Information
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Patent Application
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20040127433
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Publication Number
20040127433
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Date Filed
March 24, 200321 years ago
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Date Published
July 01, 200420 years ago
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CPC
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US Classifications
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International Classifications
Abstract
Erythromycin derivatives or salt thereof having excellent antibacterial activity against a typical acid-fast mycobacteria and useful as antibacterial agent, which is represented by the following general formula:
1
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel erythromycin derivatives or salts thereof as antibacterial agents, which have excellent antibacterial activity especially against a typical acid-fast mycobacteria including multiple drug-resistant bacteria. The present invention also relates to medicaments comprising the same as an active ingredient.
RELATED ART
[0002] Atypical acid-fast mycobacteria have low sensitivity to available antibacterial agents, and for this reason, a typical acid-fast mycobacteriosis is extremely intractable diseases. Rifampicin (The Merck Index, 12th edition, 8382) and the like are known as compounds that can be applied to similar disease to those treated by the compounds of the present invention. Furthermore, as macrolide derivatives that have a similar chemical structure to that of the compounds of the present invention, clarithromycin (The Merck Index, 12th edition, 2400), roxithromycin (The Merck Index, 12th edition, 8433), and compounds disclosed in Japanese Patent Unexamined Publication (KOKAI) No. 11-236395 are known. Clinical application of clarithromycin has been approved in the United State and other countries, which is considered as the most promising agent for the treatment of a typical acid-fast mycobacteriosis among macrolide derivatives at present. However, antibacterial activity of clarithromycin is also not sufficient as an agent for treatment of a typical acid-fast mycobacteriosis. Therefore, development of more excellent antibacterial agents has been desired.
[0003] In recent years, increase of opportunistic infections has become a big social problem. Due to increase of compromised hosts with degraded biophylaxis mechanism such as patients infected by human immunodeficiency virus (HIV), patients of cancer and diabetes, and elderly persons, increase of multiple drug-resistant bacteria whose typical examples are Methicillin-resistant Staphylococcus aureus and the like, microbial substitution of patients by these bacteria and so forth, which are causes of the increase of the opportunistic infections, chemotherapy of opportunistic infections become more difficult. Atypical acid-fast mycobacteriosis is one of the opportunistic infections which have become a problem. Atypical acid-fast mycobacteria, the causal bacteria of the a typical acid-fast mycobacteriosis, proliferate slowly, and even when they are captured by phagocytes, they can survive in the cells for a long period of time. Therefore, prolonged chemotherapy is required to treat infections by these bacteria. In particular, among the a typical acid-fast mycobacteria, almost no effective antibacterial agent is available against Mycobacterium avium complex (MAC), and accordingly, surgical treatment for the therapeutic treatment of this infection has also been studied at present. Moreover, even the aforementioned clarithromycin lacks selectivity to the a typical acid-fast mycobacteria, and clarithromycin resistant MACs have already been known. As explained above, various problems arise in chemotherapy of a typical acid-fast mycobacteriosis, for example, low sensitivity to known antibacterial agents, and conditions of high possibility of microbial substitution or emergence of resistant bacteria.
DISCLOSURE OF THE INVENTION
[0004] An object of the present invention is to provide a compound that has selective and excellent antibacterial activity against a typical acid-fast mycobacteria.
[0005] The inventors of the present invention eagerly conducted researches to achieve the aforementioned object. As a result, they found that the novel erythromycin derivatives or salts thereof according to the present invention were useful as antibacterial agents, and that they had excellent antibacterial activity particularly against a typical acid-fast mycobacteria. The present invention was achieved on the basis of the findings.
[0006] The present invention thus relates to novel erythromycin derivatives represented by the following general formula (I) or salts thereof:
2
[0007] wherein, R1 and R2 independently represent hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a saturated or unsaturated homocyclic group which may be substituted, a saturated or unsaturated heterocyclic group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, or R1 and R2 may combine together with the nitrogen atom to which they bind to form a saturated or unsaturated heterocyclic group which may further contain one or more heteroatoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom and which may be substituted, R3 represents hydrogen atom or methyl group, R5 represents hydrogen atom or hydroxyl group when R4 represents hydroxyl group, or R4 and R6 may combine together with two carbon atoms on the ring to which each of them binds to form a heterocyclic group represented by the following formula (II):
3
[0008] R6 and R7 independently represent hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, or R6 and R7 may bind together with the nitrogen atom to which they bind to form a saturated heterocyclic group which may further contain one or more heteroatoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom and which may be substituted, X represents NH or a group represented by N—O—R8, Y represents a group represented by O—C(═O)—R9 or O—C(═O)—U—R10, or represents an oxy group substituted with a heterocyclic group represented by the following formula (III):
4
[0009] Z represents oxygen atom or sulfur atom, W represents oxygen atom or nitrogen atom which may be substituted, R8 and R9 independently represents hydrogen atom, an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a saturated or unsaturated homocyclic group which may be substituted, a saturated or unsaturated heterocyclic group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, R10 represents an alkyl group which may be substituted, a saturated or unsaturated homocyclic group which may be substituted, a saturated or unsaturated heterocyclic group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, R11 represents hydrogen atom, hydroxyl group, or a group represented by O—C(═O)—R12 or O—C(═O)—V—R13, R12 and R13 independently represent an alkyl group which may be substituted, a saturated or unsaturated homocyclic group which may be substituted, a saturated or unsaturated heterocyclic group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, U and V independently represent oxygen atom or a group represented by NH.
[0010] According to the second aspect of the present invention, provided is the compound or the salt thereof wherein R3 is hydrogen atom among the compounds represented by the aforementioned general formula (I).
[0011] According to the third aspect of the present invention, provided is the compound or the salt thereof wherein Y is the oxy group substituted by the heterocyclic group represented by the aforementioned formula (III) among the compounds represented by the aforementioned general formula (I).
[0012] According to the forth aspect of the present invention, provided is the compound or the salt thereof wherein R1 is hydrogen atom among the compounds represented by the aforementioned general formula (I). It is apparent to one of ordinary skill in the art that the compounds provided may exist as tautomers, and therefore, the compounds may be present in the form represented by the aforementioned general formula (I), or may be present as isomers represented by the following general formula (IV):
5
[0013] wherein R2, R3, R4, R5, R6, R7, X, Y, and Z have the same meaning as those defined above.
[0014] According to further aspect of the present invention, provided is a medicament which comprises a compound represented by the aforementioned general formula (I) or a salt thereof as an active ingredient. The medicament provided by the present invention can be suitably used as, for example, an antibacterial agent, in particular, an agent for therapeutic or preventive treatment of a typical acid-fast mycobacteriosis.
[0015] The present invention further provides a use of the compound represented by the aforementioned general formula (I) or a pharmacologically acceptable salt thereof for the manufacture of the aforementioned medicament; and a method for therapeutic treatment of infectious diseases, in particular a method for therapeutic treatment of a typical acid-fast mycobacteriosis which comprises the step of administering to a mammal including a human a therapeutically effective amount of a compound represented by the aforementioned general formula (I) or a pharmacologically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
[0016] In the aforementioned general formula (I) according to the present invention, the alkyl group, defined as “an alkyl group which may be substituted” represented by R1, R2, R6, R7, R8, R9, R10, R12, and R13, means a linear or branched alkyl group having 1 to 14 carbon atoms. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1-ethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group, 1,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-isopropylpropyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group and the like.
[0017] In the aforementioned general formula (I) according to the present invention, the alkenyl group, defined as “an alkenyl group which may be substituted” represented by R1, R2, R6, R7, R8, and R9, means a linear or branched alkenyl group or alkapolyenyl group having 2 to 14 carbon atoms and one or more double bonds at any positions. Examples include vinyl group, allyl group, 1-methylethenyl group, propenyl group, butenyl group, butadienyl group, pentenyl group, isoprenyl group, 4-methylpentenyl group, hexenyl group, hexadienyl group, hexatrienyl group, heptenyl group, octenyl group, nonenyl group, decenyl group, undecenyl group, dodecenyl group, dodecadienyl group, tridecenyl group, tetradecenyl group, geranyl group, myrcenyl group, ocimenyl group, neryl group, linaloyl group, citronellyl group and the like. The alkynyl group, defined as “an alkynyl group which may be substituted” represented by R1, R2, R6, R7, R8, and R9, means a linear or branched alkynyl group or alkapolyynyl group having 2 to 14 carbon atoms and one or more triple bonds at any positions. Examples include ethynyl group, propynyl group, butynyl group, 1-methyl-2-propynyl group, pentynyl group, hexynyl group, hexadiynyl group, heptynyl group, octynyl group, nonynyl group, decynyl group, undecynyl group, dodecynyl group, tridecynyl group, tetradecynyl group and the like.
[0018] In the aforementioned general formula (I) according to the present invention, the saturated or unsaturated homocyclic group or saturated or unsaturated heterocyclic group represented by R1, R2, R8, R9, R10, R12, and R13 may be monocyclic or polycyclic group. Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, bicyclo[3.2.1]octyl group, bicyclo[5.2.0]nonyl group, aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, hexahydro-1H-azepinyl group, piperazinyl group, pyrazolidinyl group, imidazolidinyl group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, phenyl group, naphthyl group, pyridyl group, pyrimidyl group, pyrazinyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, furyl group, thienyl group, pyrrolyl group, benzofuranyl group, benzo[b]thienyl group, benzimidazolyl group, indolyl group, quinolyl group, isoquinolyl group, 1,2,3,4-tetrahydronaphthyl group, benzopyrrolidinyl group, cyclohexenyl group and the like. The saturated or unsaturated homocyclic group or saturated or unsaturated heterocyclic group represented by R1, R2, R8, R9, R10, R12, and R13 may be substituted.
[0019] In the aforementioned general formula (I) according to the present invention, the alkyl group substituted with a homocyclic group or the alkyl group substituted with a heterocyclic group represented by R1, R2, R6, R7, R8, R9, R10, R12, and R13 means a group formed by substitution of the aforementioned saturated or unsaturated homocyclic group or saturated or unsaturated heterocyclic group (the homocyclic group or the heterocyclic group may be substituted) on the aforementioned linear or branched alkyl group having 1 to 14 carbon atoms. Examples include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylethyl group, cyclohexylpropyl group, cyclohexylbutyl group, cyclohexylpentyl group, cyclohexylhexyl group, cyclohexylheptyl group, cyclohexyloctyl group, cyclohexylnonyl group, cyclohexyldecyl group, cyclohexylundecyl group, cyclohexyldodecyl group, cyclohexyltridecyl group, cyclohexyltetradecyl group, bicyclo[3.2.1]octylmethyl group, bicyclo[5.2.0]nonylmethyl group, aziridinylmethyl group, azetidinylmethyl group, pyrrolidinylmethyl group, pyrrolidinylethyl group, pyrrolidinylhexyl group, pyrrolidinyltetradecyl group, piperidinylmethyl group, piperidinylethyl group, piperidinylpropyl group, piperidinylhexyl group, piperidinyltetradecyl group, hexahydro-1H-azepinylmethyl group, piperazinylmethyl group, piperazinylethyl group, piperazinylpropyl group, morpholinylmethyl group, morpholinylethyl group, morpholinylpropyl group, thiomorpholinylmethyl group, thiomorpholinylethyl group, tetrahydropyranylmethyl group, tetrahydropyranylethyl group, tetrahydrothiopyranylmethyl group, tetrahydrothiopyranylethyl group, (2,3-dihydrobenzofuran-2-yl)methyl group, (2,3-dihydrobenzofuran-2-yl)ethyl group, (3,4-dihydrobenzo[b]pyran-2-yl)methyl group, (3,4-dihydrobenzo[b]pyran-2-yl)ethyl group, (2,3-dihydro-1,4-benzodioxin-2-yl)methyl group, (2,3-dihydro-1,4-benzodioxin-2-yl)ethyl group, benzyl group, phenethyl group, α-methylbenzyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, phenyltetradecyl group, naphthylmethyl group, naphthylethyl group, pyridylmethyl group, pyridylethyl group, pyridylbutyl group, pyridyldodecyl group, pyrimidylmethyl group, pyrazinylmethyl group, imidazolylmethyl group, imidazolylethyl group, imidazolylbutyl group, oxazolylmethyl group, isoxazolylmethyl group, thiazolylmethyl group, thiazolylbutyl group, isothiazolylmethyl group, furylmethyl group, furylethyl group, thenyl group, thienylethyl group, pyrrolylmethyl group, pyrrolylethyl group, benzofuranylmethyl group, benzofuranylethyl group, benzo[b]thienylmethyl group, benzo[b]thienylethyl group, benzimidazolylmethyl group, benzimidazolylethyl group, indolylmethyl group, indolylethyl group, quinolylmethyl group, quinolylethyl group, isoquinolylmethyl group, isoquinolylethyl group, 1,2,3,4-tetrahydronaphthylmethyl group, 1,2,3,4-tetrahydronaphthylethyl group, cyclohexenylethyl group and the like.
[0020] In the aforementioned general formula (I) according to the present invention, when R1 and R2, together with the nitrogen atom to which each of them binds, form the saturated or unsaturated heterocyclic group which may further contain one or more heteroatoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom and which may be substituted, said heterocyclic group may be monocyclic or polycyclic group. Examples include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, hexahydro-1H-azepinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyrazolidinyl group, imidazolidinyl group, imidazolyl group, pyrrolyl group, benzimidazolyl group, indolyl group, isoindolyl group, pyrrolinyl group, indolinyl group, isoindolinyl group, pyrazolyl group, tetrahydroquinolyl group, tetrahydroisoquinolyl group, decahydroquinolyl group, decahydroisoquinolyl group and the like.
[0021] In the aforementioned general formula (I) according to the present invention, the cycloalkyl group represented by R6 and R7 means a cycloalkyl group having 3 to 6 carbon atoms. Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. The cycloalkyl group may be substituted. When R6 and R7, together with the nitrogen atom to which each of them binds, form the saturated or unsaturated heterocyclic group which may further contain one or more heteroatoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom and which may be substituted, examples of the heterocyclic group include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, hexahydro-1H-azepinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, pyrazolidinyl group, imidazolidinyl group, In the aforementioned general formula (I) according to the present invention, when the defined group is referred to as “which may be substituted”, any substitutable groups may optionally present on said group. The number, kind, and substituting position of the substituents are not particularly limited. When two or more substituents exist, they may be the same or different. Examples of the substituents include oxo group, hydroxyl group which may be protected, an alkoxyl group which may be substituted, alkylthio group, an amino group which may be substituted, a carbamoyl group which may be substituted, an aryloxy group which may be substituted, an arylthio group, an aralkyloxy group, an aralkylthio group, a halogen atom, an alkyl group, trifluoromethyl group, an acyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group which may be substituted, an aryl group which may be substituted, an aralkyl group which may be substituted, cyano group, nitro group, guanidino group, amidino group, sulfamoyl group, carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group and the like.
[0022] As the protective group of the hydroxyl group, any group may be used so far that the group is substantially inert in a reaction system where a hydroxyl group should not participate in a reaction and the group is readily cleavable under a condition of a specific deprotective reaction. Examples include an alkanoyl group, a trialkylsilyl group, benzyl group, benzyloxycarbonyl group and the like. Examples of the alkanoyl group as the hydroxyl protective group include formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group and the like. Examples of the trialkylsilyl group as the hydroxyl protective group include trimethylsilyl group, triethylsilyl group and the like. The above alkoxyl group which may be substituted means a linear or branched alkoxyl group which may be substituted. Examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group, n-undecyloxy group, n-dodecyloxy group, n-tridecyloxy group, n-tetradecyloxy group, methoxyethoxy group and the like. The above alkylthio group means a linear or branched alkylthio group. Examples include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, n-pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, n-hexylthio group, n-heptylthio group, n-octylthio group, n-nonylthio group, n-decylthio group, n-undecylthio group, n-dodecylthio group, n-tridecylthio group, n-tetradecylthio group and the like.
[0023] Examples of the above optionally substituted amino group include amino group, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, n-hexylamino group, n-dodecyl amino group, n-tetradecylamino group, anilino group, benzylamino group, phenethylamino group, phenylpropylamino group, phenylhexylamino group, phenyldodecylamino group, phenyltetradecylamino group, pyridylmethylamino group, dimethylamino group, diethylamino group, dibenzylamino group, N-ethyl-N-methylamino group, N-methylanilino group, N-benzyl-N-methylamino group, acetylamino group, propionylamino group, tert-butoxycarbonylamino group, benzyloxycarbonylamino group and the like. Examples of the optionally substituted carbamoyl group include carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-n-propylcarbamoyl group, N-isopropylcarbamoyl group, N-n-butylcarbamoyl group, N-isobutylcarbamoyl group, N-sec-butylcarbamoyl group, N-tert-butylcarbamoyl group, N-n-pentyl carbamoyl group, N-isopentylcarbamoyl group, N-neopentylcarbamoyl group, N-tert-pentylcarbamoyl group, N-n-hexylcarbamoyl group, N-n-tetradecylcarbamoyl group, N-carboxylmethylcarbamoyl group, N-carbamoylmethylcarbamoyl group, N-aminoethylcarbamoyl group, N-dimethylaminomethylcarbamoyl group, N-phenylcarbamoyl group, N-pyridylcarbamoyl group, N-b enzylcarb amoyl group, N-pyridylmethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,N-diethylcarbamoyl group, N,N-dibenzylcarbamoyl group, N-ethyl-N-methylcarbamoyl group and the like.
[0024] The aryloxy group which may be substituted means an aryloxy group whose aryl moiety may be substituted at any position. Examples include phenoxy group, methylphenoxy group, nitrophenoxy group, chlorophenoxy group, naphthyloxy group, pyridyloxy group, pyrimidyloxy group, pyrazinyloxy group, imidazolyloxy group, oxazolyloxy group, isoxazolyloxy group, thiazolyloxy group, isothiazolyloxy group, furyloxy group, thienyloxy group, pyrrolyloxy group, benzofuranyloxy group, benzo[b]thienyloxy group, benzimidazolyloxy group, indolyloxy group, quinolyloxy group, isoquinolyloxy group, (1,2,3,4-tetrahydronaphthalen-5-yl)oxy group, (1,2,3,4-tetrahydronaphthalen-6-yl)oxy group and the like. Examples of the arylthio group include phenylthio group, naphthylthio group, pyridylthio group, pyrimidylthio group, pyrazinylthio group, imidazolylthio group, oxazolylthio group, isoxazolylthio group, thiazolylthio group, isothiazolylthio group, furylthio group, thienylthio group, pyrrolylthio group, benzofuranylthio group, benzo[b]thienylthio group, benzimidazolylthio group, indolylthio group, quinolylthio group, isoquinolylthio group, (1,2,3,4-tetrahydronaphthalen-5-yl)thio group,
[0025] (1,2,3,4-tetrahydronaphthalen-6-yl)thio group and the like. Examples of the aralkyloxy group include benzyloxy group, phenethyloxy group, phenylpropyloxy group, phenylhexyloxy group, phenyldodecyloxy group, phenyltetradecyloxy group, pyridylmethyloxy group and the like. Examples of the aralkylthio group include benzylthio group, phenethylthio group, phenylpropylthio group, phenylhexylthio group, phenyldodecylthio group, phenyltetradecylthio group, pyridylmethylthio group and the like. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, and iodine atom.
[0026] Examples of the acyl group include formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, nicotinoyl group, isonicotinoyl group, pyrimidylcarbonyl group, pyrazinylcarbonyl group, oxazolylcarbonyl group, isoxazolylcarbonyl group, thiazolylcarbonyl group, isothiazolylcarbonyl group, naphthoyl group, furoyl group, benzofuranylcarbonyl group, benzo[b]thienylcarbonyl group, benzimidazolylcarbonyl group, indolylcarbonyl group, thenoyl group, pyrrolylcarbonyl group, quinolylcarbonyl group, isoquinolylcarbonyl group, cyclohexylcarbonyl group, phenylacetyl group, naphthylacetyl group, pyridylacetyl group, pyrimidylacetyl group, pyrazinylacetyl group, imidazolylacetyl group, oxazolylacetyl group, isoxazolylacetyl group, thiazolylacetyl group, isothiazolylacetyl group, furylacetyl group, benzofuranylacetyl group, benzo[b]thienylacetyl group, benzimidazolylacetyl group, indolylacetyl group, thienylacetyl group, pyrrolylacetyl group, quinolylacetyl group, isoquinolylacetyl group, cyclohexylacetyl group, phenylpropionyl group, phenylhexylcarbonyl group, phenyldodecylcarbonyl group, phenyltetradecylcarbonyl group and the like. Examples of the cycloalkenyl group include cyclopentenyl group, cyclohexenyl group and the like.
[0027] Examples of the saturated heterocyclic group which may be substituted include aziridinyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, hexahydro-1H-azepinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, oxopyrrolidinyl group, methylpiperazinyl group, pyridylpiperazinyl group and the like. The aryl group which may be substituted means a group which may be substituted at any position of the aryl ring. Examples include optionally substituted monocyclic or polycyclic aromatic rings such as phenyl group, hydroxyphenyl group, methoxyphenyl group, aminophenyl group, acetamidephenyl group, carbamoylphenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, dichlorophenyl group, toluyl group, n-heptylphenyl group, n-tetradecylphenyl group, trifluoromethylphenyl group, biphenyl group, cyanophenyl group, nitrophenyl group, amidinophenyl group, guanidinophenyl group, sulfamoylphenyl group, naphthyl group, pyridyl group, pyrimidyl group, pyrazinyl group, imidazolyl group, furyl group, thienyl group, pyrrolyl group, benzofuranyl group, benzo[b]thienyl group, benzimidazolyl group, indolyl group, quinolyl group, isoquinolyl group, phenylimidazolyl group, phenylthiazolyl group, pyridylimidazolyl group, pyridylthiazolyl group and the like. The aralkyl group which may be substituted means an aralkyl group whose aryl group may be substituted at any position. Examples include benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, phenylheptyl group, phenyloctyl group, phenylnonyl group, phenyldecyl group, phenylundecyl group, phenyldodecyl group, phenyltridecyl group, phenyltetradecyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group, naphthyl butyl group, pyridylmethyl group, pyridylethyl group, pyridylpropyl group, pyrimidylethyl group, pyrimidylpropyl group, pyrazinylethyl group, pyrazinylpropyl group, imidazolylethyl group, imidazolylpropyl group, imidazolylbutyl group, 4-pyridylimidazolylbutyl group, oxazolylethyl group, oxazolylpropyl group, isoxazolylethyl group, isoxazolylpropyl group, thiazolylethyl group, thiazolylpropyl group, isothiazolylethyl group, isothiazolylpropyl group, furylethyl group, furylpropyl group, thienylethyl group, thienylpropyl group, pyrrolylethyl group, pyrrolylpropyl group, benzofuranylethyl group, benzofuranylpropyl group, benzo[b]thienylethyl group, benzo[b]thienylpropyl group, benzimidazolylethyl group, benzimidazolylpropyl group, indolylethyl group, indolylpropyl group, quinolylethyl group, quinolylpropyl group, quinolylbutyl group, isoquinolylethyl group, isoquinolylpropyl group, isoquinolylbutyl group and the like.
