IL128643A - Process for preparing cryptophycin compounds and some new intermediates - Google Patents
Process for preparing cryptophycin compounds and some new intermediatesInfo
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- IL128643A IL128643A IL128643A IL12864399A IL128643A IL 128643 A IL128643 A IL 128643A IL 128643 A IL128643 A IL 128643A IL 12864399 A IL12864399 A IL 12864399A IL 128643 A IL128643 A IL 128643A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
mcuTn ΌΊΊΓ2 jimmn nrrn nizrmri iron"? rvnn PROCESS FOR PREPARING CRYPTOPHYCIN COMPOUNDS AND SOME NEW INTERMEDIATES PROCESS TO PREPARE PHARMACEUTICAL COMPOUNDS This invention relates to the fields of pharmaceutical and organic chemistry and provides a process for preparing cryptophycin compounds useful as anti-microtubule agents.
Cryptophycin compounds can be useful for the treatment of cancer and neoplasms, and are thus useful pharmaceutical agents.
The literature discloses a protocol for cyclizing certain cryptophycin compounds. Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore, R. E.; Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479. This three-step sequence (hereinafter "Barrow synthetic sequence") commenced with the conversion of trichloroethyl ester to the corresponding carboxylic acid using zinc and acetic acid. Conversion of crude to the amino carboxylate was accomplished with trifluoroacetic acid followed by an aqueous basic work-up. In the final step, ring closure was achieved in the presence of pentafluorophenyldiphenylphosphinate (FDPP) in N,N-dimethylformamide to provide the desired product 3 (3 is illustrated infra, in Scheme 1 to provide further clarification) (61% after chromatography) .
In contrast, the presently claimed process provides a shorter (two-steps) process which is more adaptable for large scale or commercial preparation of the macrocyclic core of cryptophycin derivatives. The claimed process can reduce reagent expense, as well as minimize the potential waste-stream issues associated with the use of certain reagents in the Barrow synthetic sequence. Further, purification via the claimed process may be accomplished without chromatography, which is expensive and difficult to implement on a large scale.
The presently claimed invention provides a process for preparing a compound of Formula II wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromati substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, NR51R52, COR52, OR53, and Formula Ar R51 is selected from the group consisting of hydrogen and d-C3 alkyl; R52 is selected from the group consisting of hydrogen and Ci-C3 alkyl; R53 is selected from the group consisting of C1-C12 alkyl; R54 is selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci-C6alkyl (R57'R57"R57"' ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) -benzyltriphenylphosophonium, COOR57, P03H, S03H, S02R58, N(R59)R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, CH2(0)R62', - CH2OC(0)R 95 CH2N(R96)R96',COR 100 (Ci-C6alkyl)OR 100 SR' R95 is selected from the group consisting of -R98NH3; R96 and R96' are each independently selected from the group consisting of hydrogen and Ci-C6 alkyl, -R97NH3, and -R99 NR99' R99"; R97 is selected from the group consisting of Ci-C6 alkyl; R98 is selected from the group consisting of C1-C6 alkyl; R99 is Ci -C6 alkyl; R99' and R99" are each independently selected from the group consisting of hydrogen and Ci-C6 alkyl; R100 is selected from the group consisting of hydrogen, and Si (R101R102R103) ; R101 is Ca-C6 alkyl; R102 is d-C6 alkyl; R103 is Ci-C6 alkyl; R104 is selected from the group consisting of C ( 0) Ci-C6 alkylN(R106) (R59)R60, C(0)d-C6 alkylN\ fused bicyclic, and NHR105N(R106) (R59)R60; R105 is selected from the group consisting of C ( 0) Ci-C6 alkyl, Ci-C6 alkyl; R106 is selected from the group consisting of hydrogen, Ci-C6 alkyl, C( 0) 0R107 ; R107 is selected from the group consisting of hydrogen, Ci-C6 alkyl, CR108 R109 Rn0 Rloe is selected from the group consisting of hydrogen and Ci-C6 alkyl; R109 is selected from the group consisting of hydrogen and Ci-C6 alkyl; R110 is selected from the group consisting of hydrogen and Ci -Cg alkyl; R55 is selected from the group consisting of hydrogen, Ci-C6 alkyl, C (R5'R5 "R5'7'" ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61 , NHCHR61', CN, N02 , halogen, OR62, and SR63; R56 is selected from the group consisting of hydrogen, Ci -C6 alkyl, C (R57' R57" R57" ' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, HOR61, NHCHR61', (C:-C6) alkylNR59R60, CN, N02, halogen, OR104, CR104, OR62, and SR63; R57 is selected from the group consisting of hydrogen and d-Ci2 alkyl; R57' is selected from the group consisting of hydrogen, halogen, and C1 -C12 alkyl; R57" is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl; R57'" is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl; R58 is selected from the group consisting of hydrogen and d-C12 alkyl; R59 is selected from the group consisting of hydrogen, (Ci-C6) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC) ; R60 is selected from the group consisting of hydrogen and (Ci-C6) alkyl; R61 is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR6' and fluorenylmethoxycarbonyl (FMOC) ; R61' is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65' and fluorenylmethoxycarbonyl (FMOC) ; R62 is selected from hydrogen, and Ci-C6 alkyl; R62' is selected from hydrogen, OH, OR62, and Ci-C6 alkyl; R63 is selected from hydrogen and Ci-C6 alkyl; R64 is selected from the group consisting of hydrogen, (d- C6) alkyl, CH2NR66R67; R65 is selected from the group consisting of hydrogen and d- C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC) ; R65' is selected from the group consisting of hydrogen and Ci-Cg alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC); R is selected from the group consisting of hydrogen and Ci~ Cs alkyl and fluorenylmethoxycarbonyl (EMOC) R67 is selected from the group consisting of hydrogen and Ci- C6 alkyl; R3 is a lower alkyl group; R4 is H or OH; R5 is H or OH; R4 and R5 may be taken together to form a