JP2794342B2 - Ansamycin derivatives as anticancer gene agents and anticancer agents - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The present invention relates to derivatives of geldanamycin, pharmaceutically acceptable salts and prodrugs of this derivative, methods for their preparation and their derivatives, salts and prodrugs as active ingredients The present invention relates to an antitumor and oncogene product inhibiting composition comprising

Oncogene products are proteins produced by oncogenes and are involved in the transformation of normal cells into cancer cells.

Geldanamycin is an antibiotic and its preparation and use was described in US Pat. No. 3,595,955, which is hereby incorporated by reference.

No. 07 / 817,235, filed Jan. 6, 1992 and assigned to Pfizer, describes a fermentation process for the preparation of 4,5-dihydrogeldanamycin and its 18,21-hydroquinone. It states specifically.

Other derivatives of geldanamycin and their use as antitumor agents are specifically described in US Pat. No. 4,261,989.

SUMMARY OF THE INVENTION The present invention relates to compounds of the general formula: and pharmaceutically acceptable salts and prodrugs thereof (hereinafter also referred to as active compounds): ｛Wherein R ¹ and R ² are both hydrogen, or
¹ and R ² together form a single bond; R ³ is hydrogen; R ⁴ is selected from the group consisting of —OR ¹⁰ , —NHR ⁸ and halo; R ¹⁰ is hydrogen, R ¹¹ C (= O) -, R 11 SO 2 - and R ¹² R
_{^{13 NSO 2 NHC (= O)}} - is selected from the group consisting of; R ¹¹ is amino, (C ₁ -C ₈₎ alkyl, amino (C ₁ -C
₈ ) selected from the group consisting of alkyl, hydroxy (C ₁ -C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl, protected hydroxy (C ₁ -C ₈ ) alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁
—C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, selected from the group consisting of phenyl and naphthyl; or R ¹²
And R ¹³ together with the nitrogen to which they are attached are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino,
Piperazinyl, 4- (C ₁ -C ₄₎ alkyl-piperidinyloxy and N- (C ₁ -C ₄₎ to form a hydrocarbon ring residue selected from the group consisting of piperazinyl; the alkyl, phenyl and naphthyl groups, ( C ₁ −
C ₈ ) can be substituted with one or more residues selected from the group consisting of alkyl, halo, nitro, amino, azide and (C ₁ -C ₈ ) alkoxy; or R ³ and R ⁴ are both , J forms a group of the general formula = J selected from O and NOH; R ⁵ is NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are each independently hydrogen, (C _1- C ₈₎ alkyl, selected from the group consisting of (C ₃ -C ₈₎ cycloalkyl, (C ₂ -C ₈₎ alkenyl and (C ₂ -C ₈₎ alkynyl; the alkyl, alkenyl and alkynyl, optionally substituted Wherein the substitution is halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, and imidizarolyl, furyl, Contains tetrahydrofuryl Chosen (C ₂ -C ₆₎ heterocycloalkyl and (C ₂ -C ₆₎ selected from the group consisting of heterocycloalkyl aryl group; if it contains more than two carbon atoms, which is a branched, cyclic or R ⁸ and R ⁹ may be unbranched or branched, a combination of cyclic and terminally branched groups;
Together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl); or R ⁵ is R ¹⁴ O, wherein R ¹⁴ is hydrogen or (C ₁ −C
₄ ) is alkyl); R ⁶ is hydrogen or a group of the following general formula: (Where m is an integer of 0 or 1-5, and each R
⁷ is halo, azide, nitro, (C ₁ -C ₈ ) alkyl, C ₁
-C ₈ alkoxyl, phenyl and naphthyl, cyano and, R ⁸ and R ⁹ be chosen) independently from NR ⁸ R ⁹ is as defined above; with the proviso that R ¹ and R ² are both single crystal R ³ is hydrogen and R ⁴ is OR ¹⁰ (where R
^{If 10} is hydrogen, then R ⁵ is OR ^14, where
R ¹⁴ is hydrogen or methyl) or NR ⁸ R ⁹ (where HNR ⁸ R ⁹ is ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine,
Hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctyl Amine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycolamine, β-morpholinoethylamine, β-piperidinoethylamine, picolylamine,
β-pyrrolidinoethylamine, β-pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine); R ⁵ is OR ¹⁴ ; ^{When 10} is R ¹¹ C (＝ O), R ¹¹ must not be methyl.

Preferably, the compounds of the present invention are compounds of general formula I wherein: 1. R ¹ and R ² are each hydrogen; a. R ³ and R ⁶ are each hydrogen and R ⁴ Is fluoro or OR ¹⁰ , where R ¹⁰ is hydrogen, R ¹¹ C (=
O) - and _{^{R 12 R 13 NSO 2 NHC (}} O) - is selected from wherein, R ¹¹ is amino, (C ₁ -C ₈₎ alkyl, amino (C ₁
—C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl, selected from phenyl and naphthyl; R ¹² and R ¹³
Is each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl and Or R ¹² and R ¹³ together with the nitrogen to which they are attached, azilinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, or
Oxazodinyl, morpholino, piperazinyl, 4- (C ₁
-C ₄₎ alkyl-piperidinyloxy, N-(C ₁ -C ₄₎ to form a heterocyclic residue selected from the group consisting of piperazinyl; wherein are as defined above; R ⁵ is, OR ¹⁴ Or NR ⁸ R ⁹
Where i. When R ⁵ is R ⁸ R ⁹ N, R ⁸ is hydrogen and R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈₎ selected from the group consisting of alkenyl, and (C ₂ -C ₈₎ alkenyl; the alkyl, alkenyl and alkynyl is optionally substituted, the substituent is halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Where R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached, optionally substituted aziridinyl, may be a combination of a formula and an unbranched group; , Azetidinyl and pyrrolidinyl to form a heterocyclic residue selected from halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, substituted or substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl,
Iii. When R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₆ ) alkyl; provided that R ³ and R ⁶ are selected from the group consisting of carboxyl, amidino and acylamino; R ¹⁴ is not methyl when it is hydrogen and R ⁴ is OR ¹⁰ (where R ¹⁰ is hydrogen); or b. R ³ is hydrogen and R ⁴ consists of fluoro and OR ¹⁰ Selected from the group where R ¹⁰ is hydrogen, R ¹¹ C (=
O) - and _{^{R 12 R 13 NSO 2 NHC (}} O) - is selected from the group consisting of wherein, R ¹¹ is amino, (C ₁ -C ₈₎ alkyl,
Amino (C ₁ -C ₈ ) alkyl, protected amino (C _1-
C ₈ ) selected from alkyl, phenyl and naphthyl; R ¹²
And R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C _1-
C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, selected from the group consisting of phenyl and naphthyl; or R ¹² and R
¹³ is, together with the nitrogen to which they are attached, azilinylyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4- (C ₁ -C ₄ ) alkylpiperidinyl, N- (C ₁
—C ₄ ) forming a heterocyclic residue selected from the group consisting of piperazinyl; R ⁶ is a group of general formula A, wherein m is as defined above, and R ⁵ is OR ¹⁴ or NR ⁸ R ⁹ and
Where: i. When R ⁵ is R ⁸ R ⁹ N, R ⁸ is hydrogen and R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Where R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached, optionally substituted aziridinyl, may be a combination of a formula and an unbranched group; , Azetidinyl and pyrrolidinyl to form a heterocyclic residue selected from the group consisting of halo, asino, mercapto, (C ₁ -C ₈ ) alkylthio, substituted or unsubstituted amino, hydroxyl, (C _1- C ₈₎ alkoxyl, carboxyl, selected from the group consisting of amidino and acylamino;. and iii when R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈₎ alkyl; or c. R ⁶ is hydrogen , R ³ and R ⁴ are both J
R ⁵ is OR ¹⁴ or R ⁸ R ⁹ N, wherein i. When R ⁵ is R ⁸ R ⁹ N, R ⁸ is hydrogen And R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Or a combination of the formula and an unbranched group; or R ⁸ and R ⁹ together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl; ii. When R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached are a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl. form a group, this substituent is halo, cyano, mercapto, (C ₁ -C ₈₎ alkylthio, substituted or unsubstituted amino, hydroxyl, (C ₁ -C ₈₎ alkoxyl, carboxyl, amino If and iii R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈₎ alkyl;; is selected from the group consisting of Bruno and acylamino. Or d, R ³ and R ^4, both, J forms a formula = J group is O or NOH; R ⁶ is a group of the general formula a, wherein, m and R ⁷ are as defined above; R ⁵ Is R ¹⁴ O or R ⁸ R ⁹ N, where: i.When R ⁵ is R ⁸ R ⁹ N, R ⁸ is hydrogen and R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Where R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached, optionally substituted aziridinyl, may be a combination of a formula and an unbranched group; Form a heterocyclic residue selected from the group consisting of azetidinyl and pyrrolidinyl, wherein the substituent is halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, substituted or unsubstituted amino, hydroxyl, (C _1- C ₈ ) selected from the group consisting of alkoxyl, carboxyl, amidino and acylamino; and iii. When R ⁵ is ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈ ) alkyl; or 2. R ¹ and R ^2, The single crystal was formed, a. R ³ and R ⁶ are each hydrogen, R ⁴ is selected from the group consisting of fluoro and OR ^10, wherein, R ¹⁰ is hydrogen, R ¹¹ (C = O) and R ¹² R ¹³ NSO ₂ NHC (O) —, wherein R ¹¹ is amino, (C ₁ -C ₈ ) alkyl,
Amino (C ₁ -C ₈ ) alkyl, protected amino (C _1-
C ₈ ) selected from alkyl, phenyl and naphthyl; R ¹²
And R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C _1-
C ₈₎ alkyl, cyclo (C ₃ -C ₈₎ alkyl, or is selected from the group consisting of phenyl and naphthyl; R ¹² and
R ¹³ together with the nitrogen to which they are attached are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4- (C ₁ -C ₄ ) alkylpiperidinyl, N- (C ₁
When R ⁵ is OR ¹⁴ or NR ⁸ R ^9, where, i R ⁵ is ^{R 8 R 9 N,; -C} 4) to form a heterocyclic residue selected from the group consisting of piperazinyl. R ⁸ is hydrogen and R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ (heterocycloaryl) and contains more than 2 carbon atoms, it may be branched, cyclic or unbranched or branched, Where R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached, optionally substituted aziridinyl, may be a combination of a formula and an unbranched group; , Azetidinyl and pyrrolidinyl, wherein the substituent is halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈₎ alkoxyl, carboxyl, selected from the group consisting of amidino and acylamino; and, if iii R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈₎ alkyl;. However , R ¹⁰ is hydrogen R ⁵ must not be OR ¹⁴ where R ¹⁴ is
Hydrogen or methyl or NR ⁸ R ⁹ , where HNR ⁸ R ⁹
Is ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoxyethylamine, aminobutylamine, adamantylmethylamine , Cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycoamine, β-morpholinoethylamine, β
-Piperidinoethylamine, picolylamine, β-pyrrolidinoethylamine, β-pyridinylethylamine, β
R ³ is hydrogen and R ⁴ is selected from the group consisting of fluoro and OR ¹⁰ , wherein R ¹⁰ is selected from the group consisting of: -methoxyethylamine, and β-N-methylaminoethylamine; , Hydrogen, R ¹¹ C (=
O) - and _{^{R 12 R 13 NSO 2 NHC (}} O) - is selected from wherein, R ¹¹ is amino, (C ₁ -C ₈₎ alkyl, amino (C ₁
—C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl, selected from phenyl and naphthyl; R ¹² and R ¹³
Is each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl and Selected from the group consisting of naphthyl; or R ¹² and R ¹³ together with the nitrogen to which they are attached, azilinylyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl,
Oxazolidinyl, morpholino, piperazinyl, 4-
(C ₁ -C ₄₎ alkyl-piperidinyloxy, form a heterocyclic residue selected from the group consisting of N-(C ₁ -C ₄₎ piperazinyl; R
⁶ is a group of the general formula A, wherein, m is as defined above, R ⁵ is OR ¹⁴ or NR ⁸ R ^9, wherein, i. R ⁵ is R ⁸ R ⁹ N R ⁸ is hydrogen and R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Where R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached, optionally substituted aziridinyl, may be a combination of a formula and an unbranched group; Form a heterocyclic residue selected from the group consisting of azetidinyl and pyrrolidinyl, wherein the substituent is halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, substituted or unsubstituted amino, hydroxyl, (C _1- C ₈₎ alkoxyl, carboxyl, selected from the group consisting of amidino and acylamino;. and iii when R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈₎ alkyl; or c. R ⁶ is hydrogen , R ³ and R ⁴ are both J
R ⁵ is OR ¹⁴ or NR ⁸ R ⁹ , wherein i. When R ⁵ is R ⁸ R ⁹ N, R ⁸ is hydrogen Yes, R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Or a combination of the formula and an unbranched group; or R ⁸ and R ⁹ together with the nitrogen to which they are attached, a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl. Ii. When R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ are selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl, together with the nitrogen to which they are attached. form a heterocyclic ring residues, the substituents include halo, cyano, mercapto, (C ₁ -C ₈₎ alkylthio, substituted or unsubstituted amino, hydroxyl, (C ₁ -C ₈₎ alkoxyl, Cal If and iii R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈₎ alkyl; cyclohexyl, selected from the group consisting of amidino and acylamino.. Or d R ³ and R ⁴ Together form a group of the general formula ＯO or NONOH; R ⁶ is a group of the general formula A, wherein m and R ⁷ are defined as above; R ⁵ is R ¹⁴ O or R ⁸ R ⁹ N
Where i. When R ⁵ is R ⁸ R ⁹ N, R ⁸ is hydrogen and R ⁹ is
(C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂
-C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C _2-
When selected from the group consisting of C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl and containing more than 2 carbon atoms, it is branched, cyclic or unbranched or branched, ring Where R ⁵ is R ⁸ R ⁹ N, R ⁸ and R ⁹ together with the nitrogen to which they are attached, optionally substituted aziridinyl, may be a combination of a formula and an unbranched group; , Azetidinyl and pyrrolidinyl to form a heterocyclic residue selected from the group consisting of halo, asino, mercapto, (C ₁ -C ₈ ) alkylthio, substituted or unsubstituted amino, hydroxyl, (C _1- C ₈₎ alkoxyl, carboxyl, selected from the group consisting of amidino and acylamino;. and iii when R ⁵ is R ¹⁴ O, R ¹⁴ is hydrogen or (C ₁ -C ₈₎ alkyl}.

More preferred compounds of the present invention are selected from the group consisting of compounds of general formula I wherein: 1. R ¹ , R ² , R ³ and R ⁶ are each hydrogen and R ⁴ is fluoro or OR ¹⁰ where R ¹⁰ is hydrogen, R
¹¹ (= O) - and _{^{R 12 R 13 NSO 2 NHC (}} O) - is selected from wherein, R ¹¹ is amino, (C ₁ -C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, Protected amino (C ₁ -C ₈ )
Selected from alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈ ) Selected from the group consisting of alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl and naphthyl; as defined above; or R ¹² and R ¹³ together with the nitrogen to which they are attached, A heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4- (C ₁ -C ₄ ) alkylpiperidinyl, and N- (C ₁ -C ₄ ) piperazinyl Form a group; R ⁵ is R ⁸ R
⁹ N, where R ⁸ is hydrogen and R ⁹ is hydrogen, (C ₁
-C ₆₎ alkyl, (C ₂ -C ₈₎ alkenyl and (C ₂ -
C ₈ ) alkynyl; the alkyl, alkenyl and alkynyl groups are optionally substituted; the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl , (C ₁ −
C ₈ ) alkoxyl, carboxyl, amidino, acylamino, (C ₂ -C ₆ ) heterocycloalkyl and (C _2-
C ₆ ) selected from the group consisting of heterocycloaryls and containing more than 2 carbon atoms, it is a branched, cyclic or unbranched or a combination of branched, cyclic and unbranched groups, 2. R ¹ , R ² , R ³ and R ⁶ are each hydrogen and R ⁴ is fluoro or OR ¹⁰ , wherein R ¹⁰ is hydrogen, R ¹¹ C
(= O) - and _{^{R 12 R 13 NSO 2 NHC (}} O) - is selected from,
Wherein, R ¹¹ is amino, selected from (C ₁ -C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, protected amino (C ₁ -C ₈₎ alkyl, phenyl and naphthyl; R ¹² And R
¹³ is each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl And R ¹² and R ¹³ together with the nitrogen to which they are attached, is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino , piperazinyl, 4- (C ₁ -C ₄₎ alkyl-piperidinyloxy, form a heterocyclic residue selected from the group consisting of N- (C ₁ -C ₄₎ piperazinyl; R ⁵ is, R ⁸ R ⁹ N Where R ⁸ and R ⁹ together with the nitrogen to which they are attached are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkylthio, (C _2- C ₆₎ Heteroshikuroa From Kill and (C ₂ -C ₆₎ 3, which is optionally substituted with one or more groups selected from heterocycloaryl 6
R ¹ , R ² , R ³ and R ⁶ are each hydrogen and R ⁴ is fluoro or OR ¹⁰ , wherein R ¹⁰ Is hydrogen, R
¹¹ (= O) - and _{^{R 12 R 13 NSO 2 NHC (}} O) - is selected from wherein, R ¹¹ is amino, (C ₁ -C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, Protected amino (C ₁ -C ₈ )
Selected from alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈ ) Selected from the group consisting of alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl and naphthyl; as defined above; or R ¹² and R ¹³ together with the nitrogen to which they are attached, Hydrogen ring residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperosinyl, 4- (C ₁ -C ₄ ) alkylpiperidinyl and N- (C ₁ -C ₄ ) piperazinyl R ⁵ is R ¹⁴ O
Wherein R ¹⁴ is (C ₁ -C ₈ ) alkyl;
Provided that when R ¹⁰ is hydrogen, R ¹⁴ is not methyl; 4. R ¹ and R ² together form a single bond, R ³ and R
⁶ are each hydrogen and R ⁴ is fluoro or OR ¹⁰ , where R ¹⁰ is hydrogen, R ¹¹ C (＝ O) — and R ¹² R
Selected from ¹³ NSO ₂ NHC (O) —, where R ¹¹ is amino (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) Alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen,
(C ₁ -C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, dimethylamino (C ₁ -C ₈₎ alkyl, cyclo (C ₃ -C ₈₎ alkyl, selected from the group consisting of phenyl and naphthyl;
Wherein as defined above; or R ¹² and R
¹³ together with the nitrogen to which they are attached, aziridine,
Azetidine, pyrrolidone, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4
-(C ₁ -C ₄ ) alkylpiperidinyl and N- (C _1-
C ₄ ) forming a heterocyclic residue selected from the group consisting of piperazinyl; R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ is hydrogen;
R ⁹ is hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, optionally substituted (C ₃ -C ₆ ) cycloalkyl, optionally substituted (C ₂ -C ₆ ) alkenyl and Selected from (C ₂ -C ₆ ) alkynyl substituted with, and the substituents of the alkyl and alkenyl and alkynyl groups are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ )
Selected from C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl, provided that when R ¹⁰ is hydrogen, R ⁵ can be NR ⁸ R ⁹ Here, HNR ⁸ R ⁹ is ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, acrylamine, β-hydroxyethylamine, β
-Chloroethylamine, β-glycoxyethylamine,
Aminobutylamine, benzylamine, phenethylamine, dimethylamine, aminoethylamine, diglycoamine, β-morpholinoethylamine, β-piperidinoethylamine, β-pyrrolidinoethylamine, β-viridinylethylamine, β-methoxyethylamine, and β-N - is selected from the group consisting of methyl aminoethyl amine; 5. R ¹ and R ² together form a single crystal, R ³ and R
⁶ are each hydrogen and R ⁴ is fluoro or OR ¹⁰ , where R ¹⁰ is hydrogen, R ¹¹ C (＝ O) — and R ¹² R
¹³ NSO ₂ NHC (O)-, wherein R ¹¹ is amino, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl,
Selected from protected amino (C ₁ -C ₈ ) alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) Alkyl,
Dimethylamino (C ₁ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ )
Selected from the group consisting of alkyl, phenyl and naphthyl; as defined above; or R ¹² and R ¹³ together with the nitrogen to which they are attached are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
Thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4- (C ₁ -C ₄₎ alkyl-piperidinyloxy and N- (C ₁ -C ₄₎ to form a heterocyclic residue selected from the group consisting of piperazinyl; R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ and R ⁹ together with the nitrogen to which they are attached, are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C _1-
A 3-6 membered heterocycloalkyl or heterocycloaryl ring optionally substituted with a group selected from C ₆ ) alkylthio, (C ₃ -C ₈ ) heterocycloalkyl and (C ₄ -C ₈ ) heterocycloaryl Provided that R ¹⁰ is hydrogen, NR ⁸ R ⁹ cannot be derived from ethyleneamine, pyrrolidine or piperidine; 6. R ¹ and R ² together form a single crystal; ³ and R
⁶ are each hydrogen and R ⁴ is fluoro or OR ¹⁰ , where R ¹⁰ is hydrogen, R ¹¹ C (＝ O) — and R ¹² R
¹³ NSO ₂ NHC (O)-, wherein R ¹¹ is amino, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl,
Selected from protected amino (C ₁ -C ₈ ) alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) Alkyl,
Dimethylamino (C ₁ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ )
Selected from the group consisting of alkyl, phenyl and naphthyl; as defined above; or R ¹² and R ¹³ together with the nitrogen to which they are attached are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
Thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4- (C ₁ -C ₄₎ alkyl-piperidinyloxy and N- (C ₁ -C ₄₎ to form a heterocyclic residue selected from the group consisting of piperazinyl; R ⁵ is R ¹⁴ O, where R ¹⁴ is
Is hydrogen or (C ₁ -C ₈₎ alkyl, provided that when R ¹⁰ is hydrogen, R ¹⁴ can not be a hydrogen or methyl, if R ¹⁰ is ^{R 11 C (= O),} R ¹¹ cannot be methyl; 7. R ¹ , R ² and R ⁶ are each hydrogen and R ³ and R
⁴ together form a group selected from ＝ O and NONOH,
R ⁵ is R ⁸ R ⁹ N, where R ⁸ is hydrogen and R ⁹ is
Selected from hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₃ -C ₆ ) cycloalkyl (C ₂ -C ₆ ) alkenyl and (C ₂ -C ₆ ) alkynyl The substituents of the alkyl and alkenyl and alkynyl groups are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and 8. R ¹ , R ² and R ⁶ are each hydrogen, and R ³ and R ³ are selected from _2- C ₆ ) heterocycloaryl;
⁴ together form a group selected from ＝ O and NONOH,
R ⁵ is R ⁸ R ⁹ N, wherein, R ⁸ and R ^9, together with the nitrogen to which they are attached, hydroxyl, halo, cyano, (C ₁ -C ₆₎ alkoxy, (C ₁ - C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ )
Forming a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring optionally substituted with one or more groups selected from heterocycloaryl; 9. R ¹ , R ² and R ⁶ are each hydrogen , R ³ and R
⁴ together form a group selected from ＝ O and NONOH,
R ⁵ is R ¹⁴ O, wherein R ¹⁴ is hydrogen or (C ₁ -C
₈ ) is alkyl; 10. R ¹ and R ² together form a single bond, R ⁶ is hydrogen, and R ³ and R ⁴ together form a group selected from ＝ O and NONOH R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ is hydrogen and R ⁹ is
Selected from hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₃ -C ₆ ) cycloalkyl, (C ₂ -C ₆ ) alkenyl and (C ₂ -C ₆ ) alkynyl Wherein the substituents of the alkyl, alkenyl and alkynyl groups are
Selected from hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl; 11 R ¹ and R ² together form a single bond, R ⁶ is hydrogen, R ³ and R ⁴ together form a group selected from ＯO and NONOH, and R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ and R ⁹ together with the nitrogen to which they are attached are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C _1-
3-6 membered heterocycloalkyl or hetero optionally substituted with one or more groups selected from C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl Forms a cycloaryl ring; 12. R ¹ and R ² together form a single bond, R ⁶ is hydrogen, and R ³ and R ⁴ together form a group selected from ＝ O and NONOH And R ⁵ is R ¹⁴ O, wherein R ¹⁴ is hydrogen or (C ₁ -C ₈ ) alkyl; 13. R ¹ , R ² and R ³ are each hydrogen and R ⁶ Is a group of general formula A, wherein m and R ⁷ are as defined above, and R ⁴ is fluoro or OR ¹⁰ ; where R ¹⁰ is hydrogen, R ¹¹ C ( ^{= O) -, R 11 SO} 2 - and R ¹²
Selected from the group consisting of R ¹³ NSO ₂ NHC (＝ O) —;
R ¹¹ is amino, (C ₁ -C ₈ ) alkyl, amino (C _1-
C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl,
Selected from phenyl and naphthyl; R ¹² and R ¹³ are
Each independently represents hydrogen, (C ₁ -C ₈ ) alkyl, amino (C _1-
C ₈ ) alkyl, dimethylamino (C ₁ -C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl and naphthyl; the alkyl, phenyl and naphthyl groups are selected from (C ₁ -C 8 ₈₎ alkyl, halo, nitro, amino, azido and (C ₁ -C ₈₎ can be substituted with one or more residues selected from the group consisting of alkoxyl; R
⁵ is R ⁸ R ⁹ N, where R ⁸ is hydrogen, and R ⁹ is hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, optionally substituted (C _3- C ₆ ) cycloalkyl, optionally substituted (C ₂ -C ₆ ) alkenyl and optionally substituted (C _2-
C ₆₎ is selected from alkynyl, substituents of the alkyl and alkenyl and alkynyl groups, hydroxyl, halo, cyano, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆₎ alkylthio, (C ₂ -C ₆ ) Heterocycloalkyl and (C ₂
—C ₆ ) selected from heterocycloaryl; 14. R ¹ , R ² and R ³ are each hydrogen and R ⁶ is a group of general formula A wherein m and R ⁷ are as defined above And R ⁴ is fluoro or OR ¹⁰ ; wherein R ¹⁰ is hydrogen, R ¹¹ C (＝ O) —, R ¹¹ SO ₂ — and R ¹²
Selected from the group consisting of R ¹³ NSO ₂ NHC (＝ O) —;
R ¹¹ is amino, (C ₁ -C ₈ ) alkyl, amino (C _1-
C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl,
R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈₎ ) alkyl, cyclo (C ₃ -C ₈₎ alkyl, selected from the group consisting of phenyl and naphthyl; the alkyl, phenyl and naphthyl groups, (C ₁ -C ₈₎ alkyl, halo, nitro, amino, azido and ( C ₁ -C ₈ ) may be substituted with at least one residue selected from the group consisting of alkoxyl; R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ and R ⁹ are
Together with the nitrogen to which they are attached, hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂
-C ₆ ) forming a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring optionally substituted with one or more groups selected from heterocycloaryl; 15. R ¹ , R ² and R ³ are Each is hydrogen, R ⁶ is a group of general formula A, wherein m and R ⁷ are as defined above, and R ⁴ is OR ¹⁰ or fluoro; wherein R ¹⁰ is , Hydrogen, R ¹¹ C (＝ O) —, R ¹¹ SO ₂ — and R ¹²
Selected from the group consisting of R ¹³ NSO ₂ NHC (＝ O) —;
R ¹¹ is amino, (C ₁ -C ₈ ) alkyl, amino (C _1-
C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl,
R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C ₁ -C ₈₎ ) Alkyl, cyclo (C ₃ -C ₈ ) alkyl, morpholino, N-
Selected from the group consisting of methylpiperazinyl, phenyl and naphthyl; the alkyl, phenyl and naphthyl groups are selected from (C ₁ -C ₈ ) alkyl, halo, nitro, amino, azide and (C ₁ -C ₈ ) alkoxyl R ⁵ is R ¹⁴ O, wherein R ¹⁴ is hydrogen or (C ₁ -C ₈ ) alkyl; ¹ and R ² together form a single bond, R ³ is hydrogen, R ⁶ is a group of general formula A, where m and R ⁷
Is as defined above, and R ⁴ is OR ¹⁰ or fluoro; wherein R ¹⁰ is hydrogen, R ¹¹ C (＝ O) —, R
Selected from the group consisting of ¹¹ SO ₂ — and R ¹² R ¹³ NSO ₂ NHC (（O); wherein R ¹¹ is amino, (C ₁ -C ₈ ) alkyl,
Amino (C ₁ -C ₈ ) alkyl, protected amino (C _3-
C ₈ ) is selected from the group consisting of alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C _1-
C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, dimethylamino (C ₁ -C ₈₎ alkyl, cyclo (C ₃ -C ₈₎ alkyl,
Selected from the group consisting of phenyl and naphthyl; the alkyl, phenyl and naphthyl groups are (C ₁ -C ₈ ) alkyl, halo, nitro, amino, azide and (C ₁ -C ₈ )
R ⁵ can be substituted with one or more residues selected from the group consisting of alkoxyl; R ⁵ is R ⁸ R ⁹ N, where R ⁸ is hydrogen;
⁹ is hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, optionally substituted (C ₃ -C ₆ ) cycloalkyl, optionally substituted (C ₂ -C ₆ ) alkenyl and optionally Selected from substituted (C ₂ -C ₆ ) alkynyl, wherein the substituents on the alkyl and alkenyl and alkynyl groups are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkynyl,
C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl; 17. R ¹ and R ² together form a single bond, R ³ is hydrogen And R ⁶ is a group of general formula A, wherein m and R ⁷
Is as defined above, and R ⁴ is OR ¹⁰ or fluoro; wherein R ¹⁰ is hydrogen, R ¹¹ C (＝ O) —, R ¹¹
R _{2 is} selected from the group consisting of SO ₂ — and R ¹² R ¹³ NSO ₂ NHC (＝ O); wherein R ¹¹ is amino, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, protected amino (C ₃ -C ₈₎
R ¹² and R ¹³ are each independently hydrogen, (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, dimethylamino (C _1- C ₈ ) alkyl, cyclo (C ₃ -C ₈ ) alkyl, phenyl and naphthyl; the alkyl, phenyl and naphthyl groups being (C ₁ -C ₈ ) alkyl, halo, nitro, amino, azido And can be substituted with one or more residues selected from the group consisting of: (C ₁ -C ₈ ) alkoxyl; R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ and R ⁹ are Together with the nitrogen to which they are attached, hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C _1-
3-6 membered heterocycloalkyl or heterocyclo optionally substituted with at least one group selected from C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl 18. R ¹ and R ² together form a single bond, R ³ is hydrogen, and R ⁶ is a group of general formula A, wherein m and R ⁷
Is as defined above, and R ⁴ is OR ¹⁰ or fluoro; wherein R ¹⁰ is hydrogen, R ¹¹ C (＝ O) —, R ¹¹
SO ₂ — and R ¹² R ¹³ NSO ₂ NHC (＝ O) —; wherein R ¹¹ is amino, (C ₁ -C ₈ ) alkyl,
Amino (C ₁ -C ₈ ) alkyl, protected amino (C _3-
C ₈ ) is selected from the group consisting of alkyl, phenyl and naphthyl; R ¹² and R ¹³ are each independently hydrogen, (C _1-
C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, dimethylamino (C ₁ -C ₈₎ alkyl, cyclo (C ₃ -C ₈₎ alkyl,
Selected from the group consisting of phenyl and naphthyl; the alkyl, phenyl and naphthyl groups are (C ₁ -C ₈ ) alkyl, halo, nitro, amino, azide and (C ₁ -C ₈ )
R ⁵ can be substituted with one or more residues selected from the group consisting of alkoxyl; R ⁵ is R ¹⁴ O, wherein R
^14. is hydrogen or (C ₁ -C ₈ ) alkyl; 19. R ¹ and R ² are each hydrogen, R ⁶ is a group of general formula A, wherein m and R ⁷ are As defined above, R ³ and R ⁴ together form a group selected from ＯO and NONOH, wherein R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ is hydrogen And R ⁹ is hydrogen, optionally substituted (C ₁ -C ₆ )
Alkyl, optionally substituted (C ₃ -C ₆₎ cycloalkyl, optionally substituted (C ₂ -C ₆₎ substituted alkenyl and optionally (C ₂ -C ₆₎ selected from alkynyl, the alkyl and substituents alkenyl and alkynyl groups, hydroxyl, halo, cyano, (C ₁ -C ₆₎ alkoxy, (C ₁ -C ₆₎ alkylthio, (C ₂ -C ₆₎ heterocycloalkyl and (C ₂ -C ₆ ) selected from heterocycloaryl; 20. R ¹ and R ² are each hydrogen and R ⁶ has the general formula A
Wherein m and R ⁷ are as defined above, R ³ and R ⁴ together form a group selected from ＯO and NONOH, and R ⁵ is R ⁸ R ⁹ N, where R ⁸
And R ⁹ together with the nitrogen to which they are attached are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁
1 selected from —C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl
Forming a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring optionally substituted with one or more groups; 21. R ¹ and R ² are each hydrogen and R ⁶ is a group of general formula A
Wherein m and R ⁷ are as defined above, R ³ and R ⁴ together form a group selected from ＯO and NONOH, and R ⁵ is R ¹⁴ O And where R
¹⁴ is hydrogen or (C ₁ -C ₈ ) alkyl; 22. R ¹ and R ² together form a single bond, and R ⁶ is a group of general formula A, wherein m and R ⁷ is as defined above, and R ³ and R ⁴ are both ＝ O and NONOH
Wherein R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ is hydrogen, R ⁹ is hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₂
-C ₆ ) alkenyl and optionally substituted (C ₂ -C ₆ ) alkynyl, wherein the substituents of the alkyl and alkenyl and alkynyl groups are hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ )
Selected from heterocycloaryl; 23. R ¹ and R ² together form a single bond, R ⁶ is a group of general formula A, wherein m and R ⁷ are as defined above And R ³ and R ⁴ are both ＝ O and NONOH
Wherein R ⁵ is R ⁸ R ⁹ N, wherein R ⁸ and R ⁹ together with the nitrogen to which they are attached,
One selected from hydroxyl, halo, cyano, (C ₁ -C ₆ ) alkoxyl, (C ₁ -C ₆ ) alkylthio, (C ₂ -C ₆ ) heterocycloalkyl and (C ₂ -C ₆ ) heterocycloaryl Forming a 3- to 6-membered heterocycloalkyl or heterocycloaryl ring optionally substituted with the above groups; or 24. R ¹ and R ² together form a single bond;
⁶ is a group of general formula A, wherein m and R ⁷ are as defined above, and R ³ and R ⁴ together form a group selected from ＯO and NONOH; R ⁵ is R ¹⁴ O,
Here, R ¹⁴ is hydrogen or (C ₁ -C ₈ ) alkyl.

