PT98990A - PROCESS FOR THE PREPARATION OF CARBOXYLIC ACID ESTERS OF RAPAMICIN - Google Patents
PROCESS FOR THE PREPARATION OF CARBOXYLIC ACID ESTERS OF RAPAMICIN Download PDFInfo
- Publication number
- PT98990A PT98990A PT98990A PT9899091A PT98990A PT 98990 A PT98990 A PT 98990A PT 98990 A PT98990 A PT 98990A PT 9899091 A PT9899091 A PT 9899091A PT 98990 A PT98990 A PT 98990A
- Authority
- PT
- Portugal
- Prior art keywords
- carbon atoms
- alkyl
- rapamycin
- pharmaceutically acceptable
- acceptable salt
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 60
- 230000008569 process Effects 0.000 title claims description 37
- 238000002360 preparation method Methods 0.000 title claims description 8
- 150000001733 carboxylic acid esters Chemical class 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims description 144
- 229960002930 sirolimus Drugs 0.000 claims description 141
- 150000001875 compounds Chemical class 0.000 claims description 68
- -1 hydroxyphenylmethyl Chemical group 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 49
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 28
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 19
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000001475 halogen functional group Chemical group 0.000 claims description 18
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000007983 Tris buffer Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000004472 Lysine Substances 0.000 claims description 6
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 230000001506 immunosuppresive effect Effects 0.000 claims description 6
- 239000003018 immunosuppressive agent Substances 0.000 claims description 6
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- UGUBQKZSNQWWEV-UHFFFAOYSA-N 4-oxo-4-phenylmethoxybutanoic acid Chemical compound OC(=O)CCC(=O)OCC1=CC=CC=C1 UGUBQKZSNQWWEV-UHFFFAOYSA-N 0.000 claims description 5
- 206010052779 Transplant rejections Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- YRXIMPFOTQVOHG-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound OC(=O)CN(C)C(=O)OC(C)(C)C YRXIMPFOTQVOHG-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
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- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- HWBAHOVOSOAFLE-UHFFFAOYSA-N 2-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(=O)NCC(O)=O HWBAHOVOSOAFLE-UHFFFAOYSA-N 0.000 claims description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- 208000037979 autoimmune inflammatory disease Diseases 0.000 claims description 3
- 125000006301 indolyl methyl group Chemical group 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 17
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 3
- YGSRAYJBEREVRB-UHFFFAOYSA-N 5-[(2-methylpropan-2-yl)oxy]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)CCC(C(O)=O)NC(=O)OC(C)(C)C YGSRAYJBEREVRB-UHFFFAOYSA-N 0.000 claims 2
- LDRWTKQWSXGSTM-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)NC(CC(O)=O)C(=O)OCC1=CC=CC=C1 LDRWTKQWSXGSTM-UHFFFAOYSA-N 0.000 claims 1
- YMOYURYWGUWMFM-UHFFFAOYSA-N 5-[(2-methylpropan-2-yl)oxy]-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)NC(CCC(O)=O)C(=O)OC(C)(C)C YMOYURYWGUWMFM-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 230000001861 immunosuppressant effect Effects 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000010998 test method Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
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- 239000012043 crude product Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
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- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
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- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
FUNDAMENTOS DO INVENTO:BACKGROUND OF THE INVENTION:
Este invento relaciona-se com novos ésteres de rapami-cina e com um método para sua utilização no tratamento da rejeição de transplante, doença hospedeiro versus enxerto, doenças autoimunitãrias, doenças inflamatórias, e infecções por fungos. A rapamicina é um antibiótico trieno macrocíclico produzido por Streptomvces hYcrroscopicus. que se verificou ter actividade anti-fúngica, particularmente contra Candida albicans. tanto in vitro como in vivo [. Vezina et al., J. Antibiot. 28, 721 (1975); S.N. Seghal et al., J. Antibiot. 28, 727 (1975); Η.A.Baker et al., J. Antibiot. 31, 539 (1978); Patente dos E.U.A. No. 3.929.992; e Patente dos E.U.A. No. 3.993.749]. A rapamicina isoladamente (Patente dos E.U.A. No. 4.885.171) ou em combinação com picibanil (Patente dos E.U.A. No. 4.401.653) revelou ter actividade antitumoral. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] indicaram que a rapamicina é eficaz no modelo de encefalomielite alérgica experimental, um modelo para esclerose múltipla; no modelo de artrite adjuvante, um modelo para artrite reumatoide; e inibiu eficazmente a formação de anticorpos do tipo IgE.This invention relates to novel esters of rapamycin and a method for their use in the treatment of transplant rejection, host versus graft disease, autoimmune diseases, inflammatory diseases, and fungal infections. Rapamycin is a macrocyclic triene antibiotic produced by Streptomoves hroscrousus. which has been found to have antifungal activity, particularly against Candida albicans. both in vitro and in vivo [. Vezina et al., J. Antibiot. 28, 721 (1975); S.N. Seghal et al., J. Antibiot. 28, 727 (1975); Aaker et al., J. Antibiot. 31, 539 (1978); U.S. Patent No. 3,929,992; and U.S. Patent No. 3,993,749]. Rapamycin alone (U.S. Patent No. 4,885,171) or in combination with picibanil (U.S. Patent No. 4,401,653) has been shown to have antitumor activity. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)] indicated that rapamycin is effective in the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively inhibited the formation of IgE-like antibodies.
Os efeitos imunossupressores da rapamicina foram apresentados em FASEB 3, 3411 (1989), tendo a rapamicina revelado ser eficaz na inibição da rejeição de transplante (Requerimento de Patente dos E.U.A. Ser. No. 362.544 registada em 6 de Junho, 1989). A ciclosporina A e FK-506, outras moléculas macrocíclicas, também revelaram ser eficazes como agentes imunossupressores, sendo assim úteis na prevenção da rejeição do transplante [FASEB 4 3.3411 (1989); FASEB 3, 5256 (1989); e R.Y. Calne et al., Lancet 1183 (1978)].The immunosuppressive effects of rapamycin were reported in FASEB 3, 3411 (1989), with the disclosed rapamycin being effective in inhibiting transplant rejection (U.S. Patent Application Serial No. 362,544 filed June 6, 1989). Cyclosporin A and FK-506, other macrocyclic molecules, have also been shown to be effective as immunosuppressive agents, thus being useful in preventing transplant rejection [FASEB 4 3.3411 (1989); FASEB 3, 5256 (1989); and R.Y. Calne et al., Lancet 1183 (1978)].
Derivados mono- e diacilados da rapamicina (esterifiçados nas posições 28 e 43) revelaram ser úteis como agentes anti-fúngicos (Patente dos E.U.A. No. 4.316.885) e foram usados para produzir pródrogas da rapamicina solúveis na água (Patente dos E.U.A. No. 4.650.803). Recentemente, a numeração convencional para a rapamicina foi alterada; assim de acordo com a nomenclatura de Chemical Abstracts, os ésteres descritos anteriormente situar-se-iam nas posições 31 e 42. DESCRICÃO DO INVENTO:Mono- and diacylated derivatives of rapamycin (esterified at positions 28 and 43) have been found to be useful as antifungal agents (U.S. Patent No. 4,316,885) and were used to produce water soluble prodamates of rapamycin (U.S. Patent No. 4,650,803). Recently, the conventional numbering for rapamycin has been altered; thus according to the Chemical Abstracts nomenclature, the esters described above would be at positions 31 and 42. DESCRIPTION OF THE INVENTION:
Este invento proporciona derivados da rapamicina que são úteis como agentes imunossupressores, anti-inflamatõrios, e anti-fúngicos tendo a estruturaThis invention provides derivatives of rapamycin which are useful as immunosuppressive, anti-inflammatory, and anti-fungal agents having the structure
em que ou 1 ? 3 . R , R e R são cada um deles, independentemente, hidrogénio,in which or 1? 3. R 2, R 3 and R 4 are each independently hydrogen,
I I ο4 II , é — [C(CH2)mCH(CH2)nN]pC02R7 , Ο II ~C- (CH2)tX(CH2)uC02R11 ou R5 R6 Ο II -C- <iy^ COoR12. 5 R é hidrogénio, alquilo de 1-6 átomos de carbono, aralquilo de 8 q In 7-10 átomos de carbono, -(CH2)gCC>2R , -(CH2)rNR C02R , carbamil-alquilo de 2-3 átomos de carbono, aminoalquilo de 1-4 átomos de carbono, hidroxialquilo de 1-4 átomos de carbono, guanilalquilo de 2-4 átomos de carbono, mercaptoalquilo de 1-4 átomos de carbono, alquiltioalquilo de 2-6 átomos de carbono, indolilmeti-lo, hidroxifenilmetilo, imidazolilmetilo ou fenilo que é facultativamente mono-, di-, ou tri-substituido com um substituinte seleccionado de entre alquilo de 1-6 átomos de carbono, alcoxi de 1- 6 átomos de carbono, hidroxi, ciano, halo, nitro, carbalcoxi de 2- 7 átomos de carbono, trifluorometilo, amino, ou um ácido carboxílico; 6 9 . . . R e R são cada um deles, mdependentemente, hidrogénio, alquilo de 1-6 átomos de carbono, ou aralquilo de 7-10 átomos de carbono; 7 8 10 R , R , e R são cada um deles, independentemente, alquilo com 1-6 átomos de carbono, aralquilo de 7-10 átomos de carbono, fluorenilmetilo, ou fenilo que é facultativamente mono-, di- ou tri-substituido com um substituinte seleccionado de entre alquilo de 1-6 átomos de carbono, alcoxi de 1-6 átomos de carbono, 7(CH 2) m CH (CH 2) n N] p CO 2 R 7, or wherein R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkyl; R 5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 8 q In 7-10 carbon atoms, - (CH 2) g CC> 2R, - (CH 2) r NR CO 2 R, carbamyl alkyl of 2-3 atoms of carbon, aminoalkyl of 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, guanylalkyl of 2-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, alkylthioalkyl of 2-6 carbon atoms, indolylmethyl , hydroxyphenylmethyl, imidazolylmethyl or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro , carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid; 6 9. . . R and R are each independently hydrogen, alkyl of 1-6 carbon atoms, or aralkyl of 7-10 carbon atoms; R 1, R 2 and R 3 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, fluorenylmethyl, or phenyl which is optionally mono-, di-, or tri-substituted with a substituent selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms,
hidroxi, ciano, halo, nitro, carbalcoxi de 2-7 átomos de carbono, trifluorometilo, amino, ou um ácido carboxílico; R e R são cada um deles, independentemente, alquilo de 1-6 átomos de carbono, aralquilo de 7-10 átomos de carbono, ou fenilo que é facultativamente mono-, di- ou tri-substituido com um substituinte seleccionado de entre alquilo de 1-6 átomos de carbono, alcoxi de 1-6 átomos de carbono, hidroxi, ciano, halo, nitro, carbalcoxi de 2-7 átomos de carbono, trifluorometilo, amino, ou um ácido carboxílico; X é R13 X é -C-, 0, oUS; R14 ou R13 e R14 são cada um deles, independentemente, hidrogénio alquilo de 1-6 átomos de carbono; Y é CH ou N; m é 0-4; n é 0-4; p é 1-2; q é 0-4; r é 0-4; t é 0-4; u é 0-4; 5 6. em que R , R , m e n são independentes em cada uma das subunida-des οhydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid; R 1 and R 2 are each independently alkyl of 1-6 carbon atoms, aralkyl of 7-10 carbon atoms, or phenyl which is optionally mono-, di- or trisubstituted with a substituent selected from 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, cyano, halo, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, amino, or a carboxylic acid; X is R13 X is -C-, O, O; R14 or R13 and R14 are each independently hydrogen hydrogen of 1-6 carbon atoms; Y is CH or N; m is 0-4; n is 0-4; p is 1-2; q is 0-4; r is 0-4; t is 0-4; u is 0-4; Wherein R, R, m and n are independent at each of the subunits ο
IIII
[C(CH2)mCH(CH2)nN] R5 R6 quando p = 2; ou um seu sal farmacêuticamente aceitável, com a condição de que 12 3 R , R e R não sejam todos hidrogénio, ainda com a condição de 1.23. que R , R e R não sejam todos 0[C (CH 2) m CH (CH 2) n N] R 5 R 6 when p = 2; or a pharmaceutically acceptable salt thereof, with the proviso that R 1, R 2 and R 3 are not all hydrogen, yet with the proviso of 1.23. that R, R and R are not all 0
II -fC(CH2)mCH(CH2)nN]pC02R7 R5 R* e ainda com outra condição de que teu não sejam ambos 0 quando X é 0 ou S. 4 „(CH2) m CH (CH2) n N] pC02 R7 R5 R5 and further with another proviso that thy are not both 0 when X is 0 or S. 4 "
Dos compostos em que R e οOf the compounds in which R and ο
II - [C(CH2)mCH(CH2)nN]pC02R7II - [C (CH 2) m CH (CH 2) n N] p CO 2 R 7
I I R5 R6 p = 1; M = n = 0; e R5 Compostos membros preferidos são aqueles em que m = 0, n = 0, e 5 „ 8 0, n=0, ep=2;n=0, eR e -(CH ) CO R ; m = 0, Q 1 Λ " 3 " é -(CH ) NR C00R ;em=0;n=0, eR é hidrogénio, preferidos incluem também os membros em que R4 é 0 -C-(CH2)tX(CH2)uC02Ru .R 5 = R 6 = 1; M = n = 0; and R 5 Preferred member compounds are those wherein m = 0, n = 0, and 5, 8, n = 0, eps = 2, n = 0, and R e - (CH) m = 0, Q 1 Λ " 3 " and R is hydrogen, preferred also include those members wherein R 4 is 0 - (CH 2) t X (CH 2) u CO 2 R 11.
Os sais farmacêuticamente aceitáveis podem ser formados a partir de catiões inorgânicos tais como sódio, potássio, etc.; mono-, di-, e trialquil aminas de 1-6 átomos de carbono, ' por grupo alquilo e mono-, di-, e trihidroxialquil aminas de 1-6 átomos de carbono por grupo alquilo; e ácidos orgânicos tais como ácido acético, láctico, cítrico, tartárico, succínico, maleico, malónico, glucónico, etc. Sais básicos preferidos são formados a partir de catiões de sódio e tris(hidroximetil)metilamina.Pharmaceutically acceptable salts may be formed from inorganic cations such as sodium, potassium, etc .; mono-, di-, and trialkyl amines of 1-6 carbon atoms, per alkyl group and mono-, di-, and trihydroxyalkyl amines of 1-6 carbon atoms per alkyl group; and organic acids such as acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, etc. Preferred basic salts are formed from sodium and tris (hydroxymethyl) methylamine cations.
