WO1991002736A1 - Macrocyclic compounds - Google Patents

Macrocyclic compounds

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Publication number
WO1991002736A1
WO1991002736A1 PCT/GB1990/001262 GB9001262W WO1991002736A1 WO 1991002736 A1 WO1991002736 A1 WO 1991002736A1 GB 9001262 W GB9001262 W GB 9001262W WO 1991002736 A1 WO1991002736 A1 WO 1991002736A1
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WO
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Patent type
Prior art keywords
dioxa
tetramethyl
compound
dimethoxy
ll
Prior art date
Application number
PCT/GB1990/001262
Other languages
French (fr)
Inventor
David Keith Donald
David Norman Hardern
Martin Edward Cooper
Mark Furber
Masashi Hashimoto
Chiyoshi Kasahara
Takehiko Ohkawa
Original Assignee
Fisons Plc
Fujisawa Pharmaceutical Co., Ltd.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic 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
    • C07D498/18Bridged systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

Abstract

Compounds of formula (I) are described, wherein R1 represents H, OH, alkoxy or R?7COO-; R2¿ represents H; in addition, R?1 and R2¿ may together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R3 represents methyl, ethyl, propyl or allyl; R4 represents OH or alkoxy; R5 represents OH or methoxy; R6 represents OH, alkoxy or R8COO-; in wich R?7 and R8¿ have various significances including alkyl, aryl, NH¿2?, arylamino and alkylamino; and n represents 1 or 2; provided that when n is 1, then R?3¿ is allyl or propyl. Processes for their production and compositions containing them, e.g. for use as immunosuppressive agents, are also described.

Description

MACROCYCLIC COMPOUNDS

This invention relates to novel macrocyclic compounds, more particularly to novel macrocyclic immunosuppressive compounds, processes for their preparation, their use as 5 medicaments, and compositions containing them.

European Patent Application 184162 (to Fujisawa Pharmaceuticals Co Ltd) discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomvces. The macrolides are numbered FR-900506, 0 FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described.

International Patent Application WO 89/05304 (to Fisons pic) , European Patent Application 353678 (to Fujisawa Pharmaceuticals Co Ltd) , European Patent •jc Applications 349049 and 349061 (to Merck & Co Inc) and European Patent Application 356399 (to Sandoz AG) also disclose a number of macrocyclic immunosuppressant compounds.

We have now found a novel group of compounds which 2 possess certain advantageous properties over those disclosed previously.

Thus, according to the invention, we provide a compound of formula I,

25

OCH3 OCH3

wherein

R1 represents H, OH, alkoxy or R7COO-;

R2 represents H; in addition, R1 and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;

R3 represents methyl, ethyl, propyl or allyl;

R4 represents OH or alkoxy;

R5 represents OH or methoxy;

R6 represents OH, alkoxy or R8COO-; in which R7 and R8 independently represent alkyl; aryl; NH2; a 5- or 6-membered heterocyclic ring optionally substituted by alkyl or aryl; arylamino; alkylamino; N,N-dialkylamino; N,N-diarylamino; or N-alkyl-N-arylamino; each alkyl group optionally being substituted by aryl, OH, N02 or halogen; and each aryl group optionally being substituted by alkyl, OH, N02 or halogen; and n represents 1 or 2; provided that when n is 1, then R3 is allyl or propyl.

When any one of R , R , R5 and R6 represents a carbon containing group, that group preferably contains from 1 to 10 carbon atoms, more preferably from 1 to 6.

The term "alkyl" as used herein includes cyclic and branched alkyl groups, as well as straight chain alkyl groups. Preferably, R3 is ethyl.

We prefer at least one of R1 and R6 to represent OH.

When R7 or R8 is present, we prefer those groups to be selected from alkyl; NH2; piperidino; morpholino; aryl optionally substituted by halogen or OH; arylamino optionally substituted by halogen or OH; or alkylamino optionally substituted by OH; for example methyl or phenylamino.

Alkoxy groups which R1, R4 or R6 may represent Q include methoxy.

Aryl groups which R7 or R8 may comprise include phenyl.

According to the invention, we also provide a process for the production of a compound of formula I, which 5 comprises: a) selective reduction of the C2-carbonyl group in a compound of formula II,

OCH- OCH3

wherein R1 to R and n are as defined above, or b) addition of a compound of formula R4-H, wherein R4 is as defined above, across the Cl alkene group in a compound of formula III,

0CH-, OCH. wherein to R- RD and n are as defined above. In process (a) , the reduction may be achieved by the action of H2S, preferably in the presence of pyridine or an amine (for example morpholine) , in a solvent which does not adversely affect the reaction (for example dimethylformamide, pyridine or methanol) , at or around room temperature.

The preparation of many compounds of formula II is fully described in the patent applications mentioned above. Alternatively, the total synthesis of FR-900506 disclosed in European Patent Application 378318 (to Merck & Co Inc) may be modified where necessary to produce compounds of formula II. The teaching of the documents mentioned above is herein incorporated by reference.

In process (b) , the addition of water across the Cl-alkene group may be achieved by the action of dilute agueous acid (for example dilute hydrochloric acid) , in a solvent which does not adversely affect the reaction (for example water, methanol, ethanol, pyridine, ethyl acetate, dimethylformamide, dichloromethane or a mixture thereof) , at or around room temperature. The addition of an alcohol may be achieved in the presence of a small amount of acid

(for example p-toluenesulphonic acid) , in a solvent which does not adversely affect the reaction (for example the alcohol to be added, pyridine, ethyl acetate, dimethylformamide, dichloromethane or a mixture thereof) , at or around room temperature.

Compounds of formula III may be prepared from compounds of formula IV,

OCH3 0CH3

wherein R1 to R3, R5, and n are as defined above, by reduction, which may be achieved using tributyltin hydride, preferably in the presence of a catalytic amount of 2,2'-azobisisobutyronitrile, in a solvent which does not adversely affect the reaction conditions, for example anhydrous toluene, at a temperature of from room temperature to solvent reflux temperature.

Compounds of formula IV may be prepared from compounds o formula V,

wherein R1 to R3, R5, R6 and n are as defined above, by reaction with O-phenyl chlorothioformate, in a solvent which does not adversely affect the reaction (for example acetonitrile) , optionally in the presence of dimethylaminopyridine, at or around room temperature.

Compounds of formula V may be prepared from compounds of formula II, as defined above, by reduction. The reduction may be achieved using zinc powder in acetic acid at or around room temperature.

When R6 represents or comprises an OH group in the desired compound of formula I, we prefer to use process (a) to produce it.

The group R8COO- may be formed in a starting compound of formula II in which R6 represents OH using conventional techniques, for example: i) when R8 represents alkyl or aryl, an esterification reaction with an appropriate alkanoic acid or aromatic carboxylic acid may be employed, or a derivative thereof such as an acid chloride or acid anhydride; ii) when R8 represents alkylamino or arylamino, reaction with an appropriate alkyl or aryl isocyanate; alternatively a reactive intermediate may first be formed with a compound such as p-nitrophenyl chloroformate, followed by reaction with the appropriate amine compound. This latter method may be employed when R8 is NH2.