Most preferred compounds of the invention are selected from the group consisting of: 17-amino-4,5-dihydro-17-demethoxy-geldanamycin; 17-methylamino-4,5-dihydro-17-demethoxy gel Danamycin; 17-cyclopropylamino-4,5-dihydro-17-demethoxygeldanamycin; 17- (2'-hydroxyethylamino) -4,5-dihydro-17-demethoxy-geldanamycin; (2-methoxyethylamino) -4,5-dihydro-1
7-demethoxy-geldanamycin; 17- (2'-fluoroethylamino) -4,5-dihydro-17-demethoxygeldanamycin; 17- [s-(+)-2-hydroxypropylamino]-
4,5-dihydro-17-demethoxygeldanamycin; 17-azetidin-1-yl-4,5-dihydro-17-demethoxy-geldanamycin; 17- (3-hydroxyazetidin-1-yl)- 4,5-
Dihydro-17-demethoxygeldanamycin; 17-azetidin-1-yl-4,5-dihydro-11-α-
17-17-azetidin-1-yl-17-demethoxygeldanamycin; 17- (2'-cyanoethylamino) -17-demethoxygeldanamycin; 17- (2'- Fluoroethylamino) -17-demethoxygeldanamycin; 17-amino-22- (2'-methoxyphenacyl) -17-
Demethoxygeldanamycin; 17-amino-22- (3'-methoxyphenacyl) -17-
Demethoxygeldanamycin; 17-amino-22- (4'-chlorophenacyl) -17-demethoxygeldanamycin; 17-amino-22- (3 ', 4'-dichlorophenacyl)-
17-demethoxygeldanamycin; 17-amino-22- (4'-amino-3'-iodophenacyl) -17-demethoxygeldanamycin; 17-amino-22- (4'-azido-3'-iodophenacyl ) -17-Demethoxygeldanamycin; 17-amino-11-α-fluoro-17-demethoxygeldanamycin; 17-allylamino-11-α-fluoro-17-demethoxygeldanamycin; 17-propargylamino -11-α-fluoro-17-demethoxygeldanamycin; 17- (2′-fluoroethylamino) -11-α-fluoro-17-demethoxygeldanamycin; 17-azetidin-1-yl 11- ( 4'-azidophenyl) sulfamylcarbonyl-17-demethoxygeldanamycin; 17- (2'-fluoroethylamino) -11-keto-17-
Demethoxygeldanamycin; 17-azetidin-1-yl-11-keto-17-demethoxygeldanamycin; and 17- (3'-hydroxyazetidin-1-yl) -11-
Keto-17-demethoxygeldanamycin.

The present invention provides an antitumor or cancer gene product or an effective amount of general formula I for preventing or treating cancer.
Or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

The present invention also comprises administering to a mammal, including a human, an effective amount of a compound of general formula I or a pharmaceutically acceptable salt or prodrug thereof to inhibit an oncogene product. To a method of inhibiting an oncogene product in a mammal.

Further, the present invention provides ErbB-2, sr
ErbB-2 in this mammal comprising administering an effective amount of a compound of general formula I or a pharmaceutically acceptable salt or prodrug thereof to inhibit the c, lck, fyn or abl oncogene product; A method for inhibiting a src, lck, fyn or abl oncogene product.

The present invention also provides a method for administering to a mammal, including a human, an effective amount of a compound of general formula I or a pharmaceutically acceptable salt or prodrug thereof for inhibiting an antitumor or oncogene product. Comprising a method of treating or preventing cancer in this mammal.

The present invention also provides for the growth of tumors in a mammal, including a human, comprising administering to the mammal, including a human, an antitumor effective amount of a compound of general formula I, or a pharmaceutically acceptable salt or prodrug thereof. To a method of preventing or inhibiting.

The present invention also relates to a method for inhibiting growth factors comprising administering to a mammal, including a human, an amount of a compound of general formula I or a pharmaceutically acceptable salt or prodrug thereof. Methods for inhibiting growth factors, such as EGF receptor, NGF receptor, PDGF receptor and insulin receptor, which play a key role in uncontrolled cell growth.

The pharmaceutically acceptable salts of the present invention are salts that are non-toxic in the amounts administered. Since the compounds of the present invention can contain basic groups, acid addition salts are possible. As pharmaceutically acceptable acid addition salts, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate,
Examples include acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate and saccharate salts.

Representative pharmaceutically acceptable anions include acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; Salt; dihydrochloride; edetate; edisylate; estrate; esylate; fumarate; gluceptate; gluconate; glutamate; Lactate; Lactate; Lactate; Malate; Maleate; Mandelate; Mesylate; Methyl bromide; Methyl nitrate; Methyl sulfate; Vantothenate; phosphate; polygalacturonate; salicylate; stearate; subacetate; Click salts; sulfate; tannate; include and teoclate; tartrate.

Unless otherwise specified, the alkyl, alkoxy and alkenyl moieties referred to herein may include straight chain, branched and cyclic moieties and combinations thereof, and "halo" includes fluoro, chloro, bromo and iodo. included. It will be appreciated, however, that groups consisting only of one or two atoms cannot be branched or cyclic. Examples of alkyl groups include methyl, propyl, cyclopropyl, isopropyl, butyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl,
Hexyl and cyclohexyl.

Further, unless otherwise specified, “optionally substituted” means 0
To the maximum number of substituents, for example, 3 for methyl, 1 for hexyl and 5 for phenyl.

The active compounds of the invention can be administered orally, topically, parenterally, by inhalation spray, as dosage unit formulations containing future non-toxic pharmaceutically acceptable carriers, adjuvants and excipients. Or rectally.

Parenteral as used herein includes subcutaneous injection, intravenous,
Intramuscular, intrasternal injection or infusion techniques.

DETAILED DESCRIPTION OF THE INVENTION The following reaction scheme illustrates the preparation of compounds of general formula I. In the following reaction schemes and discussions, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are defined as in general formula I above.

As shown in Scheme 2, compound 2 comprises geldanamycin or 4,5-dihydrogeldanamycin 1 and amine R ⁸ R
Formed by condensation with ⁹ NH. The reaction is usually carried out at about room temperature to the reflux temperature of the solvent, preferably at about room temperature to about 65 ° C., chloroform, methylene chloride, N, N-dimethylformamide (DMF), pyridine, acetonitrile, tetrahydrofuran (THF) or It is carried out by mixing the amine and ansamycin in an inert solvent such as a lower alcohol, preferably chloroform or methylene chloride.

The conversion of 1 or 2 to 3 is by refluxing pyridinium chloroformate in methylene chloride, pyridinium dichromate in DMF, oxalyl chloride / dimethylsulfoxide (DMSO) in methylene chloride, Dess-Martin in chloroform.
Standard oxidation reagents such as periodinane, and Jones reagent in acetone, preferably Dess in chloroform
By oxidizing 2 with Martin periodinane. These reagents are used at -60 ° C with additional inert solvents.
It is recognized by those skilled in the art that it can be used at a temperature in the range of from the reflux temperature of the solvent.

The conversion of 3 to 4 is usually carried out with a base (eg, sodium acetate, pyridine, sodium carbonate, sodium hydroxide,
Potassium carbonate, and triethylamine) in water or a lower alcohol solvent in the presence of about 0 ° C. to about 100 ° C.
By reacting 3 with hydroxylamine hydrochloride. Preferably, 3 binds to hydroxylamine hydrochloride at room temperature in ethanol in the presence of triethylamine.

The conversion of 3 to 5 is usually carried out at a temperature ranging from about room temperature to the reflux temperature of the solvent, optionally in the presence of a dehydrating agent (eg, sodium sulfate, molecular sieve, and calcium sulfate), in an inert solvent (eg, Amine and 3 in halogen (C ₁ -C ₆ ) alkanes and (C ₁ -C ₆ ) alcohols) and a suitable reducing agent (eg, sodium borohydride, sodium cyanoborohydride, triacetoxyborohydride) Sodium and formic acid) under standard reductive amination conditions. Preferably, the reaction is carried out at room temperature in 1,2-dichloroethane by mixing 3, amine, sodium triacetoxyborohydride and sodium sulfate.

As shown in Scheme 2, compounds 1 or 2, polar solvents, such as dimethylformamide or in dimethyl sulfoxide (C ₁ -C ₆₎ was treated with a base such as alkoxide, followed by an appropriate alkylating agent, for example, By reacting with an alkyl halide, 6 can be selectively obtained by 22-N-alkylation. The reaction temperature is maintained at about 5 to about 65 ° C, optimally at about 5 to about 25 ° C. Alternatively, compound 1 or 2 can be reacted with anhydrous potassium carbonate and an alkyl halide in aceto at reflux.

Compound 7 can be prepared by treating compound 1 or 2 with diethylaminosulfur trifluoride (DAST). The reaction is carried out at about -78 to about 0 ° C.
At a low temperature, preferably at about -78 to about -50 ° C, in an inert solvent such as methylene chloride, chloroform and dichloroethane. Optimally, the reaction is quenched at low temperature with a dilute aqueous base, such as 5% sodium bicarbonate.

Compound 1 or 2 can be converted to an 11-O-acyl or 11-O-sulfonyl derivative by acylation or treatment with a sulfonating agent in the presence of a non-baseophile. Acylating agents include acid anhydrides, halides and isocyanates. Sulfonating agents include halogenated and anhydrous sulfonyl.

Solvents used in these reactions include various aprotic polar and non-polar media such as acetone, chloroform, ethyl acetate, DMF, pyridine, tetrahydrofuran. Bases used include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylamine and 4-dimethylaminopyridine. If desired, compound 3-7 in which R ⁵ is R ¹⁴ O is converted to compound 3-7 in which R ⁵ is R ⁸ R ⁹ N by the method of converting 1 in Scheme 1 to 2. Can be.

The preparation of other compounds of general formula I not described in detail above can be achieved using a combination of the above reactions which will be apparent to those skilled in the art in view of the foregoing disclosure.

Compounds of general formula I and pharmaceutically acceptable salts thereof,
It is useful as an anti-tumor drug (including but not limited to an anti-cancer drug) and an oncogene product inhibitor. These are useful, for example, to inhibit ErbB-2, src, lck, fyn and abl oncogene products. These are also
Useful for inhibiting certain growth factors that play important roles in uncontrolled cell growth, such as EGF derivatives, NGF receptor, PDGF receptor and insulin receptor.

The ability of the active compound to inhibit the ErbB-2 oncogene product can be measured by the following method for measuring the pl85 concentration in SKBr3 cells.

2 ml supplemented with 10% fetal calf serum and glutamine
ATCC, Rockville, Mary, in McCoy's medium
SKBr3 human breast cancer cells obtained from land were transferred to an 8-well tissue culture plate (9.5 cm2 / well, falcon, Becton, Dickenso).
n, Lincoln Park, NJ) at 5 × 10 ⁵ cells / well.
The cells are placed in a 5% CO ₂ atmosphere at 37 ° C. overnight.

Compounds are dissolved in DMSO and tested over a range of concentrations by addition to medium followed by incubation at 37 ° C. for 6 hours. At the end of the incubation, the medium is aspirated from the wells and 2 ml of TNK buffer (50 mM Tris (hydroxymethyl) aminomethane hydrochloride, 140 mM NaC
l, 3.3 mM KCl, 0.5 mM sodium orthovanadate, adjusted to pH 7.4) twice. The cells are then lysed by adding 250 μl of boiling Laemmli sample buffer (140 mM tris (hydroxymethyl) aminomethane hydrochloride, pH 6.8, 5.7% sodium dodecyl sulfate, 29% glycerol) with shaking. The cell lysate is transferred to a test tube and then placed in a boiling water bath for 5 minutes. The lysate is then sonicated using a probe sonicator and stored at -70 C until analysis.

P185 concentration of each sample is substantially Halow and Lane (Anti
bodies : ALaboratory Manual, Cold Spring Harbor Labo
ratory, 1988) by the standard immunoblotting method. A standard amount of each sample was mixed with dithiothreitol (a 1M solution was added to 10%), and a portion corresponding to 1010 μg of protein was added to a dot plotter (Mini-
fold, Schleicher and Schuell, Keene, New Hampshire)
By using a washing buffer (10 mM Tris-HCl pH
Nitrocellulose membrane (BA-S, Schleicher and Schuell, Keene, New H.) equilibrated with 7.4, 150 mM NaCl).
ampshire). The wells are washed with 200 μl of wash buffer and the immunoblocking buffer (5% in wash buffer)
Blocked by incubation with bovine serum albumin, 1% ovalbumin) and then the C-terminal domain of human p185 (standard-TANE by letter amino acid code)
The standard method (Harlow and Lane, Antibodies, ALaboratory Manual, Co.) for peptides representing PEYLGLDVPV)
ld Spring Harbor Laboratory, 1988) and affinity purified rabbit polyclonal antibody (NT
Incubate with the 1: 1000 dilution of 1) for 4 to 12 hours. The membrane is then rinsed with wash buffer for 2 minutes for 10 minutes.
Wash once for 10 minutes in wash buffer with 0.05% Trition X-100, then twice more for 10 minutes in wash buffer. The membrane was then washed with horseradish peroxidase-labeled donkey anti-rabbit antibody (Amershaw) in wash buffer.
m, Arlingston Haights, Illinois) for 20-45 minutes with shaking. The membrane was then again washed twice in wash buffer for 10 minutes,
10 minutes in wash buffer with 0.05% Triton X-100
Wash twice, then twice more in wash buffer for 10 minutes. Then, p185 was replaced with an ECL detection kit (Amersham, Arlington He
ights, Illinois) and Hyperfilm-ECL
(Amersham, Arlington Heights, Illinois). Then, p1 was determined by the densitometer of the film.
Estimate 85. IC ₅₀ values are determined with reference to the p185 content of cell samples exposed only to the carrier (DMSO) and measured as described above.

The ability of an active compound to inhibit the ErbB-2 oncogene product is determined by measuring the phosphorylation of p185 in SKBR3 and other ErbB-2-transformed cell lines by Kamps et al., Onc.
ogene , 2 , 305-315 (1988).

The ability of the active compounds to inhibit the growth of certain human carcinoma cells was determined using the SKBr3 and MCF7 cell lines, see Alley et al., Cancer
Research, 48 , 589-601 (1988). This reference is incorporated herein in its entirety.

When the compounds of general formula I and pharmaceutically acceptable salts thereof are used as antiproliferative agents, such as anticancer agents, either alone or preferably in combination with a pharmaceutically acceptable carrier or diluent, It can be administered to a mammalian patient as a pharmaceutical composition according to standard pharmaceutical practice. The compounds can be administered orally or parenterally.
Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.

Generally, the active compound will be administered when needed (eg, for 4 to 6 hours) at a dosage of from 0.1 mg to about 20 mg of drug per kg of body weight, preferably from about 0.1 mg to about 15 mg per kg of body weight. Variations will necessarily occur depending on the condition of the patient, as well as the particular compound and dosage form being administered. The compounds can be administered in combination with a pharmaceutically acceptable carrier by any of the routes set forth above, and such administration can be done in both single and multiple doses. To note.

The active compounds of the present invention can be administered orally, topically, parenterally, as dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients.
It can be administered by inhalation spray or rectally. Parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

Pharmaceutical compositions containing the active ingredient are suitable for oral use such as tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. May be suitable. Compositions intended for oral use can be prepared by any of the methods known in the art of producing pharmaceutical compositions, and such products provide pharmaceutically productive and palatable formulations And one or more drugs selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, calcium carbonate, sodium carbonate, lactose,
Inert diluents such as calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch;
Or alungic acid; a binder such as starch, gelatin or acacia; and a lubricant such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or
It can also be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. For example, U.S. Pat.
166,452; and 4,265,874 to form coated osmotic therapeutic tablets for controlled release.

Hard capsules for oral use may also be present as gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, while soft capsules are Alternatively, the active ingredient may be present as a gelatin capsule in admixture with a water or oily vehicle, for example, peanut oil, liquid paranine, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia, while dispersing or wetting agents are naturally occurring. Phosphatides, such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or polyoxyethylene Condensation products of ethylene oxide such as sorbitol monooleate with fatty acid and partial ester derived from hexitol, or derived from ethylene oxide and fatty acid and anhydrous hexitol Condensation products of ethylene oxide with partial esters, for example, be a polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl, n-propyl or p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, such as sucrose or saccharin. Sweeteners may also be included.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

Further, the pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or peanut oil; a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic or tragacanth; naturally occurring phosphatides such as soybean and lecithin; and esters or partial esters derived from fatty acids and anhydrous hexitol, for example It may also be sorbitan monooleate and the condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring agents.

Syrups and elixirs are sweeteners, for example,
It can be formulated with glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and physiological saline. Furthermore,
Sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The active compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions are:
It is a solid at normal temperatures but liquid at rectal temperatures and can therefore be prepared by mixing with a suitable non-irritating excipient which dissolves and releases the drug in the rectum. Such materials include cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the active compounds of the present invention are employed.

For administration by inhalation, the active compounds of the invention are easily delivered in the form of an aerosol spray presentation by pressurized packs or nebulizers. Preferred compositions for inhalation are powders that can be formulated as a cartridge that can be inhaled with the aid of a suitable device. In the case of a pressurized aerosol the dosage unit may be measured by providing a valve to deliver a metered amount.

One or more other active compounds can be added to the above formulations to provide a combined therapeutic formulation. Such compounds include cytostatics, cytotoxins and anti-emetic drugs conventionally used in cancer chemotherapy, such as adriamycin.

The present invention will be specifically described with reference to the following examples, but the present invention is not limited thereto. All melting points are uncorrected. In the examples, "BCO" refers to t-butoxycarbonyl.

EXAMPLES General Methods High pressure liquid chromatography (HPLC) is a 250 x 4.6 mm Dupont Zorbax eluting isocratically with two pump / mixer systems each feeding the indicated mixture of 1% methanol and hexanes in ethyl acetate.
Performed at 1.0 ml / min with 254 nm detection on a Sil ™ column. The sample to be analyzed in this way dissolves in the HPLC eluate. The ethyl acetate / hexane ratio is reported continuously in parentheses after the HPLC storage time. "Concentration in vacuum" and "co-evaporation"
Refers to removing the solvent with water suction pressure on a rotary evaporator at a bath temperature of less than 40 ° C.

Example 1 17-isopropylamino-4,5-dihydro-17-demethoxygeldanamycin 4,5-dihydro-geldanamycin in CHCl ₃ (75 mg,
(0.13 mmol) was added isopropylamine (68 μl, 0.80 mmol) and the reaction was stirred at room temperature for 24 h, at which point TLC analysis indicated that the reaction was not complete. The reaction mixture was then refluxed for 3 hours. The solvent was removed by rotary evaporation and the purple residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic layer was dried, the solvent was removed by rotary evaporation, and the crude material was purified by column chromatography (silica gel, 9: 1 CH ₂ Cl ₂ : methanol) to give the title compound as a purple solid; Yield 56
mg (72%), mp 114-115 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ
0.95 (d, 3H, J = 7Hz), 1.00 (d, 3H, J = 7Hz), 1.2 (d, 3H, J
J = 7Hz), 1.35 (d, 3H, J = 7Hz), 1.7 (s, 3H), 1.9 (s, 3
H), 2.2 (dd, 1H, J = 14.7), 2.4 (dd, 1H, J = 14Hz, 7Hz),
2.5−2.8 (m, 1H), 3.3 (m, 1H), 3.35 (s, 3H), 3.4 (s, 3
H), 3.4-3.5 (m, 1H), 3.6 (d, 1H, J = 9Hz), 3.7 (br s,
1H), 4.1 (m, 1H), 4.95 (s, 2H), 5.2 (d, 1H, J = 7HzH
z), 5.75 (d, 1H, J = 9 Hz), 6.2 (t, 1H, J = 9 Hz), 7.1 (s,
1H), 9.3 (br s, 1H); mass spectrum m / z 612 (M + N
a). The compound of Example 2-14 was prepared under the above conditions using 4,5-
Prepared from dihydrogeldanamycin and the appropriate amines.

