Patent US5912253A successfully refreshed from Google Patents.
US5912253A
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US
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Rapamycin derivatives
Assignee: Novartis AG
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Filing: 1994-12-16
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Granted: 1999-06-15
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Expires: 2014-12-16
Abstract
Abstract Novel demethoxy derivatives of rapamycin are found to have pharmaceutical utility, particularly as an immunosuppressants.
Inventors
- 👤 Sylvain Cottens
- 👤 Richard Sedrani
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 19:07
CPC Classifications
C; C07; C07D; C07D498/00; C07D498/12; C07D498/18; A; A61; A61P; A61P37/00; A61P37/02; A61P37/06; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
238 words
A compound of Formula I: ##STR4## wherein R 1 is: optionally hydroxy-substituted alkynyl; R 2 is of Formula II or Formula III: ##STR5## R 3 is: H, alkyl, alkyenyl, (optionally hydroxy-substituted) alkynyl, aryl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylamidoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl; R 4 is H or methyl, or R 4 together with R 3 forms C 2-6 alkylene; R 5 is: R 6 O--CH 2 -- wherein R 6 is H, alkyl, alkenyl, alkynyl, aryl, amino, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbinyl, formyl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylamidoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl or alkylsilyl, R 7 CO-- where R 7 is H, alkyl, hydroxy, alkoxy, aryloxy, amido, alkamido, a residue of an amino acid, or N,N-disubstituted-amido wherein each substituent of N is independently alkyl, aryl, arylakyl or alkylaryl, or both such substituents together form morpholino or piperazino, R 8 NCH-- where R 8 is alkyl, aryl, amino, alkylamino, arylamino, or arylsulfonylamino, or O,O-(alkylyne) dioxymethylyne; each X and Y is independently O, (H, OH), or (H, OR 9 ); and R 9 is: alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; "alk" or "alkyl" refer to a C 1-10 aliphatic substituent, each such "alk" or "alkyl" being optionally interrupted by an oxy (--O--) linkage; and "ar" or "aryl" refer to substituted or unsubstituted tolyl, phenyl, benzyl, or pyridyl.
Claim 2
Dependent Claim
238 words
A compound of Formula I: ##STR4## wherein R 1 is: optionally hydroxy-substituted alkynyl; R 2 is of Formula II or Formula III: ##STR5## R 3 is: H, alkyl, alkyenyl, (optionally hydroxy-substituted) alkynyl, aryl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylamidoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl, or alkylsilyl; R 4 is H or methyl, or R 4 together with R 3 forms C 2-6 alkylene; R 5 is: R 6 O--CH 2 -- wherein R 6 is H, alkyl, alkenyl, alkynyl, aryl, amino, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbinyl, formyl, thioalkyl, arylalkyl, hydroxyarylalkyl, hydroxyaryl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkoxyalkyl, hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxycarbonylamidoalkyl, arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl, carbalkoxyalkyl or alkylsilyl, R 7 CO-- where R 7 is H, alkyl, hydroxy, alkoxy, aryloxy, amido, alkamido, a residue of an amino acid, or N,N-disubstituted-amido wherein each substituent of N is independently alkyl, aryl, arylakyl or alkylaryl, or both such substituents together form morpholino or piperazino, R 8 NCH-- where R 8 is alkyl, aryl, amino, alkylamino, arylamino, or arylsulfonylamino, or O,O-(alkylyne) dioxymethylyne; each X and Y is independently O, (H, OH), or (H, OR 9 ); and R 9 is: alkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, hydroxyalkylcarbonyl, aminoalkylcarbonyl, formyl or aryl; "alk" or "alkyl" refer to a C 1-10 aliphatic substituent, each such "alk" or "alkyl" being optionally interrupted by an oxy (--O--) linkage; and "ar" or "aryl" refer to substituted or unsubstituted tolyl, phenyl, benzyl, or pyridyl.
Claim 3
Dependent Claim
50 words
A compound according to claim 1 wherein R 1 is (optionally hydroxy-substituted) alkynyl; R 2 is of formula II; R 3 is selected from H, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, and aminoalkyl; R 4 is methyl; and X and Y are independently selected from O, (H, OH) and (H, C 1-4 alkoxy).
Claim 4
Dependent Claim
11 words
A compound according to claim 2 wherein R 1 is alkynyl.
Claim 5
Dependent Claim
15 words
A compound according to claim 2 wherein R 1 is (optionally hydroxy-substituted) C 3-6 alk-2-ynyl.
Claim 6
Dependent Claim
41 words
A compound according to claim 2 wherein R 1 is (optionally hydroxy-substituted) C 3-6 alk-2-ynyl; R 2 is of Formula II; R 3 is selected from H, hydroxyalkyl, alkoxyalkyl and hydroxyalkoxyalkyl; R 4 is methyl; and X and Y are O.
Claim 7
Dependent Claim
13 words
A compound according to claim 1 wherein R 2 is of Formula III.
Claim 8
Dependent Claim
11 words
A compound according to claim 1 wherein R 1 is alkynyl.
Claim 9
Dependent Claim
15 words
A compound according to claim 1 wherein R 1 is (optionally hydroxy-substituted) C 3-6 alk-2-ynyl.