second bond between Ci3 and C1 ; R6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (Ci-C6) alkyl, (C3-C8) cycloalkyl, substituted C3-C8 cycloalkyl, substituted (Ci-C6) alkyl, a group of the formula III' R1 is selected from the group consisting of NR51R52, R53NR51R52, OR53, H and a lower alkyl group; R51 and R52 are independently selected from the group consisting of Ci~C3 alkyl; R53 is Ci- C3 alkyl; R8 is H or a lower alkyl group; or R7 and R8 ca form a cyclopropyl ring; R9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C3-C5 cycloalkyl, and benzyl; R10 is H or a lower alkyl group; R11 is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, OR18, halo, NR18'R19', N02, OPO3H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, Ci-Ce alkyl, C(0)R90 and fluorenylmethoxycarbonyl (FMOC) ; R18' is selected from the group consisting of hydrogen, (Ci-C6) alkyl and C(0)R90'; R19 is Ci-C6 alkyl, C(0)R90" and fluorenylmethoxycarbonyl (FMOC) ; R19' is selected from the group consisting of hydrogen, (Ci-C6) alkyl, and C(0)R90"'; R90, R90' , R90" , and R90'" are each independently selected from the group consisting of hydrogen, (Ci-C6) alkyl, OR91' and aryl ; R91' is selected from the group consisting of (Ci-Ce) alkyl, aryl, and hydrogen; R23 is selected from the group consisting of hydrogen and (Ci-C3) alkyl; R30 is hydrogen or Ci-C6 alkyl; or R30 may be taken together with the N at C-11 to form a three to seven membered cyclic ring; R50 is hydrogen or n is 0, 1, or 2; m is 0, 1, or 2; p is 0, l,or 2; X is selected from the group consisting of 0, C, S, NH and alkylamino; Y is selected from the group consisting of C, 0, NH, S, SO, S02 and alkylamino; Z is selected fromt he group consisting of -(CH2)n-/ -(CH2)P-0-(CH2) m- and (C3-C5) cycloalkyl; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; comprising contacting a compound of Formula III with a solven t of the formula wherein M is selected from the group consisting of hydrogen, Na, Li, K, and Cs; xcat is selected from the group consisting of 0, N, and S; ycat is selected from the group consisting of 0, N, and S; Rcatl ig selected from the group consisting of Ci~ C6 alkyl and aryl; Rcat2 s selected from the group consisting of Ci~ C6 alkyl and aryl .
Additionally, the present invention provides a new cryptoph wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, Ci -C alkyl, C2-Ci2 alkenyl, C2-Ci2 alkynyl, NR51R52 , COR52, OR53, and Formula Ar' R51 is selected from the group consisting of hydrogen and Ci-C3 alkyl; R52 is selected from the group consisting of hydrogen and Ci-C3 alkyl; R53 is selected from the group consisting of C1 -C12 alkyl; R54 is selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci -C6alkyl (R57' R57" R57"' ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) -benzyltriphenylphosophonium, COOR57 , P03H, S03H, S02R58 , N(R59)R60, NHOR61 , NHCHR61' , CN, N02, halogen, OR62, CH2(0)R62' CH2OC( 0)R9S, CH2N(R96)R96',COR100, ( Ci-C6alkyl) OR100, , and SR63; R93 is selected from the group consisting of -R98NH3; R96 and R96' are each independently selected from the group consisting of hydrogen and Cj-Ce alkyl, -R9NH3/ and -R99 NR99' R99"; R97 is selected from the group consisting of Ci -C6 alkyl; R98 is selected from the group consisting of Ci-C6 alkyl; R99 is Ci -C€ alkyl; R99' and R99" are each independently selected from the group consisting of hydrogen and Ci -C6 alkyl; R100 is selected from the group consisting of hydrogen, and Si (R101R102R103) ; R101 is Ci-C6 alkyl; R102 is Ca-Ce alkyl; R103 is Ci-C6 alkyl; R104 is selected from the group consisting of C ( 0) Ci -C6 alkylN(R106) (R59)R60, C ( 0) Ci-C6 alkylN+, fused bicyclic, and NHR105N (R106) (R9)R60; R105 is selected from the group consisting of C ( 0 ) Ci -C6 alkyl, Ci -C6 alkyl; R106 is selected from the group consisting of hydrogen, Ci-C6 alkyl, C( 0)OR107; R107 is selected from the group consisting of hydrogen, Ci-C6 alkyl, CR108 R109 R110 R108 is selected from the group consisting of hydrogen and Ci -C6 alkyl; R109 is selected from the group consisting of hydrogen and Ci-C6 alkyl; R110 is selected from the group consisting of hydrogen and Ci -C6 alkyl; R111 is selected from the group consisting of hydrogen, Ci-C6 alkyl, and C(0)0R107 R55 is selected from the group consisting of hydrogen, Ci-C6 alkyl, C (R57'R57"R57"' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R56 is selected from the group consisting of hydrogen, Ci-C6 alkyl, C (R57'R57"R57' " ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR57, P03H, S03H, S02R58, NR59R60, NHOR61, NHCHR61', (d-C6) alkylNR59R60, CN, N02, halogen, OR104, CR104, OR62, and SR63; R57 is selected from the group consisting of hydrogen and Ci-Ci2 alkyl; R57' is selected from the group consisting of hydrogen, halogen, and C:-Ci2 alkyl; R57" is selected from the group consisting of hydrogen, halogen, and Ci-Ci2 alkyl; R57'" is selected from the group consisting of hydrogen, halogen, and C1-C12 alkyl; R58 is selected from the group consisting of hydrogen and Ci-Ci2 alkyl; R59 is selected from the group consisting of hydrogen, (Ci-C6) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC) ; R60 is selected from the group consisting of hydrogen and (C,-C6) alkyl; R61 is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65' and fluorenylmethoxycarbonyl (FMOC); R61' is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65' and fluorenylmethoxycarbonyl (FMOC); R62 is selected from hydrogen, and Ci-C6 alkyl; R62' is selected from hydrogen, OH, OR62, and Ci~C6 alkyl; R63 is selected from hydrogen and Cj-C6 alkyl; R64 is selected from the group consisting of hydrogen, (Ci-C6) alkyl, CH2NR66R67; R65 is selected from the group consisting of hydrogen and Ca-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC); R65' is selected from the group consisting of hydrogen and Ci-Ce alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC) ; R66 is selected from the group consisting of hydrogen and C:~ C6 alkyl and fluorenylmethoxycarbonyl (FMOC) ; RS7 is selected from the group consisting of hydrogen and Ci-C6 alkyl; R3 is a lower alkyl group; R4 