Example 2 17-amino-4,5-dihydro-17-demethoxygeldanamycin ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95 (m, 6H), 1.5-1.8
(Including m, 8H, single methyl), 1.85 (s, 3H), 2.0 (m, 1
H), 2.35 (m, 2H), 2.6 (m, 1H), 2.7 (m, 1H), 3.2-3.5
(M, 8H, including two methyl singles), 3.8 (m, 2H), 5.0 (br
s, 2H), 5.1 (d, 1H, J = 4Hz), 5.6 (br s, 2H), 5.7 (d, 1
H, J = 10Hz), 6.2 (t, 1H, J = 7Hz), 7.05 (s, 1H), 9.15
(S, 1H); mass spectrum m / z 457 (M ⁺ ); C ₂₈ H ₄₁ N ₃ O _8.
0.5H ₂ O calculated from the theoretical value: C, 60.42; H, 7.60 ; N, 7.55%.
Found: C, 60.41; H, 7.45; N, 7.51%. Example 3 17-methylamino-4,5-dihydro-17-demethoxygeldanamycin Mp 181 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ1.0 (m, 6H), 1.5
-1.8 (m, including methyl single, 9H), 1.9 (s, 3H), 2.3-2.
8 (m, 5H), 3.2 (d, 3H, J = 7Hz), 3.3-3.45 (m, including two methyl singles, 8H), 3.45-3.55 (m, 1H), 3.6 (br d, 1
H, J = 7Hz), 3.75 (br s, 1H), 4.7 (br s, 2H), 5.2 (d, 1
H, J = 7Hz), 5.8 (d, 1H, J = 10Hz), 6.25 (t, 1H, J = 7H
z), 6.4-6.55 (m, 1H), 7.15 (s, 1H), 9.3 (brs, 1
H); mass spectrum m / z 561 (M ⁺ ); calculated from C ₂₉ H ₄₃ N ₃ O ₈ : C, 62.01; H, 7.72; N, 7.48%. Measured value: C, 61.6
0; H, 7.73; N, 7.16%. Example 4 17-cyclopropylamino-4,5-dihydro-17-demethoxygeldanamycin Mp 146-147 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.6-0.9
(M, 4H), 0.9-1.1 (m, 6H), 1.5-1.8m, including methyl single, 6H), 1.9 (s, 3H), 2.3-2.5 (m, 2H), 2.5-2.8 (m , 2
H), 2.8-3.0 (m, 2H), 3.2-3.4 (m, containing two methyl singles, 8H), 3.4-3.5 (m, 1H), 3.5-3.7 (br d, 2H) 4.9
(Br s, 2H), 5.15 (d, 1H, J = 7Hz), 5.75 (d, 1H, J = 10H
z), 6.2 (t, 1H, J = 7 Hz), 6.35 (d, 1H, J = 3), 7.1 (s, 1
H), 9.25 (br s, 1H); mass spectrum m / z 587 (M ⁺ ); C
Logical value calculated from ₃₁ H ₄₅ N ₃ O ₈ : C, 62, 40; H, 7.77; N, 7.04
%. Found: C, 62.55; H, 7.61; N, 6.83%. Example 5 17-allylamino-4,5-dihydro-17-demethoxygeldanamycin Mp 205 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.0 (m, 6H, including two methyl doubles), 1.5-1.8 (including m, 8H, single methyl), 1.9 (s, 3H), 2.2-2.5 (m, 3H), 2.5-2.8 (m, 2
H), 3.2-3.5 (m, 8H, containing two methyl groups), 3.6 (d, 1
H, J = 7Hz), 4.1 (m, 2H), 4.8 (s, 2H), 5.2 (d, 1H, J = 7H)
z), 5.25 (d, 1H, J = 10 Hz), 5.3 (s, 1H), 5.75 (d, 1H, J
= 10Hz), 5.9 (m, 1H), 6,25 (t, 1H, J = 7Hz), 6.4 (br
t, 1H), 7.25 (s , 1H), 9,25 (br s, 1H); Mass spectrum m / z610 [M + Na) ; C 31 H 45 N 3 O 8 · 0.5H 2 O calculated from the theoretical value: C, 62.40; H, 7.77; N, 7.04%. Measurements: C, 62.26; H,
7.83; N, 6.75%. EXAMPLE 6 17- (2'-hydroxyethylamino) -4,5-dihydro-17-demethoxy geldanamycin Mp129 ° C. ^{(foam); 1 H-NMR (300MHz} , CDCl 3) δ0.9-1.
1 (m, 6H), 1.6-1.8 (m, including single methyl, 8H), 1.9
(S, 3H), 2.3-2.5 (m, 3H), 2.7-2.8 (m, 2H), 3.2-3.
5 (m, containing two methyl singles, 8H), 3.55-3.65 (d, 1H, J
= 10Hz), 3.65-3.8 (m, 2H), 3.8-4.0 (m, 1H), 4.85
(Br s, 2H), 5.15 (d, 1H, J = 4Hz), 5.78 (d, 1H, J = 10H
z), 6.2 (t, 1H, J = 7 Hz), 7.1 (s, 1H), 9.21 (s, 1H);
Mass spectrum m / z 591 (M ⁺ ); calculated from C ₃₀ H ₄₅ N ₃ O ₉ : C, 60.90; H, 7.67; N, 7.10%. Measurements: C, 60.40; H,
7.89; N, 6.63%. Example 7 17- (2′-methoxyethylamino) -4,5-dihydro-17-demethoxygeldanamycin Mp 115 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.8-1.
0 (m, 6H), 1.5-1.8 (m, including single methyl, 7H), 1.
85 (br s, 3H), 2.2-2.5 (m, 3H), 2.5-2.8 (m, 2H), 3.
2-3.5 (m, containing 3 methyl singles, 12H), 3.5-3.8 (m,
5H), 5.0 (br s, 2H), 5.15 (d, 1H, J = 7Hz), 5.7 (d, 1H,
J = 10Hz), 6.2 (br t, 1H, J = 7Hz), 6.55 (br s, 1H), 7.
1 (s, 1H), 9.25 (br s, 1H); mass spectrum m / z 605 (M
⁺ ); Calculated from C ₃₁ H ₄₇ N ₃ O ₉ : C, 61.47; H, 7.82; N,
6.94%. Measurements: C, 61.0; H, 7.58; N, 6.71%. Example 8 17- (2'-fluoroethylamino) -4,5-dihydro-17-demethoxygeldanamycin Mp 157 ° C (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.0 (m,
5H), 1.6-1.8 (m, including methyl single, 8H), 1.9 (s, 3
H), 2.0-2.1 (br s, 1H), 2.2-2.5 (m, 3H), 2.6-2.8
(M, 2H), 3.2-3.7 (m, containing two methyl singles, 8H), 3.
7−4.0 (m, 2H), 4.55 (t, 1H, J = 7Hz), 4.7−4.85 (m, 3
H), 5.2 (d, 1H, J = 7Hz), 5.8 (d, 1H, J = 10Hz), 6.25
(T, 1H, J = 7Hz), 6.4 (t, 1H, J = 7Hz), 7.15 (s, 1H), 9.
2 (s, 1H); mass spectrum m / z 593 (M ⁺ ). Example 9 17- (2′-methylthioethylamino) -4,5-dihydro-17-demethoxygeldanamycin Mp 110 ° C. (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ1.0 (m,
6H), 1.5-1.75 (m, including methyl single, 8H), 1.85 (s, 3
H), 2.1 (s, 3H), 2.2−2.4− (m, 3H), 2.5−2.8 (m, 4
H), 3.2-3.5 (m, containing two methyl singles, 8H), 3.5-3.
8 (m, 4H), 5.0 (s, 2H), 5.15d, 1H, J = 4Hz), 5.75 (d, 1
H, J = 10Hz), 6.2 (t, 1H, J = 7Hz), 6.6 (t, 1H, J = 4Hz),
7.1 (s, 1H), 9.2 (s, 1H); mass spectrum m / z 644 (M
+ Na); C ₃₁ H ₄₇ N ₃ O ₈ S. Theoretical value calculated from 0.5 H ₂ O: C, 59.
03; H, 7.67; N, 6.66%. Found: C, 58.87; H, 7.67; N, 6.60
%. Example 10 17- [S-(+)-2'-hydroxypropylamino]
-4,5-dihydro-17-demethoxygeldanamycin ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95 (d, 3 H, J = 7 Hz), 1.0
(D, 3H, J = 7 Hz), 1.3 (d, 3H, J = 7 Hz), 1.5-1.75 (m, including methyl single, 6H), 1.85 (s, 3H), 2.25-2.45 (m, 2
H), 2.6-2.7 (m, 1H), 3.2-3.5 (m, including two methyl singles, 8H), 3.5-3.7 (m, 2H), 4.05 (m, 1H), 4.9 (s, 2)
H), 5.15 (d, 1H, J = 7 Hz), 5.8 (d, 1H, J = 7 Hz), 6.2 (t,
1H, J = 7Hz), 6.7 (dr s, 1H), 7.05 (s, 1H), 9.2 (br s,
1H); mass spectrum m / z 605.3 (M +). Example 11 17- (2'-cyanoethylamino) -4,5-dihydro-1
7-demethoxygeldanamycin Mp130-140 ° C (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
0 (m, 6H), 1.5-1.8 (m, including methyl single, 8H), 1.9
(S, 3H), 2.0-2.2 (m, 2H), 2.4 (q, 2H, J = 7Hz), 2.6-
2.8 (m, 4H), 3.2-3.5 (m, including two methyl singles, 8
H), 3.6 (br d, 1H, J = 7 Hz), 3.85 (q, 2H, J = 7 Hz), 4.75
(Br s, 2H), 5.2 (d, 1H, J = 7Hz), 5.75 (d, 1H, J = 10H
z), 6.2 (q, 2H, J = 7 Hz), 7.15 (s, 1H), 9.15 (s, 1H);
Mass spectrum m / z 600 (M ⁺ ); Calculated from C ₃₁ H ₄₄ N ₄ O ₈ : C, 61.98; H, 7.38; N, 9.33%. Measurements: C, 61.30; H,
7.31; N, 9.12%. Example 12 17-azetidin-1-yl-4.5-dihydro-17-demethoxygeldanamycin Mp 110 ° C. (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95
(D, 3H, J = 7Hz), 1.0 (d, 3H, J = 7Hz), 1.7 (s, 3H), 1.6
−1.8 (m, 9H), 1.9 (s, 3H), 2.2 (dd, 1H, J = 14Hz, 7H
z), 2.3-2.55 (m, 4H), 2.65 (d, 1H, J = 14Hz), 2.75
(M, 1H), 3.35 (m, 1H), 3.38 (s, 3H), 3.4 (s, 3H), 3.5
(M, 1H), 3.6 (d, 1H, J = 10Hz), 4.5−4.8 (m, 6H), 5.2
(D, 1H, J = 7 Hz), 5.7 (d, 1H, J = 10 Hz), 6.25 (t, 1H, J =
10Hz), 7.0 (s, 1H), 9.3 (br s, 1H); mass spectrum m
/ z587 (M ⁺ ). Example 13 17- (3'-hydroxyazetidin-1-yl) -4,5
-Dihydro-17-demethoxygeldanamycin Mp (amorphous); ¹ H-NMR (300 MHz, CDCl ₃ ) δ1.0 (m, 6
H), 1.5-1.8 (m, containing one methyl single, 8H), 1.9 (s,
3H), 2,2 (m, 1H), 2.35 (m, 2H), 2.6 (br d, 1H, J = 14H)
z), 2.75 (m, 1H), 3.2-3.5 (m, including two methyl singles, 8H), 3.6 (d, 1H, J = 10 Hz), 4.3-4.6 (m, 2H), 4.7
(M, 1H), 4.75-5.0 (m, 4H), 5.15 (d, 1H, J = 4Hz), 5.8
(D, 1H, J = 10Hz), 6.2 (brt, 1H, J = 7Hz), 6.95 (s, 1
H), 9.2 (s, 1H); mass spectrum m / z 626 (M + Na); C
₃₁ H ₄₅ N ₃ O ₉ Calculated: C, 61.68; H, 7.51; N, 6.96
%. Found: C, 61.21; H, 7.51; N, 6.75%. Example 14 17- (3'-methoxyazetidin-1-yl) -4,5-
Dihydro-17-demethoxygeldanamycin Mp 118 ° C (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.0 (m,
6H, 2 methyl doubles), 1.5-1.8 (m, 8H, including 1 methyl), 1.9 (s, 3H), 2.0-2.3 (m, 1H), 2.4 (m, 2H), 2.5
-2.8 (m, 2H), 3.2-3.5 (m, 11H, including three methyl singles), 3.6 (m, 1H), 4.0 (d, 1H, J = 7 Hz), 4.2 (m, 1H), Four.
3-4.6 (m, 2H), 4.6-4.9 (m, 4H), 5.2 (d, 1H, J = 4H
z), 5.8 (d, 1H, J = 10 Hz), 6.25 (brt, 1H, J = 7 Hz), 7.0
(S, 1H), 9.25 (s, 1H); mass spectrum m / z 640 (M + N
_{a); C 32 H 47 N} 3 O 9 · H 2 O calculated from the theoretical value: C, 60.84; H, 7 .
18; N, 6.65%. Found: C, 60.74; H, 7.54; N, 6.75%. Example 15 17-azetidin-1-yl-4.5-dihydro-11-α-
Fluoro-17-demethoxygeldanamycin A solution of diethylaminosulfur trifluoride (DAST) (0.154 g, 0.960 mmol, 0.127 ml) dissolved in 3 ml of methylene chloride was added to the flame-dried flask under nitrogen and external dry ice was added. / Cooled to −68 ° C. in an acetone bath. 17-Azetidin-1-yl-4,5-dihydro-17-demethoxygeldanamycin (0.188 g, 0.320 mmol) dissolved in 15 ml of methylene chloride was added dropwise. After 0.5 hour, 5 ml of 5% aqueous NaHCO ₃ was added slowly at about -68 ° C. After warming to room temperature, the product was extracted into 100 ml of methylene chloride. The organic layer was washed with 3 × 50 ml of water and 2 × 5 ml of brine, dried over MgSO ₄ , filtered and concentrated to a purple solid, which was purified by flash column chromatography using 5:95 methanol: chloroform. Purified. The desired product, Rf =. (42 (1: 9 methanol: chloroform) material was dissolved in a minimum amount of ethyl acetate and precipitated with hexanes; yield 0.096 g (51%),
mp 104 ° C (decomposition) ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.00 (d, J
= 8Hz, 3H, 14-CH 3), 1.06 (d, J = 8Hz, 3H, 10-CH 3), 1.4
(Br m, 2H, H- 13), 1.56 (s, 3H, 8-CH 3), 1.75 (m, 1H, H
−14), 1.89 (s, 3H, 2-CH ₃ ), 2.20 (dd, J = 8.5Hz, 16Hz,
1H, H-15), 2.4 (brm, 3H, 3'azetidine CH ₂ and H-
5), 2.66 (dd, J = 7 Hz, 16 Hz, 1H, H-15), 2.75 (br d, J
= 26Hz, 1H, H-10), 3.25 (m, 1H, H-4), 3.4 (br s, 7H,
_{6-OCH 3, 12-OCH} 3 and H-4), 3.60 (br m, 1H, H-1
2), 4.40 (br d, J = 44 Hz, 1H, H-11), 4.65 (br m, 7H, NH
₂ and 2 'and 7' azetidine CH ₂ and H-6),
5.06 (d, J = 8Hz, 1HH-7), 5.62 (d, J = 9Hz, 1H, H-
9), 6, 13 (brt, 1H, H-3), 6.96 (s, 1H, H-19), 9.27
(S, 1H, NH-22); m / z 612. (M ++ Na); IR (KBr, cm ^-1 )
_{1735,1695,1650; C 31 H 44 FN 3} O 7 · 0.25H 2 O calculated from the theoretical value: C, 62.66; H, 7.96 ; N, 7.0%. Found: C, 62.38; H, 7.5
3; N, 6.97%. Example 16 17-allylamino-4,5-dihydro-11-α-fluoro-17demethoxygeldanamycin The title compound was converted to 17-allylamino-4,5-dihydro-1
Prepared from 7-demethoxygeldanamycin by the method of Example 15. Yield 0.079 g (44%), mp 84 ° C (decomposition); ¹
H-NMR (300 MHz, CDCl ₃ ) δ 1.02 (d, 3H, J = 8 Hz, 14-C
_{H 3), 1.07 (d,} 3H, J = 8Hz, 10-CH 3), 1.45 (br m, 2H, H-
13), 1.60 (s, 3H , 8-CH 3), 1.7 (m, 2H, H-5), 1.83 (b
rm, 1H, H-14) , 1.90 (s, 3H, CH 3), 2.30 (dd, J = 8.5Hz,
16Hz, 1H, H-15), 2.4 (m, 2H, H-4), 2.70 (dd, J = 7Hz,
16Hz, 1H, H-15), 2.75 (br d, J = 26Hz, 1H, H-10), 3.26
(M, 1H, H-6 ), 3.40 and 3.43 (br s, 6H, COH 3), 3.57
(Br m, 1H, H- 12) 4.08 (br t, 2H, allylic CH _2), 4.35
(Br d, J = 47Hz, 1H, H-11), 4.65 (br m, 2H, NH 2), 4.07
(S, 1H, H-7 ), 5.25 (br d, 2H, vinylic _{CH 2), d, J =} 9H
z, 1H, H-9), 5.9 (m, 2H, H-5 and vinyl CH), 6.1
5 (br t, 1H, H-3), 6.32 (br t, 1H, NH), 7.15 (s, 1H, H
-19), 9.25 (s, 1H, NH-22); m / z 612. (M ++ Na); IR
^{(KBr, cm -1) 1730,1695,1655;} C 31 H 44 FN 3 O 7 · 0.25H theoretical value calculated from the _{2 O; C, 62.66; H} , 7.96; N, 7.07%. measured value:
C, 62.53; H, 7.32; N, 6.97%. Example 17 17-azetidin-1-yl-4,5-dihydro-11-keto-17-demethoxygeldanamycin from 17-azetidin-1-yl-4,5-dihydro-17-demethoxygeldanamycin Prepared by the method of Example 76; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.0 (d, 3 H, J = 6),
1.3 (d, 3H, J = 6), 135-1.5 (m, 2H), 1.5-1.8 (m, 6
H), containing a single methyl), 1.9 (s, 3H), 2.15-2.3 (m, 2
H), 2.45-2.5 (m, 2H), 2.6 (6m, 1H), 3.15 (m, 1H), 3.
35 (s, 3H), 3.4 (s, 3H), 3.55 (m, 1H), 4.0 (m, 1H), 4.
65 (m, 4H), 4.8 (br s2H), 5.0 (d, 1H, J = 6H), 5.55
(D, 1H, J = 8Hz), 6.2.25 (m, 1H), 6.92 (s, 1H), 9.2
(S, 1H), mass spectrum m / z 608 (M + Na; Example 18 17-azetidin-1-yl-17-demethoxygeldanamycin) Geldanamycin (14.0 g, 25.0 mmol) was flame dried under nitrogen. Added to the flask and slurried in 350 ml of methylene chloride, azetidine (2.85 g, 49.9 mmol, 3.36 ml) in 10 ml of methylene chloride was added dropwise.
The yellow suspension turned purple during the addition. After 1 hour, the reaction mixture was evaporated to dryness and the residue was dissolved in 50 ml of chloroform and precipitated with 600 ml of hexanes. Filtration and 70
By vacuum drying at ℃ to give the pure product in a yield 14.2g (97%); 225C; 1 H-NMR (300MHz, CDCl 3) δ0.94 (br t,
6H, 10-CH ₃ and _{14-CH 3), 1.2 (} m, 1H, H-13), 1.65
(M, 1H, H-13), 1.73 (m, 1H, H-14), 1.76 (s, 3H, 8-CH
_{3), 2.0 (s, 3H} , 2-5CH 3), 2.17 (dd, J = 12Hz, 16Hz, 1H, H
−15), 2.40 (p, J = 8 Hz, 2H, 3 ′ azetidine CH ₃ ), 2.56
(D, J = 16Hz, 1H, H-15), 2.67 (m, 1H, H-10), 3.20 (s,
_{3H, OCH 3), 3.30 (} s, 3H, OCH 3), 3.40 (m, 1H, H-12), 3.5
0 (m, 1H, H-11), 4.25 (d, J = 10.5Hz, 1H, H-6), 4.5-
4.9 (m, 6H, 2 'and 4' azetidine CH ₂ and NH _2), 5.
13 (s, 1H, H-7), 5.79 (t, J = 9Hz, 1H, H-5), 5.87
(D, J = 9 Hz, 1H, H-9), 6.53 (t, J = 9 Hz, 1H, H-4), 6.
88 (d, J = 9 Hz, 1H, H-3), 7.06 (s, 1H, H-19), 9.13
(S, 1H, NH-22); m / z 608. (M ++ Na); IR (KBr, cm ^-1 )
_{1730,1680,1645; C 31 H 43 N 3} O 8 calculated the theoretical value from: C, 63.5
4; H, 7.40; 7.17%. Found: C, 63.09; H, 7.33; N, 685%. Example 19 17-propargylamino-17-demethoxygeldanamycin Propargylamine hydrochloride (0.200 g, 2.180 mmol) and triethylamine (0.2206 g, 2.180 mmol, 0.303 ml) were added to a nitrogen and flame dried flask and added to a flask.
Slurried in ml of chloroform. After 10 minutes, geldanamycin (0.200 g, 0.3567 mmol) was added to the mixture and the reaction was stirred at room temperature overnight. The solution turned from pale yellow to dark orange / red. The reaction mixture was diluted with 50 ml of chloroform and washed with 3 × 25 ml of IN hydrochloric acid. The organic layer was then dried over magnesium sulfate, filtered, and evaporated to dryness to give a crude purple residue. The crude product is then
Using 0g of silica gel 3:97 isopropyl alcohol: 0.015g (7%) was purified by flash column chromatography eluting with methylene chloride to give pure purple product mp172 ℃; ¹ H- NMR (300MHz, CDCl ₃ ) δ
0.96-1.10 (m, 1H, H-13), 1.00 (d, J = 8Hz, 3H, 10-C
H ₃ ), 1.01 (d, J = 8 Hz, 3H, 14−CH ₃ ), 1.62-1.90 (br m,
2H, H-13, H- 14), 1.76 (s, 3H, 8-CH 3), 2.04 (s, 3H, 2
_{-CH 3), 2.34-2.47 (br m} , 1H, H-15), 2.42 (s, 1H, acetylene CH), 2.68-2.81 (br m, 2H, H-10, H-15), 3.2
8 (s, 3H, OCH ₃ ), 3.47 (s, 3H, OCH ₃ ), 3.49 (br m, 1H, H−
12), 3.61 (br m, 1H, H-11), 4.02 (d, J = 6 Hz, 1H, H-
6), 4.31 (s, 1H, 11-OH), 4.32 (m, 2H, propargyl CH
_{2) 4.77 (br m, 2H} , NH 2), 5.21 (s, 1H, H-7), 5.87 (t,
J = 9Hz, 1H, H-5) 5.90 (d, J = 9Hz, 1H, H-9), 6.32 (b
rt, 1H, NH), 6.60 (t, J = 9 Hz, 1H, H-4), 6.97 (d, J = 9
Hz, 1H, H-3), 7.32 (s, 1H, H-19), 9.09 (s, 1H, NH-2)
2); m / z 606.3 (M ++ Na); IR (KBr, cm ^-1 ) 2120,1730,1
695,1645; theoretical value calculated from C ₃₁ H ₄₁ N ₃ O ₈・ 3.50H ₂ O: C, 5
7.55; H, 7.47; N, 6.49%. Measurements; C, 57.55; H, 6, 14; N, 6.23
%. Example 20 17- (2'Cyanoethylamino) -17-demethoxygeldanamycin Geldanamycin (0.200 g, 0.3567 mmol) was added to a flame-dried flask under nitrogen and slurried in 5 ml of chloroform. . 3-aminopropionitrile
0.153 g (2.18 mmol, 0.16 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was light yellow to dark red /
It turned orange. An additional 0.161 ml of 3-aminopropionitrile was added and the reaction mixture was refluxed for 8 hours.
Dilute the cooled reaction mixture with 75 ml chloroform and add 3x
Washed with 50 ml of water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The purple residue was recrystallized from a minimum amount of hot ethyl acetate to give 0.160 g (75%) of pure purple product, mp 152 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ.
0.74-0.91 (br m, 1H, H-13), 0.82 (d, J = 7HPz, 3H, 10
−CH ₃ ), 0.82 (d, J = 7 Hz, 3H, 14−CH ₃ ), 1.45−1.7 (br
m, 2H, H-13, H-14), 1.61 (s, 3H, 3-CH 3), 1.81 (s, 3H,
_{2-CH 3), 1.93-2.09 (} br m, 1H, H-15), 2.49-2.64
(M, 4H, β- ethyl _{CH 2, H-10, H} -15), 3.08 (s, 3H, OC
_{H 3), 3.19 (s,} 3H, OCH 3), 2.28 (br m, 1H, H-12), 3.39
(M, 1H, 11-H), 3.62-3.79 (br m, 2H, α-ethyl C
_{H 2), 4.12 (d,} J = 9Hz, 1H, H-6), 4,62 (br m, 2H, N
_{H 2), 5.00 (s,} 1H, H-7), 5.62-5.72 (br m, 2H, H-5, H
−9), 5.96 (brt, 1H, NH), 6.40 (t, J = 9 Hz, 1H, H−
4), 6.78 (d, J = 9Hz, 1H, H-3), 7.12 (s, 1H, H-19),
8.82 (s, 1H, NH-22); m / z 621.3 (M ++ Na); IR (KBr, c
_{^{m -1) 1730,1690,1650,1585,1480; C 31 H}} 42 N 4 O 8 calculated the theoretical value from: C, 62.19; H, 7.07 ; N, 9.35%. Found: C, 62.02;
H, 6.63; N, 9.09%. Example 21 17- (2'-Fluoroethylamino) -17-demethoxygeldanamycin 17- (2'-fluoroethylamino) -17-demethoxygeldanamycin was prepared by the method of Example 19.
After flash column chromatography of the crude residue on 200 g of silica gel, eluting with 20% acetone in methylene chloride, 0.060 g (28%) of pure purple product was obtained, mp 176 ° C .; ¹ H _{-NMR (300MHz, CDCl 3) δ0.87} (d, J = 7Hz, 3H, 10-C
_{H 3), 0.91 (d,} J = 7Hz, 3H, 14-CH 3), 1.55-1.73 (br m,
3H, H-13, H- 14), 1.70 (s, 3H, 8-CH 3), 1.92 (s, 3H, 2
−CH ₃ ), 2.21 (dd, J = 8 Hz, 16 Hz, 1 H, H−15), 2.62 (br
m, 2H, H-10, H-15), 3.14 (s, 3H, OCH 3), 3.24 (s, 3H, OC
_{H 3), 3.35 (br m} , 1H, H-12), 3.48 (br m, 1H, H-11),
3.59−3.91 (br m, 2H, α-ethyl CH ₂ ), 4.19 (d, J = 9H
z, 1H, H-6), 4.65 (two brt, J = 46Hz, 5Hz, 2H, β-
Ethyl _{CH 2), 4.52-4.79 (br m} , 2H, NH 2), 5.07 (s, 1H, H
-7), 5.72 (br m, 2H, H-5, H-9), 6.29 (br t, 1H, N
H), 6.48 (t, J = 9 Hz, 1H, H-4), 6.85 (d, J = 9 Hz, 1H, H
-3), 7.14 (s, 1H, H-19), 8.97 (s, 1H, NH-22); m / z5
19.3. (M +); IR (KBr, cm ^-1 ) 1742,1655,1585; C ₃₀ H ₄₂ N
₃ O ₈ calculated the theoretical value from: C, 60.90; H, 7.15 ; N, 7.10%. Found: C, 60.65; H, 6.90; N, 6.92%. Example 22 17-tert-butylamino-17-demethoxygeldanamycin Geldanamycin (0.200 g, 0.3567 mmol) was slurried in 5 ml of tert-butylamine at reflux in a flame-dried flask under nitrogen overnight. I made it. The reaction color changed from yellow to dark purple. The reaction mixture was evaporated to dryness. The residue was dissolved in 50 ml of chloroform. The chloroform solution was washed with 3x25ml saline and 3x25ml water. The organic layer was dried over magnesium sulfate, filtered,
Evaporated to dryness. Using 200 g of silica gel, the crude product
Purified by flash column chromatography eluting with 10% acetone / methylene chloride; yield 0.053 g (25
%) Mp 102 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.89
(D, J = 5Hz, 3H , 10-CH 3), 0.94 (d, J = 5Hz, 3H, 14-C
H ₃ ), 1.39 (s, 9H, t-butyl CH ₃ ), 1.49-1.80 (br m, 3
H, H-13, H- 14), 1.74 (s, 3H, 8-CH 3), 198 (s, 3H, 3-C
_{H 3), 2.27 (br m} , 1H, H-15), 2.65 (br m, 2H, H-10, H-
15), 3,21 (s, 3H , OCH 3), 3.30 (s, 3H, OCH 3), 3.99 (br
m, 1H, H-12), 3.45 (br m, 1H, H-11), 4.17 (br m, 1H, 1
1-OH), 4.23 (d, J = 7 Hz, 1H, H-6), 4.72-4.91 (br
_{m, 2H, NH 2),} 5.13 (s, 1H, H-7), 5.82 (br m, 3H, H-5, H
−9, NH), 6.51 (t, J = 7 Hz, 1H, H-4), 6.87 (d, J = 7 Hz,
1H, H-3), 7.18 (s, 1H, H-19), 8.96 (s, 1H, NH-22);
m / z 601.4 (M +); IR (KBr, cm ^-1 ) 1720,1685,1645,158
5,1560; C ₃₂ H ₄₇ N ₃ O ₈ Calculated theoretical: C, 63.87; H, 7.8
7; N, 6.98%. Found: C, 63.91; H, 7.95; N, 6.03%. Example 23 17- (2'-Mercaptoethylamino) -17-demethoxy-geldanamycin Geldanamycin (0.200 g, 0.3567 mmol) was added to a flame-dried flask under nitrogen and slurried in 5 ml of pyridine. . Thiazolidine (0.194 g, 2.18 mmol, 0.171 ml) was added and the reaction mixture was heated at 70 ° C. for 2 hours. The reaction mixture was evaporated to dryness in vacuo. The crude product is
Purification by flash column chromatography using 200 g of silica gel, eluting with 4% methanol in methylene chloride, gave a pure purple product of 0.041 g (20%) mp 156 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.99 (d, J = 5H
_{z, 6H, 10-CH 3} , 14-CH 3), 1.63-1.81 (br m, 3H, H-13, H
−14), 1.78 (s, 3H, 8-CH ₃ ), 2.01 (s, 3H, 2-CH ₃ ) 2.47
(M, 1H, H-15), 2.64-2.79 (br m, 2H, H-10, H-15),
2.83−3.00 (br m, 2H, 2′-CH ₂ ), 3.25 (s, 3H, OCH ₃ ),
3.35 (s, 3H, OCH ₃ ), 3.42 (m, 1H, H-12), 3.55 (m, 1H, H
−11), 3.87 (m, 2H, 1′-CH ₂ ), 4.10 (br m, 1H, 11−O
H), 4.29 (d, J = 9Hz, 1H, H-6), 4.92 (br m, 2H, NH 2)
5.16 (s, 1H, H-7), 5.81-5.89 (br m, 2H, H-5, H-
9), 6.48 (br t, 1H, NH), 6.55 (t, J = 9Hz, 1H, H-4),
6.94 (d, J = 9Hz, 1H, H-3), 7.24 (s, 1H, H-19), 9.12
(S, 1H, NH-22 ); m / z642.3 (M ++ Na); IR (CHCl 3, cm
_{^{-1) 1730,1690,1655,1575; C 30 H 44}} N 3 O 8 S · H 2 O calculated from the theoretical value: C, 57.67; H, 7.41 ; N, 6.72%. Measurements: C, 57.44;
H, 6.37; N, 6.72%. Example 24 17- [2'Methylthio) ethylamino] -17-demethoxy-geldanamycin Geldanamycin (0.200 g, 0.3567 mmol) was added to a flame-dried flask under nitrogen and slurried in 5 ml of chloroform. . 2- (Methylthio) ethylamine (0.199 g, 2.18 mmol) was added and the reaction was stirred at room temperature for 36 hours. The reaction mixture was diluted with 75 ml of chloroform and washed with 2 × 50 ml of 1N hydrochloric acid, 2 × 50 ml of brine and 3 × 50 ml of water. The organic layer is dried over magnesium sulfate,
Filter and evaporate to dryness. The crude product was purified by flash column chromatography on 200 g of silica gel, eluting with 3% acetonitrile in ethyl ether, to give 0.095 g (43%) of pure purple product with mp 157 ° C .;
¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.09 (d, J = 7 Hz, 3H, 14-C
_{H 3), 1.14 (d,} J = 7Hz, 3H, 10-CH 3), 1.71-1.89 (dr m,
3H, H-13, H- 14), 1.98 (s, 2H, 8CH 3), 2.13 (s, 3H, 2-C
_{H 3), 2.22 (s,} 3H, SCH 3), 2.46 (dd, J = 7Hz, 13Hz, 1H, H-
15), 2.79 (d, J = 13 Hz, 1H, H-15), 2.72-2.92 (br m, 3
_{H, 2'-CH 2, H} -10), 3.36 (s, 3H, OCH 3), 3.46 (s, 3H, OC
_{H 3), 3.54 (m,} 1H, H-12), 3.68 (t, J = 7Hz, 1H, H-11),
3.72−3.86 (br m, 1H, 1′CH ₂ ), 3.86−3.95 (br m, 1H,
_{1'CH 2), 4.41 (d,} J = 7Hz, 2H, H-6,11-OH), 4.93 (br
_{m, 2H, NH 2),} 5.28 (s, 1H, H-7), 5.91-6.04 (br m, 2H,
H-5, H-9), 6.62-6.74 (br m, 2H, H-4, NH), 7.03
(D, J = 7Hz, 1H, H-3), 7.37 (s, 1H, H-19), 9.22 (s, 1
H, NH-22); m / z642.3 (M ++ Na); IR (CHCl 3, cm -1) 17
_{35,1685,1650,1570; C 31 H 45 N 3} O 8 S · 1.5H 2 O calculated from the theoretical value: C, 57.56; H, 7.48 ; N, 6.49%. Measurements: C, 57.30; H,
6.87; N, 6.21%. Example 25 17-[(S) -2'azetidinecarboxylic acid] -17-demethoxygeldanamycin Geldanamycin (0.200 g, 0.3567 mmol) was added to a flame-dried flask under nitrogen and 5 ml of chloroform was added. Slurry in. (S)-in 2 ml of pyridine
2-azetidinecarboxylic acid (0.200 g, 1.978 mmol)
And triethylamine ((0.200 g, 1.978 mmol,
0.275 ml) was added. The reaction mixture was stirred at room temperature for 36 hours, refluxed for 4 hours, cooled to room temperature, diluted with 75 ml of chloroform and washed with 2 × 50 ml of 1N hydrochloric acid. Organic layer, 3x50
Extracted with ml of 1N NaOH. The pooled basic phases were acidified to pH = 6 with 1N hydrochloric acid and extracted with 3 × 75 ml of chloroform. The combined chloroform layers were dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was dissolved in a minimum amount of ethyl acetate and precipitated with hexane to obtain 0.056 g (25%),
Pure purple product with mp 210 ° C. (decomposition) obtained; ¹ H-NMR
(C ₅ D ₅ N) δ1.29-1.47 (br m, 6H, 10-CH ₃ , 14-CH ₃ ),
1.94-2.22 (br m, 3H, H-13, H-14), 2.09 (s, 3H, 8-CH
_{3), 2.23 (s, 3H} , 2-CH 3), 2.49 (br m, 1H, H-15), 2.81
(T, J = 7Hz, 1H, H-10), 2.99 (br m, 1H, 4 'azetidine-CH), 3.28 (br m, 1H, 4' azetidine-CH), 3.42 (s, 3
_{H, OHC 3), 3.50 (} s, 3H, OCH 3), 3.81 (m, 1H, H-12), 4.14
(M, 1H, H-11), 4.34 (br m, 1H, 3'azetidine-CH),
4.89 (br m, 1H, 3 'azetidine-CH), 5.01 (d, J = 7 Hz, 1
H, H-6), 5.79 (m, 1H, 2'azetidine-CH), 5.91 (s, 1
H, H-7), 6.21 (t, J = 7Hz, 1H, H-5), 6.47 (d, J = 7H
z, 1H, H-9), 6.60 (t, J = 7Hz, 1H, H-4), 7.41-7.54
(Br m, 2H, H-3, H-19), 9.57 (s, 1H, NH-22); m / z 652.
3 (M ++ Na); IR (CHCl 3, cm -1) 1730,1695,1645,1585;
_{C 32 H 43 N 3 O 10} · 3H 2 O was calculated from the theoretical value: C, 56.21; H, 7.2
2; N, 6.14%. Found: 56.16; H, 6.13; N, 6.04%. The compounds of Examples 26-31 were prepared from geldanamycin and the appropriate amines by the method of Example 1 above.