Os compostos deste invento podem ser preparados por acilação da rapamicina com um agente de acilação tendo estruturas gerais οThe compounds of this invention may be prepared by acylation of rapamycin with an acylating agent having general structures
II X“[C(CH2)mCH(CH2)nN]pC02R7 , I ι R5 R6 Ο X—C-(CH2)tX(CH2)uC02R11 , or Ο X-C-{r ^-COjR12 onde X é OH na presença de um reagente de acoplamento, tal como diciclohexilcarbodiimida. Os compostos deste invento podem também ser preparados usando um anidrido mixto do ácido carboxílico descrito anteriormente como a espécie acilante. Alternativamente, a espécie acilante pode ser um haleto ácido, onde X pode ser Cl, Br, ou I. Os grupos acilantes usados para preparar os compostos deste invento encontram-se comercialmente disponíveis ou podem ser preparados por métodos que são apresentados na bibliografia. A actividade imunossupressiva foi avaliada num processo de teste farmacológico padronizado in vitro para medir a proliferação de linfocitos (LAF) e em dois processos de teste farmacológico padronizados in vivo. 0 primeiro processo in vivo foi um processo de teste de ganglio linfático popliteo (PLN) que mediu o efeito de compostos deste invento numa reacção linfocitária mixta e o segundo processo in vivo avaliou o tempo de sobrevivência de um enxerto de pele apertado. 0 processo de proliferação de timocitos induzida por comitogénio (LAF) foi usado como uma medição in vitro dos efeitos 11Wherein X is OH in the presence of (C 1 -C 4) alkyl, or a pharmaceutically acceptable salt thereof, a coupling reagent, such as dicyclohexylcarbodiimide. The compounds of this invention may also be prepared using a mixed carboxylic acid anhydride described above as the acylating species. Alternatively, the acylating species may be an acid halide where X may be Cl, Br, or I. The acylating groups used to prepare the compounds of this invention are commercially available or can be prepared by methods which are presented in the literature. Immunosuppressive activity was evaluated in an in vitro standardized pharmacological test procedure to measure lymphocyte proliferation (LAF) and in two in vivo standardized pharmacological test procedures. The first in vivo procedure was a popliteal lymph node (PLN) test procedure which measured the effect of compounds of this invention on a mixed lymphocyte reaction and the second in vivo procedure evaluated the survival time of a tight skin graft. The process of comitogen-induced thymocyte proliferation (LAF) was used as an in vitro measurement of the effects 11
imunossupressores de compostos representativos. Resumidamente, células do timo de ratinhos BALB/c normais são cultivadas durante 72 horas com PHA e IL-1 e submetidas timidina triciada durante as últimas seis horas. As células são cultivadas com e sem várias concentrações de rapamicina, ciclosporina A, ou composto do teste. As células são recolhidas e incorporadas; a radioactivida-de é determinada. A inibição da proliferação linfocitãria é avaliada em alteração percentual em contagens por minuto em relação a controlos não tratados com a droga. Os resultados são expressos pela relação que se segue, ou como a inibição percentual da proliferação linfocitária de 1 μΜ. „ . 3 . 3 . . células timo controlo H - células timo tratadas H -rapamicina 3 3immunosuppressants of representative compounds. Briefly, thymus cells from normal BALB / c mice are cultured for 72 hours with PHA and IL-1 and subjected to tritiated thymidine during the last six hours. Cells are cultured with and without various concentrations of rapamycin, cyclosporin A, or test compound. Cells are harvested and incorporated; the radioactivity is determined. Inhibition of lymphocyte proliferation is evaluated in percent change in counts per minute relative to controls not treated with the drug. The results are expressed by the following relationship, or as the percent inhibition of lymphocyte proliferation of 1 μΜ. ". 3. 3. . thymus cells control H - treated thymus cells H -rapamycin 3 3
células timo controlo H - células tratadas ciomposto teste HThymus control cells H - treated cells ciomposite H test
Ocorre uma reacção linfocitária mixta (MLR) quando células linfoides de animais genéticamente distintos são combinadas em cultura de tecido. Cada uma estimula a outra de modo a desenvolver-se até blástula o que resulta num aumento da síntese de ADN que pode ser quantificado pela incorporação de timidina tritiada. Visto que a estimulação de uma MLR é uma função de disparidade nos antigénios de Histocompatibilidade Principal, um teste com ganglio linfático popliteo (PLN) in vivo correlaciona--se intimamente com a doença hospedeiro versus enxerto. Resumidamente, células do baço irradiadas de dadores BALB/c são injecta-das na almofada da pata posterior direita de ratinhos C3H recipientes. A droga é administrada diãriamente, per os do Dia 0 ao Dia 4. No Dia 3 e Dia 4, timidina tritiada é administrada i.p., b.i.d.. No Dia 5, os ganglios linfáticos politeos são removidos e dissolvidos, e a radioactividade é medida. 0 PLN esquerdo correspondente serve de controlo para o PLN da pata posterior injecta-da. A supressão percentual é calculada usando os animais não tratados com droga como controlo alogénico. A rapamicina numa dose de 6 mg/kg, p.o. deu origem a 86% de supressão, enquanto que a ciclosporina A na mesma dose deu origem a 43% de supressão. Os resultados são expressos pela relação que se segue:A mixed lymphocyte reaction (MLR) occurs when lymphoid cells from genetically distinct animals are combined in tissue culture. Each stimulates the other so as to develop to blastula which results in an increase in DNA synthesis that can be quantified by the incorporation of tritiated thymidine. Since stimulation of an MLR is a disparity function in Major Histocompatibility antigens, a popliteal lymph node (PLN) test in vivo correlates closely with host versus graft disease. Briefly, spleen cells irradiated from BALB / c donors are injected into the right hind paw pad of recipient C3H mice. The drug is administered daily, per day from Day 0 to Day 4. On Day 3 and Day 4, tritiated thymidine is administered i.p., b.i. .. On Day 5, the polypeptide lymph nodes are removed and dissolved, and the radioactivity is measured. The corresponding left PLN serves as control for the PLN of the injected hindpaw. Percent suppression is calculated using non-drug treated animals as allogeneic control. Rapamycin at a dose of 6 mg / kg, p.o. gave 86% suppression, while cyclosporin A at the same dose gave 43% suppression. The results are expressed by the following relation:
Ratinho C3H controlo células ^H-PLN - Ratinho C3H tratado rapamicina células %-PLN Ratinho C3H controlo células ^H-PLN- Ratinho Tratado - composto células ^H-PLN O segundo processo de teste in vivo tem como finalidade determinar o tempo de sobrevivência do enxerto de pele de aperto a partir de dadores DBA/2 machos transplantados para recipientes BAlB/c machos. 0 método é adaptado a partir de Billingham R.E. and Medawar P.B., J. Exp. Biol. 28:385-402, (1951). Resumidamente, um enxerto de pele por aperto a partir do dador é enxertado no dorso do recipiente como um homoenxerto, e é usado um autoen-xerto na mesma região como controlo. Os recipientes são tratados ou com várias concentrações de ciclosporina A como controlo do teste ou com o composto do teste, intraperitonealmente. Os recipientes não tratados servem como controlo da rejeição. O enxerto é monitorizado diariamente e as observações são registadas até o enxerto se tornar seco e formar uma crosta escurecida. Este é considerado como o dia da rejeição. O tempo de sobrevivência médio do enxerto (número de dias ± S.D.) do grupo de tratamento com a droga é comparado com o do grupo de controlo. O quadro que se segue resume os resultados de compostos representativos deste invento nestes processos de teste padronizados. \ 13 QUADRO 1 LAF PLN Enxerto Pele Composto (taxa) (taxa) (dias + SD) Exemplo 1 1,8 0,61 12,0±1,6 Exemplo 2 0,33 0,62 11,5+0,6 Exemplo 3 0,20 + 9,0±0,9 Exemplo 4 4,9 0,18 12,3±0,5 Exemplo 5 0,006 + 8,8±0,9 Exemplo 6 5,4 0,33 11,5±3,5 Exemplo 7 3% a ΙμΜ** + 7,7+1,5 Exemplo 8 0,03 0,41 + Exemplo 9 0.96 1,34 10,3±0,8 Exemplo 10 2,0 0,96++ 12,7±1,2 Exemplo 11 0,004 + 10,5±1,3 Exemplo 12 19,8 -2,87 12,0±2,0 Exemplo 13 22% a ΙμΜ + 7,0±0,6 Exemplo 14 0,37 + 8,2±1,2 Exemplo 15 0,9 0,69 10,7±1,2 14 14Mouse C3H control cells ^ H-PLN - mouse C3H treated rapamycin cells% -PLN mouse C3H control cells ^ H-PLN- Treated mouse - compound cells ^ H-PLN The second in vivo test procedure is to determine the survival time of the tightening skin graft from male DBA / 2 donors transplanted into male BALB / c containers. The method is adapted from Billingham R.E. and Medawar P.B., J. Exp. Biol. 28: 385-402, (1951). Briefly, a graft skin graft from the donor is grafted onto the back of the recipient as a homograft, and a self-grafting is used in the same region as control. The containers are treated either with various concentrations of cyclosporin A as test control or with the test compound, intraperitoneally. Untreated containers serve as control of rejection. The graft is monitored daily and observations are recorded until the graft becomes dry and forms a darkened crust. This is considered as the day of rejection. The mean graft survival time (number of days ± S.D.) of the drug treatment group is compared with that of the control group. The table below summarizes the results of representative compounds of this invention in these standardized test procedures. TABLE 1 LAF PLN Graft Skin Composite (rate) (rate) (days + SD) Example 1 1.8 0.61 12.0 ± 1.6 Example 2 0.33 0.62 11.5 + 0.6 Example 3 0.20 ± 9.0 ± 0.9 Example 4 4.9 0.18 12.3 ± 0.5 Example 5 0.006 + 8.8 ± 0.9 Example 6 5.4 0.33 11.5 ± 3.5 Example 7 3% a ΙμΜ ** + 7.7 + 1.5 Example 8 0.03 0.41 + Example 9 0.96 1.34 10.3 ± 0.8 Example 10 2.0 0.96 ++ 12.7 ± 1.2 Example 11 0.004 + 10.5 ± 1.3 Example 12 19.8 -2.87 12.0 ± 2.0 Example 13 22% a ΙμΜ + 7.0 ± 0.6 Example 14 0.37 + 8.2 ± 1.2 Example 15 0.9 0.69 10.7 ± 1.2 14 14
QUADRO 1 (Continuação^ LAF PLN Enxerto Pele Composto (taxai (taxai (dias + SD1 Exemplo 16 3,27 1/04## 12,7+0,9 Exemplo 17 0,56 1,68### 10,2±1,7 Exemplo 18 0,02 1,11## 8,0±1,7 Exemplo 19 0,01 0,48 8,0±0,9 Exemplo 20 0,97 0,70 9,3±1,6 Exemplo 21 0,22 -1,93 12,0±1,7 Exemplo 22 0,22 0,41 10,2±1,2 Exemplo 23 0,18 0,39 10,8±0,8 Exemplo 24 0,00 0,09 7,8±1,7 Rapamicina 1/0 1,0 12,0±1,7 * 0 cálculo das taxas foi descrito supra. ** Resultado expresso como inibição percentual da proliferação linfocitária a ΙμΜ Não avaliado ++ Resultados obtidos usando cremofore/etanol como veículo de administração. Taxas de 0,33 e 1,07 foram também obtidas usando carboximetilcelulose como um veículo para administração . ## Resultados obtidos usando cremofore/etanol como um veículo para administração. Taxas de 0,20 e 1,08 foram também obtidas usando carboximetil celulose como um veículo para administração. ### Uma taxa de 0,42 foi também obtida para este composto.TABLE 1 (Continued) LAF PLN Compound Skin Graft (taxai (taxai (days + SD1) Example 16 3.27 1/04 ## 12.7 + 0.9 Example 17 0.56 1.68 ### 10.2 ± 1.7 Example 18 0.02 1.11 ## 8.0 ± 1.7 Example 19 0.01 0.48 8.0 ± 0.9 Example 20 0.97 0.70 9.3 ± 1.6 Example 21 0.22 -1.93 12.0 ± 1.7 Example 22 0.22 0.41 10.2 ± 1.2 Example 23 0.18 0.39 10.8 ± 0.8 Example 24 0, 00 0.09 7.8 ± 1.7 Rapamycin 1/0 1.0 12.0 ± 1.7 * Calculation of the rates was described supra. ** Result expressed as percent inhibition of lymphocyte proliferation at ΙμΜ Not evaluated ++ Results obtained using cremofore / ethanol as a delivery vehicle Rates of 0.33 and 1.07 were also obtained using carboxymethylcellulose as a vehicle for administration. and 1.08 were also obtained using carboxymethyl cellulose as a vehicle for administration. A rate of 0.42 was also obtained for this compound.
Os resultados destes processos de teste farmacológico padronizado demonstra a actividade imunossupressora tanto in vitro como in vivo para os compostos deste invento. Taxas 15 4The results of these standard pharmacological test procedures demonstrate immunosuppressive activity both in vitro and in vivo for the compounds of this invention. Rates 15 4
relativas nos processos de teste LAF e PLN indicam supressão da proliferação de células T. Como os enxertos de pele com aperto transplantados são rãpidamente rejeitados no espaço de 6-7 dias sem a utilização de um agente imunossupressor, o tempo de sobrevivência aumentado do enxerto de pele quando tratado com os compostos deste invento demonstra ainda a sua utilidade como agentes imunossupressores. Embora pareça que o composto apresentado pelos Exemplos 12 e 21 possam causar proliferação de células T no processo de teste PLN, pensa-se que uma taxa negativa neste processo do teste juntamente com um tempo de sobrevivência aumentado observado no processo de teste de enxerto de pele indica uma proliferação de células T„mvA„A>íie, que são implica-relative in the LAF and PLN test procedures indicate suppression of T cell proliferation. As transplanted tightening skin grafts are rapidly discarded within 6-7 days without the use of an immunosuppressive agent, the increased survival time of the graft skin when treated with the compounds of this invention further demonstrates their utility as immunosuppressive agents. While it appears that the compound shown in Examples 12 and 21 can cause proliferation of T cells in the PLN test procedure, it is believed that a negative rate in this test procedure coupled with an increased survival time observed in the skin graft test procedure indicates a proliferation of " mvA " A > T cells, which are
SUpreSSOraS das na supressão da resposta imunitária, (ver, I. Roitt et al. Immunology, C.V. Moseby Co. 1989, p 12.8-12.11). A actividade anti-fúngica dos compostos deste invento foi medida contra 5 estirpes de Candida albicans usando um processo de teste de placa para medição da inibição. 0 que se segue representa o processo típico usado. 0 composto a ser testado foi colocado em discos de placa 1/4" secas com esterilização, e deixado secar. Placas de agar foram semeadas com fungos e deixadas solidificar. Os discos impregnados foram colocados na superfície Agar semeada e incubados durante o tempo requerido para uma determinada cultura. Os resultados são expressos em MIC (/jg/ml) para inibir o crescimento. Os resultados deste processo de teste revelaram que os compostos deste invento possuem actividade anti-fúngica; contudo, foi surpreendente o facto dos compostos deste invento serem menos activos do que o composto afim, rapamicina.(See, I. Roitt et al., Immunology, C.V. Moseby Co. 1989, p 12.8-12.11). The antifungal activity of the compounds of this invention was measured against 5 strains of Candida albicans using a plate test method for inhibition measurement. The following represents the typical process used. The compound to be tested was placed on 1/4 plate discs " dried with sterilization, and allowed to dry. Agar plates were seeded with fungi and allowed to solidify. The impregnated discs were placed on the seeded agar surface and incubated for the time required for a given culture. Results are expressed as MIC (μg / ml) to inhibit growth. The results of this test procedure revealed that the compounds of this invention possess antifungal activity; however, it was surprising that the compounds of this invention are less active than the like compound, rapamycin.
. *. *
Quadro 2Table 2
Estirpe de Candida albicansStrain of Candida albicans
Composto ATCC 10231 ATCC 38246 ATCC 38247 ATCC 38248 3669 Exemplo 1 >0,4 >0,4 >0,4 >0,4 0,4 Exemplo 2 0,1 0,2 0,2 0,2 0,1 Exemplo 3 0,4 >0,4 >0,4 >0,4 0,4 Exemplo 4 0,1 0,4 0,1 0,1 0,2 Exemplo 5 >0,4 >0,4 >0,4 >0,4 >0,4 Exemplo 6 0,1 >0,4 0,2 0,4 >0,4 Exemplo 7 + + + + + Exemplo 8 >0,4 >0,4 >0,4 >0,4 >0, Exemplo 9 0,4 >0,4 0,4 >0,4 >0, Exemplo 10 0,2 >0,4 0,2 0,4 0, Exemplo 11 >0,4 >0,4 >0,4 >0,4 >0, Exemplo 12 0,2 >0,4 0,1 0,2 0, Exemplo 13 >0,4 >0,4 >0 / 4 >0,4 >0, Exemplo 14 >0,4 >0,4 >0,4 >0,4 >0, Exemplo 15 >0,4 0,4 >0,4 0,4 0, Exemplo 16 0,2 0,1 0,4 0,1 0, Exemplo 17 >0,4 0,2 >0,4 0,2 0, Exemplo 18 0,4 >0,4 >0,4 >0,4 >0, Exemplo 19 0,4 >0,4 0,4 >0,4 >0, 17Compound ATCC 10231 ATCC 38246 ATCC 38247 ATCC 38248 3669 Example 1> 0.4> 0.4> 0.4> 0.4 0.4 Example 2 0.1 0.2 0.2 0.2 0 , 1 Example 3 0.4 > 0.4 > 0.4 > 0.4 0.4 Example 4 0.1 0.4 0.1 0.1 0.2 Example 5 > 0.4 > > 0.4> 0.4> 0.4> 0.4 Example 6 0.1 > 0.4 0.2 0.4 > 0.4 Example 7 + > > 0.4> 0.4> 0.4> 0.4> 0, Example 9 0.4> 0.4 0.4> 0.4 <0, Example 10 0.2 > 0.4 0.2 0.4 0, Example 11> 0.4> 0.4> 0.4> 0.4> 0, Example 12 0.2> 0.4 , 1 0.2 0, Example 13> 0.4> 0.4> 0/4> 0.4> 0, Example 14> 0.4> 0.4> 0.4 > 0.4 > 0, Example 15 > 0.4 > 0.4 < 0.4 > 0, Example 16 < 0.2 > , 4 0.2 > 0.4-0.0, Example 18 0.4 > 0.4 > 0.4 > 0.4 > 0, Example 19 0.4 > 0.4 , 4 > 0.4 > 0.17
Quadro 2* (Continuação)Table 2 (Continued)
Estirpe de Candida albicans Comoosto ATCC 10231 ATCC 38246 ATCC 38247 ATCC 38248 3669 Exemplo 20 0,1 0,4 0,1 0,1 0,2 Exemplo 21 0,4 >0,4 0,4 >0,4 >0,4 Exemplo 22 0,2 >0,4 0,2 0,4 >0,4 Exemplo 23 0,1 >0,4 0,2 0,4 >0,4 Exemplo 24 >0,4 >0,4 >0,4 >0,4 >0,4 Rapamicina 0,003 0,025 0,003 0,006 0,025 expresso camo MIC ^g/ml) + não avaliadoStrain of Candida albicans Comoosto ATCC 10231 ATCC 38246 ATCC 38247 ATCC 38248 3669 Example 20 0.1 0.4 0.1 0.1 0.2 Example 21 0.4 > 0.4 > 0.4 >; 0.4 Example 22 0.2 > 0.4 0.2 0.4 > 0.4 Example 23 0.1 > 0.4 0.2 0.4 > 0.4 Example 24 > 0.4 > 0.4 > 0.4 > 0.4 > 0.4 Rapamycin 0.003 0.025 0.003 0.006 0.025 expressed non-titrated MIC >
Tendo como base os resultados destes processos de teste farmacológico, os compostos são úteis no tratamento da rejeição de transplantes tais como, coração, rim, fígado, medula óssea, e transplantes de pele; de doenças autoimunitárias tais como, lupus, artrite reumatoide, diabetes mellitus, miastenia gravis, e esclerose múltipla; e doenças inflamatórias tais como psoríase, dermatite, eczema, seborreia, doença inflamatória do intestino; e infecções por fungos.Based on the results of these pharmacological test procedures, the compounds are useful in the treatment of rejection of transplants such as heart, kidney, liver, bone marrow, and skin transplants; of autoimmune diseases such as, lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, and multiple sclerosis; and inflammatory diseases such as psoriasis, dermatitis, eczema, seborrhoea, inflammatory bowel disease; and fungal infections.