is H or OH; R5 is H or OH; R4 and R5 may be taken together to form a second bond between Ci3 and Cu," R6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (Ci-C6) alkyl, (C3-C8) cycloalkyl, substituted C3-C8 cycloalkyl, substituted (C:-C6) alkyl, a group of the formula III' and a group of the formula III' R7 is selected from the group consisting of NR51R52, R53NR51R52, OR53, H and a lower alkyl group; R51 and R52 are independently selected from the group consisting of Ci-C3 alkyl; R53 is Ci-C3 alkyl; R8 is H or a lower alkyl group; or R7 and R8 can form a cyclopropyl ring; R9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C3-C5 cycloalkyl, and benzyl; R10 is H or a lower alkyl group; R11 is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, OR18, halo, NR18'R19', N02, OPO3H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, Ci-C6 alkyl, C(0)R90 and fluorenylmethoxycarbonyl (FMOC) ; R18' is selected from the group consisting of hydrogen, (Ci-C6) alkyl and C(0)R90'; R19 is Ci-C6 alkyl, C(0)R90" and fluorenylmethoxycarbonyl (FMOC) ; R19' is selected from the group consisting of hydrogen, (Ci-Ce) alkyl, and C(0)R90"'; R90, R90', R90", and R90'" are each independently selected from the group consisting of hydrogen, (Ci-C6) alkyl, OR91' and aryl; R91' is selected from the group consisting of (Ci-C6) alkyl, aryl, and hydrogen; R23 is selected from the group consisting of hydrogen and (C1-C3) alkyl; R30 is hydrogen or Ci-C6 alkyl; or R30 may be taken together with the N at C-11 to form a three to seven membered cyclic ring; R50 is hydrogen or n is 0, 1, or 2; m is 0, 1, or 2; p is 0, l,or 2; X is selected from the group consisting of 0, C, S, NH and alkylamino; Y is selected from the group consisting of C, 0, NH, S, SO, S02 and alkylamino; Z is selected fromt he group consisting of -(CH2)n-/ ~(CH2)p-0-(CH2)m- and (C3-C5) cycloalkyl; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof.
As used herein, the term "simple alkyl" shall refer to C1-C7 alkyl wherein the alkyl may be saturated, unsaturated, branched, or straight chain. Examples include, but are in no way limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, propenyl, ethenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, methylated pentyl groups and the like. The term "alkenyl" refers to an alkyl group, as defined above, having from one to three double bonds. The term "alkynyl" refers to an alkyl group, as defined above, having at least one triple bond. It is especially preferred that alkynyl has only one triple bond. The term Ci-Cn' alkyl; wherein n' is an integer from 1 to 12 means an alkyl group having from one to the indicated number of carbon atoms. The Ci-Cn' alkyl can be straight or branched chain.
As used herein, the term "B-ring Οχ-Οβ alkyl" refers to saturated, unsaturated, branched and straight chain alkyl wherein the B-ring Ci~C6 alkyl group may include up to three (3) non-carbon substituents. Such non-carbon substituents are most preferredly selected from the group consisting of OH, SCH2phenyl, NH2, CO, CONH2, CO2H, PO3H2/ S02R21 wherein R21 is selected from hydrogen and C1-C3 alkyl; As used herein, the term " (Ci-Ce) alkyl linker" refers to C1-C6 alkyl group having from zero to three substituents selected from the group consisting of C\-Ce alkyl, H2 and amino acid.
As used herein the term "amino acid" means an organic acid containing an amino group. The term includes both naturally occuring and synthetic amino acids, therefore, the amino group can be, but is not required to be, attached to the carbon next to the acid. The term shall refer to, but is in no way limited to (CH2) 2 H2COOH, (CH2) 3NH2COOC (CH3) 3, CH2 H2COOC (CH3) 3, CH2CH(NH2)CH2COOH, CH2CH(NH2)CH2COOC(CH3)3/ and the like.
As used herein, the term "carbohydrate" refers to a class of substituents made up of carbon, hydrogen, and oxygen wherein hydrogen and oxygen are in the same proportions as in water or nearly the proportions as water. The term "carbohydrate" further refers to an aldehyde or ketone alcohol or a compound which on hydrolysis produces and aldehyde or ketone. The term "carbohydrate" is as commonly understood by the skilled artisan. For example, the term refers to, but is in no way limited to, C12H22O11 and C6H10O5.
As used herein, the term "amino sugar" refers to a carbohydrate group containing from one to three amino substituents at any available position on the carbohydrate molecule .
As used herein, the term "saccharide" refers to carbohydrate subunits to form disaccharides or polysaccharides. The term means for example, but in no way limited to, lactose, maltose, sucrose, fructose, starch, and the like.
As used herein, the term "substituted phenyl" shall refer to a phenyl group with from one to three non-hydrocarbon substituents which may be independently selected from the group consisting of simple alkyl, CI, Br, F, and I.
As used herein, the term "substituted benzyl" shall refer to a benzyl group with from one to three non-hydrocarbon substitutents which may be independently selected from the group consisting of simple alkyl, Cl, Br, F, and I wherein such substituents may be attached at any available carbon atom.
As used herein "B-ring heterocyclic group" refers to aromatic or unsaturated rings which contain one or more non-carbon substituent selected from the group consisting of oxygen, nitrogen, and sulfur. Especially preferred B-ring heterocyclic groups are selected from, but not limited to, the group consisting of R20 is selected from hydrogen and C1-C6 alkyl. wherein R20 is selected from hydrogen and C1-C6 alkyl.
It is especially preferred that "B-ring heteroaromatic group" refers to a substituent selected the group consisting of: As used herein "cycloalkyl" refers to a saturated C-C cycloalkyl group wherein such group may include from zero to three substituents selected from the group consisting of C1-C3 alkyl, halo, and OR22 wherein R22 is selected from hydrogen and C1-C3 alkyl. Such substituents may be attached at any available carbon atom. It is especially preferred that cycloalkyl refers to substituted or unsubstituted cyclohexyl.