[0028] Examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, n-hexyloxycarbonyl group, n-heptyloxycarbonyl group, n-octyloxycarbonyl group, n-nonyloxycarbonyl group, n-decyloxycarbonyl group, n-undecyloxycarbonyl group, n-dodecyloxycarbonyl group, n-tridecyloxycarbonyl group, n-tetradecyloxycarbonyl group and the like. Examples of the aryloxycarbonyl group include phenoxycarbonyl group, naphthyloxycarbonyl group, pyridyloxycarbonyl group, pyrimidyloxycarbonyl group, pyrazinyloxycarbonyl group, imidazolyloxycarbonyl group, oxazolyloxycarbonyl group, isoxazolyloxycarbonyl group, thiazolyloxycarbonyl group, isothiazolyloxycarbonyl group, furyloxycarbonyl group, thienyloxycarbonyl group, pyrrolyloxycarbonyl group, benzofuranyloxycarbonyl group, benzo[b]thienyloxycarbonyl group, benzimidazolyloxycarbonyl group, indolyloxycarbonyl group, quinolyloxycarbonyl group, isoquinolyloxycarbonyl group and the like. Examples of the aralkyloxycarbonyl group include benzyloxycarbonyl group, phenethyloxycarbonyl group, phenylhexyloxycarbonyl group, phenyldodecyloxycarbonyl group, phenyltetradecyloxycarbonyl group, naphthylmethyloxycarbonyl group, pyridylmethyloxycarbonyl group, pyrimidylmethyloxycarbonyl group, pyrazinylmethyloxycarbonyl group, imidazolylmethyloxycarbonyl group, oxazolylmethyloxycarbonyl group, isoxazolylmethyloxycarbonyl group, thiazolylmethyloxycarbonyl group, isothiazolylmethyloxycarbonyl group, furylmethyloxycarbonyl group, thienylmethyloxycarbonyl group, pyrrolylmethyloxycarbonyl group, benzofuranylmethyloxycarbonyl group, benzo[b]thienylmethyloxycarbonyl group, benzimidazolylmethyloxycarbonyl group, indolylmethyloxycarbonyl group, quinolylmethyloxycarbonyl group, isoquinolylmethyloxycarbonyl group and the like.
[0029] Examples of the alkylsulfinyl group include methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, n-pentylsulfinyl group, isopentylsulfinyl group, neopentylsulfinyl group, tert-pentylsulfinyl group, n-hexylsulfinyl group, n-heptylsulfinyl group, n-octylsulfinyl group, n-nonylsulfinyl group, n-decylsulfinyl group, n-undecylsulfinyl group, n-dodecylsulfinyl group, n-tridecylsulfinyl group, n-tetradecylsulfinyl group and the like. Examples of the arylsulfinyl group include phenylsulfinyl group, naphthylsulfinyl group, pyridylsulfinyl group, pyrimidylsulfinyl group, pyrazinylsulfinyl group, imidazolylsulfinyl group, oxazolylsulfinyl group, isoxazolylsulfinyl group, thiazolylsulfinyl group, isothiazolylsulfinyl group, furylsulfinyl group, thienylsulfinyl group, pyrrolylsulfinyl group, benzofuranylsulfinyl group, benzo[b]thienylsulfinyl group, benzimidazolylsulfinyl group, indolylsulfinyl group, quinolylsulfinyl group, isoquinolylsulfinyl group and the like. Examples of the aralkylsulfinyl group include benzylsulfinyl group, phenethylsulfinyl group, phenylhexylsulfinyl group, phenyldodecylsulfinyl group, phenyltetradecylsulfinyl group, naphthylmethylsulfinyl group, pyridylmethylsulfinyl group, pyrimidylmethylsulfinyl group, pyrazinylmethylsulfinyl group, imidazolylmethylsulfinyl group, oxazolylmethylsulfinyl group, isoxazolylmethylsulfinyl group, thiazolylmethylsulfinyl group, isothiazolylmethylsulfinyl group, furylmethylsulfinyl group, thienylmethylsulfinyl group, pyrrolylmethylsulfinyl group, benzofuranylmethylsulfinyl group, benzo[b]thienylmethylsulfinyl group, benzimidazolylmethylsulfinyl group, indolylmethylsulfinyl group, quinolylmethylsulfinyl group, isoquinolylmethylsulfinyl group and the like.
[0030] Examples of the alkylsulfonyl group include mesyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, tert-pentylsulfonyl group, n-hexylsulfonyl group, n-heptylsulfonyl group, n-octylsulfonyl group, n-nonylsulfonyl group, n-decylsulfonyl group, n-undecylsulfonyl group, n-dodecylsulfonyl group, n-tridecylsulfonyl group, n-tetradecylsulfonyl group and the like. Examples of the arylsulfonyl group include phenylsulfonyl group, naphthylsulfonyl group, pyridylsulfonyl group, pyrimidylsulfonyl group, pyrazinylsulfonyl group, imidazolylsulfonyl group, oxazolylsulfonyl group, isoxazolylsulfonyl group, thiazolylsulfonyl group, isothiazolylsulfonyl group, furylsulfonyl group, thienylsulfonyl group, pyrrolylsulfonyl group, benzofuranylsulfonyl group, benzo[b]thienylsulfonyl group, benzimidazolylsulfonyl group, indolylsulfonyl group, quinolylsulfonyl group, isoquinolylsulfonyl group and the like. Examples of the aralkylsulfonyl group include benzylsulfonyl group, phenethylsulfonyl group, phenylhexylsulfonyl group, phenyldodecylsulfonyl group, phenyltetradecylsulfonyl group, naphthylmethylsulfonyl group, pyridylmethylsulfonyl group, pyrimidylmethylsulfonyl group, pyrazinylmethylsulfonyl group, imidazolylmethylsulfonyl group, oxazolylmethylsulfonyl group, isoxazolylmethylsulfonyl group, thiazolylmethylsulfonyl group, isothiazolylmethylsulfonyl group, furylmethylsulfonyl group, thienylmethylsulfonyl group, pyrrolylmethylsulfonyl group, benzofuranylmethylsulfonyl group, benzo[b]thienylmethylsulfonyl group, benzimidazolylmethylsulfonyl group, indolylmethylsulfonyl group, quinolylmethylsulfonyl group, isoquinolylmethylsulfonyl group and the like.
[0031] Examples of the alkyl group or cycloalkyl group which may be a substituent include those explained above.
[0032] In the compounds of the present invention represented by the aforementioned general formula (I), when the above defined group or functional group, or a part of the above defined group or functional group is a group or functional group corresponding to a “saturated homocyclic group”, “saturated heterocyclic group”, “unsaturated homocyclic group”, or “unsaturated heterocyclic group”, said cyclic groups substitute/bind at any position on a substitutable/bindable atom on a ring, unless substituting/binding position is specifically defined.
[0033] The compounds of the present invention represented by the aforementioned general formula have asymmetric carbon atoms, and accordingly, stereoisomers such as optical isomers, diastereoisomers, and geometrical isomers may exist. These isomers and mixtures thereof, and salts thereof also fall within the scope of the present invention. Among the compounds of the present invention represented by the aforementioned general formula (I), the compounds wherein R1 is hydrogen atom may exist as the tautomers represented by the general formula (IV). Said isomers and salt thereof as well as stereoisomers thereof based on asymmetric carbon atoms also fall within the scope of the present invention.
[0034] The compounds represented by the aforementioned general formula (I) can be converted into salts, if desired, preferably into pharmacologically acceptable salts. The salt formed can be converted into compounds in free forms. Examples of the salts of the compounds of the present invention represented by the aforementioned general formula (I) include acid addition salts or alkali addition salts. Examples of the acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, hydroiodide and phosphate, organic acid salts such as acetate, propionate, butyrate, isobutyrate, formate, valerate, isovalerate, pivalate, trifluoroacetate, acrylate, maleate, tartrate, citrate, oleate, laurate, stearate, enanthate, caprylate, caprate, palmitate, myristate, heptadecanoate, succinate, lactobionate, glutarate, sebacate, gluconate, glycolate, sorbate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, phthalate, terephthalate, cinnamate, p-toluenesulfonate, laurylsulfate, gluceptate, malate, malonate, aspartate, glutamate, adipate, oxalate, nicotinate, picrate, thiocyanate, undecanoate, mandelate, fumarate, 10-camphorsulfonate, lactate, 5-oxotetrahydrofuran-2-carboxylate and 2-hydroxyglutarate. Examples of alkali addition salts include, for example, mineral alkali salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, and organic base salts such as ethanolamine salt and N,N-dialkylethanolamine salt, and salts of the optically active substance thereof.
[0035] The compounds of the present invention represented by the aforementioned general formula (I) or salts thereof can exist in the forms of any crystals depending on manufacturing conditions, or may exist as any hydrates or solvates formed with organic solvents. These crystalline forms, hydrates, and solvates, and mixtures thereof also fall within the scope of the present invention.
[0036] Preferred compounds of the present invention include the compounds set out below. However, the present invention is not limited to these compounds. In the compounds shown in the tables below, it should be understood that the compounds wherein R1 is hydrogen atom may exist as tautomers as explained above, and such tautomers also fall within the scope of preferred compounds. In the table, Me represents methyl group, Et represents ethyl group, n-Pr represents n-propyl group, i-Pr represents isopropyl group, n-Bu represents n-butyl group, i-Bu represents isobutyl group, sec-Bu represents sec-butyl group, tert-Bu represents tert-butyl group, n-Pent represents n-pentyl group, i-Pent represents isopentyl group, neoPent represents neopentyl group, tert-Pent represents tert-pentyl group, n-Hex represents n-hexyl group, n-Hept represents n-heptyl group, n-Oct represents n-octyl group, n-Non represents n-nonyl group, n-Dec represents n-decyl group, n-Undec represents n-undecyl group, n-Dodec represents n-dodecyl group, n-Tridec represents n-tridecyl group, n-Tetradec represents n-tetradecyl group, and Ac represents acetyl group.
1|
|
|
6
|
Compound
No.NR1R2
|
1NH2
2NHMe
3NHEt
4NH-n-Pr
5NH-i-Pr
6NH-n-Bu
7NH-n-Pent
8NH-n-Hex
9NH-n-Oct
10NH-n-Dec
11NH-n-Dodec
12NH-n-Tetradec
|
137
|
148
|
159
|
1610
|
1711
|
1812
|
1913
|
2014
|
2115
|
2216
|
23NMe2
24NEt2
25NMe-n-Dec
26NMe-n-Tetradec
|
2717
|
2818
|
2919
|
3020
|
3121
|
3222
|
3323
|
3424
|
3525
|
3626
|
3727
|
3828
|
3929
|
4030
|
4131
|
4232
|
4333
|
4434
|
4535
|
4636
|
4737
|
4838
|
4939
|
5040
|
5141
|
5242
|
5343
|
5444
|
5545
|
5646
|
5747
|
5848
|
5949
|
6050
|
6151
|
6252
|
6353
|
6454
|
6555
|
6656
|
6757
|
6858
|
6959
|
7060
|
7161
|
7262
|
7363
|
7464
|
7565
|
7666
|
7767
|
7868
|
7969
|
8070
|
8171
|
8272
|
8373
|
8474
|
8575
|
8676
|
8777
|
8878
|
8979
|
9080
|
9181
|
9282
|
9383
|
9484
|
9585
|
9686
|
9787
|
9888
|
9989
|
10090
|
10191
|
10292
|
10393
|
10494
|
10595
|
10696
|
10797
|
10898
|
10999
|
110100
|
111101
|
112102
|
113103
|
114104
|
115105
|
116106
|
117107
|
118108
|
119109
|
120110
|
121111
|
122112
|
123113
|
124114
|
125115
|
126116
|
127117
|
128118
|
129119
|
130120
|
131121
|
132122
|
133123
|
134124
|
135125
|
136126
|
137127
|
138128
|
139129
|
140130
|
141131
|
142132
|
143133
|
144134
|
145135
|
146136
|
147137
|
148138
|
149139
|
150140
|
151141
|
152142
|
153143
|
154144
|
155145
|
156146
|
157147
|
158148
|
159149
|
160150
|
161151
|
162152
|
163153
|
164154
|
165155
|
166156
|
167157
|
168158
|
169159
|
170160
|
171161
|
172162
|
173163
|
174164
|
175165
|
176166
|
177167
|
178168
|
179169
|
180170
|
181171
|
182172
|
183173
|
184174
|
185175
|
186176
|
187177
|
188178
|
189179
|
190180
|
191181
|
192182
|
193183
|
194184
|
195185
|
196186
|
197187
|
198188
|
199189
|
200190
|
201191
|
202192
|
203193
|
204194
|
205195
|
206196
|
207197
|
208198
|
209199
|
210200
|
211201
|
212202
|
213203
|
214204
|
215205
|
216206
|
217207
|
218208
|
219209
|
220210
|
221211
|
222212
|
223213
|
224214
|
225215
|
226216
|
227217
|
228218
|
229219
|
230220
|
231221
|
232222
|
233223
|
234224
|
235225
|
236226
|
237227
|
238228
|
239229
|
240230
|
241231
|
242232
|
243233
|
244234
|
245235
|
246236
|
247237
|
248238
|
249239
|
250240
|
251241
|
252242
|
253243
|
254244
|
255245
|
256246
|
257247
|
258248
|
259249
|
260250
|
261251
|
262252
|
263253
|
264254
|
265255
|
266256
|
267257
|
268258
|
269259
|
270260
|
271261
|
272262
|
273263
|
274264
|
275265
|
276266
|
277267
|
278268
|
279269
|
280270
|
281271
|
282272
|
283273
|
284274
|
285275
|
286276
|
287277
|
288278
|
289279
|
290280
|
291281
|
292282
|
293283
|
294284
|
295285
|
296286
|
297287
|
298288
|
299289
|
300290
|
301NH-neo-Pent
|
302291
|
303292
|
304293
|
305294
|
306295
|
307296
|
308297
|
309298
|
310299
|
311300
|
312301
|
313302
|
314303
|
315304
|
316305
|
317306
|
318307
|
319308
|
320309
|
321310
|
322311
|
[0037]
2
|
|
|
312
|
|
Compound
|
No.
R8
|
|
323
H
|
324
Me
|
325
Et
|
326
n-Pr
|
327
i-Pr
|
328
n-Bu
|
329
i-Bu
|
330
sec-Bu
|
331
tert-Bu
|
332
n-Pent
|
333
i-Pent
|
334
neo-Pent
|
335
tert-Pent
|
|
336
313
|
|
337
314
|
|
338
315
|
|
339
n-Hex
|
|
340
316
|
|
341
317
|
|
342
318
|
|
343
319
|
|
344
320
|
|
345
321
|
|
346
322
|
|
347
323
|
|
348
324
|
|
349
325
|
|
350
n-Hept
|
351
n-Oct
|
352
n-Non
|
353
n-Dec
|
354
n-Undec
|
355
n-Dodec
|
356
n-Tridec
|
357
n-Tetradec
|
|
358
326
|
|
359
327
|
|
360
328
|
|
361
329
|
|
362
330
|
|
363
331
|
|
364
332
|
|
365
333
|
|
366
334
|
|
367
335
|
|
368
336
|
|
369
337
|
|
370
338
|
|
371
339
|
|
372
340
|
|
373
341
|
|
374
342
|
|
375
343
|
|
376
344
|
|
377
345
|
|
378
346
|
|
379
347
|
|
380
348
|
|
381
349
|
|
382
350
|
|
383
351
|
|
384
352
|
|
385
353
|
|
386
354
|
|
387
355
|
|
388
356
|
|
389
357
|
|
390
358
|
|
391
359
|
|
392
360
|
|
393
361
|
|
394
362
|
|
396
363
|
|
397
364
|
|
398
365
|
|
399
366
|
|
400
367
|
|
401
368
|
|
402
369
|
|
403
370
|
|
404
371
|
|
405
372
|
|
406
373
|
|
407
374
|
|
408
375
|
|
409
376
|
|
410
377
|
|
411
378
|
|
412
379
|
|
413
380
|
|
414
381
|
|
415
382
|
|
416
383
|
|
417
384
|
|
418
385
|
|
419
386
|
|
420
387
|
|
421
388
|
|
422
389
|
|
423
390
|
|
424
391
|
|
425
392
|
|
426
393
|
|
427
394
|
|
428
395
|
|
429
396
|
|
430
397
|
|
431
398
|
|
432
399
|
|
433
400
|
|
434
401
|
|
435
402
|
|
436
403
|
|
437
404
|
|
438
405
|
|
439
406
|
|
440
407
|
|
441
408
|
|
442
409
|
|
443
410
|
|
444
411
|
|
445
412
|
|
446
413
|
|
447
414
|
|
448
415
|
|
449
416
|
|
450
417
|
|
451
418
|
|
452
419
|
|
453
420
|
|
454
421
|
|
455
422
|
|
456
423
|
|
457
424
|
|
458
425
|
|
459
426
|
|
460
427
|
|
461
428
|
|
462
429
|
|
463
430
|
|
464
431
|
|
465
432
|
|
466
433
|
|
467
434
|
|
468
435
|
|
469
436
|
|
470
437
|
|
471
438
|
|
472
439
|
|
473
440
|
|
474
441
|
|
475
442
|
|
476
443
|
|
477
444
|
|
478
445
|
|
479
446
|
|
480
447
|
|
481
448
|
|
482
449
|
|
483
450
|
|
484
451
|
|
485
452
|
|
486
453
|
|
487
454
|
|
488
455
|
|
489
456
|
|
490
457
|
|
491
458
|
|
492
459
|
|
493
460
|
|
494
461
|
|
495
462
|
|
496
463
|
|
497
464
|
|
498
465
|
|
499
466
|
|
500
467
|
|
501
468
|
|
502
469
|
|
503
470
|
|
504
471
|
|
505
472
|
|
506
473
|
|
507
474
|
|
508
475
|
|
509
476
|
|
510
477
|
|
511
478
|
|
512
479
|
|
513
480
|
|
514
481
|
|
515
482
|
|
516
483
|
|
[0038]
3
|
|
|
484
|
|
Compound
|
No.
R11
|
|
517
H
|
518
OH
|
519
O2C-n-Pr
|
521
O2CEt
|
522
O2C-n-Bu
|
523
O2C-sec-Bu
|
524
O2C-tert-Bu
|
525
O2C-n-Hex
|
526
O2C-n-Tetradec
|
|
527
485
|
|
528
486
|
|
529
487
|
|
530
488
|
|
531
489
|
|
532
490
|
|
533
491
|
|
534
492
|
|
535
493
|
|
536
494
|
|
537
495
|
|
538
496
|
|
539
497
|
|
540
498
|
|
541
499
|
|
542
500
|
|
543
501
|
|
544
502
|
|
545
503
|
|
546
504
|
|
547
505
|
|
548
506
|
|
549
507
|
|
550
508
|
|
551
509
|
|
552
510
|
|
553
511
|
|
554
512
|
|
555
513
|
|
556
514
|
|
557
515
|
|
558
516
|
|
559
517
|
|
560
518
|
|
561
519
|
|
562
520
|
|
563
521
|
|
564
522
|
|
565
523
|
|
566
524
|
|
567
525
|
|
568
526
|
|
569
527
|
|
570
528
|
|
571
529
|
|
572
530
|
|
573
531
|
|
574
532
|
|
575
533
|
|
576
534
|
|
577
535
|
|
578
536
|
|
579
537
|
|
580
538
|
|
581
539
|
|
582
540
|
|
583
O2COMe
|
584
O2COEt
|
585
O2CO-n-Tetradec
|
|
586
541
|
|
587
542
|
|
588
543
|
|
589
544
|
|
590
545
|
|
591
546
|
|
592
547
|
|
593
548
|
|
594
549
|
|
595
O2CNHMe
|
596
O2CNHEt
|
597
O2CNH-n-Tetradec
|
|
598
550
|
|
599
551
|
|
600
552
|
|
601
553
|
|
602
554
|
|
603
555
|
|
604
556
|
|
605
557
|
|
606
558
|
|
607
559
|
|
608
560
|
|
609
561
|
|
610
562
|
|
[0039]
4
|
|
|
563
|
|
Compound
|
No.
R9
|
|
611
H
|
612
Me
|
613
n-Pent
|
614
n-Hex
|
615
n-Tetradec
|
|
616
564
|
|
617
565
|
|
618
566
|
|
619
567
|
|
620
568
|
|
621
569
|
|
622
570
|
|
623
571
|
|
624
572
|
|
625
573
|
|
626
574
|
|
627
575
|
|
628
576
|
|
629
577
|
|
630
578
|
|
631
579
|
|
632
580
|
|
633
581
|
|
634
582
|
|
635
583
|
|
636
584
|
|
637
585
|
|
638
586
|
|
639
587
|
|
640
588
|
|
641
589
|
|
642
590
|
|
643
591
|
|
644
592
|
|
645
593
|
|
646
594
|
|
647
595
|
|
648
596
|
|
649
597
|
|
650
598
|
|
651
599
|
|
652
600
|
|
653
601
|
|
654
602
|
|
655
603
|
|
656
604
|
|
657
605
|
|
658
606
|
|
659
607
|
|
660
608
|
|
661
609
|
|
662
610
|
|
663
611
|
|
664
612
|
|
665
613
|
|
666
614
|
|
667
615
|
|
668
616
|
|
669
617
|
|
670
618
|
|
671
619
|
|
672
620
|
|
673
621
|
|
674
622
|
|
675
623
|
|
676
624
|
|
677
625
|
|
678
626
|
|
679
627
|
|
680
628
|
|
681
629
|
|
682
630
|
|
[0040]
5
|
|
|
631
|
|
Compound
|
No.
U-R10
|
|
683
OMe
|
684
OEt
|
685
O-n-Pr
|
686
O-i-Pr
|
687
O-n-Bu
|
688
O-n-Tetradec
|
|
689
632
|
|
691
633
|
|
692
634
|
|
693
635
|
|
694
636
|
|
695
637
|
|
696
638
|
|
697
639
|
|
698
640
|
|
699
641
|
|
700
642
|
|
701
643
|
|
702
644
|
|
703
645
|
|
704
646
|
|
705
647
|
|
706
648
|
|
707
649
|
|
708
650
|
|
709
651
|
|
710
652
|
|
711
653
|
|
712
NHMe
|
713
NH-n-Tetradec
|
|
714
654
|
|
715
655
|
|
716
656
|
|
717
657
|
|
718
658
|
|
719
659
|
|
720
660
|
|
721
661
|
|
722
662
|
|
723
663
|
|
724
664
|
|
725
665
|
|
726
666
|
|
[0041]
6
|
|
|
667
|
|
Compound
|
No.