Os compostos podem ser administrados puros ou com um veículo farmacêutico a um mamífero necessitado desse tratamento. 0 veículo farmacêutico pode ser sólido ou líquido.The compounds may be administered neat or with a pharmaceutical carrier to a mammal in need of such treatment. The pharmaceutical carrier may be solid or liquid.
Um veículo sólido pode incluir uma ou mais substancias que podem também actuar como agentes de aromatização, lubrificantes, solubilizadores, agentes de suspensão, agentes de enchimento, agentes de deslizamento, auxiliares de compressão, agentes de ligação ou agentes de desintegração dos comprimidos; pode tambémA solid carrier may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents; may also
ser um material encapsulante. Em pós, o veiculo é um sólido finamente dividido que se apresenta misturado com o ingrediente activo finamente dividido. Em comprimidos, o ingrediente activo é misturado com um veículo tendo as necessárias propriedades de compressão em proporções apropriadas e é prensado no formato e tamanho desejados. Os pós e comprimidos contêm de preferência até 99% do ingrediente activo. Veículos sólidos apropriados incluem, por exemplo, fosfato de cálcio, estearato de magnésio, talco, açucares, lactose, dextrina, amido, gelatina, celulose, metil celulose, carboximetil celulose de sódio, polivinilpirrolidona, ceras com baixo ponto de fusão e resinas permutadores de iões.be an encapsulating material. In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in appropriate proportions and pressed into the desired size and shape. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ions.
Veículos líquidos são usados na preparação de soluções, suspensões, emulsões, xaropes, elixires e composições pressurizadas. 0 ingrediente activo pode ser dissolvido ou suspenso num veículo líquido farmacêuticamente aceitável tal como água, um solvente orgânico, uma mistura de tanto óleos como gorduras farmacêuticamente aceitáveis. 0 veículo líquido pode conter outros aditivos farmacêuticos apropriados tais como solubilizado-res, emulsificadores, tampões, preservativos, edulcorantes, agentes de aromatização, agentes de suspensão, agentes de espes-samento, corantes, reguladores da viscosidade, estabilizadores e osmo-reguladores. Exemplos apropriados de veículos líquidos para administração oral e parentérica incluem água (parcialmente contendo aditivos tal como referido anteriormente, por exemplo derivados da celulose, de preferência solução de carboximetil celulose de sódio), álcoois (incluindo álcoois monohídricos e álcoois polihídricos, por exemplo glicois) e seus derivados, e óleos (por exemplo óleo de côco e óleo de araquis fraccionados). Para administração parentérica, o veículo pode também ser um éster oleoso tal como oleato de etilo e miristato de isopropilo. Veículos líquidos estéreis são úteis em composições sob a forma líquida estéril para administração parentérica. 0 veículo líquido 19 para composições pressurizadas pode ser hidrocarboneto halogenado ou outro propulsor farmacêuticamente aceitável.Liquid carriers are used in the preparation of solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both pharmaceutically acceptable oils and fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity regulators, stabilizers and osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as mentioned above, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example, coconut oil and fractionated arachis oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier 19 for pressurized compositions may be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
Composições farmacêuticas líquidas que são soluções ou suspensões estéreis podem ser utilizadas para, por exemplo, injecção intramuscular, intraperitoneal ou subcutânea. Soluções estéreis podem também ser administradas intravenosamente. 0 composto pode também ser administrado oralmente sob uma forma de composição líquida ou sólida.Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. The compound may also be administered orally in a liquid or solid composition form.
De preferência, a composição farmacêutica apresenta-se sob a forma de unidade de dosagem, por exemplo sob a forma de comprimidos ou de cápsulas. Nessa forma, a composição é sub-divi-dida em dose unitária contendo quantidades apropriadas do ingrediente activo; as formas de unidade de dosagem podem ser composições embaladas, por exemplo, pós embalados, frascos, ampolas, seringas cheia préviamente ou saquinhos contendo líquidos. A forma de unidade de dosagem pode ser, por exemplo, ela própria uma cápsula ou comprimido, ou pode ser o número apropriado de qualquer uma dessas composições sob forma embalada. A dose a ser usada no tratamento deve ser determinada subjectivamente pelo médico assistente.Preferably, the pharmaceutical composition is in unit dosage form, for example in the form of tablets or capsules. In that form, the composition is subdivided into a unit dose containing appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example, prepackaged powders, vials, ampoules, pre filled syringes or sachets containing liquids. The unit dosage form may be, for example, itself a capsule or tablet, or may be the appropriate number of any such compositions in packaged form. The dose to be used for treatment should be determined subjectively by the attending physician.
Além disso, os compostos deste invento podem ser utilizados como uma solução, creme, ou loção por formulação com veículos farmacêuticamente aceitáveis contendo 0,1-5 por cento, de preferência 2%, de composto activo que pode ser administrado a uma superfície afectada por fungos.In addition, the compounds of this invention may be used as a solution, cream, or lotion by formulation with pharmaceutically acceptable carriers containing 0.1-5 percent, preferably 2%, active compound that can be administered to a surface affected by fungi.
Os exemplos que se seguem ilustram a preparação de compostos representativos deste invento. EXEMPLO 1 Éster-42-Rapamicina com N-Γ(l.l-dimetiletoxilcarbonill-qlicilqli-cinaThe following examples illustrate the preparation of representative compounds of this invention. EXAMPLE 1 Ester-42-Rapamycin with N-β- (1,1-dimethylethoxylcarbonyl) -cyclicquinoline
Em condições anidras, uma solução de rapamicina (3 g, 3,28 mrnole) e N-[(1,1-dimetiletoxi)carbonil]-glicilglicina (3,04 g, 13,1 mrnole) em 40 ml de diclorometano anidro foi tratada com diciclohexilcarbodiimida (1,35 g, 6,56 mrnole) seguindo-se 4-dime-tilaminopiridina (0,8 g, 6,56 mrnole). Após agitação à temperatura ambiente durante 48 horas, o sólido precipitado foi recolhido e lavado com diclorometano. Os filtrados combinados foram absorvidos directamente para gel de sílica Merck 60 por adição do gel e evaporação até à secura. Cromatografia luminosa do material préabsorvido (usando uma eluição em gradiente com acetato de etilo-tolueno de 2:1 a 1:0 v/v) proporcionou 1,05 g (28,3%) do composto do título isolado como um solvato a três quartos de tolueno, juntamente com o diéster-31,42 do Exemplo 2. Análise HPLC revelou que o monoéster é uma mistura 8,3:1 de dois confór-meros. 1H RMN (CDC13, 400 MHz): S 1,46 (m, 9H, COOBut), 1,654 (s, 3H), CH3C=C) , 1,751 (s, 3H, CH3C=C) , 3,14 (s, 3H, CI^O) , 3,33 (s, 3H, CH30), 3,36 (s, 3H, CH30), 4,18 (d, 1H, CHOH), 4,75 (m, 1H, 42-CHO), 4,79 (s, 1H, OH); MS Elev. Sep. (FAB ião neg.) Cale. para c60H39N3Oi7:1127.6504, massa medida 1127.6474.Under anhydrous conditions, a solution of rapamycin (3 g, 3.28 mmol) and N - [(1,1-dimethylethoxy) carbonyl] glycylglycine (3.04 g, 13.1 mmol) in anhydrous dichloromethane (40 mL) (1.35 g, 6.56 mmol) followed by 4-dimethylaminopyridine (0.8 g, 6.56 mmol). After stirring at room temperature for 48 hours, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were absorbed directly onto Merck silica gel 60 by addition of the gel and evaporation to dryness. Light chromatography of the preabsorbed material (using gradient elution with 2: 1 to 1: 0 v / v ethyl acetate-toluene) afforded 1.05 g (28.3%) of the title compound isolated as a solvate three quarts of toluene together with the diester 31.42 of Example 2. HPLC analysis revealed that the monoester is an 8.3: 1 mixture of two confections. 1H NMR (CDCl3, 400 MHz): δ 1.46 (m, 9H, COOBut), 1.654 (s, 3H), CH3C = C), 1.751 (s, 3H, CH3C = C), 3.14 (s, 3H), 3.33 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.18 (d, 1H, CHOH), 4.75 (m, 1H, CHO), 4.79 (s, 1H, OH); MS Elev. Sep. (FAB ion neg.) Calc. for c60H39N3O17: 1127.6504, metered mass 1127.6474.
Anal. Cale. para C60H3gN3017*0,75PhCH3: C,65,45;H,8,33;N,3,51 Encontrados: C,65,23;H,8,32;N,3,86Anal. Calc. for C60 H30 N3 O177 * 0.75 P CHCl3: C, 65.45 H, 8.33; N, 3.51 Found: C, 65.23; H, 8.32; N, 3.86
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do amino ácido apropriado 21The following representative compounds may be prepared from rapamycin and the appropriate amino acid 21
substituído terminalmente em N utilizando o método usado para preparar o composto do título no Exemplo 1. com N-[(fluorenilmetoxi)carbonil]-alanilseri- com N-[(fluorenilmetoxi)carbonil]-glicilgli-terminally N-substituted using the method used to prepare the title compound in Example 1. with N - [(fluorenylmethoxy) carbonyl] alanylserine with N - [(fluorenylmethoxy) carbonyl] -glycyl-
Éster-42-Rapamicina na Éster-42-Rapamicina cina Éster-42-Rapamicina Éster-4 2-Rapamicina ginina Éster-42-Rapamicina Éster-42-Rapamicina -N-etilalanina Éster-4 3-Rapamicina nilfenilalanina Éster-42-Rapamicina glicina com N-[(etoxi)carbonil]-arginilmetionina com N-[(4'-clorofenoxi)carbonil]-histidilar- com N-[(fenoxi)carbonil]-triptofanilleucina com N-[(fenilmetoxi)carbonil)]-N-metilglicil- com N-[(fenilmetoxi)carbonil]-N-metil-B-ala- com N-[(1,1-dimetiletoxi)carbonil]-cisteinil-Ester-42-Rapamycin in Ester-42-Rapamycin cine Ester-42-Rapamycin Ester-4 2-Rapamycin gynein Ester-42-Rapamycin Ester-42-Rapamycin N-ethylalanine Ester-4 3-Rapamycin nylphenylalanine Ester-42-Rapamycin glycine with N - [(ethoxy) carbonyl] arginylmethionine with N - [(4'-chlorophenoxy) carbonyl] -histidyl- with N - [(phenoxy) carbonyl] -tryptophanyl ketine with N - [(phenylmethoxy) carbonyl] -N N-methylglycine with N - [(phenylmethoxy) carbonyl] -N-methyl-B-ala with N - [(1,1-dimethylethoxy) carbonyl] -cysteinyl-
Exemplo 2Example 2
Diéster-31.42-Rapamicina com N-f(lf1-dimetiletoxi^carbonill-qli-cilglicina 0 composto do título (1,85 g, 42%) foi separado do monoéster-42 tal como foi descrito no Exemplo 1 e isolado com um solvato de três quartos de tolueno. Análise HPLC revelou que o diéster era uma mistura 8.1:1 de conformeros. 22 1H RMN (CDC13, 400 MHz): 8 1,452 (m, 18H, COOBut), 1,6612 (S, 3H, CH3C=C), 1,7815 (S, 3H, CH3C=C), 3,14 (S, 3H, OCH3), 3,34 (s, 3H, =CH3), 3,35 (S, 3H, OCH3), 4,52 (s, 1H, OH), 4,79 (m, 1H, 42-CHO); MS Elev. Sep. (FAB ião neg.): Cale para C6gHio7N5°21 1341,7458, massa medida: 1341,7463. )The title compound (1.85 g, 42%) was separated from the monoester-42 as described in Example 1 and isolated with a solvate of three (1) -dimethylsilyloxycarbonyl- (m, 18H, COOBut), 1.6612 (S, 3H, CH3 C = C), 1.38 (s, 3H) (S, 3H, OCH3), 3.34 (s, 3H, = CH3), 3.35 (s, 3H, OCH3), 3.78 , 52 (s, 1H, OH), 4.79 (m, 1H, 42-CHO), MS (Sep) (FAB ion neg.): Calc'd for CgHH7NN °O 13 21 1341.7458, measured mass: 1341.7463 .)
Anal. Cale. para C6gH107N5O21*0,75PhCH3: C,63,17;H,8,06;N,4,96 Encontrados: C,62,83;H,8,09;N,5,00Anal. Calc. for C 6 H 10 7 N 5 O 2 • 0.75 P CH 3: C, 63.17: H, 8.06: N, 4.96 Found: C, 62.83; H, 8.09; N, 5.00
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do amino ácido apropriado substituído terminalmente em N utilizando o método usado para preparar o composto do título no Exemplo 2.The following representative compounds may be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 2.
Diéster-31,42-Rapamicina nilserina Diéster-31,42-Rapamicina cilglicina Diéster-31,42-Rapamicina Diéster-31,42-Rapamicina dilarginina Diéster-31,42-Rapamicina cina Diéster-31,42-Rapamicina glicil-N-etil-alanina Diéster-31,42-Rapamicina -B-alanilfenil-alanina Diéster-31,42-Rapamicina teinilglicina com N-[(fluorenilmetoxi)carbonil]-ala- com N-[(fluorenilmetoxi)carbonil]-gli- com N-[(etoxi)carbonil]-atginilmetionina com N-[(4'-clorofenoxi)carbonil]-histi- com N-[(fenoxi)carbonil]-triptofanilleu- com N-[(fenilmetoxi)carbonil)]-N-metil- com N-[(fenilmetoxi)carbonil)]-N-metil- com N-[(1,1-dimetiletoxi)carbonil]-cis- iDyster-31.42-Rapamycin Nilserine Diester-31.42-Rapamycin Cylglycine Diester-31.42-Rapamycin Diester-31.42-Rapamycin Dilarginine Diester-31.42-Rapamycin Cine Diester-31.42-Rapamycin Glycyl-N- ethyl-alanine Diester-31.42-Rapamycin-B-alanylphenylalanine Diester-31.42-Rapamycin theinylglycine with N - [(fluorenylmethoxy) carbonyl] -ala- with N - [(fluorenylmethoxy) carbonyl] -glycine N - [(ethoxy) carbonyl] -atginylmethionine with N - [(4'-chlorophenoxy) carbonyl] -histidine with N - [(phenoxy) carbonyl] -tryptophanyl with N - [(phenylmethoxy) carbonyl] -N-methyl - with N - [(phenylmethoxy) carbonyl)] - N-methyl- with N - [(1,1-dimethylethoxy) carbonyl]
Exemplo 3Example 3
Diéster-31,42-Rapamicina com Ν-Γ(1,1-dimetiletoxi)carbonill-N-me-tilglicinaDiester-31.42-Rapamycin with Ν-Γ (1,1-dimethylethoxy) carbonyl-N-methylglycine
Em condições anidras, uma solução de rapamicina (2 g, 2,18 mmole) arrefecida com gelo e Na-Boc sarcosina (1,65 g, 8,75 mmole) em 20 ml de diclorometano anidro foi tratada com diciclo-hexilcarbodiimida (1,8 g, 8,7 mmole) seguindo-se 4-dimetilamino-piridina (1 g, 8,7 mmole). Após agitação durante a noite à temperatura ambiente, o sólido precipitado foi recolhido e lavado com diclorometano. Os filtrados combinados foram evaporados até â secura para dar origem a um sólido amorfo de côr ambar (3 g). 0 produto crú foi purificado por cromatografia luminosa (sobre silica Merck 60, eluição com hexano-acetato de etilo 1:1, v/v) para proporcionar o composto do título (0,75 g, 27,4%) juntamente com monoéster-42 do Exemplo 4. Análise HPLC revelou que o diéster é uma mistura 19,8:1 confórmeros. A multiplicidade dos picos de RMN sugeriu a presença de rotâmeros de amida. XH RMN (CDC13, 400 MHz): δ 1,411, 1,438, 1,448 e 1,474 (m, 18 H, COOBut), 2,91 (m, 6H, NCH3), 3,14 (s, 3H, CH30), 3,34 (s, 3H, CH30), 3,37 (S, 3H, CH30), 4,73 (amplo, 1H, 42-CHO), 4,82 (2s, 1H, OH); MS Elev. Sep. (FAB ião neg.): Cale. para C67H1Q5N3019 1255,7342, massa medida 1255,7289.Under anhydrous conditions, an ice cold solution of rapamycin (2 g, 2.18 mmol) and Na-Boc sarcosine (1.65 g, 8.75 mmol) in 20 mL of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide (1 , 8 g, 8.7 mmol) followed by 4-dimethylamino pyridine (1 g, 8.7 mmol). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were evaporated to dryness to give an amorphous amber solid (3 g). The crude product was purified by flash chromatography (on Merck silica 60, elution with hexane-ethyl acetate 1: 1, v / v) to provide the title compound (0.75 g, 27.4%) along with monoester- 42 of Example 4. HPLC analysis showed the diester to be a 19.8: 1 mixture. The multiplicity of the NMR peaks suggested the presence of amide rotamers. 1 H NMR (CDCl 3, 400 MHz): δ 1.411, 1.438, 1.448 and 1.474 (m, 18 H, COOBut), 2.91 (m, 6H, NCH 3), 3.14 (s, 3H, CH 3) 34 (s, 3H, CH3), 3.37 (s, 3H, CH3), 4.73 (broad, 1H, 42-CHO), 4.82 (2s, 1H, OH); MS Elev. Sep. (FAB ion neg.): Calc. for C67H1Q5N3019 1255.7342, measured mass 1255.7289.