As used herein "Lower alkoxyl group" means any alkyl group of one to five carbon atoms bonded to an oxygen atom. As used herein "lower alkyl group" means an alkyl group of one to five carbons and includes linear and non-linear hydrocarbon chains, including for example, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, methylated butyl groups, pentyl, tert pentyl, sec-pentyl, and methylated pentyl groups. As used herein "allylically substituted alkene" means any alkene having from one to seven carbon atoms which contains an alkyl substitution on it. As used herein the term "unsaturated lower alkyl" means a lower alkyl group as defined supra, wherein from one to two double bonds are present in the unsaturated lower alkyl substituent. A preferred unsaturated lower alkyl is -CH2~CH=CH2. The term "lower alkyl-C3~C5 cycloalkyl" refers to C-C alkyl substituted with a C3-Cscycloalkyl group. A preferred lower alkyl-C3~C5 cycloalkyl group is -CH2-cyclopropyl; wherein the group is attached to the cryptophycin core structure at R9 via the CH2.
As used herein "epoxide ring" means a three-membered ring whose backbone consists of two carbons and an oxygen atom. As used herein, "aziridine ring" means a three-membered ring whose backbone consists of two carbon atoms and a nitrogen atom. As used herein "sulfide ring" means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom. As used herein "episulfide ring" means a three-membered ring whose backbone consists of two carbon atoms and a sulfur atom. As used herein "sulfate group" means a five membered ring consisting of a carbon-carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom. As used herein "cyclopropyl ring" means a three member ring whose backbone consists of three carbon atoms. As used herein, "monoalkylphosphate ring" means a five membered ring consisting of a carbon-carbon-oxygen-phosphorous-oxygen backbone with two additional oxygen atoms, one of which bears a lower alkyl group, connected to the phosphorous atom.
As used herein, "simple unsubstituted group" refers to common aromatic rings having 4n+2 π electrons in a monocyclic conjugated system, for example, but not limited to: furyl, pyrrolyl, thienyl, pyridyl and the like, or a bicyclic conjugated system, for example but not limited to indolyl or naphthyl .
As used herein "simple substituted aromatic group" refers to a phenyl group substituted with a single group selected from the group consisting of halogen and lower alkyl group.
As used herein, the term "fused bicyclic" refers to two joined ring systems which are optionally independently saturated, unsaturated, or aromatic. Such groups include but are in no way limited to naphthyl, groups which fuse an unsaturated ring with an aromatic ring, groups having a heterocyclic group fused with a heteroaromatic group, and a heterocyclic group fused with an aromatic group. The fused bicyclic is optionally substituted with one or more substituents selected from the group consisting of Ci-C6 alkyl and halogen.
As used herein, "heteroaromatic group" refers to aromatic rings which contain one or more non-carbon atoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is most preferred that the heteroaromatic group will have from three to eight members in the ring. It is especially preferred that the number of non-carbon members will be from one to three.
As used herein, the term "heterocyclic" refers to saturated or unsaturate d rings containing one or more non carbon atoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. It is most preferred that the heterocyclic group will have from three to eight members in the ring. It is especially preferred that the number of non-carbon members will be from one to three .
As used herein, "halogen" or "halo" refers to those members of the group on the periodic table historically known as halogens. Methods of halogenation include, but are not limited to, the addition of hydrogen halides, substitution at high temperature, photohalogenation, etc., and such methods are known to the skilled artisan. Especially preferred halogens are chloro, bromo, fluoro, and iodo. For some purposes within the scope of this invention, chloro, bromo and fluoro are especially preferred halogens.
Compounds of Formula III are particularly useful for the preparation of cryophycin compounds.
The starting material corresponding to a compound of Formula 1 as illustrated in Scheme 1 can be prepared using the disclosures available to the skilled artisan. See Barrow, id. The processes for preparing compound 2 as illustrated in Scheme 1' used TFA; however, the artisan will recognize that alternative agents can be used in this process. Likewise, the basic workup uses sodium hydroxide; however, the artisan will appreciate that other basic agents can be effective as well.
The processes to prepare the compounds of this invention most preferably are completed in the presence of a solvent. The skilled artisan can select appropriate solvents using known methodologies. While in no way limiting the scope of the present invention, some preferred solvents are provided for the guidance of the artisan, including, but not limited to, a solvent selected from the group consisting of toluene, Ν,Ν-dimethylformamide, ethyl acetate, tetrahydrofuan, and acetonitrile.
The reaction time is related to the starting materials and operating temperature. The optimum reaction time for a given process is, as always, a compromise which is determined by considering the competing goals of throughput, which is favored by short reaction times, and maximum yield, which is favored by long reaction times.
The process of this invention can be further illustrated by the following Scheme 1' : And more particularly, Scheme 1 As illustrated above, the catalyst is most preferrably selected from the group consisting of alky and aryl substituted metal carboxylates, carboxylic acids, and other bifunctional compounds according to the Formula IV.
Especially preferred catalysts are selected from the group consisting of 2-hydroxypyridine, tetrabutylammonium cyanide and sodium benzoate/n-tetrabutylNHS0 .
The following is provided to further illustrate the advantages of the claimed process: As shown in Table 1, 2-hydroxypyridine (entries 2-4) and tetrabutylammonium benzoate (entry 5) have been shown to significantly accelerate the macrolactamization process. In contrast, ring closure was very slow when the reaction was allowed to stir at room temperature without catalyst (entry 1) . Although not listed in Table 1, tetrabutylammonium cyanide (NaBU4NCN + NaCN) also promoted macrolactamization of 2. As shown in Table 1/ the 2 and 3 refer to the structures of Scheme 1 wherein Ar is phenyl.
TABLE 1 Entry Catalyst Stoichiometry % Conversion (Equivalents) of 2 to 3 after 6h of reaction (HPLC) 1 None 4.7 2 2- 0.5 41.9 Hydroxypyridi ne 3 2- 1 44.8 Hydroxypyridi ne 4 2- 5 40.2 Hydroxypyridi ne Sodium 1 / 0.1 41.0 benzoate / nBUNHS04 Example 1 Cryptophycin-51 (3) .
