CA2028220A1 - Azoxy compounds - Google Patents
Azoxy compoundsInfo
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- CA2028220A1 CA2028220A1 CA002028220A CA2028220A CA2028220A1 CA 2028220 A1 CA2028220 A1 CA 2028220A1 CA 002028220 A CA002028220 A CA 002028220A CA 2028220 A CA2028220 A CA 2028220A CA 2028220 A1 CA2028220 A1 CA 2028220A1
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Abstract
ABSTRACT
A novel 2-imino derivative of an antifungal product KA-7367A represented by formula,
A novel 2-imino derivative of an antifungal product KA-7367A represented by formula,
Description
\
~ ~ 2 ~ ç~
SPECIFICATION
AZOXY COM:PO~JNDS
TECHNICAL FIELD
This invention relates to a novel azoxy com-pound, and more specifically to an azoxy compound which is a 2-imino derivative of an antifungal product KA-7367, a process for producing same and its use as an antifungal agent.
TECHNICAL BACKGROUND
The present inventors found before that Streptomyces sp. KC-7367 (FERM BP-1277) separated from a soil in Maniwa-gun, Okayama, Japan produces a product showing high antifunal activity, further isolated two antifungal products, KA-7367A and KA-7367~ from the liquid culture medium, and identified and proposed them (refer to Japanese Laid-open Patent Application No.
6248/89, European Patent Laid-open Specificat:ion No.
~2,001).
Said antifungal products KA-7367A and KA-7367B
are represented by the following formula.
5' 3' 1' N X
6' ~ ~ / ~ / \ ~ ` ~ 2 \
CH3 4' 2' N ¦ CH3 (A) `: O 4 CH3 , O
..
X=-C- : KA-7367A
OH
X=-CH- : KA-7367B
Though the antifungal products KA-7367A and KA-73676B themselves show quite excellent antifungal activity, the present inventors have eagerly made studies to synthesize stable derivatives having by far better antifungal activity, and consequently found that 2-imino derivatives formed by converting a carbonyl group in the .
: ::
~ 3 ``
~ ~ 2 ~ ç~
SPECIFICATION
AZOXY COM:PO~JNDS
TECHNICAL FIELD
This invention relates to a novel azoxy com-pound, and more specifically to an azoxy compound which is a 2-imino derivative of an antifungal product KA-7367, a process for producing same and its use as an antifungal agent.
TECHNICAL BACKGROUND
The present inventors found before that Streptomyces sp. KC-7367 (FERM BP-1277) separated from a soil in Maniwa-gun, Okayama, Japan produces a product showing high antifunal activity, further isolated two antifungal products, KA-7367A and KA-7367~ from the liquid culture medium, and identified and proposed them (refer to Japanese Laid-open Patent Application No.
6248/89, European Patent Laid-open Specificat:ion No.
~2,001).
Said antifungal products KA-7367A and KA-7367B
are represented by the following formula.
5' 3' 1' N X
6' ~ ~ / ~ / \ ~ ` ~ 2 \
CH3 4' 2' N ¦ CH3 (A) `: O 4 CH3 , O
..
X=-C- : KA-7367A
OH
X=-CH- : KA-7367B
Though the antifungal products KA-7367A and KA-73676B themselves show quite excellent antifungal activity, the present inventors have eagerly made studies to synthesize stable derivatives having by far better antifungal activity, and consequently found that 2-imino derivatives formed by converting a carbonyl group in the .
: ::
~ 3 ``
2-position of K~-7367A into an imino exhibit quite high antifungal activity and excellent stability and are useful as antifungal agents; as a result, they have completed this invention.
