-naphthyl, 2-naphthyl.
Examples for heteroaryl are thiazole, oxazole, imidazole, pyridine, pyrazole, pyrimidine, pyrazine, triazine, benzthiazole, benzoxazole, benzimidazole.
Examples of sulfonium groups are dimethylsulfonium, S-methyl-S-phenylsulfonium, S-methyl-S-allylsulfonium, S-methyl-S-carboxamidomethyl-sulfonium, S-dodecyl-S-methylsulfonium.
Examples for groups of the formula V are N-methyl-pyridinium-2-ylthio, N-methyl-pyridinium-4-ylthio, N-methyl-triazinylthio, N-methyl-benzthiazol-2-ylthio, pyridinium-2-ylthio toluenesulfonate, pyridinium-4-ylthio toluenesulfonate, pyridinium-2-ylthio methanesulfonate.
Compounds of the formula I in which C is a sarcosine substituted by S—R2 are prepared by forming polyanions from cyclosporins in which C is sarcosine and reacting these polyanions with appropriate sulfur electrophiles like disulfides, thiolsulfinates, sulfenyl halides, or disulfide-derived sulfonium salts. The polyanions are in turn prepared by treating the cyclosporins in an appropriate solvent at low temperature with an excess of a strong base. Examples for strong bases are alkali amides like lithium amide, natrium amide, lithium diisopropylamide or lithium hexamethyl disilazide. Examples for inert solvents used for these reactions are tetrahydrofurane, dioxane, diethylether, methyl tert-butylether, or liquid ammonia.
Compounds of the formula I in which C is sarcosine substituted by S—R2 are furthermore pre

Affiliated with

Also associated with

Rating

Cyclosporins does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyclosporins, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclosporins will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3140436