CA1159054A - Acyl derivatives of rapamycin - Google Patents

Acyl derivatives of rapamycin

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Publication number
CA1159054A
CA1159054A CA000382848A CA382848A CA1159054A CA 1159054 A CA1159054 A CA 1159054A CA 000382848 A CA000382848 A CA 000382848A CA 382848 A CA382848 A CA 382848A CA 1159054 A CA1159054 A CA 1159054A
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Prior art keywords
rapamycin
carbon atoms
mono
halo
disubstituted
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CA000382848A
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French (fr)
Inventor
Sumanas Rakhit
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Wyeth Canada Inc
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Ayerst Mckenna and Harrison Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

Disclosed are monoacyl and diacyl derivatives of rapamycin, processes for their preparation, methods of using the derivatives and pharma-ceutical compositions of the derivatives. The derivatives are useful, inter alia, as antifungal antibiotics.

Description

1 1 5905ll ACYL DERIVATIVES OF RAPAMYCIN
~e~
This invention relates to novel monoacyl and diacyl derivatives of rapamyein, to processes for their preparation, to methods of using the 5 derivatives and to pharmaceutical compositions of the derivatives. The derivatives are useful as antifungal antibiotics.
Rapamycin is an antifungal antibiotic described by C. Vezina et al, J. Antibiot., 28, 721(1975), S.N. Sehgal et aL, J. Antibiot., 28, 727 (1975), S.N. Sehgal et al., U.S. Patent 3,929,992, issued December 30,1975 lQ and S~N. Sehgal et al., U.S. Patent 3,993,749, issued November 23,1976.
The structure of rapamycin is described by D.C. Neil, et al., Can. J. Chem., 56, 2491 (1978). Rapamycin is e2ctracted from a streptomycete (Streptomyces hygroscopicus) isoIated from an Easter Island soil sample and is particularly effective against Candida albicans both in vitro and in vivo, H.A. Baker __ _ ._ et al., J. Antibiot., 31, 539 (1978). A report by R.R. Martel et al, Can. J.
Physiol., 55, 48 (1977) describes the use of rapamycin for the prevention OI the development of experimental immunopathies. Recently, rapamycin was shown to be an effective agent for treating carcinogenic tumors in a mammal by S.N. Sehgal and C. Ve~ina, Belgium Patent No. 877,700, January
2~ 1~, 1980.
Summary of the Invention The compounds of this invention are monoacyl or diacyl derivatives of rapamycin wherein the acyl is selected from the group of a]iphatic acyl having 1 to 10 carbon atoms; benzoyl; benzoyl mono- or disubstituted with 25 lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl sub-stituted aliphatic acyl wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is ~msubstituted or mono- or disubstituted with lower alkyl~ halo, lower alkoxy, hydroxy or trifluoromethyl.
Preferred compounds of this invention are monoacyl or diacyl 30 derivatives of rapamycin wherein the acyl is selected from an aliphatic acyl having 2 to 6 carbon atoms.

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An antifungal composition is provided by combining an antifungally effective amount of the monoacyl or diacyl derivative of rapamycin with a pharmaceutically acceptable cerrier.
The monoacyl and diacyl derivatives of rapamycin inhibit the growth of pathogenic fungi in a mammal by administering to the mamm~l an effective antifung~l amount of the monoacyl or diacyl derivative of rapa-mycin.
Detailed Description of the Invention The term '~ower ~lkyl" as used herein means straight chain alkyl radicals containing from one to six carbon atoms and branched chain alkyl radicals containing from three to four carbon atoms and includes methyl, ethyl, propyl9 1-methylethyl, butyl, l,l~imethylethyl, pentyl, hexyl and the like.
The term '~ower alkoxy" as used herein means straight chain alkoxy radicals containing from one to six carbon atoms and branched chain alkoxy radicals containing three or four carbon atoms and includes methoxy, ethoxy, l-methylethoxy, butoxy, hexanoxy and the like.
The term "halot' as used herein means halogens and includes fluorine, chlorine, bromine and iodine, unless stated otAerwise.
The term "aliphatic acyl" as used herein means straight chain l-oxoalkyl raàicals containing from one to ten carbon ~toms and branched chain l-oxoalkyl radicals containing four to ten ~arbon atoms and includes formyl, acetyl, l-oxopropyl, l-oxobutyl, 292-dimethyl-l-oxopropyl, I-oxohexyl, l-ox~3-ethylpentyl and the like.
The term "organic proton acceptor" as used herein means the organic bases or amines, for instancey triethylamine, wridine, N-ethylmor-pholine, 1~5-diazabicyclo[4.3.0] non-5-ene and the like.
The monoacyl end diacyl derivatives of rapamycin are useful as antifungal agents against pathogenic fungi; for example, Candida albicans.
30 The inhibitory activity of the derivatives are especially pronounced against Candida albicans. Against this fungi, the monoacetyl derivative exhibits a MIC of 0!04 mcg/ml and the diacetyl derivative exhibits a MIC of 2.5 mcg/ml.