DISCLOSURE OF INVENTION
This invention is to provide an azoxy compound represented by formula N--A--Y--Z
N
CH3 N ¦ c~3 (I) wherein A denotes -O-, -OCO-, -NH-, -NHCO-, -HNCS- or -N~_~N-, Y denotes a single bond or a linear or branched alkylene group with 1 to 6 carbon atoms or a linear or branched alkenylene group with 2 to 6 carbon atoms, and said a:Lkylene or alkenylene group may optionally be ~substituted by a halogen atom, a phenyl group or a halophenyl group, Z denotes a hydrogen atorn, an alkoxy group with 1 to 5 carbon atoms, a carboxyl group, an alkoxycarbonyl group with 2 to 6 carbon atoms, a phenyl group that may optionally have 1 to 3 substituents selected from a halogen atom, an alkoxy group with 1 to 5 carbon atoms, a car-boxyl group, a nitro group, a sulfonyl group and a N-methyl-N-alpha-naphthylmethylamino-methyl group, a phenoxy group in which a benz-ene ring may optionally be substituted by 1 to 3 halogen atoms, a naphthyl group, a cyano group, a pyridyl group, an oxopyridyl group, a imidazolyl group, a furyl group, a thienyl 2~'322~ `"
group or a group of formula ~1 -N or -N~_~N-R3 Rl and R2 are the same or different and each denotes a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, a phenyl group, a naphthyl alkyl group, a phenylalkyl group with 7 to 10 carbon atoms, a naphthylalkyl group with 11 to 14 carbon atoms or an amino group, and R3 denotes an alkyl group with 1 to 3 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, a benzoyl group or an alkanoyl group with 2 to 6 carbon atoms that may optionally be substituted by a phenyl group or a halophenyl group, pro~ided when A is the group of formula -N~_JN-, Z is a hydrogen atom, and its salt.
In the definitions of the substituents in the above formula ~I), examples of the linear or branched alkylene group with 1 to 6 carbon atoms include methyl-ene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene and hexamethylene. Examples of the linear or branched alkenylene group with 2 to 6 carbon atoms are vinylene, propenylene and isoprenylene.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Examples of the halophenyl group include o-, m- and p-chlorophenyls, o-, m- and p~fluorophenyls, 2,6-dichlorophenyl, 2,4~dichlorophenyl, 3,4-dichlorophenyl, 2,6-difluorophenyl, 2,4-difluoro-phenyl, 3,4-difluorophenyl, 2,4,6-trichlorophenyl and 2,4,6-trifluorophenyl.
The alkyl group is linear or branched. Ex-, ~ !
", .:
' '.' ' ' ` : ' ' '` ~' ' ~
.
~ ': ' , ,, 2 ~ C~ ~ 2 amples thereof include methyl, ethyl, n-propyl and iso-propyl.
The alkoxy group is an alkyloxy yroup whose alkyl moiety is linear or branched. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. The alkoxycarbonyl group is an alkyloxycarbonyl group whose alkoxy moiety has the above meaning. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and n-butoxycarbonyl.
Examples of the phenylalkyl group with 7 to 10 carbon atoms include benzyl and phenethyl. Examples of the naphthylalkyl group with 11 to 14 carbon atoms in-clude alpha-naphthylmethyl, beta-naphthylmethyl, alpha-naphthylethyl and beta-naphthylethyl. Examples of the alkanoyl group with 2 to 6 carbon atoms include ac~tyl, propionyl, butyryl, isobutyryl and valeryl.
Preferable examples of the compound of formula (I) provided by this invention are as follows.
(1) Compound of formula (I) wherein A is ~O-, Y is a single bond, or a linear or branched alkylene group with 1 to 4 carbon atoms or a linear alkenylene group with 2 to 4 carbon atoms that may obtionally be substi-tuted by 1 to 3 halogen atoms or halophenyl groups, Z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms, a carbonyl group, a phenyl group that may optionally have 1 to 2 substituents selected from a halogen atom and a carboxyl group, a cyano group or a group of formula .. ;
.. ... . .
2 ~ ~ $ ~d ~'J ~ ' -N or -N~-JN-R3 ~2 Rl and R2 are the same or different and each is an alkyl group with 1 to 3 carbon atoms, and R3 is a benzoyl group.
(2) Compound of formula (I) wherein A is -OC0-.
Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms, and Z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms or a phenyl group that may optionally have 1 to 3 halogen atoms.
(3) Compound of formula (I) wherein A is -NH-, Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms that may optionally be substituted by a phenyl group or a halophenyl grou]?t Z is a hydrogen atom, an alkoxycarbonyl group with 2 to 4 carbon atoms or a phenyl group that may optionally be substituted by a sulfonyl group.