Similarly, R7COO- groups may be formed in a starting compound of formula II in which R1 represents OH. This reaction may occur simultaneously with the formation of R8COO- groups as described above, in which case R7 and R8 will be the same. Of course, where necessary, the OH group that R1 or R6 represents may be protected using conventional protecting group chemistry [as described in "Protective Groups in Organic Chemistry", ed: J W F McOmie, Plenum Press (1973) , and "Protective Groups in Organic Synthesis", T W Greene, Wiley-Interscience (1981)], to ensure that R7 and R8 are different, or to allow one or other of R1 and R6 to be deprotected to OH after formation of the C2-methylene group or formation of the R7COO- or R8COO- group.

When process (a) is employed, R7COO- or R8COO- groups may be introduced before or after the reduction step.

In order to produce a compound of formula I in which R1 and R2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached. the double bond may be introduced by dehydration of a corresponding compound of formula I in which R1 represents OH and R2 represents H, or a starting comσund may be used which already contains the group. Such a dehydration may be carried out in a solvent which does not adversely affect the reaction (eg toluene) , in the presence of a trace amount of acid (eg p-toluenesulphonic acid) , at a temperature of from 50 to 100βC.

The compounds of formula I may be isolated from their reaction mixtures using conventional techniques.

The compounds of formula I are useful because they possess pharmacological activity in animals; in particular they are useful because they possess immunosuppressive activity, eg in the tests set out in Tests A, B and C. Thus the compounds are indicated for use in the treatment or prevention of resistance to transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin, cornea, etc; and of autoimmune, inflammatory, proliferative and hyperproliferative diseases, and of cutaneous manifestations of immunologically-mediated diseases: for example rheumatoid arthritis, lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitides, seborrheic dermatitis. Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias. Alopecia areata , etc .

The compounds of the invention are also indicated in the treatment of reversible obstructive airways disease.

Further, the compounds of the invention are indicated in the treatment of a disease selected from intestinal inflammations/allergies such as Coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; and food related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract, for example migraine, rhinitis and eczema.

The compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic microorganisms and the like.

We therefore provide the use of compounds of formula I as pharmaceuticals.

Further, we provide the use of a compound of formula I in the manufacture of a medicament for use as an immunosuppressive agent.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired (eg topical, parenteral or oral) and the disease indicated. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from 0.001 to 20mg per kg of animal body weight.

For man the indicated total daily dosage is in the range of from O.Olmg to lOOOmg and preferably from 0.5mg to lOOmg, which may be administered, for example twice weekly, or in divided doses from 1 to 6 times a day or in sustained release form. Thus unit dosage forms suitable for administration, eg oesophageally, comprise from O.Olmg to 500mg, and preferably 0.5mg to lOOmg of the compound preferably admixed with a solid or liquid pharmaceutically acceptable diluent, carrier or adjuvant.

According to our invention we also provide a pharmaceutical composition comprising preferably less than 80%, and more preferably less than 50% by weight, of a compound of fomula I in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes; and for inhalation compositions - coarse lactose. The compound of formula I preferably is in a form having a mass median diameter of from 0.01 to 10/xm. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol) , sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form. For the treatment of reversible obstructive airways disease, we prefer the compound of formula I to be administered by inhalation to the lung, especially in the form of a powder. According to a further aspect of the invention, there is provided a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula I, as defined above, to a patient.

The compounds of formula I have the advantage that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed or have other useful pharmacological properties, than compounds previously used in the therapeutic fields mentioned above.

The compounds of formula I have a number of chiral centres and may exist in a variety of stereoisomers. The invention provides all optical and stereoisomers, as well as racemic mixtures. The isomers may be resolved or separated by conventional techniques.

However, the preferred stereochemistry of various chiral carbon atoms are shown in formula la.

wherein R1 to R6 and n are as first defined above. Test A Mixed Lymphocyte Reaction (MLR) I

The MLR test was performed in microtitre plates, with each well containing 5 x 105 C57BL/6 responder cells (H-2b) , 5 x 105 mitomycin C treated (25μg/ml mitomycin C at 37βC for 30 minutes and washed three times with RPMI 1640 medium) BALB/C stimulator cells (H-2d) in 0.2ml RPMI 1640 medium supplemented with 10% fetal calf serum, 2mM sodium hydrogen carbonate, penicillin (50/_g/ml) and streptomycin (50μg/ml) . The cells wer incubated at 37βC in a humidified atmosphere of 5% carbon dioxide and 95% of air for 68 hours and pulsed with 3H-thymidine (0.5μCi) 4 hours before the cells were collected. The object compound of this invention was dissolved in ethanol and further diluted in RPMI 1640 medium and added to the cultures to give final concentrations of O.lμg/ml or less.

Test B

Mixed Lymphocyte Reaction fMLR) II The MLR test was performed in 96-well microtitre plates with each well containing 3 x 105 cells from each of two responding donors in a final volume of 0.2ml RPMI 1640 medium supplemented with 10% human serum, L-glutamine and penicillin/streptomycin. The compound under test was dissolved at lOmg/ml in ethanol and further diluted in RPMI 1640. The cells were incubated at 37βC in a humidified atmosphere at 5% carbon dioxide for 96 hours. 3H-thymidine (O.δμCi) was added for the final 24 hours of the incubation to provide a measure of proliferation. Test C

Graft versus Host Assay fGVH)

Spleen cells from DA and DAxLewis Fl hybrid rats were prepared at approximately 108 cells/ml. 0.1ml of these suspensions were injected into the rear footpads of DAxLewis Fl rats (left and right respectively) . Recipient animals aere dosed with the compound under test, either orally or subcutaneously, on days 0-4. The assay is terminated on day 7 when the popliteal lymph nodes of the animals are removed and weighed. The increase in weight of the left node relative to the wieght of the right is a measure of the GVH response.

The invention is illustrated, but in no way limited by, the following Examples. Example l

14-Acetoxγ-12-f2-(4-acetoxy-3-methoxycyclohexyl)-1- methγlvinγll-17-allyl-l-hydroxy-23.25-dimethoxy-13.19,21.27- tetramethyl-11.28-dioxa-4-azatricvclor22.3.1.04' 1octacos- 5 18-ene-3.10.16-trione a) 1 -Acetoxy-12-r2- (4-acetoxy-3-methoxycyclohexyl)-1- ethylvinyl ~-17-allyl-l.2-dihydroxy-23.25-dimethoxy-

13.19.21,27-tetramethyl-ll,28-dioxa-4-azatricγclo f22.3.1.0 '9loctacos-18-ene-3.10.16-trione 0 To a solution of 14-acetoxy-12-[2-(4-acetoxy-

3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-l-hydroxy- 23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4- azatπcyclo[22.3.1.0*' ]octacos-18-ene-2,3,10,16-tetraone (the first compound of Example 6, EP 184162) (5.4g) in 5 acetic acid (120ml) was added zinc powder (25g) portionwise and the suspension was vigorously stirred for 13 hours at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a pale yellow powder (4.48g). lg of the powder was purified by 0 silica gel column chromatography eluting first with ethyl acetate/hexane [1:1] then ethyl acetate to give the subtitle compound (486mg) as white powder. MS (FAB): 912 (M+Na)+ mp: 93-96βC