Claim 10
Dependent Claim
15 words
A compound according to claim 1 wherein R 1 is prop-2-ynyl, but-2-ynyl, pent-2-ynyl or 4-hydroxy-but-2-ynyl.
Claim 11
Dependent Claim
19 words
A compound according to claim 1 selected from: i) 16-demothoxy-16-(pent-2-ynyl)oxy-rapamycin ii) 16-demothoxy-16-(but-2-ynyl)oxy-rapamycin iii) 16-demothoxy-16-(propargyl)oxy-rapamycin iv) 16-demothoxy-16-(4-hydroxy-but-2-ynyl)oxy-rapamycin, and v) 16-demothoxy-40-O-(2-methoxyethyl)-16-(pent-2-ynyl)oxy-rapamycin.
Claim 12
Dependent Claim
9 words
The compound according to claim 1 which is 16-demethoxy-16-(pent-2-ynyl)oxy-rapamycin.
Claim 13
Dependent Claim
321 words
A process for making a compound of Formula I of claim 1 comprising one or more of the following steps: i. Reacting rapamycin or a derivative thereof with SeO 2 and a compound R 1 --OH under suitable reaction conditions, wherein R 1 is as defined as for Formula I, or reacting rapamycin or a derivative thereof with an acid and a compound R 1 --OH in a suitable aprotic solvent; ii. When the compound desired is of Formula I where R 2 is of Formula II and R 3 is other than H, reacting rapamycin or a derivative thereof with an organic radical attached to a leaving group R 3 --Z where R 3 is an organic radical as defined in Formula I which is desired as the O-substituent, and Z is the leaving group in the presence of a suitable acid, or in the presence of a suitable base; iii. When the compound desired is of Formula I where R 2 is of formula III, reacting rapamycin or a derivative thereof with morpholinosulphur trifloride to obtain the aldehyde compound, then optionally oxidizing the aldehyde to the carboxylic acid or reducing the aldehyde to the corresponding alcohol; and further optionally (a) O-substituting the alcohol thus obtained, as in step ii, or (b) reacting the carboxylic acid thus obtained with an amine or alcohol in the presence of an activating or coupling reagent to give the desired amide or ester compounds respectively, or (c) condensing the aldehyde thus obtained with the desired amine or alkylenediol, respectively, under acidic conditions to obtain the iminomethyl or dioxymethylyne compounds respectively; iv. When the compound desired is of formula I where X is other than O, reducing a rapamycin or derivative (in O-protected form) at the 32-keto to obtain the alcohol and optionally further O-substituting as in step ii; v. Optionally protecting and deprotecting as necessary; and recovering the compound of Formula I thus obtained.
Claim 14
Dependent Claim
18 words
A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable diluent or carrier.
Claim 15
Dependent Claim
17 words
A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable diluent or carrier.
Claim 16
Dependent Claim
89 words
A method of treating or preventing any of the following conditions: (i) autoimmune disease (ii) acute rejection of an organ or tissue transplant (iii) chronic rejection of an organ or tissue transplant (iv) hyperacute rejection of an organ or tissue transplant (v) graft v. host disease transplant (vi) asthma (vii) multidrug resistance (viii) tumors or hyper proliferactive disorders (ix) fungal infections (x) inflammation (xi) infection by pathogens having Mip or Mip-like factors comprising administering to a patient in need thereof an effective amount of a compound of claim 1.
Claim 17
Dependent Claim
64 words
A method of treating or preventing any of the following conditions: (i) autoimmune disease (ii) acute rejection of an organ or tissue transplant (iii) chronic rejection of an organ or tissue transplant (iv) hyperacute rejection of an organ or tissue transplant (v) graft v. host disease transplant comprising administering to a patient in need thereof an effective amount of a compound of claim 1.
Claim 18
Dependent Claim
64 words
A method of treating or preventing any of the following conditions: (i) autoimmune disease (ii) acute rejection of an organ or tissue transplant (iii) chronic rejection of an organ or tissue transplant (iv) hyperacute rejection of an organ or tissue transplant (v) graft v. host disease transplant comprising administering to a patient in need thereof an effective amount of a compound of claim 9.
Claim 19
Dependent Claim
91 words
A method of treating or preventing any of the following conditions: (i) autoimmune disease (ii) acute rejection of an organ or tissue transplant (iii) chronic rejection of an organ or tissue transplant (iv) hyperacute rejection of an organ or tissue transplant (v) graft v. host disease transplant comprising administering to a patient in need thereof an effective amount of a compound of claim 9 in combination with one or more of: cyclosporin, ascomycin and immunosuppressive analogs thereof; corticosteroids, cyclophosphamide, azathioprene, methotrexate, brequinar, leflunomide, mizoribine, immunosuppressive monoclonal antibodies, anti-viral drugs, and antibiotics.
Claim 20
Dependent Claim
24 words
A method of treating or preventing asthma comprising administering to a patient in need thereof an effective amount of a compound of claim 9.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2002-06-14 | 2002-12-14 | 2003-06-15 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2006-06-14 | 2006-12-14 | 2007-06-15 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2010-06-14 | 2010-12-14 | 2011-06-15 | $7700.00 | Window Closed / Lapsed |