Anal. Cale. para nc;No0. _ : C,64,04;H,8,42;N,3,34 67 105 3 19Anal. Calc. for nc; Found: C, 64.04; H, 8.42; N, 3.34 67 105 3 19
Encontrados: C,64,14;H,8,74;N,3,63Found: C, 64.14; H, 8.74; N, 3.63
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do amino ácido apropriado substituído terminalmente em N utilizando o método usado para preparar o composto do título no Exemplo 3. 24 24 Diéster-31,42-Rapamicina com Diéster-31,42-Rapamicina com alanina Diéster-31,42-Rapamicina com nil]-isoleucina Diéster-31,42-Rapamicina com tamina Diéster-31,42-Rapamicina com Diéster-31,42-Rapamicina com nobutírico Diéster-31,42-Rapamicina com -aminoheptanoico Diéster-31,42-Rapamicina com Exemplo 4 Éster-31.42-Rapamicina com tilcrlicina N-[(etoxi)carbonil]tirosina N-[(fluorenilmetoxi)carbonil]-fenil· N-[(3',4',5'-trihidroxifenoxi)carbo· N-[(1,1-dimetiletoxi)carbonil)-glu· N-[(fenoxi)carbonil]-N-metilalanina ácido N—[(propiloxi)carbonil]-4-ami ácido N-[(fenilmetoxi)carbonil]-7 N-[(fluorenilmetoxi)carbonil]serina N-Γ(1,1-dimetiletoxi)carbonil1-N-meThe following representative compounds can be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 3. Diester-31.42-Rapamycin with Diester-31, 42-Rapamycin with alanine Diester-31.42-Rapamycin with nil] -isoleucine Diester-31.42-Rapamycin with tamin Diester-31.42-Rapamycin with Diester-31.42-Rapamycin with nobutyric Diester-31.42-Rapamycin with N-[(ethoxy) carbonyl] tyrosine N - [(fluorenylmethoxy) carbonyl] -phenyl · N - [(3 ', 4', 7 ' 5'-trihydroxyphenoxy) carbon · N - [(1,1-dimethylethoxy) carbonyl] -glu · N - [(phenoxy) carbonyl] -N-methylalanine N - [(propyloxy) carbonyl] -4- [(phenylmethoxy) carbonyl] -7 N - [(fluorenylmethoxy) carbonyl] serine N - [(1,1-dimethylethoxy) carbonyl] -N-
Em condições anidras, uma solução de rapamicina (0,95 » CL *Under anhydrous conditions, a solution of rapamycin (0.95% CL *
g, 1,02 mmole) arrefecida com gelo e N -Boc sarcosina (0,21g, 1,1 mmole) em 20 ml de diclorometano anidro foi tratada com diciclo-hexilcarbodiimida (1,8 g, 8,7 mmole) seguindo-se 4-dimetilamino-piridina (0,21 g, 1 mmole). Após agitação durante 4 horas à temperatura ambiente, o sólido precipitado foi recolhido e lavado com diclorometano. Os filtrados combinados foram concentrados in vacuo para dar origem a um sólido amorfo de côr ambar. Cromato-grafia luminosa do produto crú (sobre sílica merck 60, eluição com hexano-acetato de etilo 1:1 v/v para remover o diéster do Exemplo 3, seguindo-se clorofórmio-acetato de etilo-metanol 75:25:1 v/v) proporcionou o composto do título purificado parcialmente (0,38 g, 35%). O produto puro foi obtido por HPLC 25 preparativa (Waters Prp 500, gel de sílica, clorofórmio-acetato de etilo-metanol 75:25:1 v/v, taxa de fluxo 250 mL/min). Análise HPLC revelou que o éster é uma mistura 6,6:1 de dois confórmeros. A multiplidade de picos com RMN sugere a presença de rotâmeros de amida. XH RMN (CDC13, 400 MHz): S 1,42-1,46 (ds, 9H, COOBut), 2,91 (ds, 3H, NCH3), 1,644 (s, 3H, CH3C=C), 1,738 (s, 3H, CH3C=C), 3,12 (s, 3H, CH30), 3,32 (s, 3H), CH30), 3,35 (s, 3H, CH30), 4,18 (d, 1H, CHOH), 4,71 (amplo, 1H, 42-CHO), 4,78 (amplo s, 1H, OH); MS Elev. sep. (FAB ião neg.): Cale. para C59H92N2°i6 1084,6446, massa medida 1084,6503.g, 1.02 mmol) and N-Boc sarcosine (0.21 g, 1.1 mmol) in anhydrous dichloromethane (20 mL) was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmol) was added 4-dimethylamino pyridine (0.21 g, 1 mmol). After stirring for 4 hours at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give an amorphous amber solid. Chromatography of the crude product (on silica merck 60, elution with 1: 1 v / v hexane-ethyl acetate to remove the diester of Example 3, followed by 75: 25: 1 chloroform-ethyl acetate-methanol / v) afforded the partially purified title compound (0.38 g, 35%). The pure product was obtained by preparative HPLC (Waters Prp 500, silica gel, 75: 25: 1 v / v chloroform-ethyl acetate-methanol, flow rate 250 mL / min). HPLC analysis revealed that the ester is a 6.6: 1 mixture of two conformers. The multiplicity of NMR peaks suggests the presence of amide rotamers. 1 H NMR (CDCl 3, 400 MHz): δ 1.42-1.46 (ds, 9H, COOBut), 2.91 (ds, 3H, NCH3), 1.644 (s, 3H, CH3 C = C), 1.738 , 3.32 (s, 3H, CH 3), 3.35 (s, 3H, CH 3), 4.18 (d, 1H, CHOH), 4.71 (broad, 1H, 42-CHO), 4.78 (broad s, 1H, OH); MS Elev. sep. (FAB ion neg.): Calc. for C59H92N2O6 1084.6446, measured mass 1084.6503.
Anal. Cale. para C59Hg2N2016: C,62,59;H,8,54;N,2,58 Encontrados: C,65,25;H,8,52;N,2,42Anal. Calc. for C 59 H 21 N 2 O 16: C, 62.59; H, 8.54; N, 2.58 Found: C, 65.25; H, 8.52; N, 2.42
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do amino ácido apropriado substituido terminalmente em N utilizando o método usado para preparar o composto do título no Exemplo 4. Éster-42-Rapamicina com N-[(etoxi)carbonil]tirosina Éster-42-Rapamicina com N-[(fluorenilmetoxi)carbonil]-fenilalani- na Éster-42-Rapamicina com N-[(3',4',5'-trihidroxifenoxi)carbonil]--isoleucina Éster-42-Rapamicina com N-[(1,1-dimetiletoxi)carbonil)-glutamina Éster-42-Rapamicina com N-[(fenoxi)carbonil]-N-metilalanina Éster-42-Rapamicina com ácido N-[(propiloxi)carbonil]-4-aminobu-tírico Éster-42-Rapamicina com ácido N-[(fenilmetoxi)carbonil]-7-amino-heptanoicoThe following representative compounds can be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 4. N-ethoxy-carbonyl] tyrosine Ester-42-Rapamycin with N - [(fluorenylmethoxy) carbonyl] -phenylalanine Ester-42-Rapamycin with N - [(3 ', 4', 5'-trihydroxyphenoxy) carbonyl] -isoleucine Ester-42-Rapamycin with N - [(1,1-dimethylethoxy) carbonyl) -glutamine Ester-42-Rapamycin with N - [(phenoxy) carbonyl] -N-methylalanine Ester-42-Rapamycin with N - [(propyloxy) carbonyl] -4- -aminobutyric acid Ester-42-Rapamycin with N - [(phenylmethoxy) carbonyl] -7-aminoheptanoic acid
Diéster-31,42-Rapamicina com N-[(fluorenilmetoxi)carbonil]serina 26Diester-31.42-Rapamycin with N - [(fluorenylmethoxy) carbonyl] serine 26
Exemplo 5Example 5
Diéster-31,42-Rapamicina com ácido 5-(l«l-dimetiletoxi)-2-rrfl.l--dimetiletoxi)carbonil)aminol-5-oxopentanoicoDiester-31.42-Rapamycin with 5- (1-dimethylethoxy) -2- (1-dimethylethoxy) carbonyl) aminol-5-oxopentanoic acid
Em condições anidras, uma solução de rapamicina (4 g, 4,37 mmol) arrefecida pelo gelo e N -Boc-T-terc-butilester de ácido L-glutâmico (4,9 g, 16,1 mmole) em 40 ml de diclorometano seco foi tratada com diciclohexilcarbodiimida (1,8 g, 8,7 mmole) seguindo-se 4-dimetilaminopiridina (1 g, 8,7 mmole). Após agitação durante a noite à temperatura ambiente, o sólido precipitado foi recolhido e lavado com diclorometano. Os filtrados combinados foram concentrados in vacuo para proporcionar 11 g de um sólido amorfo de côr ambar. 0 produto crú foi purificado por cromatogra-fia luminosa (sobre sílica Merck 60, gradiente de eluição com hexano-acetato de etilo de 2:1 a 1:1, v/v) para proporcionar 4,52 g (69,6%) do composto do título juntamente com o monoéster-42 do Exemplo 6. Análise HPLC revelou que o diéster consistia numa mistura 6,6:1 de dois confórmeros. ΧΗ RMN (CDC13, 400 MHz): S 1,42 (m, 36 H, COOBut), 1,646 (s, 3H, CH3C=C) , 1,701 (s, 3H, CH3C=C) , 3,13 (s, 3H, CI^O) , 3,34 (s, 3H, CH30), 3,36 (S, 3H, CH30), 4,735 (m, 2H, 0H+42-CH-0); MS Sep.Under anhydrous conditions, an ice cold solution of rapamycin (4 g, 4.37 mmol) and L-glutamic acid N-Boc-T-tert-butyl ester (4.9 g, 16.1 mmol) in 40 ml of dichloromethane was treated with dicyclohexylcarbodiimide (1.8 g, 8.7 mmol) followed by 4-dimethylaminopyridine (1 g, 8.7 mmol). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to provide 11 g of an amorphous solid of amber. The crude product was purified by flash chromatography (on silica Merck 60, gradient elution with hexane-ethyl acetate from 2: 1 to 1: 1, v / v) to provide 4.52 g (69.6%) of of the title compound together with the monoester-42 of Example 6. HPLC analysis revealed that the diester consisted of a 6.6: 1 mixture of two conformers. ¹H NMR (CDCl,, 400 MHz): δ 1.42 (m, 36 H, COOBut), 1.646 (s, 3H, CHCC CC), 1.701 (s, 3H, CHCC CC), 3.13 (s, 3H, Cl2 O), 3.34 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.735 (m, 2H, OH + 42-CH-O); MS Sep.
Elev. (FAB ião neg.): calc. para C79Hi25N3°23 1483/8715/ massa medida 1483,8714.He v. (FAB ion neg.): Calc. for C79 H25 N3 O23 1483/8715 / metered mass 1483.8714.
Anal. Calc. para C79H125N3C>23: C,63,90;H,8,49;N,2,83 Encontrados: C,63,63;H,8,41;N,2,44Anal. Calc. for C79 H125 N3 C > 23: C, 63.90; H, 8.49; N, 2.83 Found: C, 63.63; H, 8.41; N, 2.44
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do amino ácido apropriado substituído terminalmente em N utilizando o método usado para preparar o composto do título no Exemplo 5. 27The following representative compounds can be prepared from rapamycin and the appropriate N-terminally substituted amino acid using the method used to prepare the title compound in Example 5. 27
Diéster-31,42-Rapamicina com ácido 6-(fenilmetoxi)-2-[[fluorenil-metoxi)carbonil]-amino]-6-oxohexanoicoDiester-31.42-Rapamycin with 6- (phenylmethoxy) -2 - [[fluorenylmethoxy) carbonyl] amino] -6-oxohexanoic acid
Diéster-31,42-Rapamicina com ácido 6-(4/-metilfenoxi)-3-[[(fenilmetoxi) carbonil]-amino-6-oxohexanoicoDiester-31.42-Rapamycin with 6- (4-methylphenoxy) -3 - [[(phenylmethoxy) carbonyl] amino-6-oxohexanoic acid
Diéster-31/42-Rapamicina com ácido 6-(etoxi)-4-[[(fenoxi)carbonil ] amino ] -6-oxohexanoicoDiester-31/42-Rapamycin with 6- (ethoxy) -4 - [[(phenoxy) carbonyl] amino] -6-oxohexanoic acid
Diéster-31,42-rapamicina com ácido 6-(metoxi)-5-[[(etoxi)carbonil] amino]-6-oxohexanoicoDiester-31.42-rapamycin with 6- (methoxy) -5 - [[(ethoxy) carbonyl] amino] -6-oxohexanoic acid
Diéster-31,42-Rapamicina de ácido 4-(fenoxi)-2-[N-[(1,1-dimetil-etoxi)carbonil]-N-metilamino]-4-oxobutanoicoDiester-31.42-Rapamycin 4- (phenoxy) -2- [N - [(1,1-dimethylethoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid
Diéster-31,42-Rapamicina com 4-(fenilmetoxi)-3-[N-[(metoxi)carbonil] -N-metilamino] -4-oxobutanoicoDiester-31.42-Rapamycin with 4- (phenylmethoxy) -3- [N - [(methoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid
Exemplo 6 Éster-42-rapamicina com ácido 5-(1.l-dimetiletoxil-2-Γ Γ f1.1-dime-tiletoxi]carbonil1amino1-5-oxopentanoico 0 composto do título (1,14 g, 20,6%) foi separado do diéster-31,42 tal como foi descrito no Exemplo 5 e isolado como o solvato com um quarto de hidrato/acetato de mono-etilo. Análise HPLC revelou que o monoéster é uma mistura 11,5:1 de dois confór-meros. 28 XH RMN (CDC13, 400 MHz): S 1,425 (m, 18H, COOBut), 1,643 (s, 3H, CH3C=C), 1,737 (s, 3H, CH3C=C), 3,13 (s, 3H, CH30), 3,32 (s, 3H, CH30), 3,36 (s, 3H, CH30), 4,17 (d, 1H, CHOH), 4,71 (Μ, 1H, 42-CHO), 4,785 (s, 1H, OH); MS Elev. Sep. (FAB ião neg.): Cale. para ^N-CL _ 1198,7127, massa medida 1198,7077.Example 6 Ester-42-rapamycin with 5- (1,1-dimethylethoxyl-2 - [(1,1-dimethylethoxy) carbonyl] amino] -5-oxopentanoic acid The title compound (1.14 g, 20.6% was separated from the diester-31.42 as described in Example 5 and isolated as the one-fourth hydrate / monoethyl acetate solvate. HPLC analysis revealed that the monoester is an 11.5: 1 mixture of two mono- (s, 3H, CH3 C = C), 3.13 (s, 3H, CH3 C = C), 1.737 (s, 3H, CH3 C = C) 3H), 3.32 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.17 (d, 1H, CHOH), 4.71 (m, 1H, , 4,785 (s, 1H, OH), MS Elev. Sep. (FAB ion neg.): Calc'd for N-Cl 1198.7127, metered mass 1198.7077.