DISCLOSURE OF INVENTION
This invention is to provide an azoxy compound represented by formula N--A--Y--Z
N
CH3 N ¦ c~3 (I) wherein A denotes -O-, -OCO-, -NH-, -NHCO-, -HNCS- or -N~_~N-, Y denotes a single bond or a linear or branched alkylene group with 1 to 6 carbon atoms or a linear or branched alkenylene group with 2 to 6 carbon atoms, and said a:Lkylene or alkenylene group may optionally be ~substituted by a halogen atom, a phenyl group or a halophenyl group, Z denotes a hydrogen atorn, an alkoxy group with 1 to 5 carbon atoms, a carboxyl group, an alkoxycarbonyl group with 2 to 6 carbon atoms, a phenyl group that may optionally have 1 to 3 substituents selected from a halogen atom, an alkoxy group with 1 to 5 carbon atoms, a car-boxyl group, a nitro group, a sulfonyl group and a N-methyl-N-alpha-naphthylmethylamino-methyl group, a phenoxy group in which a benz-ene ring may optionally be substituted by 1 to 3 halogen atoms, a naphthyl group, a cyano group, a pyridyl group, an oxopyridyl group, a imidazolyl group, a furyl group, a thienyl 2~'322~ `"
group or a group of formula ~1 -N or -N~_~N-R3 Rl and R2 are the same or different and each denotes a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, a phenyl group, a naphthyl alkyl group, a phenylalkyl group with 7 to 10 carbon atoms, a naphthylalkyl group with 11 to 14 carbon atoms or an amino group, and R3 denotes an alkyl group with 1 to 3 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, a benzoyl group or an alkanoyl group with 2 to 6 carbon atoms that may optionally be substituted by a phenyl group or a halophenyl group, pro~ided when A is the group of formula -N~_JN-, Z is a hydrogen atom, and its salt.
In the definitions of the substituents in the above formula ~I), examples of the linear or branched alkylene group with 1 to 6 carbon atoms include methyl-ene, ethylene, trimethylene, propylene, tetramethylene, ethylethylene, pentamethylene and hexamethylene. Examples of the linear or branched alkenylene group with 2 to 6 carbon atoms are vinylene, propenylene and isoprenylene.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine. Examples of the halophenyl group include o-, m- and p-chlorophenyls, o-, m- and p~fluorophenyls, 2,6-dichlorophenyl, 2,4~dichlorophenyl, 3,4-dichlorophenyl, 2,6-difluorophenyl, 2,4-difluoro-phenyl, 3,4-difluorophenyl, 2,4,6-trichlorophenyl and 2,4,6-trifluorophenyl.
The alkyl group is linear or branched. Ex-, ~ !
", .:
' '.' ' ' ` : ' ' '` ~' ' ~
.
~ ': ' , ,, 2 ~ C~ ~ 2 amples thereof include methyl, ethyl, n-propyl and iso-propyl.
The alkoxy group is an alkyloxy yroup whose alkyl moiety is linear or branched. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. The alkoxycarbonyl group is an alkyloxycarbonyl group whose alkoxy moiety has the above meaning. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and n-butoxycarbonyl.
Examples of the phenylalkyl group with 7 to 10 carbon atoms include benzyl and phenethyl. Examples of the naphthylalkyl group with 11 to 14 carbon atoms in-clude alpha-naphthylmethyl, beta-naphthylmethyl, alpha-naphthylethyl and beta-naphthylethyl. Examples of the alkanoyl group with 2 to 6 carbon atoms include ac~tyl, propionyl, butyryl, isobutyryl and valeryl.
Preferable examples of the compound of formula (I) provided by this invention are as follows.
(1) Compound of formula (I) wherein A is ~O-, Y is a single bond, or a linear or branched alkylene group with 1 to 4 carbon atoms or a linear alkenylene group with 2 to 4 carbon atoms that may obtionally be substi-tuted by 1 to 3 halogen atoms or halophenyl groups, Z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms, a carbonyl group, a phenyl group that may optionally have 1 to 2 substituents selected from a halogen atom and a carboxyl group, a cyano group or a group of formula .. ;
.. ... . .
2 ~ ~ $ ~d ~'J ~ ' -N or -N~-JN-R3 ~2 Rl and R2 are the same or different and each is an alkyl group with 1 to 3 carbon atoms, and R3 is a benzoyl group.