25 13C NMR (CDC13) S : 207.7, 206.3, 172.9, 170.9, 170.1, 170.0, 169.9, 169.4, 169.3, 99.1, 97.1, 68.1 b) l4-Acetoxy-12-r2-(4-acetoχy-3-methoxycyclohexγl)-l- ethylvinyl1-17-allyl-23.25-dimethoxy-13.19.21.27- tetramethγl-1.2-thiooxomethγlenedioxy-ll.28-dioxa-4- azatricyclor22.3.1.04 '9]octacos-18-ene-3.10.16-trione To a mixture of the product of step (a) (243mg) and dimethylaminopyridine (333mg) in anhydrous acetonitrile (5ml) was added O-phenyl chlorothiofor ate (68.7mg) and the reaction was stirred for 15 minutes at ambient temperature. The solution was diluted with diethyl ether (15ml) and washed with brine, dried (MgS04) , and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane [1:1] to give the subtitle compound (240 mg) . MS (FAB): 954 (M+Na)+

13C NMR (CDC13) δ: 207.6, 188.4, 170.3, 169.6, 168.9, 161.4, 111.7, 54.7, 52.4 c) 14-Acetoxy-12-r2- (4-acetoxy-3-methoxycyclohexγl)-1- methylvinyl]-17-allyl-23.25-dimethoxy-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricvclo[22.3.1.0 '91octacosa -1.18-diene-3.10.16-trione To a mixture of the product of step (b) (486mg) and 2,2•-azobisisobutyronitrile (catalytic amount) in anhydrous toluene (9ml) was added tributyltin hydride (0.8ml) and the reaction mixture was heated at reflux for 15 minutes. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane [1:1] to give the subtitle compound (188mg) . MS (FAB): 973 (M+Na)+ 13C NMR (CDCI3) δ : 207.3, 172.0, 170.3, 170.2, 169 . 5 , 168 . 0 , 95. 7 , 55. 8 , 36 . 2 d) 14-Acetoxy-12-r2-(4-acetoxy-3-methoxycyclohexyl)-1- methylvinyl1-17-allyl-l-hvdroxy-23.25-dimethoxy-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclof22.3.1.04 91octacos- 18-ene-3.10.16-trione

The product of step (c) (lOOmg) was dissolved in a mixture of IN aqueous hydrochloric acid (0.2ml) and methanol (0.5ml). The solution was allowed to stand at ambient temperature for 16 hours and then the solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel eluting with ethyl acetate/hexane [1:2] to give the title compound (67mg) . MS (FAB): 896 (M+Na)+

13C NMR (CDC13) 5: 208.1, 173.8, 170.4, 169.8, 169.2, 98.3, 52.9, 52.6, 37.1 Example 2

12- 2-f4-Acetoxy-3-methoxycycloheχyl)-l-methylvinyl1- 17-allyl-l-hvdroxy-23.25-dimethoxy-13.19.21.27-tetramethyl- ll.28-dioxa-4-azatricyclor22.3.1.0 91octacos-18-ene- 3.10.16-trione a) 12-r2- (4-Acetoxy-3-methoxycvclohexyl)-l-methylvinyl]- 17-allyl-l.2-dihydroxy-23.25-dimethoxy-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclof22.3.1.04'91octacos- 18-ene-3.10.16-trione Following the method of Example 1(a) above, the subtitle compound (246mg) was prepared from 12-[2-(4-acetoxy-3- methoxycyclohexyl)-1-methylvinyl]-17-allyl-l-hydroxy-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3 . 1. 04 , 9 ] octacosa-14 , 18-diene-2 , 3 , 10 , 16-tetraone (the second compound of Example 6, EP 184162) (lg) .

MS (FAB): 854 (M+Na)+

13C NMR (CDC13) δ : 208.5, 171.5, 171.0, 170.3, 98.8, 82.9, 80.3, 76.4, 75.4, 73.8, 71.7, 67.9 b) 12- 2- (4-Acetoxy-3-methoxycyclohexyl)-l-methylvinyl]- 17-allγl-23.25-dimethoxy-13.19.21.27-tetramethyl-l.2- thiooxomethγlenedioxy-11.28-dioxa-4-azatricvclo- r22,3.1.0 ,9loctacos-18-ene-3.10.16-trione The subtitle compound (168mg) was prepared from the product of step (a) following the method of Example 1(b) . MS (FAB): 896 (M+Na)+

13C NMR (CDCI3) δ : 210.0, 188.6, 170.4, 169.0, 162.0, 111.5, 85.4, 80.4, 78.5, 76.0, 75.7, 74.1, 71.9 c) (IE)-12-r2-f4-Acetoxy-3-methoxycyclohexyl)-1- ethylvinyl]-17-allyl-23.25-dimethoxy-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclor22.3.1.04'9] octacosa-1.18-diene-3.10.16-trione and

(1Z)-12-f2-(4-Acetoxy-3-methoxycvclohexyl)-1- methylvinyl1-17-allyl-23.25-dimethoxy-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclor22.3.1.04'9] octacosa-1.18-diene-3.10.16-trione

The subtitle compounds (88mg and 33mg respectively) were prepared from the product of step (b) (160mg) following the method of Example 1(c).

MS (FAB): 820 (M+Na)+ (both compounds)

(IE)-compound 210.2, 171.8, 170.3, 167.6, 95.8, 80.4, 76.6, 76.2, 75.6, 75.2, 73.2, 55.9 (C9) , 36.8 (C5)

(1Z) -compound 210.3, 170.3, 170.1, 166.2, 163.6,

100.3, 80.6, 80.4, 80.1, 76.8, 75.6, 73.5, 51.3 (C9) , 43.5

(C5) 5 d) 12-f 2- (4-Acetoxy-3-methoxycyclohexyl)-1-methylvinyl1-

17-allyl-l-hydroxy-23.25-dimethoxγ-13.19.21.27-tetramethyl-

11.28-dιoxa-4-azatπcyclo f 22.3.1.0 ' 1 octacos-18-ene-

3.10.16-trione

The title compound (31mg) was prepared from the 0 (IE)-compound of step (c) (60mg) following the method of

Example 1(d). Similarly, the title compound was also prepared from the (1Z)-compound of step (c) .

MS (FAB): 838 (M+Na)+ 13C NMR (CDC13) δl 211.3, 173.7, 170.4, 169.8, 98.2, 5 81.0, 80.4, 76.4, 75.6, 74.2, 70.3

Example 3

14-Acetoxy-12-T2-(4-acetoxy-3-methoxycyclohexyl)-1- methylvinyl]-17-allyl-l.23.25-trimethoxy-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclor22.3.1.04'9]octacos- 20 18-ene-3.10.16-trione

To a solution of the product of Example 1(c) (80mg) in anhydrous methanol (lml) was added a 0.1M solution of p-toluenesulphonic acid monohydrate in methanol (0.25ml).

After being stirred for 30 minutes, the solvent was 2 evaporated and the residue was purified by preparative thin layer chromatography eluted with ethyl acetate/hexane [1:1] to give the title compound (38mg) .

MS (FAB): 910 (M+Na)+ 13C NMR (CDCI3) δ 208.3, 171.2, 170.0, 169.6,

100.0, 55.7, 53.2, 47.2, 39.4

Example 4

17-Allyl-1.14-dihvdroxy-12-r2-f4-hvdroxy-3- 5 methoxycvclohexyl)-1-methylvinyl]-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricγclo f22.3.1.04'9]octacos-18-ene-3.10.16-trione

Hydrogen sulphide was bubbled through a solution of

17-Allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- 0 methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-

13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo

[22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone

(FR-900506, EP 184162) (160mg) in dimethylformamide (5ml) and pyridine (1ml) for 4 hours at room temperature. After 5 standing overnight elemental sulphur had precipitated.