OO luz Δ XOOO light Δ XO
Anal. Cale. para ,-Η-„·CH_COOEt·0,25 H_0: 65 102 2 18 3 2 C,64,13;H,8,60;N,2,17 Encontrados: C,64,18;H,8,52;N,2,01Anal. Calc. for -CH 3 COOEt · 0.25 H 2 O: 65 102 2 18 3 2 C, 64.13; H, 8.60; N, 2.17 Found: C, 64.18; H, 8.52 N, 2.01
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do amino ácido apropriado substituído terminalmente em N utilizando o método usado para preparar o composto do título no Exemplo 6. Êster-42-Rapamicina com ácido 6-(fenilmetoxi)-2-[[fluorenilmeto-xi)carbonil]-amino]-6-oxohexanoico Éster-42-Rapamicina com ácido 6-(4'-metilfenoxi)-3-[[(fenilmeto-xi)carbonil]amino]-6-oxohexanoico Éster-42-Rapamicina com ácido 6-(etoxi)-4-[[(fenoxi)carbonil]amino] -6-oxo-hexanoico Éster-42-Rapamicina com ácido 6-(metoxi)-5-[[(etoxi)carbonil]amino] -6-oxo-hexanoico Éster-42-Rapamicina com ácido 4-(fenoxi)-2-[N-[(1,1-dimetileto-xi)carbonil]-N-metilamino]-4-oxobutanoico Éster-42-Rapamicina com ácido 4-(fenilmetoxi)-3-[N-[(metoxi)carbonil] -N-metilamino] -4-oxobutanoicoThe following representative compounds can be prepared from rapamycin and the appropriate N-terminally-substituted amino acid using the method used to prepare the title compound in Example 6. ß-Rapamycin with 6- (phenylmethoxy) -2- - [[fluorenylmethoxy-carbonyl] amino] -6-oxohexanoic acid Ester-42-Rapamycin with 6- (4'-methylphenoxy) -3 - [[(phenylmethoxy) carbonyl] amino] -6-oxohexanoic acid Ester Rapamycin with 6- (ethoxy) -4 - [[(phenoxy) carbonyl] amino] -6-oxohexanoic acid Ester-42-Rapamycin with 6- (methoxy) -5 - [[(ethoxy) carbonyl] ] amino] -6-oxohexanoic acid Ester-42-Rapamycin with 4- (phenoxy) -2- [N - [(1,1-dimethylethoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid Ester- 42-Rapamycin with 4- (phenylmethoxy) -3- [N - [(methoxy) carbonyl] -N-methylamino] -4-oxobutanoic acid
Exemplo 7Example 7
Diéster-31.42-Rapamicina com ácido 2-ΓΓ(1.1-dimetiletoxi)carbo-nillaminol-4-oxo-4-(fenilmetoxi^ butanoicoDiester-31.42-Rapamycin with 2 - [(1, 1-dimethylethoxy) carbonylamino] -4-oxo-4- (phenylmethoxy) butanoic acid
Em condições anidras, 295 mg (1,21 mmol) de cloreto de 2,4,6-triclorobenzoilo foram adicionados a uma solução de 391 mg (1,21 mmol) de éster β-benzilico de ácido Nra_Boc_L_aspSrtico e 170 μΐι (1,21 mmol) de Et3N em l ml de THF â temperatura ambiente. Após agitação durante 30 minutos, 500 mg (0,55 mmol) de rapami-cina e 295 mg (2,42 mmol) de dimetilaminopiridina foram adicionados e a reacção foi deixada a agitar durante a noite. A mistura da reacção foi então filtrada e o filtrado foi concentrado in vacuo. 0 produto puro (200 mg, 25%) foi obtido por HPLC preparativa (coluna de 5 cm, 40% acetato de etilo-hexano). 0 produto foi isolado sob a forma de heptahidrato. -½ RMN (CDC13, 400 MHz) S 7,347 (s, 10 H, Ar), 6,223, 5,126 (S, 4 H, CH2Ph), 4,698 (m, 1 H, CH-C02), 4,587 (m, 2 Η, NH), 3,353 (s, 3 H, CH30), 3,337 (s, 3 H, CH30), 3,301 (s, 3 H, CH30), 2,775 (m, 4 H, CH2C02); IV (KBr) 3420 (OH), 2935 (CH), 2920 (CH), 1730 (C=0), 1650, 1500, 1455, 1370, 1170 cm”1; MS (FAB ião neg.) 1523 (M~), 1433, 297, 248, 205, 148, 44, 25 (100).Under anhydrous conditions, 295 mg (1.21 mmol) of 2,4,6-trichlorobenzoyl chloride were added to a solution of 391 mg (1.21 mmol) of Nra_Boc_Lastrastic acid β-benzyl ester and 170 μΐι (1, 21 mmol) of Et 3 N in 1 mL of THF at room temperature. After stirring for 30 minutes, 500 mg (0.55 mmol) of rapamycin and 295 mg (2.42 mmol) of dimethylaminopyridine were added and the reaction was allowed to stir overnight. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The pure product (200 mg, 25%) was obtained by preparative HPLC (5 cm column, 40% ethyl acetate-hexane). The product was isolated as the heptahydrate. 1 H NMR (CDCl 3, 400 MHz): 7.37 (s, 10 H, Ar), 6.223, 5.136 (S, 4 H, CH 2 Ph), 4.698 (m, 1 H, CH- CO 2), 4.587 (m, 2 Η , 3.353 (s, 3 H, CH 3), 3.377 (s, 3 H, CH 3), 3.301 (s, 3 H, CH 3), 2.775 (m, 4 H, CH 2 CO 2); IR (KBr) 3420 (OH), 2935 (CH), 2920 (CH), 1730 (C = O), 1650, 1500, 1455, 1370, 1170 cm -1; MS (FAB ion neg.) 1523 (M +), 1433, 297, 248, 205, 148, 44, 25 (100).
Anal. Cale. para C83H117N3023*7H2° C,60,40;H,7,09;N,2,54Anal. Calc. for C83 H117 N3 O23 • 7H2 O: C, 60.40: H, 7.09; N, 2.54
Encontrados C,60,54;H,7,28;N,2,56 30 30Found: C, 60.54; H, 7.28; N, 2.56 30 30
Exemplo 8Example 8
Diéster-31,42-Rapamicina com ácido 3-ΓΓ(1.l-dimetiletoxilcarbo-nillaminol-4-oxo-4-(fenilmetoxi)butanoicoDiester-31.42-Rapamycin with 3 - [(1,1-dimethylethoxylcarbamoyl) -4-oxo-4- (phenylmethoxy) butanoic acid
Em condições anidras, 532 mg (2,18 mmol) de cloreto de 2,4,6-triclorobenzoilo em 1 ml de THF foi adicionado a uma solução de 704 mg (2,18 mmol) de éster α-benzílico de ácido Na-Boc-L-aspártico e 303 μΐ (2,18 mmol) de Et^N em 5 ml de THF à temperatura ambiente. Após agitação durante 20 minutos, a mistura da reacção foi filtrada sobre vidro aglomerado, e o precipitado foi lavado com THF. O filtrado foi concentrado in vacuo para dar origem a um óleo espesso. 0 óleo foi dissolvido em 5 ml de benzeno e 1,00 g (1,09 mmol) de rapamicina e 532 mg (4,36 mmol) de dimetilaminopiridina em 1 ml de benzeno foram adicionados gota a gota. A reacção foi agitada durante 2 horas, vertida para acetato de etilo, e lavada consecutivamente com HC1 0,5 N e solução salina. A solução foi seca sobre sulfato de sódio, decantada, concentrada in vacuo para dar origem a um sólido espumoso, que foi purificado por croraatografia luminosa numa coluna 60 mm x 100 mm de sílica (20-40% acetato de etilo/hexano como eluente) para dar origem a 532 mg (33%) do composto do título que foi isolado sob a forma de hidrato. ΧΗ RMN (CDC13, 400 MHz) S 7,362 (S, 10 H, Ar)/ 5,193 (s, 4 H, ÇH2Ph), 4,596 (m, 1 H, ÇH-C02), 4,586 (m, 2 Η, NH)/ 3,336 (s, 3 H, ÇH30), 3,306 (s, 3 H, ÇH30), 3,145 (s, 3 H, ÇH30) , IV (KBr) 3410 TOH) , 2950 (CH) , 2920 "(CH) , 1735 (C=C) , 1710~(C=0) , 1640, 1490, 1445, 1350, 1150 cm”1; MS (FAB ião neg.) 1524 (M_1), 1434, 297, 248, 232, 214, 205, 167, 148, 42(100), 26.Under anhydrous conditions, 532 mg (2.18 mmol) of 2,4,6-trichlorobenzoyl chloride in 1 ml of THF was added to a solution of 704 mg (2.18 mmol) of N α- Boc-L-aspartic acid and 303 μl (2.18 mmol) of Et3 N in 5 mL of THF at room temperature. After stirring for 20 minutes, the reaction mixture was filtered over agglomerated glass, and the precipitate was washed with THF. The filtrate was concentrated in vacuo to give a thick oil. The oil was dissolved in 5 ml of benzene and 1.00 g (1.09 mmol) of rapamycin and 532 mg (4.36 mmol) of dimethylaminopyridine in 1 ml of benzene were added dropwise. The reaction was stirred for 2 hours, poured into ethyl acetate, and washed consecutively with 0.5N HCl and brine. The solution was dried over sodium sulfate, decanted, concentrated in vacuo to give a foamy solid which was purified by flash chromatography on a 60 mm x 100 mm silica (20-40% ethyl acetate / hexane as eluent) to give 532 mg (33%) of the title compound which was isolated as the hydrate. 1 H NMR (CDCl3, 400 MHz): Î'7.362 (S, 10 H, Ar), 5.193 (s, 4 H, CH 2 Ph), 4.596 (m, 1 H, CH- (CH 3) 3,36 (s, 3 H, CH 3), 3.306 (s, 3 H, CH 3), 3.145 (s, 3 H, CH 3), IR (KBr) 3410 TOH), 2950 (CH) , 1735 (C = C), 1710 (C = O), 1640, 1490, 1445, 1350, 1150 cm-1; MS (FAB ion neg.) 1524 (M_1), 1434, 297, 248, 232, 214, 205, 167, 148, 42 (100), 26.
Anal. Cale. para C83H117N3023,H20: C,65,38;H,7,73;N,2,76 Encontrados: C,64,85;H,7,67;N,2,56Anal. Calc. Calc'd for CHHH77N23O2323N₂O23H₂O: H₂O: C, 65.38; H, 7.73; N, 2.76 Found: C, 64.85; H, 7.67; N, 2.56
Exemplo 9 Éster-42-Rapamicina com ácido 3-Γ Γ (l.l-dimetiletoxi)carbonillami-nol-4-OXO-4-(fenilmetoxi)butanoico 0 composto do título (374 mg, 23%) foi preparado pelo método descrito no Exemplo prévio e foi separado do composto descrito no Exemplo anterior por cromatografia luminosa (20-40% acetato de etilo/hexano como o eluente) e isolado sob a forma de sesquihidrato. 1H RMN (CDC13, 400MHz) S 7,356 (s, 5 H, Ml), 5,185 (s, 2 H, ÇH2Ph) , 4,635 (m, 1 H, ÇH.CC>2), 4,582 (m, 1 Η, NH) , 3,330 (s, 6 H,“ÇH30) , 3,135 (s, 3H, ^0) ; IV (KBr) 3410 (OH), 2950 (CH) , 2920 "(CH) , 1735 (C=0) , 1710~ (C=0) , 1640, 1490, 1445, 1350, 1150 cm-1; MS (FAB ião neg.) 1218 (M~), 1127, 590, 168, 42, 25, 17 (100) .The title compound (374 mg, 23%) was prepared by the method described in Example 1. The title compound (374 mg, 23%) was prepared by the method described in Example and separated from the compound described in the previous Example by flash chromatography (20-40% ethyl acetate / hexane as eluent) and isolated as the sesquihydrate. 1 H NMR (CDCl 3, 400MHz): 7.356 (s, 5 H, MH), 5.185 (s, 2 H, CH 2 Ph), 4.635 (m, 1 H, CH 2), 4.582 (m, 1 Η NH ), 3.330 (s, 6 H, δH30), 3.135 (s, 3H, CH2); IR (KBr) 3410 (OH), 2950 (CH), 2920 " (CH), 1735 (C = O), 1710 (C = O), 1640, 1490, 1445, 1350, 1150 cm -1; MS (FAB ion neg.) 1218 (M +), 1127, 590, 168, 42, 25, 17 (100).
Anal. Cale. para Cc„HQQNo0 ·1,5Η_0: C,63,64;H,8,21;N,2,22 o / yo z j.o zAnal. Calc. for C ""HQNNOO · 1.5Η0: C, 63.64; H, 8.21; N, 2.22.
Encontrados: C,63,64;H,7,51;N,2,13Found: C, 63.64; H, 7.51; N, 2.13
Exemolo 10 Éster-42-Rapamicina com ácido 5-(1,l-dimetiloxil-4-Γ Γ Cl.1-dimeti-loxi)carbonillaminol-5-oxopentanoicoExemolo 10 Ester-42-Rapamycin with 5- (1,1-dimethyloxyl-4 - [(1,1-dimethyloxy) carbonyl] amino] -5-oxopentanoic acid
Em condições anidras, uma solução de rapamicina (4 g, 4,37 mmole) arrefecida pelo gelo e éster Na-Boc-a-terc-butílico de ácido L-glutâmico (4, 9 g, 16,1 mmole) em 40 ml de diclorome-tano anidro foi tratada com carbodiimida de diciclohexilo (1,8 g, 8,7 mmole) seguindo-se 4-dimetilamino piridina (1 g, 8,7 mmole). Após agitação durante a noite à temperatura ambiente, o sólido precipitado foi recolhido e lavado com diclorometano. Os 32 filtrados combinados foram concentrados in vacuo para dar origem a 9 g de um sólido amorfo de cor ambar. 0 produto crú foi purificado por cromatografia luminosa (em sílica Merck 60, gradiente de eluição com hexano-acetato de etilo de 2:1 a 3:2, v/v) para proporcionar 1,35 g (25,7%) do composto do título juntamente com o diéster-31,42 do Exemplo 11. Análise HPLC revelou que o monoés-ter é uma mistura 7,5:1 de dois confórmeros. 2Η RMN (CDC13, 400 MHz): S 1,43 (s, 9H, COOBut) e 1,46 (s, 9H, COOBut), 1,65 (ε, 3H, CH3C=C), 1,75 (s, 3H, CH3C=C), 3,14 (s, 3H, CH30), 3,34 (s, 3H, CH30), 3,38 (s, 3H, CH30), 4,18 (d, 1H, ÇH-OH), 4,65 (m, 1H, 42-CHO), 4,80 (s, 1H, OH); MS Elev. Sep. (FAB ião neg.): Cale. para C65H102N2°18: 1198>7126/ massa medida 1198,7135.Under anhydrous conditions, an ice cold solution of rapamycin (4 g, 4.37 mmol) and L-glutamic acid Na-Boc-α-tert-butyl ester (4.9 g, 16.1 mmol) in 40 mL of anhydrous dichloromethane was treated with dicyclohexyl carbodiimide (1.8 g, 8.7 mmol) followed by 4-dimethylamino pyridine (1 g, 8.7 mmol). After stirring overnight at ambient temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give 9 g of an amber amorphous solid. The crude product was purified by flash chromatography (on silica Merck 60, elution gradient with hexane-ethyl acetate from 2: 1 to 3: 2, v / v) to provide 1.35 g (25.7%) of the title compound of the title together with the diester-31.42 of Example 11. HPLC analysis revealed that the monoester-ter is a 7.5: 1 mixture of two conformers. NMR (CDCl3, 400 MHz): δ 1.43 (s, 9H, COOBut) and 1.46 (s, 9H, COOBut), 1.65 (ε, 3H, CH3 C = C), 1.75 (S, 3H, CH3), 3.34 (s, 3H, CH3), 3.38 (s, 3H, CH3), 4.18 (d, 1H, CH3) -OH), 4.65 (m, 1H, 42-CHO), 4.80 (s, 1H, OH); MS Elev. Sep. (FAB ion neg.): Calc. for C65H102N2O18: 1198 > 7126 / mass measured 1198.7135.
Anal. Cale. para c65H102N20i8: c/65/09/*H/8/57/'N/2/34 Encontrados: C,65,04;H,8,33;N,2,64Anal. Calc. for C65H102N2O8: c / 65/09 / * H / 8/57 / 'N / 2/34 Found: C, 65.04; H, 8.33; N, 2.64
Exemolo 11Exemolo 11
Diester-31.42-Rapamicina com ácido 5-fl.l-dimetiletoxi^-4-rr(1.1--dimetiletoxi)carbonillaminol-5-oxopentanoico O composto do título (0,83 g, 12,8%) foi preparado juntamente com o monoéster-42 tal como foi descrito no Exemplo 10. Análise HPLC revelou que o diéster é uma mistura 7,7:1 de dois confórmeros. 33 ΧΗ ΚΜΝ (CDC13, 400MHz): δ 1,43 (s, 18Η, COOBut), 1,46 (s, 18H, COOBut), 1,659 (S, 3H, CH3C=C), 1,759 (s, 3H, CH3C=C), 3,14 (s, 3H, CH30) , 3,34 (S, 3H, C^O) , 3,38 (s, 3H, C^O) , 4,66 (m, 1H, 42.-CHO) , 4,72 (s, 1H, OH); MS Elev. Sep. (FAB ião neg.): Cale. para C7gHi25N3°23: 1483/8704/ massa medida 1483,8636.Diester-31.42-Rapamycin with 5-fluoro-1-dimethylethoxy-4- (1-dimethylethoxy) carbonylamino] -5-oxopentanoic acid The title compound (0.83 g, 12.8%) was prepared along with monoester-42 as described in Example 10. HPLC analysis revealed that the diester is a 7.7: 1 mixture of two conformers. Δ (CDCl 3, 400MHz): δ 1.43 (s, 18Η, COOBut), 1.46 (s, 18H, COOBut), 1.659 (s, 3H, CH3C = C), 1.759 (s, 3H, = C), 3.14 (s, 3H, CH3), 3.34 (s, 3H, CH2 O), 3.38 (s, 3H, CH2 O), 4.66 (m, 1H, 42 CHO), 4.72 (s, 1H, OH); MS Elev. Sep. (FAB ion neg.): Calc. for C7 H25 N3 O3: 1483/8704 / metered mass 1483.8636.