Compound 1 (as illustrated by Scheme 1 supra.) (10.2 g, 11.2 mmol) was cooled to 0 °C and dissolved in trifluoroacetic acid (TFA) (50 mL) . The resulting solution was stirred at 0 °C for 30 min and was then concentrated under reduced pressure. The resultant syrup was diluted with toluene (250 mL) and washed with IN NaOH (2x100 mL) using brine (50 mL) to break up emulsions. The aqueous extracts were back-extracted with fresh toluene (1x50 mL) and the organic phases were combined and dried (MgS04) . TLC analysis indicated no trace of starting 1. The filtered solution of amino ester 2 was diluted to 500 mL and 2-hydroxypyridine (5.34, 56.2 mmoles) was added. The resulting clear, pale yellow solution was allowed to stir at room temperature for 14 h. The reaction mixture became turbid so the suspension was diluted with CH2CI2 (250 mL) to assure solubility of product. The mixture was washed with saturated, aqueous NaHC03 (3 x 100 mL) and brine (1 x 100 mL) . The aqueous extracts were back-extracted with CH2CI2 (1 x 100 mL) and the organic extracts were combined, dried (MgSCXj ) , and concentrated to a thick syrup. A solution of hexanes and EtOAc (100 mL, 1:1 v/v) was added and the solution was cooled to 0 °C. Spontaneous crystallization occurred after 30 min. The mixture was filtered, and the filtrate was concentrated and induced to crystallize two additional times. The collected crops were combined to give 5.04 g (69%) of compound 3 (LSN 354504) as a white powder. HPLC (85:15 CH3CN / E2O, 0.05% TFA in both organic and aqueous phases; flow 1 mL / min; wavelength: 225 nm; column: Zorbax SB-C18) Rt = 6.09 min 95% pure. λΕ NMR (300 MHz, CDCI3) d 7.32-7.17 (m, 8H) ; 7.04 (dd, 1H, J= 2.2, 8.4); 6.82 (d, 1H, J= 8.5); 6.76 (m, 1H) ; 6.39 (d, 1H, J= 15.9); 5.99 (dd, 1H, J= 8.8, 15.8); 5.73 (dd, 1H, J= 2.3, 16.4); 5.50 (d, 1H, J= 7.8); 5.03 (m, 1H) ; 4.83 (dd, 1H, J = 3.3, 9.9); 4.73 (ABq, 1H, J= 6.4); 3.86 (s, 3H) ; 3.39 (dd, 1H, J = 8.6, 13.5); 3.10 (m, 2H) ; 2.53 (m, 2H) ; 2.36 (m, 1H) ; 1.62 (m, 3H) ; 1.21 (s, 3H) ; 1.14 (s, 3H) ; 1.11 (d, 3H, J = 6.9) .71 (app. t, 6H, J = 6.0) .
Claims (13)
1. We claim: wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromati substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, Ci-Ci2 alkyl, C2-C]2 alkenyl, C2-Ci2 alkynyl, NRS1R52, COR52, OR53, and Formula Ar R is selected from the group consisting of hydrogen and C-:-C3 alkyl; R52 is selected from the group consisting of hydrogen and C-:-C3 alkyl; R53 is selected from the group consisting of CT-CTC alkyl; R54 is selected from the group consisting of hydrogen, C-,-C, alkyl, d-C6alkyl (R5 'R57"R57"' ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) -benzyltriphenylphosophonium, COOR5\ P03H, S03H, S02R58, N(R59)R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, CH2(0)R62', - CH20C<0)R95, CH2N(R96)R96',COR100, (C,-C6alkyl ) OR100, , and SR63; R95 is selected from the group consisting of -R98NH3; R96 and R96' are each independently selected from the group consisting of hydrogen and d-d alkyl, -R?'NH<, and -R NR ' R99"; R97 is selected from the group consisting of d~C6 alkyl; R98 is selected from the group consisting of d-C6 alkyl; R99 is Ci-C6 alkyl; R99' and R99" are each independently selected from the group consisting of hydrogen and C]-C6 alkyl; R100 is selected from the group consisting of hydrogen, and Si (R:olR102R103) ; R101 is d-C6 alkyl; R102 is Ci-C6 alkyl; R103 is d-C6 alkyl; R104 is selected from the group consisting of C(0)Ci-C6 alkylN(R106) (R59)R60, C(0)d-C6 alkylN*, fused bicyclic, and NHR105N(R106) (R59)R60; R105 is selected from the group consisting of C(0)Cj-C, alkyl, Ci-C6 alkyl; R106 is selected from the group consisting of hydrogen, alkyl, C(0)OR107; R107 is selected from the group consisting of hydrogen, Ci-C, alkyl, CR103 R109 Rno R108 is selected from the group consisting of hydrogen and d-Ce alkyl; R109 is selected from the group consisting of hydrogen and d-Ce alkyl; Rno is selected from the group consisting of hydrogen and d-C6 alkyl; R111 is selected from the group consisting of hydrogen, C^-d. alkyl, and C(0)OR107 R55 is selected from the group consisting of hydrogen, Ci-Ct. alkyl, C (R57' R5 " R57"' ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR57, POjH, SO?H, S02R58, NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR", and SRb3; R56 is selected from the group consisting of hydrogen, C-.-C alkyl, C ( R5 ' R57" R57'" ) , simple unsubstituted aromatic, simple substituted aromatic, phenyl, COOR57, PO÷H, SO.*H, SO.R58, NR59R60, NHOR61, NHCHR61', (C -Ce) alkylNR^R"1"" , CN, N02, halogen, OR104, CR10\ OR62, and SR63; R57 is selected from the group consisting of hydrogen and C.-C12 alkyl; R57' is selected from the group consisting of hydrogen, halogen, and C1 -C12 alkyl; R57" is selected from the group consisting of hydrogen, halogen, and C3-C12 alkyl; R57'" is selected from the group consisting of hydrogen, halogen, and C: -Ci 2 alkyl; R58 is selected from the group consisting of hydrogen and C:-C12 alkyl; R59 is selected from the group consisting of hydrogen, (C)-C6) alkyl, tert-butoxycarbonyl, carbo-tert-butoxy (t-BOC) and fluorenylmethoxycarbonyl (FMOC) ; R60 is selected from the group consisting of hydrogen and ( Ci-C6) alkyl; R61 is selected from the group consisting of hydrogen, OR'"', CH2NHR65, NHR65' and fluorenylmethoxycarbonyl (FMOC) ; R61' is selected from the group consisting of hydrogen, ORb4, CH2NHR65, NHR65' and fluorenylmethoxycarbonyl (FMOC) ; R62 is selected from hydrogen, and Ci -Cc alkyl; R62' is selected from hydrogen, OH, OR°J, and Ci~Cf, alkyl; R63 is selected from hydrogen and CJ -CR alkyl; R is selected from the group consisting of hydrogen, (C-:-C6) alkyl, CH2NR66R67; R65 is selected from the group consisting of hydrogen and C -C6 alkyl, NH2/ and fluorenylmethoxycarbonyl (FMOC) ; R65' is selected from the group consisting of hydrogen and C3-C6 alkyl, NH2, and fluorenylmethoxycarbonyl (FMOC) ; R66 is selected from the group consisting of hydrogen and C.