(2) Compound of formula (I) wherein A is -OC0-.
Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms, and Z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms or a phenyl group that may optionally have 1 to 3 halogen atoms.
(3) Compound of formula (I) wherein A is -NH-, Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms that may optionally be substituted by a phenyl group or a halophenyl grou]?t Z is a hydrogen atom, an alkoxycarbonyl group with 2 to 4 carbon atoms or a phenyl group that may optionally be substituted by a sulfonyl group.
(4) Compound of formula (I) wherein A is -N~CO-, Y is a single bond or a linear alkylene or alkenylene group with 1 to 4 carbon atoms which may optionally be substituted by 1 to 3 halogen atoms, phenyl groups or halo-phenyl groups, : - . ::
.; , ;, .: . ; - :
.. ~: , ~ ~ 2 ~ 2 ~ ~
z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms, a phenyl group that may optionally have 1 to 2 substituents selected from a halogen atom, an alkoxy group with 1 to 3 carbon atoms, a nitro group and a N-methyl-N-alpha-naphthyl-methylaminomethyl group, a phenoxy group in which a benzene ring may optionally be substituted by 1 to 2 halogen atoms, a naphthyl group, a pyridyl group, an oxopyr-idino group, an imidazolyl group, a furyl group, a thienyl group or a group of for-mula ~Rl -N or ~N~-/N-R3 Rl and R2 are the sarne or different and each is a hydrogen atom, an alkyl group with 1 to 3 carbon al:oms, a phenyl group or a naphthyl group with 11 to 12 ca.rbon atoms, R3 is an alkoxy group with 1 to 3 carbon atoms or an alkanoyl group with 2 to 4 carbon atoms that may optionally be substi-tuted by a halophenyl group.
.; , ;, .: . ; - :
.. ~: , ~ ~ 2 ~ 2 ~ ~
z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms, a phenyl group that may optionally have 1 to 2 substituents selected from a halogen atom, an alkoxy group with 1 to 3 carbon atoms, a nitro group and a N-methyl-N-alpha-naphthyl-methylaminomethyl group, a phenoxy group in which a benzene ring may optionally be substituted by 1 to 2 halogen atoms, a naphthyl group, a pyridyl group, an oxopyr-idino group, an imidazolyl group, a furyl group, a thienyl group or a group of for-mula ~Rl -N or ~N~-/N-R3 Rl and R2 are the sarne or different and each is a hydrogen atom, an alkyl group with 1 to 3 carbon al:oms, a phenyl group or a naphthyl group with 11 to 12 ca.rbon atoms, R3 is an alkoxy group with 1 to 3 carbon atoms or an alkanoyl group with 2 to 4 carbon atoms that may optionally be substi-tuted by a halophenyl group.
(5) Compound of formula (I) wherein A is -NHCS~, Y is a single bond, and Z is a group of formula ~ 1 ~N
R~ and R2 are the same or different and each is a hydrogen atom, an alkyl group :: . : : . ~ :
2 ~
with 1 to 3 carbon atoms, a phenyl group or an am1no group.
~6) Compound of ~ormula ~I) wherein A is --N N-, Y is a linear alkylene group with 1 to 4 carbon atoms, and Z is a hydrogen atom.
Typical examples of the compound in this inven-tion are as follows.