Example 26 17-histamino-17-demethoxygeldanamycin Mp 150 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.98
(Duplicate d, 6H), 1.68 (m, 1H,) 1.77 (s, 3H), 2.02
(S, 3H), 2.43 (t, 1H, J = 7Hz), 2.6-2.8 (m, 2H), 2.94
(T, 2H, J = 5Hz), 3.23 (s, 3H), 3.39 (s, 3H), 3.40 (m,
1H), 3.52 (m, 1H), 3.7-3.9 (m, 2H), 4.27 (d, 1H, J = 9
Hz), 4.88 (dr exchangeable, 2H), 5.13 (s, 1H), 5.85 (m, 2
H), 6.56 (t, 1H, J = 12Hz), 6.75 (m, 1H), 6.92 (m, 2
H), 7.19 (s, 1H ), 7.61 (s, 1H), 9.17 (s, 1H); Mass spectrum ^{m / z640 (M +);} C 35 H 45 N 5 O 8 · 0.5 ( ethyl acetate)
Calculated from: C, 61.48; H, 7.22; N, 10.24%. Found: C, 61.06sH, 7.35; N, 10.32%. Example 27 17-furfurylamino-17-demethoxygeldanamycin Mp 122-130 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
09 (duplicate d, 6H), 1.75 (m, 1H), 1.79 (s, 3H), 1.98
(S, 3H), 2.42 (dd, 1H, J = 7Hz, 6Hz), 2.72 (m, 2H), 3.2
3 (s, 3H), 3.37 (s, 3H), 3.48 (m, 1H), 3.59 (m, 1H),
4.18 (br exchangeable, 1H), 4.29 (d, 1H, J = 9Hz, 4.67 (dd, 1
H, J = 9Hz, 5Hz), 4.73 (dd, 1H, J = 9Hz, 5Hz), 4.88 (br exchangeable, 2H), 5.18 (s, 1H), 5.89 (m, 2H), 6.28 (m, 1
H), 6.34 (m, 1H), 6.42 (m, 1H), 6.57 (t, 1H, J = 12H
z), 6.94 (d, 1H, J = 12 Hz), 7.28 (s, 1H), 7.41 (s, 1
H), 9.11 (s, 1H ); Mass spectrum ^{m / z626 (M +);} C 33 H
₄₃ N ₃ O ₉ , 0.33 Theoretical value calculated from CHCl ₃ : C, 62.31; H, 6.9
0; N, 6.54%. Found: C, 62.28; H, 6.78; N, 6.63%. Example 28 17-tetrahydrofurfurylamino-17-demethoxygeldanamycin Mp 157-166 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
05 (duplicate d, 6H), 1.7 (m, 2H), 1.87 (s, 3H), 1.9-
2.1 (m, 3H), 2.05 (s, 3H), 2.38 (m, 1H), 2.70 (m, 2
H), 3.27 (s, 3H), 3.34 (s, 3H), 3.45 (m, 1H), 3.53
(M, 2H), 3.82 (m, 1H), 3.93 (m, 1H), 4.09 (m, 1H), 4.
27 (d, 1H, J = 8 Hz), 4.88 (br exchangeable, 2H), 5.128 (s, 1
H), 5.7-6.0 (m, 2H), 6.56 (m, 2H), 6.93 (d, 1H, J = 11
Hz), 7.26 (s, 1H), 9.17 (s, 1H); mass spectrum m / z6
^{32 (M + +2): C} 33 H 47 N 3 O 9 calculated the theoretical value from: C, 62.94;
H, 7.52; N, 6.69%. Found: C, 62.92; H, 7.57; N, 6.39%. Example 29 17-tetramethylguanidino-17-demethoxygeldanamycin Mp 140-145 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
0 (duplicate d, 6H), 1.70 (m, 1H), 1.77 (s, 3H), 2.02
(S, 3H), 2.51 (m, 2H), 2.76 (br s, 6H), 2.83 (s, 6
H), 3.26 (s, 3H), 3.38 (s, 3H), 3.42 (m, 1H), 3.60
(M, 1H), 4.28 (d, 1H, J = 9Hz), 5.15 (s, 1H), 5.83 (t,
1H, J = 7Hz), 5.95 (m, 1H), 6.57 (t1H, J = 12Hz), 6.97
(Br d, 1H, J = 12Hz), 7.07 (s, 1H), 9.36 (br s, 1H);
Mass spectrum m / z646 (M + 2) ; C 33 H 49 N 5 O 8 · 0.2CHCl
Theoretical value calculated from ₃ : C, 60.55; H, 7.56; N, 10.64%. Found: C, 60.57; H, 7.67; N, 10.59%. Example 30 17-β-alanyl-17-demethoxygeldanamycin Mp 143-147 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ0.
99 (duplicate d, 6H), 1.67 (m, 1H), 1.79 (s, 3H), 2.03
(S, 3H), 2.32 (m, 1H), 2.69 (m, 3H), 3.22 (s, 3H), 3.
32 (s, 3H), 3.42 (m, 1H), 3.55 (m, 1H), 3.82 (m, 2H),
4.28 (d, 1H, J = 9), 5.08 (br s, 2H), 5.19 (s, 1H), 5.
83 (m, 2H), 6.58 (m, 2H), 6.91 (d, 1H, J = 12 Hz), 7.25
(S, 1H), 9.09 (s, 1H); mass spectrum m / z 640 (M + N
a); Theoretical value calculated from C ₃₁ H ₄₃ N ₃ O ₁₀・ H ₂ O: C, 58.66; H,
6.99; N, 6.62%. Found: C, 58.98; H, 7.03; N, 6.60%. Example 31 17-Homohistamino-17-demethoxygeldanamycin Mp 128-136 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ )
87 (d, 3H, J = 7Hz), 0.98 (d, 3H, J = 7Hz), 1.7 (m, 3H),
1.76 (s, 3H), 1.98 (s, 3H), 2.12 (m, 4H), 2.5-2.7
(M, 3H), 3.21 (s, 3H), 3.32 (s, 3H), 3.4−3.55 (m, 4
H), 4.05 (m, 2H), 4.27 (d, 1H, J = 9 Hz), 4.85 (br interchangeable, 2H), 5.13 (s, 1H), 5.85 (m, 2H), 6.22 (m, 1H) ,
6.57 (t, 1H, J = 11Hz), 6.88 (m, 2H), 7.08 (s, 1H), 7.2
6 (s, 1H), 7.53 (s, 1H), 9.09 (s, 1H); Mass spectrum m / z654 (M + 1) ; C 34 H 47 N 5 O 8 · 0.1CH 2 Cl 2 calculated the theoretical value from: C, 61.84; H, 7.18; N, 10.57%. Measurements: C, 61.90;
H, 7.49; 10.29%. Example 32 17-amino-22- (4 -'- fluorophenacyl) -17
-Demethoxygeldanamycin 17-amino-17-demethoxydanamycin (0.254 g,
0.465 mmol) was dissolved in 5 ml of anhydrous dimethyl sulfoxide in a flame dried glassware. Potassium t-butoxide (0.054 g, 0.468 mmol) was added and under nitrogen.
The solution was stirred at room temperature for 30 minutes. P-Fluorophenacyl bromide (0.102 g, 0.479 mmol) is added and the solution is allowed to stand at room temperature.
Stir for 1.5 hours. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate,
Filtered and evaporated in vacuo. The resulting purple residue was subjected to flash chromatography on silica gel, eluting with 2% methanol in chloroform, to give a purple solid; yield 0.270 g (66%): mp 183-185 ° C.
(Decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.61 (d, J = 7 Hz, 2
_{H, 14-CH 3),} 078 (Rb m, 1H, H-13), 0.93 (d, J = 7Hz, 3
_{H, 10-CH 3),} 1.30 (s, 3H, 8-CH 3), 1.49 (br m, 1H, H-1
3), 1.82 (dd, J = 15Hz and 4Hz, 1H, H-15), 1.92 (s, 3
_{H, 2-CH 3),} 2.02 (br s, 1H, 11-OH), 2.20 (br m, 2H, H
−10 and H−14), 2.77 (dd, J = 15Hz and 4Hz, 1H, H
−15), 2.84 (br d, J = 10 Hz, 1H, H−12), 3.23 (s, 3H, OC
_{H 3), 3.27 (s,} 3H, OCH 3), 3.54 (d, J = 9Hz, 1H, H-11),
4.19 (t, J = 9Hz, 1H, H-6), 4.41 (d, J = 16Hz, 1H, α-C
_{H 2), 4.95 (d,} J = 9Hz, 1H, H-7), 4.97 (s, 2H, NH 2), 5.
12 (d, J = 8Hz, 1H, H-9), 5.20 (t, J = 9Hz, 1H, H-5),
5.40 (br s, 2H, NH ₂ ), 5.84 (s, 1H, H-19), 5.96 (d, J =
_{17Hz, 1H, α-CH 2} ), 6.35 (t, J = 10Hz, 1H, H-4), 7.03
(D, J = 13Hz, 1H, H-3), 7.12 (m, 2H, aromatic), 7.99
(M, 2H, ^{aromatic); m / z704 (M +} + Na); IR (KBr, cm -1) 172
_{2,1691,1675,1659,1580,1504; C 36 H 44 N 33} O 9 F calculated the theoretical value from: C, 63.42; H, 6.51 ; N, 6.16%. Measurements: C, 63.40;
H, 6.65; N, 5.84%. The compounds of Examples 33 to 45 were prepared from the appropriately substituted phenacyl bromides by the method of Example 32.