Dilute hydrochloric acid and ethyl acetate were then added, and the organic extract was separated, dried

(MgS04) ,filtered and evaporated to an oil in vacuo.

Chromatography on silica eluting with ethyl acetate gave 20 the title compound (120mg) as a foam.

13C NMR δ: (major rotamer) 214.0 (C16) ; 173.9 (C3) ;

169.2 (CIO); 141.05 (C19) ; 135.36 (C41) ; 132.33 (C29) ;

128.7 (C31) ; 121.25 (C18) ; 116.4 (C42) ; 98.39 (Cl) ; 84.1

(C34); 70.54 (C24); 69.32 (C14) ; 53.3 (C17) ; 52.5 (C9) ;

25 48.26 (C20) ; 42.53 (C15) ; 42.23 (C5) ; 40.33 (C13) ; 38.35

(C27) ; 37.17 (C2) ; 35.75 (C40) ; 36.17 (C22) ; 32.49 (C26) ;

31.21 (C36) ; 30.60 (C37) ; 26.51 (C8) ; 25.67 (C21) ; 24.34 (C6) ; 20.90 (C7); 18.57 (C44) ; 16.78 (C47) ; 15.64 (C43) ; 14 . 39 (C30) ; 9 . 73 (C39 )

MS (FAB): 790 [M+H]+; 812 [M+Na]+; 874 [M+Rb]+ Example 5

17-Allγl-l-hγdroxy-23.25-dimethoxγ-12-r2-n-methoxγ-4- phenylcarbamoyloxycvclohexyl)-1-methylvinyl]-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricvclor22.3.1.04'9]octacos- 18-ene-3.10.16-trione a) 17-Allyl-l-hydroxy-23.25-dimethoxy-12-[2-(3-methoxy-4- phenylcarbamoyloxycyclohexyl)-1-methγlvinγll-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclor22.3.1.0 '9]octacos- 14.18-diene-2.3.10.16-tetraone

To a mixture of 17-allyl-ι-hydroxy-12-[2-(4-hydroxy- 3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04,9]octacosa-14,18-diene-2,3,10,16-tetraone (the second compound of Example 17, EP 184162) (Ig) and pyridine (1.77g) in anhydrous dichloromethane (10ml) was added phenyl isocyanate (1.28g), and the mixture was stirred for 16 hours at ambient temperature. The reaction mixture was washed with IN aqueous hydrochloric acid solution, water, aqueous sodium bicarbonate solution and brine successively, and dried over magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with a mixture of dichloromethane and diethyl ether [2:1] to give the subtitle compound (l.Olg). MS (FAB): 927 (M+Na)+

13, NMR (CDC13) δ : 200.1, 198.7, 195.8, 191.2, 169.0, 168.6, 165.7, 164.8, 152.9, 147.8, 146.4, 137.8, 128.8, 127.5, 123.1, 118.5, 98.6, 97.7 b) 17-Allyl-l.2-dihvdroxy-23.25-dimethoxy-12- ~ 2- (3-methoxy -4-phenylcarbamoyloxycvclohexyl)-1-methylvinyl]-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclor22.3.1.04'9]octacos- 18-ene-3.10.16-trione

Following the method of Example 1(a), the subtitle compound (263mg) was obtained from the product of step (a) (900mg) . MS (FAB): 931 (M+Na)+ c) 17-Allyl-23.25-dimethoxγ-12-r2-(3-methoxy-4- phenylcarbamoyloxycyclohexyl)-l-methylvinyll-13.19.21.27- tetramethγl-1.2- (thiooxomethylenedioxy)-11.28-dioxa-4- azatricvclof22.3.1.0 '91octacos-18-ene-3.10.16-trione Following the method of Example 1(b), the subtitle compound (156mg) was obtained from the product of step (b) (233 mg) . MS (FAB): 973 (M+Na)+

13C NMR (CDC13) δ: 210.0, 188.5, 138.0, 128.4, 123.6, 118.4, 111.6, 54.7, 52.7 d) flE)-17-Allyl-23.25-dimethoxy-12-r2-(3-methoxy-4- phenylcarbamoyloxycyclohexyl)-1-methylvinyl]-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclor22.3.1.04'9]octacosa -1.18-diene-3.10.16-trione and flZ)-17-Allyl-23.25-dimethoxy-12-r2-(3-methoxy-4- phenylcarbamoyloxycyclohexyl)-1-methylvinγl]-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricγclor22.3.1.04'9]octacosa -1.18-diene-3.10.16-trione

Following the method of Example 1(c), the subtitle compounds (86mg and 23mg respectively) were prepared from the product of step (c) (140mg) .

MS (FAB): (both compounds) 897 (M+Na)+

13C NMR (CDC13) δ :

(IE)-compound 210.0, 171.9, 170.4, 167.7, 152.9, 137.9, 128.0, 123.0, 118.5, 95.8 (C2) , 55.9 (C9) , 36.9 (C5) (lZ)-COmpound 210.0, 170.1, 166.2, 163.6, 152.9,

137.8, 128.8, 123.1, 118.5, 100.0 (C2) ; 51.3 (C9) ; 43.6

(C5) e) 17-Allyl-l-hvdroxy-23.25-dimethoxy-12-f2-(3-methoxy-4- Phenylcarbamoyloxycyclohexyl)-1-methylvinyl1-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricvclo[22.3.1.04'91octacos-

18-ene-3.10.16-trione

Following the method of Example 1(d), the title compound

(44mg) was obtained from the (IE)-compound of step (d) (60mg) . Similarly, the title compound was also prepared from the (1Z)-compound of step (d) .

MS (FAB): 915 (M+Na)+ 13C NMR (CDCI3) δ : 211.1, 173.7, 169.8, 137.8,

128.8, 123.1, 118.5, 52.6, 52.5, 37.8 Example 6

17-Allγl-12-r2-[4-f4-fluorophenylcarbamoyloxy)-3- methoxycyclohexyl]-1-methylvinγl]-l-hydroxy-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricγclo r22.3.1.04'9]octacos-18-ene-3.10.16-trione a) 17-Allyl-12-r2-r4-(4-fluorophenγlcarbamoyloxy)-3- ethoxycyclohexyl1-1-methylvinγl]-l-hydroxy-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo f22.3.1.04'9]octacosa-14.18-diene-2.3.10.16-tetraone The subtitle compound (1.18g) was prepared from 17-allyl- l-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28- dioxa-4-azatricyclo[22.3.1.04'9]octacosa-14,18-diene- 2,3,10,16-tetraone (the second compound of Example 17, EP 184162) (l.lg) and 4-fluorophenyl isocyanate following the method of Example 5(a). MS (FAB): 946 (M+Na)+ b) 17-Allyl-12-f2-r4-f4-fluorophenylcarbamoyloxy)-3- methoxycyclohexyl]-1-methylvinyl1-1.2-dihvdroxy-23.25- dimethoxy-13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricvclo f22.3.1.04'91octacos-18-ene-3.10.16-trione