NR6R7
|
|
727
NH2
|
728
NHMe
|
729
NMeEt
|
730
NMe-n-Pr
|
731
NMe-i-Pr
|
732
NMe-n-Hex
|
733
NMe-n-Tetradec
|
|
734
668
|
|
735
669
|
|
736
670
|
|
737
671
|
|
738
672
|
|
739
673
|
|
740
674
|
|
741
NEt2
|
|
742
675
|
|
743
676
|
|
744
677
|
|
745
678
|
|
746
679
|
|
747
680
|
|
748
681
|
|
749
682
|
|
750
683
|
|
751
684
|
|
752
685
|
|
753
686
|
|
754
687
|
|
755
688
|
|
756
689
|
|
757
690
|
|
758
691
|
|
759
692
|
|
760
693
|
|
761
694
|
|
762
695
|
|
763
696
|
|
764
697
|
|
765
698
|
|
766
699
|
|
767
700
|
|
768
701
|
|
769
702
|
|
770
703
|
|
771
704
|
|
772
705
|
|
773
706
|
|
774
707
|
|
775
708
|
|
776
709
|
|
777
710
|
|
778
711
|
|
779
712
|
|
780
713
|
|
781
714
|
|
782
715
|
|
783
716
|
|
784
717
|
|
785
718
|
|
786
719
|
|
787
720
|
|
788
721
|
|
789
722
|
|
790
723
|
|
791
724
|
|
792
725
|
|
793
726
|
|
794
727
|
|
795
728
|
|
796
729
|
|
797
730
|
|
798
731
|
|
799
732
|
|
800
733
|
|
801
734
|
|
802
735
|
|
803
736
|
|
804
737
|
|
805
738
|
|
806
739
|
|
807
740
|
|
808
741
|
|
809
742
|
|
810
743
|
|
811
744
|
|
812
745
|
|
813
746
|
|
814
747
|
|
815
748
|
|
816
749
|
|
817
750
|
|
818
751
|
|
819
752
|
|
820
753
|
|
821
754
|
|
822
755
|
|
823
756
|
|
824
757
|
|
825
758
|
|
826
759
|
|
827
760
|
|
828
761
|
|
829
762
|
|
830
763
|
|
831
764
|
|
832
765
|
|
833
766
|
|
834
767
|
|
835
768
|
|
836
769
|
|
837
770
|
|
838
771
|
|
839
772
|
|
840
773
|
|
841
774
|
|
842
775
|
|
843
776
|
|
844
777
|
|
845
778
|
|
846
779
|
|
847
780
|
|
848
781
|
|
849
782
|
|
850
783
|
|
851
784
|
|
852
785
|
|
853
786
|
|
854
787
|
|
855
788
|
|
856
789
|
|
857
790
|
|
858
791
|
|
859
792
|
|
860
793
|
|
861
794
|
|
862
NEt-n-Pr
|
863
NEt-n-Tetradec
|
|
864
795
|
|
865
796
|
|
866
797
|
|
867
798
|
|
868
799
|
|
869
800
|
|
870
801
|
|
[0042]
7
|
|
|
802
|
|
Compound
|
No.
R3
NR1R2
|
|
|
871
H
803
|
|
872
H
804
|
|
873
H
805
|
|
874
Me
806
|
|
875
Me
807
|
|
876
Me
808
|
|
[0043]
8
|
|
|
809
|
|
Compound
|
No.
R3
NR1R2
|
|
|
877
H
810
|
|
878
H
811
|
|
879
H
812
|
|
880
Me
813
|
|
881
Me
814
|
|
882
Me
815
|
|
[0044]
9
|
|
|
816
|
|
Compound
|
No.
W
|
|
883
NH
|
884
N-n-Tetradec
|
|
885
817
|
|
886
818
|
|
[0045]
10
|
|
|
819
|
|
Compound
|
No.
NR1R2
R5
X
Z
|
|
|
887
820
OH
HN
O
|
|
888
821
H
822
O
|
|
889
823
OH
824
S
|
|
890
825
OH
826
S
|
|
[0046]
11
|
|
|
827
|
|
Compound
|
No.
R8
|
|
891
H
|
892
Me
|
893
Et
|
894
n-Pr
|
895
i-Pr
|
896
n-Bu
|
897
i-Bu
|
898
sec-Bu
|
899
tert-Bu
|
900
n-Pent
|
901
i-Pent
|
902
neo-Pent
|
903
tert-Pent
|
|
904
828
|
|
905
n-Hex
|
906
n-Hept
|
907
n-Oct
|
908
n-Non
|
909
n-Dec
|
910
n-Undec
|
911
n-Dodec
|
912
n-Tridec
|
913
n-Tetradec
|
|
914
829
|
|
915
830
|
|
916
831
|
|
917
832
|
|
918
833
|
|
919
834
|
|
920
835
|
|
921
836
|
|
922
837
|
|
923
838
|
|
924
839
|
|
925
840
|
|
926
841
|
|
927
842
|
|
928
843
|
|
929
844
|
|
930
845
|
|
931
846
|
|
932
847
|
|
933
848
|
|
934
849
|
|
935
850
|
|
936
851
|
|
937
852
|
|
938
853
|
|
939
854
|
|
940
855
|
|
941
856
|
|
942
857
|
|
943
858
|
|
944
859
|
|
945
860
|
|
946
861
|
|
947
862
|
|
948
863
|
|
949
864
|
|
950
865
|
|
951
866
|
|
952
867
|
|
953
868
|
|
954
869
|
|
955
870
|
|
956
871
|
|
957
872
|
|
958
873
|
|
959
874
|
|
960
875
|
|
961
876
|
|
962
877
|
|
963
878
|
|
964
879
|
|
965
880
|
|
966
881
|
|
967
882
|
|
968
883
|
|
969
884
|
|
970
885
|
|
971
886
|
|
972
887
|
|
973
888
|
|
974
889
|
|
975
890
|
|
976
891
|
|
977
892
|
|
978
893
|
|
979
894
|
|
980
895
|
|
981
896
|
|
982
897
|
|
983
898
|
|
984
899
|
|
985
900
|
|
986
901
|
|
987
902
|
|
988
903
|
|
989
904
|
|
990
905
|
|
[0047]
12
|
|
|
906
|
|
Compound
|
No.
NR1R2
R3
R8
|
|
|
991
907
Me
908
|
|
992
909
Me
910
|
|
993
911
Me
912
|
|
994
913
H
n-Oct
|
|
995
914
Me
n-Oct
|
|
996
915
Me
n-Oct
|
|
997
916
Me
n-Oct
|
|
[0048]
13
|
|
|
917
|
|
Compound
|
No.
NR1R2
R8
R9
|
|
|
998
918
919
920
|
|
999
921
922
923
|
|
1000
924
925
926
|
|
1001
927
928
929
|
|
[0049]
14
|
|
|
930
|
|
Compound
|
No.
NR1R2
|
|
1002
NH2
|
1003
NHMe
|
1004
NHEt
|
1005
NH-n-Pr
|
1006
NH-i-Pr
|
1007
NH-n-Bu
|
1008
NH-n-Pent
|
1009
NH-n-Hex
|
1010
NH-n-Hept
|
1011
NMe2
|
|
1012
931
|
|
1013
932
|
|
1014
933
|
|
1015
934
|
|
1016
935
|
|
1017
936
|
|
1018
937
|
|
1019
938
|
|
1020
939
|
|
1021
940
|
|
1022
941
|
|
1023
942
|
|
1024
943
|
|
1025
944
|
|
1026
945
|
|
1027
946
|
|
1028
947
|
|
1029
948
|
|
1030
949
|
|
1031
950
|
|
1032
951
|
|
1033
952
|
|
1034
953
|
|
1035
954
|
|
1036
955
|
|
1037
956
|
|
1038
957
|
|
1039
958
|
|
1040
959
|
|
1041
960
|
|
1042
961
|
|
1043
962
|
|
1044
963
|
|
1045
964
|
|
1046
965
|
|
1047
966
|
|
1048
967
|
|
1049
968
|
|
1050
969
|
|
1051
970
|
|
1052
971
|
|
1053
972
|
|
1054
973
|
|
1055
974
|
|
1056
975
|
|
1057
976
|
|
1058
977
|
|
1059
978
|
|
1060
979
|
|
1061
980
|
|
1062
981
|
|
1063
982
|
|
1064
983
|
|
1065
984
|
|
1066
985
|
|
1067
986
|
|
1068
987
|
|
1069
988
|
|
1070
989
|
|
1071
990
|
|
1072
991
|
|
1073
992
|
|
1074
993
|
|
1075
994
|
|
1076
995
|
|
1077
996
|
|
1078
997
|
|
1079
998
|
|
1080
999
|
|
1081
1000
|
|
1082
1001
|
|
1083
1002
|
|
1084
1003
|
|
1085
1004
|
|
1086
1005
|
|
1087
1006
|
|
1088
1007
|
|
1089
1008
|
|
[0050]
15
|
|
|
1009
|
|
Compound
|
No.
R11
|
|
1090
H
|
1091
OH
|
1092
O2CEt
|
1093
O2C-n-Pr
|
1094
O2-i-Pr
|
1095
O2C-n-Bu
|
|
1096
1010
|
|
1097
1011
|
|
1098
1012
|
|
1099
1013
|
|
1100
1014
|
|
1101
1015
|
|
1102
1016
|
|
1103
1017
|
|
1104
1018
|
|
1105
1019
|
|
1106
1020
|
|
1107
1021
|
|
1108
1022
|
|
1109
1023
|
|
1110
1024
|
|
1111
1025
|
|
1112
1026
|
|
1113
1027
|
|
1114
1028
|
|
1115
1029
|
|
1116
1030
|
|
1117
1031
|
|
[0051]
16
|
|
|
1032
|
|
Compound
|
No.
R9
|
|
|
1118
1033
|
|
1119
1034
|
|
1120
1035
|
|
1121
1036
|
|
1122
1037
|
|
1123
1038
|
|
1124
1039
|
|
1125
1040
|
|
1126
1041
|
|
1127
1042
|
|
1128
1043
|
|
1129
1044
|
|
1130
1045
|
|
1131
1046
|
|
1132
1047
|
|
1133
1048
|
|
1134
1049
|
|
1135
1050
|
|
1136
1051
|
|
1137
1052
|
|
1138
1053
|
|
1139
1054
|
|
1140
1055
|
|
1141
1056
|
|
1142
1057
|
|
1143
1058
|
|
1144
1059
|
|
1145
1060
|
|
[0052]
17
|
|
|
1061
|
|
Compound
|
No.
U—R10
|
|
|
1146
1062
|
|
1147
1063
|
|
1148
1064
|
|
1149
1065
|
|
[0053]
18
|
|
|
1066
|
|
Compound
|
No.
NR6R7
|
|
1150
NH2
|
1151
NHMe
|
1152
NMeEt
|
1153
NMe-n-Pr
|
1154
NMe-i-Pr
|
1155
NEt2
|
|
1156
1067
|
|
1157
1068
|
|
1158
1069
|
|
1159
1070
|
|
1160
1071
|
|
1161
1072
|
|
1162
1073
|
|
1163
1074
|
|
1164
1075
|
|
1165
1076
|
|
1166
1077
|
|
1167
1078
|
|
1168
1079
|
|
1169
1080
|
|
[0054]
19
|
|
|
1081
|
|
Compound
|
No.
R3
NR1R2
|
|
|
1170
H
1082
|
|
1171
H
1083
|
|
1172
H
1084
|
|
1173
Me
1085
|
|
1174
Me
1086
|
|
1175
Me
1087
|
|
[0055]
20
|
|
|
1088
|
|
Compound
|
No.
R3
NR1R2
|
|
|
1176
H
1089
|
|
1177
H
1090
|
|
1178
H
1091
|
|
1179
Me
1092
|
|
1180
Me
1093
|
|
1181
Me
1094
|
|
[0056]
21
|
|
|
1095
|
|
Compound
|
No.
NR1R2
W
|
|
|
1182
1096
1097
|
|
1183
1098
1099
|
|
1184
1100
1101
|
|
1185
1102
1103
|
|
1186
1104
1105
|
|
1187
1106
1107
|
|
[0057]
22
|
|
|
1108
|
|
Compound No.
NR1R2
R3
R5
Z
|
|
|
1188
1109
H
H
O
|
|
1189
1110
H
H
O
|
|
1190
1111
H
H
O
|
|
1191
1112
H
OH
S
|
|
1192
1113
H
OH
S
|
|
1193
1114
H
OH
S
|
|
1194
1115
Me
OH
O
|
|
1195
1116
Me
OH
O
|
|
1196
1117
Me
OH
O
|
|
[0058]
23
|
|
|
1118
|
|
Compound
|
No.
NR1R2
R9
|
|
|
1197
1119
1120
|
|
1198
1121
1122
|
|
1199
1123
1124
|
|
1200
1125
1126
|
|
1201
1127
1128
|
|
1202
1129
1130
|
|
[0059]
24
|
|
|
1131
|
|
Com-
|
pound
|
No.
NR1R2
R8
|
|
|
1203
NHMe
1132
|
|
1204
NHEt
1133
|
|
1205
NH-n-Pr
1134
|
|
1206
NH-n-Bu
1135
|
|
1207
NH-n-Hex
1136
|
|
1208
1137
1138
|
|
1209
1139
1140
|
|
1210
1141
1142
|
|
1211
1143
1144
|
|
1212
1145
1146
|
|
1213
1147
1148
|
|
1214
1149
1150
|
|
1215
1151
1152
|
|
1216
1153
1154
|
|
1217
1155
1156
|
|
1218
1157
1158
|
|
1219
1159
1160
|
|
[0060]
25
|
|
|
1161
|
|
Compound
|
No.
NR1R2
|
|
1220
NH-n-Pr
|
1221
NH-i-Pr
|
1222
NH-n-Bu
|
1223
NMe2
|
1224
NEt2
|
|
1225
1162
|
|
1226
1163
|
|
1227
1164
|
|
1228
1165
|
|
1229
1166
|
|
1230
1167
|
|
1231
1168
|
|
1232
1169
|
|
1233
1170
|
|
1234
1171
|
|
1235
1172
|
|
1236
1173
|
|
1237
1174
|
|
1238
1175
|
|
1239
1176
|
|
1240
1177
|
|
1241
1178
|
|
1242
1179
|
|
1243
1180
|
|
1244
1181
|
|
1245
1182
|
|
1246
1183
|
|
1247
1184
|
|
1248
1185
|
|
1249
1186
|
|
1250
1187
|
|
1251
1188
|
|
1252
1189
|
|
1253
1190
|
|
1254
1191
|
|
1255
1192
|
|
1256
1193
|
|
1257
1194
|
|
1258
1195
|
|
1259
1196
|
|
1260
1197
|
|
1261
1198
|
|
1262
1199
|
|
1263
1200
|
|
1264
1201
|
|
1265
1202
|
|
[0061] The novel erythromycin derivatives represented by the aforementioned general formula (I) of the present invention can be prepared by, for example, the methods explained below. However, the method for preparing the compounds of the present invention is not limited to these methods.
[0062] According to the first embodiment of the method for preparing the compounds of the present invention, the compounds represented by the aforementioned general formula (I) can be prepared by reacting the compound represented by the following general formula (V):
1203
[0063] wherein R3, R4, R5, R6, R7, X, and Y have the same meaning as those defined above, with the compound represented by the following general formula (VI):
R14—N═C=Z (VI)
[0064] wherein Z has the same meaning as that defined above, and R14 represents an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a saturated or unsaturated homocyclic group which may be substituted, a saturated or unsaturated heterocyclic group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, in the presence or absence of lithium chloride in the absence or presence of a solvent. Alternatively, the target compound can be prepared by reacting the compound represented by the aforementioned general formula (V) with the compound represented by the following general formula (VII) in the presence or absence of a base in the absence or presence of a solvent:
R15R16N—C(=Z)-Q (VII)
[0065] wherein Z has the same meaning as that defined above, and R15 and R16 independently represent an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a saturated or unsaturated homocyclic group which may be substituted, a saturated or unsaturated heterocyclic group which may be substituted, an alkyl group substituted with a saturated or unsaturated homocyclic group which may be substituted, or an alkyl group substituted with a saturated or unsaturated heterocyclic group which may be substituted, or R15 and R16 may combine together with the nitrogen atom to which they bind to form a saturated or unsaturated heterocyclic group which may further contain one or more heteroatoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom and which may be substituted, and Q represents a chlorine atom or 1-imidazolyl group.
[0066] Example of the base used in the above method for preparation include, for example, organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,2,2,6,6-pentamethylpiperidine and the like, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like. The solvent used in the above method for preparation may be any solvent so long as it, per se, is inert in the reaction and does not inhibit the reaction. Examples include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as acetone, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolan, tetramethylene sulfoxide, and hexamethylenephosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, organic base solvents such as pyridine, picoline, lutidine, and collidine, or mixed solvents thereof. The reaction is performed at a temperature ranging from under ice-cooling to 200° C.
[0067] According to the second embodiment of the method for preparing the compounds of the present invention, the compounds represented by the following general formula (VIII) which fall within the compounds represented by the aforementioned general formula (I):
1204
[0068] wherein R3, R4, R5, R6, R7, X, Y, and Z have the same meaning as those defined above, in which R1 and R2 combine together with the nitrogen atom to which they bind to form 1-imidazolyl group, can be prepared by reacting the compound represented by the aforementioned general formula (V) with the N,N′-carbonyldiimidazole or N,N′-thiocarbonyldiimidazole represented by the following general formula (IX) in the presence or absence of a base in the absence or presence of a solvent:
1205
[0069] wherein Z has the same meaning as that defined above.
[0070] Example of the base used in the above method for preparation include, for example, organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-dim ethylaminopyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,2,2,6,6-pentamethylpiperidine and the like, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like. The solvent used in the above method for preparation may be any solvent so long as it, per se, is inert in the reaction and does not inhibit the reaction. Examples include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as acetone, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolan, tetramethylene sulfoxide, and hexamethylenephosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, organic base solvents such as pyridine, picoline, lutidine, and collidine, or mixed solvents thereof. The reaction is performed at a temperature ranging from under ice-cooling to 200° C.
[0071] According to the third embodiment of the method for preparation of the compounds of the present invention, the compound represented by the aforementioned general formula (I) can be prepared by reacting the compound represented by the aforementioned general formula (VIII) which is obtained in the above second method, with the compound represented by the following general formula (X):
NHR1R2 (X)
[0072] wherein R1 and R2 have the same meaning as those definedabove, in the presence or absence of a base in the absence or presence of a solvent.
[0073] The compound represented by the aforementioned general formula (VIII) obtained in the second method can be used as a raw material for the third method without isolation and purification to obtain the compound of the present invention.
[0074] Example of the base used in the above method for preparation include, for example, organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,2,2,6,6-pentamethylpiperidine and the like, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like. The solvent used in the above method for preparation may be any solvent so long as it, per se, is inert in the reaction and does not inhibit the reaction. Examples include halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as acetone, acetonitrile, N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, tetramethylene sulfolan, tetramethylene sulfoxide, and hexamethylenephosphoric triamide, ester solvents such as methyl acetate and ethyl acetate, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, organic base solvents such as pyridine, picoline, lutidine, and collidine, or mixed solvents thereof. The reaction is performed at a temperature ranging from under ice-cooling to 200° C.
[0075] According to the forth embodiment of the method for preparation of the compounds of the present invention, the compounds among those represented by the aforementioned general formula (I) wherein a substituent on the optionally substitutable functional group is carboxyl group can be prepared by hydrolysis of compounds wherein a substituent on the optionally substitutable functional group is a substituted carboxyl group such as alkoxycarbonyl group, aryloxycarbonyl group, or aralkyloxycarbonyl group.
[0076] The hydrolysis can be performed by a method known per se under an acidic or alkaline condition in the presence or absence of a cation scavenger such as anisole and thioanisole in a solvent. For acidic hydrolysis, acids such as hydrochloric acid, an ethyl acetate solution of hydrogen chloride, an ethanolic solution of hydrogen chloride, sulfuric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid, and acetic acid can be used. For basic hydrolysis, bases such as hydroxides, carbonates, hydrogencarbonates, or alcoholate of an alkali metal such as sodium and potassium or of alkaline-earth metal such as magnesium and calcium can be used. As solvent for the hydrolysis, water, organic solvents such as methanol, ethanol, n-propanol, tetrahydrofuran, ethyl acetate, methylene chloride, 1,2-dichloroethane, 1,4-dioxane, N,N-dimethylformamide, and water-containing solutions of the above organic solvents may be used. The reaction can be carried out at a temperature ranging from 0° C. to the reflux temperature of a solvent.
[0077] According to the fifth embodiment of the method for preparation of the compounds of the present invention, the compounds among those represented by the aforementioned general formula (I) wherein a substituent on the optionally substitutable functional group is an amino group can be prepared by hydrolysis or hydrogenolysis using a metal catalyst of compounds wherein a substituent on the optionally substitutable functional group is a substituted amino group such as benzylamino group, benzyloxycarbonylamino group, tert-butoxycarbonylamino group.
[0078] The hydrolysis can be performed by a method known per se according to the forth preparation method.
[0079] The hydrogenolysis can be performed by using a metal catalyst such as platinum, palladium/carbon, Raney nickel, and Pearlman's reagent in a solvent such as water, methanol, ethanol, n-propanol, acetic acid, and a mixed solvent thereof in the presence or absence of an acid such as hydrochloric acid at a temperature ranging from room temperature to the reflux temperature of the solvent under a hydrogen pressure ranging from normal pressure to 200 Pa.
[0080] The compound represented by the aforementioned general formula (V), used as the starting material for preparation of the compound of the present invention, can be prepared by referring to, for example, the publications set out below. Examples of the publication as references for preparation methods include Journal of Medicinal Chemistry, 17, 953, 1974; Journal of Medicinal Chemistry, 38, 1793, 1995; Japanese Patent Unexamined Publication No. (Sho)58-159500; Japanese Patent Unexamined Publication No. (Sho)61-225194; Japanese Patent Unexamined Publication No. (Sho)62-81399; Japanese Patent Unexamined Publication No. (Sho)62-292795; Japanese Patent Unexamined Publication No. (Sho)63-107921; Japanese Patent Unexamined Publication No. (Hei)5-255375; Japanese Patent Unexamined Publication No. (Hei)8-53355; Japanese Patent Unexamined Publication No. (Hei)8-104638; Japanese Patent Unexamined Publication No. (Hei)10-67795; Japanese Patent Unexamined Publication No. (Hei)11-116593; Japanese Patent Unexamined Publication No. (Hei)11-236395; U.S. Pat. No. 6,034,069 and the like. According to the method described therein, each of the compounds in the following scheme can be prepared, wherein R3, R4, R5, R6, R7, R9, R10, R11, U, and X have the same meaning as those defined above.