.~ . ..

1 lS~O~i~
-3- A~IP-~681 The antifungal activity of the derivatives are demonstrated in standard tests used for this purpose, for example, in the tests described in "Antiseptics, Disinfectants, Fungicides and Sterilization", G.~. Reddish, Ed., 2nd ed., Lea and Febiger, Philadelphia, 1957 or by D.C:. Grove and W.A.
Randall in "Assay Methods of Antibiotics", Med. Encycl. Inc.~ New York 1955.
Wnen the rapamycin derivative of this invention is employed as an antifungal agent in a mammal, it can be used alone or in ~ombination with pharmaceuti~ally acceptable carriers, the proportion of which is deter-mined by the solubility and chemical nat~re of the compound, chosen route of administration and standard biological practice. For example, an antifungallye~fective amount of the derivative c~n be administered orall~ in solid form containing such excipients as starch, sugar, certain types of clay and so forth. SimilarIy, such an amount can be administered oral~y in the form of solutions or suspensions, or the derivative can be injected parenterally.
~or parenteral administration the derivative can be used in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isot~nic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 ~oleate esters of sorbitol and its anhydrides copolymer}æed with ethylene oxide) and the like.
The dosage of the present derivative wilI vary with the form of administration and the particular derivative chosen. ~urthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small dosages substantially less than the ~?timum dose of the derivative. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In genersl, the derivative of this invention is most desirably administered at a concen-tration level that will generally afford antifungally effe~tive resu}ts without causing any harrnful or deleterious side effects ~nd prefer~bly at a level that is in a range of from about 1.0 mg to about 250 mg per kilo per day, although as aforementioned variations will occur. However, a dosage level .

l 1~9~5~
-4- AHP-7681 that is in the range of from about 10 mg to about lOû mg per kilo per day is most desirably employed in order to achieve effective results.
In addition, the derivative can be employed topically. For to~ical application it may be formldated in the form of solùtions, creams or lotions
5 in pharmaceutically acceptable vehicles containing 0.1- 5 per cent, preferably2 per cent of the agent, and may be administered topically to the infected area of the skin.
The derivative also can be used for cleaning and disinfecting laboratory equipment, surgical instruments, locker rooms, or shower rooms 10 of sensitive fungus organisms. For such purposes it is preferred to use 0.1-10% solutions of the derivative in a lower alkanol, preferably methanol, diluted with 10 -100 volumes of water containing 0.001- 0.1% of a non-ionic surface-active agent, for example, Polysorbate* 80 U.S.P., immediately before applying it to the objects to be cleaned and disinfected.
In addition to use as an antifungal agent, the monoacyl and diacyI
derivatives of rapamycin can be useful as anticancer or antitumor ugents.
The derivatives can be used to treat carcinogenic tumors in a marnmal by administering to the mammal an antitumor effective amount of the derivative.
More specifically, the derivatives can reduce tumor size in and prolong sur-20 vival time of a tumor bearing mammal. The effectiveness of the derivatives in this respect can be demonstrated in the laboratory with rodents having transplanted tumors. Details of methods used to evaluate this effect are described in various publications; for example, R.I. ~eran et al., Cancer Chemother. Rep., Part 3, 3, (No. 2)1-103 (1972) and references therein.
25 In addition, the protocols for the antitumor tests are available from the National Cancer ~stitute, Bethesda, Maryl~nd, U.S.A. The mode of adminis-tration and compositions of the derivatives are similar to those described above for antifungal use.
The acyl derivatives of rapamycin are prepared by the acylation 30 of rapamycin. Acylation of rapamycin with an acylating agent selected from an alkanoyl iodide, bromide or chloride having two to ten carbon atoms, benzoyl bromide or chloride, benzoyl bromide or chloride mono- or disubstituted * Trademark I .,.
:

~ 15g~54 with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, or phenyl substituted alkanoyl bromide or chloride wherein the alkanoyl po~tion has two to ten carbon atoms and the phenyl is unsubstituted or mon~ or disub-stituted with lower aL'cyl, halo, lower alkoxy, hydroxy or trifluoromethyl 5 in the presence of an organic proton acceptor, preferably triethylamine or pyridine, at 0 to 50 C for 0.5 to 10 hours gives the corresponding monoacyl or diacyl derivative of rapamycin wherein the acyl portion contains two to ten carbon atoms. Replacement of the above described acylating agent with the corresponding anhydride also gives the corresponding monoacyl 10 or diacyl derivative of rapamycin. The above acylations can be conducted in an inert organic solvent such as benzene, chloroform or dichloromethane or an excess OI the organic proton acceptor can serve as the sol~ent. In the case of preparing the mono- and diformyl derivative, a preferred reagent is formic acetic anhydride ~prepared from acetic anhydride and I`ormic aeid)~
15 The formyl derivatives can also be obtained by the use of formic ~cid in the presence of ~ acid catalyst, fvr instance, ~toluenes~~ acid, sulfuric acid or perchloric acid. Use of about 0.7 to 1.5 molar equivalents of the acylating agent gives a separable mixture of the monoacyl and diacyl deri-vatives wherein the monoacyl derivative predominates whereas use of about 20 1.5 to 5 molar equivalents of the acylating agent gives a separable mixture of the monoacyl and diacyl derivatives wherein the diacyl derivative pr~
dominates. When the acylation involves acetylation, a preferred method of acetylation is the reaction of rapamycin with acetic anhydride rn an excess of the organic proton acceptor at 0 to 10 C for about one to three hours 25 to obtain a separable mixture of the monoacetyl and diacetyI derivatives of rapamycin.
The following example illustrates further this invention.

Monoacetyl and Di~ce~l Derivatives of Rapamycin A solution of 300 mg of rapamycin in 5 ml of dry pyridine was cooled in an ice bath. To this solution, 2.5 ml of acetic anhydride was added and the mixture was stirred at 0 to 5 C for 2 hr. The excess of anhydride was decomposed by careful addition of methanol ~d the mixture was poured into ice containing 2N hydrochloric acid. The precipitated solids were extr~ctedwith ethyl acetate. The ethyl acetate extract was washed with wat~r, dried ~ 1~905~

over sodium sul~ate and evaporated. The oily residue was chromatographed over silica gel using 20% ethyI acetate in benzene. The appropriate initial fractions were collected, evapor~ted and crystallized from chloroform-hexsne to give rapamycin diacetate (0.165 g): mp 92-93 C; ir (CHCI3) 3400,1730, 1640 and 1620 cm 1; uv max ~MeOH) 288 ( ~= 366), 227 (~ = 484) and 267 nm (~ = 363); and nmr (CDC13) ~ 2.05 (s, 3H). The appropriate later fractions were collected, evaporated and crystallized from ben2ene-hexane to give rapamycin monoacetate (0.058 g): mp 101-102 C; ir (CHC13) 3400,1730,1640 and 162û ¢m 1; uv max (MeOH) 288 ( ~ = 374)9 277 ( ~ = 49~? and 267 nm (~ - 372); ~nd nmr (CDC13) ~ 2.05 (s, 3H3 and 2.1 (s, 3H).

Claims (12)