Anal. Cale. para C79H125N3°23: c/63/90/H,8,49;N,2,83 Encontrados: C,63,68;H,8,60;N,3,20Anal. Calc. for C79 H125 N3 O3: 63/90 / H, 8.49, N, 2.83 Found: C, 63.68; H, 8.60; N, 3.20
Exemplo 12 Éster-42-Ranamicina com Na,N6-bisf fl,l-dimetiletoxi)carbonin-L--lisinaExample 12 Ester-42-Ranamycin with Na, N 6 -bisf fl, 1-dimethylethoxy) carbonin-L-lysine
Em condições anidras, uma solução de rapamicina (3 g, 3,28 mmole) e Na,Ne-bis-Boc-L-lisina (4,5 g, 13 mmole) em 40 ml de diclorometano anidro foi tratada com diciclohexilcarbodiimida (1,35 g, 6,56 mmole) seguindo-se 4-dimetilaminopiridina (0,8 g, 6,56 mmole). Apôs agitação durante a noite à temperatura ambiente, o sólido precipitado foi recolhido e lavado com diclorometano. Os filtrados combinados foram concentrados in vacuo para dar origem a um sólido amorfo de côr ambar. Cromatografia luminosa do produto crú (em sílica Merck 60, eluição com hexano-acetato de etilo 1:1 v/v) deu origem ao composto do título parcialmente purificado. O produto puro (0,8 g, 19,6%) foi obtido por HPLC preparativa (Waters prep 500, gel de sílica, hexano-acetato de etilo 3:2 v/v, taxa de fluxo 250 ml/min). Análise HPLC revelou que o monoéster é uma mistura 9:1 de dois confórmeros. 34Under anhydrous conditions, a solution of rapamycin (3 g, 3.28 mmol) and Na, N-bis-Boc-L-lysine (4.5 g, 13 mmole) in 40 ml of anhydrous dichloromethane was treated with dicyclohexylcarbodiimide , 35 g, 6.56 mmole) followed by 4-dimethylaminopyridine (0.8 g, 6.56 mmole). After stirring overnight at room temperature, the precipitated solid was collected and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give an amorphous amber solid. Light product chromatography (on silica Merck 60, elution with 1: 1 v / v hexanes-ethyl acetate) gave the partially purified title compound. The pure product (0.8 g, 19.6%) was obtained by preparative HPLC (Waters prep 500, silica gel, 3: 2 v / v hexane-ethyl acetate, flow rate 250 ml / min). HPLC analysis revealed that the monoester is a 9: 1 mixture of two conformers. 34
H RMN (CDCl3r^ 400 . g 1^438 (m, 9H, COOBut), 1,455 (s, 9H, COOBut), 1,652 (s, 3H, CH3C=C), 1,752 (s, 3H, CH3C=C), 3,14 (s, 3H, CH30), 3,33 (S, 3H, OE^O) , 3,37 (s, 3H, 0^0) , 4,18 (d, 1H, CHOH), 4,72 (m, 1H, 42-CHO), 4,79 (s, 1H, OH); MS Elev. Sep. (FAB ião neg.): Cale. para C67Hio7N3°i8: 1241,7549, massa medida 1241,7604. C,64,76;H,8,68;N,3,38(S, 3H, CH 3 C = C), 1.752 (s, 3H, CH 3 C = C), 1.65 (s, 9H, COOBut), 1.652 (s, 3H, CH 3 C = (S, 3H, CH3), 3.33 (s, 3H, OE3 O), 3.37 (s, 3H, CH3), 4.18 (d, 1H, 72 (m, 1H, 42-CHO), 4.79 (s, 1H, OH), MS Elev. Sep. (FAB ion neg.): Calc'd for C 67 H 17 N 3 O 8: 1241.7549, metered mass 1241.7604 C, 64.76, H, 8.68, N, 3.38
Anal. Cale. para C„H.. _„N_0. „ . * 67 107 3 18;Anal. Calc. for C HH _ NN₂O.. ". * 67,107 18;
Encontrados; C,64,58;H,9,01;N,3,10Found; C, 64.58; H, 9.01; N, 3.10
Exemplo 13Example 13
Diéster-31,42-Rapamicina com Na.Ne-bisr(1.1-dimetiletoxi)carbo-nill-L-lisinaDiester-31.42-Rapamycin with Na.N-bis-bis (1,1-dimethylethoxy) carbonyl-L-lysine
Sob uma atmosfera de azoto, uma solução de Na,Ne bis-Boc-L-lisina (1,038 g, 3 mmole) e trietilamina (0,42 ml, 3 mmole) em 10 ml de THF anidro foi tratada numa porção com cloreto de 2,4,6-triclorobenzoilo(0,73 g, 3 mmole). Depois de agitar durante 20 minutos à temperatura ambiente, o sólido precipitado foi recolhido e o filtrado foi concentrado in vacuo. 0 anidrido mixto resultante foi dissolvido em 5 ml de benzeno e adicionado a uma solução agitada de rapamicina (1 g, 1,09 mmole) contendo 4-dimetilamino piridina (0,59 g, 4,8 mmole) em 10 ml de benzeno. Após agitação à temperatura ambiente durante a noite, o sólido precipitado foi recolhido e o filtrado foi evaporado até à secura (espuma amarela). O produto crú foi purificado por cromatografia luminosa (sobre sílica Merck 60, fazendo-se a eluição com hexano--acetato de etilo 1:1) para proporcionar o composto do título (1,15 g, 67%). Análise HPLC revela que o diéster é uma mistura 9:1 de dois confórmeros. 35 1H RMN (CDCl^, 400 MHz): 5 1,426 (m, 9H, COOBut), 1,438 (s, 9H, COOBut), 1,443 (S, 9H, COOBut), 1,446 (S, 9H, COOBut), 3,141 (s, 3H, CH30), 3,36 (s, 3H, CH30), 3,378 (s, 3H, CH30), 4,68-4,76 (m, 2H, OH e 42.-CHO); MS elev. sep. (FAB ião neg.): Cale. para C83H135N5°23 1569/9526» massa medida 1569,9537.Under a nitrogen atmosphere, a solution of Na, Ne bis-Boc-L-lysine (1.038 g, 3 mmol) and triethylamine (0.42 mL, 3 mmol) in 10 mL of anhydrous THF was treated in a portion with 2,4,6-trichlorobenzoyl chloride (0.73 g, 3 mmol). After stirring at room temperature for 20 minutes, the precipitated solid was collected and the filtrate was concentrated in vacuo. The resulting mixed anhydride was dissolved in 5 ml of benzene and added to a stirred solution of rapamycin (1 g, 1.09 mmol) containing 4-dimethylamino pyridine (0.59 g, 4.8 mmol) in 10 ml of benzene. After stirring at room temperature overnight, the precipitated solid was collected and the filtrate evaporated to dryness (yellow foam). The crude product was purified by flash chromatography (on silica Merck 60, eluting with 1: 1 hexane-ethyl acetate) to provide the title compound (1.15 g, 67%). HPLC analysis shows that the diester is a 9: 1 mixture of two conformers. 1 H NMR (CDCl 3, 400 MHz): δ 1.426 (m, 9H, COOBut), 1.438 (s, 9H, COOBut), 1.443 (S, 9H, COOBut), 1.446 (S, 9H, s, 3H, CH3), 3.36 (s, 3H, CH3), 3.378 (s, 3H, CH3), 4.68-4.76 (m, 2H, OH and 42.-CHO); MS elev. sep. (FAB ion neg.): Calc. for C83 H13 N5 O3 1569/9526, measured mass 1569.9537.
Anal. Cale. para Cg3H135N5023: C,63,46;H,8,66;N,4,46 Encontrados: C, 63,06;H,8,84;N,4,09Anal. Calc. Calc'd for C 19 H 38 N 5 O 2: C, 63.46: H, 8.66: N, 4.46 Found: C, 63.06; H, 8.84; N, 4.09
Exemplo 14Example 14
Tris fmonobenzilsuccinato^-14.31,42-Rapamicina A uma solução de 5,0 g (5,47 mmol) de rapamicina, 3,41 g (16,41 mmol) de succinato de monobenzilo, e 3,15 g (16,41 mmol) de clorohidreto de l-(3-dimetilaminopropil)-3-etilcarbodiimida em 20 ml de diclorometano seco foram adicionados 200 mg de 4-dime-tilaminopiridina. A solução foi agitada à temperatura ambiente durante 3 dias. A mistura da reacção foi vertida para HCl 2N e extraída três vezes com acetato de etilo. As camadas orgânicas foram combinadas, lavadas com solução salina, secas sobre sulfato de sódio anidro, e concentradas in vacuo para dar origema uma espuma amarelo claro. Cromatografia luminosa sobre uma coluna 60 mm x 150 mm de gel de sílica fazendo-se a eluição com 20% de acetato de etilo/hexano a 75% de acetato de etilo/hexano deu origem a três fraeções. A fraeção #1, após concentração, deu origem a 330 mg (4,1%) de tris(monobenzilsuccinato)-14,31,42-ra-pamicina puro. 36To a solution of 5.0 g (5.47 mmol) of rapamycin, 3.41 g (16.41 mmol) of monobenzyl succinate, and 3.15 g (16.41 mmol) mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 20 ml of dry dichloromethane was added 200 mg of 4-dimethylaminopyridine. The solution was stirred at room temperature for 3 days. The reaction mixture was poured into 2N HCl and extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light yellow foam. Light chromatography on a 60 mm x 150 mm silica gel column eluting with 20% ethyl acetate / hexane to 75% ethyl acetate / hexane gave three fractions. Fraction # 1, after concentration, gave 330 mg (4.1%) of pure tris (monobenzylsuccinate) -14,31,42-ra-kamycin. 36
2H RMN (CDC13, 400 MHz) S 7,353 (bs, 15 H, arom), 5,168 (d, J=2,0 HZ, 1 H, ÇH-02C), 5,148 (m, 6H, Çl^Ph) , 4,672 (m, 1 H, C02ÇH-CH0Me) , 3,355 (s, 3 H, QigO-) , 3,337 (s, 3 H, ^0-), 3,327 (s, 3 H, CH30-), 2,697 (m, 12 h7 O^ÇH^ÇH^CC^C^Ph) , l7745 (s, 3 H, ÇH3C=C),_1,655 (s, 3 H, ÇH3C=C); IV (KBr) 3450 (OH), 2950 (CH),”l745 (C=0), 1650, 1460, 1385, 1360, 1160, 1105, 995 cm"1.1 H NMR (CDCl 3, 400 MHz): δ 7.353 (bs, 15 H, arom), 5.168 (d, J = 2.0 Hz, 1 H, CH2 CH2), 5.148 (m, 6H, (m, 1 H, CH2 CO2 CH3), 3.335 (s, 3H, CH2), 3.337 (s, 3H, CH2), 3.327 (s, 3H, CH3) (s, 3H, CH3 C = C), 1.655 (s, 3H, CH3 C = C); IR (KBr) 3450 (OH), 2950 (CH), 11745 (C = O), 1650, 1460, 1385, 1360, 1160, 1105, 995 cm -1.
Anal. Cale. para c84H109NO2i’3 H2° c/66'27/*H/7/56;N,0,92Anal. Calc. for C84 H109NO2 Â · 3 H2 O / 66.27 / * H / 7/56; N, 0.92
Encontrados C,65,96;H,7,24;N,1,00Found: C, 65.96; H, 7.24; N, 1.00
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do meio éster-ácido apropriado utilizando o método usado para preparar o composto do título no Exemplo 14.The following representative compounds can be prepared from rapamycin and the appropriate ester-acid medium using the method used to prepare the title compound in Example 14.
Tris(monometilsuccinato)-14,31,42-RapamicinaTris (monomethylsuccinate) -14,31,42-Rapamycin
Tris(monofenil-3',3'-dimetilglutarato)-14,31,42-RapamicinaTris (monophenyl-3 ', 3'-dimethylglutarate) -14,31,42-Rapamycin
Tris(mono t-butil-3'-metilglutarato)-14,31,42-RapamicinaTris (mono t-butyl-3'-methylglutarate) -14,31,42-Rapamycin
Tris(monobenziltiodiglicolato)-14,31,42-RapamicinaTris (monobenzylthiodiglycolate) -14,31,42-Rapamycin
Tris(monohexildiglicolato)-14,31,42-RapamicinaTris (monohexyldiglycolate) -14,31,42-Rapamycin
Tris(monopropilftalato)-14,31,42-RapamicinaTris (monopropylphthalate) -14,31,42-Rapamycin
Tris(monoetil-2',6'-piridinedicarboxilato)-14-31-42-Rapamicina Exemplo 15Tris (monoethyl-2 ', 6'-pyridinedicarboxylate) -14-31-42-Rapamycin Example 15
Bis(monobenzilsuccinato)-31,42-Rapamicina A fraeção #2, obtida a partir do processo utilizado no Exemplo 14, deu origem a 1,25 g (17,7%) de bis(monobenzilsuccina-to)-31,42-rapamicina pura após concentração. 37Fraction # 2, obtained from the procedure used in Example 14, gave 1.25 g (17.7%) of bis (monobenzylsuccin-to) -31,42-diisopropylethylamine rapamycin after concentration. 37
-½ RMN (CDC13, 400 MHz) δ 7,351 (bs, 10 H, aromV. 5,168 (d, J = 2,0 Hz, 1 H, ÇH-02C), 5,125 (m, 4H, CH2Ph), 4,680 (m, 1 H9, C02ÇH-CH0Me) , 3,356 (s, 3 H, ÇI^O-) , 3,329 (s, 3 H, ÇI^O-) . 3,146 (S, 3 H, ÇH30-) , 2,639 (m, 8 h7 02CÇHgÇHgC02CH2Ph) , l7748 (s, 3 H, ÇH3C=C),“l,654 (S, 3 H, ÇH3C=C); IV (KBr) 3450 (OH), 2940 (CH),_1740 (C=0), 1650, 1455, 1380, 1355, 1160, 1105, 995 cm"1; MS /FAB ião neg.) 1294 (M-), 1202, 1103, 1012, 590, 511, 475, 297, 207, 167, 148, 99 (100); MS Elev. Sep. (FAB ião neg.) Cale. para C73HggN0lg 1293,68108, encontrados 1293,6811.1 H NMR (CDCl 3, 400 MHz) δ 7.351 (bs, 10 H, arom 5.18 (d, J = 2.0 Hz, 1 H, CH 2 O), 5.125 (m, 4H, CH 2 Ph), 4.680 , 3.356 (s, 3 H, CH 2 O-), 3.329 (s, 3 H, CH 2 OH), 3.146 (S, 3 H, CHH-), 2.639 (m, IR (KBr) 3450 (OH), 2940 (CH), 1740 (C = CH3), 1.40 (s, 3H) (M-), 1202, 1103, 1012, 590, 511, 475, 297, 207, 167 (M-), 1650, 1455, 1380, 1355, 1160, 1105, 995 cm " , 148, 99 (100); MS Elev. Sep. (FAB ion neg.) Calc. Calc'd for C73 H19 NN2 O 1293.68108, found 1293.6811.
Análise Cale. para C73HggNOig · H20 C,66,82;H,7,70;N,1,07Calc'd. Calc'd for C73 H20 NO5 · H2 O C, 66.82, H, 7.70, N, 1.07
Encontrados C,67,17;H,7,67;N,1,23Found: C, 67.17; H, 7.67; N, 1.23
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do meio éster-ácido apropriado utilizando o método usado para preparar o composto do título no Exemplo 15.The following representative compounds can be prepared from rapamycin and the appropriate ester-acid medium using the method used to prepare the title compound in Example 15.
Bis(monometilsuccinato)-31,42-RapamicinaBis (monomethylsuccinate) -31.42-Rapamycin
Bis(monofenil-3',3'-dimetilglutarato)-31,42-RapamicinaBis (monophenyl-3 ', 3'-dimethylglutarate) -31,42-Rapamycin
Bis(mono t-butil-3'-metilglutarato)-31,42-RapamicinaBis (mono t-butyl-3'-methylglutarate) -31.42-Rapamycin
Bis(monobenziltiodiglicolato)-31,42-RapamicinaBis (monobenzylthiodiglycolate) -31.42-Rapamycin
Bis(monohexildiglicolato)-31,42-RapamicinaBis (monohexyldiglycolate) -31.42-Rapamycin
Bis(monopropilftalato)31,42-RapamicinaBis (monopropylphthalate) 31.42-Rapamycin
Bis(monoetil-2',6'-piridinedicarboxilato)-31,42-RapamicinaBis (monoethyl-2 ', 6'-pyridinedicarboxylate) -31,42-Rapamycin
I 38 RMN (CDCl^, 400 MHz) 6 7,355 (bs, 5 H, arom) , 5,141 (m, 2 H, OÍ2Ph), 4,680 (itl, 1 H, C02ÇH-CH0Me) , 3,364 (s, 3 H, ÇI^O-) , 3,333 (s7 3 H, ÇH30-), 3,141 (S, 3 H, ÇH3O-), 2,698 “(m, 4 H, Q2CCH2CH2CQ2CH2Ph), 1,751 (S, 3 H, ÇH3C=C), 1,655 (S, 3 H, ÇH C=C); IV (KBr) 3450 (OH), 2940 (CH),~1740 (C=0), 1645, 1455, — -1 1380, 1165, 1105, 990 cm ; MS /FAB ião neg.) 1103 (M-) , 1045, 1012, 624, 590, 167, 99 (100); MS Elev. Sep. (FAB ião neg.) Cale. para c62H89N0i6 1103/6181, encontrados 1103,6048.1 H NMR (CDCl 3, 400 MHz)? 7.355 (bs, 5 H, arom), 5.141 (m, 2 H, CH2 CH2), 4.680 (b1, 1 H, CO2 CH2 CH3 Me), 3.364 (s, (M, 4H, CH2CH2 CH2 CH2 CH2 CH2), 1.751 (S, 3 H, CH3 C = C), 3.15 (s, 3 H, CH3 O-), 3.31 (s, 3H, CH3) 1.655 (S, 3 H, CH C = C); IR (KBr) 3450 (OH), 2940 (CH), ~ 1740 (C = O), 1645, 1455, -11380, 1165, 1105, 990 cm; MS / FAB ion neg.) 1103 (M-), 1045, 1012, 624, 590, 167, 99 (100); MS Elev. Sep. (FAB ion neg.) Calc. for c62H89NO66 1103/6181, found 1103,6048.