2-Hydroxyimino-2-deoxo-KA-7367A, 2-Methoxyimino-2-deoxo-KA-7367A, 2-(~-Ethoxy-ethoxyimino)-2-deoxo-KA-7367A, 2-Carboxymethoxyimino-2-deoxo-KA-7367A, 2-(1~Carboxy-l-methylethoxyimino)-2-deoxo-KA-7367A, 2-Acetoxyimino-2-deoxo-KA-7367A, 2-Benzoyloxyimino-2-deoxo-KA-7367A, 2-(p-Chlorobenzoyloxyimino)-2-deoxo-KA-7367A, 2-Semicarbazono-2-deoxo-KA-7367A, 2-Thiosemicarbazono-2-deoxo-~A-7367A, 2-Acetylhydrazono-2~-deoxo-KA-7367A, 2-(1-Imidazolylacetylhydrazono)-2-deoxo-KA-7367A, 2-(3-Pyridylacetylhydrazono)-2-deoxo KA~7367A, 2-(2,4-Dichlorophenylacetylhydrazono)-2-deoxo-KA-7367A, 2-(alpha-Naphthylacetylhydrazono)-2-deoxo-KA-7367A, 2-(4-Acetylpiperazinyl-acetylhydrazono)-2-3~ deoxo~KA-7367A, 2-[4-(2,6-Dichlorophenylacetyl)-l-piperazinyl-acetylhydrazono]-2-deoxo-KA-7637A, 2-[(2,6-Difluorophenyl)acetylhydrazono]-2-deoxo-KA-7367A, 2-[2,6-Dimethoxyphenyl~acetylhydrazono]-2-deoxo-KA-7367A, :
2 ~ 2 ~
2-~2-Furylcarbonylhydrazono)-2-deoxo-KA-7367A, 2-Thenoylhydrazono-2-deoxo-KA-7367A, 2-Isonicotinoylhydrazono-2-deoxo-KA-7367A, 2-Nicotinoylhydrazono-2-deoxo-KA-7367A, 2-(p-Chlorophenylacetylhydrazono)-2-deoxo-KA-7367A, 2-~2,4'-Dichlorodiphenylacetylhydrazono)-2-deoxo-KA-7367A, and 2-(2,4-dichlorodiphenylacetylhydrazono)-2-deoxo-KA-7367A
Basic products of the compound in this inven-tion may take a form of acid addition salts. Examples of an acids capable of forming such acid addition salts are inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, earbonic aeid and nitric aeid; and organie aeids such as acetie aeid, fumaric acid, malie aeid, citric acid, mandelic aeid, sueeinie aeid, p-toluenesulfonie acid and methanesulfonic acid. Pharmaceutieally, veterinarily, agrieulturally or horticulturaly permissible substances may also selectively be used depending on the use of the compound in this invention~
Aeid produets of the eompound in this invention may take a form of salts such as alkali metal salts, e.g.
sodium salts and potassium salts, alkaline earth metal salts, e.g. calcium salts and quaternary ammonil~ salts.
The eompound in this invention ean be produced by, for example, reacting the antifungal product KA-7367A
~: O
of formula A wherein X is -C- with a compound represent-ed by formula H2N-A-Y-Z (II) wherein A, Y and Z have the above meanings, or its salt, and converting the resulting compound of formula (I) into a salt if required.
,. : :,, ' ' ~,-, . :
"3 ~ 3 The reaction between the KA-7367~ product and the compound of formula (II) or its salt can usually be carried out in a suitable solvent and optionally in the presence of a base at a temperature of about -10C to a reflux temperature of a solvent, preferably about 5C to about 100C. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol; halogenated hydrocarbons such as chloroform and methylene chloride;
hydrocarbons such as benzene, toluene, xylene and cyclo-hexane; and ethers such as ether, dioxane and tetra-hydrofurane.
Examples of the base that can optionally be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; and orgnaic bases such as triethylamine, pyridine and 4-methylaminopyridine. These bases can be usually 0.1 to 100 equivalents, especially 1 to 10 equi-valents per mol of the KA-7367A product.
The proportion of the compound of formula (II) or its salt relative to the RA-7367 product is not strictly limited but can be variecl depending on -the type, etc. of the compound of formula (]I). The compound of formula (II) or its salt is usually 1 to 10 mols~ pre-ferably 2 to 5 mols per ~ol of the KA-7367 product.
The resulting compound of formula (I) can be converted into the acid addition salt, if required, by the ~eaction with the aforesaid acid.
Isolation and purification of the finai com-pound can be carried out by methods known per se, e.g.
chromatography (e.g. silica gel chromatography and silica gel preparative thin layer chromatography), extraction, distillation and crystallization.
The KA-7367A product used as a starting mate-rial in the above process is a known product descri~ed in European Patent Laid-open Specification No. 282,001.
J ~
Examples of the compound of formula (II) in-clude hydroxylamine (NH2OH), o-alkyl-substituted-hydroxylamine (NH2-O-Y-Z), o-acyl-substituted-hydroxylamine (NH2-OCO-Y-Z), semicarbazide ~Rl ~Rl (MH2-NHCO-N ), thiosemicarbazide (NH2-N~CS-N ), hydrazine (NH2-NH2), acyl-substituted hydrazine ( ~ -NHCO-Y-Z) and N-amino-N'-substituted pipera~ine (NH2-N N-y_z).