Following the method of Example 1(a), the subtitle compound (0.58g) was obtained from the product of step (a) (l.Og) . MS (FAB): 950 (M+Na)+ c) 17-Allyl-12-r2-r4-f4-fluorophenylcarbamoyloxy)-3- methoxycyclohexyl]-1-methylvinyll-23.25-dimethoxy-

13.19.21.27-tetramethyl-l.2-fthiooxomethylenedioxy)-11.28- dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-3.10.16- trione

Following the method of Example 1(b), the subtitle compound (430mg) was obtained from the product of step (b) (580mg) . MS (FAB): 992 (M+Na)+ d) (IE)-17-Allyl-12-f2-f4- (4-fluorophenylcarbamoyloxy)-3- methoxycyclohexyl]-1-methylvinyl1-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo r22.3.1.04 91octacosa-1.18-diene-3.10.16-trione and r1Z)-17-Allyl-12-r2-r4- 14-fluorophenylcarbamoyloxy)- 3-methoxycyclohexyl]-l-methylvinyl1-23.25-dimethoxy- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricvclo- f22.3.1.04'91octacosa-1.18-diene-3.10.16-trione The subtitle compounds (lOlmg and 31mg respectively) were prepared from the product of step (c) (330 mg) following the method of Example 1(c). mp: (IE)-compound 103-104*C

(1Z)-compound 94-95"C MS (FAB): (both compounds) 915 (M+Na)+ 13C NMR (CDC13) δ : [(IE)-compound] 210.0, 171.9,

170.3, 167.7, 161.0, 156.2, 153.3, 138.0, 135.8, 134.0,

131.4, 127.9, 124.3, 120.1, 116.0, 115.5, 115.0, 95.7, 55.9, 52.0, 36.8 e) 17-Allyl-12-r2-r4- -fluorophenylcarbamoγloxy)-3- methoxycvclohexyl]-1-methylvinyl]-l-hydroxy-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricvclo f22.3.1.0 91octacos-18-ene-3.10.16-trione

The title compound (24mg) was prepared from the

(IE)-compound of step (d) (50mg) following the method of Example 1(d). Similarly, the title compound was also prepared from the (1Z)-compound of step (c) .

MS (FAB): 933 (M+Na)+

Example 7

!-Hydroxy-12-r2-r4-f f2R)-2-hydroxypropyl-carbamoyloxy]-3- methoxycvclohexyl]-1-methylvinyl]-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-17-propyl-4-azatricvclo r22.3.1.0 /91octacos-18-ene-3.10.16-trione a) 17-Allyl-l-hvdroxy-12-r2-f4-r f2R)-2- hvdroxypropylcarbamoyloxy1-3-methoxycyclohexyl1-1- methylvinyll-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricvclor22.3.1.04/91octacosa-14.18-diene- 2.3.10.16-tetraone 5 To a mixture of 17-allyl-l,14-dihydroxy-12-

[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone (FR-900506, EP 184162) (400mg) and pyridine (420mg) in 0 anhydrous dichloromethane (8ml) was added p-nitrophenyl chloroformate (400mg) , and the mixture was stirred for one hour at ambient temperature. (2R)-3-amino-2-propanol (375mg) was then added and after stirring for an additional hour at ambient temperature, an additional portion of 5 (2R)-3-amino-2-propanol (150 mg) was added. After stirring for 30 minutes, the mixture was washed with brine, dried over magnesium sulphate, and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-hexane [4:1] 0 to give the subtitle compound (188mg) . MS (FAB): 909 (M+Na)+ mp: 94-96βC

13C NMR (CDC13) δ : 200.0, 198.7, 195.8, 191.6, 169.0, 166.6, 165.7, 164.9, 156.7, 147.9, 146.5, 128.6,

25127.2, 98.4, 97.6, 66.8 b) l-hvdroxy-12-f2-[4-ff2R)-2-hydroxypropylcarbamoyloxyl-

3-methoxycyclohexyl1-1-methylvinyl]-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-17-propyl-4-azatricvclo r22.3.1.04'9 ~octacos-18-ene-2.3.10.16-tetraone A solution of the product of step (a) (70mg) in acetic acid (lml) was suspended with 5% palladium-on-carbon (lOmg) , and the reaction mixture was stirred for 4 hours under a

5 hydrogen atmosphere at one atmosphere pressure. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate to give the subtitle compound (28mg) . 0 MS (FAB): 913 (M+Na)+ 13C NMR (CDC13) δ : 212.2, 210.9, 196.5, 193.4, 170.3, 169.1, 156.7, 98.1, 97.0, 66.9 c) l-Hydroxy-12-f2-r4-f (2R)-2-hγdroxγpropyl-carbamoyloxyl- 3-methoxycyclohexyl1-1-methylvinyl]-23.25-dimethoxy- 5 13.19.21.27-tetramethyl-ll.28-dioxa-17-propyl-4-azatricyclo f22.3.1.0 '91octacos-18-ene-3.10.16-trione

The title compound (72mg) was prepared from the product of step (b) (140mg) following the method of Example 4. MS (FAB) : 899 (M+Na)+

20 13C NMR (CDCI3) _: 212.2, 174.0, 173.7, 169.9, 169.8, 156.8, 98.2, 97.9, 70.3, 70.0, 38.4, 37.8 Example 8

17-Allyl-l-hydroxy-23.25-dimethoxy-12-r2- (3-methoxy- 4-morpholinocarbonyloxycyclohexγl)-1-methylvinγl]-

25 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo- f22.3.1.04 91octacos-18-ene-3.10.16-trione a) 17-Allyl-l-hydroxy-23.25-dimethoxy-12-r2-(3-methoxy-4- morpholinocarbonγloxycyclohexγl)-1-methylvinyll-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclof22.3.1.0 *91octacosa -14.18-diene-2.3.10.16-tetraone

The subtitle compound (1.59g) was prepared from 17-allyl-l- hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-diσxa-4- azatricyclo[22.3.1.04*9]octacosa-14,18-diene-2,3,10,16- tetraone (the second compound of Example 17, EP 184162) (2.0g) and morpholine following the method of Example 7(a). MS (FAB): 921 (M+Na)+ 13C NMR (CDC13) δ ~ 200.0, 198.7, 195.7, 191.3 169.0, 168.6, 165.7, 164.8, 154.9, 147.8, 146.4, 128.7, 127.4, 98.5, 97.6, 66.4 b) 17-Allyl-l.2-dihvdroxy-23.25-dimethoxy-12-f2- (3-methoxy -4-morpholinocarbonyloxycyclohexyl)-1-methylvinyl]- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo [22.3.1.0 9]octacos-18-ene-3.10.16-trione

The subtitle compound (1.59g) was prepared from the product of step (a) (1.59g) following the method of Example 1(a). MS (FAB): 925 (M+Na)+ c) 17-Allyl-23.25-dimethoxγ-12-[2-f3-methoxy-4- morpholinocarbonyloxycyclohexyl)-1-methylvinyl1-13.19.21.27- tetramethyl-1.2-fthiooxomethylenedioxy)-11.28-dioxa-4- azatricvclor22.3.1.04 9loctacos-l8-ene-3.10.16-trione The subtitle compound (0.771g) was obtained from the product of step (b) following the method of Example 1(b). MS (FAB): 968 (M+Na)+