Anal. Cale. para c62H89N016·Η20 C,66,36;H,8,02;N,1,24 Encontrados C,66,02;H,7,69;N,1,26Anal. Calc. for C62 H89 N06 · 20 C, 66.36, H, 8.02, N, 1.24 Found: C 66.02, H 7.69, N, 1.26
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do meio éster-ácido apropriado utilizando o método usado para preparar o composto do título no Exemplo 16. (Monometilsuccinato)-42-Rapamicina (Monofenil-3',3'-dimetilglutarato)-42-Rapamicina (Mono t-butil-3'-metilglutarato)-42-Rapamicina (Monobenziltiodiglicolato)-42-Rapamicina (Monohexildiglicolato)-42-Rapamicina (Monopropilftalato)-42-Rapamicina (Monoetil-2',6,-piridinecarboxilato)-42-RapamicinaThe following representative compounds can be prepared from rapamycin and the appropriate ester-acid medium using the method used to prepare the title compound in Example 16. (Monomethylsuccinate) -42-Rapamycin (Monophenyl-3 ', 3'- dimethylglutarate) -42-Rapamycin (Mono-t-butyl-3'-methylglutarate) -42-Rapamycin (Monobenzylthiodiglycolate) -42-Rapamycin (Monohexyldiglicolato) -42-Rapamycin (Monopropylphthalate) -42-Rapamycin (Monoethyl- -pyridinecarboxylate) -42-Rapamycin
Exemplo 17Example 17
Bishemiglutarato-31,42-Rapamicina A uma solução de 2,0 g (2,2 mmol) de rapamicina em 10 ml de diclorometano seco foram adicionados 1,24 g (10,9 mmol) de anidrido glutárico seguindo-se 881 ul (861 mg, 10,9 mmol) de piridina. A isto adicionaram-se 200 mg de 4-dimetilaminopiridina 39Bishemiglutarate-31.42-Rapamycin To a solution of 2.0 g (2.2 mmol) of rapamycin in 10 ml of dry dichloromethane was added 1.24 g (10.9 mmol) of glutaric anhydride followed by 881 ul 861 mg, 10.9 mmol) of pyridine. To this was added 200 mg of 4-dimethylaminopyridine 39
e a mistura da reacção foi deixada sob refluxo durante 8 horas. A solução foi arrefecida até à temperatura ambiente, vertida para HC1 2 N, e extraída três vezes com diclorometano. Os extractos orgânicos combinados foram lavados com solução salina, secas sobre sulfato de sódio anidro, decantadas, e concentradas in vacuo para dar origem a uma espuma amarela. 0 produto crú foi purificado por HPLC de fase reversa numa coluna C^g fazendo-se a eluição começando com 60% de acetonitrilo/água. Foram recolhidos, após concentração, 586 mg (24%) de bishemiglutarato-31-42-rapami-cina. ΧΗ RMN (CDClg, 400 MHz) δ 5,398 (m, 1 H, -CC^CHCHOMe). 4,683 (m, 1 H, -CC>2ÇHCH0Me) , 3,364 (S, 3 H, ÇH30-) , 3,362 (S, 3 H, ÇH30-) , 3,106 (s, 3 H9, ÇS30-) , 2,407 (m, 8 H, -O^CÇH^C^ÇE^CX^H) , 1,960 (m, 4 H, -02CCH2Çh^CH2C02H), 1,770 (s, 3 H, ÇH3C=C), 1,653 (s, 3 H, ÇH3C=C); 13C RMN (CDC1 , MHz) 211,45 (C=Õ), 206,84 (C=0), 200,44 (C=0), 177,83 (C=0), 177,04 (C=0), 172,43 (C=0), 171,20 (C=0), 165,27 (C=0), 159,08 (C=0); IV (KBr) 3430 (OH), 2940 (CH), 2880 (CH), 1745 (C=0), 1685, 1625, 1580, 1450, 1385, 1330, 1200, 1140, 1100, 990 cm”1; MS (FAB ião neg.) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ião neg.) Cale. para c61H9o°i9N (M-H) 1140,6107, Encontrados 1140,6106.and the reaction mixture was allowed to reflux for 8 hours. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on a C18 column and eluted starting with 60% acetonitrile / water. 586 mg (24%) of bishemiglutarate-31-42-rapamycin were collected after concentration. ¹H NMR (CDCl,, 400 MHz) δ 5.388 (m, 1 H, -CH₂CHCHOMe). (M, 1 H, -CH 2 -C H 3 O), 3.364 (s, 3 H, CH 3 -), 3.362 (s, 3 H, CH 3 -), (M, 4 H, -OCH 2 CH 2 CH 2 CH 2 CH 2), 1.770 (s, 3 H, CH 3 C = C), 1.653 (s, 3 H, CH 3 C = C); 13 C NMR (CDCl3, MHz) 211.45 (C = O), 206.84 (C = O), 200.44 (C = O), 177.83 (C = O), 177.04 (C = O) ), 172.43 (C = O), 171.20 (C = O), 165.27 (C = O), 159.08 (C = O); IR (KBr) 3430 (OH), 2940 (CH), 2880 (CH), 1745 (C = O), 1685, 1625, 1580, 1450, 1385, 1330, 1200, 1140, 1100, 990 cm -1; MS (FAB ion neg.) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ion neg.) Calc. for C 61 H 9 O 9 N (M-H) 1140.6107, Found 1140.6106.
Anal. Cale. para C61H9()019N ·Η20 C,63,15;H,8,02;N,1,20 Encontrados C,63,35;H,7,88;N,1,40Anal. Calc. Calc'd for C61 H9 N3 O: C, 63.15; H, 8.02; N, 1.20 Found: C, 63.35; H, 7.88; N, 1.40
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do anidrido apropriado utilizando o método usado para preparar o composto do título no Exemplo 17.The following representative compounds can be prepared from rapamycin and the appropriate anhydride using the method used to prepare the title compound in Example 17.
Bishemi-3'-metilglutarato-31,42-RapamicinaBishemi-3'-methylglutarate-31.42-Rapamycin
Bishemi-3',3'-dimetilglutarato-31,42-Rapamicina Bishemi-3'-oxoglutarato-31,42-Rapamicina Bishemi-3'-tioglutarato-31,42-Rapamicina Bishemi-ftalato-31,42-RapamicinaBishemi-3 ', 3'-dimethylglutarate-31.42-Rapamycin Bishemi-3'-oxoglutarate-31.42-Rapamycin Bishemi-3'-thioglutarate-31.42-Rapamycin Bishemi-phthalate-31.42-Rapamycin
Bishemi-2',3'-piridine dicarboxilato-31-42-Rapamicina IBishemi-2 ', 3'-pyridine dicarboxylate-31-42-Rapamycin I
Exemplo 18Example 18
Sal bissódico de hemiqlutarato-31-42-Rapamicina , Bis-31/42.hemiglutarato de rapamicina purificado 8740 mg, 649 umol), preparado tal como foi descrito no Exemplo 4, foi dissolvido em 5 ml de 95% de etanol e foram adicionados 107 mg (1,27 mmol) de bicarbonato de sódio. Adicionou-se água (1 ml) para dissolver completamente o sal. Uma vez dissolvida, a solução amarelo claro foi concentrada in vacuo para dar origem a um sólido amarelo espumoso. A espuma foi seca numa pistola de secagem durante 24 horas, submetida a refluxo sobre acetona sob pressão reduzida para dar origem a 520 mg do sal bissódico. ΧΗ RMN (dg-DMSO, 400 MHz) δ 5,235 (m, 1 H, -CH^C) , 4,498 (m, 1 H, Me0CHÇH02C-), 3,287 (s, 6 H, 2 ÇH30-), 3,236 (s, 3 H, ÇH30-), 2,245 (m, 8 H, O^ÇH^^ÇHgCC^-) , l7712 (S, 3 H, ÇH3C=C) , 1,593 (S, 3 H, ÇH3C=C); IV (KBr) 3420 (OH), 2920 (CH),~1725 (C=0), 1675, 1620, 1560, 1450, 1400, 1375, 1230, 1195, 1130, 1090, 980 cm 1; MS (FAB ião neg.) 1112 (M-l, ácido livre), 994, 589, 475, 297, 167, 148, 117, 99 (100); MS Elev. Sep. (FAB ião neg.) Cale. para C61Hg9OigNNa (M-Na) 1162,5926, Encontrados 1162,5899.Rapamycin-31-42-Rapamycin bisylated bis-31 / 42.hemiglutarate, 8740 mg, 649 μmol), prepared as described in Example 4, was dissolved in 5 ml of 95% ethanol and added 107 mg (1.27 mmol) of sodium bicarbonate. Water (1 ml) was added to completely dissolve the salt. Once dissolved, the pale yellow solution was concentrated in vacuo to give a yellow foamy solid. The foam was dried on a drying gun for 24 hours, refluxed over acetone under reduced pressure to give 520 mg of the bis (disodium salt). Δ NMR (d6 -DMSO, 400 MHz) δ 5.235 (m, 1 H, -CH2 C), 4.488 (m, 1H, MeOHCH2 O-), 3.277 (s, 6 H, 2 Î'H30-), 3.266 , 3.45 (s, 3 H, CH3 C = C), 1.593 (S, 3 H, CH3 C = C), 1.59 (s, 3H); IR (KBr) 3420 (OH), 2920 (CH), -1725 (C = O), 1675, 1620, 1560, 1450, 1400, 1375, 1230, 1195, 1130, 1090, 980 cm -1; MS (FAB negative ion) 1112 (M-1, free acid), 994, 589, 475, 297, 167, 148, 117, 99 (100); MS Elev. Sep. (FAB ion neg.) Calc. Calc'd for C61 H9 O9 NNa (M-Na) 1162.5926, Found 1162.5899.
Anal. Cale. para C61HggOigNNa2·Η20 C,60,85;H,7,56;N,1,16Anal. Calc. Calc'd for C 61 H 9 O 6 N 2 O 2 · C 20, 60.85, H, 7.56, N, 1.16
Encontrados C,60,67;H,7,36;N,1,58 41Found: C, 60.67; H, 7.36; N, 1.58.
Exemplo 19Example 19
Sal bistrometamina de bishemicrlutarato-31,4 2-RapamicinaBistrymetamide salt of bishemicrlutarate-31.4 2-Rapamycin
Bis-31,42 hemiglutarato de rapamicina purificado (950 mg, 833 umol), preparado tal como foi descrito no Exemplo 4, foi dissolvido em 5 ml de 95% de etanol e foram adicionados 197 mg (1,63 mmol) de tris(hidroximetil)metilamina. Adicionou-se água (1 ml) até se dissolver completamente a amina. Uma vez dissolvida, a solução amarela foi concentrada in vacuo para dar origem a um sólido amarelo espumoso. A espuma muito higroscópica foi seca numa pistola de secagem durante 24 horas, sendo submetida a refluxo sobre acetona sob pressão reduzida para dar origem a 900 mg (78%) de sal bistrometamina. 1H RMN (dg-DMSO, 400 MHz) S 5,253 (m, 1 H, -CHC^Cl. 4,523 (m, 1 H, Me0CHÇH02C-), 3,347 (s, 6 H, 2 ÇH30-), 3,276 (s, 3 H, ÇH30-), 2,289 (m, 8 H, C^CÇH^C^CC^-) , l,681_(s, 3 H, ÇH3C=C), 1,595_ (s, 3 H, ÇH3C=C); IV (KBr) 3400 (OH), 2920 (CH), 1730 (C=0), 1620, 1555, 1450, 1400, 1370, 1185, 1060, 980 cm”1; MS (FAB ião neg.) 1140 (M-H, ácido livre), 1028, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ião neg.) Cale. para C61H9()0lgN (M-H, ácido livre) 1140,6107, Encontrados 1140,6069.Purified purified amoxyglutarate bis-31.42 (950 mg, 833 μmol), prepared as described in Example 4, was dissolved in 5 ml of 95% ethanol and 197 mg (1.63 mmol) of tris hydroxymethyl) methylamine. Water (1 ml) was added until the amine was completely dissolved. Once dissolved, the yellow solution was concentrated in vacuo to give a yellow foamy solid. The very hygroscopic foam was dried on a drying gun for 24 hours, refluxed over acetone under reduced pressure to give 900 mg (78%) of bromethamine salt. 1 H NMR (d 6 -DMSO, 400 MHz): δ 5.253 (m, 1 H, -CHCl 3), 4.523 (m, 1 H, MeOH CH 2 O-), 3.347 (s, 6 H, (S, 3 H, CH3 C = C), 1.595 (s, 3 H, CH3 C = C ) IR (KBr) 3400 (OH), 2920 (CH), 1730 (C = O), 1620, 1555, 1450, 1400, 1370, 1185, 1060, 980 cm-1; (MH, free acid), 1028, 167, 148, 131 (100), 113: MS Elev. Sep. (FAB ion neg.) Calc'd for C61 H9 N3 O4 N (MH, free acid) 1140.6107, Found 1140 , 6069.
Anal. calc. para c69H1()3025N3 *2 H20 C,58,77;H,7,58;N,2,98Anal. calc. Calc'd for C69 H11 N3 O2: C, 58.77; H, 7.58; N, 2.98
Encontrados C,58,47;H,7,94;N,3,58Found: C, 58.47; H, 7.94; N, 3.58
Exemplo 20Example 20
Hemi-3'-oxoqlutarato-42-Rapamicina A uma solução de 3,0 g (3,3 mmol) de rapamicina em 20 ml de diclorometano seco foram adicionados 1,90 g (16,4 mmol) de 42Hemi-3'-oxoqlutarate-42-Rapamycin To a solution of 3.0 g (3.3 mmol) of rapamycin in 20 ml of dry dichloromethane was added 1.90 g (16.4 mmol) of
anidrido diglicólico seguindo-se 1,32 ml (1,29 g, 16,4 mmol) de piridina. A isto foram adicionados 200 mg de 4-dimetilaminopiri-dina e a mistura da reacção foi deixada a agitar à temperatura ambiente durante 2 dias. A solução foi arrefecida até à temperatura ambiente, vertida para HC1 2 N, e extraída três vezes com diclorometano. Os extractos orgânicos combinados foram lavados com solução salina, secos sobre sulfato de sódio anidro, decantados, e concentrados in vacuo para dar origem a uma espuma amarela. 0 produto crú foi purificado por meio de HPLC de fase reversa numa coluna Clg fazendo-se a eluição começando com 60% de acetonitrilo/ãgua. Após concentração, foram isolados 870 mg (26%) de hemi-3'-oxoglutarato-42-rapamicina e 500 mg (13%) de bishemi--3'-oxoglutarato-Sl,42-rapamicina. ΧΗ RMN (CDC13, 400 MHz) 5 4,768 (m, 1 H, CC>2ÇH-CHOMe) , 4,250 (m, 4 H, 02CCH20CH2C02^. 3,356 (s, 3 H, ÇH30-), 3,331 (s, 3 H, ÇH30-), 3,139 (S, 3 H, ÇH30-), 1,759 (S, 3~H, ÇH3C=C), 1,653 (s, 3 H, ÇH3C=C) ,* IB (KBr) 3420 (OH) , 2920 (CH) , ~2875 (CH) , 1740 (C=0), 1720 (C=0), 1640, 1625, 1445, 1370, 1320, 1200, 1135, 1095, 980 cm”1; MS (FAB ião neg.) 1028 (Μ - H), 327, 167 (100), 148, 133, 115; MD Eelb. Sep. (FAB ião neg.) Cale. para C55H2g017N (M-H) 1028,5597, Encontrados 1028,5599.diglycol anhydride followed by pyridine (1.32 ml, 1.29 g, 16.4 mmol). To this were added 200 mg of 4-dimethylaminopyridine and the reaction mixture was allowed to stir at room temperature for 2 days. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on a Cl 2 column by eluting starting with 60% acetonitrile / water. After concentration, 870 mg (26%) of hemi-3'-oxoglutarate-42-rapamycin and 500 mg (13%) of bishemi-3'-oxoglutarate-S, 42-rapamycin were isolated. 1 H NMR (CDCl3, 400 MHz) Î'4.768 (m, 1 H, CH 2 CH 2 CH 3), 4.250 (m, 4 H, OCHâ,,CHâ,,CHâ,,COâ,,Oâ,,), 3.356 (s, 3 H, CHâ,ƒ-), 3.331 (s, 3 H (KBr): 3420 (M + H) +, 1 H-NMR (DMSO-d 6):? , 2920 (CH), 2875 (CH), 1740 (C = O), 1720 (C = O), 1640, 1625, 1445, 1370, 1320, 1200, 1135, 1095, 980 cm -1 MS (FAB 1028 (Μ-H), 327, 167 (100), 148, 133, 115, Found: 1028.5599 (M + H) +. .
Anal. Cale. para C55H83OiyN· 3 H20 C,60,97;H,8,22;N,1,29Anal. Calc. for C 55 H 83 O 13 N 3 H 2 0 C, 60.97, H, 8.22, N, 1.29
Encontrados C, 61,33;H,7,74;N,1,69Found: C, 61.33; H, 7.74; N, 1.69
Os compostos representativos que se seguem podem ser preparados a partir de rapamicina e do anidrido apropriado utilizando o método usado para preparar o composto do título no Exemplo 20.The following representative compounds can be prepared from rapamycin and the appropriate anhydride using the method used to prepare the title compound in Example 20.