The compound of formula (I) in this invention : 10 has high antifungal activity, and exhibits excellent antifungal activity to fungi that infect warm-blooded animals including human, such as Candida, Cryptococcus, Aspergillus, Trichophyton, etc. and fungi that infect agricultural and horticultural crops and fruit trees, such as Piricularia, Botrytis, Saccharomyces, Septoria, etc.
The minimum inhibitory concentrations (~g/ml), relative to test fungi, oE some of the typical compounds in this invention produced in Examples to be described later were measured, and the results are tabulated below.
2 ~ 2 ~
Table 1 Minimum inhibitory concentration (~g/ml)*
Test Compound Test fungi Example No.) Candida Cystococcus Trichophyton Trichophyton albicans neoformans men~agrophytes rubrus 1 12.5 25 12.5 3.1 3 25 50 25 6.25 4 12.5 25 12.5 3.1 12.5 25 12.5 3.1 ~4 25 50 12.5 6.25 12.5 3.1 27 100 100 12.5 6.25 34 3.1 3.1 3.1 1.6 3.1 6.25 6.25 3.1 43 106 3.1 6.25 3.1 47 6.25 50 25 12.5 48 1.6 6.25 3.1 1.6 ~9 1.6 6.25 3.1 1.6 52 3.1 12.5 6.25 3.1 53 3.1 12.5 6.25 3.1 54 3.1 12.5 6.25 3.1 61 0.8 6.25 3.1 1.6 62 1.6 12~5 6.25 3.1 67 1.~ 6.25 3.1 3.1 68 3.2 6.25 6.25 6.25 12.5 71 6.25 12~5 6.25 6.25 74 1.6 6.25 ~.25 3.1 78 0.8 6.25 3.1 3.1 79 _ 1.6 6.25 3.1 1.6 , - ., ~ .
2 ~ J r;J "
*The minimum inhibitory concentrations were measured by an agar dilution method using a Sabouraud's dextrose medium in accordance with a standard method of Nippon Ragaku Ryoho Gakkai tChemical Therapy Academy).
The compound in this invention is low in tox-icity. For example; acute toxicities LD50 to mice of the compounds in Examples 1 and 4 to be described later are both more than 100 mg/kg (intravenous administration).
It has been confirmed that when KA-7367A is left to stand in serum at 37C for 4 hours and then subjected to measurement by thin layer chromatography and biological verification using Candida albicans, it is almost decomposed, whereas the compounds in this inven-tion are little decomposed.
As stated above, the compounds in this inven-tion have excellent antifungal activity to fungi that infect warm-blooded animals including humans and fungi that infect agricultural and horticllltural crops and fruit trees, and are useful as antifungal agents for medical, veterinary, agricultural and horticultural usages.
The compounds or their salts in this invention, when used as antifungal agents, can be prepared in dosage forms suited for various usag~s. For example, when the compounds or their salts in this invention are used as medicines or veterinary drugs (animal drugs), it is possible that adjuvants such as a vehicle, a binder, a lubricantr a disintegrator, a coating, an emulsifier, a suspending agent, a solvent, a stabilizer~ an absorption aid, an ointment base, etc. can properly be added thereto and they are prepared into dosage forms for oral admini-stration, adminîstration by injection, subcutaneous injection and external use.
Examples of the preparations for oral admini-stration are granules, tablets, sugar coated tablets~capsules~ pills, liquid preparations, emulsions and .:
.
C~ 2~``3 suspensions. Examples of the preparations for admini-stration by injection are preparations for intravenous injection, subcutaneous injection and instillation.
Examples of the preparations for intrarectal administra-tion are suppositories and soft elastic capsules. Ex-amples of the preparations for external use are oint-ments, lotions, liniments and creams. Dosage forms such as eye drops, ear drops, etc. are also available.
The compounds or their salts in this invention, when used as agricultural and horticultural antifungal agents, can take dosage forms such as liquid prepara-tions, emulsions, granules, powders, dusts and pastes.