13C NMR (CDCI3) δ : 211.4, 210.0, 188.4, 170.8 169.6, 169.0, 168.8, 162.0, 154.9, 111.5, 97.9 d) .lE)-17-Allyl-23.25-dimethoxy-12-r2-(3-methoxy-4- morpholinocarbonyloxycyclohexyl)-l-methylvinyl1-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclo-T22.3.1.04 '9]octacos -1.18-diene-3.10.16-trione and (lZ)-17-Allyl-23.25-dimethoxy-12-r2-(3-methoxγ-4- morpholinocarbonyloxycyclohexyl)-l-methylvinyll-13.19.21.27- tetramethyl-ll.28-dioxa-4-azatricyclo-f22.3.1.04 '9]octacos -1.18-diene-3.10.16-trione The subtitle compounds (190mg and 66mg respectively) were prepared from the product of step (c) (77lmg) following the method of Example 1(c) (190 mg) . mp: (IE)-compound 82-83°C (1Z)-compound 62-63°C MS (FAB): (both compounds) 891 (M+Na)+ 13C NMR (CDC13) δ :

(IE)-compound 210.0, 170.7, 170.3, 167.6, 154.9, 95.8,

66.3, 55.9, 36.2

(1Z)-compound 210.0, 170.1, 166.2, 163.6, 154.9, 100.3,

66.4, 51.3, 38.7 e) 17-Allyl-l-hydroxy-23.25-dimethoxy-12-r2-(3-methoxy-

4-morpholinocarbonyloxycvclohexyl)-1-methylvinyl1-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricγclo-

[22.3.1.04 91octacos-18-ene-3.10.16-trione

The title compound (116mg) was prepared from the (IE)-compound of step (d) (178mg) following the method of

Example 1(d). Similarly, the title compound was also prepared from the (1Z)-compound.

MS (FAB): 909 (M+Na)+ 13C NMR (CDCI3) δ : 211.2, 173.7, 169.7, 154.9, 98.1,

66.4, 52.6, 52.4, 37.8

Example 9 l-Hydroxy-12-T2-(4-hydroxy-3-methoxycvclohexyl)-1-

5 methylvinyll-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-17-propyl-4-azatricyclor22.3.1.04'9]octacos-18-ene- 3.10.16-trione

Hydrogen sulphide gas was bubbled through a previously degassed solution of l-hydroxy-12-[2-(4-hydroxy- 0 3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-

13,19,21,27-tetramethyl-ll,28-dioxa-17-propyl-4-azatricyclo [22.3.1.0 '9]octacos-18-ene-2,3,10,16-tetraone (the compound of Example 11, WO 89/05304) (lg) in dry pyridine (5ml) for 3 hours at room temperature. After a further 3 5 hours at room temperature, the reaction mixture was poured into dilute aqueous hydrochloric acid (1M, 100ml) and this was extracted with diethyl ether (100ml) . The ether extracts were then washed with water (20ml) and brine

(20ml) before being dried (MgS04) , filtered and

20 evaporated to an oil in vacuo. Chromatography on silica eluting with dichloromethane in an increasing acetone gradient then gave the title compound as a foam (683mg) . MS (FAB): 860 (M+Rb)+; 798 (M+Na)+; 776 (M+H)+ 13C NMR (CDCI3) δ : 98.4 (Cl) ; 170 (C3) ; 173.9 (CIO);

25 81.2 (C12) ; 212.5 (C16) ; 122.8 (C18) ; 130.2 (C19) ; 140.5 (C29) ; 131.1 (C31) ; 84.1 (C34) Example 10 12-r2-(4-Carbamoyloxy-3-methoxycyclohexyl)-1-methylvinyl1-1- hγdroxy-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28-dioxa- 17-propyl-4-azatricvclo-[22.3.1.04'91octacos-18-ene- 3.10.16-trione

The title compound (68mg) was prepared from the title compound of Example 9 (166mg) and ammonia following the method of Example 7(a). MS (FAB): 841 (M+Na)+ 13C NMR (CDC13) δ : 211.9, 173.7, 169.8, 156.5, 98.2,

52.8, 52.4, 37.9 Example 11

1-Hvdroxy-12-r2-T4-(3-hvdroxypropy1carbamoyloxy)-3- methoxycyclohexyl1-1-methylvinyl]-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-17-propyl-4-azatricyclo r22.3.1.0 '9]octacos-18-ene-3.10.16-trione The title compound (26mg) was prepared from the title compound of Example 9 (94mg) and 3-hydroxypropylamine following the method of Example 7(a).

MS (FAB): 899 (M+Na)+ 13C NMR (CDCI3) δ : 212.4, 174.2, 173.8, 170.0, 169.8, 157.2, 98.3, 98.0

Example 12

17-Allyl-14-(4-chlorophenylcarbamoyloxy)-12-f2-f4-(4- chlorophenylcarbamoyloxy)-3-methoxycvclohexyn-1- ethylvinyl1-l-hvdroxy-23.25-dimethoxy-13.19.21.27- tetramethyl-11.28-dioxa-4-azatricyclor22.3♦1.04 '9]octacos-

18-ene-3.10.16-trione

The title compound (16mg) was prepared from the title compound of Example 4 (l.Og) and 4-chlorophenylamine following the method of Example 7(a). MS (FAB): 1120 (M+Na)+ 13C NMR (CDC13) δ : 208.2, 174.3, 169.5, 152.8, 152.2, 140.5, 136.4, 135.7, 132.0, 138.8, 128.1, 121.3, 5 119.7, 116.1, 98.3 Example 13

17-Allyl-1.14-dihvdroxy-12-r2-f3.4-dihydroxycyclohexyl)-l- methylvinyll-23.25-dimethoxy-13.19.21.27-tetramethyl-ll.28- dioxa-4-azatricyclo[22.3.1.04'91octacos-18-ene-3.10.16- 0 trione

Hydrogen sulphide gas was bubbled through a solution of 17-allyl-l,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28- dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene-2,3,10,16- 5 tetraone (FR-901154, EP 353678) (40mg) in pyridine (2ml) and dimethylformamide (0.1ml) for 2 hours at room temperature. After standing for 4 hours at room temperature, dilute aqueous hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The 0 ethyl acetate extract was then dried (MgS04) , filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with ethyl acetate then gave the title compound as a foam (20mg) . MS (FAB): 860 (M+Rb)+; 798 (M+Na)+; 776 (M+H)+;

13C NMR (CDCI3) δ : 214.1 (C16) ; 174 (C3) ; 169.3 (CIO); 141.9 (C19) ; 135.4 (C41) ; 132.5 (C29) ; 128.8 (C31) ; 121.3 (C18) ; 116.5 (C42) ; 98.5 (Cl) ; 48.4 (C20) ; 20.6 (C7) ; 9.7 (C39 ) Example 14 fl7S)-17-Allyl-1.14-dihvdroxy-12-r2-(4-hvdroxy-3- methoxycyclohexyl)-1-methylvinyl]-23.25-dimethoxy- 13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo r22.3.1.04'9]octacos-18-ene-3.10.16-trione 17-Allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (the compound of Example 2, EP 356399) (50mg) was heated in tetrahydrofuran containing diethylamine and triethylamine (0.1ml of each) under reflux for 30 hours in a nitrogen atmosphere. The cooled reaction mixture was then poured into dilute aqueous hydrochloric acid (10ml) and this was extracted with diethyl ether (20ml) . After washing with water (10ml) and brine (10ml) , the extracts were dried (MgS04) , filtered, and evaporated to an oil in vacuo. Chromatography on silica eluting with dichloromethane/acetonitrile [2:1] then gave the title compound as a foam (15mg) .

