Rapamycin derivatives

Details Rapamycin derivatives Rapamycin derivatives

1999-07-19

2001-03-13

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06200985

ABSTRACT:

The present invention relates to rapamycin derivatives, a process for their production, their use as a pharmaceutical and pharmaceutical compositions containing them.
Rapamycin is a known macrolide antibiotic produced by
Streptomyces hygroscopicus,
having the structure depicted in Formula A:
See, e.g., McAlpine, J. B., et al.,
J. Antibiotics
(1991) 44: 688; Schreiber, S. L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat. No. 3,929,992. (There have been various numbering schemes proposed for rapamycin. To avoid confusion, when specific rapamycin derivatives are named herein, the names are given with reference to rapamycin using the numbering scheme of formula A.) Rapamycin is a potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability. Moreover, rapamycin is insoluble and lacks stability, making it difficult to formulate stable galenic compositions.
Numerous derivatives of rapamycin are known. Certain 40-O-substituted rapamycins are described in, e.g., in U.S. Pat. No. 5,258,389 and WO 94/09010 (O-alkyl rapamycins); WO 92/05179 (carboxylic acid esters), U.S. Pat. No. 5,118,677 (amide esters), U.S. Pat. No. 5,118,678 (carbamates), U.S. Pat. No. 5,100,883 (fluorinated esters), U.S. Pat. No. 5,151,413 (acetals), and U.S. Pat. No. 5,120,842 (silyl ethers).
It has now surprisingly been discovered that certain novel derivatives of rapamycin have an improved pharmacologic profile over rapamycin, and exhibit greater stability.
According to the invention, there is provided a compound of Formula I
wherein
R
1
is alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, benzyl, alkoxybenzyl or chlorobenzyl,
R
2
is selected from formula II or formula III:
wherein
R
3
is selected from H, alkyl, alkenyl, alkynyl, aryl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl and alkylsilyl;
R
4
is H, methyl or together with R
3
forms C
2-6
alkylene;
R
5
is R
6
O—CH
2
—, wherein R
6
is selected from H, alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, alkylcarbonyloxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, alkylcarbonylaminoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl and carbalkoxyalkyl;
R
7
CO—, wherein R
7
is selected from H, alkyl, hydroxy, alkoxy, aryloxy, amino, alkylamino, a residue of an amino acid, or N,N-disubstituted-amino wherein the substituents (a) are selected from alkyl, aryl or arylalkyl or (b) form a heterocyclic structure; R
8
NCH—, wherein R
8
is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino; —O—CH—O—; or substituted dioxymethylyne;
Y is selected from O, (H, OH), and (H, OR
9
) wherein R, is selected from C
1-4
alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; and
X is OH or H;
wherein “alk” or “alkyl” refers to a C
1-10
aliphatic substituent optionally interrupted by an oxy linkage; and “ar” or “aryl” refers to a monocyclic, optionally heterocyclic, optionally substituted, C
4-14
aromatic substituent,
provided that, when X is OH, R
1
is alkyl and R
2
is a residue of formula II, then R
3
is other than H.
Any “alk” moiety or “alkyl” mentioned above may be branched, linear or cyclic; preferably it is a C
1-6
aliphatic substituent optionally interrupted by an oxy linkage, more preferably uninterrupted by oxy.
Examples of “ar” moiety or “aryl” mentioned above and optionally substituted may include e.g. phenyl, benzyl, tolyl, pyridyl and the like.
When R
1
is chlorobenzyl or alkoxybenzyl, the substituent is preferably in ortho.
When R
7
CO— is N,N-disubstituted-carbamoyl, it may be e.g. N-methy1-N-(2-pyridin-2-yl-ethyl)-carbamoyl, (4-methyl-piperazin-1-yl)-carbonyl or (morpholinyl)carbonyl.