1206
[0081] The medicament comprising, as an active ingredient, at least one substance selected from the group consisting of the novel erythromycin derivatives represented by the aforementioned general formula (I) thus prepared and pharmacologically acceptable salt thereof, and hydrate thereof and solvate thereof may be generally administered as oral formulations such as capsules, tablets, subtilized granules, granules, powders, syrups, dry syrups, solutions and the like, or as injections, suppositories, eye drops, eye ointments, ear drops, nasal drops, inhalants, dermal preparations and the like. These formulations can be prepared according to ordinary methods by addition of pharmacologically and pharmaceutically acceptable additives. As additives for oral formulations and suppositories, pharmaceutical ingredients such as, for example, excipients such as lactose, D-mannitol, corn starch and crystalline cellulose; disintegrating agents such as carboxymethylcellulose, calcium carboxymethylcellulose, partly pregelatinized starch, croscarmellose sodium, and crospovidone; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone; lubricants such as magnesium stearate, talc, hardened oil, dimethylpolysiloxane, hydrated silicon dioxide, colloidal silicon dioxide, and carnauba wax; coating agents such as hydroxypropylmethylcellulose, sucrose, and titanium oxide; plasticizers such as polyethylene glycol, triethyl citrate, and glycerin fatty acid esters; base materials such as polyethylene glycol and hard fat and the like may be used. For injections, eye drops, ear drops, and nasal drops, pharmaceutical ingredients such as, for example, dissolving agents and dissolving aids that can constitute aqueous preparations or preparations to be dissolved upon use such as distilled water for injection, physiological saline, and propylene glycol; pH modifiers such as inorganic or organic acids and bases; isotonic agents such as sodium chloride, glucose, and glycerin; stabilizers such as benzoic acid, citric acid, sodium bisulfate and the like may be used. For eye ointments and dermal preparations, pharmaceutical ingredients suitable for ointments, creams, and patches such as white soft paraffin, macrogol, grycerin, liquid paraffin, higher alcohols, fatty acid esters, glycerin fatty acid esters, polyethylene glycol fatty acid esters, carboxyvinyl polymers, acryl-type adhesives, rubber-type adhesives, silicone resins, cotton cloth and the like may be used. For inhalants, propellants such as carbon dioxide, propane, nitrogen gas and the like; dissolving aids such as ethanol, propylene glycol and the like; surfactants such as sorbitan trioleate and the like; and excipients such as lactose and the like may be used.
[0082] When the medicament of the present invention is administered to a patient, doses may be appropriately chosen depending on symptoms of the patient or route of administration. For example, generally for an adult, a daily dose (weight of an active ingredient) of about 10 to 2,000 mg for oral administration, or about 1 to 1,000 mg for parenteral administration may be administered once a day or several times as divided portions. It is desirable that the doses are suitably increased or decreased depending on the purpose of therapeutic or preventive treatment, a part of infection and a type of pathogenic bacteria, the age and symptoms of a patient and the like.
EXAMPLES
[0083] The present invention will be explained more concretely by Examples. However, the scope of the present invention is not limited to these examples. The abbreviations in the tables have the following meanings: Me, methyl group; Et, ethyl group; n-Pr, n-propyl group; n-Bu, n-butyl group; n-Hex, n-hexyl group; n-Oct, n-octyl group; n-Dec, n-decyl group; n-Dodec, n-dodecyl group; n-Tetradec, n-tetradecyl group; Ac, acetyl group.
4″-O-Acetyl-2′-O-phenylaminocarbonylerythromycin A 9-[O-(n-octyl)oxime]
[0084] To a solution of 0.50 g of 4″-O-acetylerythromycin A 9-[O-(n-octyl)oxime] in 5.0 ml of tetrahydrofuran, 0.12 ml of phenyl isocyanate was added, and the mixture was stirred at room temperature for 30.5 hours. And then, the reaction mixture was stirred at 50° C. of outer temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was added with water, and alkalified by saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate: n-heptane=1:1) to obtain 0.50 g of a colorless amorphous solid. NMR spectrum 6 (CDCl3)ppm:0.81(3H,t,J=7.5 Hz),0.88(3H,t,J=7 Hz),0.97(3H,d,J=7.5 Hz),1.00-1.78(44H,m),1.83-2.00(2H,m),2.12(3H,s),2.28(6H,s),2.40(1H,d,J=15.5 Hz),2.58-2.65(2H,m),2.77-2.85(1H,m),3.08(1H,s),3.10(3H,s),3.52(1H,d,J=8 Hz),3.55-3.70(2H,m), 3.67(1H,s),3.94-4.02(2H,m),3.96(1H,d,J=10.5 Hz),4.42(1H,s),4.43-4.50(1H,m),4.47(1H,d,J=7.5 Hz),4.74(1H,d,J=10 Hz),4.76(1H,dd,J=10.5, 7.5 Hz),4.90(1H,d,J=4.5 Hz),5.08(1H,d d,J=11, 2 Hz),7.04(1H,t,J=7.5 Hz),7.22-7.32(2H,m),7.45(2H,d,J=7.5 Hz)
[0085] In accordance with the method of Example 1, the compounds of Examples 2 through 34 were obtained.
26|
|
|
1207
|
ExampleR8NR1R2Description and physical properties
|
212081209colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.75 (28H, m), 0.84(3H, t, J=7.5 Hz), 0.95(3H, d, J=7.5 Hz), 1.05(3H, d, J=6.5 Hz), 1.87-2.02(2H, m), 1.92(3H, s), 2.31(6H, s), 2.39(1H, d, J=15.5 Hz), 2.58-2.74(2H, m), 2.82-2.92(1H, m), 3.16 (1H, s), 3.26(3H, s), 3.41(3H, s), 3.47(1H, d, J=7.5 Hz), 3.51-3.88(4H, m), 3.57(2H, t, J=4.5 Hz), 3.84(1H, s), 3.94(1H, d, J=10 Hz), 4.24(1H, dd, J=
#, 5 Hz), 4.30-4.60(2H, m), 4.33(1H, s), 4.48(1H, d, J=7.5 Hz), 4.63-4.80(1H, m), 4.65(1H, d, J=10 Hz), 4.87(1H, d, J=4.5 Hz), 5.08-5.25(3H, m), 5.40-5.53(1H, m), 7.20-7.40 (5H, m)
|
312101211colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.78-1.83 (49H, m), 0.83(3H, t, J=7.5 Hz), 0.95(3H, d, J=8 Hz), 1.02(3H, d, J=7.5 Hz), 1.85-2.00(2H, m), 2.09(3H, s), 2.30(6H, s), 2.40(1H, d, J=15.5 Hz), 2.55-2.73(4H, m), 2.82-2.92(1H, m), 3.07-3.24(2H, m), 3.10(1H, s), 3.29(3H, s), 3.51 (1H, d, J=6.5 Hz), 3.57-3.75(2H, m), 3.64(1H, s), 3.90-4.03(3H, m), 4.29-4.40(1H, m), 4.45 (1H, s), 4.53(1H, d,
#J=7.5 Hz), 4.60-4.83(2H, m), 4.68(1H, d, J=10 Hz), 4.94(1H, d, J=4.5 Hz), 5.07-5.17(1H, m), 7.10-7.35(5H, m)
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412121213pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.78-2.10 (48H, m), 0.85(3H, t, J=7.5 Hz), 1.01(3H, d, J=7.5 Hz), 2.02(3H, s), 2.25(6H, s), 2.40(1H, d, J=15.5 Hz), 2.56-2.68(2H, m), 2.78-2.90(1H, m), 3.11(1H, s), 3.28(3H, s), 3.49(1H, d, J=7.5 Hz), 3.57-3.71(2H, m), 3.65(1H, s), 3.90-4.02 (3H, m), 4.34-4.45(1H, m), 4.43(1H, s), 4.51(1H, d, J=8 Hz), 4.54-4.70(2H, m), 4.67(1H, d, J=10 Hz), 4.67
#(1H, d, J=10 Hz), 4.76(1H, dd, J=16, 6.5 Hz), 4.91(1H, d, J=4.5 Hz), 5.11(1H, dd, J=11, 2 Hz), 5.75-5.82 (1H, m), 7.40-7.48(1H, m), 7.55-7.65(1H, m), 7.74(1H, d, J=7.5 Hz), 8.00-8.10(1H, m)
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512141215colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.82(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.10-1.79(29H, m), 1.83-1.99(2H, m), 2.06-2.18(2H, m), 2.12(3H, s), 2.28(6H, s), 2.40(1H, d, J=14.5 Hz), 2.58-2.68(2H, m), 2.77-2.86(1H, m), 3.07(1H, brs), 3.10(3H, s), 3.50(1H, d, J=7.5 Hz), 3.53-3.73(2H, m), 3.69 (1H, s), 3.94(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25
#(2H, m), 4.35(1H, s), 4.40-4.52 (1H, m), 4.45(1H, d, J=7.5 Hz), 4.73(1H, d, J=10 Hz), 4.75(1H, dd, J=10.5, 8 Hz), 4.89(1H, d, J=4.5 Hz), 5.08(1H, dd, J=11, 2 Hz), 6.88-6.96 (3H, m), 7.00-7.10(1H, m), 7.24-7.34(4H, m), 7.42-7.48(2H, m)
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612161217colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.95(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.08-1.75(28H, m), 1.88-1.99(2H, m), 1.94(3H, s), 2.10-2.17(2H, m), 2.31(6H, s), 2.38(1H, d, J=14.5 Hz), 2.58-2.70(2H, m), 2.80-2.90(1H, m), 3.11(1H, s), 3.26(3H, s), 3.49 (1H, d, J=5.5 Hz), 3.58-3.78(2H, m), 3.70(1H, s), 3.96(1H, d, J=9 Hz), 4.05(2H, t, J=6 Hz), 4.15-4.45(4H,
# (4H, m), 4.38(1H, s), 4.48-4.60(1H, m), 4.50(1H, d, J=8 Hz), 4.62-4.80(1H, m), 4.66 (1H, d, J=10 Hz), 4.91(1H, d, J=4.5 Hz), 5.11 (1H, dd, J=11, 2 Hz), 5.30-5.40(1H, m), 6.88-6.95(3H, m), 7.22-7.35(7H, m)
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712181219colorless needles (recry. solv.: EtOH) m.p. 104.5-107.5° C. NMR spectrum δ (CDCl3) ppm: 0.82-0.92 (6H, m), 1.02(3H, d, J=6.5 Hz)), 1.07-1.80(28H, m), 1.85-1.9(2H, m), 2.00-2.18(2H, m), 2.03 (3H, s), 2.29(6H, s), 2.39(1H, d, J=15.5 Hz), 2.62-2.72(2H, m), 2.78-2.87(1H, m), 3.12(1H, s), 3.29(3H, s), 3.47(1H, d, J=6.5 Hz), 3.60-3.75(2H, m), 3.67(1H, s), 3.83(3H, s), 3.95(1H, d, J=10 Hz), 4.05(2H, t,
#J=6.5 Hz), 4.15-4.25(2H, m), 4.28-4.39(2H, m), 4.38(1H, s), 4.45 (1H, dd, J=15.5, 6 Hz), 4.52(1H, d, J=7.5 Hz), 4.63-4.75(1H, m), 4.66(1H, d, J=10 Hz), 4.92 (1H, d, J=4.5 Hz), 5.06-5.16(1H, m), 5.28-5.35 (1H, m), 6.85(1H, d, J=8.5 Hz), 6.88-6.95(4H, m), 7.20-7.42(3H, m), 7.33(1H, d, J=7.5 Hz)
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812201221colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.75 (28H, m), 0.85(3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.04(3H, d, J=7.5 Hz), 1.88-2.19(4H, m), 1.98(3H, s), 2.32(6H, s), 2.39(1H, d, J=15.5 Hz), 2.61-2.71(2H, m), 2.82-2.90(1H, m), 3.11(1H, brs), 3.26(3H, s), 3.49(1H, d, J=6.5 Hz), 3.60-3.73(2H, m), 3.70(1H, s), 3.80(3H, s), 3.96(1H, d, J=9 Hz), 4.05(2H, t, J=6.5 Hz), 4.16-4.26(3H, m),
#4.32-4.42(1H, m), 4.37(1H, brs), 4.48-4.57(1H, m), 4.51(1H, d, J=7.5 Hz), 4.66(1H, d, J=10 Hz), 4.70(1H, dd, J=10.5, 8 Hz), 4.92(1H, d, J=3.5 Hz), 5.08-5.15(1H, m), 5.32-5.39(1H, m), 6.75-6.98(6H, m), 7.20-7.32 (3H, m)
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912221223colorless needles (recry. solv.: EtOH) m.p. 104.5-105.5° C. NMR spectrum δ (CDCl3) ppm: 0.92-1.75 (28H, m), 0.85(3H, t, J=7.5 Hz), 0.95(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.89-2.02(2H, m), 1.96(3H, s), 2.06-2.18(2H, m), 2.31(6H, s), 2.38(1H, d, J=15.5 Hz), 2.58-2.72(2H, m), 2.80-2.92(1H, m), 3.11(1H, s), 3.26(3H, s), 3.49 (1H, d, J=7.5 Hz), 3.59-3.77(2H, m), 3.70 (1H, s), 3.79(3H, s), 3.96(1H,
#d, J=10 Hz), 4.05 (2H, t, J=6.5 Hz), 4.13-4.24(3H, m), 4.28-4.40 (1H, m), 4.38(1H, s), 4.42-4.55(1H, m), 4.50 (1H, d, J=8 Hz), 4.61-4.75(1H, m), 4.66(1H, d, J=10 Hz), 4.92(1H, d, J=3.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 5.24-5.30(1H, m), 6.84(2H, d, J=8.5 Hz), 6.87-6.96(3H, m), 7.20-7.30(2H, m), 7.23 (2H, d, J=8.5 Hz)
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1012241225colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.75 (28H, m), 0.85(3H, t, J=7.5 Hz), 0.91(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.85-2.20(4H, m), 1.97(3H, s), 2.27(6H, s), 2.40(1H, d, J=15.5 Hz), 2.55-2.70(2H, m), 2.79-2.90(1H, m), 3.11(1H, s), 3.27(3H, s), 3.47(1H, d, J=7.5 Hz), 3.55-3.73(2H, m), 3.69(1H, s), 3.95(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.26(2H, m), 4.30-4.45
#(2H, m), 4.37(1H, s), 4.48(1H, d, J=8 Hz), 4.53(1H, dd, J=15.5, 6.5 Hz), 4.60-4.72(1H, m), 4.67(1H, d, J=10 Hz), 4.91(1H, d, J=3.5 Hz), 5.08-5.14(1H, m), 5.40-5.51(1H, m), 6.85-6.95(3H, m), 6.98-7.18(2H, m), 7.20-7.30(3H, m), 7.40-7.48(1H, m)
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1112261227colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.80 (28H, m), 0.86(3H, t, J=7.5 Hz), 0.92(3H, d, J=7.5 Hz), 1.02(3H, d, J=6.5 Hz), 1.85-2.20(4H, m), 1.98(3H, s), 2.28(6H, s), 2.40(1H, d, J=15.5 Hz), 2.55-2.70(2H, m), 2.80-2.90(1H, m), 3.11 (1H, s), 3.28(3H, s), 3.48(1H, d, J=6.5 Hz), 3.55-3.75(2H, m), 3.69(1H, s), 3.95(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.27(2H, m), 4.32-4.45
#(2H, m), 4.37(1H, s), 4.48(1H, d, J=7.5 Hz), 4.57(1H, dd, J=16, 6.5 Hz), 4.61-4.72(1H, m), 4.67(1H, d, J=10 Hz), 4.91(1H, d, J=3.5 Hz), 5.09-5.17(1H, m), 5.50-5.60(1H, m), 6.85-6.95(3H, m), 7.15-7.40(5H, m), 7.40-7.50(1H, m)
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1212281229colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.77 (28H, m), 0.86(3H, t, J=7.5 Hz), 0.93(3H, d, J=7.5 Hz), 1.02(3H, d, J=7.5 Hz), 1.85-2.20(4H, m), 1.98(3H, s), 2.28(6H, s), 2.40(1H, d, J=15.5 Hz), 2.56-2.70(2H, m), 2.80-2.90(1H, m), 3.11 (1H, s), 3.29(3H, s), 3.48(1H, d, J=7.5 Hz), 3.56-3.73(2H, m), 3.69(1H, s), 3.96(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.27(2H, m), 4.31-
#4.45(2H, m), 4.38(1H, s), 4.48(1H, d, J=8 Hz), 4.55 (1H, dd, J=16, 6.5 Hz), 4.60-4.72 (1H, m), 4.67(1H, d, J=10 Hz), 4.91(1H, d, J=4.5 Hz), 5.07-5.17(1H, m), 5.55-5.65(1H, m), 6.85-6.95(3H, m), 7.05-7.15(1H, m), 7.20-7.30 (3H, m), 7.43-7.50(1H, m), 7.53(1H, d, J=8 Hz)
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1312301231colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.92-1.77(28H, m(), 0.96(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.82(3H, s), 1.87-2.00(2H, m), 2.05-2.20(2H, m), 2.28(6H, s), 2.34(3H, s), 2.40(1H, d, J=15.5 Hz), 2.52-2.73 (2H, m), 2.80-2.92(1H, m), 3.11(1H, s), 3.28 (3H, s), 3.48(1H, d, J=7.5 Hz), 3.53-3.76(2H, m), 3.71(1H, s), 3.96(1H, d, J=10 Hz), 4.05(2H, t, J=6.5
#Hz), 4.15-4.27(3H, m), 4.32-4.50(1H, m), 4.38(1H, s), 4.45(1H, d, J=8 Hz), 4.58(1H, dd, J=14.5, 7.5 Hz), 4.64(1H, d, J=10 Hz), 4.68 (1H, dd, J=10.5, 8 Hz), 4.90(1H, d, J=4.5 Hz), 5.08-5.17(1H, m), 5.30-5.40(1H, m), 6.85-6.95(3H, m), 7.10-7.45(6H, m)
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1412321233colorless amorphous solid NMR spectrum δ (CDCl3) ppn: 0.80-1.78 (28H, m), 0.85(3H, t, J=7.5 Hz), 0.91(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.84-2.00(2H, m), 1.90(3H, s), 2.05-2.20(2H, m), 2.29(6H, s), 2.40(1H, d, J=15.5 Hz), 2.55-2.70(2H, m), 2.80-2.90(1H, m), 3.11(1H, s), 3.25(3H, s), 3.48 (1H, d, J=7.5 Hz), 3.55-3.75(2H, m), 3.70(1H, s), 3.95(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.26
#(2H, m), 4.32-4.52(2H, m), 4.37 (1H, s), 4.47(1H, d, J=7.5 Hz), 4.60-4.77(2H, m), 4.66(1H, d, J=10 Hz), 4.90(1H, d, J=3.5 Hz), 5.08-5.15(1H, m), 5.56-5.66(1H, m), 6.85-6.95(3H, m), 7.20-7.40(3H, m), 7.46-7.57(1H, m), 7.63(1H, d, J=8 Hz), 7.69(1H, d, J=8 Hz)
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1512341235pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.34 (36H, m), 0.86(3H, t, J=7.5 Hz), 1.01(3H, d, J=6.5 Hz), 2.01(3H, s), 2.25(6H, s), 2.40(1H, d, J=15.5 Hz), 2.55-2.70(2H, m), 2.78-2.90(1H, m), 3.10(1H, s), 3.28(3H, s), 3.46(1H, d, J=6.5 Hz), 3.56-3.75(2H, m), 3.67(1H, s), 3.94(1H, d, J=10 Hz), 4.05(2H, t, J=6 Hz), 4.15-4.25(2H, m), 4.30-4.42(1H, m), 4.35(1H, s), 4.50(1H, d, J=7.5 Hz),
#4.53-4.70(2H, m), 4.67(1H, d, J=10 Hz), 4.76(1H, dd, J=16.5, 6 Hz), 4.91(1H, d, J=4.5 Hz), 5.09-5.15(1H, m), 6.85-6.95 (3H, m), 7.20+124 7.70(1H, m), 7.74(1H, d, J=7.5 Hz), 8.00-8.12(1H, m)
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1612361237pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.06-1.78(28H, m), 1.88-2.02(2H, m), 1.97(3H, s), 2.06-2.20(2H, m), 2.29(6H, s), 2.41(1H, d, J=14.5 Hz), 2.55-2.72(2H, m), 2.82-2.92(1H, m), 3.10(1H, brs), 3.27(3H, s), 3.50(1H, d, J=8.5 Hz), 3.55-3.75(2H, m), 3.71 (1H, s), 3.96(1H, d, J=9 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25
#(2H, m), 4.30(1H, dd, J=16.5 Hz), 4.33-4.45(1H, m), 4.37(1H, s), 4.49(1H, d, J=8 Hz), 4.60-4.75(2H, m), 4.68(1H, d, J=10 Hz), 4.90(1H, d, J=4.5 Hz), 5.11(1H, dd, J=11.5, 1.5 Hz), 5.73-5.83(1H, m), 6.87-6.95(3H, m), 7.25-7.30(2H, m), 7.40-7.55(1H, m), 7.66(1H, d, J=7.5 Hz), 8.10-8.14(1H, m), 8.22(1H, s)
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171238NHEtcolorless needles (recry. solv.: EtOH) m.p. 102-103.5° C. NMR spectrum δ (CDCl3) ppm: 0.84(3H, t, J=7.5 Hz), 0.97(3H, d, J=8 Hz), 1.03(3H, d, J=6.5 Hz), 1.04-1.78(31H, m), 1.88-2.00(2H, m), 2.08-2.18(2H, m), 2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=15.5 Hz), 2.62-2.74(2H, m), 2.84-2.93(1H, m), 3.10(1H, s), 3.13-3.40(2H, m), 3.30(3H, s), 3.50(1H, d, J=6.5 Hz), 3.62-3.72(2H, m), 3.67(1H, s), 3.96(1H, d,
#9 Hz), 4.05 (2H, t, J=6 Hz), 4.15-4.25(2H, m), 4.30-4.40 (1H, m), 4.37(1H, s), 4.52(1H, d, J=7.5 Hz), 4.62-4.73(1H, m), 4.68(1H, d, J=10 Hz), 4.77-4.87(1H, m), 4.94(1H, d, J=3.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 6.88-6.95(3H, m), 7.22-7.30(2H, m)
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181239NH-n-Prcolorless solid (recry. solv.: CH3CN) m.p. 97.5-100° C. NMR spectrum δ (CDECl3) ppm: 0.84(3H, t, J=7.5 Hz), 0.93(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.02(3H, d, J=7.5 Hz), 1.07-1.85(30H, m), 1.88-2.00(2H, m), 2.05-2.20(2H, m), 2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=14.5 Hz), 2.60-2.75(2H, m), 2.82-2.93(1H, m), 3.05-3.25(2H, m), 3.10(1H, s), 3.30(3H, s), 3.50 (1H, d, J=6.5 Hz), 3.60-