Hemi-3'-metilglutarato-42-Rapamicina Hemi-3',3'-dimetilglutarato-42-RapamicinaHemi-3'-methylglutarate-42-Rapamycin Hemi-3 ', 3'-dimethylglutarate-42-Rapamycin
Hemi-3'-tioglutarato-42-Rapamicina Hemi-ftalato-42-RapamicinaHemi-3'-thioglutarate-42-Rapamycin Hemi-phthalate-42-Rapamycin
Hemi-2',3'-piridine dicarboxilato-42-RapamicinaHemi-2 ', 3'-pyridine dicarboxylate-42-Rapamycin
Exemplo 21Example 21
Bishemi-3'-oxoqlutarato-31.42-Rapamicina A uma solução de 5,0 g (5,47 mmol) de rapamicina em 20 ml de diclorometano seco foram adicionados 3,17 g (27,3 mmol) de anidrido diglicólico seguindo-se 2,17 ml (2,12 g, 27,3 mmol) de piridina. A isto adicionaram-se 400 mg de 4-dimetilaminopiridina e deixou-se a mistura da reacção a agitar sob refluxo dutrante 24 horas. A solução foi arrefecida à temperatura ambiente, vertida para HCl 2N, e extraída três vezes com diclorometano. Os extrac-tos orgânicos combinados foram lavado com solução salina, secos sobre sulfato de sódio anidro, decantados, e concentrados in vacuo para dar origem a uma espuma amarela, O produto crú foi purificado por HPLC de fase reversa numa coluna C_ 0 fazendo-se a eluição com 60% de acetonitrilo/água. Apôs concentração, foram isolados 1,75 g (28%) de bishemi-3'-oxoglutarato-31,42-rapamici-na. 44 XH RMN (CDC13, 400 MHz) δ 4,785 (m, 1 H, CC^CHCHOMe) . 4,260 (m, 8 H, O^ÇH^OÇHgCC^) , 3,360 (s, 3 H, ÇH30-) , 3,343 (s, 3 H, 0^0-) , 3,143 (S, 3H, ÇH30-), 1,775 (s, 3 H, ÇH3C=C), 1,656 (s, 3 H, ÇH3C=C); 13c RMN TcDC13, MHz) 211,12 (0=0)7207,73 (C=0), 193,11 (C=0), 171,90 (C=0), 171,59 (0=0), 170,15 (C=0), 169,35 (C=0), 168,83 (C=0), 166,63 (C=0); IV (KBr) 3420 (OH), 2920 (CH), 2850 (CH), 1740 (C=0), 1645, 1625, 1440, 1370, 1190, 11300, 980 cirf1; MS (FAB ião neg.) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ião neg.) Cale. para C5gH86021N (M-H) 1144,5701, Encontrados 1144,5702.Bishemi-3'-oxoqlutarate-31.42-Rapamycin To a solution of 5.0 g (5.47 mmol) of rapamycin in 20 ml of dry dichloromethane was added diglycolic anhydride (3.17 g, 27.3 mmol) 2.17 ml (2.12 g, 27.3 mmol) of pyridine. To this was added 400 mg of 4-dimethylaminopyridine and the reaction mixture was allowed to stir under reflux for 24 hours. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on a C20 column, eluting with 60% acetonitrile / water. After concentration, 1.75 g (28%) of bishemi-3'-oxoglutarate-31,42-rapamycin was isolated. 1 H NMR (CDCl3, 400 MHz) δ 4.785 (m, 1 H, CH3 CHCHOMe). 4.260 (m, 8H, OCH3), 3.360 (s, 3 H, CH3 -), 3.343 (s, 3H, OCH2), 3.143 (S, 3H, CH3 -), 1.775 (s, 3 H, CH3 C = C), 1.656 (s, 3 H, CH3 C = C); 13 C NMR (CDCl3, 13 MHz) 211.12 (C = O), 7207.73 (C = O), 193.11 (C = O), 171.90 (C = O), 171.59 (C = O), 170.15 (C = O), 169.35 (C = O), 168.83 (C = O), 166.63 (C = O); IR (KBr) 3420 (OH), 2920 (CH), 2850 (CH), 1740 (C = O), 1645, 1625, 1440, 1370, 1190, 11300, 980, cir. MS (FAB ion neg.) 1140 (M-H), 1122, 1026, 990, 946, 913, 590, 475, 435, 321, 167, 148, 131 (100), 113; MS Elev. Sep. (FAB ion neg.) Calc. Calc'd for C5 H8 N2 O2 N (M-H) 1144.5701, Found 1144.5702.
Anal. Cale. para C5gH87021N C,61,82;H,7,56;N,1,22Anal. Calc. Calc'd for C5 H8 N2 O2 N: C, 61.82; H, 7.56; N, 1.22
Encontrados C,61,59;H,7,36;N,1,84Found: C, 61.59; H, 7.36; N, 1.84
Exemplo 22Example 22
Sal dissódico de bishemi-3 '-oxocrlutarato-31-42-RapamicinaDisodium salt of bishemi-3'-oxyocrutarate-31-42-Rapamycin
Hemi-3'-oxoglutarato de bis-31,42 purificado (720 mg, 629 umol), preparado pelo processo utilizado no Exemplo 8, foi dissolvido em 10 ml de 95% de etanol e 106 mg (1,26 mmol) de bicarbonato de sódio e água. Adicionou-se água (1 ml) a fim de dissolver completamente o sal. Uma vez dissolvido, a solução amarelo claro foi concentrada in vacuo para dar origem a um sólido amarelo espumoso. A espuma foi seca numa pistola de secagem durante 48 horas, submetendo-se a refluxo sobre dicloro-metano sob pressão reduzida para dar origem a 435 mg (58%) de sal dissódico. 45 ΧΗ RMN (dg-DMSO, 400 MHz) 5 4,975 (m, 1 H, -CHOgC). 4,593 (m, 1 H, MeOCHÇH02C-), 4,135 (s, 2H, -Q2CCH20CH2C02R^. 3,617 (s, 2 H, -02CCH20CH2C02R). 3,299 (s, 6 H, 2 ÇH30-), 3,232 (s, 3 H, Çí^O-), I, 614 (S, 3 H, ÇH3C=C), 1,553 (s, 3~H, ÇH3C=C); IV (KBr) ~3420 (OH), 2920 (CH), 1735 (C=0), 1615, 1445, 1395, 1380, 1320, 1220, 1130, 1090, 980 cm"*1; MS (FAB ião nef.) 1188 (M-l), 1166 (M-Na), 1144, 1051, 1028, 590, 459, 167, 155 (100), 148, 133, 115.Purified bis-31.42 hemi-3'-oxoglutarate (720 mg, 629 μmol), prepared by the procedure used in Example 8, was dissolved in 10 ml of 95% ethanol and 106 mg (1.26 mmol) of bicarbonate sodium and water. Water (1 ml) was added to completely dissolve the salt. Once dissolved, the pale yellow solution was concentrated in vacuo to give a yellow foamy solid. The foam was dried on a drying gun for 48 hours, refluxed over dichloromethane under reduced pressure to give 435 mg (58%) of disodium salt. 45 ¹ NMR (d6 -DMSO, 400 MHz) Î'4.975 (m, 1 H, -CHOgC). 4.593 (m, 1 H, MeOH CH 2 CO-), 4.135 (s, 2H, -CH 2 CH 2 CH 2 CO 2 R 3, 3.617 (s, 2 H, -O 2 CCH 2 CH 2 CO 2 R), 3.299 (s, 6 H, 2 H CH 3) IR (KBr) -3420 (OH), 2920 (CH), 1735 (s, 3 H, CH3 C = C), 1.553 (s, 3 H, CH3 C = (M-Na), 1144 (M), 1166 (M-Na), 1144, 1051 (C = O), 1615, 1445, 1395, 1380, 1220, 1130, 1090, 980 cm- , 1028, 590, 459, 167, 155 (100), 148, 133, 115.
Anal. Cale. para C5gHg5021NNa2*2 H20 C,57,79;H,7,26;N,1,14Anal. Calc. for C 55 H 50 N 2 O 2 • 2 H 2 O: C, 57.79, H, 7.26, N, 1.14
Encontrados C, 57,94;H,7,11;N,1,26Found: C, 57.94; H, 7.11; N, 1.26
Exemplo 23Example 23
Sal bistrometamina de bishemi-3'-oxocílutarato-3l.42-RapamicinaBishemi-3'-oxocyluterato-3,14-Rapamycin salt
Hemi-3'-oxoglutarato bis-31,42 de rapamicina purificado (1.01 g, 882 umol), preparado pelo processo do Exemplo 8, foi dissolvido em 10 ml de 95% de etanol e adicionaram-se 213 mg (1,76 mmol) de tris(hidroximetil)-metilamina. Adicionou-se água (1 ml) para dissolver completamente a amina. Uma vez dissolvida, a solução amarela foi concentrada in vacuo para dar origem a um sólido amarelo espumoso. A espuma muito higroscópica foi seca numa pistola de secagem durante 48 horas, submetendo a refluxo sobre diclorometano sob pressão reduzida para dar origem a 805 mg (66%) de sal bistrometamina. 46 2Η RMN (dg-DMSO, 400 MHz) S 4,955 (m, 1 H, -CHC^Cl. 4,600 (m, 1 H, MeOCHCHC>2C-) , 4,149 (s, 2 Η, -O^C^OÇHgCC^R) , 3,770 (s, 2 H, -02CSí^0CH2C02R) , 3,407 (s, 6 H, 2 CH^O-) , 3,257 (s, 3 H, C^O-) . I, 806 (S, 3 H, ÇH3C=C), 1,614 (s, 3~H, ÇH3C=C); IV (KBr) ~3400 (OH), 2920 (CH), 1730 (C=0), 1620, 1550, 1450, 1395, 1370, 1200, 1060, 985 cm”1; MS (FAB ião neg.) 1144 (M-H, ácido livre), 1028, 167, 148, 133, (100), 115.Hemi-3'-oxoglutarate bis-31.42 purified rapamycin (1.01 g, 882 μmol) prepared by the procedure of Example 8 was dissolved in 10 ml of 95% ethanol and 213 mg (1.76 mmol ) of tris (hydroxymethyl) -methylamine. Water (1 ml) was added to completely dissolve the amine. Once dissolved, the yellow solution was concentrated in vacuo to give a yellow foamy solid. The very hygroscopic foam was dried on a drying gun for 48 hours, refluxing over dichloromethane under reduced pressure to give 805 mg (66%) of bistromethamine salt. NMR (d6 -DMSO, 400 MHz): δ 4.955 (m, 1 H, -CHCl3), 4.600 (m, 1 H, MeOCHCHC> 2C-), 4.149 (s, 2 Î', -O- , 3.407 (s, 6H, 2CH₂O-), 3.257 (s, 3 H, C O-O-), 1.80 (s, 2 H, -O₂CH₂O 0CH₂CO₂R,) IR (KBr) -3400 (OH), 2920 (CH), 1730 (C = O), 1620, 1550, 1450, 1395 (s, 3 H, CH3 C = C) , 1370, 1200, 1060, 985 cm-1; MS (FAB negative ion) 1144 (MH, free acid), 1028, 167, 148, 133, (100), 115.
Anal. Cale. para C67H109°27N3*H2° C'57'22;H,7,90;N,2,98Anal. Calc. Calc'd for C 67 H 109 N 2 O 2 · H 2 O: C, 57.22; H, 7.90; N, 2.98
Encontrados C,57,26;H,7,90;N,3,15Found: C, 57.26; H, 7.90; N, 3.15
Exemplo 24Example 24
Bishemisuccinato-31.42-Rapamicina A uma solução de 2,0 g (2,2 mmol) de rapamicina em 10 ml de diclorometano seco foram adicionados 1,19 g (10,9 mmol) de anidrido succínico seguindo-se 881 uL (861 mg, 10,9 mmol) de piridina. A isto foram adicionados 200 mg de 4-dimetilaminopiri-dina e a mistura da reacção foi submetida a refluxo durante 24 horas. A solução foi arrefecida até à temperatura ambiente, vertida para HC1 2 N, e extraída três vezes com diclorometano. Os extractos orgânicos combinados foram lavados com solução salina, secos sobre sulfato de sódio anidro, e concentrados in vacuo para dar origem a uma espuma amarela. O produto crú foi purificado por HPLC de fase reversa numa coluna Clg com gradiente de eluição comçando com 20% acetonitrilo/água até 60% acetonitrilo/água. Foram recolhidos, após concentração, 770 mg (31%) de bishemisuc-cinato-31,42-rapamicina. O Hemisuccinato bis-31,42 de rapamicina purificado (770 mg, 686 umol) foi dissolvido em 10 ml de 95% de etanol e foram adicionados 166 mg (1,37 mmol) de tris(hidroximetil)metilamina. 47Bishemisuccinate-31.42-Rapamycin To a solution of 2.0 g (2.2 mmol) of rapamycin in 10 ml of dry dichloromethane was added 1.19 g (10.9 mmol) of succinic anhydride followed by 881 μl (861 mg , 10.9 mmol) of pyridine. To this were added 200 mg of 4-dimethylaminopyridine and the reaction mixture was refluxed for 24 hours. The solution was cooled to room temperature, poured into 2N HCl, and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow foam. The crude product was purified by reverse phase HPLC on an elution gradient Cl 2 column starting with 20% acetonitrile / water to 60% acetonitrile / water. 770 mg (31%) of bishemisuccinate-31,42-rapamycin were collected after concentration. The purified bis-31.42 Hemisuccinate of purified rapamycin (770 mg, 686 μmol) was dissolved in 10 ml of 95% ethanol and 166 mg (1.37 mmol) of tris (hydroxymethyl) methylamine was added. 47
Adicionou-se água (1 ml) para dissolver completamente a amina. Uma vez dissolvida, a solução amarela foi concentrada in vacuo para dar origem a um sólido amarelo espumoso. A espuma muito higroscómica foi seca numa pistola de secagem durante 24 horas, submetida a refluxo sobre acetona sob pressão reduzida para dar origem a 890 mg (95%) do sal bistrometamina. 0 sal bistrometano foi avaliado nos processos de teste farmacológico padronizados. -½ RMN (dg-DMSO, 400 MHz) , 5,231 (m, 1 H, -CHO^ . 4,554 (m, 1 H, Me0CHÇH02C-), 3,426 (s, 6 H, ÇÍ^O-), 3,249 (s, 3 H, ÇI^O-), 2,431 (m, 8 Η, O CCH2CH2C02-), 1,700 7s, 3 H, ÇH3C=C), 1,554 (s, 3 H, CH3C=C); 13C RMN (dg-DMSO), 211,28 (C=0), _205,23 (C=0), 199,59 (C=0), 174,86 (C=0), 173,62 (C=0), 171,72 (C=0), 171,50 (C=0), 166,56 (C=0), 166,53 (C=0); IV (KBr) 3420 (OH), 2040 (CH), 1735 (C=0), 1630, 1580, 1460, 1400, 1380, 1170, 1070, 990 cm_1; MS (FAB ião neg.) 1112 (M-l, ácido livre), 994, 859, 475, 297, 167, 148, 117,99 (100).Water (1 ml) was added to completely dissolve the amine. Once dissolved, the yellow solution was concentrated in vacuo to give a yellow foamy solid. The highly hygroscopic foam was dried on a drying gun for 24 hours, refluxed over acetone under reduced pressure to give 890 mg (95%) of the bromethamine salt. Bistromethane salt was evaluated in the standard pharmacological test procedures. 1 H NMR (CDCl 3): δ (DMSO, 400 MHz), 5.231 (m, 1 H, -CHO), 4.554 (m, 1 H, MeOH, CH 2 O-), 3.446 (s, 6 H, CH 2 O-), 3.249 , 3.31 (m, 8Η, OCH₂CH₂CO₂-), 1.700 7s, 3 H, CH 3 C = C), 1.554 (s, 3 H, CH 3 C = C); 13 C NMR (d6 -DMSO), 211.28 (C = O), -205.23 (C = O), 199.59 (C = O), 174.86 (C = O), 173.62 (C = 0), 171.72 (C = O), 171.50 (C = O), 166.56 (C = O), 166.53 (C = O); IR (KBr) 3420 (OH), 2040 (CH), 1735 (C = O), 1630, 1580, 1460, 1400, 1380, 1170, 1070, 990 cm -1; MS (FAB negative ion) 1112 (M-1, free acid), 994, 859, 475, 297, 167, 148, 117.99 (100).
Análise Cale. para C67H109O25N3*2 H2° C*57,80;H,8,12;N,3,01 Encontrados C,57,91;H,8,21;N,2,37Calc'd. for C 67 H 10 9 O 25 N 3 • 2 H 2 O • 57.80 H, 8.12 N, 3.01 Found: C, 57.91; H, 8.21; N, 2.37
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US07/657,294 US5130307A (en) | 1990-09-28 | 1991-02-19 | Aminoesters of rapamycin |
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US4316885A (en) * | 1980-08-25 | 1982-02-23 | Ayerst, Mckenna And Harrison, Inc. | Acyl derivatives of rapamycin |
US4650803A (en) * | 1985-12-06 | 1987-03-17 | University Of Kansas | Prodrugs of rapamycin |
JPH04230389A (en) * | 1990-07-16 | 1992-08-19 | American Home Prod Corp | Rapamycin derivative |
JP3140228B2 (en) * | 1992-02-17 | 2001-03-05 | ファイザー製薬株式会社 | Novel macrocyclic lactone and its producing bacteria |
-
1991
- 1991-09-17 PT PT98990A patent/PT98990A/en not_active Application Discontinuation
- 1991-09-18 MX MX9101139A patent/MX9101139A/en unknown
- 1991-09-19 HU HU9300776A patent/HUT65763A/en unknown
- 1991-09-19 AU AU86599/91A patent/AU653175B2/en not_active Expired - Fee Related
- 1991-09-19 EP EP19910919248 patent/EP0549727A1/en not_active Ceased
- 1991-09-19 JP JP3516749A patent/JPH06501012A/en active Pending
- 1991-09-19 IE IE330291A patent/IE913302A1/en unknown
- 1991-09-19 WO PCT/US1991/006824 patent/WO1992005179A1/en not_active Application Discontinuation
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1993
- 1993-03-18 FI FI931203A patent/FI931203A7/en not_active Application Discontinuation
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HU9300776D0 (en) | 1993-06-28 |
FI931203A0 (en) | 1993-03-18 |
WO1992005179A1 (en) | 1992-04-02 |
FI931203A7 (en) | 1993-03-18 |
AU653175B2 (en) | 1994-09-22 |
IE913302A1 (en) | 1992-02-25 |
MX9101139A (en) | 1992-05-04 |
HUT65763A (en) | 1994-07-28 |
EP0549727A1 (en) | 1993-07-07 |
AU8659991A (en) | 1992-04-15 |
JPH06501012A (en) | 1994-01-27 |
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