Example 33 17-amino-22- (2 ', 4'-diethylphenacyl)-
17-Demethoxygeldanamycin The residue obtained by evaporation of the ethyl acetate is purified by Chromatotron ™ using 2% methanol in chloroform and again 1% methanol in chloroform to give a substantially pure product. The containing fractions were obtained and evaporated in vacuo to give a red solid which was purified by preparative HPLC on a Zorbax ™ column eluting with 54: 1: 45 ethyl acetate: methanol: hexanes. Further purification. The fractions containing the pure material were evaporated in vacuo, then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark pinkish-red solid; yield 0.002 g (0.6
%) Mp 154 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.55 (d, J = 6 Hz, 3
_{H, 14-CH 3),} 0.89 (d, J = 6Hz, 3H, 10-CH 3), 2.76 (m, 2
H, H-10, H-15), 3.04-3.19 (m, 1H, H-12), 3.11 (s, 3
_{H, OCH 3), 3.17 (} s, 3H, OCH 3), 3.47 (m, 1H, H-11), 4.12
(T, J = 7Hz, 1H, H-6), 4.21 (d, J = 15Hz, 1H, α-CH),
4.43 (br s, 2H, NH ₂ ), 4.83 (d, J = 7Hz, 1H, H-7), 4.89
−5.07 (m, 2H, NH ₂ ), 5.04 (d, J = 7 Hz, 1H, H-9), 5.10
(T, J = 7Hz, 1H, H-5), 5.71 (d, J = 15Hz, 1H, α-CH),
5.80 (s, 1H, H-19), 6.22 (t, J = 7Hz, 1H, H-4), 6.81
-7.03 (m, 3H, H- 3, aromatic), 7.5 (d, J = 7Hz, 1H, ^{aromatic); m / z714 (M +} + Na); IR (KBr, cm -1) 1720,1670, 165
5,1580; C ₃₈ H ₄₉ O ₉・ 0.5H ₂ O Calculated from C: 65.12;
H, 7.19; N, 6.07%. Found: C, 55.38; H, 6.89; N, 5.99%. Example 34 17-amino-22- (2'-methoxyphenacyl) -17-
Demethoxygernamycin yield 0.110 g (34%): mp 165-168 ° C; ¹ H-NMR (300 MHz,
CDCl ₃ ) δ 0.72 (d, J = 7 Hz, 3H, 14-CH ₃ ), 0.84 (m, 1H, H
-13), 1.03 (d, J = 7Hz, 3H, 10-CH 3), 1.40 (s, 3H, 8-C
_{H 3), 1.49 (m,} 1H, H-13), 1.90 (dd, J = 12Hz and 4 Hz,
1H, H-15), 2.03 (s, 3H, 2-CH 3), 2.24 (br m, 2H, H-10
And H-14), 2.41 (s, 1H, 11-OH), 2.94 (m, 2H, H-1
2 and H-15), 3.30 (s , 3H, OCH 3), 3.34 (s, 3H, OC
_{H 3), 3.62 (d,} J = 8Hz, 1H, H-11), 3.97 (s, 3H, OCH 3),
4.28 (t, J = 10Hz, 1H, H-6), 4.51 (d, J = 19Hz, 1H, α-
CH ₂ ), 4.60 (br s, 2H, NH ₂ ), 5.02 (d, J = 10 Hz, 1 H, H−
7), 5.10 (br s, 2H, NH 2), 5.20 (d, J = 9Hz, 1H, H-
9), 5.27 (t, J = 12 Hz, 1H, H-5), 5.86 (d, J = 17 Hz, 1
H, α-CH ₂ ), 5.98 (s, 1H, H-19), 6.40 (t, J = 13 Hz, 1H,
H-4), 7.03 (m, 2H, aromatic), 7.56 (m, 1H, aromatic), 7.
90 (m, 1H, aromatic); m / z 694 (M ⁺ ); IR (KBr, cm- ¹ ) 1732,
1678,1661,1584. Example 35 17-amino-22- (3'-methoxyphenacyl) -17-
Demethoxygeldanamycin The residue obtained by evaporation of the ethyl acetate was dissolved in 1 ml of chloroform and precipitated with hexanes to give a salmon-coloured solid; yield 0.151 g (48%): mp 165-168. ° C; ¹ H-NMR (300
_{MHz, CDCl 3) δ0.67 (d} , J = 9Hz, 3H, 14-CH 3), 0.78 (m, 1
H, H-13), 0.98 (d, J = 9Hz, 3H, 10-CH 3), 1.32 (s, 3H, 8
−CH ₃ ), 1.43 (m, 1H, H-13), 1.83 (dd, J = 15 Hz and 5
Hz, 1H, H-15) , 1.92 (s, 3H, 2-CH 3), 2.10-2.27 (br
m, 2H, H-10 and H-14), 2.42 (s, 1H, 11-OH), 2.82
−2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OC
_{H 3), 3.28 (s,} 3H, OCH 3), 3.58 (d, J = 11Hz, 1H, H-11),
_{3.81 (s, 3H, OCH 3} ), 4.22 (t, J = 10Hz, 1H, H-6), 4.40
(D, J = 18Hz, 1H, α-CH ₂ ), 4.68 (br s, 2H, NH ₂ ), 4.99
(D, J = 9Hz, 1H , H-7), 5.15 (br s, 2H, NH 2), 5.16 (d,
J = 11Hz, 1H, H-9), 5.21 (t, J = 11Hz, 1H, H-5), 5.90
(S, 1H, H-19 ), 5.97 (d, J = 17Hz, 1H, α-CH 2), 6.35
(T, J = 12Hz, 1H, H-3), 7.2 (d, J = 11Hz, 1H, H-3),
7.12 (dd, J = 8 Hz and 5 Hz, 1 H, aromatic), 7.38 (t, J = 10
Hz, 1H, aromatic), 7.42 (d, J = 6 Hz, 1H, aromatic), 7.49 (d
d, J = 8 Hz and 5 Hz, IH, ^{aromatic): m / z716 (M +} + Na); IR
^{_{(CH 2 Cl 2, cm -1}} ) 1733,1672,1661,1585. Example 36 17-Amino-22-(4'-methoxyphenacyl) -17
Demethoxygeldanamycin The residue obtained by evaporation of ethyl acetate was dissolved in 1 ml of chloroform and precipitated with hexanes to give a salmon-colored solid; yield 0.205 g (64%): mp175-178. ° C; ¹ H-NMR (300
MHz, CDCl ₃ ) δ 0.65 (d, J = 9 Hz, 3H, 14-CH ₃ ), 0.76 (m, 1
H, H-13), 0.98 (d, J = 8Hz, 3H, 10-CH 3), 1.32 (s, 3H, 8
−CH ₃ ), 1.43 (m, 1H, H-13), 1.82 (dd, J = 15 Hz and 5
Hz, 1H, H-15) , 1.92 (s, 3H, 2-CH 3), 2.10-2.28 (br
m, 2H, H-10 and H-14), 2.40 (s, 1H, 11-OH), 2.81
−2.89 (m, 2H, H-12 and H-15), 3.22 (s, 3H, OC
_{H 3), 3.28 (s,} 3H, OCH 3), 3.57 (d, J = 13Hz, 1H, H-11),
_{3.83 (s, 3H, -OCH 3} ), 4.21 (t, J = 11Hz, 1H, H-6), 4.3
6 (d, J = 17 Hz, 1 H, α-CH ₂ ), 4.67 (br s, 2 H, NH ₂ ), 4.98
(D, J = 10Hz, 1H , H-7), 5.11 (br s, 2H, NH 2), 5.13
(D, J = 12Hz, 1H, H-9), 5.21 (t, J = 12Hz, 1H, H-5),
5.89 (s, 1H, H- 19), 5.94 (d, J = 18Hz, 1H, α-CH 2), 6.
33 (t, J = 13 Hz, 1H, H-4), 6.91 (m, 2H, aromatic), 7.08
(D, J = 13 Hz, 1H, H-3), 7.89 (m, 2H, aromatic); m / z 691
(M ⁺ ) and 713 (M ⁺ + Na); IR (CH ₂ Cl ₂ , cm ⁻¹ ) 1732,16
73,1661,1586,1507. Example 37 17-Amino-22- (2'-chlorophenacyl) -17-demethoxygeldanamycin The residue obtained by evaporation of the ethyl acetate was treated with 2-4 in chloroform. Centrifugally accelerated radial thin-layer chromatography (Chromatotro
Purification by n ^R) give a fraction containing the pure product,
This was evaporated in vacuo to give a red solid; yield 0.138 g
(43%): ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.72 (d, J = 7 Hz, 3
_{H, 14-CH 3),} 0.83 (m, 1H, H-13), 1.03 (d, J = 6Hz, 3H, 1
_{0-CH 3), 1.40 (} s, 3H, 8-CH 3), 1.49 (br m, 1H, H-1
3), 1.91 (dd, J = 13 Hz and 6 Hz, 1H, H-15), 1.99 (s, 3
_{H, 2-CH 3),} 2.18-2.31 (br m, 2H, H-10 and H-1
4), 2.43 (s, 1H , 11-OH), 2.38-2.46 (m, 2H, H-12 and H-15), 3.25 (s , 3H, OCH 3), 3.33 (s, 3H, OCH 3) , 3.6
3 (d, J = 8Hz, 1H, H-11), 4.22 (t, J = 10Hz, 1H, H-6),
4.49 (d, J = 19Hz, 1H, α-CH 2), 4.62 (br s, 2H, NH 2),
5.02 (d, J = 9Hz, 1H, H-7), 5.19 (s, 2H, NH 2), 5.21
(D, J = 12Hz, 1H, H-9), 5.30 (t, J = 11Hz, 1H, H-5),
5.40 (br s, 2H, NH ₂ ), 5.83 (d, J = 18Hz, 1H, α-CH ₂ ),
6.15 (s, 1H, H-19), 6.39 (t, J = 12Hz, 1H, H-4), 6.96
(D, J = 12Hz, 1H, H-3), 7.38-7.43 (m, 1H, aromatic),
7.48 (m, 2H, aromatic), 7.67 (m, 1H, aromatic), m / z 720 (M
^{+ + Na); IR (KBr} , cm -1) 1722,1680,1661,1590; C 36 H 44 Cl
N ₃ O ₉ calculated the theoretical value from: C, 61.93; H, 6.35 ; N, 6.02%. Found: C, 60.59; H, 6.18; N, 5.54%. Example 38 17-Amino-22- (4'-chlorophenacyl) -17-demethoxygeldanamycin The residue obtained by evaporation of ethyl acetate was dissolved in 2 ml of chloroform and precipitated with hexanes to give salmon. Color solid was obtained; yield 0.087 g (27%): mp 175-178 ° C .; ¹ H-NMR (300
MHz, CDCl ₃ ) δ0.66 (d, J = 7Hz, 14−CH ₃ ), 0.76 (m, 1H, H
-13), 0.98 (d, J = 6Hz, 3H, 10-CH 3), 1.33 (s, 3H, 8-C
_{H 3), 1.43 (m,} 1H, H-13), 1.83 (dd, J = 15Hz and 4 Hz,
1H, H-15), 1.95 (s, 3H, 2-CH 3), 2.10-2.27 (br m, 2
H, H-10 and H-14), 2.41 (s, 1H, 11-OH), 2.81-2.
89 (m, 2H, H- 12 and H-15), 3.22 (s , 3H, OCH 3), 3.3
0 (s, 3H, OCH ₃ ), 3.58 (d, J = 11Hz, 1H, H-11), 3.81 (s,
3H, OCH ₃ ), 4.21 (t, J = 10Hz, 1H, H-6), 4.36 (d, J = 17
Hz, 1H, α-CH ₂ ), 4.54 (br s, 2H, NH ₂ ), 4.99 (d, J = 10H
z, 1H, H-7) , 5.13 (br s, 2H, NH 2), 5.15 (d, J = 10Hz, 1
H, H-9), 5.22 (t, J = 12Hz, 1H, H-5), 5.89 (s, 1H, H
−19), 5.97 (d, J = 17 Hz, 1 H, α-CH ₂ ), 6.34 (t, J = 12 H
z, 1H, H-4), 7.01 (d, J = 12Hz, 1H, H-3), 7.43 (d, J
= 9Hz, 2H, aromatic), 7.87 (d, J = 9Hz, 2H, aromatic); m / z 72
^{0 (M + + Na);} . IR (CH 2 Cl 2, cm -1) 1733,1677,1662,1584 obtained by evaporation of Example 39 17-Amino-22-phenacyl-demethoxygeldanamycin ethyl acetate The residue obtained was purified by Chromatotron ™ using 2% methanol in chloroform to give a fraction containing the pure product, which was evaporated in vacuo to give a red solid; 0.161 g (53%) mp188-
191 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.68 (d, J =
_{5Hz, 3H, 14-CH 3} ), 0.80 (m, 1H, H-13), 0.98 (d, J = 5H
_{z, 3H, 10-CH 3} ), 1.35 (s, 3H, 8-CH 3), 1.43 (m, 1H, H-1
3), 1.85 (dd, J = 3 Hz, J = 10 Hz, 1H, H-15), 1.96 (s, 3H,
_{2-CH 3), 2.11-2.29 (} br m, 2H, H-10, H-14), 2.39
(S, 1H, 11-OH), 2.85 (m, 2H, H-12, H-15), 3.21 (s, 3
H, OCH ₃ ), 3.26 (s, 3H, OCH ₃ ), 3.60 (dd, J = 3Hz, J = 7Hz,
1H, H-11), 4.21 (t, J = 9Hz, 1H, H-6), 4.39 (d, J = 15
Hz, 1H, α-CH), 4.61 (br s, 2H, NH ₂ ), 5.03-5.19 (m, 2
_{H, NH 2), 5.16 (} d, J = 8Hz, 1H, H-9), 5.71 (t, J = 8Hz, 1
H, H-5), 5.89 (s, 1H, H-19), 6.00 (d, J = 15Hz, 1H, α
−CH), 6.35 (t, J = 8 Hz, 1H, H-4), 7.05 (d, J = 8 Hz, 1
H, H-3), 7.46 (d, J = 6Hz, 2H, aromatic), 7.60 (d, J = 6H
z, 1H, aromatic), 7.93 (d, J = 6Hz, 2H, aromatic); m / z686 (M
⁺ + Na), 664 (M ⁺ + H); IR (KBr, cm ^-1 ) 1720, 1670, 165
5,1580.C Theoretical value calculated from ₃₆ H ₄₅ N ₃ O ₉ , 0.5 H ₂ O: C, 64.2
7; H, 6.89; N, 6.27%. Found: C, 64.13; H, 6.33; N, 6.19
%. Example 40 17-amino-22- (3 ', 4'-dichlorophenacyl)-
17-Demethoxygeldanamycin The residue obtained by evaporation of ethyl acetate was purified using Zorbax,
Further purification by preparative HPLC eluting with 59: 1: 40 ethyl acetate: methanol: hexanes. The fractions containing the pure material were evaporated in vacuo, then dissolved in a minimal amount of chloroform and precipitated with hexanes to give a dark pinkish red solid; yield 0.134 g (40%) mp176-1
78 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.63 (d, J = 7 Hz, 3H, 14
−CH ₃ ), 0.74 (m, 1H, H−13), 0.98 (d, J = 8 Hz, 3H, 10−C
_{H 3), 1.31 (s,} 3H, 8-CH 3), 1.42 (m, 1H, H-13), 1.82
(Dd, J = 15Hz and 5Hz, 1H, H-15), 1.92 (s, 3H, 2-C
_{H 3), 2.09-2.24 (br m} , 2H, H-10 and H-14), 2.42
(S, 1H, 11-OH), 2.78-2.88 (m, 2H, H-12 and H-1
5), 3.21 (s, 3H , OCH 3), 3.27 (s, 3H, OCH 3), 3.57 (d, J
= 10Hz, 1H, H-11), 4.18 (t, J = 11Hz, 1H, H-6), 4.36
(D, J = 19Hz, 1H , α-CH 2), 4.69 (br s, 2H, NH 2), 4.98
(D, J = 11Hz, 1H, H-7), 5.12 (d, J = 11Hz, 1H, H-9),
5.16 (br s, 2H, NH ₂ ), 5.21 (t, J = 11Hz, 1H, H-5), 5.8
5 (s, 1H, H- 19), 5.92 (d, J = 18Hz, 1H, α-CH 2), 6.34
(T, J = 12Hz, 1H, H-3), 6.98 (d, J = 12Hz, 1H, H-3),
7.57 (d, J = 9 Hz, aromatic), 7.76 (dd, J = 9 Hz and 4 Hz, 1
H, aromatic), 8.01 (d, J = 4 Hz, 1H, aromatic); m / z732
(M ⁺ ); IR (CH ₂ Cl ₂ , cm ⁻¹ ) 1731,1704,1673,1661,1583. Example 41 17-amino-22- (4′-aminophenacyl) -17-demethoxygeldana Mycin The product obtained from 4-aminophenacyl chloride was a pink solid. Yield 0.066 g (21%) mp 188 ° C. (decomposition); ¹ H-NMR (300 MH, CDCl ₃ ) δ 0.71 (d, J = 8 Hz, 3 H, 14
−CH ₃ ), 0.86 (br m, 1H, H-13), 1.04 (d, J = 8 Hz, 3H, 10
_{-CH 3), 1.39 (s,} 3H, 8-CH 3), 1.49 (br m, 1H, H-13),
1.90 (dd, J = 13Hz, 5Hz, 1H, H-15), 2.00 (s, 3H, 2-C
_{H 3), 2.22 (br m} , 2H, H-10, H-14), 2.48 (br s, 1H, -O
H), 2.92 (m, 2H, H-12 and H-15), 3.29 (s, 3H, OC
_{H 3), 3.33 (s,} 3H, OCH 3), 3.62 (d, J = 10Hz, 1H, H-11),
_{4.28 (s, 2H, NH 2} ), 4.29 (t, J = 9Hz, 1H, H-6), 4.37
(D, J = 18Hz, 1H , α-CH 2), 4.75 (br s, 2H, NH 2), 5.03
(D, J = 9Hz, 1H , H-7), 5.18 (br s, 2H, NH 2), 5.21 (d,
J = 9Hz, 1H, H-9), 5.26 (t, J = 13Hz, 1H, H-5), 5.95
(D, J = 18Hz, 1H , α-CH 2), 5.96 (s, 1H, H-19), 6.49
(T, J = 10Hz, 1H, H-4), 6.66 (d, J = 9Hz, 2H, aromatic),
7.18 (d, J = 13Hz, 1H, H-3), 7.78 (d, J = 9Hz, 2H, ^{aromatic); m / z701 (M +} + Na); IR (KBr, cm -1) 1718,1708, 165
Example 42 17-Amino-22- (4'-cyanophenacyl) -17-demethoxygeldanamycin The residue obtained by evaporation of ethyl acetate was applied to a Zorbax column at 59: 1: 40. Further purification by preparative HPLC eluting with a mixture of ethyl acetate: methanol: hexanes. The fractions containing the pure material were evaporated in vacuo, then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark pinkish-red solid; yield 0.
0296 g (8.4%) mp 186 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl
₃ ) δ0.71 (d, J = 6Hz, 3H, 14−CH ₃ ), 0.83 (br m, 1H, H−
13), 1.04 (d, J = 6Hz, 3H, 10-CH 3), 1.39 (s, 3H, 8-C
_{H 3), 1.48 (m,} 1H, H-13), 1.90 (dd, J = 11Hz and 5 Hz,
1H, H-15), 1.99 (s, 3H, 2-CH 3), 2.25 (br m, 2H, H-10
And H-14), 2.41 (s, 1H, -OH), 2.92 (m, 2H, H-12
And H-15), 3.27 (s , 3H, OCH 3), 3.34 (s, 3H, OC
_{H 3), 3.64 (d,} J = 11Hz, 1H, H-11), 4.23 (t, J = 10Hz, 1
H, H-6), 4.45 (d, J = 18Hz, 1H, α-CH 2), 4.61 (br s,
_{2H, NH 2), 5.05 (} d, J = 10Hz, 1H, H-7), 5.20 (br s, 2H,
_{NH 2), 5.21 (d,} J = 11Hz, 1H, H-9), 5.29 (t, J = 11Hz, 1
H, H-5), 5.96 (s, 1H, H-19), 6.02 (d, J = 18Hz, 1H, α
−CH ₂ ), 6.40 (t, J = 11 Hz, 1H, H-4), 7.00 (d, J = 11H
z, 1H, H-3), 7.84 (d, J = 8Hz, 2H, aromatic), 8.08 (d, J
= 8 Hz, 2H, ^{aromatic); m / z712 (M +} + Na); IR (KBr, cm -1) 2
_{220,1721,1701,1672,1655,1580; C 36 H 44 N 4} O 11 calculated the theoretical value from: C, 64.52; H6.44; N , 8.13%. Measurements: C, 58.56; H,
5.81; N, 7.33%. Example 43 17-amino-22- (2'-nitrophenacyl) -17-demethoxygeldanamycin Yield 0.0689 g (21%) mp 165 ° C (decomposition); ¹ H-NMR (300 M
Hz, CDCl ₃ ) δ 0.70 (d, J = 7 Hz, 3H, 14-CH ₃ ), 0.82 (m, 1
H, H-13), 1.03 (d, J = 7Hz, 3H, 10-CH 3), 1.40 (s, 3H, 8
−CH ₃ ), 1.52 (m, 1H, H-13), 1.90 (dd, J = 14 Hz and 4
Hz, 1H, H-15) , 2.00 (s, 3Hz, 2-CH 3), 2.08 (s, 1H, 11-
OH), 2.26 (br m, 2H, H-10 and H-14), 2.90 (m, 2H,
H-12 and H-15), 3.19 (s , 3H, OCH 3), 3.33 (s, 3H, O
CH ₃ ), 3.64 (d, J = 10 Hz, 1H, H-11), 4.15 (t, J = 10 Hz, 1
H, H-6), 4.42 (d, J = 18Hz, 1H, α-CH 2), 5.01 (d, J =
10Hz, 1H, H-7) , 5.10 (br s, 2H, NH 2), 5.20 (d, J = 9H
z, 1H, H-9) , 5.23 (br s, 2H, NH 2), 5.26 (t, J = 13Hz, 1
H, H-5), 5.63 (d, J = 18Hz, 1H, α-CH 2), 6.38 (t, J =
12Hz, 1H, H-7), 6.52 (s, 1H, H-19), 6.87 (d, J = 12H
z, 1H, H-3), 7.63 (m, 1H, aromatic), 7.69 (m, 1H, aromatic), 7.80 (m, 1H, aromatic), 8.20 (m, 1H, aromatic); m / z73
1 (M ⁺⁺ Na); IR (KBr, cm- ¹ ) 1718,1671,1657,1580,152
_{1; (C 36 H 44 N} 4 O 11) calculated the theoretical value from: C, 61.00; H, 6.2
6; N, 7.91%. Found: C, 59.92; H, 6.10; N, 7.71%. Example 44 17-amino-22- (3'-nitrophenacyl) -17-demethoxygeldanamycin Yield 0.0225 g (6.9%): ¹ H-NMR (300 MHz, CDCl ₃ ) δ
0.71 (d, J = 8Hz, 3H, 14-CH 3), 0.88 (m, 1H, H-13), 1.0
4 (d, J = 8Hz, 3H, 10-CH 3), 1.34 (s, 3H, 8-CH 3), 1.42
(M, 1H, H-13), 1.90 (dd, J = 13Hz and 5Hz, 1H, H-1
5), 2.00 (s, 3H , 2-CH 3), 2.25 (br m, 2H, H-10 and H-14), 2.42 (br s, 1H, -OH), 2.93 (m, 2H, H- 12 and H-15), 3.29 (s , 3H, OCH 3), 3.34 (s, 3H, OCH 3), 3.6
4 (d, J = 10Hz, 1H, H-11), 4.23 (t, J = 9Hz, 1H, H-6),
4.52 (d, J = 18Hz, 1H, α-CH 2), 4.62 (br s, 2H, NH 2),
5.06 (d, J = 9Hz, 1H, H-7), 5.15 (br s, 2H, NH 2), 5.21
(D, J = 9Hz, 1H, H-9), 5.30 (t, J = 13Hz, 1H, H-5),
5.98 (s, 1H, H- 19), 6.06 (d, J = 18Hz, 1H, α-CH 2), 6.
41 (t, J = 9Hz, 1H, H-4), 7.00 (d, J = 13Hz, 1H, H-
3), 7.76 (t, J = 8 Hz, 1H, aromatic), 8.32 (d, J = 8 Hz, 1H,
Arom), 8.52 (d, J = 8Hz, 1H, aromatic), 8.83 (s, 1H, ^{aromatic); m / z731 (M +} + Na); IR (KBr, cm -1) 1719,1664,16
Example 45 17-Amino-22- (4'-nitrophenacyl) -17-demethoxygeldanamycin The residue obtained by evaporation of ethyl acetate was applied to a Zorbax column at 59: 1. Further purification by preparative HPLC eluting with: 40 ethyl acetate: methanol: hexanes. The fractions containing the pure material were evaporated in vacuo, then dissolved in a minimum amount of chloroform and precipitated with hexanes to give a dark pinkish-red solid; yield 0.0175 g (1.3
%): Mp; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.70 (d, J = 7 Hz, 3
_{H, 14-CH 3),} 0.82 (m, 1H, H-13), 1.02 (d, J = 7Hz, 3H, 1
_{0-CH 3), 1.38 (} s, 3H, 8-CH 3), 1.50 (m, 1H, H-13), 1.
90 (dd, J = 16Hz and 4Hz, 1H, H-15), 2.00 (s, 3H, 2-C
_{H 3), 2.25 (br m} , 2H, H-10 and H-14), 2.50 (br s,
1H, 11-OH), 2.89 (m, 2H, H-12 and H-15), 3.27
_{(S, 3H, OCH 3)} , 3.33 (s, 3H, OCH 3), 3.63 (d, J = 10Hz, 1
H, H-11), 4.23 (t, J = 10Hz, 1H, H-6), 4.50 (d, J = 18
Hz, 1H, α-CH ₂ ), 4.77 (s, 2H, NH ₂ ), 5.03 (d, J = 10 Hz, 1
H, H-7), 5.20 (d, J = 11 Hz, 1H, H-9), 5.25 (brs, 2
_{H, NH 2), 5.28 (} t, J = 11Hz, 1H, H-5), 5.96 (s, 1H, H-1
9), 6.03 (d, J = 18 Hz, 1H, α-CH ₂ ), 6.40 (t, J = 12 Hz, 1
H, H-4), 6.99 (d, J = 12Hz, 1H, H-3), 8.15 (d, J = 9H
z, 2H, aromatic), 8.37 (d, J = 9Hz, 1H, aromatic); m / z731 (M
⁺ + Na); IR (KBr, cm ^-1 ) 1660, 1590. Example 46 17-amino-22 (4'-azidophenacyl) -17-demethoxygeldanamycin 17-amino-17-demethoxygeldanamycin ( 0.50
(0 g, 0.92 mmol) was dissolved in 25 ml of acetone (stored over potassium carbonate) and 1.27 g of potassium carbonate was added (9.17 mmol, 10 equivalents). The reaction was stirred in the dark for 24 hours, filtered, concentrated in vacuo to a residue, which was flash chromatographed over silica gel with 69: 1: 30 ethyl acetate: methanol: hexanes. The product was dissolved in 1 ml of chloroform and precipitated with hexanes to give a pinkish-red solid: yield 0.095 g (15
%): Mp 165-167; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.65 (d, J
= 8Hz, 3H, 14-CH 3), 0.76 (m, 1H, H-13), 0.97 (d, J = 8
_{Hz, 3H, 10-CH 3} ), 1.32 (s, 3H, 8-CH 3), 1.42 (m, 1H, H-
13), 1.82 (dd, J = 15Hz and 5Hz, 1H, H-15), 1.91 (s,
_{3H, 2-CH 3),} 2.09-2.27 (br m, 2H, H-10 and H-1
4), 2.41 (br s, 1H, 11-OH), 2.79-2.90 (m, 2H, H-12
And H-15), 3.21 (s , 3H, OCH 3), 3.27 (s, 3H, OC
_{H 3), 3.58 (d,} J = 11Hz, 1H, H-11), 4.20 (t, J = 10Hz, 1
H, H-6), 4.36 (d, J = 17Hz, 1H, α-CH 2), 4.65 (br s,
_{2H, NH 2), 4.98 (} d, J = 10Hz, 1H, H-7), 5.11 (br s, 2H,
_{NH 2), 5.14 (d,} J = 10Hz, 1H, H-9), 5.20 (t, J = 12Hz, 1
H, H-5), 5.89 (s, 1H, H-19), 5.95 (d, J = 17Hz, 1H, α
−CH), 6.33 (t, J = 13 Hz, 1H, H-4), 7.02 (d, J = 13 Hz,
1H, H-3), 7.08 (d, J = 9Hz, 2H, aromatic), 7.91 (d, J = 9
Hz, 2H, ^{aromatic); m / z705 (M +} + H); C 36 H 44 N 6 O 9 · 0.2H 2 O
, Calculated from: C, 58.37; H, 6.53; N, 11.34%. Found: C, 58.37; H, 5.85; N, 11.08% Example 47 17-Amino-22 (4'-amino-3'-iodophenacyl) -17-demethoxygeldanamycin Potassium chloride (0.022 g, 0.29 mmol) ) Was dissolved in 1 ml of water and poured into iodine monochloride (0.043 g, .27 mmol). This mixture was poured into a solution of the title compound of Example 41 (0.139 g, 0.2 mmol) in 24 ml of 0.1 N hydrochloric acid and 3 ml of methanol. After stirring at room temperature for 2 hours, the reaction was stopped with sodium bisulfite. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 3N hydrochloric acid, saturated sodium bicarbonate, water and brine, dried over magnesium sulfate,
Filtered. The residue obtained by removing the solvent was dissolved in 1 ml of chloroform and precipitated with hexanes to obtain a salmon-colored solid; yield 0.099 g (60%): ¹ H-NMR (300 MHz, CDCl ₃₎ )
δ0.66 (d, J = 7Hz, 3H, 14-CH 3), 0.75 (m, 1H, H-13),
0.98 (d, J = 6Hz, 3H, 10-CH 3), 1.34 (s, 3H, 8-CH 3), 1.
47 (m, 1H, H-13), 1.91 (m, 1H, H-15), 1.95 (s, 3H, 2-
_{CH 3), 2.10-2.29 (br m} , 2H, H-10 and H-14), 2.59
(S, 1H, 11-OH), 2.78-2.92 (m, 2H, H-12 and H-1
5), 3.25 (s, 3H , OCH 3), 3.29 (s, 3H, OCH 3), 3.59 (d, J
= 10Hz, 1H, H-11), 4.24 (t, J = 10Hz, 1H, H-6), 4.32
(D, J = 18Hz, 1H, α-CH ₂ ), 4.56 (s, 2H, NH ₂ ), 4.95 (d,
J = 10Hz, 1H, H- 7), 5.04 (br s, 2H, NH 2), 5.15 (d, J =
11Hz, 1H, H-9), 5.22 (t, J = 11Hz, 1H, H-5), 5.58 (b
rs, 2H, NH ₂ ), 5.88 (d, J = 18Hz, 1H, α-CH ₂ ), 5.89 (s,
1H, H-19), 6.37 (t, J = 12Hz, 1H, H-4), 6.60 (dd, J =
9Hz and 3Hz, 1H, aromatic, 7.06 (d, J = 12Hz, 1H, H-
3), 7.71 (dd, J = 9 Hz and 2 Hz, 1 H, aromatic), 8.22 (d
d, J = 2 Hz and 3 Hz, 1 H, aromatic) IR (KBr, cm ^-1 ) 1715,16
60,1610,1580. The pickling solution was neutralized with sodium bicarbonate and extracted with ethyl acetate. Washing the ethyl acetate extract with water and brine,
Dry over magnesium sulfate, filter and remove
41 title compounds were recovered in 0.045 g (27%) yield.

Example 48 17-amino-22 (4'-azido-3'-iodophenacyl) -17-demethoxygeldanamycin 17-amino-22 (4'-amino-
3'-Iodophenacyl) -17-demethoxygeldanamycin (0.036 g, 0.44 mmol) was dissolved in 89 ml of methanol, cooled to 0 ° C and protected from light. 45 to this solution
ml of 1N hydrochloric acid and 45 ml of 0.5N sodium nitrite were added. After stirring for 15 minutes, an additional 45 ml of 0.5N sodium azide was added and the reaction mixture was stirred at 0 ° C. for another 15 minutes. The resulting solution was extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried over magnesium sulfate, filtered and removed to give a red glass which was dissolved in 1 ml of ethyl acetate and precipitated with hexanes. Yield 0.027 g (72%): ¹ H-NMR (300 MHz, CDCl ₃ ) δ0.
69 (d, J = 7Hz, 3H, 14-CH 3), 0.79 (m, 1H, H-13), 1.03
(D, J = 8Hz, 3H , 10-CH 3), 1.50 (s, 3H, 8-CH 3), 1.89
(M, 2H, H-13 and H-15), 1.99 (s , 3H, 2-CH 3), 2.1
1-2.32 (br m, 2H, H-10 and H-14), 2.53 (brs, 1
H, 11-OH), 2.81-2.95 (m, 2H, H-12 and H-15), 3.
_{28 (s, 3H, OCH 3} ), 3.32 (s, 3H, OCH 3), 3.62 (d, J = 9Hz, 1
H, H-11), 4.22 (t, J = 12Hz, 1H, H-6), 4.41 (d, J = 17
_{Hz, 1H, α-CH 2} ), 4.80 (br s, 2H, NH 2), 5.02 (d, J = 9H
z, 1H, H-7) , 5.16-5.31 (br s, 4H, NH 2, H-9, and H
-5), 5.92 (s, 1H, H-19), 5.99 (d, J = 18Hz, 1H, α-C
_{H 2), 6.40 (t,} J = 14Hz, 1H, H-4), 7.03 (d, J = 14Hz, 1
H, H-3), 7.12 (m, 1H, aromatic), 8.00 (m, 2H, aromatic),
8.40 (m, 1H, aromatic); IR (KBr, cm ^-1 ) 1722,1680,1661,1
580. The compounds of Examples 49 and 50 were prepared by the method of Example 32.

Example 49 17-amino-22 (4'phenylphenacyl) -17-demethoxygeldanamycin Yield 0.119 g (35%): mp 193-195 ° C (decomposition); ¹ H-NMR
(300MHz, CDCl ₃ ) δ0.72 (d, J = 7Hz, 3H, 14-CH ₃ ), 0.83
(M, 1H, H-13 ), 1.04 (d, J = 7Hz, 3H, 10-CH 3), 1.40
(S, 3H, 8-CH 3), 1.49 (m, 1H, H-13), 1.90 (dd, J = 16H
z and 5Hz, 1H, H-15) , 2.00 (s, 3H, 2-CH 3), 2.25 (br
m, 2H, H-10 and H-14), 2.47 (s, 1H, 11-OH), 2.91
(M, 2H, H-12 and H-15), 3.31 (s , 3H, OCH 3), 3.33
_{(S, 3H, OCH 3)} , 3.64 (d, J = 10Hz, 1H, H-11), 4.29 (t, J
= 10Hz, 1H, H-6 ), 4.49 (d, J = 18Hz, 1H, α-CH 2), 4.7
2 (br s, 2H, NH ₂ ), 5.04 (d, J = 10Hz, 1H, H-7), 5.17
(Br s, 2H, NH ₂ ), 5.21 (d, J = 11Hz, 1H, H-9), 5.28
(T, J = 11Hz, 1H, H-5), 5.99 (s, 1H, H-19), 6.09 (d,
J = 18Hz, 1H, α- CH 2), 6.41 (t, J = 12Hz, 1H, H-4), 7.
13 (d, J = 12Hz, 1H, H-3), 7.47 (m, 3H, aromatic), 7.12
(M, 3H, aromatic), 7.74 (d, J = 8Hz, 2H, aromatic), 8.05
(D, J = 8Hz, 2H , ^{aromatic); m / z731 (M +} + Na). Example 50 17-amino-22 (2-acetonaphthyl) -17-demethoxygeldanamycin The crude title compound prepared from 2- (2'-bromoacetyl) naphthalene was dissolved in 1 ml of chloroform and treated with hexanes. Precipitate to give salmon solid; yield 0.163g
(50%): mp 185-187 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.7
1 (d, J = 8Hz, 3H, 14-CH 3), 0.82 (m, 1H, H-13), 1.02
(D, J = 7Hz, 3H , 10-CH 3), 1.40 (s, 3H, 8-CH 3), 1.49
(M, 1H, H-13), 1.89 (dd, J = 15Hz and 5Hz, 1H, H-1
5), 2.00 (s, 3H , 2-CH 3), 2.22 (br m, 2H, H-10 and H-14), 2.44 (s , 1H, 11-OH), 2.91 (m, 2H, H- 12 and H-15), 3.30 (s , 3H, OCH 3), 3.33 (s, 3H, OCH 3), 3.5
1 (d, J = 11 Hz, 1H, H-11), 4.30 (t, J = 11 Hz, 1H, H-
6), 4.59 (d, J = 19 Hz, 1H, α-CH ₂ ), 4.68 (brs, 2H, NH
₂ ), 5.02 (d, J = 10 Hz, 1H, H-7), 5.15 (brs, 2H, N
_{H 2), 5.20 (d,} J = 13Hz, 1H, H-9), 5.28 (t, J = 13Hz, 1
H, H-5), 6.00 (s, 1H, H-19), 6.20 (d, J = 17Hz, 1H, α
−CH ₂ ), 6.40 (t, J = 12 Hz, 1H, H-4), 7.13 (d, J = 13 H
z, 1H, H-3), 7.54-7.68 (m, 2H, aromatic), 7.87-8.02
(M, 2H, aromatic), 8.51 (s, 1H, aromatic); m / z 714 (M ⁺ ) and 736 (M ⁺ + Na ⁺ ); IR (CH ₂ Cl ₂ , cm ⁻¹ ) 1733,1677, 166
Example 51 17-Azetidin-1-yl-11-α-fluoro-17-demethoxygeldanamycin 17-azetidin-1-yl-17-demethoxygeldana, which is the title compound of Example 18. Mycin (0.200g, 0.342
Mmol) into a flame dried flask under nitrogen.
Dissolved in 15 ml of methylene chloride. The mixture was cooled to −68 ° C. in an external dry ice / acetone bath and then DAST (0.055 g, 0.342 mmol, 0.045 g) in 2.5 ml of methylene chloride.
ml) solution was added dropwise. After 1 hour, 5 ml of 5% aqueous NaHCO ₃
Was added slowly and the product was extracted into 100 ml of methylene chloride. The organic layer was washed with 3 × 50 ml of water and 2 × 50 ml of brine, dried over MgSO ₄ , filtered and the solvent was removed to give a purple solid. This was purified by flash column chromatography using 5% methanol in chloroform. The desired product, a material with Rf = .42 (1: 9 methanol: chloroform) (0.058 g, 29%) was dissolved in a minimum amount of ethyl acetate and precipitated with hexanes; yield 0.042 g
(21%), mp 128 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ )
δ1.05 (m, 6H, 10- CH 3 and _{14-CH 3), 1.25 (} br t, J =
15Hz, 1H, H-13), 1.55 (brt, J = 15Hz, 1H, H-13), 1.78
(S, 3H, 8-CH 3), 1.96 (br m, 1H, H-14), 2.03 (s, 3H, 2
−CH ₃ ), 2.23 (dd, J = 8.5 Hz, 16 Hz, 1H, H−15), 2.40 (br
m, 2H, 3 'azetidine CH ₂ ), 2.55 (dd, J = 7Hz, 16Hz, 1H, H
−15), 2.80 (br d, J = 26 Hz, 1H, H−10), 3.35 (s, 3H, OC
_{H 3), 3.37's, 3H} , OCH 3), 3.53 (br m, 1H, H-12), 4.39
(D, J = 9Hz, 1H , H-6), 4.0 (br m, 7H, NH 2 and 2 'and 4' azetidine CH ₂ and H-11), 5.60 (d , J = 9H
z, 1H, H-9), 5.70 (s, 1H, H-7), 5.88 (t, J = 9Hz, 1H,
H-5), 6.55 (t, J = 9 Hz, 1H, H-4), 6.96 (d, J = 9 Hz, 1
H, H-3), 7.05 (s, 1H, H-19), 9.33 (s, 1H, NH-22); m
/z610.(M++Na);IR(KBr,cm ^-1) 1735,1690,1650; C
₃₁ H ₄₂ FN ₃ O ₇・ 5H ₂ O Calculated: C, 54.93; H, 7.73;
N, 6.20%. Found: C, 55.07; H, 6.23; N, 6.07%. The compounds of Examples 52-58 were prepared from the appropriately substituted 17-amino-17-demethoxygeldanamycin derivative in Example 51.
Prepared by the method described in