#3.75(2H, m), 3.67(1H, s), 3.97(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25(2H, m), 4.28-4.40(1H, m), 4.37(1H, s), 4.52(1H, d, J=7.5 Hz), 4.62-4.73(1H, m), 4.68(1H, d, J=10 Hz), 4.76-4.85(1H, m), 4.94(1H, d, J=4.5 Hz), 5.12(1H, dd, J=10.5, 2 Hz), 6.85-6.95(3H, m), 7.20-7.30(2H, m)
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191240NH-n-Bucolorless needles (recry. solv.: CH3CN) m.p. 90-95° C. NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.93(3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.07-1.80(32H, m), 1.86-2.00(2H, m), 2.05-2.20(2H, m), 2.10(3H, s), 2.30(6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-2.75(2H, m), 2.82-2.93(1H, m), 3.10 (1H, s), 3.11-3.26(2H, m), 3.30(3H, s), 3.50 (1H, d, J=7.5 Hz), 3.60-
#3.75(2H, m), 3.67(1H, s), 3.97(1H, d, J=9 Hz), 4.05(2H, t, J=6 Hz), 4.15-4.25(2H, m), 4.30-4.40(1H, m), 4.38(1H, s), 4.52(1H, d, J=7.5 Hz), 4.62-4.72(1H, m), 4.68(1H, d, J=10 Hz), 4.74-4.82(1H, m), 4.94(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 6.85-6.95 (3H, m), 7.20-7.30(2H, m)
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201241NH-n-Hexcolorless solid (recry. solv.: EtOH) m.p. 95-98° C. NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.90(3H, t, J=7 Hz), 0.96(3H, d, J=8 Hz), 1.03(3H, d, J=6.5 Hz), 1.08-1.80(36H, m), 1.88-2.00(2H, m), 2.04-2.18(2H, m), 2.10 (3H, s), 2.31(6H, s), 2.40(1H, d, J=14.5 Hz), 2.60-2.73(2H, m), 2.81-2.93(1H, m), 3.05-3.23 (2H, m), 3.10(1H, s), 3.30(3H, s), 3.49(1H, d, J=6.5 Hz), 3.60-3.78(2H,
#m), 3.67(1H, s), 3.97 (1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.27(2H, m), 4.29-4.41(1H, m), 4.37(1H, s), 4.53 (1H, d, J=8 Hz), 4.62-4.72(1H, m), 4.68(1H, d, J=10 Hz), 4.73-4.80(1H, m), 4.94(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 6.88-6.95 (3H, m), 7.24-7.30(2H, m)
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1242
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ExampleNR1R2Description and physical properties
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211243colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.76-1.75(34H, m), 0.82(3H, t, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.80-1.98(2H, m), 2.05-2.18(2H, m), 2.10(3H, s), 2.23(3H, s), 2.27-2.37(1H, m), 2.40 (1H, d, J=15.5 Hz), 2.55-2.69(3H, m), 2.77-2.85(1H, m), 3.07 (1H, s), 3.08(3H, s), 3.47-3.60(1H, m), 3.50(1H, d, J=7.5 Hz), 3.62-3.72(1H, m), 3.70(1H, s), 3.94(1H, d, J=10 Hz), 4.06(2H, t, J=6 Hz), 4.18-4.25
#(2H, m), 4.35(1H, s), 4.43(1H, d, J=7.5 Hz), 4.45-4.53(1H, m), 4.70-4.79(1H, m), 4.75(1H, d, J=10 Hz), 4.88(1H, d, J=4.5 Hz), 5.08(1H, dd, J=11.5, 2 Hz), 6.87-6.96(3H, m), 7.00-7.10(1H, m), 7.20-7.40(5H, m), 7.43-7.50(2H, m)
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221244colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 09.93-1.72(34H, m), 1.03(3H, d, J=7.5 Hz), 1.85-2.00(2H, m), 1.90 (3H, s), 2.05-2.18(2H, m), 2.26(3H, s), 2.32-2.43(1H, m), 2.39 (1H, d, J=15.5 Hz), 2.55-2.74(3H, m), 2.80-2.90(1H, m), 3.11(1H, s), 3.26(3H, s), 3.49(1H, d, J=6.5 Hz), 3.55-3.75(2H, m), 3.71(1H, s), 3.96(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.17-4.26(3H, m), 4.37(1H, s),
#4.40(1H, d, J=6 Hz), 4.48(1H, d, J=7.5 Hz), 4.58 (1H, dd, J=15.5, 7.5 Hz), 4.64-4.75(1H, m), 4.66(1H, d, J=10 Hz), 4.90(1H, d, J=3.5 Hz), 5.11(1H, dd, J=11, 2 Hz), 5.36-5.46 (1H, m), 6.88-6.95(3H, m), 7.22-7.33(7H, m)
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231245colorless solid (recry. solv.: EtOH) m.p. 86-87.5° C. NMR spectrum δ (CDCl3) ppm: 0.80-1.72(28H, m), 0.86(3H, t, J=7.5 Hz), 0.89(3H, d, J=7.5 Hz), 0.96(3H, t, J=6.5 Hz), 1.02 (3H, d, J=6.5 Hz), 1.80-2.18(4H, m), 2.01(3H, s), 2.24(3H, s), 2.30-2.42(1H, m), 2.39(1H, d, J=15.5 Hz), 2.50-2.75(3H, m), 2.78-2.88(1H, m), 3.11(1H, s), 3.28(3H, s), 3.47(1H, d, J=6.5 Hz), 3.58-3.72(2H, m), 3.68(1H, s), 3.83(3H, s), 3.95(1H,
#d, J=9 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25(2H, m), 4.27-4.77(1H, m), 4.66(1H, d, J=10 Hz), 4.92(1H, d, J=3 Hz), 5.11(1H, dd, J=10.5, 2 Hz), 5.24-5.34(1H, m), 6.82-6.96(5H, m), 7.18-7.36(4H, m)
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241246colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.92-1.75(34H, m), 1.03(3H, d, J=6.5 Hz), 1.86-2.00(2H, m), 1.93 (3H, s), 2.03-2.19(2H, m), 2.26(3H, s), 2.31-2.43(1H, m), 2.39 (1H, d, J=15.5 Hz), 2.55-2.72(3H, m), 2.81-2.92(1H, m), 3.10 (1H, s), 3.26(3H, s), 3.49(1H, d, J=6.5 Hz), 3.55-3.73(2H, m), 3.70 (1H, s), 3.79(3H, s), 3.95(1H, d, J=10 Hz), 4.05(2H, t, J=6 Hz), 4.15-4.25(3H, m),
#4.30-4.45(1H, m), 4.36(1H, s), 4.49(1H, d, J=7.5 Hz), 4.56(1H, dd, J=15.5, 7.5 Hz), 4.66(1H, d, J=10 Hz), 4.70 (1H, dd, J=10, 8 Hz), 4.90(1H, d, J=3.5 Hz), 5.11(1H, dd, J=11, 2 Hz), 5.35-5.43(1H, brs), 6.68-6.97(5H, m), 7.15-7.35(4H, m)
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251247colorless needles (recry. solv.: EtOH) m.p. 99-100° C. NMR spectrum δ (CDCl3) ppm: 0.84(3H, t, J=7.5 Hz), 0.92-1.72(34H, m), 1.03(3H, d, J=7.5 Hz), 1.88-2.00(2H, m), 1.92 (3H, s), 2.05-2.18(2H, m), 2.26(3H, s), 2.32-2.42(1H, m), 2.39(1H, d, J=15.5 Hz), 2.55-2.71(3H, m), 2.82-2.92(1H, m), 3.11(1H, s), 3.26(3H, s), 3.49(1H, d, J=7.5 Hz), 3.56-3.75(2H, m), 3.70 (1H, s), 3.79(3H, s), 3.95(1H, d, J=9 Hz), 4.05(2H, t,
#J=6 Hz), 4.10-4.25(2H, m), 4.15(1H, dd, J=14.5, 4.5 Hz), 4.33-4.43(1H, m), 4.38(1H, s), 4.45-4.55(1H, m), 4.48(1H, d, J=7.5 Hz), 4.61-4.75 (1H, m), 4.66(1H, d, J=10 Hz), 4.90(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11.5, 1.5 Hz), 5.27-5.35(1H, m), 6.84(2H, d, J=8.5 Hz), 6.88-6.96(3H, m), 7.20-7.30(2H, m), 7.23(2H, d, J=8.5 Hz)
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261248pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.22(39H, m), 0.86 (3H, t, J=7.5 Hz), 1.01(3H, d, J=6.5 Hz), 2.01(3H, s), 2.19(3H, s), 2.26-2.37(1H, m), 2.41(1H, d, J=15.5 Hz), 2.46-2.72(3H, m), 2.80-2.90(1H, m), 3.10(1H, s), 3.27(3H, s), 3.47(1H, d, J=7.5 Hz), 3.55-3.72(2H, m), 3.68(1H, s), 3.94(1H, d, J=10 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25(2H, m), 4.30-4.45(1H, m), 4.35(1H, s), 4.49(1H, d, J=7.5
#Hz), 4.53-4.71(2H, m), 4.67(1H, d, J=10 Hz), 4.76(1H, dd, J=16, 6.5 Hz), 4.91(1H, d, J=4.5 Hz), 5.08-5.13(1H, m), 6.85-6.95(3H, m), 7.20-7.30(2H, m), 7.40-7.50(1H, m), 7.53-7.65(1H, m), 7.70-7.78(1H, m), 8.02-8.20(1H, m)
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271249pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.85(3H, t, J=7.5 Hz), 0.90-1.82(28H, m), 0.93(3H, t, J=7 Hz), 0.97(3H, d, J=7.5 Hz), 1.03 (3H, d, J=6.5 Hz)(, 1.88-2.00(2H, m), 1.96(3H, s), 2.02-2.18 (2H, m), 2.25(3H, s), 2.30-2.45(1H, m), 2.41(1H, d, J=15.5 Hz), 2.55-2.72(3H, m), 2.82-2.92(1H, m), 3.10(1H, s), 3.26(3H, s), 3.50(1H, d, J=7.5 Hz), 3.54-3.73(2H, m), 3.71(1H, s), 3.97(1H, d, J=10 Hz), 4.05
#(2H, t, J=6.5 Hz) 4.15-4.33(2H, m), 4.28(1H, dd, J=16.5 Hz), 4.35-4.55(1H, m), 4.37(1H, s), 4.47(1H, d, J=8 Hz), 5.11(1H, dd, J=11, 2 Hz), 5.70-5.78(1H, m), 6.86-6.96(3H, m), 7.20-7.30(2H, m), 7.45-7.55(1H, m), 7.67(1H, d, J=7.5 Hz), 8.05-8.22(1H, m), 8.18(1H, s)
|
28NHEtcolorless needles (recry. solv.: CH3CN)
m.p. 97.5-99° C.
NMR spectrum δ (CDCl3) ppm: 0.90-1.75(30H, m), 0.84
(3H, t, J=7.5 Hz), 0.96(3H, d, J=8 Hz), 1.00(3H, d, J=7.5 Hz), 1.02
(3H, t, J=6.5 Hz), 1.85-2.00(3H, m), 2.05-2.18(2H, m), 2.10
(3H, s), 2.26(3H, s), 2.33-2.45(1H, m), 2.40(1H, d, J=15.5 Hz), 2.53-
2.77(3H, m), 2.82-2.95(1H, m), 3.10(1H, s), 3.16-3.38(2H,
m), 3.29(3H, s), 3.49(1H, d, J=6.5 Hz), 3.60--3.73(2H, m), 3.68
(1H, s), 3.96(1H, d, J=9 Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25(2H,
m), 4.30-4.42(1H, m), 4.38(1H, s), 4.49(1H, d, J=7.5 Hz), 4.62-
4.72(1H, m), 4.68(1H, d, J=10 Hz), 4.85-5.00(1H, m), 4.93
(1H, d, J=3.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 6.86-6.96(3H, m), 7.24-
7.30(2H, m)
29NH-n-Prcolorless solid (recry. solv.: CH3CN)
m.p. 94-97° C.
NMR spectrum δ (CDCl3) ppm: 0.80-1.75(36H, m), 0.84(3H,
t, J=7.5 Hz), 0.93(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.87-
2.00(2H, m), 2.04-2.18(2H, m), 2.09(3H, s), 2.26(3H, s), 2.32-
2.45(1H, m), 2.40(1H, d, J=14.5 Hz), 2.54-2.78(3H, m), 2.82-
2.95(1H, m), 3.05-3.23(2H, m), 3.09(1H, s), 3.29(3H, s), 3.49
(1H, d, J=6.5 Hz), 3.60-3.75(2H, m), 3.67(1H, s), 3.97(1H, d, J=10
Hz), 4.05(2H, t, J=6.5 Hz), 4.15-4.25(2H, m), 4.30-4.42(1H,
m), 4.36(1H, s), 4.50(1H, d, J=7.5 Hz), 4.62-4.72(1H, m), 4.68
(1H, d, J=10 Hz), 4.82-4.90(1H, m), 4.93(1H, d, J=3.5 Hz), 5.12
(1H, dd, J=11, 2 Hz), 6.85-6.95(3H, m), 7.20-7.30(2H, m)
30NH-n-Bucolorless needles (recry. solv.: CH3CN)
m.p. 89-92.5° C.
NMR spectrum δ (CDCl3) ppm: 0.84(3H, t, J=7.5 Hz), 0.88-
1.78(38H, m), 0.93(3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.88-
2.00(2H, m), 2.05-2.18(2H, m), 2.09(3H, s), 2.26(3H, s), 2.32-
2.45(1H, m), 2.40(1H, d, J=14.5 Hz), 2.54-2.77(3H, m), 2.80-
2.95(1H, m), 3.08-3.25(2H, m), 3.10(1H, s), 3.29(3H, s), 3.49
(1H, d, J=7.5 Hz), 3.60-3.75(2H, m), 3.68(1H, s), 3.96(1H, d, J=9
Hz), 4.05(2H, t, J=6 Hz), 4.15-4.26(2H, m), 4.29-4.42(1H, m),
4.38(1H, s), 4.50(1H, d, J=7.5 Hz), 4.61-4.74(1H, m), 4.68(1H,
d, J=10 Hz), 4.78-4.88(1H, m), 4.93(1H, d, J=4.5 Hz), 5.12(1H,
dd, J=11, 2 Hz), 6.85-6.95(3H, m), 7.20-7.30(2H, m)
31NH-n-Hexcolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.84(3H, t, J=7.5 Hz), 0.89
(3H, t, J=7 Hz), 0.95(3H, d, J=8 Hz), 1.00(3H, t, J=7.5 Hz), 1.03
(3H, d, J=7.5 Hz), 1.08-1.70(36H, m), 1.89-1.98(2H, m), 2.08-
2.16(2H, m), 2.09(3H, s), 2.26(3H, s), 2.32-2.45(1H, m), 2.40
(1H, d, J=15.5 Hz), 2.54-2.75(3H, m), 2.83-2.93(1H, m), 3.06-
3.25(2H, m), 3.10(1H, s), 3.29(3H, s), 3.49(1H, d, J=7.5 Hz), 3.60-
3.72(2H, m), 3.68(1H, s), 3.96(1H, d, J=9 Hz), 4.05(2H, t, J=6.5
Hz), 4.15-4.25(2H, m), 4.30-4.40(1H, m), 4.38(1H, s), 4.50
(1H, d, J=7.5 Hz), 4.62-4.72(1H, m), 4.67(1H, d, J=10 Hz), 4.79-
4.85(1H, m), 4.93(1H, d, J=3 Hz), 5.12(1H, dd, J=11, 2 Hz), 6.88-
6.95(3H, m), 7.23-7.30(2H, m)
|
|
1250
|
ExampleR7Description and physical properties
|
32n-Prcolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.77-1.77(51H, m), 0.96
(3H, d, J=7.5 Hz), 1.04(3H, d, J=7.5 Hz), 1.87-2.03(2H, m),
1.93(3H, s), 2.20-2.43(1H, m), 2.25(3H, s), 2.39(1H, d, J=14.5
Hz), 2.45-2.54(1H, m), 2.60-2.72(2H, m), 2.81-2.92(1H, m),
3.12(1H, s), 3.26(3H, s), 3.51(1H, d, J=7.5 Hz), 3.57-3.75
(2H, m), 3.68(1H, s), 3.92-4.03(3H, m), 4.25(1H, d, J=15.5, 5
Hz), 4.33-4.59(2H, m), 4.46(1H, s), 4.50(1H, d, J=8 Hz), 4.66
(1H, d, J=10 Hz), 4.71(1H, dd, J=10, 8 Hz), 4.91(1H, d, J=4.5
Hz), 5.07-5.18(1H, m), 5.27-5.38(1H, m), 7.22-7.35(5H, m)
33n-Hexcolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.81-1.75(57H, m), 0.96
(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.87-2.03(2H, m),
1.94(3H, s), 2.20-2.43(1H, m), 2.26(3H, s), 2.39(1H, d, J=15.5
Hz), 2.47-2.56(1H, m), 2.60-2.72(2H, m), 2.80-2.92(1H, m),
3.12(1H, s), 3.26(3H, s), 3.51(1H, d, J=6.5 Hz), 3.57-3.75(2H,
m), 3.68(1H, s), 3.92-4.05(3H, m), 4.21-4.58(3H, m), 4.47
(1H, s), 4.52(1H, d, J=7.5 Hz), 4.66(1H, d, J=10 Hz), 4.71(1H,
dd, J=9.5, 7.5 Hz), 4.92(1H, d, J=5 Hz), 5.12(1H, dd, J=11, 2 Hz),
5.21-5.33(1H, m), 7.20-7.40(5H, m)
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|
1251
|
ExampleDescription and physical properties
|
34colorless solid (recry. solv.: CH3CN)
m.p. 107-110° C.
NMR spectrum δ (CDCl3) ppm: 0.86(3H, t, J=7.5 Hz), 0.92(3H, d, J=7.5 Hz),
1.04(3H, d, J=7.5 Hz), 1.10-1.78(28H, m), 1.85-2.00(2H, m), 2.05-2.20(2H,
m), 2.13(1H, s), 2.23-2.35(1H, m), 2.30(6H, s), 2.55-2.70(2H, m), 2.77-2.90
(1H, m), 3.03(1H, t, J=9.5 Hz), 3.14(1H, s), 3.28(3H, s), 3.42-3.55(1H, m), 3.51(1H,
d, J=7.5 Hz), 3.62-3.75(1H, m), 3.70(1H, s), 3.93-4.08(1H, m), 3.99(1H, d, J=9 Hz),
4.05(2H, t, J=6.5 Hz), 4.15-4.26(2H, m), 4.30-4.56(2H, m), 4.41(1H, s), 4.50
(1H, d, J=7.5 Hz), 4.62-4.73(1H, m), 4.89(1H, d, J=4.5 Hz), 4.91-5.01(1H, m), 5.11
(1H, dd, J=11, 2 Hz), 6.85-6.95(3H, m), 7.20-7.40(7H, m)
|
4″-O-Acetyl-2′-O-(1-imidazolylcarbonyl)erythromycin A 9-[O-(3-cyclo-hexylpropyl)oxime]
[0086] To a solution of 0.50 g of 4″-O-acetylerythromycin A 9-[O-(3-cyclohexyl-propyl)oxime] in 5.0 ml of dried toluene, 0.11 g of N,N′-carbonyldiimidazole was added, and the mixture was stirred at 80° C. of outer temperature for 21 hours. The reaction mixture was added with water, and alkalified by saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was added with n-heptane and heated, and filtrated under hot condition. The filtrate was cooled and the precipitated crystals were collected by filtration to obtain 0.56 g of a colorless solid. Recrystallization from diisopropyl ether gave a colorless solid having the melting point of from 136.5 to 137.5° C.
[0087] NMR spectrum δ (CDCl3)ppm:0.72-2.00(48H,m),0.77(3H,d,J=7.5 Hz),0.81(3H,t,J=7.5 Hz),2.12(3H,s),2.27(6H,s),2.41(1H,d,J=15.5 Hz),2.59-2.64(1H,m),2.77-2.86(2H,m),3.08(1H,s),3.39(3H,s),3.55(1H,d,J=6.5 Hz),3.58(1H,s),3.60-3.72(1H,m),3.77-3.87(1H,m),3.94-4.02(3H,m),4.27-4.34(1H,m),4.42(1H,s),4.60-4.80(2H,m),4.70(1H,d,J=10 Hz),4.80-4.90(2H,m),4.97(1H,d,J=5 Hz),5.09(1H,dd,J=11, 2.5 Hz),7.08(1H,s),7.40(1H,s),8.06(1H,s)
[0088] In accordance with the method of Example 35, the compounds of Examples 36 through 39 were obtained.
27|
|
ExampleR8R7Description and physical properties
|
|
|
1252
|
|
361253Etcolorless prisms (recry. solv.: AcOEt) m.p. 143-145.5° C. NMR spectrum δ (CDCl3) ppm: 0.75-2.00 (45H, m), 0.80(3H, d, J=7.5 Hz), 0.81(3H, t, J=7.5 Hz), 0.91(3H, t, J=7 Hz), 1.04(3H, d, J=6.5 Hz), 2.11(3H, s), 2.22(3H, s), 2.30-2.40(1H, m), 2.41(1H, d, J=15.5 Hz), 2.50-2.67(2H, m), 2.78-2.92(2H, m), 3.08(1H, s), 3.39(3H, s) 3.56(1H, d, J=6.5 Hz), 3.59(1H, s), 3.60-3.73 (1H, m), 3.77-3.88(1H, m), 3.90-
#4.03(3H, m), 4.25-4.36(1H, m), 4.42(1H, s), 4.70(1H, d, J=10 Hz), 4.79-4.90(2H, m), 4.98(1H, d, J=5 Hz), 5.10(1H, dd, J=11, 2.5 Hz), 7.08(1H, s), 7.39 (1H, s), 8.06(1H, s)
|
37n-OctMecolorless solid
(recry. solv.: AcOEt-n-Heptane)
m.p. 135-139° C.
NMR spectrum δ (CDCl3) ppm: 0.77 (3H, d,
J=7.5 Hz), 0.81(3H, t, J=7.5 Hz), 0.88(3H, t, J=
7 Hz), 1.00-1.70(38H, m), 1.04(3H, d, J=7.5
Hz), 1.75-1.95(4H, m), 2.12(3H, s), 2.27(6H,
s), 2.41(1H, d, J=15.5 Hz), 2.58-2.65(1H, m),
2.77-2.85(2H, m), 3.08(1H, s), 3.39(3H, s),
3.55(1H, d, J=6.5 Hz), 3.59(1H, s), 3.62-3.71
(1H, m), 3.77-3.84(1H, m), 3.96(1H, d, J=8.5 Hz),
3.99(2H, t, J=7 Hz), 4.27-4.33(1H, m), 4.42
(1H, s), 4.70(1H, d, J=10 Hz), 4.80-4.87(2H,
m), 4.97(1H, d, J=5 Hz), 5.09(1H, dd, J=11, 2.5
Hz), 7.08(1H, s), 7.40(1H, s), 8.06(1H,s)
|
1254
|
|
3812551256colorless needles (recry. solv.: AcOEt-n-Heptane) m.p. 175.5-176.5° C. NMR spectrum δ (CDCl3) ppm: 0.75(3H, d, J=7.5 Hz), 0.80(3H, t, J=7.5 Hz), 0.95(3H, d, J=6.5 Hz), 1.01(3H, d, J=6.5 Hz), 1.05-1.70(18H, m), 1.82(1H, s), 1.85-2.00(3H, m), 2.13-2.30 (1H, m), 2.24(6H, s), 2.51-2.85(5H, m), 2.97-3.08 (1H, m), 3.10(1H, s), 3.47(1H, d, J=5 Hz), 3.58-3.78(1H, m), 3.64(1H, s), 3.70(1H, d, J=14.5 Hz),
#3.73(1H, d, J=14.5 Hz), 3.94-4.10(2H, m), 4.01(1H, d, J=8 Hz), 4.41(1H, s), 4.72(1H, dd, J=1.05, 7.5 Hz), 5.12(1H, d, J=11 Hz), 5.17(1H, dd, J=11.5, 2 Hz), 7.11(1H, s), 7.15-7.20(3H, m), 7.25-7.43(7H, m), 8.10(1H, s)
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3912571258colorless needles (recry. solv.: AcOEt-n-Heptane) m.p. 173.5-174° C. NMR spectrum δ (CDCl3) ppm: 0.74(3H, d, J=8 Hz), 0.81(3H, t, J=7.5 Hz), 0.97(3H, d, J=6.5 Hz), 0.98(3H, d, J=6.5 Hz), 1.03-1.73(17H, m), 1.85-1.97(1H, m), 2.07(1H, s), 2.14-2.29 (1H, m), 2.24(6H, s), 2.52-2.66(2H, m), 2.72-2.83 (1H, m), 2.93-3.03(1H, m), 3.09(1H, s), 3.38 (1H, d, J=4.5 Hz), 3.61-3.75(3H, m), 3.71(1H, s), 3.95
#(1H, d, J=7.5 Hz), 4.09-4.20(2H, m), 4.30-4.44(2H, m), 4.35(1H, s), 4.71(1H, dd, J=10.5, 7.5 Hz), 5.11(1H, d, J=11 Hz), 5.18(1H, dd, J=11, 2.5 Hz), 6.91-7.01(3H, m), 7.10(1H, s), 7.24-7.45(7H, m), 8.11(1H, s)
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4″-O-Acetyl-2′-O-benzylaminocarbonylerythromycin A 9-[O-(3-cyclo-hexylpropyl)oxime]
[0089] To a solution of 0.50 g of 4″-O-acetyl-2′-O-(1-imidazolylcarbonyl)erythromycin A 9-[O-(3-cyclohexylpropyl)oxime] in 5.0 ml of tetrahydrofuran, 0.06 ml of benzylamine was added. Under nitrogen atmosphere, the mixture was stirred at room temperature for 2 hours. And then, the reaction mixture was added with 0.50 ml of water, and stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was added with water and alkalified by saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate) to obtain 0.24 g of a colorless amorphous solid.