When R
5
is substituted dioxymethylyne, it may be e.g. O,O-(alkylene)-dioxy-methylyne, i.e. wherein the 2 oxygens are linked by an alkylene group.
In the compounds of formula I, the following significances are preferred either individually or in any combination or sub-combination:
1. X is OH and R, is C
3-10
alkynyl or C
3-10
hydroxyalkynyl, preferably C
3-10
-alk-2-ynyl or C
3-10
hydroxyalk-2-ynyl, more preferably C
3-6
alk-2-ynyl;
2. X is H and R
1
is C
1-10
alkyl, C
3-10
alk-2-enyl, C
3-10
hydroxyalk-2-enyl, C
3-10
alk-2-ynyl, C
3-10
hydroxyalk-2-ynyl or C
1-10
alkoxyC
1-10
alkyl, preferably C
1-6
alkyl or C
3-6
alk-2-ynyl, more preferably C
1-4
alkyl, most preferably methyl;
3. C
3-6
alkynyl as R
1
is 2-propynyl or pent-2-ynyl, preferably pent-2-ynyl;
4. Y is O, (H, OH) or (H, C
1-4
alkoxy), preferably O;
5. R
2
is a residue of formula II;
6. In the residue of formula II, R
3
is H, C
1-6
hydroxyalkyl, hydroxy-C
1-6
alkoxy-C
1-6
alkyl, (C
1-6
alkyl)-carbonyl-amino-C
1-6
-alkyl, C
1-6
alkoxy-C
1-6
alkoxy or amino-C
1-6
alkyl, preferably H, hydroxyethyl, hydroxypropyl, hydroxyethoxyethyl, methoxyethyl or acetylaminoethyl; especially H when X is H or when X is OH and R
1
is alkynyl;
7. In the residue of formula II, R
4
is methyl.
8. R
2
is a residue of formula III wherein R
5
is R
6
OCH
2
— wherein R
6
is selected from H, C
1-6
alkyl, C
3-6
alk-2-enyl, C
3-6
alk-2-ynyl, aryl; C
1-6
alkyl-carbonyl, arylcarbonyl, hydroxyC
1-6
alkyl, C
1-6
alkoxy-C
1-6
alkyl or aminoC
1-6
alkyl; R
7
CO— wherein R
7
is selected from H, hydroxy, C
1-6
alkoxy, amino, C
1-6
alkylamino, a residue of an amino acid or N,N-disubstituted amino wherein the substituents (a) are selected from C
1-6
alkyl or aryl or (b) form a heterocyclic structure; R
8
NCH— wherein R
8
is alkyl, aryl, amino, alkylamino, arylamino, hydroxy, alkoxy or arylsulfonylamino; —O—CH—O—; or substituted dioxymethylyne.
Preferred compounds are compounds of formula Ia
wherein R
1
, R
2
and Y are as defined above, preferably have any of the preferred significances given under 1. and 3. to 8. above;
and of formula Ib
wherein R
1
, R
2
and Y are as defined above, preferably have any of the preferred significances given under 2. to 8. above.
Especially preferred compounds include
(i) 32-deoxo-rapamycin;
(ii) 16-O-pent-2-ynyl-32deoxo-rapamycin;
(iii) 16-O-pent-2-ynyl-32-deoxo40-O-(2-hydroxy-ethyl)rapamycin
(iv) 16-O-pent-2-ynyl-32(S)-dihydro-rapamycin;
(v) 16-O-pent-2-ynyl-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin;
(vi) 32(S)-dihydro-40-O-(2-methoxyethyl-rapamycin;
(vii) 32(S)-dihydro-40O-(2-hydroxyethyl)rapamycin.
Compounds of formula I may exhibit isomerism and accordingly further isomeric forms will exist. It will be understood that the present invention embraces compounds of formula I, the individual isomers of formula I′
wherein R
1
, R
2
, Y and X are as defined above, as well as isomeric mixtures thereof.
The individual isomers may be separated by analogy to methods known in the art.
The present invention also provides a process for the production of the compounds of formula I which process comprises
a) to produce a compound of formula I wherein X is H, reductively eliminating the carbonyl in position 32 of a compound of formula IVa
wherein R
1
, R
2
and Y are as defined above, in protected or unprotected form,
and, where required, removing the protecting groups present; or
b) to produce a compound of formula I wherein X is OH, stereoselectively reducing the carbonyl in position 32 of a compound of formula IVa as defined above; or
c) converting a compound of formula I wherein R
1
is alkyl to provide a compound of formula I wherein R
1
is other than alkyl.
In process step a),

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