-C6 alkyl and fluorenylmethoxycarbonyl (FMOC) ; R67 is selected from the group consisting of hydrogen and C:-C6 alkyl; R3 is a lower alkyl group; R4 is H or OH; R5 is H or OH; R4 and R5 may be taken together to form a second bond between C13 and Cn," R6 is a substituent selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkyoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (Ci-C6) alkyl, (C3-C8) cycloalkyl, substituted C3-C8 cycloalkyl, substituted (Ci-C6) alkyl, a group of the formula III' and a group of the formula III1 1: III' ' R7 is selected from the group consisting of NR51R52, R"NR51R5: , OR53, H and a lower alkyl group; R51 and R52 are independently selected from the group consisting of C!-C3 alkyl; R53 is Cj-C3 alkyl; R8 is H or a lower alkyl group; or R7 and R8 can form a cyclopropyl ring; R9 is selected from the group consisting of H, a lower alkyl group, unsaturated lower alkyl, lower alkyl-C3-C5 cycloalkyl, and benzyl; R10 is H or a lower alkyl group; R11 is selected from the group consisting of hydrogen, OH, lower alkyl group, substituted phenyl, benzyl, substituted benzyl and phenyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, OR18, halo, NR18'R19', N02/ OP03H2, 0R19pnenyl, SCH2phenyl, CONH2, C02H, P03H , S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, d-Ce alkyl, C(0)R90 and fluorenylmethoxycarbonyl (FMOC) ; R18' is selected from the group consisting of hydrogen, (C-.-C6) alkyl and C(0)R90'; R19 is C!-Cs alkyl, C(0)R90" and fluorenylmethoxycarbonyl (FMOC) ; R19' is selected from the group consisting of hydrogen, (C--C6) alkyl, and C(0)R90"'; R90, R90', R90", and R90'" are each independently selected from the group consisting of hydrogen, (Ci-C6) alkyl, OR91' and aryl; R91' is selected from the group consisting of (Cj-Cb) alkyl, aryl, and hydrogen; R23 is selected from the group consisting of hydrogen and (Ci-C3) alkyl; R30 is hydrogen or Ci-C6 alkyl; or R may be taken together with the N at C-11 to form a three to seven membered cyclic ring; R50 is hydrogen or n is 0, 1, or 2; m is 0, 1, or 2; p is 0, l,or 2; X is selected from the group consisting of 0, C, S, NH and alkylamino; Y is selected from the group consisting of C, 0, NH, S, SO, S02 and alkylamino; Z is selected fromt he group consisting of -((¾)„-/ -(<-¾);-0-(CH2 ) m- and (C3-C3) cycloalkyl; ZZ is selected from the group consisting of a simple unsubstituted aromatic group and a simple substituted aromatic group; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of Claim 1 wherein the compound of Formula III is defined as follows: wherein Ar is phenyl or any simple unsubstituted or subst aromatic or heteroaromatic group, C1-C12 alkyl, Ci alkene, C1-C12 alkyne, NR51R52, OR53, Formula Ar' R51 is selected from the group consisting of hydrogen and C1-C3 alkyl; R52 is selected from the group consisting of hydrogen and C3.-C3 alkyl; R53 is selected from the group consisting of C1-C12 alkyl; R54 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR57, PO3H, SO3H, SO2R58, NR59R60 NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R55 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR57, PO3H, SO3H, SO2R58, NR59R60 NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R56 is selected from the group consisting of hydrogen, C1-C6 alkyl, simple aromatic, phenyl, COOR57, P03H, SO3H, SO2R58/ NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R57 is selected from the group consisting of hydrogen and C1-C12 alkyl; R58 is selected from the group consisting of hydrogen and C1-C12 alkyl; R59 is selected from the group consisting of hydrogen, (Ci~ Ce) alkyl and fluorenylmethoxycaronyl (FMOC) ; R60 is selected from the group consisting of hydrogen and (Ci-Ce) alkyl; R61 is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 and fluorenylmethoxycaronyl (FMOC) ; R61' is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 and fluorenylmethoxycaronyl (FMOC); R62 is selected from hydrogen and C1-C6 alkyl; R63 is selected form hydrogen and C1-C6 alkyl; R64 is selected from the group consisting of hydrogen, (Ci-C6) alkyl, CH2NR66R67 R65 is selected from the group consisting of hydrogen and C1-C6 alkyl, NH2, and fluorenylmethoxycaronyl (FMOC) ; R66 is selected from the group consisting of hydrogen and C1-C6 alkyl and fluorenylmethoxycaronyl ( FMOC) ; R67 is selected from the group consisting of hydrogen and C1-C6 alkyl; R3 is a lower alkyl group; R4 is H or OH; R5 is H or OH; R4 and R5 may be taken together to form a second bond between C13 and C14 ; R6 is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B- ring ( C1-C6 ) alkyl, ( C3-C8 ) cycloalkyl, substituted C3-C 8 cycloalkyl, substituted ( C1-C6 ) alkyl, a group of the formula III ' : nd a group of the formula III R7 is H or a lower alkyl group; R8 is H or a lower alkyl group; R9 is H or a lower alkyl group; R10 is H or a lower alkyl group; R11 is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, (C1-C6) alkyl , OR18, halo, NR18'R19', N02 OPO4H2, OR19phenyl, SCH2phenyl, CONH2, C02H, P03H2, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, and C1-C6 alkyl; R18' is selected from the group consisting of hydrogen and (Ci-C6) alkyl; R19 is Ci-C6 alkyl; R19' is selected from the group consisting of hydrogen and (Ci-C6) alkyl; R23 is selected from the group consisting of hydrogen and (C1-C3) alkyl; R30 is hydrogen or C1-C6 alkyl; R50 is hydrogen or n is 0, 1, or 2; p is 0, 1, or 2; m is 0, 1, or 2; q is 2, 3, or 4; X is 0, NH or alkylamino; Y is C, 0, NH, S, SO, S02 or alkylamino; Z is selected from the group consisting of -(CH2)n-, - (CH2) p-O- (CH2)m- and (C3-C5) cycloalkyl ; ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group; or a pharmaceutically acceptable salt thereof.