[0090] NMR spectrum δ (CDCl3)ppm:0.80-2.05(45H,m),0.85(3H,t,J=7.5 Hz),0.96(3H,d,J=6.5 Hz),1.04(3H,d,J=6.5 Hz),1.95(3H,s),2.31(6H,s),2.39(1H,d,J=15.5 Hz),2.57-2.72(2H,m),2. 80-2.92(1H,m),3.12(1H,s),3.26(3H,s),3.51(1H,d,J=6.5 Hz),3.58-3.75(2H,m),3.68(1H,s),3. 90-4.04(3H,m),4.26(1H,dd,J=15, 4.5 Hz),4.30-4.60(2H,m),4.46(1H,s),4.52(1H,d,J=7.5 Hz),4.62-4.77(1H,m),4.66(1H,d,J=10 Hz),4.92(1H,d,J=4.5 Hz),5.07-5.18(1H,m),5.30-5.40(1 H,m),7.20-7.40(5H,m)
[0091] In accordance with the method of Example 40, the compounds of Examples 41 through 99 were obtained.
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1259
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ExampleNR1R2Description and physical properties
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411260colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.77-1.80(47H, m), 0.81 (3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.83-2.01(2H, m), 2.12 (3H, s), 2.28(6H, s), 2.40(1H, d, J=14.5 Hz), 2.56-2.70(2H, m), 2.76-2.87(1H, m), 3.07(1H, s), 3.10(3H, s), 3.52(1H, d, J=7.5 Hz), 3.55-3.70(2H, m), 3.67(1H, s), 3.91-4.05(3H, m), 4.40-4.53(1H, m), 4.42(1H, s), 4.47(1H, d, J=8 Hz), 4.74(1H, d, J=10 Hz), 4.76 (1H, dd, J=
#10.5, 7.5 Hz), 4.89(1H, d, J=4.5 Hz), 5.08(1H, dd, J=11.2 Hz), 7.01-7.12(1H, m), 7.29(2H, t, J=8 Hz), 7.45(2H, d, J=8 Hz)
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421261colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.83(43H, m), 0.85 (3H, t, J=7.5 Hz), 0.91(3H, d, J=7.5 Hz), 1.04(3H, d, J=7.5 Hz), 1.88-2.00(2H, m), 2.04(3H, s), 2.32(6H, s), 2.39(1H, d, J=15.5 Hz), 2.60-2.95(5H, m), 3.10(1H, s), 3.20-3.58(2H, m), 3.27(3H, s), 3.51(1H, d, J=7.5 Hz), 3.59-3.84(2H, m), 3.65(1H, s), 3.92-4.04 (3H, m), 4.30-4.38(1H, m), 4.44(1H, s), 4.52(1H, d, J=7.5 Hz), 4.60-4.78(1H, m),
#4.67(1H, d, J=10 Hz), 4.80-4.90(1H, m), 4.94(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 7.12-7.37(5H, m)
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431262colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.00(47H, m), 0.84 (3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.01(3H, d, J=6.5 Hz), 2.09 (3H, s), 2.31(6H, s), 2.39(1H, d, J=14.5 Hz), 2.55-2.72(4H, m), 2.83-2.91(1H, m), 3.08(1H, s), 3.20-3.27(2H, m), 3.29(3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.75(2H, m), 3.63(1H, s), 3.93-4.04(3H, m), 4.30-4.40(1H, m), 4.43(1H, s), 4.53(1H, d, J=7.5 Hz), 4.62-4.75(1H, m),
#4.68(1H, d, J=10 Hz), 4.78-4.88(1H, m), 4.94 (1H, d, J=4.5 Hz), 5.07-5.15(1H, m), 7.10-7.22(3H, m), 7.24-7.40(2H, m)
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441263colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.83(47H, m), 0.84 (3H, t, J=7.5 Hz), 0.95(3H, d, J=8 Hz), 1.03(3H, d, J=6.5 Hz), 1.88-1.99(2H, m), 2.08(3H, d, J=8 Hz), 2.39(1H, d, J=15.5 Hz), 2.58-2.70(4H, m), 2.83-2.91(1H, m), 3.10(1H, s), 3.17-3.38(2H, m), 3.28(3H, s), 3.51(1H, d, J=7.5 Hz), 3.61-3.71(2H, m), 3.66 (1H, s), 3.94-4.01(3H, m), 4.30-4.38(1H, m), 4.45(1H, s), 4.53 (1H, d, J=7.5 Hz),
#4.62-4.70(1H, m), 4.67(1H, d, J=10 Hz), 4.75-4.84(1H, m), 4.94(1H, d, J=4.5 Hz), 5.13(1H, dd, J=11, 2 Hz), 7.13-7.20(3H, m), 7.25-7.30(2H, m)
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451264colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.82(43H, m), 0.84 (3H, t, J=7.5 Hz), 0.88(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.84-1.98(2H, m), 2.09(3H, s), 2.39(1H, d, J=15.5 Hz), 2.57-2.77(3H, m), 3.10(1H, s), 3.31(3H, s), 3.49(1H, d, J=6.5 Hz), 3.53-3.78(4H, m), 3.62(1H, s), 3.88-4.12(5H, m), 4.28-4.40 (1H, m), 4.43(1H, s), 4.56(1H, d, J=7.5 Hz), 4.60-4.75(1H, m), 4.67(1H, d, J=10 Hz), 4.92(1H,
#d, J=4.5 Hz), 5.05-5.14(1H, m), 5.20-5.30(1H, m), 6.88(2H, d, J=8 Hz), 6.90-7.00(1H, m), 7.20-7.35(2H, m)
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461265colorless amorphous solid NMR spectrum δ (DMSO-d6) ppm: 0.75-1.78(46H, m), 0.79 (3H, t, J=7.5 Hz), 0.84(3H, d, J=7.5 Hz), 1.80-1.98(2H, m), 2.02 (3H, s), 2.23(6H, s), 2.32(1H, d, J=15.5 Hz), 2.60-2.80(3H, m), 2.73(3H, s), 3.21(3H, brs), 3.37(1H, brs), 3.43(1H, d, J=6.5 Hz), 3.45-3.55(1H, m), 3.62(1H, s), 3.64(1H, s), 3.68-3.78(1H, m), 3.85-3.95(4H, m), 4.20-4.35(2H, m), 4.53(1H, d, J=10 Hz), 4.55 (1H, dd, J=10.5, 7.5
#Hz), 4.66(1H, d, J=8 Hz), 4.84(1H, d, J=5 Hz), 5.09(1H, dd, J=10, 2.5 Hz), 7.20-7.35(5H, m)
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471266colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.79-1.79(43H, m), 0.84 (3H, t, J=7.5 Hz), 0.94(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.86-1.97(2H, m), 2.02(3H, s), 2.30(6H, s), 2.40(1H, d, J=14.5 Hz), 2.55-2.75(2H, m), 2.80-2.92(1H, m), 3.10(1H, s), 3.29(3H, s), 3.51(1H, d, J=7.5 Hz), 3.59-3.75(2H, m), 3.65(1H, s), 3.91-4.04(3H, m), 4.30-4.80(4H, m), 4.43(1H, s), 4.55(1H, d, J=7.5 Hz), 4.67(1H, d, J=10
#Hz), 4.93(1H, d, J=3.5 Hz), 5.06-5.17(1H, m), 5.81-5.92(1H, m), 7.17(1H, dd, J=6.5, 5 Hz), 7.38(1H, d, J=8 Hz), 7.59-7.68(1H, m), 8.52(1H, d, J=5 Hz),
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481267colorless solid (recry. solv.: AcOEt-m-Heptane) m.p. 117.5-118.5° C. NMR spectrum δ (CDCl3) ppm: 0.80-1.77(43H, m), 0.85(3H, t, J=7.5 Hz), 0.94(3H, d, J=6.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.88-2.00(2H, m), 1.94(3H, s), 2.29(6H, s), 2.40(1H, d, J=14.5 Hz), 2.55-2.71(2H, m), 2.79-2.90(1H, m), 3.12(1H, s), 3.26(3H, s), 3.51 (1H, d, J=7.5 Hz), 3.57-3.72(2H, m), 3.69(1H, s), 3.93-4.01(3H, m), 4.24(1H, dd, J=15.5, 4.5
#Hz), 4.37-4.52(1H, m), 4.45(1H, s), 4.49 (1H, d, J=7.5 Hz), 4.55-4.71(2H, m), 4.67(1H, d, J=10 Hz), 4.90 (1H, d, J=3.5 Hz), 5.08-5.13(1H, m), 5.57-5.65(1H, m), 7.20-7.25 (1H, m), 7.67(1H, d, J=8 Hz), 8.51(1H, dd, J=4.5, 1.5 Hz), 8.56(1H, s)
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491268colorless solid (recry. solv.: AcOEt-n-Heptane) m.p. 121-125° C. NMR spectrum δ (CDCl3) ppm: 0.80-2.11(46H, m), 0.85(3H, t, J=7.5 Hz), 0.99(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.97(3H, s), 2.30(6H, s), 2.41(1H, d, J=15.5 Hz), 2.55-2.70(2H, m), 2.80-2.93(1H, m), 3.11(1H, s), 3.26(3H, s), 3.52(1H, d, J=7.5 Hz), 3.57-3.74(2H, m), 3.69(1H, s), 3.92-4.05(3H, m), 4.17(1H, dd, J=16.5, 5 Hz), 4.38-4.57(1H, m),
#4.44(1H, s), 4.49(1H, d, J=8 Hz), 4.59-4.75(3H, m), 4.91(1H, d, J=4.5 Hz), 5.05-5.18(1H, m), 5.68-5.80(1H, m), 7.20-7.35(2H, m), 8.53(1H, dd, J=4.5, 1 Hz)
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501269colorless needles (recry. colv.: AcOEt-n-Heptane)-i-PrO2) m.p. 202-203° C. NMR spectrum δ (CDCl3) ppm: 0.80-2.00(45H, m), 0.84(6H, t, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 2.05(3H, s), 2.30(6H, s), 2.39 (1H, d, J=15.5 Hz), 2.60-2.72(2H, m), 2.74-2.85(1H, m), 2.92-3.15(2H, m), 3.09(1H, s), 3.30(3H, s), 3.48-3.72(4H, m), 3.49(1H, d, J=6.5 Hz), 3.63(1H, s), 3.90-4.03(3H, m), 4.30-4.38(1H, m), 4.43 (1H, s), 4.54(1H,
#d, J=7.5 Hz), 4.60-4.78(1H, m), 4.67(1H, d, J=10 Hz), 4.93(1H, d, J=4.5 Hz), 5.11(1H, dd, J=11, 1 Hz), 5.36-5.46 (1H, m), 7.10-7.22(1H, m), 7.18(1H, d, J=7.5 Hz), 7.56-7.63(1H, m), 8.51(1H, d, J=4.5 Hz)
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511270colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.77-1.82(43H, m), 0.81 (3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.83-1.95(3H, m), 2.12(3H, s), 2.33(6H, s), 2.40(1H, d, J=15.5 Hz), 2.50-2.59(1H, m), 2.75-2.90(2H, m), 3.07(1H, s), 3.32(3H, s), 3.55(1H, d, J=7.5 Hz), 3.58(1H, s), 3.60-3.80(2H, m), 3.87(3H, s), 3.92-4.03(3H, m), 4.30-4.41(1H, m), 4.44(1H, s), 4.62(1H, d, J=8 Hz), 4.69(1H, d,
#J=10 Hz), 4.78(1H, dd, J=10.5, 7.5 Hz), 4.95(1H, d, J=5 Hz), 5.08(1H, dd, J=11, 2 Hz), 6.87(1H, dd, J=8, 1 Hz), 6.92-7.04(2H, m), 7.17(1H, s), 8.11(1H, d, J=6.5 Hz)
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521271colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.79-1.80(46H, m), 0.82 (3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.83-2.00(2H, m), 2.12 (3H, s), 2.27(6H, s), 2.40(1H, d, J=15.5 Hz), 2.58-2.68(2H, m), 2.77-2.87(1H, m), 3.08(1H, s), 3.13(3H, s), 3.52(1H, d, J=7.5 Hz), 3.55-3.72(2H, m), 3.67(1H, s), 3.80(3H, s), 3.90-4.05(3H, m), 4.37-4.53(1H, m), 4.43(1H, s), 4.46(1H, d, J=7.5 Hz), 4.68-4.80(1H, m), 4.73(1H, d,
#J=10 Hz), 4.89(1H, d, J=4.5 Hz), 5.08(1H, dd, J=11, 2.5 Hz), 6.59(1H, dd, J=8, 2 Hz), 6.98(1H, d, J=8 Hz), 7.10-7.20(1H, m), 7.15(1H, s), 7.22-7.30(1H, m)
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531272pale brown amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.77(43H, m), 0.82 (3H, t, J=7.5 Hz), 0.98(3H, d, J=6.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.85-1.99(2H, m), 2.12(3H, s), 2.29(6H, s), 2.40(1H, d, J=15.5 Hz), 2.58-2.65(2H, m), 2.78-2.86(1H, m), 3.08(1H, s), 3.09(3H, s), 3.52(1H, d, J=7.5 Hz), 3.55-3.70(2H, m), 3.67(1H, s), 3.78(3H, s), 3.93-4.00(3H, m), 4.40-4.50(1H, m), 4.42(1H, s), 4.47(1H, d, J=8 Hz), 4.72(1H, d,
#J=10 Hz), 4.75(1H, dd, J=10.5, 7.5 Hz), 4.90(1H, d, J=4.5 Hz), 5.09(1H, dd, J=11, 2 Hz), 6.84(2H, d, J=9 Hz), 7.08-7.22(1H, m), 7.34(2H, d, J=9 Hz)
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541273pale brown amorphous solid NMR spectrum δ (CDCl3) ppm: 0.78-1.80(43H, m), 0.82 (3H, t, J=7.5 Hz), 0.98(3H, d, J=6.5 Hz), 1.02(3H, d, J=6.5 Hz), 1.85-2.00(2H, m), 2.12(3H, s), 2.26(6H, s), 2.40(1H, d, J=15.5 Hz), 2.57-2.68(2H, m), 2.78-2.87(1H, m), 3.08(1H, s), 3.10(3H, s), 3.51(1H, d, J=7.5 Hz), 3.54-3.74(2H, m), 3.69(1H, s), 3.85(3H, s), 3.87(3H, s), 3.93-4.03(3H, m), 4.38-4.53(1H, m), 4.42(1H, s), 4.45(1H, d, J=7.5
#Hz), 4.70-4.78(1H, m), 4.73(1H, d, J=9 Hz), 4.89(1H, d, J=4.5 Hz), 5.09(1H, dd, J=11, 2 Hz), 6.77-6.83 (1H, m), 6.92(1H, dd, J=8.5, 2 Hz), 7.15(1H, s), 7.19-7.30(1H, m)
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551274pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.77-1.80(43H, m), 0.82 (3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.85-2.01(2H, m), 2.12(3H, s), 2.27(6H, s), 2.42(1H, d, J=15.5 Hz), 2.52-2.68(2H, m), 2.77-2.87(1H, m), 3.08(1H, s), 3.13(3H, s), 3.45-3.75(2H, m), 3.50(1H, d, J=7.5 Hz), 3.70(1H, s), 3.81 (3H, s), 3.84(6H, s), 3.90-4.04(3H, m), 4.35-4.55(2H, m), 4.42 (1H, s), 4.73(1H, dd, J=
#10.5, 8 Hz), 4.75(1H, d, J=10 Hz), 4.89(1H, d, J=3.5 Hz), 5.09(1H, dd, J=11.5, 2 Hz), 6.79(2H, s), 7.30-7.45 (1H, m)
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561275pale yellow needles (recry. solv.: AcOEt-n-Heptane) m.p. 151-154° C. NMR spectrum δ (CDCl3) ppm: 0.77-1.97(42H, m), 0.81 (3H, t, J=7.5 Hz), 0.88(3H, t, J=7 Hz), 0.95(3H, d, J=7.5 Hz), 1.01 (3H, d, J=6.5 Hz), 2.11(3H, s), 2.32(6H, s), 2.43(1H, d, J=15.5 Hz), 2.52-2.60(1H, m), 2.75-2.92(2H, m), 3.06(1H, s), 3.39(3H, s), 3.54(1H, d, J=6.5 Hz), 3.59(1H, s), 3.60-3.82(2H, m), 3.90-4.03(3H, m), 4.28-4.45 (1H, m), 4.40
#(1H, s), 4.64-4.80(2H, m), 4.69(1H, d, J=10 Hz), 4.98(1H, d, J=5 Hz), 5.08(1H, dd, J=11, 2.5 Hz), 7.08-7.17(1H, m), 7.60-7.70(1H, m), 8.23(1H, dd, J=8.5, 2 Hz), 8.59-8.65(1H, m), 9.81(1H, s)
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571276colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.75(49H, m), 1.03 (3H, d, J=6.5 Hz), 1.85-1.99(2H, m), 2.03(3H, s), 2.29(6H, s), 2.38 (1H, d, J=15.5 Hz), 2.60-2.71(2H, m), 2.77-2.86(1H, m), 3.12 (1H, s), 3.29(3H, s), 3.49(1H, d, J=7.5 Hz), 3.60-3.70(2H, m), 3.65 (1H, s), 3.83(3H, s), 3.93-4.00(3H, m), 4.27-4.50(3H, m), 4.45 (1H, s), 4.53(1H, d, J=7.5 Hz), 4.62-4.71(1H, m), 4.66(1H, d, J=10 Hz), 4.92(1H, d,
#J=3.5 Hz), 5.11(1H, dd, J=10.5, 2 Hz), 5.25-5.32(1H, m), 6.85(1H, d, J=8.5 Hz), 6.87-6.95(1H, m), 7.20-7.28(1H, m), 7.33(1H, d, J=7.5 Hz)
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581277colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.78-1.76(43H, m), 0.85 (3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.88-2.00(2H, m), 1.98(3H, s), 2.31(6H, s), 2.39(1H, d, J=15.5 Hz), 2.59-2.70(2H, m), 2.80-2.89(1H, m), 3.11(1H, brs), 3.26(3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.71(2H, m), 3.68(1H, s), 3.80 (3H, s), 3.94-4.01(3H, m), 4.21(1H, dd, J=15.5, 5 Hz), 4.30-4.49 (1H, m), 4.45(1H, s),
#4.50-4.57(1H, m), 4.52(1H, d, J=7.5 Hz), 4.62-4.72(1H, m), 4.66(1H, d, J=10 Hz), 4.91(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 5.30-5.40(1H, m), 6.79(1H, dd, J=8, 2 Hz), 6.87(1H, s), 6.82-6.92(1H, m), 7.20-7.28(1H, m)
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591278colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.81-1.75(43H, m), 0.85 (3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz) 1.87-2.00(2H, m), 1.96(3H, s), 2.31(6H, s), 2.38(1H, d, J=15.5 Hz), 2.57-2.68(2H, m), 2.81-2.90(1H, m), 3.12(1H, s), 3.26(3H, s), 3.51(1H, d, J=7.5 Hz), 3.60-3.71(2H, m), 3.68(1H, s), 3.80(3H, s), 3.93-4.01(3H, m), 4.19(1H, dd, J=14.5, 4.5 Hz), 4.32-4.55 (2H, m), 4.45(1H, s), 4.52
#(1H, d, J=8 Hz), 4.62-4.73(1H, m), 4.66 (1H, d, J=10.5 Hz), 4.92(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz),m 5.21-5.28(1H, m), 6.84(2H, d, J=9 Hz), 7.23(2H, d, J=9 Hz)
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601279pale yellow amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.79(43H, m), 0.85 (3H, t, J=7.5 Hz), 0.98(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.87-2.04(2H, m), 1.97(3H, s), 2.29(6H, s), 2.41(1H, d, J=15.5 Hz), 2.55-2.72(2H, m), 2.81-2.92(1H, m), 3.11(1H, s), 3.27(3H, s), 3.52(1H, d, J=7.5 Hz), 3.56-3.76(2H, m), 3.69(1H, s), 3.93-4.05(3H, m), 4.23-4.57(2H, m), 4.44(1H, s), 4.50(1H, d, J=7.5 Hz), 4.61-4.78(2H, m),
#4.68(1H, d, J =10 Hz), 4.91(1H, d, J=3.5 Hz), 5.11(1H, dd, J=11, 2 Hz), 5.69-5.83(1H, m), 7.48(1H, t, J=8 Hz), 7.60-7.74(1H, m), 8.05-8.15(1H, m), 8.18(1H, s)
|
611280pale brown amorphous solid NMR spectrum δ (CDCl3) ppm: 0.81-1.80(43H, m), 0.85 (3H, t, J=7.5 Hz), 0.99(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz), 1.89-2.01(2H, m), 1.96(3H, s), 2.30(6H, s), 2.41(1H, d, J=15.5 Hz), 2.56-2.70(2H, m), 2.81-2.90(1H, m), 3.10(1H, s), 3.26(3H, s), 3.53(1H, d, J=7.5 Hz), 3.57-3.72(2H, m), 3.69(1H, s), 3.94-4.01(3H, m), 4.27(1H, dd, J=16, 4.5 Hz), 4.39-4.51(1H, m), 4.44 (1H, s), 4.50(1H, d,
#J=8 Hz), 4.60-4.75(2H, m), 4.68(1H, d, J=10 Hz), 4.91(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11.5, 1.5 Hz), 5.75-5.82(1H, m), 7.50(2H, d, J=8.5 Hz), 8.17(2H, d, J=8.5 Hz)
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621281colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.80(43H, m), 0.85 (3H, mt, J=7.5 Hz), 0.99(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.85-2.03(2H, m), 1.96(3H, s), 2.29(6H, s), 2.40(1H, d, J=15.5 Hz), 2.55-2.70(2H, m), 2.82-2.93(1H, m), 3.11(3H, s), 3.26(3H, s), 3.52(1H, d, J=7.5 Hz), 3.57-3.75(2H, m), 3.69(1H, s), 3.91-4.05 (3H, m), 4.24(1H, dd, J=16.5, 5 Hz), 4.38-4.55(1H, m), 4.44(1H, s), 4.50(1H, d, J=
#7.5 Hz), 4.60-4.75(2H, m), 4.68(1H, d, J=10 Hz), 4.78-5.00(2H, m), 4.91(1H, d, J=4.5 Hz), 5.08-5.18(1H, m), 5.70-5.80(1H, m), 7.47(2H, d, J=8 Hz), 7.86(2H, d, J=8 Hz)
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631282colorless solid (recry. solv.: Et2O) m.p. 180-183.5° C. NMR spectrum δ (CDCl3) ppm: 0.78-1.78(43H, m), 0.84 (3H, t, J=7.5 Hz), 0.92(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.87-2.01(2H, m), 1.95(3H, s), 2.32(6H, s), 2.39(1H, d, J=14.5 Hz), 2.54-2.71(2H, m), 2.80-2.92(1H, m), 3.06-3.35 (1H, m), 3.10(1H, s), 3.23(3H, s), 3.51(1H, d, J=6.5 Hz), 3.57-3.75(3H, m), 3.67(1H, s), 3.92-4.07(4H, m), 4.24-4.56
#(2H, m), 4.43(1H, s), 4.49(1H, d, J=7.5 Hz), 4.60-4.78(1H, m), 4.66 (1H, d, J=9 Hz), 4.90(1H, d, J=3.5 Hz), 5.04-5.28(1H, m), 5.11 (1H, dd, J=11, 2 Hz), 6.99(1H, s), 7.04(1H, s), 7.53(1H, s)
|
641283colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.88-2.00(50H, m), 0.83 (3H, t, J=7.5 Hz), 0.94(3H, d, J=7.5 Hz), 1.02(3H, d, J=7.5 Hz), 2.08(3H, s), 2.26(6H, s), 2.39(1H, d, J=15.5 Hz), 2.58-2.68 (2H, m), 2.82-2.91(1H, m), 3.06-3.19(1H, m), 3.10(1H, s), 3.22-3.44(1H, m), 3.27(3H, s), 3.51(1H, d, J=7.5 Hz), 3.59-3.72(2H, m), 3.65(1H, s), 3.92-4.10(5H, m), 4.29-4.40(1H, m), 4.43(1H, s), 4.52(1H, d, J=7.5
#Hz), 4.60-4.72(1H, m), 4.68(1H, d, J=10 Hz), 4.93(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2.5 Hz), 7.28(1H, s), 7.30(1H, dd, J=8, 4.5 Hz), 7.54(1H, s), 8.08(1H, ddd, J=8, 2, 2 Hz), 8.43-8.50(1H, m), 8.95(1H, d, J=2 Hz)
|
6565NH2colorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-1.74(45H, m), 0.84
(3H, t, J=7.5 Hz), 0.99(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz),
1.86-2.00(2H, m), 2.10(3H, s), 2.32(6H, s), 2.40(1H, d, J=
15.5 Hz), 2.60-2.68(2H, m), 2.83-2.91(1H, m), 3.10(1H, s),
3.27(3H, s), 3.51(1H, d, J=6.5 Hz), 3.59-3.70(2H, m), 3.68(1H,
s), 3.95-4.00(3H, m), 4.33-4.42(1H, m), 4.44(1H, s), 4.50(1H,
d, J=8 Hz), 4.61-4.70(1H, m), 4.68(1H, d, J=10 Hz), 4.92(1H,
d, J=4.5 Hz), 5.11(1H, dd, J=11, 2.5 Hz)
66NHMecolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-2.00(45H, m), 0.84
(3H, t, J=7.5 Hz), 0.94(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz),
2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=15.5 Hz), 2.57-
2.96(3H, m), 2.80(3H, d, J=4.5 Hz), 3.11(1H, s), 3.29(3H, s), 3.51
(1H, d, J=6.5 Hz), 3.57-3.72(2H, m), 3.66(1H, s), 3.90-4.05
(3H, m), 4.30-4.60(1H, m), 4.44(1H, s), 4.50(1H, d, J=7.5 Hz),
4.60-4.75(1H, m), 4.68(1H, d, J=10 Hz), 4.80-5.00(1H, m), 4.93
(1H, d, J=4.5 Hz), 5.12 (1H, dd, J=11, 2 Hz)
67NHEtcolorless solid (recry. solv.: CH3CN)
m.p. 109-113° C.