Example 52 17-amino-11-α-fluoro-17-demethoxygeldanamycin yield 0.155 g (44%), mp> 250 ° C. (decomposition); ¹ H-NMR (3
_{00MHz, CDCl 3) δ0.80 (d} , 3H, J = 8Hz, 10-CH 3), 0.90
(D, 3H, J = 8Hz , 14-CH 3), 0.93 (br m, 1H, H-13), 1.35
(Br t, 1H, H- 13), 1.60 (s, 3H, 8-CH 3), 1.85 (s, 3H, 2
_{-CH 3), 1.85 (br m} , 1H, H-14), 1.85-2.1 (br m, 2H, H
−15), 2.64 (br d, J = 26 Hz, 1H, H−10), 3.16 (s, 6H, OC
_{H 3), 3.26 (br m} , 1H, H-12), 4.28 (d, J = 9Hz, 1H, H-
6), 4.45 (br d, J = 47 Hz, 1H, H-11), 4.60 (br m, 2H, N
_{H 2), 4.95 (s,} 1H, H-7), 5.07 (br s, 2H, NH 2), 5.45
(D, J = 9 Hz, 1H, H-9), 5.70 (t, J = 9 Hz, 1H, H-5), 6.
35 (t, J = 9Hz, 1H, H-3), 6.80 (d, J = 9Hz, 1H, H-3),
7.05 (S, 1H, H-19), 9.0 (s, 1H, NH-22); m / z 570.
++ Na); IR (KBr, cm -1) 1715,1685,1670; C 28 H 38 FN 3 O 7
・ Theoretical value calculated from 0.25H ₂ O: C, 60.91; H, 7.03; N, 7.61
%. Found: C, 60.78; H, 6.87; N, 7.43%. Example 53 17-isopropylamino-11-α-fluoro-17-demethoxygeldanamycin yield 0.035 g (16%), mp 132 ° C .; ¹ H-NMR (300 MHz, CDCl
_{3) δ0.85 (m, 6H,} 10-CH 3, 14-CH 3), 0.85 (m, 1H, H-1
3), 1.07 and 1.11 (br d, J = 8Hz, 6H, isopropyl C
_{H 3), 1.38 (br m} , 1H, H-13), 1.60 (s, 3H, 8-CH 3), 1.7
1 (br m, 1H, H -14), 1.75 (s, 3H, 2-CH 3), 2.15 (dd, J
= 8.5Hz, 16Hz, 1H, H-15), 2.45 (dd, J = 7Hz, 16Hz, 1H, H
−15), 2.65 (br d, J = 26 Hz, 1H, H−10), 3.19 and 3.2
0 (br s, 6H, OCH 3), 3.35 (br m, 1H, H-12), 3.95 (m, 1
H, isopropyl CH), 4.22 (d, J = 9 Hz, 1H, H-6), 4.30
(Br d, J = 47Hz, 1H, H-11), 4.65 (br m, 2H, NH 2), 5.04
(S, 1H, H-7), 5.46 (d, J = 9 Hz, 1H, H-9), 5.73 (t, J
= 9Hz, 1H, H-5), 5.94 (br d, J = 10.5Hz, 1H, NH), 6.40
(T, J = 9Hz, 1H, H-4), 6.80 (d, J = 9Hz, 1H, H-3), 7.
05 (s, 1H, H-19), 9.15 (s, 1H, NH-22); m / z 612. (M +
+ Na); IR (KBr, cm -1) 1740,1705,1655; C 31 H 44 FN 3 O 7 ·
0.5H ₂ O Theoretical values calculated from C, 62.19; H, 7.57; N, 7.01%.
Found: C, 62.36; H, 7.48; N, 6.81%. Example 54 17-cyclopropylamino-11-α-fluoro-17-demethoxygeldanamycin yield 0.056 g (25%), mp 119 ° C. (decomposition); ¹ H-NMR (300
MHz, CDCl ₃ ) δ0.70 (m, 2H, cyclopropyl CH ₂ ), 0.86
(M, 3H, cyclopropyl CH ₂ and H-13), 0.92 (d , 3H,
_{J = 8Hz, 10-CH 3} ), 1.00 (d, 3H, J = 8Hz, 14-CH 3), 1.53
(Br m, 1H, H- 13), 1.70 (s, 3H, 8-CH 3), 1.95 (s, 3H, 2
−CH ₃ ), 2.00 (br m, 1H, H−14), 2.62 (dd, J = 8.5Hz, 16
Hz, 1H, H-15) 2.70 (br d, J = 26Hz, H-10), 2.80 (m, 1
H, cyclopropyl CH), 2.90 (dd, J = 7Hz, 16Hz, H-15),
_{3.33 (s, 6H, OCH 3} ), 3.45 (br m, 1H, H-12), 4.33 (d, J
= 9Hz, 1H, H-6), 4.36 (br d, J = 47Hz, 1H, H-11), 4.7
(Br m, 2H, NH ₂ ), 5.10 (s, 1H, H-7), 5.55 (d, J = 9Hz,
1H, H-9), 5.75 (t, J = 9Hz, 1H, H-5), 6.20 (br t, 1
H, NH), 6.46 (t, J = 9Hz, 1H, H-4), 6.90 (d, J = 9Hz, 1H
-H-3), 7.15 (s, 1H, H-19), 9.15 (s, 1H, NH-22);
m / z610. (M ++ Na); IR (KBr, cm- ¹ ) 1740, 1690, 1630; C
₃₁ H ₄₂ FN ₃ O ₇・ Theoretical value calculated from 1.5H ₂ O: C, 60.57; H, 7.3
7; N, 6.83%. Found: C, 60.43; H, 6.83%. Example 55 17-allylamino-11-α-fluoro-17-demethoxygeldanamycin yield 0.049 g (25%), mp 110-112 ° C .; ¹ H-NMR (300 MH
z, CDCl ₃ ) δ0.85 (d, 3H, J = 8Hz, 10−CH ₃ ), 0.88 (d, 3H,
_{J = 8Hz, 14-CH 3} ), 1.45 (br m, 2H, H-13), 1.63 (s, 3H,
_{8-CH 3), 1.86 (} s, 3H, 2-CH 3), 1.88 (br m, 1H, H-1
4), 2.20 (dd, J = 8.5 Hz, 15 Hz, 1H, H-15), 2.55 (dd, J =
7Hz, 16Hz, 1H, H-15), 2.80 (br d, J = 26Hz, 1H, H-10),
_{3.20 (s, 6H, OCH 3} ), 3.33 (br m, 1H, H-12), 3.95 (bt
t, 2H, Arles property _{CH 2), 4.23 (d,} J = 9Hz, 1H, H-6), 4.26
(Br d, J = 49Hz, 1H, H-11), 4.57 (br m, 2H, NH 2), 5.03
(S, 1H, H-7 ), 5.15 (br d, 2H, vinylic CH _2), 5.45
(D, J = 9 Hz, 1H, H-9), 5.55 (m, 2H, H-5 and vinyl CH), 6.10 (br t, 1H, NH), 6.40 (t, J = 9 Hz, 1H, H −
4), 6.80 (dS, J = 9 Hz, 1H, H-3), 7.07 (s, 1H, H-1
9), 9.13 (s, 1H, NH-22); m / z 608. (M ++ Na); IR (KB
^{r, cm -1) 1740,1700,1655; C} 31 H 42 FN 3 O 7 · 0.75H 2 O calculated from the theoretical value: C, 61.93; H, 7.24 ; N, 6.98%. Measured value: C, 61.
87, H, 6.93; N, 7.00%. Example 56 17-propargylamino-11-α-fluoro-17-demethoxygeldanamycin yield 0.051 g (27%), mp 111 ° C. (decomposition); ¹ H-NMR (300
_{MHz, CDCl 3) δ0.83 (br} m, 1H, H-13), 0.95 (d, 3H, J = 8
Hz, 10−CH ₃ ), 0.98 (d, 3H, J = 8 Hz, 14−CH ₃ ), 1.53 (br
m, 1H, H-13) , 1.73 (s, 3H, 8-CH 3), 1.95 (s, 3H, 2-C
H ₃ ), 1.94 (br m, 1H, H-14), 2.35 (s, 1H, acetylene C
H), 2.35 (dd, J = 8.5 Hz, 16 Hz, 1H, H-15), 2.58 (dd, J =
7Hz, 16Hz, 1H, H-15), 2.65 (br d, 1H, H-10), 3.3 (s, 6
_{H, OCH 3), 3.45 (} br m, 1H, H-12), 4.20 (br s, 2H, propargyl _{CH 2), 4.33 (d,} J = 9Hz, 1H, H-6), 4.36 (br
d, J = 47Hz, 1H, H-11), 4.8 (br m, 2H, NH 2), 5.13 (s, 1
H, H-7), 5.57 (d, J = 9Hz, 1H, H-9), 5.85 (t, J = 9H
z, 1H, H-5), 6.13 (br t, 1H, NH), 6.50 (t, J = 9Hz, 1H,
H-4), 6.90 (d, J = 9 Hz, 1H, H-3), 7.20 (s, 1H, H-1
9), 9.13 (s, 1H, NH-22); m / z 608. (M ++ Na); IR (KB
^{r, cm -1) 2120,1735,1695,1635; C} 31 H 40 FN 3 O 7 · 0.75H 2 O calculated from the theoretical value: C, 62.14; H, 6.98 ; N, 7.01%. measured value:
C, 61.99; H, 6.71; N, 6.90%. Example 57 17- (2'-cyanoethylamino) -11-α-fluoro-17-demethoxygeldanamycin Yield 0.026 g (14%), mp 122-24 ° C. (decomposition); ¹ H-NMR
(300 MHz, CDCl ₃ ) δ 1.15 (br m, 1H, H-13), 1.12 (d, 3
H, J = 8Hz, 10- CH 3), 1.17 (d, 3H, J = 8Hz, 14-CH 3), 1.6
5 (br t, 1H, H -13), 1.75 (s, 3H, 8-CH 3), 1.90 (s, 3H,
2-CH ₃ ), 2.1 (br m, 1H, H-14), 2.40 (dd, J = 8.5 Hz, 16
Hz, 1H, H-15), 2.65 (dd, J = 7Hz, 16Hz, 1H, H-15), 2.83
(T, J = 8Hz, 2H, β-ethyl CH ₂ ), 2.93 (br d, J = 26Hz, 1
H, H-10), 3.46 (s, 6H, OCH 3), 3.45 (br m, 1H, H-12),
3.56 (q, J = 8 Hz, 2H, α-ethyl CH ₂ ), 4.46 (d, J = 9 Hz, 1
H, H-6), 4.55 (br d, J = 47Hz, 1H, H-11), 4.85 (br
_{m, 2H, NH 2),} 5.26 (s, 1H, H-7), 5.73 (d, J = 9Hz, 1H, H
-9), 6.00 (t, J = 9 Hz, 1H, H-5), 6.07 (br t, 1H, N
H), 6.65 (t, J = 9Hz, H-4), 7.07 (d, J = 9Hz, 1H, H-
3), 7.35 (s, 1H, H-19), 9.25 (s, 1H, NH-22); m / z 62
3. (M ++ Na); IR (KBr, cm ^-1 ) 2350, 1730, 1695, 1630; C
₃₁ H ₄₁ FN ₄ O ₇ Calculated: C, 61.99; H, 6.88; N, 9.33
%. Found: C, 61.52; H, 6.91; N, 9.25%. Example 58 17- (2'-Fluoroethylamino) -11-α-fluoro-17-demethoxygeldanamycin Yield 0.064 g (32%), mp 134 ° C (decomposition); ¹ H-NMR (300
_{MHz, CDCl 3) δ1.05 (br} m, 1H, H-13), 1.03 (d, 3H, J = 8
_{Hz, 10-CH 3),} 1.07 (d, 3H, J = 8Hz, 14-CH 3), 1.57 (br
t, 1H, H-13) , 1.77 (s, 3H, 8-CH 3), 2.0 (br m, 1H, H-1
4), 2.05 (s, 3H , 2-CH 3), 2.35 (dd, J = 8.5Hz, 16Hz, 1H,
H-15), 2.63 (dd, J = 7 Hz, 16 Hz, 1H, H-15), 2.83 (br
d, J = 26Hz, 1H, H-10), 3.4 (s, 6H, OCH 3), 3.53 (br m, 1
H, H-12), 3.85 (two brdm, J = 27 Hz, 2H, α-ethyl C
_{H 2), 4.4 (d,} J = 9Hz, 1H, H-6), 4.45 (br d, J = 47Hz, 1
H, H-11), 4.65 (2 single brd t, J = 47Hz, 7Hz , 2H, β- ethyl _{CH 2), 4.75 (br m} , 2H, NH 2), 5.23 (s, 1H, H-7) ,
5.63 (d, J = 9 Hz, 1H, H-9), 5.90 (t, J = 9 Hz, 1H, H-
5), 6.25 (br t, 1H, NH), 6.57 (t, J = 9Hz, 1H, H-4),
6.97 (d, J = 9 Hz, 1H, H-3), 7.25 (s, 1H, H-19), 9.25
(S, 1H, NH-22); m / z 596. (M ++ Na); IR (KBr, cm ^-1 )
_{1740,1700,1630; C 30 H 41 F 2} N 3 O 7 calculated the theoretical value from: C, 6
0.69; H, 6.96; N, 7.07%. Measurements: C, 60.23; H, 6.99; N, 7.02
%. Example 59 11-α-Fluoro-geldanamycin The title compound was prepared from geldanamycin by the method of Example 51; yield 0.064 g (32%), mp 232 ° C. (dec); ¹ H-NMR (300 MHz). , CDCl ₃ ) δ0.87 (d, 3H, J = 8Hz, 10
−CH ₃ ), 1.00 (d, 3H, J = 8Hz, 14−CH ₃ ), 1.0 (br m, 1H, H
-13), 1.4 (br t, 1H, H-13), 1.73 (s, 3H, 8-CH 3), 1.
95 (s, 3H, 2- CH 3), 1.9 (br m, 1H, H-14), 2.25 (dd, 1
H, J = 7Hz, 16Hz, 1H, H-15), 2.45 (dd, J = 8.5Hz, 16Hz, 1
H, H-15), 2.75 (br d, J = 26Hz, 1H, H-10), 3.3 (s, 3H,
_{OCH 3), 3.34 (s,} 3H, OCH 3), 3.4 (br m, 1H, H-12), 4.05
(S, 3H, 17-OCH 3), 4.27 (d, J = 9Hz, 1H, H-6), 4.57
(Br d, J = 47Hz, 1H, H-11), 4.7 (br m, 2H, NH 2), 5.05
(S, 1H, H-7), 5.53 (d, J = 9Hz, 1H, H-9), 5.85 (t, J
= 9Hz, 1H, H-5), 6.50 (t, J = 9Hz, 1H, H-4), 6.85
(D, J = 9 Hz, 1H, H-3), 7.20 (s, 1H, H-19), 8.65 (s, 1
H, NH-22); m / z 585. (M ++ Na); IR (KBr, cm ^-1 ) 1740,
_{1705,1655; C 29 H 39 FN 2} O 8 · 0.25H 2 O calculated from the theoretical value:
C, 61.41; H, 7.02; N, 4.93%. Measurements: C, 61.03; H, 6.55; N,
4.92%. Example 60 17- (S) -2'-hydroxypropylamino-11-α
-Fluoro-17-demethoxygeldanamycin The title compound of Example 59 (0.307 g, 0.546 mmol)
Was slurried in 6 ml of chloroform and (S) -2-hydroxypropylamine (0.205 g, 2.73
Mmol). The reaction mixture was diluted with 50 ml of chloroform and washed with 3 × 50 ml of saline and 3 × 50 ml of water. The organic layer was dried over MgSO _4, filtered, and evaporated in vacuo to a purple solid. Pure product was obtained by flash column chromatography on silica gel, extracting with 3% methanol in chloroform; yield 0.070 g (21%), mp
119 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95 (br t,
7H, H-13 and 10-CH ₃ and γ- propyl CH _3), 1.25
(D, 3H, J = 8Hz , 14-CH 3), 1.50 (br t, 1H, H-13), 1.70
(S, 3H, 8-CH 3), 1.9 (br m, 1H, H-14), 1.97 (s, 3H, 2
−CH ₃ ), 2.33 (dd, J = 8.5 Hz, 16 Hz, 1H, H−15), 2.53 (d
d, J = 7Hz, 16Hz, 1H, H-15), 2.75 (br d, J = 26Hz, 1H, H-
10), 3.30 (s, 6H, OCH ₃ ), 3.30 (m, 1H, α-propyl C
H), 3.45 (br m, 1H, H-12), 3.57 (m, 1H, α-propyl C)
H), 4.0 (m, 1H, β-propyl CH), 4.33 (d, J = 9 Hz, 1H, H
-6), 4.37 (br d, J = 27 Hz, 1H, H-11), 4.75 (br m, 2
H, NH ₂ ), 5.15 (s, 1H, H-7), 5.55 (d, J = 9Hz, 1H, H-
9), 5.85 (t, J = 9 Hz, 1H, H-5), 6.43 (br t, 1H, NH),
6.50 (t, J = 9Hz, 1H, H-4), 6.90 (d, J = 9Hz, 1H, H-
3), 7.15 (s, 1H, H-19), 9.23 (s, 1H, NH-22); m / z 62
8. (M ++ Na); IR (KBr, cm -1) 1735,1695,1655; C 31 H 44
Theoretical value calculated from FN ₃ O ₈・ 0.25H ₂ O: C, 61.01; H, 7.35; N,
6.88%. Found: C, 60.90; H, 7.40; N, 6.74%. Example 61 17-allylamino-11-aminocarbonyl-17-demethoxygeldanamycin 17-allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) in 5 ml of chloride in a flame-dried flask under nitrogen. Dissolved in methylene and cooled to 0 ° C. Sodium isocyanide (0.311 g, 0.478 mmol) and trifluoroacetic acid (0.545 g, 4.78 mmol,
0.368 ml) was added during 10 minutes. After stirring at room temperature for 16 hours, the reaction mixture was diluted with 200 ml of water and extracted with 3 × 150 ml of chloroform. The combined organic layers were washed with 2 × 100 ml of water, dried over sodium sulfate, filtered and evaporated in vacuo to give a residue of 0.236 g, which was a 69: 1: 30 ethyl acetate: methanol: hexanes Flash chromatography on 80 g of silica gel, eluting with. The fractions containing the pure product were evaporated, dissolved in 2 ml of chloroform and then precipitated with hexanes; 0.062 g (2
9%) mp 214-216 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.93
(D, J = 8Hz, 3H , 10-CH 3), 0.98 (d, J = 8Hz, 3H, 14-C
_{H 3), 1.26 (br m} , 1H, H-13), 1.50 (m, 1H, H-13), 1.69
(S, 3H, 8-CH 3), 1.77 (br m, 1H, H-14), 1.96 (s, 3H, 2
_{-CH 3), 2.24 (dd,} J = 16Hz and 7Hz, 1H, H-15) , 2.56
(M, 1H, H-15), 2.85 (m, 1H, H-10), 3, 31 (s, 3H, OC
_{H 3), 3.22 (s,} 3H, OCH 3), 3.46 (br m, 1H, H-12), 4.05
(Br t, 2H, allylic CH ₂ ), 4.39 (br m, 2H, NH ₂ ), 4.43
(Br d, J = 9Hz, 1H, H-6), 4.71 (v br s, 2H, NH 2), 4.7
5 (m, 1H, H- 11), 5.15-5.3 (m, 4H, vinylic CH _2, H-7, H
-9), 5.73-5.9 (br m, 2H, H-5, vinyl CH), 6.15
(Br t, 1H, NH), 6.48 (t, J = 9Hz, 1H, H-4), 7.11 (s, 1
H, H-19), 7.23 (br m, 1H, H-3), 9.20 (s, 1H, NH-2)
2); m / z 651. (M ++ Na); IR (KBr, cm ^-1 ) 1740, 1725, 17
_{05,1680,1645,1585,1470; C 32 H 44 N 4} O 9 · 1.5H 2 O calculated from the theoretical value: C, 58.61; H, 7.22 ; N, 8.54%. Measurements: C, 58.5
0; H, 6.51; N, 8.48%. Example 62 17-azetidin-1-yl-11-N-BOC-β-alanyl-17-demethoxygeldanamycin Title compound of Example 18 17-azetidin-1-yl-17
-Demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 6 ml of dry methylene chloride and N-BOC-β
-Treated with alanine (0.077 g, 0.409 mmol), dicyclohexylcarbodiimide (0.084 g, 0.409 mmol) and dimethylaminopyridine (DMAP) (0.050 g, 0.409 mmol). After 24 hours, the mixture was filtered to remove dicyclohexylurea and concentrated in vacuo to a residue, which was dissolved in 200 ml of ethyl acetate and washed with 2 × 100 ml each of 1N hydrochloric acid, water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give a purple residue (0.240 g). This was chromatographed on silica gel eluting with 69: 1: 30 ethyl acetate: methanol: hexanes. Evaporation of the fractions containing the pure product gave a residue, which was dissolved in 1 ml of chloroform and precipitated with 100 ml of hexane; yield 0.098 g (38%) mp122-125.
° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.87 (d, J = 8 Hz, 3H, 10 −
_{CH 3), 0.95 (d,} J = 8Hz, 3H, 14-CH 3), 1.17 (m, 1H, H-1
3), 1.6 (m, 1H , H-14), 1.63 (s, 3H, 8-CH 3), 1.90 (m,
1H, H-15), 1.95 (s, 3H, 2-CH 3), 2.35 ( pent, J = 8H
z, 2H, 3'-azedin CH ₂ ), 2.46 (m, 2H, α-alanyl C
_{H 2), 2.6-2.8 (m,} 2H, H-15, H-10), 3.25 (s, 3H, OC
H ₃ ), 3.27 (s, 3H, OCH ₃ ), 3.35 (m, 2H, β-alanyl C
_{H 2), 3.66 (m,} 1H, H-12), 4.46 (d, J = 8Hz, 1H, H-6),
4.55 (t, J = 8Hz, 4H, 2 ' and 4' azetidine CH _2), 4.4
−4.9 (br s, 2H, NH ₂ ), 5.06 (d, J = 12Hz, 1H, H−11), 5.
15 (brt, 1H, alanyl NH), 5.27 (d, J = 11 Hz, 1H, H-
9), 5.53 (brs, 1H, H-7), 5.80 (t, J = 9.1 Hz, H-
5), 6.45 (t, J = 9 Hz, 1H, H-4), 6.90 (s, 1H, H-19),
7.00 (m, J = 9 Hz, 1H, H-3), 9.40 (s, 1H, NH-22); m / z7
59. (M ++ Na); IR (KBr, cm ^-1 ) 1732,1645,1583,1541,
_{1477; C 39 H 56 N 4} O 11 · 2H 2 O was calculated from the theoretical value: C, 59.08;
H, 7.63; N, 7.07%. Found: C, 59.20; H, 7.11; N, 7.16%. Example 63 17-azetidin-1-yl-11-β-alanyl-17-demethoxygeldanamycin The product of Example 62 (0.050 g, 0.066 mmol) was added in 1 ml
In trifluoroacetic acid at 0 ° C. After 10 minutes, the reaction mixture was evaporated to a residue in vacuo, which was dissolved in 0.3 ml of methanol and precipitated with 20 ml of isopropyl ether; 0.35 g (71%) mp 138-142 ° C .; ¹ H-NMR ( 300MHz, CDC
l ₃ ) δ 0.84 (d, J = 8 Hz, 3H, 10−CH ₃ ), 0.96 (d, J = 8 Hz, 3
_{H, 14-CH 3),} 1.24 (m, 1H, H-13), 1.55 (m, 1H, H-13),
1.61 (s, 3H, 8- CH 3), 1.94 (s, 3H, 2-CH 3), 1.96 (m, 1
H, H-15), 2.35 (pent, J = 8Hz, 2H, 3'-azetidine CH
₂ ), 2.6-2.8 (m, 4H, α-alanyl CH ₂ and H-15 and H-10), 3.18 (m, 2H, β-alanyl CH ₂ ), 3.25 (s, 6
H, OCH ₃ ), 3.65 (m, 1H, H-12), 4.43 (brs, 1H, H-6),
4.57 (m, 4H, 2 'and 4' azetidine CH _2), 5.0-5.5
(Br s, 2H, NH ₂ ), 5.15 (d, J = 12Hz, 1H, H-11), 5.3 (br
m, 1H, H-9), 5.4 (br s, 1H, H-7), 5.78 (t, J = 9Hz,
1H, H-5), 6.44 (t, J = 9Hz, 1H, H-4), 6.85-7.00
(M, J = 9Hz, 1H, H-3), 6.93 (s, 1H, H-19), 8.16 (br
s, 2H, alanyl _{NH 2), 9.35 (s,} 1H, NH-22);. m / z657 (M
++ H); IR (KBr, cm ^-1 ) 1731,1688,1647,1583,1601,15
_{41,1474; C 34 H 48 N 4} O 9 · 3H 2 O was calculated from the theoretical value: C, 52.4
2; H, 6.72; N, 6.79%. Measurements: C, 52, 23; H, 6.22; N, 6.61
%. Example 64 17-azetidin-1-yl-11- [N- (4-azidobenzoyl) -β-alanyl] -17-demeoxygeltanamycin The title compound of Example 63 (0.020 g, 0.026 mmol)
Was dissolved in 0.5 ml of anhydrous dimethylformamide,
Treated with azidobenzoic acid N-hydroxysuccinimide ester (0.007 g, 0.025 mmol) and triethylamine (0.0025 g, 0.025 mmol, 0.0034 ml). 3
After hours, the reaction mixture was diluted with 200 ml of ethyl acetate and 2x1
Washed with 00 ml water, 1N hydrochloric acid and brine. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to a residue. Dissolve the residue in 0.5 ml of chloroform and add 70 ml
Of hexanes, filtered and dried in vacuo; 0.0
12 g (61%) mp123-6 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ0.
85 (d, J = 8Hz, 3H, 10-CH 3), 0.94 (d, J = 8Hz, 3H, 14-CH
_{3), 1.15 (m, 1H} , H-13), 1.63 (s, 3H, 8-CH 3), 1.85
(M, 1H, H-15 ), 1.95 (s, 3H, 2-CH 3), 2.35 ( pent, J
= 8Hz, 2H, 3 'azetidine _{CH 2), 2.6 (t,} J = 8Hz, 2H, α-
Alanyl _{CH 2), 2.7-2.9 (m,} 2H, H-15 and H-10),
3.26 (s, 3H, OCH ₃ ), 3.29 (s, 3H, OCH ₃ ), 3.56 (m, 1H, β
- alanyl _{CH 2), 3.70 (m,} 1H, H-12), 3.82 (m, 1H, β-
Alanyl _{CH 2), 4.4-4.9 (m,} 7H, H-6), 2 ' and 4'
Azetidine CH ₂ , NH ₂ ), 5.10 (d, J = 12 Hz, 1H, H-11), 5.3
(Br m, 1H, H-9), 5.53 (br s, 1H, H-7), 5.79 (t, J
= 9,1H, H-5), 6.45 (t, J = 9.1, H-4), 6.91 (s, 1
H, H-19), 6.9-7.0 (m, 2H, H-3, NH), 6.98 (ABq d, J
= 10 Hz, 2H, aromatic CH), 7.75 (ABq of d, J = 10Hz, 2H, aromatic CH), 8.16 (br s, 2H, alanyl _{NH 2), 9.38 (s,} 1H, NH-
twenty two). Example 65 17-azetidin-1-yl-11-acetyl-17-demethoxygeldanamycin The title compound of Example 18 17-azetidin-1-yl-17
-Demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 ml of methylene chloride in a flame-dried flask under nitrogen and acetic anhydride (0.070 g, 0.683 mmol, 0.064 ml), DMAP (0.042 g, 0.341 mmol) and 0.105 g (1.04 mmol, 0.145m) of triethylamine
Processed in l). After 3 hours, the mixture was diluted with 200 ml of methylene chloride and washed with 100 ml of water and 2 × 100 ml of brine. The organic layer is dried over sodium sulfate, filtered, and
Evaporated to 0.30 g residue. The residue was subjected to flash chromatography on 120 g of silica gel using 2.5% methanol in chloroform to give 0.120 g of pure product, which was recrystallized from 10 ml of toluene; 0.080 g (37%) mp195 ° C (decomposition); ¹ H-NMR (300 MHz, C
DCl ₃ ) δ 0.93 (m, 6H, 14-CH ₃ and 10-CH ₃ ), 1.1-1.3
(M, 2H, H-13), 1.55 (m, 1H, H-14), 1.65 (s, 3H, 8-CH
_{3), 1.95 (s, 3H} , 2-CH 3), 1.96 (s, 3H, acetyl CH _3),
2.0 (m, 1H, H- 15), 2.35 ( pent, J = 8Hz, 2H, 3'- azetidine _{CH 2), 2.6-2.85 (m,} 2H, H-15, H-10), 3.29 (s,
3H, OCH ₃ ), 3.31 (s, 3H, OCH ₃ ), 3.60 (Sept, J = 8Hz, 1
H, isopropyl CH), 3.63 (m, 1H, H-12), 4.45 (dJ = 8H
z, 1H, H-6) , 4.55 (t, J = 8Hz, 4H, 2 ' and 4' azetidine _{CH 2), 4.73 (br s} , 2H, NH 2), 5.0 (m, 1H, H-11) ,Five.
75 (d, J = 11 Hz, 1H, H-9), 5.41 (brs, 1H, H-7), 5.7
8 (t, J = 9Hz, 1H, H-5), 6.46 (t, J = 9Hz, 1H, H-4),
6.91 (s, 1H, H-19), 7.10 (m, J = 9 Hz, 1H, H-3), 9.34
(S, 1H, NH-22); m / z 650. (M ++ Na); IR (KBr, C
M ^-1 ), 1735,1685,1645; calculated from C ₃₃ H ₄₅ N ₃ O ₉ :
C, 63.14; H, 7.26; N, 6.69%. Measurements: C, 63.36; H, 6.94; N,
6.55.Example 66 17-azetidin-1-yl-11-aminocarbonyl-17
-Demethoxygeldanamycin 17-azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341
Mmol) in the manner described in Example 61; yield 0.083 g
(39%) mp 168-171 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.98
(D, J = 8Hz, 3H , 10-CH 3), 1.01 (d, J = 8Hz, 3H, 14-C
_{H 3), 1.3 (br m} , 2H, H-13), 1.73 (s, 3H, 8-CH 3), 1.75
(Br m, 1H, H- 14), 2.02 (s, 3H, 2-CH 3), 2.15 (m, 1H, H
-15), 2.40 (pent, J = 8Hz, 2H, 3'-azetidine C
_{H 2), 2.67 (m,} 1H, H-15), 2.87 (m, 1H, H-10), 3.36
_{(S, 6H, OCH 3)} , 3.60 (m, 1H, H-12), 4.39 (br m, 2H, N
_{H 2), 4.5 (br d} , J = 9Hz, 3H, H-6, NH 2), 4.64 (br t, J =
8 Hz, 6H, 2 'and 4' azetidine _{CH 2, NH 2), 4.86} (m, 1
H, H-11), 5.35 (d, J = 12Hz, 1H, H-9), 5.40 (br s, 1
H, H-7), 5.83 (br t, J = 9Hz, 1H, H-5), 6.54 (t, J =
9Hz, 1H, H-4), 6.97 (s, 1H, H-19), 7.21 (br m, 1H, H
-3), 9.36 (s, 1H, NH-22); m / z 629. (M +); IR (KB
^{r, cm -1) 1720,1686,1648,1533,1475; C} 32 H 44 N 4 O 9 · H 2 O calculated from the theoretical value: C, 59.42; H, 7.61 ; N, 8.66%. measured value:
C, 59.67; H, 6.81; N, 8.38%. Example 67 17-allylamino-11-isopropylsulfamylcarbonyl-17-demethoxygeldanamycin 17-allylamino-17-demethoxygeldanamycin (0.200 g, 0.34 mmol) in a flame-dried flask under nitrogen And dissolved in 5 ml of methylene chloride and cooled to 0 ° C. Chlorosulfonyl isocyanide (0.080 mg, 0.564 mmol, 0.049 ml) was added dropwise over 10 minutes. After stirring for 1 hour in a cool place, isopropylamine (0.066 g, 1.
(13 mmol, 0.096 ml) was added and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was diluted with 100 ml of chloroform and extracted with 10 ml of water. The aqueous layer was back-extracted with 3 × 100 ml of chloroform. 3x75ml pooled organic layer
Extracted with 1N NaOH. The combined basic layers were washed with 3 × 100 ml of chloroform. The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with 3 × 100 ml of chloroform. These latter organic extracts were pooled, washed with 2 × 100 ml of brine, dried over sodium sulfate, filtered and evaporated in vacuo to 0.213 g of solid. Flash chromatography on silica gel, eluting with 5% methanol in chloroform, gave the pure title compound, which was dissolved in 1 ml of chloroform, precipitated with hexanes, filtered and dried in vacuo; yield 0.061 g (25%) mp137-139 ° C; ¹ H-NMR
(300MHz, CDCl ₃ ) δ 0.94 (d, 3H, J = 8HZ, 10-CH ₃ ), 0.98
(D, 3H, J = 8Hz , 14-CH 3), 1.1 (m, 6H, isopropyl C
_{H 3), 1.3-1.55 (br m} , 2H, H-13), 1.65 (s, 3H, 8-C
_{H 3), 1.70 (br m} , 1H, H-14), 1.95 (s, 3H, 2-CH 3), 2.1
3 (m, 1H, H-15), 2.27 (dd, J = 7Hz, 16Hz, 1H, H-15), 3.
00 (m, 1H, H- 10), 3.25 and 3.27 (br s, 6H, OCH 3), 3.
5 (m, 1H, isopropyl CH), 3.57 (br m, 1H, H-12), 4.0
5 (br t, 2H, allylic _{CH 2), 4.43 (br m} , 1H, H-6), 4.7
(Br m, 2H, NH ₂ ), 4.9 (br s, 1H, NH), 5.02 (br d, J = 11
Hz, H-11), 5.2 (br d, 2H, vinyl CH ₂ ), 5.38 (br m, 2
H, H-7 and H-9), 5.75 (t, J = 9 Hz, 1H, H-5), 5.
85 (m, 1H, vinyl CH), 6.27 (br t, 1H, NH), 6.45 (t, J
= 9Hz, 1H, H-4), 7.03 (br m, 1H, H-3), 7.10 (s, 1H,
H-19), 9.30 (s, 1H, NH-22); m / z 722. (M ++ Na); IR
(KBr, cm ^-1 ), 1737, 1690, 1645; theoretical value calculated from C ₃₅ H ₅₁ N ₅ O ₁₁ S · 0.5 H ₂ O: C, 55.39; H, 6.91; N, 9.23%. measured value:
C, 55.36; H, 6.95; N, 9.19%. The compounds of Examples 68 and 69 were prepared by the method of Example 67 from the appropriate 17-demethoxy-geldanamycin.