3. A compound of Claim 1 wherein Ar is selected from the group consisting of phenyl, aromatic, or simple substituted aromatic.
4. A compound of Claim 2 wherein Ar is a parafluoro substituted phenyl ring.
5. A compound of Claim 1 wherein R30 is hydrogen, R7 and R8 are each methyl, X is 0, Y is 0, and R50 is a group of the formula t PCT US97/15668 -33-
6. A compound of Claim 1 wherein R is hydrogen, one of R7 and R8 is methyl, X is 0, Y is 0, and 1" is a group of the formula
7. A process for preparing a compound of Formula II wherein Ar is selected from the group consisting of phenyl, any simple unsubstituted aromatic, simple substituted aromatic, substituted heteroaromatic group, unsubstituted heteroaromatic group, heterocyclic, C-^- iz alkyl, C^-Ci-alkenyl, C2-Ci2 alkynyl, NR51R52, COR52, OR53, and Formula Ar' R51 is selected from the group consisting of hydrogen and C.-C3 alkyl; R52 is selected from the group consisting of hydrogen and C.-C3 alkyl; R53 is selected from the group consisting of CT-C^ alkyl; R54 is selected from the group consisting of hydrogen, d-C,-alkyl, Cj-Cealkyl (R57'R57"R57'" ) , simple unsubstituted aromatic, simple substituted aromatic, heterocyclic, phenyl, halogen, 4- ( tert-butyldimethylsiloxy) - benzyltriphenylphosophonium, COOR57, P03H, S03H, S02R58, N(R59)R60, NHOR61 , NHCHR61', CN, N02, halogen, OR", CH2(0)R62', - CH2OC(0)R95, CH2N(R96)R96',COR100, ( C,-C6alkyl ) OR100, , and SR63; R95 is selected from the group consisting of -R9bNH:,; R96 and R96' are each independently selected from the group consisting of hydrogen and d~C6 alkyl, -R97NH3, and -R99 NR99' R99"; R97 is selected from the group consisting of -d alkyl; R98 is selected from the group consisting of d~d alkyl; R99 is Ci-C6 alkyl; R99' and R99" are each independently selected from the group consisting of hydrogen and Ci-C6 alkyl; R100 is selected from the group consisting of hydrogen, and Si
8. A process of Claim 7 wherein the solvent is selected from the group consisting of toluene, N,N-dimethylformamide, ethyl acetate, tertrahydrofuran and acetonitrile .
9. A process of Claim 7 wherein the Formula II compound is defined as follows: wherein Ar is phenyl or any simple unsubstituted or substituted aromatic or heteroaromatic group, C1-C12 alkyl, C1-C12 alkene, C1-C12 alkyne, NR51R52, OR53, Formula Ar ' R51 is selected from the group consisting of hydrogen and C1-C3 alkyl; R52 is selected from the group consisting of hydrogen and C1-C3 alkyl; R53 is selected from the group consisting of C1-C12 alkyl; R54 is selected from the group consisting of hydrogen, Ci-Ce alkyl, simple aromatic, phenyl, COOR57, P03H, SO3H, SO2R58, NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R55 is selected from the group consisting of hydrogen, Ci-Ce alkyl, simple aromatic, phenyl, COOR57, P03H, SO3H, SO2R58, NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R56 is selected from the group consisting of hydrogen, Ci-Ce alkyl, simple aromatic, phenyl, COOR57, PO3H, SO3H, SO2R58, NR59R60, NHOR61, NHCHR61', CN, N02, halogen, OR62, and SR63; R57 is selected from the group consisting of hydrogen and C1-C12 alkyl; R58 is selected from the group consisting of hydrogen and C1-C12 alkyl; R59 is selected from the group consisting of hydrogen, (Ci~ C6) alkyl and fluorenylmethoxycaronyl (FMOC) ; R60 is selected from the group consisting of hydrogen and (Ci-Ce) alkyl; R61 is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 and fluorenylmethoxycaronyl (FMOC); R61' is selected from the group consisting of hydrogen, OR64, CH2NHR65, NHR65 and fluorenylmethoxycaronyl (FMOC) ; R62 is selected from hydrogen and C1-C6 alkyl; R63 is selected form hydrogen and C1-C6 alkyl; R64 is selected from the group consisting of hydrogen, (Ci~ C6) alkyl, CH2NR66R67 t O 98/09601 PCT/US97/15668 -41- R65 is selected from the group consisting of hydrogen and Ci~C6 alkyl, NH2 and fluorenylmethoxycaronyl (FMOC); R66 is selected from the group consisting of hydrogen and Ci~C6 alkyl and fluorenylmethoxycaronyl (FMOC) ; R67 is selected from the group consisting of hydrogen and C1-C6 alkyl; R3 is a lower alkyl group; R4 is H or OH; R5 is H or OH; R4 and R5 may be taken together to form a second bond between C13 and C14; R6 is selected from the group consisting of benzyl, hydroxybenzyl, alkoxybenzyl, halohydroxybenzyl, dihalohydroxybenzyl, haloalkoxybenzyl, or dihaloalkoxybenzyl group, B-ring heteroaromatic, substituted heteroaromatic, B-ring (C1-C6) alkyl, (C3-C8) cycloalkyl, substituted C3-C8 cycloalkyl, substituted ( i-C^) alkyl, a group of the formula II I ' : nd a group of the formula I I I ' ' : R7 is H or a lower alkyl group; R8 is H or a lower alkyl group; R9 is H or a lower alkyl group; R10 is H or a lower alkyl group; R11 is selected from the group consisting of H, OH, simple alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl; R15, R16, and R17 are each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, OR18, halo, NR18'R19', NO2, OP04H2 OR19phenyl, SCH2phenyl, CONH2, C02H, PO3H2, S02R23, and ZZ; R18 is selected from the group consisting of hydrogen, aryl, and C1-C6 alkyl; R18' is selected from the group consisting of hydrogen and (d-Ce) alkyl; R19 is Ci-C6 alkyl; R19' is selected from the group consisting of hydrogen and (Ci-C6) alkyl; R23 is selected from the group consisting of hydrogen and (C1-C3) alkyl; R30 is hydrogen or C1-C6 alkyl; R50 is hydrogen or n is 0, 1, or 2; p is 0, 1, or 2; m is 0, 1, or 2; q is 2, 3, or 4; X is 0, NH or alkylamino; Y is C, 0, NH, S, SO, S02 or alkylamino; Z is selected from the group consisting of -(CH2)n-, - (CH2)p-0- (CH2)m- and (C3-C5) cycloalkyl ; ZZ is selected from the group consisting of an aromatic group and a substituted aromatic group.