NMR spectrum δ (CDCl3) ppm: 0.80-1.80(46H, m), 0.83
(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.03(3H, d, J=7.5 Hz),
1.87-2.00(2H, m), 2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=15.5
Hz), 2.60-2.75(2H, m), 2.82-2.95(1H, m), 3.10(1H, s), 3.13-3.40
(2H, m), 3.30(3H, s), 3.52(1H, d, J=7.5 Hz), 3.60-3.80(2H, m),
3.65(1H, s), 3.90-4.08(3H, m), 4.30-4.40(1H, m), 4.45(1H, s),
4.52 (1H, d, J=6.5 Hz), 4.62-4.72(1H, m), 4.68(1H, d, J=10 Hz),
4.75-4.85(1H, m), 4.95(1H, d, J=4.5 Hz), 5.13 (1H, dd, J=11, 2.5
Hz)
68NH-n-Prcolorless solid (recry. solv.: CH3CN)
m.p. 108-112° C.
NMR spectrum δ (CDCl3) ppm: 0.80-1.80(45H, m), 0.84
(3H, t, J=7.5 Hz), 0.93(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz),
1.03(3H, d, J=6.5 Hz), 1.87-2.00(2H, m), 2.10(3H, s), 2.31(6H, s),
2.40(1H, d, J=14.5 Hz), 2.60-2.75(2H, m), 2.83-2.95(1H, m),
3.05-3.25(2H, m), 3.11(1H, s), 3.30(3H, s), 3.52(1H, d, J=6.5 Hz),
3.60-3.79(2H, m), 3.65(1H, s), 3.92-4.05(3H, m), 4.30-4.40
(1H, m), 4.45(1H, s), 4.52(1H, d, J=8 Hz), 4.62-4.72(1H, m), 4.68
(1H, d, J=10 Hz), 4.75-4.85(1H, m), 4.95(1H, d, J=4.5 Hz), 5.13
(1H, dd, J=11, 2 Hz)
69NH-n-Bucolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.77-1.80(47H, m), 0.84
(3H, t, J=7.5 Hz), 0.93(3H, t, J=7.5 Hz), 0.97(3H, d, J=8 Hz), 1.03
(3H, d, J=7.5 Hz), 1.85-2.14(2H, m), 2.10(3H, s), 2.31(6H, s),
2.40(1H, d, J=14.5 Hz), 2.60-2.73(2H, m), 2.82-2.94(1H, m), 3.05-
3.38(2H, m), 3.11(1H, s), 3.30(3H, s), 3.52(1H, dd, J=6.5 Hz),
3.60-3.75(2H, m), 3.66(1H, s), 3.85-4.05(3H, m), 4.30-4.40
(1H, m), 4.45(1H, s), 4.53(1H, d, J=8 Hz), 4.60-4.72(1H, m), 4.74-
4.80(1H, m), 4.68(1H, d, J=10 Hz), 4.95(1H, d, J=4.5 Hz), 5.12
(1H, dd, J=11.5, 2 Hz)
70NH-n-Hexcolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-1.80(51H, m), 0.84
(3H, t, J=7.5 Hz), 0.90(3H, t, J=6.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.03
(3H, d, J=6.5 Hz), 1.87-2.00(2H, mk), 2.10(3H, s), 2.31(6H, s),
2.40(1H, d, J=15.5 Hz), 2.60-2.72(2H, m), 2.84-2.91(1H, m),
3.09-3.23(2H, m), 3.11(1H, s), 3.30(3H, s), 3.51(1H, d, J=6.5 Hz),
3.61-3.72(2H, m), 3.65(1H, s), 3.95-4.00(3H, m), 4.30-4.38
(1H, m), 4.45(1H, s), 4.54(1H, d, J=7.5 Hz), 4.63-4.70(1H, m), 4.68
(1H, d, J=10 Hz), 4.72-4.78(1H, m), 4.95(1H, d, J=4.5 Hz), 5.13
(1H, dd, J=11, 2.5 Hz)
71NH-n-Octcolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-2.00(57H, m), 0.84
(3H, t, J=7.5 Hz), 0.88(3H, t, J=6.5 Hz), 0.96(3H, d, J=8 Hz),
1.03(3H, d, J=7.5 Hz), 2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=
14.5 Hz), 2.60-2.74(2H, m), 2.83-2.92(1H, m), 3.10-3.38(2H,
m), 3.11(1H, s), 3.30(3H, s), 3.51(1H, d, J=7.5 Hz), 3.61-
3.73(2H, m), 3.65(1H, s), 3.93-4.03(3H, m), 4.29-4.40(1H, m),
4.46(1H, s), 4.53(1H, d, J=7.5 Hz), 4.62-4.72(1H, m), 4.68
(1H, d, J=10 Hz), 4.74-4.82(1H, m), 4.95(1H, d, J=5 Hz), 5.12
(1H, dd, J=11, 2 Hz)
72NH-n-Deccolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-1.83(59H, m), 0.84
(3H, t, J=7.5 Hz), 0.88(3H, t, J=6.5 Hz), 0.96(3H, d, J=7.5 Hz),
1.03(3H, d, J=7.5 Hz), 1.87-2.00(2H, m), 2.10(3H, s), 2.31
(6H, s), 2.40(1H, d, J=14.5 Hz), 2.60-2.72(2H, m), 2.83-2.94
(1H, m), 3.05-3.25(2H, m), 3.11(1H, s), 3.30(3H, s), 3.51(1H, d,
J=6.5 Hz), 3.60-3.77(2H, m), 3.65(1H, s), 3.90-4.05(3H, m),
4.30-4.40(1H, m), 4.46(1H, s), 4.53(1H, d, J=7.5 Hz), 4.62-
4.71(1H, m), 4.68(1H, d, J=10 Hz), 4.73-4.82(1H, m), 4.95(1H,
d, J=4.5 Hz), 5.09-5.16(1H, m)
73NH-n-Dodeccolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-2.00(65H, m), 0.84
(3H, t, J=7.5 Hz), 0.88(3H, t, J=7 Hz), 0.96(3H, d, J=8 Hz), 1.03
(3H, d, J=7.5 Hz), 2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=15.5
Hz), 2.60-2.75(2H, m), 2.82-2.93(1H, m), 3.08-3.25(2H, m),
3.11(1H, s), 3.30(3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.80(2H,
m), 3.65(1H, s), 3.93-4.03(3H, m), 4.30-4.40(1H, m), 4.45
(1H, s), 4.53(1H, d, J=7.5 Hz), 4.62-4.72(1H, m), 4.68(1H, d, J=
10 Hz), 4.74-4.82(1H, m), 4.95(1H, d, J=4.5 Hz), 5.12(1H, dd,
J=11, 2.5 Hz)
74NH-n-Tetradeccolorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-2.00(69H, m), 0.84
(3H, t, J=7.5 Hz), 0.88(3H, t, J=7 Hz), 0.96(3H, d, J=8 Hz), 1.03
(3H, d, J=6.5 Hz), 2.10(3H, s), 2.31(6H, s), 2.40(1H, d, J=15.5
Hz), 2.60-2.74(2H, m), 2.85-2.93(1H, m), 3.10-3.23(2H, m),
3.11(1H, s), 3.30(3H, s), 3.51(1H, d, J=7.5 Hz), 3.61-3.73
(2H, m), 3.65(1H, s), 3.93-4.03(3H, m), 4.30-4.40(1H, m), 4.46
(1H, s), 4.53(1H, d, J=8 Hz), 4.63-4.72(1H, m), 4.68(1H, d, J=
10 Hz), 4.74-4.82(1H, m), 4.95(1H, d, J=5 Hz), 5.12(1H, dd, J=
11, 2.5 Hz)
75NMe2colorless needles (recry. solv.: i-PrO2)
m.p. 105-108.5° C.
NMR spectrum δ (CDCl3) ppm: 0.76-2.00(45H, m), 0.84
(3H, t, J=7.5 Hz), 0.92(3H, d, J=7.5 Hz), 1.04(3H, d, J=7.5
Hz), 2.10(4H, s), 2.31(6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-
3.00(9H, m), 3.12(1H, s), 3.34(3H, s), 3.50(1H, d, J=6.5 Hz),
3.58-3.80(2H, m), 3.63(1H, s), 3.92-4.00(3H, m), 4.28-
4.40(1H, m), 4.47(1H, s), 4.60-4.75(3H, m), 4.98(1H, d, J=5
Hz), 5.13(1H, dd, J=11, 2 Hz)
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761284colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.00(46H, m), 0.84 (3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 2.10(3H, s), 2.23(6H, s), 2.27-2.48(2H, m), 2.31(6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-2.75(2H, m), 2.82-2.93 (1H, m), 3.11(1H, s), 3.20-3.40(2H, m), 3.31(3H, s), 3.52(1H, d, J=7.5 Hz), 3.60-3.78(2H, m), 3.65(1H, s), 3.92-4.05(3H, m), 4.28-4.40(1H, m), 4.68(1H, d, J=10 Hz),
#4.96(1H, d, J=5 Hz), 5.12(1H, dd, J=11, 2.5 Hz)
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771285colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.79-1.85(45H, m), 0.84 (3H, t, 7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.82-2.00(2H, m), 2.10(3H, s), 2.21(6H, s), 2.25-2.45(2H, m), 2.31(6H, s), 2.40(1H, d, J=14.5 Hz), 2.60-2.75 (2H, m), 2.80-2.93(1H, m), 3.11(1H, s), 3.15-3.40(2H, m), 3.31 (3H, s), 3.50(1H, d, J=7.5 Hz), 3.60-3.75(2H, m), 3.65 (1H, s), 3.92-4.03(3H, m), 4.30-4.40(1H, m), 4.45
#(1H, s), 4.57(1H, d, J=7.5 Hz), 4.60-4.75(1H, m), 4.68(1H, d, J=10 Hz), 4.95(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2.5 Hz), 5.30-5.40(1H, m)
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781286colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.80(43H, m), 0.84 (3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.02(3H, d, J=6.5 Hz), 1.87-2.00(2H, m), 2.10(3H, s), 2.29(6H, s), 2.39(1H, d, J=15.5 Hz), 2.61-2.72(2H, m), 2.84-2.92(1H, m), 3.12 (1H, s), 3.28(3H, s), 3.51(1H, d, J=7.5 Hz), 3.62-3.73(2H, m), 3.66(1H, s), 3.93-4.11(5H, m), 4.28-4.37(1H, m), 4.46(1H, s), 4.56(1H, d, J=7.5 Hz), 4.63-4.70(1H,
#m), 4.67(1H, d, J=10 Hz), 4.94(1H, d, J=5 Hz), 5.12(1H, dd, J=11, 2 Hz), 5.17 (1H, d, J=12.5 Hz), 5.20(1H, d, J=12.5 Hz), 5.31-5.36(1H, m), 7.31-7.40(5H, m)
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791287colorless needles (recry. solv.: i-Pr2O-Et2O) m.p. 104.5-106° C. NMR spectrum δ (CDCl3) ppm: 0.80-2.00(48H, m), 0.84(3H, t, J=7.5 Hz), 0.97(3H, d, J=7.5 Hz), 1.03 (3H, d, J=6.5 Hz), 2.11(3H, s), 2.31(6H, s), 2.40(1H, d, J=15 Hz), 2.60-2.75(2H, m), 2.85-2.95(1H, m), 3.12 (1H, s), 3.30(3H, s), 3.52(1H, d, J=6.5 hz), 3.57-3.80(3H, m), 3.88-4.05(5H, m), 4.21(2H, q, J=7 Hz), 4.30-4.40 (1H, m), 4.46(1H,
#s), 4.57(1H, d, J=6.5 Hz), 4.62-4.74 (1H, m), 4.68(1H, d, J=10 Hz), 4.95(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2.5 Hz), 5.25-5.35(1H, m)
|
801288colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.79-2.00(50H, m), 0.84(3H, t, J=7.5 Hz), 0.95(3H, d, J=8 Hz), 1.03(3H, d, J=6.5 Hz), 2.10(3H, s), 2.25-2.45(2H, m), 2.29(6H, s), 2.40 (1H, d, J=15.5 Hz), 2.60-2.72(2H, m), 2.82-2.93(1H, m), 3.11(1H, s), 3.13-3.38(2H, m), 3.30(3H, s), 3.51(1H, d, J=7.5 Hz), 3.60-3.72(2H, m), 3.66(1H, s), 3.92-4.03(3H, m), 4.13(2H, q, J=7 Hz), 4.30-4.42(1H, m), 4.45 (1H, s),
#4.52(1H, d, J=8 Hz), 4.60-4.73(1H, m), 4.68(1H, d, J=10 Hz), 4.91-5.06(1H, m), 4.93(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz)
|
811289colorless solid (recry. solv.: i-Pr2O-n-Heptane) m.p. 139-142° C. NMR spectrum δ (CDCl3) ppm: 0.80-2.02(48H, m), 0.84(3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 2.10(3H, s), 2.28(6H, s), 2.40(1H, d, J=15.5 Hz), 2.58-2.70(2H, m), 2.81-2.93(1H, m), 3.10(1H, s), 3.20-3.82(6H, m), 3.28(3H, s), 3.52(1H, d, J=7.5 Hz), 3.67(1H, s), 3.92-4.04(3H, m), 4.25-4.55(1H, m), 4.45 (1H, s), 4.50(1H, d,
#J=7.5 Hz), 4.60-4.75(1H, m), 4.68(1H, d, J=10 Hz), 4.92(1H, d, J=3.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 5.15-5.25(1H, m),
|
821290colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.85(43H, m), 0.86(3H, t, J=7.5 Hz), 0.96(3H, d, J=7.5 Hz), 1.00 (3H, d, J=6.5 Hz), 1.87-2.00(2H, m), 2.09(3H, s), 2.24(6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-2.74(2H, m), 2.83-3.00(1H, m), 2.95(1H, dd, J=17, 4.5 Hz), 3.05(1H, dd, J=17, 4.5 Hz), 3.12(1H, s), 3.31(3H, s), 3.51 (1H, d, J=6.5 Hz), 3.60-3.80(2H, m), 3.64(1H, s), 3.90-4.03(3H, m), 4.27-4.38
#(1H, m), 4.47(1H, s), 4.57-4.75(3H, m), 4.67(1H, d, J=10 Hz), 4.96(1H, d, J=5.5 Hz), 5.00-5.20(1H, m), 5.04(1H, d, J=12.5 Hz), 5.07(1H, d, J=12.5 Hz), 5.13(1H, d, J=12 Hz), 5.16(1H, d, J=12 Hz), 5.58-5.67(1H, m), 7.20-7.40(10H, m)
|
831291colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.00(51H, m), 0.85(3H, t, J=7.5 Hz), 0.94(3H, d, J=7.5 Hz), 1.01 (3H, d, J=6.5 Hz), 2.10(3H, s), 2.26(6H, s), 2.39(1H, d, J=15.5 Hz), 2.60-2.76(2H, m), 2.82-2.95(1H, m), 3.02-3.22(2H, m), 3.12(1H, s), 3.31(3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.80(2H, m), 3.64(1H, s), 3.90-4.03 (3H, m), 4.25-4.37(1H, m), 4.40-4.50(1H, m), 4.48 (1H, s), 4.57-4.80(3H, m),
#4.67(1H, d, J=10 Hz), 4.96-(1H, d, J=5 Hz), 5.02-5.30(6H, m), 7.20-7.40(10H, m)
|
841292colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.07(55H, m), 0.84(3H, t, J=7.5 Hz), 0.98(3H, d, J=8 Hz), 1.02 (3H, d, J=6.5 Hz), 2.10(3H, s), 2.32(6H, s), 2.39(1H, d, J=14.5 Hz), 2.58-2.80(2H, m), 2.84-2.95(1H, m), 3.10(1H, s), 3.32(3H, s), 3.44-3.59(1H, m), 3.53(1H, d, J=6.5 Hz), 3.61-3.80(2H, m), 3.64(1H, s), 3.92-4.04 (3H, m), 4.29-4.39(1H, m), 4.40-4.60(1H, m), 4.46(1H, s), 4.54(1H, d, J=7.5 Hz),
#4.63-4.73(1H, m), 4.67 (1H, d, J=10 Hz), 4.96(1H, d, J=4.5 Hz), 5.14(1H, dd, J=11, 2 Hz)
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851293colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.84(45H, m), 0.84(3H, t, J=7.5 Hz), 0.96(3H, d, J=8 Hz), 1.04 (3H, d, J=7.5 Hz), 1.87-2.22(8H, m), 2.10(3H, s), 2.31 (6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-2.77(2H, m), 2.81-2.91(1H, m), 3.12(1H, s), 3.20-3.38(2H, m), 3.31 (3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.75(2H, m), 3.65 (1H, s), 3.93-34.03(3H, m), 4.30-4.38(1H, m), 4.46 (1H, s), 4.55(1H, d, J=7.5
#Hz), 4.62-4.72(1H, m), 4.68 (1H, d, J=10 Hz), 4.95(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2.5 Hz), 5.46(1H, s)
|
861294colorless needles (recry. solv.: AcOEt-n-Heptane) m.p. 188-189.5° C. NMR spectrum δ (CDCl3) ppm: 0.78-2.00(49H, m), 0.84 (3H, t, J=7.5 Hz), 0.92(3H, d, J=7.5 Hz), 1.04(3H, d, J=7.5 Hz), 2.10 (3H, s), 2.32(6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-2.68(1H, m), 2.72-2.80(1H, m), 2.84-2.93(1H, m), 3.12(1H, s), 3.20-3.53 (4H, m), 3.35(3H, s), 3.50(1H, d, J=6 Hz), 3.60-3.80(2H, m), 3.63 (1H, s), 3.92-4.02(3H, m), 4.30-
#4.40(1H, m), 4.47(1H, s), 4.67 (1H, d, J=7.5 Hz), 4.68(1H, d, J=10 Hz), 4.73(1H, dd, J=10, 7.5 Hz), 4.98(1H, d, J=5 Hz), 5.13(1H, dd, J=10.5, 2 Hz)
|
871295colorless needles (recry. solv.: i-Pr2O-Et2O) m.p. 158.5-159.5° C. NMR spectrum δ (CDCl3) ppm: 0.80-2.00(51H, m), 0.84 (3H, t, J=7.5 Hz), 0.93(3H, d, J=8 Hz), 1.04(3H, d, J=7.5 Hz), 2.10 (3H, s), 2.32(6H, s), 2.40(1H, d, J=15.5 Hz), 2.63-2.76(2H, m), 2.85-2.93(1H, m), 3.12(1H, s), 3.17-3.79(6H, m), 3.34(3H, s), 3.51(1H, d, J=6.5 Hz), 3.63(1H, s), 3.93-4.04(3H, m), 4.29-4.36 (1H, m), 4.47(1H, s), 4.64
#(1H, d, J=7.5 Hz), 4.68(1H, d, J=10 Hz), 4.72(1H, dd, J=10.5, 7.5 Hz), 4.97(1H, d, J=5 Hz), 5.13(1H, dd, J=11, 2 Hz)
|
881296colorless solid (recry. solv.: i-Pr2O-n-Heptane) m.p. 123-127° C. NMR spectrum δ (CDCl3) ppm: 0.78-2.05(51H, m), 0.84 (3H, t, J=7.5 Hz), 1.04(3H, df, J=6.5 Hz), 2.10(3H, s), 2.30(6H, s), 2.39(1H, d, J=15.5 Hz), 2.60-2.80(2H, m), 2.82-2.92(1H, m), 3.12 (1H, s), 3.28-3.80(6H, m), 3.34(3H, s), 3.51(1H, d, J=6.5 Hz), 3.63(1H, s), 3.92-4.03(3H, m), 4.27-4.40(2H, m), 4.46(1H, s), 4.62-4.77(2H, m), 4.68(1H, d, J=
#10.5 Hz), 4.98(1H, d, J=5 Hz), 5.08-5.18(1H, m)
|
891297colorless needles (recry. solv.: n-Heptane) m.p. 129.5-131.5° C. NMR spectrum δ (CDCl3) ppm: 0.80-2.00(46H, m), 0.85 (3H, t, J=7.5 Hz), 0.93(3H, d, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 2.10(3H, s), 2.31(6H, s), 2.39(1H, d, J=14.5 Hz), 2.61-2.94(7H, m), 3.12(1H, s), 3.25-3.80(6H, m), 3.33(3H, s), 3.51(1H, d, J=6.5 Hz), 3.63(1H, s), 3.85-4.05(3H, m), 4.27-4.37(1H, m), 4.47(1H, s), 4.64(1H, d, J=8 Hz), 4.68(1H, d, J=9
#Hz), 4.73(1H, dd, J=10.5, 7.5 Hz), 4.97(1H, d, J=5 Hz), 5.13(1H, dd, J=11, 2.5 Hz)
|
901298colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.78-2.00(45H, m), 0.84 (3H, t, J=7.5 Hz), 0.93(3H, d, J=8 Hz), 1.04(3H, d, J=7.5 Hz), 2.11(3H, s), 2.31(6H, s), 2.40(1H, d, J=15.5 Hz), 2.60-2.80(2H, m), 2.82-2.93(1H, m), 3.10(1H, s), 3.35(3H, s), 3.42-3.83(11H, m), 3.62(1H, s), 3.92-4.04(3H, m), 4.26-4.37 (1H, m), 4.45(1H, s), 4.68(1H, d, J=7.5 Hz), 4.69(1H, d, J=10 Hz), 4.74(1H, dd, J=10.5, 8 Hz), 4.97(1H, d, J=
#5 Hz), 5.12 (1H, dd, J=11, 2.5 Hz), 6.63-6.72(2H, m), 7.45-7.55(1H, m), 8.17-8.23(1H, m)
|