Example 68 17-β-fluoroethylamino-11-isopropylsulfamylcarbonyl-17-demethoxygeldanamycin Yield 0.122 g (38%) mp 142-146 ° C. (decomposition); ¹ H-NMR
(300 MHz, CDCl ₃ ) δ 0.93 (d, 3H, J = 8 Hz, 10−CH ₃ ), 0.97
(D, 3H, J = 8Hz , 14-CH 3), 1.07 (d, J = 8Hz, 6H, isopropyl _{CH 3), 1.36 (br m} , 1H, H-13), 1.46 (br m, 1H, H -1
3), 1.63 (br s, 4H, 8CH 3 and H-14), 1.94 (s , 3H, 2
−CH ₃ ), 2.1 (br m, 1H, H-15), 2.82 (dd, J = 7 Hz, 16 Hz,
1H, H-15), 2.95 (br m, 1H, H-10), 3.24 (s, 3H, OC
_{H 3), 3.26 (s,} 3H, OCH 3), 3.49 ( concept, J = 8Hz, 1H, isopropyl CH), 3.59 (br m, 1H, H-12), 3.77 (2 two b
rd m, J = 23Hz, 2H, α-ethyl CH ₂ ), 4.43 (br s, 1H, H−
6), 4.56 (two brd, t, J = 47Hz, 7Hz, 2H, β-ethyl CH
₂ ), 4.8 (br m, 2H, NH ₂ ), 5.02 (br d, 2H, H-11 and N
H), 5.75 (t, J = 9 Hz, 1H, H-5), 5.86 (br d, 2H, H-7)
And H-9), 6.25 (br t, 1H, NH), 6.45 (t, J = 9 Hz, 1
H, H-4), 7.00 (br s, 1H, H-3), 7.10 (s, 1H, H-1)
9), 7.55 (brs, 1H, NH), 9.25 (s, 1H, NH-22); m / z 778.
(M ++ Na); IR (KBr, cm ^-1 ) 1735,1690,1645,1590,148
0; theoretical value calculated from C ₃₄ H ₅₀ FN ₅ O ₁₁ S: C, 60.69; H, 6.96;
N, 7.07%. Found: C, 60.23; H, 6.99; N, 7.02%. Example 69 17-β-dianoethylamino-11-isopropylsulfamylcarbonyl-17-demethoxygeldanamycin Yield 0.037 g (11%) mp 150 ° -154 ° C. (decomposition); ¹ H-NMR
(300 MHz, CDCl ₃ ) δ 0.98 (d, 6H, J = 8 Hz, 10-Me and 14
−Me), 1.08 (d, J = 8 Hz, 6H, isopropyl CH ₃ ), 1.37 (b
rm, 1H, H-13), 1.5 (brt, 1H, H-13), 1.65 (s, 3H, 8-
Me), 1.75 (br m, 1H, H-14), 1.95 (s, 3H, 2-Me), 2.04
(M, 1H, H-15 ), 2.66 (t, J = 8Hz, 2H, β- ethyl CH _2),
2.78 (m, 1H, H-15), 3.00 (br m, 1H, H-10), 3.26 (s, 3
H, COH ₃ ), 3.28 (s, 3H, OCH ₃ ), 3.50 (Sept, J = 8Hz, 1H,
Isopropyl CH ₃ ), 3.56 (br m, 1H, H-12), 3.77 (br
m, 2H, α-ethyl CH ₂ ), 4.40 (br d, J = 9Hz, 1H, H-6),
4.75 (br m, 2H, NH ₂ ), 4.93 (br s, 1H, NH), 4.98R (br
d, 1H, H-11), 5.34 (brm, 2H, H-7 and H-9), 5.7
6 (t, J = 9Hz, 1H, H-5), 5.96 (br t, 1H, NH), 6.45 (t,
J = 9Hz, 1H, H-4), 7.00 (br s, 1H, H-3), 7.13 (s, 1
H, H-19), 7.38 (brs, 1H, NH), 9.15 (s, 1H, NH-22); m
/ z785. (M ++ Na); IR (KBr, cm ^-1 ), 2320, 1730, 1690, 1
640,1580,1480; theoretical value calculated from C ₃₅ H ₅₀ N ₆ O ₁₁ S · 1.25H ₂ O: C, 54.78; H, 6.63; N, 10.95%. Measurements: C, 54.75; H, 6.
16; N, 10.71%. Example 70 17-azetidin-1-yl-11-isopropylsulfamylcarbonyl-17-demethoxygeldanamycin 17-azetidin-1-yl-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) Dissolve in 5 ml of methylene chloride in a flame-dried flask under nitrogen and
And cooled. Chlorosulfonyl isocyanide (0.053m
g, 0.376 mmol, 0.033 ml) was added dropwise over 10 minutes. After stirring in the cold for 2 hours, isopropylamine (0.044 g, 0.75 mmol, 0.064 ml) was added and the reaction mixture was allowed to warm to room temperature over 1 hour. 100 m of reaction mixture
Diluted with 1 methylene chloride and extracted with 2 × 100 ml 1N NaOH. The combined basic layers were washed with 3.times.150 ml of methylene chloride and then acidified to pH 3 with 1N hydrochloric acid. The acidic aqueous layer was extracted with 3 × 150 ml of methylene chloride. These latter organic extracts were pooled, dried over sodium sulfate, filtered and evaporated in vacuo to 0.121 g of solid, which was added to 1 ml
In methylene chloride, precipitated with hexanes, filtered and dried in vacuo; 0.110 g (43%) mp 145-48 ° C; ¹ H-N
MR (300 MHz, CDCl ₃ ) δ 0.90 (d, J = 8 Hz, 3H, 14-CH ₃ ), 0.
96 (d, J = 8Hz, 3H, 10-CH 3), 1.14 (d, J = 8Hz, 6H, isopropyl _{CH 3), 1.3 (m,} 1H, H-13), 1.5 (m, 1H, H- 13), 1.
6 (m, 1H, H- 14), 1.64 (s, 3H, 8-CH 3), 1.94 (s, 3H, 2-
CH ₃ ), 2.0 (m, 1H, H-15), 2.36 (p, J = 8 Hz, 2H, 3 ′ azetidine CH ₂ ), 2.73 (dd, J = 8 Hz and 16 Hz, 1 H, H-15),
2.9 (m, 1H, H- 10), 3.25 (s, 3H, OCH 3), 3.27 (s, 3H, OCH
₃ ), 3.52 (Sept, J = 8Hz, 1H, Isopropyl CH), 3.63
(M, 1H, H-12), 4.43 (m, 1H, H-6), 4.57 (t, J = 8Hz, 4
H, 2 'and 4' azetidine _{CH 2) 4.78 (br s,} 2H, NH 2),
5.0 (brs, 1H, H-11), 5.86 (m, 2H H-7 and H-
9), 5.75 (t, J = 9 Hz, 1H, H-5), 6.45 (t, J = 9 Hz, 1H, H
-4), 6.9 (s, 1H, H-19), 6.95 (m, J = 9Hz, 1H, H-
3), 7.45 (m, 1H, NH), 9.35 (s, 1H, NH-22); m / z 772.
(M ++ Na); IR ( KBr, cm -1) 1735,1685,1645; C 35 H 51 N 5
Theoretical value calculated from O ₁₁ S ・ 1.25H ₂ O: C, 54.43; H, 6.98; N,
9.07%. Found: C, 54.42; H, 6.54; N, 8.73%. Example 71 17-β-cyanoethylamino-4,5-dihydro-11-isopropylsulfamylcarbonyl-17-demethoxygeldanamycin The title compound was prepared from the compound of Example 11 by the method of Example 70.

Yield 0.087 g (46%) mp 128-132 ° C (decomposition); ¹ H-NMR
_{(30MHz, CDCl 3) δ0.92 (} d, J = 8Hz, 3H, 10-CH 3), 0.93
(D, J = 8 Hz, 3H, 14-CH ₃ ), 1.07 (d, J = 8 Hz, 3 H, isopropyl CH ₃ ), 1.09 (d, J = 8 Hz, 3 H, isopropyl CH ₃ ), 1.17
(Br m, 1H, H-13), 1.36 (br t, 1H, H-13), 1.43 (s, 3
_{H, 8-CH 3),} 1.46 (br m, 1H, H-14), 1.58 (m, 2H, H-
5), 1.75 (s, 3H , 2-CH 3), 2.00 (dd, J = 14Hz and 6H
z, 1H, H-15), 2.23 (m, 2H, H-4), 2.56 (t, J = 8Hz, β
- ethyl _{CH 2), 2.77 (m,} 1H, H-15), 3.06 (br m, 1H, H-
10), 3.25 (s, 3H , OCH 3), 3.27 (s, 3H, OCH 3), 3.35 (br
m, 1H, H-12), 3.47 (Sept, J = 8Hz, 1H, Isopropyl C)
H), 3.66 (br m, 2H, α-ethyl CH ₂ ), 4.5-4.63 (br m,
3H, H-6, NH ₂ and NH), 4.85 (d, J = 6Hz, 1H, H-7), 5.
05 (br s, 1H H-7), 5.74 (d, J = 9Hz, 1H, H-9), 5.87
(Br t, 1H, NH), 6.26 (t, J = 7Hz, 1H, H-3), 7.05 (s, 1
H, H-19), 7.40 (br s, 1H, NH), 9.00 (s, 1H, NH-22); m
/ z787. (M ++ Na); IR (KBr, cm ^-1 ), 2320, 1730, 1690, 1
_{645,1580,1480; C 35 H 52 N 6} O 11 · 0.25H 2 O calculated from the theoretical value: C, 54.71; H, 6.75 ; N, 10.93%. Found: C. 54.48; H, 6.8
8; N, 10.68%. Example 72 17-azetidin-1-yl-11- (4'-azidophenyl) sulfamylcarbonyl-17-demethoxygeldanamycin 17-azetidin-1-yl-17-, the title compound of Example 18 Demethoxygeldanamycin (0.250 g, 0.427
Mmol) in a flame-dried flask under nitrogen
In methylene chloride and cooled to 0 ° C. Chlorosulfonyl isocyanide (0.099mg, 0.704mmol, 0.061m
l) was added dropwise over 10 minutes. After stirring for 1 hour in a cool place, 4-azidoaniline (0.126 g, 0.938 mmol)
Was added and the reaction mixture was warmed to room temperature for 1 hour.
The reaction mixture is evaporated to dryness and the residue is treated with 3 in chloroform.
Flash chromatography on 120 g of silica gel using% methanol gave the pure product, which was
Dissolved in 1 ml of chloroform and precipitated with hexanes; yield 0.059 g (17%) mp 152-54 ° C; ¹ H-NMR (300 MHz,
CDCl ₃ ) δ 0.85 (d, J = 8 Hz, 3H, 14−CH ₃ ), 0.94 (d, J = 8H
_{z, 3H, 10-CH 3} ), 1.2 (m, 1H, H-13), 1.36-1.7 (m, 2H, H
-13 and H-14), 1.6 (s , 3H, 8-CH 3), 1.94 (br s, 4
H, 2-CH ₃ and H-15), 2.35 (pent J = 8Hz, 2H, 3 '
- azetidine _{CH 2), 2.65-2.9 (br m} , 2H, H-10 and H
−15), 3.24 (brs, 6H, COH ₃ ), 3.64 (m, 1H, H−12), 4.4
6 (br s, 1H, H-6), 4.55 (t, J = 8Hz, 4H, 2 'and 4'
Azetidine _{CH 2), 4.85-5.1 (br s} , 2H, NH 2 and H-
7), 5.85 (br s, 1H H-11), 5.48 (br s, 1H, H-9),
5.77 (br t, J = 9Hz, 1H, H-5), 6.45 (t, J = 9Hz, 1H, H-
4), 6.86 (s, 1H, H-19), 6.8-7.15 (m, 5H, H-3 and aromatic CH), 7.8 (vbrd s, 1H, NH), 9.35 (s, 1H, NH-) Two
2); m / z 847. (M ++ Na); IR (KBr, cm ^-1 ), 2108, 1737, ¹
689,1647,1584,1481; C ₃₈ H ₄₈ N ₈ O ₁₁ S. Theoretical value calculated from 1.5H ₂ O: C, 53, 57; H, 5.86; N, 13.15%. Measurements: C, 53.70;
H, 5.57; N, 13.02%. Example 73 17-allylamino-11-azetidin-1-ylsulfamylcarbonyl-17-demethoxygeldanamycin 17-allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol)) in a flame under nitrogen Dissolved in 5 ml of methylene chloride in a dry flask and cooled to 0 ° C. Chlorosulfonyl isocyanide (0.053 mg, 0.376
Mmol, 0.031 ml) was added dropwise over 10 minutes. After stirring in the cold for 1 hour, azetidine (0.043 g, 0.75 mmol, 0.051 ml) was added and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was evaporated to a residue and flash column chromatography on 60 g silica gel eluted with 69: 1: 30 ethyl acetate: methanol: hexanes to give the pure target compound, which was combined with 1 ml of Dissolved in chloroform, precipitated with hexanes and dried in vacuo; yield 0.102 g (40%) mp134-137
° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.92 (d, 3 H, J = 8 Hz, 10 −
CH ₃ ), 1.01 (d, 3H, J = 8Hz, 14−CH ₃ ), 1.4 (br m, 1H, H−
13), 1.5 (brm, 2H, H-13 and H-14), 1.65 (s, 3H, 8
_{-CH 3), 1.95 (s,} 3H, 2-CH 3), 2.13 (m, 1H, H-15), 2.0
5-2.2 (m, 3H, H- 15 and azetidine 3'-CH _2), 2.78
(Dd, J = 6 Hz and 15 Hz, 1H, H-15), 2.93 (m, 1H, H-1
0), 3.26 (s, 3H , OCH 3), 3.28 (s, 3H, OCH 3), 3.63 (br
m, 1H, H-12) , 3.95-4.05 (br, m, 6H, allylic CH ₂ and azetidine 2 'and _{4'CH 2), 4.45 (br s} , 1H, H-
6), 4.7 (br m, 2H, NH ₂ ), 5.02 (br d, J = 11Hz, 1H, H-1
1), 5.2 (m, 2H, vinylic CH ₂ ), 5.4 (br m, 2H, H-7 and H-9), 5.73-5.93 (m, 2H, H-5 and vinylic C)
H), 6.25 (br t, 1H, NH), 6.45 (t, J = 9Hz, 1H, H-4),
7.03 (br m, 1H, H-3), 7.10 (s, 1H, H-19), 9.32 (s, 1
H, NH-22); m / z 769. (M ++ Na); IR (KBr, cm- ¹ ) 1734,
1691, 1645, 1579, 1474; C ₃₅ H ₄₉ N ₅ O ₁₁ S. Theoretical value calculated from 0.75 H ₂ O: C, 55.21; H, 6.69; N, 9.19%. Measured value; C, 55.1
9; H, 6.18; N, 9.20%. Example 74 17-azetidin-1-yl-11-piperazinylsulfamylcarbonyl-17-demethoxygeldanamycin 17-azetidin-1-yl-17-demethoxygeldanamycin, which is the title compound of Example 18. (0.50 g, 0.854 mmol) was dissolved in 5 ml of methylene chloride in a flame-dried flask under nitrogen and cooled to 0 ° C. Chlorosulfonyl isocyanide (0.133mg, 0.939mmol, 0.082ml)
Was added dropwise over 10 minutes. After stirring in the cold for 1 hour, piperazine (0.162 g, 1.88 mmol) was added and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture is evaporated to dryness and the residue is subjected to flash chromatography on 200 g of silica gel with 20% methanol in chloroform to give the pure product, which is dissolved in 5 ml of chloroform and treated with 150 ml of hexanes. Precipitated; yield
0.161 g (24%) mp 180-182 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ )
δ 0.86 (m, 3H, 14-CH ₃ ), 0.9 (m, 3H, 10-CH ₃ ), 1.6 (s,
3H, 8-CH ₃ ), 1.94 (br s, 2-CH ₃ ), 2.35 (pent, J = 8H
z, 2H, 3'azetidine _{CH 2), 3.25 (br s} , 6H, OCH 3), 3.6
4 (m, 1H, H-12), 4.46 (br s, 1H, H-6), 4.6 (t, J = 8H
z, 4H, 2 'and 4' azetidine _{CH 2), 6.43 (br t} , 1H, H
-4), 6.9 (s, 1H, H-19), 9.35 (s, 1H, NH-22), other protons were observed, but less clearly identified; m / z 799. (M ++ Na); IR (KBr, cm ^-1 ) 1734,1689,164
6,1600,1471; C ₃₃ H ₅₂ N ₆ O ₁₁ S ・ 2H ₂ O calculated theoretical value:
C, 53.19; H, 6.94; N, 10.34%. Measurements: C, 52.90; H, 6.81; N,
10.13%. Example 75 17-azetidin-1-yl-11- (4'-methyl-1 '
-Biperazinyl) -sulfamylcarbonyl-17-demethoxygeldanamycin 17-azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341
Mmol) in a flame-dried flask under nitrogen
In methylene chloride and cooled to 0 ° C. Chlorosulfonyl isocyanide (0.053mg, 0.376mmol, 0.033m
l) was added dropwise over 10 minutes. After stirring for 1 hour in a cold place, N-methylpiperazine (0.075 g, 0.75 mmol,
0.083 ml) was added and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was diluted with 100 ml of chloroform and extracted with 100 ml of water and 2 × 100 ml of brine. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to 0.280 g solid. This was subjected to flash chromatography on silica gel using 10% methanol in chloroform to give the pure product; yield 0.114 g (42
%) Mp 147-49 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.11 (d, J
= 8Hz, 3H, 14-CH 3), 1.21 (d, J = 8Hz, 3H, 10-CH 3), 1.5
5 (m, 1H, H-13), 1.72 (m, 1H, H-13), 1.83 (m, 1H, H-1
4), 1.86 (s, 3H , 8-CH 3), 2.2 (br s, 4H, 2-CH 3 and H-15), 2.53 (s , 3H, N-CH 3), 2.60 (br t, J = 8Hz, 2H,
3'azetidine _{CH 2), 2.70 (br s} , 4H, piperazinyl C
_{H 2), 2.9-3.1 (m,} 2H, H-10 and H-15), 3.53 (s , 6
H, OCH ₃ ), 3.86 (m, 1H, H-12), 4.69 (brs, 1H, H-6),
4.82 (t, J = 8Hz, 4H, 2 ' and 4' azetidine CH _2), 5.1
5 (br s, 2H, NH ₂ ), 5.72 (br s, 1H, H-7), 5.57 (br d,
1H H-11), 5.66 (br s, 1H, H-9), 6.00 (t, J = 9Hz, 1
H, H-5), 6.68 (t, J = 9Hz, 1H, H-4), 7.15 (s, 1H, H-
19), 7.24 (brs, 1H, H-3), 7.45 (s, 1H, NH), 9.60
(S, 1H, NH-22); m / z 813. (M ++ Na); IR (KBr, cm ^-1 )
_{1738,1688,1646,1583,1471; C 37 H 54 N 6} O 11 S · H 2 O calculated from the theoretical value: C, 54.94; H, 6.97 ; N, 10.39%. Measured value: C, 54.9
2; H, 6.87; N, 10.25%. Example 76 17-allylamino-11-keto-17-demethoxygeldanamycin 17-allylamino-17-demethoxygeldanamycin (90 mg, 0.15 mmol) was dissolved in CHCl ₃ (4 ml) and added to Dess-Martin. Periodinane (382 mg, 0.90 mmol) was added and the reaction was heated at reflux. After 1 hour, the reaction was complete, the reaction mixture was diluted with CHC _3. Organic layer
Washed with ₂ S ₂ O ₃ , saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was removed by evaporation and the residue was recrystallized from ethyl acetate / hexanes to give a yield of 84 mg (96
%) Of 17-allylamino-11-keto-17-demethoxygeldanamycin as pale red crystals; mp 112-118 ° C.
(Decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.02 (d, 3 H, J = 7 H
z) 1.25 (d, 3H, J = 7Hz), 1.48 (m, 2H), 1.75 (m, 1H),
1.80 (s, 3H), 1.98 (s, 3H), 2.32 (dd, 1H, J = 14Hz, 15H
z), 2.58 (dd, 1H, J = 14Hz, 7Hz) 3.29 (duplicate s, 6H), 3.66
(M, 1), 4.08 (m, 3H), 4.28 (d, 1H, J = 8Hz), 4.82 (br
Exchangeable, 2H), 5.18-5.3 (m, 3H), 5.55 (z, 1H, J = 9H)
z), 5.8-6.0 (m, 3H), 6.83 (br interchangeable, 1H) 6.49 (t,
1H, J = 11Hz), 6.92 (d, 1H, J = 11Hz), 7.19 (s, 1H), 9.2
2 (s, 1 H); mass spectrum m / z 585. (M + 2); C ₃₁ H ₄₁ N
Theoretical value calculated from ₃ O ₈ · 0.5 (ethyl acetate): C, 63.14;
H, 7.23; N, 6.69%. Found: C, 63.19; H, 7.06%; N, 6.92
%. The 11-keto compounds of Examples 77-87 were prepared by oxidation of the appropriate 17-amino substituted 17-demethoxygeldanamycin by the method of Example 76.