10. A process of Claim 7 wherein the solvent is toluene .
11. A process of Claim 7 wherein Ar is aromatic or substituted aromatic.
12. A process of Claim 7 wherein R30 is hydrogen, R7 and R8 are each methyl, X is 0, Y is 0, and R50 is a group of the formula
13. A process of Claim 7 wherein R is hydrogen, one of R- and R8 is methyl, X is O, Y is 0, and R50 is a group of the formula lONiTi JIN mi si
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2543796P | 1996-09-06 | 1996-09-06 | |
| PCT/US1997/015668 WO1998009601A2 (en) | 1996-09-06 | 1997-09-05 | Process to prepare pharmaceutical compounds |
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| IL128643A true IL128643A (en) | 2006-04-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| IL12864397A IL128643A0 (en) | 1996-09-06 | 1997-09-05 | Process to prepare pharmaceutical compounds |
| IL128643A IL128643A (en) | 1996-09-06 | 1999-02-21 | Process for preparing cryptophycin compounds and some new intermediates |
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| IL12864397A IL128643A0 (en) | 1996-09-06 | 1997-09-05 | Process to prepare pharmaceutical compounds |
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| EP (1) | EP0934250A4 (en) |
| JP (1) | JP2001500128A (en) |
| KR (1) | KR20010029475A (en) |
| AU (1) | AU4334397A (en) |
| BR (1) | BR9711695A (en) |
| CA (1) | CA2264527A1 (en) |
| HU (1) | HUP0000212A3 (en) |
| IL (2) | IL128643A0 (en) |
| WO (1) | WO1998009601A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE19911088A1 (en) * | 1999-03-12 | 2000-09-28 | Fraunhofer Ges Forschung | Assembly device for manually assembling mechanical, electromechanical and/or optical components has device for operating mounting tool as well as operation element for moving assembly head |
| EP2266607A3 (en) | 1999-10-01 | 2011-04-20 | Immunogen, Inc. | Immunoconjugates for treating cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5952298A (en) * | 1993-12-21 | 1999-09-14 | The University Of Hawaii | Cryptophycins |
| AU695873B2 (en) * | 1993-12-21 | 1998-08-27 | University Of Hawaii | New cryptophycins |
| AP737A (en) * | 1995-03-07 | 1999-03-15 | Univ Hawaii | New cryptophycins from synthesis. |
| AU6904896A (en) * | 1995-08-30 | 1997-03-19 | Eli Lilly And Company | Pharmaceutical compounds |
| JP2000502351A (en) * | 1995-12-22 | 2000-02-29 | イーライ・リリー・アンド・カンパニー | Pharmaceutical compounds |
| ATE201018T1 (en) * | 1996-02-27 | 2001-05-15 | Lilly Co Eli | CRYPTOPHYCIN DERIVATIVES AND THEIR USE AS ANTIMICROTUBULAR AGENTS |
-
1997
- 1997-09-05 WO PCT/US1997/015668 patent/WO1998009601A2/en not_active Application Discontinuation
- 1997-09-05 CA CA002264527A patent/CA2264527A1/en not_active Abandoned
- 1997-09-05 KR KR1019997001858A patent/KR20010029475A/en not_active Application Discontinuation
- 1997-09-05 EP EP97941436A patent/EP0934250A4/en not_active Withdrawn
- 1997-09-05 BR BR9711695-5A patent/BR9711695A/en unknown
- 1997-09-05 IL IL12864397A patent/IL128643A0/en not_active IP Right Cessation
- 1997-09-05 AU AU43343/97A patent/AU4334397A/en not_active Abandoned
- 1997-09-05 JP JP10512938A patent/JP2001500128A/en active Pending
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1999
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| KR20010029475A (en) | 2001-04-06 |
| BR9711695A (en) | 2000-03-08 |
| IL128643A0 (en) | 2000-01-31 |
| AU4334397A (en) | 1998-03-26 |
| WO1998009601A3 (en) | 1998-04-23 |
| CA2264527A1 (en) | 1998-03-12 |
| HUP0000212A3 (en) | 2001-12-28 |
| EP0934250A4 (en) | 2004-08-11 |
| JP2001500128A (en) | 2001-01-09 |
| EP0934250A2 (en) | 1999-08-11 |
| HUP0000212A2 (en) | 2000-07-28 |
| WO1998009601A2 (en) | 1998-03-12 |
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