911299colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-2.00(47H, m), 0.84 (3H, t, J=7.5 Hz), 0.95(3H, d, J=7.5 Hz), 1.03(3H, d, J=6.5 Hz), 2.10(3H, s), 2.25-2.74(13H, m), 2.28(3H, s), 2.31(6H, s), 2.83-2.92(1H, m), 3.12(1H, brs), 3.16-3.37(2H, m), 3.31 (3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.75(2H, m), 3.64 (1H, s), 3.92-4.04(3H, m), 4.30-4.40(1H, m), 4.46(1H, s), 4.56 (1H, d, J=8 Hz), 4.62-4.74(1H, m), 4.68(1H, d,
#J=10 Hz), 4.96(1H, d, J=5 Hz), 5.13(1H, dd, J=11, 2.5 Hz), 5.34-5.44(1H, m)
|
921300colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.85(45H, m), 0.84 (3H, t, J=7.5 Hz), 0.96(3H, d, J=6.5 Hz), 1.03(3H, d, J=6.5 Hz), 1.87-2.01(2H, m), 2.08(3H, s), 2.23(1H, d, J=15.5 Hz), 2.32(6H, s), 2.45-2.73(8H, m), 2.82-2.94(1H, m), 3.10 (3H, s), 3.12(1H, s), 3.20-3.57(7H, m), 3.60-3.75(2H, m), 3.64(1H, s), 3.91-4.03(3H, m), 4.24-4.34(1H, m), 4.46(1H, s), 4.52-4.75(1H, m), 4.57(1H, d, J=7.5 Hz), 4.63
#(1H, d, J=10 Hz), 4.93(1H, d, J=4.5 Hz), 5.13(1H, dd, J=10.5, 2 Hz), 5.78-5.89(1H, m), 6.58-6.68(2H, m), 7.49(1H, ddd, J=8.5, 8, 2 Hz), 8.20(1H, dd, J=5, 2 Hz)
|
931301colorless amorphous solid NMR spectrum δ (CDCl3) ppm: 0.80-1.85(43H, m), 0.84 (3H, t, J=7.5 Hz), 0.95(3H, d, J=8 Hz), 1.04(3H, d, J=6.5 Hz)m 1.87-2.00(2H, m), 2.11(3H, s), 2.31(6H, s), 2.36-2.55(6H, m), 2.40(1H, d, J=14.5 Hz), 2.60-2.77(2H, m), 2.80-2.90 (1H, m), 3.11(1H, s), 3.22-3.42(2H, m), 3.32(3H, s), 3.52(1H, d, J=6.5 Hz), 3.60-3.77(6H, m), 3.64(1H, s), 3.93-4.03 (3H, m), 4.28-4.38(1H, m), 4.44(1H, s), 4.58
#(1H, d, J=7.5 Hz), 4.63-4.73(1H, m), 4.68(1H, , J=10 Hz), 4.96(1H, d, J=4.5 Hz), 5.06-5.17(1H, m), 5.12(1H, dd, J=11, 2 Hz)
|
|
1302
|
ExampleDescription and physical properties
|
94colorless amorphous solid
NMR spectrum δ (CDCl3) ppm: 0.80-2.10(42H, m), 0.85(3H, t, J=7.5 Hz),
0.88(3H, t, J=7 Hz), 0.95(3H, d, J=6.5 Hz), 1.04(3H, d, J=7.5 Hz), 1.95
(3H, s), 2.31(6H, s), 2.39(1H, d, J=15.5 Hz), 2.59-2.70(2H, m), 2.82-2.90
(1H, m), 3.12(1H, s), 3.26(3H, s), 3.51(1H, d, J=6.5 Hz), 3.60-3.72(2H, m),
3.68(1H, s), 3.94-4.06(3H, m), 4.26(1H, dd, J=14.5, 5 Hz), 4.33-4.60(2H,
m), 4.46(1H, s), 4.51(1H, d, J=7.5 Hz), 4.66(1H, d, J=10 Hz), 4.70(1H, dd, J=
10, 8 Hz), 4.92(1H, d, J=4.5 Hz), 5.12(1H, dd, J=11, 2 Hz), 5.32-5.42(1H,
m), 7.20-7.37(5H, m)
|
|
1303
|
ExampleNR1R2Description and physical properties
|
951304colorless solid (recry. solv.: CH3CN) m.p. 97-100° C. NMR spectrum δ (CDCl3) ppm: 0.80-1.75(43H, m), 0.85(3H, t, J=7.5 Hz), 0.90(3H, d, J=7.5 Hz), 0.96(3H, t, J=7 Hz), 1.03(3H, d, J=6.5 Hz), 1.85-2.10(2H, m), 2.00(3H, s), 2.24(3H, s), 2.30-2.43(1H, m), 2.39(1H, d, J=15.5 Hz), 2.50-2.90(4H, m), 3.12(1H, s), 3.28(3H, s), 3.49(1H, d, J=6.5 Hz), 3.58-3.73(2H, m), 3.66(1H, s), 3.83(3H, s), 3.90—4.03(3H,
#m), 4.25-4.58(3H, m), 4.45(1H, s), 4.53(1H, d, J=7.5 Hz), 4.60-4.78(1H, m), 4.66(1H, d, J=10 Hz), 4.92(1H, d, J=3.5 Hz), 5.10-5.15(1H, m), 5.22-5.33(1H, m), 6.80-6.95(2H, m), 7.20-7.28(1H, m), 7.30-7.38(1H, m)
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961305colorless amorphopus solid NMR spectrum δ (CDCl3) ppm: 0.80-1.75(46H, m), 0.85(3H, t, J=7.5 Hz), 0.98(3H, t, J=7 Hz), 1.04(3H, d, J=7.5 Hz), 1.85-2.00(2H, m), 1.94(3H, s), 2.26(3H, s), 2.30-2.43(1H, m), 2.39(1H, d, J=15.5 Hz), 2.55-2.75(3H, m), 2.80-2.92(1H, m), 3.11(1H, s), 3.26(3H, s), 3.51(1H, d, J=7.5 Hz), 3.58-3.72(2H, m), 3.68(1H, s), 3.79(3H, s), 3.90-4.05(3H, m), 4.19(1H, dd, J=15.5, 4.5 Hz), 4.30-4.80
#(3H, m), 4.45(1H, s), 4.50(1H, d, J=8 Hz), 4.66(1H, d, J=10 Hz), 4.91(1H, d, J=3.5 Hz), 5.10-5.16(1H, m), 5.30-5.44(1H, m), 6.79(1H, d, J=8.5 Hz), 6.87(1H, s), 6./90(1H, d, J=7.5 Hz), 7.15-7.30(1H, m)
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971306colorless needles (recry. solv.: CH3CN) m.p. 125-128° C. NMR spectrum δ (CDCl3) ppm: 0.80-1.75(49H, m), 0.85(3H, t, J=7.5 Hz), 1.04(3H, d, J=6.5 Hz), 1.87-2.00(2H, m), 1.92(3H, s), 2.26(3H, s), 2.32-2.44(1H, m), 2.39 (1H, d, J=14.5 Hz), 2.54-2.73(3H, m), 2.80-2.93(1H, m), 3.12(1H, s), 3.26(3H, s), 3.51(1H, d, J=7.5 Hz), 3.58-3.75 (2H, m), 3.68(1H, s), 3.79(3H, s), 3.91-4.05(4H, m), 4.15 (1H, dd, J=14.5,
#3.5 Hz), 4.31(1H, d, J=6 Hz), 4.33-4.56 (2H, m), 4.46(1H, s), 4.60-4.78(1H, m), 4.66(1H, d, J=10 Hz), 4.91(1H, d, J=3.5 Hz), 5.08-5.15(1H, m), 5.25-5.37 (1H, m), 6.84(2H, d, J=8.5 Hz), 7.23(2H, d, J=8.5 Hz)
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|
1307
|
ExampleR8R9Description and physical properties
|
9813081309colorless solid (recry. solv.: AcOEt-n-Heptane) m.p. 179-180° C. NMR spectrum δ (CDCl3) ppm: 0.75-1.65(23H, m), 0.82(3H, t, J=7.5 Hz), 1.02(3H, d, J=6.5 Hz), 1.80 (1H, s), 1.88-2.02(3H, m), 2.15-2.36(1H, m), 2.31 (6H, s), 2.51-2.81(5H, m), 2.97-3.08(1H, m), 3.15 (1H, s), 3.43(1H, d, J=4.5 Hz), 3.61-3.73(3H, m), 3.94-4.10(2H, m), 3.99(1H, d, J=8 Hz), 4.28-4.50(2H, m), 4.46(1H, s), 4.61(1H, dd,
#J=10.5, 8 Hz), 4.86-4.96(1H, m), 5.10(1H, d, J=11 Hz), 5.21(1H, dd, J=11, 2 Hz), 7.14-7.40(15H, m)
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9913101311colorless solid (recry. solv.: AcOEt-n-Heptane) m.p. 145-146° C. NMR spectrum δ (CDCl3) ppm: 0.83(3H, t, J=7.5 Hz), 0.89(3H, d, J=8 Hz), 0.93(3H, d, J=6 Hz), 0.99 (3H, d, J=6.5 Hz), 1.05-1.67(17H, m), 1.89-2.04(1H, m), 2.00(1H, s), 2.14-2.35(1H, m), 2.30(6H, s), 2.48-2.57(1H, m), 2.62-2.70(1H, m), 2.72-2.83(1H, m), 2.95-3.06(1H, m), 3.15(1H, s), 3.33(1H, d, J=4.5 Hz), 3.58-3.74(1H, m), 3.64(2H,
#s), 3.77(1H, s), 3.90 (1H, d, J=7.5 Hz), 4.10-4.21(2H, m), 4.28-4.50(4H, m), 4.40(1H, s), 4.58(1H, dd, J=10, 7.5 Hz), 4.92-5.01(1H, m), 5.09(1H, d, J=11 Hz), 5.22(1H, dd, J=11, 2 Hz), 6.91-7.01(3H, m), 7.15-7.40(11H, m)
|
4″-O-Acetyl-2′-O-benzylaminocarbonyl-3′-N-demethyl-3′-N-ethyl-erythromycin A 9-[O-(3-cyclohexylpropyl)oxime]
[0092] To a solution of 0.50 g of 4″-O-acetyl-3′-N-demethyl-N-ethylerythromycin A 9-[O-(3-cyclohexylpropyl)oxime] in 5.0 ml of toluene, 0.12 g of N,N′-carbonyl-diimidazole was added, and the mixture was stirred at 80° C. of outer temperature for 19 hours. And then, the reaction mixture was added with 0.06 g of N,N′-carbonyl-diimidazole, and stirred at 80° C. of outer temperature for 2.5 hours. And then, the reaction mixture was added with 0.12 ml of benzylamine, and stirred at 80° C. of outer temperature for 4 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate:ammonia water=50:0.1) to obtain 0.13 g of a pale yellowish amorphous solid.
[0093] NMR spectrum δ (CDCl3)ppm:0.80-1.76(52H,m),0.85(3H,t,J=7.5 Hz),1.86-2.01(2H,m), 1.91(3H,s),2.27(3H,s),2.32-2.45(1H,m),2.39(1H,d,J=14.5 Hz),2.55-2.76(3H,m),2.81-2.94 (1H,m),3.12(1H,s),3.26(3H,s),3.51(1H,d,J=6.5 Hz),3.56-3.75(2H,m),3.69(1H,s),3.89-4.04 (3H,m),4.22(1H,dd,J=15.5, 4.5 Hz),4.33-4.80(2H,m),4.45(1H,s),4.50(1H,d,J=7.5 Hz),4.58(1H,dd,J=15, 7 Hz),4.66(1H,d,J=10 Hz),4.91(1H,d,J=3.5 Hz),5.07-5.17(1H,m),5.33-5.47(l H,m),7.22-7.36(5H,m)
[0094] In accordance with the method of Example 100, the compound of Example 101 was obtained.
29|
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|
1312
|
ExampleDescription and physical properties
|
101pale brown amorphous solid
NMR spectrum δ(CDCl3)ppm: 0.60-2.00(51H, m), 0.83(3H,
t, J=7.5 Hz), 2.10(3H, s), 2.20-2.45(1H, m), 2.37(6H, s),
2.60-2.67(1H, m), 2.73-3.00(5H, m), 3.13(1H, s),
3.37-3.50(1H, m), 3.60-3.78(2H, m), 3.64(1H, s),
3.86-4.02(3H, m), 4.17-4.38(1H, m), 4.47(1H, s),
4.58-4.71(1H, m), 4.63(1H, d, J=7.5Hz), 4.90
(1H, d, J=3.5Hz), 5.11(1H, dd, J=11, 2.5Hz),
5.45-5.59(1H, m), 7.10-7.40(5H, m), 8.13(1H, brs)
|
4″-O-Acetyl-2′-O-(1-(S)-5-amino-1-carboxylpentylaminocarbonyl)-erythromycin A 9-[O-(3-cyclohexylpropyl)oxime]
[0095] To a solution of 0.70 g of 4″-O-acetyl-2′-O-(1-(S)-1-benzyloxycarbonyl-5-benzyloxycarbonylaminopentylaminocarbonyl)erythromycin A 9-[O-(3-cyclohexyl-propyl)oxime] in 70 ml of methanol, 70 mg of 5% palladium carbon was added, and the mixture was hydrogenated at room temperature for 1.5 hours under hydrogen atmospheric condition. And then, the mixture was added with 70 mg of 5% palladium carbon and 50 ml of methanol, and hydrogenated at 50° C. for 2 hours under hydrogen atmospheric condition. The catalyst was filtered off, and the solvent was evaporated to obtain a pale brown solid. Recrystallization from a mixed solvent of ethyl acetate and diisopropyl ether gave 0.19 g of a pale brown solid having the melting point of from 158 to 161° C.
[0096] NMR spectrum δ (CDCl3)ppm:0.77-2.15(54H,m),0.84(3H,t,J=7 Hz),0.95(3H,d,J=7.5 Hz),1.03(3H,d,J=6.5 Hz),2.10(3H,s),2.30(6H,s),2.39(1H,d,J=14.5 Hz),2.55-3.05(5H,m),3. 13(1H,brs),3.33(3H,s),3.53(1H,d,J=5.5 Hz),3.58-3.80(2H,m),3.63(1H,s),3.85-4.13(4H,m),4.20-4.75(3H,m),4.43(1H,brs),4.68(1H,d,J=10 Hz),4.92-5.00(1H,m),5.05-5.18(1H,m),5.6-5.85(1H,m)
4″-O-Acetyl-2′-O-benzylaminocarbonylerythromycin A 9-[O-(3-phenoxy-propyl)oxime].L-(+)-tartrate
[0097] The compound obtained in Example 6 was converted into the L-(+)-tartrate of the compound in a conventional manner. Recrystallization from acetonitrile gave colorless needles having the melting point of from 140.5 to 142° C.
[0098] NMR spectrum δ (CDCl3)ppm:0.86(3H,t,J=7.5 Hz),0.86(3H,d,J=8 Hz),1.01(3H,d,J=6.5 Hz),1.06-1.78(33H,m),1.87-2.18(5H,m),2.08(3H,s),2.38(1H,d,J=15.5 Hz),2.60-2.7O(1H,m),2.73-2.89(1H,m),2.79(6H,s),3.12(1H,brs),3.29(3H,s),3.48(1H,d,J=6 Hz),3.60-3.77(2H, m),3.64(1H,s),3.83-3.95(1H,m),3.93(1H,d,J=9 Hz),4.04(2H,t,J=6.5 Hz),4.16-4.26(4H,m), 4.31(2H,s),4.36(1H,brs),4.41(1H,dd,J=156.5 Hz),4.67(3H,d,J=10 Hz),4.72(3H,d,J=7.5H z),4.83(1H,dd,J=11, 7.5 Hz),4.95(1H,d,J=5 Hz),5.12(1H,dd,J=11, 2 Hz),6.18-6.25(1H,m),6. 82-6.95(2H,m),6.90(1H,d,J=8 Hz),7.18-7.40(7H,m)
[0099] In order to evaluate excellent efficacy of the compounds of the present invention, their antibacterial spectrums against a typical acid-fast mycobacteria were measured. Clarithromycin, rifampicin and 4″-O-acetylerythromycin A 9-(O-methyloxime) [a compound disclosed in the Japanese Patent Unexamined Publication (KOKAI) No.63-107921/1988] were used as reference compounds. Ac in the formula represents acetyl group.
1313
[0100] Antibacterial Activity Against a Typical Acid-Fast Mycobacteria
[0101] Antibacterial activities (minimum inhibitory concentrations) against clinical isolates of a typical acid-fast mycobacteria were measured by the agar dilution method according to the standard method of the Japan Society of Chemotherapy. About 5 μl of bacterial suspension (adjusted to 106 CFU/ml) were spotted on the 7H11 agar plates containing the test compounds. The minimum inhibitory concentrations were determined by the growth or no growth of the bacteria after incubation at 37° C. for 7 days. The results are shown in the following table. The abbreviation M in the table represents Mycobacterium. The compounds of the present invention had more excellent antibacterial activity than the reference compounds against a typical acid-fast mycobacteria including clarithromycin-resistant strains (M.avium 20092 and other bacteria).
30|
|
Antibacterial spectrum (Minimum inhibitory concentration μg/ml)
|
|
ExampleExampleExampleExampleExampleExample
Strain679151826
|
M. avium 200340.100.100.200.100.200.10
M. avium 200450.200.200.390.200.200.20
M. avium 200920.100.100.200.100.200.20
M. avium 200960.100.200.200.200.200.20
M. intracellulare0.200.100.200.200.200.20
20066
M. intracellulare0.200.200.390.200.200.20
20067
M. intracellulare0.200.200.390.100.390.10
20073
M. intracellulare0.200.200.390.200.200.20
20075
|
ReferenceReferenceReference
ExampleExampleExamplecompoundcompoundcompound
Strain404994123
|
M. avium 200340.390.780.393.1312.5>50
M. avium 200450.780.780.781.563.1312.5
M. avium 200920.780.780.39>5050>50
M. avium 200960.780.780.39>503.13>50
M. intracellulare0.201.560.393.133.1312.5
20066
M. intracellulare0.781.560.391.561.566.25
20067
M. intracellulare0.781.560.391.563.1312.5
20073
M. intracellulare0.781.560.393.133.1312.5
20075
|
Industrial Applicability
[0102] The novel erythromycin derivatives and salts thereof have excellent antibacterial activity against a typical acid-fast mycobacteria including m
Claims
- 1. A novel erythromycin derivative represented by the following general formula or a salt thereof:
- 2. The compound or the salt thereof according to claim 1, wherein R3 is hydrogen atom.
- 3. The compound or the salt thereof according to claim 1 or claim 2, wherein Y is the oxy group substituted by a heterocyclic group represented by the following formula:
- 4. The compound or the salt thereof according to any one of claims 1 to 3, wherein R1 is hydrogen atom.
- 5. A medicament comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingreident.
- 6. The medicament according to claim 5, which is an antibacterial agent.
- 7. The medicament according to claim 5, which is used for therapeutic and/or preventive treatment of an a typical acid-fast mycobacteriosis.
- 8. A use of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof for manufacture of the medicament according to any one of claims 5 to 7.
- 9. A method for therapeutic treatment of an infectious disease which comprises the step of administering to a mammal including a human a therapeutically effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof.
- 10. The method according to claim 9, wherein the infectious disease is an a typical acid-fast mycobacteriosis.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 2000-293754 |
Sep 2000 |
JP |
|
| 2001-63034 |
Mar 2001 |
JP |
|
PCT Information
| Filing Document |
Filing Date |
Country |
Kind |
| PCT/JP01/08388 |
9/26/2001 |
WO |
|