MS (FAB): 875 [M+Rb]+; 813 [M+Na]+; 791 [M+H]+; 773 [M-0H]+; 755 [M+H-2H20]+ 13C NMR (CDC13) δ : 214.4 (C16) ; 174.5 (C3) ; 169.7 (CIO); 139.2 (C19) ; 135.6 (C41) ; 132.9 (C29) ; 127.7 (C31) ; 121.8 (C18); 116.7 (C42) ; 98.2 (Cl) ; 84.2 (C34) ; 70.3 (C24); 70 (C14); 53.1 (C17) ; 52.4 (C9) ; 46.9 (C20) ; 42.6 (C5) ; 41.4 (C15) ; 30.2 (C21) ; 26.7 (C8) ; 24.5 (C6) ; 20.6 (C7) ; 20.4 (C44) ; 17.7 (C43) ; 16.9 (C47) ; 14 .8 (C30) ; 9 . 5

(C39)

Example 15

17-Ethyl-1.14-dihvdroxy-12-r2-f4-hvdroxy-3- 5 methoxycyclohexyl)-1-methylvinyl]-23.25-dimethoxy-

13.19.21.27-tetramethyl-ll.28-dioxa-4-azatricyclo

[22.3.1.04,91octacos-18-ene-3.10.16-trione

Hydrogen sulphide gas was bubbled through a solution of

17-ethyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- 0 methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-

13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo

[22.3.1.04'9]octacos-18-ene-2,3,10,16-tetraone (FR-900520 from EP 184162, also known as 'ascomycin') (lOOmg) and dimethylformamide (O.l l) in pyridine (3ml) for one hour at 5 room temperature. The reaction mixture was then stored for

60 hours at room temperature before being poured into a mixture of dilute aqueous hydrochloric acid (IN) and ethyl acetate. The ethyl acetate layer was separated, dried

(MgS04) , filtered and evaporated in vacuo to an oil. 20 Chromatography on silica eluting with ethyl acetate then gave the title compound as a foam (35mg) .

MS (FAB): 862 [M+Rb]+; 760 [M+H]+ 13C NMR (CDC13) δ 215.1 (C16) ; 173.9 (CIO); 169.3

(C3); 141 (C19) ; 132.4 (C29) ; 128.6 (C31) ; 121.9 (C18) ; 2598.4 (Cl) ; 84.1 (C34) ; 55 (C9) ; 52.5 (C17) ; 48.4 (C20) ;

38.3 (C13); 34.6 (C27) ; 25.6 (C21) ; 11.7 (C30) ; 9.6 (C39)

Example 16

The compound of Example 1 was tested according to Test A above, and found to suppress the mixed lymphocyte reaction by 50% (IC50) at a concentration of 2.4xlO~8M.

Claims

CLAIMS :
1. A compound of formula I,
OCH3 OCH3
wherein
R1 represents H, OH, alkoxy or R7COO-;
R2 represents H; in addition, R1 and R2 may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
R3 represents methyl, ethyl, propyl or allyl;
R4 represents OH or alkoxy;
R5 represents OH or methoxy;
R6 represents OH, alkoxy or R8COO-; in which R7 and R8 independently represent alkyl; aryl; NH2; a 5- or 6-membered heterocyclic ring optionally substituted by alkyl or aryl; arylamino; alkylamino; N,N-dialkylamino; N,N-diarylamino; or N-alkyl-N-arylamino; each alkyl group optionally being substituted by aryl, OH, Nθ2 or halogen; and each aryl group optionally being substituted by alkyl, OH, N02 or halogen; and n represents 1 or 2; provided that when n is 1, then R3 is allyl or 5 propyl.
2. A compound of formula I as defined in claim 1, wherein R3 is ethyl.
3. A compound of formula I as defined in claim 1, wherein at least one of R1 and R6 is OH. 0 4. A compound of formula I as defined in claim 1, wherein R7 and R8 are selected from alkyl; NH2; piperidino; morpholino; aryl optionally substituted by halogen or OH; arylamino optionally substituted by halogen or OH; or alkylamino optionally substituted by OH. 5 5. A compound of formula I as defined in claim 1, which is
14-Acetoxy-12-[2-(4-acetoxy-3-methoxycyclohexyl)-1- methylvinyl]-17-allyl-l-hydroxy-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 '9]octacos-
20 18-ene-3,10,16-trione,
12-[2-(4-Acetoxy-3-methoxycyclohexyl)-1-methylvinyl]- 17-allyl-l-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 3,10,16-trione,
25 14-Acetoxy-12-[2-(4-acetoxy-3-methoxycyclohexyl)-1- methylvinyl]-17-allyl-l,23,25-trimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 '9]octacos- 18-ene-3,10,16-trione, 17-Allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-3,10,16-trione, 17-Allyl-l-hydroxy-23,25-dimethoxy-12-[2-(3-methoxy-4- phenylcarbamoyloxycyclohexyl)-1-methylvinyl]-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos- 18-ene-3,10,16-trione,
17-Allyl-12-[2-[4-(4-fluorophenylcarbamoyloxy)-3- methoxycyclohexyl]-1-methylvinyl]-l-hydroxy-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04'9]octacos-18-ene-3,10,16-trione, l-Hydroxy-12-[2-[4-[ (2R)-2-hydroxypropyl-carbamoyloxy]- 3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy- . 13,19,21,27-tetramethyl-ll,28-dioxa-17-propyl-4-azatricyclo [22.3.1.04'9]octacos-18-ene-3,10,16-trione,
17-Allyl-l-hydroxy-23,25-dimethoxy-12-[2-(3-methoxy- 4-morpholinocarbonyloxycyclohexyl)-1-methylvinyl]- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo- [22.3.1.04'9]octacos-18-ene-3,10,16-trione, l-Hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28- dioxa-17-propyl-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 3,10,16-trione, 12-[2-(4-Carbamoyloxy-3-methoxycyclohexyl)-1- methylvinyl]-l-hydroxy-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-17-propyl-4-azatricyclo- [22.3.1.04'9]octacos-18-ene-3,10,16-trione, l-Hydroxy-12-[2-[4-(3-hydroxypropylcarbamoyloxy)-3- methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-17-propyl-4-azatricyclo [22.3.1.04'9]octacos-18-ene-3,10,16-trione, 17-Allyl-14-(4-chlorophenylcarbamoyloxy)-12-[2-[4-(4- chlorophenylcarbamoyloxy)-3-methoxycyclohexyl]-1- ethylvinyl]-l-hydroxy-23,25-dimethoxy-13,19,21,27- tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos- 18-ene-3,10,16-trione, 17-Allyl-l,14-dihydroxy-12-[2-(3,4-dihydroxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl- ll,28-dioxa-4-azatricyclo[22.3.1.04'9]octacos-18-ene- 3,10,16-trione,
(17S)-17-Allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyσlo [22.3.1.04'9]octacos-18-ene-3,10,16-trione, or
17-Ethyl-l,14-dihydroxy-12-[2-(4-hydroxy-3- methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy- 13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo [22.3.1.04 '9]octacos-18-ene-3,10,16-trione.
6. The use of a compound of formula I, as defined in claim 1, as a pharmaceutical.
7. A pharmaceutical composition comprising a compound of formula I, as defined in claim 1, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
8. The use of a compound of formula I, as defined in claim 1, in the manufacture of a medicament for use as an immunosuppressive agent.
9. A method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, to a patient.
10. A process for the production of a compound of formula I as defined in claim 1, which comprises: a) selective reduction of the C2-carbonyl group in a compound of formula II,
0CH30CH3
wherein R1 to R6 and n are as defined above, or b) addition of a compound of formula R -H, wherein R4 is as defined above, across the Cl alkene group in a compound of formula III,
OCH , OCH.
wherein R1 to R3, R5, R6 and n are as defined above.
PCT/GB1990/001262 1989-08-18 1990-08-10 Macrocyclic compounds WO1991002736A1 (en)