-7- AHP-7681 (Canada) The embodiments of this invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for preparing a monoacyl or diacyl derivative of rapamycin wherein the acyl is selected from the group of aliphatic acyl having 1 to 10 carbon atoms; benzoyl; benzoyl mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl; and phenyl substituted aliphatic acyl wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl; which comprises one of the following processes:
(a) acylating rapamycin in the presence of a proton acceptor with an acylating agent selected from an alkanoyl iodide, bromide or chloride having 2 to 10 carbon atoms, benzoyl bromide or chloride, benzoyl bromide or chloride mono- or disubstituted with lower alkyl halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted alkanoyl bromide or chloride wherein the alkanoyl portion has two to ten carbon atoms and the phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy, or trifluoromethyl to obtain the corresponding monoacyl or diacyl derivative of rapamycin wherein the acyl is selected from aliphatic acyl having 2 to 10 carbon atoms, benzoyl, benzoyl mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted aliphatic acyl wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono-or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl;
(b) acylating rapamycin in the presence of an organic acceptor with an acylating agent selected from a lower alkanoic acid anhydride in which the alkanoyl portions each have 2 to 10 carbon atoms, benzoic acid anhydride, benzoic acid anhydride in which each phenyl portion thereof is mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or tri-fluoromethyl, and a phenyl substituted alkanoic acid anhydride wherein each alkanoyl portion has 2 to 10 carbon atoms and each phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl to obtain the corresponding monoacyl or diacyl derivative of rapamycin wherein the acyl is selected from aliphatic acyl having 2 to 10 carbon atoms, benzoyl, benzoyl mono- disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted aliphatic acyl wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl; or (c) acylating rapamycin with formic acetic anhydride, or formic acid in the presence of an acid catalyst, to obtain the monoformyl or diformyl derivative of rapamycin.
2. The process of claim 1 for preparing the monoacyl or diacyl derivative of rapamycin wherein the acyl is selected from aliphatic acyl having 2 to 10 carbon atoms, benzoyl, benzoyl mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted aliphatic acyl, wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl wherein the acylating agent is selected from an alkanoyl iodide, bromide or chloride having 2 to 10 carbon atoms, benzoyl bromide or chloride, benzoyl bromide or chloride mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted alkanoyl bromide or chloride wherein the alkanoyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono-or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoro-methyl.
3. The process of claim 1 for preparing monoacyl or diacyl derivative of rapamycin wherein the acyl is selected from aliphatic acyl having 2 to 10 carbon atoms, benzoyl, benzoyl mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted aliphatic acyl wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, wherein the acylating agent is selected from a lower alkanoic acid anhydride in which the alkanoyl portions each have 2 to 10 carbon atoms, benzoic acid anhydride, benzoic acid anhydride in which each phenyl portion thereof is mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and a phenyl substituted alkanoic acid anhydride wherein each alkanoyl portion has 2 to 10 carbon atoms and each phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl to obtain the corresponding mono-acyl or diacyl derivative of rapamycin wherein the acyl is selected from ali-phatic acyl having 2 to 10 carbon atoms, benzoyl, benzoyl mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, and phenyl substituted aliphatic acyl wherein the aliphatic acyl portion has 2 to 10 carbon atoms and the phenyl is unsubstituted or mono- or disubstituted with lower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl.
4. The process of claim 1 for preparing the monoformyl or diformyl derivative of rapamycin wherein the acylating agent is formic acetic anhydride, or formic acid in the presence of an acid catalyst.
5. The process of claim 1 for preparing a monoacyl or diacyl de-rivative of rapamycin wherein the acyl is an aliphatic acyl having 2 to 6 carbon atoms and the acylating agent is selected from an alkanoyl iodide, bromide or chloride having 2 to 6 carbon atoms and a lower alkanoic acid anhydride in which the alkanoyl portions each have 2 to 10 carbon atoms.
6. The process of claim 1 for preparing rapamycin monoacetate or rapamycin diacetate wherein the acylating agent is acetic anhydride.
7. A monoacyl or diacyl derivative of rapamycin, as defined in claim 1, when prepared by the process of claim 1 or an obvious chemical equivalent thereof.
8. A monoacyl or diacyl derivative of rapamycin, as defined in claim 2, when prepared by the process of claim 2 or an obvious chemical equivalent thereof.
9. A monoacyl or diacyl derivative of rapamycin, as defined in claim 3, when prepared by the process of claim 3 or an obvious chemical equivalent thereof.
10. The monoformyl ordiformyl derivatives of rapamycin when prepared by the process of claim 4 or an obvious chemical equivalent thereof.
11. A monoacyl or diacyl derivative of rapamycin wherein the acyl is an aliphatic acyl having 2 to 6 carbon atoms when prepared by the process of claim 5 or an obvious chemical equivalent thereof.
12. Rapamycin monoacetate or rapamycin diacetate when prepared by the process of claim 6 or an obvious chemical equivalent thereof.
CA000382848A 1980-08-25 1981-07-30 Acyl derivatives of rapamycin Expired CA1159054A (en)

Applications Claiming Priority (2)

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US06/181,252 US4316885A (en) 1980-08-25 1980-08-25 Acyl derivatives of rapamycin
US181,252 1980-08-25

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EP (1) EP0046661B1 (en)
JP (1) JPS57118586A (en)
AT (1) ATE7920T1 (en)
CA (1) CA1159054A (en)
DE (1) DE3164177D1 (en)
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