Example 77 17-cyclopropylamino-11-keto-17-demethoxygeldanamycin Mp 110-115 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ )
75−0.95 (m, 4H), 1.03 (d, 3H, J = 7Hz), 1.24 (d, 3H, J
= 7Hz), 1.72 (m, 1H), 1.79 (s, 3H), 1.98 (s, 3H), 2.7
8 (m, 3H), 3.32 (S, 3H), 3.4-3.5 (m, 4H), 4.08 (m, 2
H), 4.28 (d, 1H, J = 8 Hz), 4.81 (br exchangeable, 2H), 5.15
(S, 1H), 5.57 (d, 1H, J = 10Hz), 5.71 (t, 1H, J = 7Hz),
6.26 (br s, 1H), 6.51 (t, 1H, J = 12Hz), 6.92 (d, 1H, J
= 12Hz), 7.15 (s, 1H), 9.22 (s, 1H); mass spectrum
m / z 606. (M + Na) S Example 78 17-isopropylamino-11-keto-17-demethoxygeldanamycin Mp 105-111 ° C. (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
02 (d, 3H, J = 7Hz), 1.25 (duplicate, 9H), 1.48 (m, 2
H), 1.75 (m, 1H), 1.80 (s, 3H), 1.98 (s, 3H), 2.27 (d
d, 1H, J = 14Hz, 5Hz), 2.66 (dd, 1H, J = 14Hz, 7Hz), 3.32
(Duplicate s, 6H), 3.67 (m, 1H), 3.98 (m, 1H), 4.09 (t, 1H,
J = 5Hz), 4.38 (d, 1H, J = 9Hz), 4.82 (br interchangeable, 2
H), 5.17 (s, 1H), 5.54 (d, 1H, J = 9 Hz), 5.83 (t, 1H, J
= 7Hz), 6.17 (d, 1H, J = 9Hz), 6.49 (t, 1H, J = 11Hz),
6.92 (d, 1H, J = 11 Hz), 7.17 (s, 1H), 9.27 (s, 1H); mass spectrum m / z 587. (M + 2); C ₃₁ H ₄₃ N ₃ O ₈ .0.2 CH ₂ Cl
Theoretical value calculated from ₂ : C, 62.22; H, 7.20; N, 6.98%. Found: C, 62.16; H, 7.0; N, 6.75%. Example 79 17-methylamino-11-keto-17-demethoxygeldanamycin Mp 108-120 ° C (dec); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
05 (d, 3H, J = 7Hz), 1.23 (d, 3H, J = 7Hz), 1.48 (m, 2
H), 1.80 (s, 3H), 1.97 (s, 3H), 2.43 (dd, 1H, J = 14Hz,
7Hz), 2.68 (dd, 1H, J = 14Hz, 7Hz), 3.17 (s, 3H), 3.30
(Duplicate s, 6H), 3.68 (m, 1H), 4.11 (t, 1H, J = 5Hz), 4.32
(D, 1H, J = 8Hz), 4.80 (br exchangeable, 2H), 5.21 (s, 1
H), 5.53 (d, 1H, J = 10 Hz), 5.83 (t, 1H, J = 7 Hz), 6.51
(T, 1H, J = 12Hz), 6.92 (d, 1H, J = 10Hz), 7.19 (s, 1
H), 9.28 (s, 1H); mass spectrum m / z 580. (M + N
a). Example 80 17- (2'-hydroxyethylamino) -11-keto-17
-Demethoxygeldanamycin Mp 108-111 ° C (decomposition); ¹ H-NMR (R300MHz, CDCl ₃ ) δ
1.07 (d, 3H, J = 7Hz), 1.25 (d, 3H, J = 7Hz), 1.51 (m, 2
H), 1.76 (m, 1H), 1.81 (s, 3H), 1.98 (s, 3H), 2.32 (d
d, 1H, J = 14Hz, 4Hz), 2.63 (dd, 1H, J = 14Hz, 7Hz), 3.34
(Duplicate s, 6H), 3.62 (m, 3H), 3.88 (t, 2H, J = 5Hz), 4.09
(TS, 1H, J = 5Hz), 4.28 (d, 1H, J = 9Hz), 4.8 (br interchangeable, 2H), 5.18 (S, 1H), 5.53 (d, 1H, J = 13Hz), 5.79 ( d,
1H, J = 8Hz), 6.48 (t, 1H, 14Hz), 6.92 (d, 1H, J = 14H)
z), 7.18 (S, 1H), 9.25 (s, 1H); mass spectrum m / z 58
9. (M + 2); C 30 H 41 N 3 O 9 calculated the theoretical value from: C, 61.32;
H, 7.03; N, 7.15%. Found: C, 60.96; H, 7.12; N, 6.90%. Example 81 17- (2'-methoxyethylamino) -11-keto-17-
Demethoxygeldanamycin Mp130-134 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
05 (d, 3H, J = 7Hz), 1.24 (d, 3H, J = 7Hz), 1.82 (m, 2
H), 1.85 (s, 3H), 2.00 (s, 3H), 2.34 (dd, 1H, J = 14Hz,
5Hz), 2.62 (dd, 1H, J = 14Hz, 7Hz), 3.33 (duplicate s, 6H),
3.40 (s, 3H), 3.6-3.7 (m, 5H,) 4.10 (m, 2H), 4.31
(D, 1H, J = 9Hz), 4.8 (br exchangeable, 2H), 5.22 (s, 1H),
5.55 (d, 1H, J = 10 Hz), 5.82 (t, 1H, J = 7 Hz), 6.49 (t, 1
H, J = 12Hz), 6.92 (d, 1H, J = 10Hz), 7.18 (s, 1H), 9.24
(S, 1H); mass spectrum m / z603 (M + 2) ;. C 31 H 43 N 3
O ₉ calculated the theoretical value from: C, 61.79; H, 7.20 ; N, 6.98%. Found: C, 61.75SH, 7.02; N, 6.86%. Example 82 17- (2'methylthioethylamino) -11-keto-17-
Demethoxygeldanamycin Mp95-100 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ1.0
5 (d, 3H, J = 7Hz), 1.23 (d, 3H, J = 7Hz), 1.48 (m, 2H),
1.80 (m, 1H), 1.81 (s, 3H), 1.95 (s, 3H), 2.11 (s, 3
H), 2.32 (dd, 1H, J = 14Hz, 5Hz), 2.63 (dd, 1H, J = 14Hz,
5Hz), 2.76 (t, 2H, J = 7Hz), 3.32 (overlap s, 6H), 3.67
(T, 2H, J = 7Hz), 3.67 (single proton under triple), 4.0
8 (t, 1H, J = 5 Hz.), 4.37 (d, 1H, J = 7 Hz), 4.8 (brs, 2
H), 5.18 (s, 1H), 5.52 (d, 1H, J = 9 Hz), 5.83 (apparent t, 1H, J = 9 Hz), 6.50 (t, 1H, J = 10 Hz), 6.92 (br d, 1
H, J = 12 Hz), 7.19 (s, 1H), 9.21 (s, 1H); mass spectrum m / z 620. (M + 2); theoretical value calculated from C ₃₁ H ₄₃ N ₃ O ₈ S: C, 60.27H , 7.02; N, 6.80%. Measurements: C, 60.16; H, 6.82;
N, 6.67%. Example 83 17- (2'-fluoroethylamino) -11-keto-17-
Demethoxygeldanamycin Mp-99-105 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ
1.04 (d, 3H, J = 7Hz), 1.25 (d, 3H, J = 7Hz), 1.50 (m, 2
H), 1.80 (m, 1H), 1.81 (s, 3H), 1.99 (s, 3H), 2.31 (d
d, 1H, J = 14Hz, 5Hz), 2.62 (dd, 1H, J = 14Hz, 9Hz), 3.31
(Duplicate s, 6H), 3.68 (dd, 1H, J = 9Hz, 7Hz), 3.77 (m, 1
H), 3.84 (m, 1H), 4.10 (t, 1H, J = 6 Hz), 4.30 (d, 1H, J
= 8Hz), 4.54 (t, 1H, J = 5Hz), 4.70 (t, 1H, J = 5Hz), 5.
19 (s, 1H), 5.54 (d, 1H, J = 9 Hz), 5.83 (t, 1H, J = 9H)
z), 6.28 (t, 1H, J = 6 Hz), 6.50 (t, 1H, J = 12 Hz), 6.93
(D, 1H, J = 12Hz ), 7.20 (s, 1H), 9.17 (s, 1H); Mass spectrum m / z591 (M + 2) ;. Was calculated from _{C 30 H 40 N 3 O 8} · 1 / 12CHCl 3 Theory: C, 60.26; H, 6.84; N, 7.01%. measured value:
C, 60.57; N, 6.54; N, 6.87%. Example 84 17- (2'-cyanoethylamino) -11-keto-17-demethoxygeldanamycin Mp 102-107 ° C (dec); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
07 (d, 2H, J = 7Hz), 1.25 (d, 3H, J = 7Hz), 1.53 (m, 2
H), 1.80 (m, 1H), 1.81 (s, 3H), 2.00 (s, 3H), 2.27 (d
d, 1H, J = 14Hz, 5Hz), 2.58 (dd, 1H, J = 14Hz, 6Hz), 2.69
(T, 2H, J = 8Hz), 3.32 (s, 3H), 3.33 (s, 3H), 3.71 (d
d, 1H, J = 9 Hz, 7 Hz), 3.80 (q, 2H, J = 7 Hz), 4.07 (m, 1
H), 4.29 (d, 1H, J = 8Hz), 4.8 (br s, 2H), 5.17 (s, 1
H), 5.55 (d, 1H, J = 9 Hz), 5.84 (apparent t, 1H, J = 9H)
z), 6.02 (t, 1H, J = 6 Hz), 6.51 (t, 1H, J = 11 Hz), 6.94
(Br d, 1H, J = 12 Hz), 7.22 (s, 1H), 9.09 (s, 1H); mass spectrum m / z 619. (M + Na); theoretical value calculated from C ₃₁ H ₄₀ N ₄ O ₈ : C , 62.40; H, 6.76; N, 9.39%. Measurements: C, 61.81;
H, 6.45; N, 9.06%. Example 85 17-azetidin-1-yl-11-keto-17-demethoxygeldanamycin Mp 112-116 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
02 (d, 3H, J = 7Hz), 1.37 (d, 3H, J = 7Hz), 1.48 (m, 2
H), 1.67 (m, 1H), 1.82 (s, 3H), 1.97 (s, 3H), 2.22 (d
d, 1H, J = 14Hz, 5Hz), 2.42 (m, 2H), 2.58 (dd, 1H, J = 14H
z, 7Hz), 3.30 (overlap s, 6H), 3.61 (m, 1H), 5.15 (t, 1H, J
= 5Hz), 4.17 (t, 1H, J = 8Hz), 4.62 (t, 4H, J = 7Hz), 4.
80 (br s, 2H), 5.19 (s, 1H), 5.51 (d, 1H, J = 10Hz), 5.
76 (t, 1H, J = 10 Hz), 6.48 (t, 1H, J = 12 Hz), 6.90 (br
. d, 1H, 12Hz), 6.97 (s, 1H), 9.25 (S, 1H); Mass spectrum ^{m / z583 (M +);} C 31 H 41 N 3 calculated from O ₈ theoretical value: C, 6
3.79; H, 7.08; N, 7.20%. Found: C, 63.83; H, 7.11; N, 6.84
%. Example 86 17- (3′-hydroxyazetidin-1-yl) -11-
Keto-17-demethoxygeldanamycin Mp145 ° C. (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ1.0
(D, 3H, J = 4Hz), 1.2-1.3 (m, 6H), 1.4 (m, 2H), 1.7
(M, 1H), 1.8 (s, 3H), 2.15 (s, 2H), 2.2 (d, 2H, J = 4H
z), 2.5 (m, 1H), 3.3 (two single, 6H), 3.6 (m, 1H),
3.8 (br s, 1H), 4.15 (m, 1H), 4.3 (d, 1H, J = 7Hz), 4.3
5-4.5 (m, 2H), 4.5-4.9 (M, 3H), 5.0-5.2 (m, 3H),
5.5 (d, 1H, J = 7Hz), 5.8 (m, 1H), 6.5 (t, 1H, J = 10H
z), 6.9 (d, 1H, J = 14 Hz), 7.0 (s, 1H), 9.2 (s, 1H);
. Mass spectrum m / z622 (M + 2) ; C 31 H 43 N 3 O 9 · H 2 O calculated from the theoretical value: C, 60.28; H, 7.02 ; N, 6.80%. measured value:
C, 60.76; H, 7.10; N, 6.36%. Example 87 17- (3'-Methoxyazetidyl-1-yl) -11-keto-17-demethoxygeldanamycin Mp 128 ° C (foam); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.0
(D, 3H, J = 7Hz), 1.25 (m, 6H), 1.45 (m, 2H), 1.6-1.8
5 (including m, 4H, methyl 1), 1.9-2.1 (m, 4H, methyl 1
Weight), 2.1-2.3 (m, 1H) 2.95-3.25 (m, 1H), 3.3
(M, 9H, including three methyl singles), 3.6 (m, 1H), 4.0-4.
3 (m, 3H), 4.35-4.5 (m, 2H), 4.6-4.8 (m, 2H), 5.1
(Br s, 2H), 52 (s, 1H), 5.5 (d, 1H, J = 10Hz), 5.8 (m,
1H), 6.5 (t, 1H, J = 12 Hz), 6.9 (d, 1H, J = 12 Hz), 7.0
(S, 1H), 9.25 (s, 1H); mass spectrum m / z 636. (M +
_{Na); C 32 H 43 N} 3 O 9 calculated the theoretical value from: C, 62.63; H, 7.06 ;
N, 6.85%. Found: C, 62.23, H, 7.19; N, 6.70%. Example 88 17-Methylamino-11- (2'-morpholinoethylamino) -17-demethoxygeldanamycin Sodium triacetoxyborohydride (152 mg, 0.72 mmol) in dichloroethane (4 ml) in a dry flask was prepared. Sonicated until a fine suspension was formed. The mixture was removed from the sonicator and treated with N-aminoethylmorpholine (47 μl, 0.36 mmol) and a small amount of sodium sulfate crystals. Then 11-keto-17-methylamino-17-demethoxygeldanamycin (100 mg, 0.1
8 mmol) and the mixture was stirred at room temperature for 24 hours.
The reaction mixture was washed with saturated sodium carbonate and brine, and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by column chromatography (silica gel, 10% methanol in methylene chloride) to give the title compound as a purple solid; yield 87 mg, (71% ), Mp119-120
° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.90 (d, 3H, J = 7 Hz), 1.
00 (d, 3H, J = 7Hz), 1.42 (m, 2H), 1.59 (m, 1H), 1.65
(S, 3H), 1.95 (s, 3H), 2.03 (br s, 1H), 2.25 (dd, 1H,
J = 8Hz), 2.68 (m, 3H), 2.81 (m, 2H), 3.15 (d, 3H, J = 7
Hz), 3.22 (s, 3H), 3.28 (s, 3H), 3.52 (m, 1H), 3.62
(T, 4H, J = 4Hz), 4.44 (br d, 1H, J = 10Hz), 4.75 (br
s, 1H), 5.40 (s, 1H), 5.55 (d, 1H, J = 10Hz), 5.78 (dd,
1H, J = 8Hz), 6.28 (d, 1H, J = 7Hz), 6.45 (t, 1H, J = 13H)
z), 7.00 (m, 1H), 7.05 (s, 1H), 9.40 (s, 1H); mass spectrum m / z 672 (M ⁺ ). The compounds of Examples 89-95 were prepared using the reductive amination method of Example 88 from 11-keto-17- (methylamino) -17-demethoxygeltanamycin and the appropriate amines.

Example 89 11-benzylamino-17-methylamino-17-demethoxygeldanamycin Mp 123-126 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.91 (d, 3
H, J = 8Hz), 0.98 (d, 3H, J = 8Hz), 1.35 (m, 1H), 1.58
(M, 2H), 1.66 (m, 1H), 1.70 (s, 3H), 1.95 (s, 3H), 2.
32 (dd, 1H, J = 8 Hz), 2.75 (dd, 1H, J = 8 Hz, 12 Hz), 2.93
(M, 1H), 3.08 (s, 4H), 3.12 (d, 3H, J = 8Hz), 3.15 (s,
6H), 3.46 (d, 1H, J = 8 Hz), 3.61 (d, 1H, J = 24 Hz), 3.78
(D, 1H, J = 24 Hz), 4.30 (d, 1H, J = 8 Hz), 4.75 (brs, 2
H), 5.35 (s, 1H), 5.70 (m, 2H), 6.28 (d, 1H, J = 8Hz),
6.43 (t, 1H, J = 12 Hz), 7.01 (br d, 1H, J = 16 Hz), 7.08
(S, 1H), 7.20 (m, 5H), 9.42 (s, 1H); mass spectrum
m / z 649. (M + 1). Example 90 11-cyclopropylamino-17-methylamino-17-demethoxygeldanamycin Mp 120-123 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.30 (m, 4
H), 0.93 (d, 3H, J = 8 Hz), 1.02 (d, 3H, J = 8 Hz), 1.40
(M, 2H), 1.72 (s, 3H), 1.80 (br s, 1H), 1.99 (s, 3
H), 2.15 (s, 1H), 2.32 (dd, 1H, J = 8Hz, 13Hz), 3.00
(M, 1H), 3.18 (d, 3H, J = 7Hz), 3.28 (s, 3H), 3.30 (s,
3H), 3.57 (m, 1H), 4.39 (d, 1H, 8Hz), 4.84 (brs, 2
H), 5.63 (d, 1H, J = 8Hz), 5.80 (dd, 1H, J = 8Hz, 8Hz),
6.32 (d, 1H, J = 7Hz), 6.51 (t, 1H, J = 13Hz), 7.01 (br
d, 1H, 17 Hz), 7.09 (s, 1H), 9.44 (s, 1H); mass spectrum m / z 600. (M + 1). Example 91 11-isoamylamino-17-methylamino-17-demethoxygeldanamycin Mp 108-110 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.90 (d, 3
H, J = 8Hz), 1.00 (d, 3H, J = 8Hz), 1.22-1.60 (m, 5H),
1.63 (m, 1H), 1.65 (s, 3H), 1.95 (s, 3H), 2.29 (dd, 1
H, J = 7Hz), 2.53 (m, 1H), 2.75 (m, 2H), 2.90 (m, 1H),
3.13 (d, 3H, J = 7Hz), 3.23 (s, 3H), 3.28 (s, 3H), 3.52
(M, 1H), 4.90 (br s, 2H), 5.35 (s, 1H), 5.60 (br d, 1
H, J = 8), 5.75 (dd, 1H, J = 8Hz), 6.30 (d, 1H, J = 7H)
z), 6.43 (t, 1H, J = 12Hz), 7.02 (s, 1H), 7.09 (br s, 1
H), 9.38 (s, 1H); mass spectrum m / z 629. (M +
1). Example 92 11- (2'-hydroxyethylamino) -17-methylamino-17-demethoxygeldanamycin Mp (oil); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95 (d,
3H, J = 7Hz), 1.09 (d, 3H, J = 7Hz), 1.45 (m, 1H), 1.58
(M, 2H), 1.72 (s, 3H), 2.00 (s, 3H), 2.30 (dd, 1H, J =
8Hz), 3.02 (m, 9H), 3.20 (d, 3H, J = 7Hz), 3.28 (s, 3
H), 3.35 (s, 3H), 3.62 (m, 3H), 4.55 (br s, 1H), 4.90
(Br s, 2H), 5.40 (br s, 1H), 5.63 (d, 1H, J = 10Hz),
5.81 (dd, 1H, J = 8Hz), 6.36 (d, 1H, J = 7Hz), 6.50 (t, 1
H, J = 13Hz), 7.08 (m, 1H), 7.12 (s, 1H), 9.40 (s, 1
H); mass spectrum m / z 603. (M + 1). Example 93 11- (3'-dimethylaminopropylamino) -17-methylamino-17-demethoxygeldanamycin Mp 105-108 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95 (d, 3
H, J = 7Hz), 1.03 (d, 3H, J = 7Hz), 1.48 (m, 1H), 1.65
(M, 3H), 1.70 (s, 3H), 1.98 (s, 3H), 2.20 (s, 6H), 2.
28 (m, 3H), 2.65 (m, 1H), 2.70 (m, 2H), 2.84 (dd, 1H, J
= 7Hz), 2.90 (m, 1H), 3.20 (d, 3H, J = 7Hz), 3.29 (s, 3
H), 3.33 (s, 3H), 3.57 (m, 1H), 4.48 (d, 1H, J = 13H)
z), 4.80 (br s, 2H), 5.41 (br s, 1H), 5.62 (br d, 1H,
J = 13Hz), 5.81 (dd, 1H, J = 8Hz), 6.32 (d, 1H, J = 7H
z), 6.49 (t, 1H, J = 13 Hz), 7.09 (m, 1H), 7.10 (s, 1
H), 9.43 (s, 1H );. Mass spectrum m / z644 (M ^{+ +}
1). Example 94 11-allylamino-17-methylamino-17-demethoxygeldanamycin Mp 123-125 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.95 (d, 3
H, J = 7Hz), 1.03 (d, 3H, J = 7Hz), 1.41 (m, 1H), 1.52
(M, 1H), 1.72 (s, 3H), 1.84 (m, 2H), 2.00 (s, 3H), 2.
36 (dd, 1H, J = 7Hz), 2.80 (m, 2H), 3.00 (m, 1H), 3.20
(D, 3H, J = 7Hz), 3.25 (s, 3H), 3.32 (s, 3H), 3.58 (m,
1H), 4.42 (d, 1H, J = 10Hz), 4.80 (br s, 2H), 5.08 (d
d, 2H, J = 16Hz), 5.40 (s, 1H), 5.65 (d, 1H, J = 13Hz),
5.83 (m, 2H), 6.32 (d, 1H, J = 7Hz), 6.50 (t, 1H, J = 13H)
z), 7.05 (m, 1H), 7.10 (s, 1H), 9.45 (s, 1H); mass spectrum m / z 599. (M ⁺⁺ 1). Example 95 17-azetidin-1-yl-11-oximino-17-demethoxygeldanamycin 17-azetidin-1-yl-11-keto-17-demethoxygeldanamycin in ethanol (0.10 g, 0.17 mmol )) Add a solution of hydroxyamine hydrochloride (0.10 g, 1.42 mmol) and triethylamine (0.2
ml) solution was added. The reaction mixture was stirred for 2.5 hours at room temperature, the solvent was removed by rotary evaporation, the residue was dissolved in CHCl _3. The chloroform solution was washed with water, dried over sodium sulfate, and the solvent was removed by rotary evaporation. Column chromatography of the residue (silica gel, 15% acetone in CHCl ₃ )
To give 17-azetidino-11-oxyimino-17
-Demethoxygeldanamycin (70 mg, 68%) was obtained as a purple powder. Mp130-145 ° C (decomposition); ¹ H-NMR (300M
Hz, CDCl ₃ ) 0.98 (d, 3H, J = 7 Hz), 1.17 (d, 3H, J = 7H
z), 1.37 (m, 2H), 1.54 (m, 1H), 1.81 (s, 2H), 1.95
(S, 3H), 2.25 (dd, 1H, J = 14Hz, 4Hz), 2.41 (m, 2H), 2.
61 (dd, 1H, J = 14Hz, 3Hz), 3.20 (s, 3H), 3.28 (s, 3H),
4.02 (m, 2H), 4.13 (d, 1H, J = 8Hz), 4.65 (t, 1H, J = 8H
z), 5.01 (br exchangeable, 2H), 5.09 (s, 1H), 5.37 (br d,
1H, 10Hz), 5.74 (t, 1H, J = 10Hz), 6.45 (t, 1H, J = 12H
z), 6.89 (br s, 1H), 6.97 (s, 1H), 9.27 (s, 1H); Mass spectrum m / z586 (M-2) ;. C 31 H 42 N theoretical values were calculated from ₄ O ₈ : C, 62.19; H, 7.07; N, 9.36%. Measurements: C, 61.76;
H, 6.88; N, 9.14%. The compounds of Examples 96-99 were prepared by the method of Example 95 from the appropriate 11-keto-17-demethoxygeldanamycin.

Example 96 17- (2'-methoxyethylamino) -11-oxyimino-17-demethoxygeldanamycin Mp 119-127 ° C (decomposition); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.
03 (d, 3H, J = 7 Hz), 1.18 (d, 3H, J = 7 Hz), 1.39 (m, 1
H), 1.84 (s, 3H), 1.86 (m, 1H), 1.98 (s, 3H), 2.32 (d
d, 1H, J = 14Hz, 4Hz), 2.68 (dd, 1H, J = 14Hz, 7Hz), 3.21
(S, 3H), 3.27 (s, 3H), 3.38 (s, 3H), 3.58 (m, 2H), 3.
62 (m, 2H), 3.95 (m, 2H), 4.12 (d, 1H, J = 8Hz), 4.90
(Br s, 1H), 5.11 (s, 1H), 5.38 (br d, 1H, J = 8Hz), 5.
75 (t, 1H, J = 10Hz), 6.50 (m, 2H), 6.9 (br s, 1H), 7.1
7 (s, 1H), 9.25 (s, 1H); mass spectrum m / z 616.
(M ⁺ ). Example 97 17-cyclopropylamino-11-oxyimino-17-demethoxygeldanamycin Mp (amorphous); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.7-0.9
(M, 4H), 1.0 (d, 3H, J = 7 Hz), 1.2 (d, 3H, J = 7 Hz), 1.3
−1.6 (m, 3H), 1.8 (s, 3H), 1.95 (m, 1H), 2.0 (s, 3
H), 2.7 (m, 1H), 2.9 (m, 2H), s, 3H), 3.3 (s, 3H), 4.0
5 (br s, 2H), 4.15 (d, 1H, J = 7Hz), 5.13 (d, 2H, J = 10H
z), 5.45 (d, 1H, J = 10 Hz), 5.8 (t, 1H, J = 10 Hz), 6.3
(D, 1H, J = 3Hz), 6.48 (t, 1H, J = 10Hz), 6.9 (br d, 1H,
10Hz), 7.08 (m, 1H), 7.15 (s, 1H), 9.28 (brs, 1H);
Mass spectrum m / z621 (M + Na) ;. C 31 H 42 N 4 O 8 · 0.5H 2 O
Calculated from: C, 61.27; H, 7.13; N, 9.22%. Found: C, 61.74; H, 7.25; N, 8.71%. Example 98 17-isopropylamino-11-oxyimino-17-demethoxygeldanamycin Mp 158-160 ° C; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 1.0 (d, 3H,
J = 7Hz), 1.15 (d, 3H, J = 7Hz), 1.2 (d, 3H, J = 7Hz), 1.
3 (d, 3H, J = 7Hz), 1.45-1.6 (brt, 1H), 1.7-1.9 (m,
4H), 2.0 (s, 3H), 2.2 (br d, 1H, J = 14), 2.75 (t, 1H, J
= 14Hz), 3.15 (s, 3H), 3.25 (s, 3H), 3.8−4.05 (m, 3
H), 4.1 (d, 1H, J = 10), 5.1 (s, 1H), 5.25-5.5 (br d,
3H), 5.7 (t, 1H, J = 10 Hz), 6.2 (d, 1H, J = 10 Hz), 6.4
(T, 1H, J = 10Hz), 6.75 (br d, 1H), 7.1 (s, 1H), 9.25
(Br s, 1H); mass spectrum m / z 623. (M + Na); C ₃₁ H
₄₄ N ₄ O ₈・ 1.5H ₂ O Calculated: C, 59.32; H, 7.55, N,
8.93%. Found: C, 59.27; H, 7.07; N, 8.66%. Example 99 17-allylamino-11-oxyimino-17-demethoxygeldanamycin Mp 135 [deg.] C; mass spectrum m / z 621 (M + Na).

Continuation of front page (56) References JP-A-55-111469 (JP, A) JP-A-55-111470 (JP, A) JP-A-55-113767 (JP, A) (58) Fields investigated (Int) .Cl. ⁶ , DB name) C07D 225/06

Claims (10)

(57) [Claims] (1) a compound of the following general formula, a pharmaceutically acceptable salt thereof or a prodrug thereof; Wherein R ¹ and R ² are both hydrogen; R ³ is hydrogen; R ⁴ is selected from the group consisting of OR ¹⁰ , NHR ⁸ and halo; R ¹⁰ is hydrogen, R ¹¹ C (= O)-, and R ¹¹ SO ² -and R
_{^{12 R 13 NSO 2 NHC (=}} O) - is selected from the group consisting of; R ¹¹ is amino (C ₁ -C ₈₎ alkyl, amino (C ₁ -C ₈₎
Alkyl, hydroxy (C ₁ -C ₈ ) alkyl, protected amino (C ₁ -C ₈ ) alkyl, protected hydroxy (C ₁ -C ₈ ) alkyl
-C ₈₎ alkyl, selected from the group consisting of phenyl and naphthyl; R ¹² and R ¹³ are hydrogen, (C ₁ -C ₈₎ alkyl, amino (C ₁ -C ₈₎ alkyl, dimethylamino (C ₁ - C ₈₎ alkyl, cyclo (C ₃ -C ₈₎ alkyl, or is selected from the group consisting of phenyl and naphthyl; or R ¹² and R
^13, together with the nitrogen to which they are attached, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4- (C ₁ -C ₄₎ alkyl-piperidinyloxy and N-
Forming a heterocyclic residue selected from the group consisting of (C ₁ -C ₄ ) piperazinyl; the alkyl, phenyl and naphthyl groups are (C ₁ -C ₈ ) alkyl, halo, nitro, amino, azide and (C ₁ -C ₄ ) piperazinyl; ₁ -C ₈₎ can be substituted with one or more residues selected from the group consisting of alkoxyl; or, R ³ and R ⁴ are both the general formulas = J group J is selected from O and NOH R ⁵ is NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are independently:
Selected from the group consisting of hydrogen, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; Alkynyl is optionally substituted and the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, and Imijizaroriru, furyl, selected from the group consisting of (C ₂ -C ₆₎ heterocycloalkyl and (C ₂ -C ₆₎ heterocycloaryl groups selected from the group comprising tetrahydrofuryl); carbon more than two If it contains an atom, it may be branched, cyclic or unbranched or a combination of branched, cyclic and unbranched groups; or R ⁸ and R ⁹ are
Together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl); or R ⁵ is R ¹⁴ O, wherein R ¹⁴
Is hydrogen or (C ₁ -C ₈₎ alkyl), R ₆
Is hydrogen or a group of the following general formula (Where m is an integer of 0 or 1-5, and each R
⁷ is halo, azide, nitro, (C ₁ -C ₈ ) alkyl, C ₁
-C ₈ alkoxyl, phenyl and naphthyl, cyano and, R ⁸ and R ⁹ be chosen) independently from NR ⁸ R ⁹ is as defined above; provided that, R ⁵ is OR ^14, R
^{When 10} is R ¹¹ C (＝ O), R ¹¹ must not be methyl. 2. The compound according to claim 1, wherein R ³ and R ⁴ together form a group of the general formula ＯO. 3. The compound according to claim 1, wherein R ³ and R ⁴ together form a group of the general formula NONOH. 4. A compound of the following general formula, a pharmaceutically acceptable salt thereof or a prodrug thereof: R ¹ and R ² together form a single bond; or R ³ and R ⁴ together form a group of the general formula = J wherein J is selected from O and NOH; R ⁵ Is NR ⁸ R ⁹ (where R ⁸ and R ⁹ are independently
Selected from the group consisting of hydrogen, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl; Alkynyl is optionally substituted and the substituents are halo, cyano, mercapto, (C ₁ -C ₈ ) alkylthio, optionally substituted amino, hydroxyl, (C ₁ -C ₈ ) alkoxyl, carboxyl, amidino, acylamino, and Imijizaroriru, furyl, selected from the group consisting of (C ₂ -C ₆₎ heterocycloalkyl and (C ₂ -C ₆₎ heterocycloaryl groups selected from the group comprising tetrahydrofuryl); carbon more than two If it contains an atom, it may be branched, cyclic or unbranched or a combination of branched, cyclic and unbranched groups; or R ⁸ and R ⁹ are
Together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl); or R ⁵ is R ¹⁴ O, wherein R ¹⁴
Is hydrogen or (C ₁ -C ₈₎ alkyl), R ₆
Is hydrogen or a group of the following general formula (Where m is an integer of 0 or 1-5, and each R
⁷ is halo, azide, nitro, (C ₁ -C ₈ ) alkyl, C ₁
-C ₈ alkoxyl, phenyl and naphthyl, cyano and, R ⁸ and R ⁹ be chosen) independently from NR ⁸ R ⁹ is as defined above; however, a single bond R ¹ and R ² are both When formed, R ³ is hydrogen and R ⁴ OR ¹⁰ and R ¹⁰ are hydrogen, R ⁵ is OR ¹⁴ (where R ¹⁴ is hydrogen or methyl) or NR ⁸ R ⁹ (here In, HNR ⁸ R ⁹ is ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine,
Heptylamine, octylamine, allylamine, β-
Hydroxyethylamine, β-chloroethylamine, β
-Glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine, piperidine, dimethylamine, aminoethylamine, diglycol Amine, β-morpholinoethylamine, β-piperidinoethylamine, picolylamine, β-pyrrolidinoethylamine, β-pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine) Must not be; R ⁵ is O
If R ¹⁴ and R ¹⁰ is R ¹¹ C (＝ O), then R ¹¹ must not be methyl. 5. The compound according to claim 4, wherein R ³ and R ⁴ together form a group of the general formula ＯO. 6. The compound according to claim 4, wherein R ³ and R ⁴ together form a group of the general formula NONOH. 7. A pharmaceutical composition for preventing or inhibiting tumor growth in mammals, comprising a compound according to claim 1 in an antitumor effective amount. 8. A pharmaceutical composition for inhibiting an oncogene product in a mammal, comprising a compound according to claim 1 in an amount effective to inhibit the oncogene product. 9. A pharmaceutical composition for preventing cancer in a mammal, comprising a compound according to claim 1 in an amount effective for inhibiting oncogene products or for preventing tumors. 10. An EG in a mammal comprising an amount of the compound of claim 1 effective to inhibit a growth factor.
Pharmaceutical compositions that inhibit growth factors, such as F receptor, NGF receptor, PDGF receptor and insulin receptor, which play important roles in uncontrolled cell proliferation.