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GB8918927A GB8918927D0 (en) 1989-08-18 1989-08-18 Compounds
GB8918927.8 1989-08-18
GB8922653A GB8922653D0 (en) 1989-10-09 1989-10-09 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same
GB8922653.4 1989-10-09
GB9012426.4 1990-06-04
GB9012426A GB9012426D0 (en) 1990-06-04 1990-06-04 Tricyclo compounds,a process for their production and a pharmaceutical composition containing the same

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US5143918A (en) * 1990-10-11 1992-09-01 Merck & Co., Inc. Halomacrolides and derivatives having immunosuppressive activity
EP0509795A2 (en) * 1991-04-17 1992-10-21 American Home Products Corporation Carbamates of rapamycin
WO1992018506A1 (en) * 1991-04-11 1992-10-29 Pfizer, Inc. Novel immunosuppressant agent from streptomyces braegensis
US5162334A (en) * 1991-05-13 1992-11-10 Merck & Co., Inc. Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity
US5189042A (en) * 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
EP0515071A3 (en) * 1991-05-13 1993-03-03 Merck & Co. Inc. O-aryl, o-alkyl, o-alkenyl and o-alkynylmacrolides having immunosuppressive activity
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
US5208228A (en) * 1989-11-13 1993-05-04 Merck & Co., Inc. Aminomacrolides and derivatives having immunosuppressive activity
WO1993011130A1 (en) * 1991-12-03 1993-06-10 Smithkline Beecham Plc Rapamycin derivative and its medicinal use
US5258389A (en) * 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5284840A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
US5284877A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
US5310903A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. Imidazolidyl rapamycin derivatives
US5310901A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynlheteroarylrapamycin derivatives
EP0642516A4 (en) * 1991-09-05 1994-06-15 Abbott Lab Macrocyclic immunomodulators.
US5441977A (en) * 1992-09-24 1995-08-15 American Home Products Corporation 21-norrapamycin
US5506233A (en) * 1992-03-02 1996-04-09 Pfizer Inc. Desosamino derivatives of macrolides as immunosuppressants and antifungal agents
US5532248A (en) * 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
US5534632A (en) * 1991-09-05 1996-07-09 Abbott Laboratories Macrocyclic carbamate immunomodulators
US5612316A (en) * 1992-03-02 1997-03-18 Pfizer Inc. Fluorosugar derivatives of macrolides
US5631235A (en) * 1992-03-02 1997-05-20 Pfizer, Inc. 2-Aminosugar derivatives of macrolides
US5686424A (en) * 1992-04-08 1997-11-11 Miles Inc. 2-oxoethyl derivatives as immunosuppressants
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
US5747465A (en) * 1992-03-02 1998-05-05 Pfizer Inc. Sugar derivatives of macrolides
US5925649A (en) * 1995-04-06 1999-07-20 Novartis Ag Ascomycins
WO2005052542A3 (en) * 2003-11-21 2005-12-01 Dade Behring Inc Method and composition useful for determining fk 506
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection

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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5208228A (en) * 1989-11-13 1993-05-04 Merck & Co., Inc. Aminomacrolides and derivatives having immunosuppressive activity
US5143918A (en) * 1990-10-11 1992-09-01 Merck & Co., Inc. Halomacrolides and derivatives having immunosuppressive activity
WO1992018506A1 (en) * 1991-04-11 1992-10-29 Pfizer, Inc. Novel immunosuppressant agent from streptomyces braegensis
EP0509795A3 (en) * 1991-04-17 1994-03-23 American Home Prod
EP0509795A2 (en) * 1991-04-17 1992-10-21 American Home Products Corporation Carbamates of rapamycin
US5162334A (en) * 1991-05-13 1992-11-10 Merck & Co., Inc. Amino O-alkyl, O-alkenyl and O-alkynlmacrolides having immunosuppressive activity
EP0515071A3 (en) * 1991-05-13 1993-03-03 Merck & Co. Inc. O-aryl, o-alkyl, o-alkenyl and o-alkynylmacrolides having immunosuppressive activity
US5532248A (en) * 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
US5250678A (en) * 1991-05-13 1993-10-05 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity
US5189042A (en) * 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
US5708002A (en) * 1991-09-05 1998-01-13 Abbott Laboratories Macrocyclic immunomodulators
US5534632A (en) * 1991-09-05 1996-07-09 Abbott Laboratories Macrocyclic carbamate immunomodulators
EP0642516A4 (en) * 1991-09-05 1994-06-15 Abbott Lab Macrocyclic immunomodulators.
EP0642516A1 (en) * 1991-09-05 1995-03-15 Abbott Laboratories Macrocyclic immunomodulators
US5208241A (en) * 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
WO1993011130A1 (en) * 1991-12-03 1993-06-10 Smithkline Beecham Plc Rapamycin derivative and its medicinal use
US5491229A (en) * 1991-12-03 1996-02-13 Smithkline Beecham Plc Rapamycin derivative
US5631235A (en) * 1992-03-02 1997-05-20 Pfizer, Inc. 2-Aminosugar derivatives of macrolides
US5612316A (en) * 1992-03-02 1997-03-18 Pfizer Inc. Fluorosugar derivatives of macrolides
US5563135A (en) * 1992-03-02 1996-10-08 Pfizer Inc. Desosamino derivatives of macrolides
US5506233A (en) * 1992-03-02 1996-04-09 Pfizer Inc. Desosamino derivatives of macrolides as immunosuppressants and antifungal agents
US5747465A (en) * 1992-03-02 1998-05-05 Pfizer Inc. Sugar derivatives of macrolides
US5686424A (en) * 1992-04-08 1997-11-11 Miles Inc. 2-oxoethyl derivatives as immunosuppressants
US5284840A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
US5284877A (en) * 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
US5441977A (en) * 1992-09-24 1995-08-15 American Home Products Corporation 21-norrapamycin
US5258389A (en) * 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5310901A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynlheteroarylrapamycin derivatives
US5310903A (en) * 1993-03-05 1994-05-10 Merck & Co., Inc. Imidazolidyl rapamycin derivatives
US5693648A (en) * 1994-09-30 1997-12-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynyl-macrolides having immunosuppressive activity
US5925649A (en) * 1995-04-06 1999-07-20 Novartis Ag Ascomycins
WO2005052542A3 (en) * 2003-11-21 2005-12-01 Dade Behring Inc Method and composition useful for determining fk 506
US7186518B2 (en) * 2003-11-21 2007-03-06 Dade Behring Inc. Method and composition useful for determining FK 506
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection

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EP0487593A1 (en) 1992-06-03 application

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