The dose of the compound in this invention, when administered to the warm-blooded animals including humans, can vary over a wide range depending on types, conditions, weights and sexes of animals being admini-stered, doctor's judgement, etc. Generally, it is about 0.1 to about 500 mg/kg~weight per day, and the compound can be administered either once or in divided portions a day.
When the compound in this invention is used as an agricultural and horticultural agent, it can be appli-ed to a habitat area of fungi as an agent for soil treat-ment, an agent for treatment of stems and leaves, etc.
25 Its dose can be e.g. about 0.005 to about 5 kg/ha.
PREFE~ABLE EMBODIMENTS IN WORKING INVE~TION
The following Referential Examples, Examples and Preparation Examples illustrate this invention more speci~ically.
Streptomyces sp. KC-7367 strain (FERM BP-1277) grown in a potato dextrose agar slant culture medium was inoculated in a liquid culture medium having a composi-tion of 1 % of a soluble starch, 1 % of glucose, 1 % of a 35 soybean powder, 0.5 % of a corn steep liquor, 0.05 % of magnesium sulfate heptahydrate, 0.3 % of calcium carbon-.
. ' ' ate and 0.0005 ~ of cobalt chloride hexahydrate, said liquid culture medium being adjusted to pH of 7.5. It was cultivated at 28C for 2 days to form a seed liquid culture medium.
' 5 Ten liters of a liquid culture medium having a composition of 1 % of a soluble starch, 0.5 ~ of poly-peptone S, 0.2 % of a yeast extract, 0.05 % of magnesium sulfate heptahydrate, 000005 ~ of cobalt chloride hexa-hydrate and 0.2 % of a cotton seed oil, said liquid culture medium being adjusted to pH of 7.5, was charged in a 30-liter jar fermenter. One hundred milliliters of the above seed liquid culture medium was inoculated in said culture medium, and cultivated at a cultivation temperature of 28C and an aeration rate of 5 liters/min with 300 rpm for 2 days.
After the cultivation was over, the liquid culture was filtered and 40 liters of the filtrate was adsorbed on Diaion HP-20 column (6 x 70 cm). After this column was washed with a small amount of a 50 % ethanol solution, elution was conducted with methanol. Fractions having antifungal activity to Cand:ida albicans were gathered and concentrated to dryne~ss under reduced pres-sure. The residue was dissolved in 200 ml of ethyl acetate, and the solution was washed with 100 ml of a 5 %
2s sodium bicarbonate aqueous solution, 100 ml of 0.02 N
hydrochloric acid and then 100 ml of water.
An ethyl acetate layer was concentrated to dryness under reduced pressure, and the residue was dissolved in a small amount of methanol and purified by gel chromatography using Toyopearl TSKHW-40 tcolumn: 2 x 90 cm, eluent: methanol~. Active fractions were gathered, concentrated under reduced pressure and developed by preparative thin layer chromatography [eluent: benzene-ethyl acetate (10:1)] using silicagel 60F254 (Merck).
Active fractions of RfO.53 (KA-7367A) and RfO.22 (KA-7367B) were gathered and eluted with ethyl acetate. The ~ ~ .
: , - , . .:
:
~ ~ ~.J ~ ) 2 2 eluate was concentrated under reduced pressure, and the residue was dissolved in methanol. This was purified by gel chromatography (column: 1.5 x 90 cm, eluent: meth-anol) using Sephadex L~-20. ~ctive fractions were gather-ed and concentrated under reduced pressure. There re-sulted 30 mg of KA-7367A and 3 mg of KA-7367B as color-less oils.
KA-7367B (78 mg~ was dissolved in 3 ml of methylene chloride, and 37 mg of pyridinium trifluoro-acetate and 243 mg of pyridinium dichromate were added, followed by stirring the mixture at room temperature.
Five hours later, 247 mg of pyridinium chromate was added, and the mixture was further stirred at room tem-perature for 15 hours. To the reac~ion solution wasadded 20 ml of diethyl ether, and impurities were removed by suction filtration using celite, followed by concen-trating the filtrate under reduced pressure. As a result, 101 mg of a crude oil was obtained. When the crude oil was purified by silica gel chromatography [eluent: benz-ene-ethyl acetate t50:1)], 19 mg of a colorless oil was provided.
Physicochemical and biological properties of said oil agreed with those of KA-7367A obtained in ~5 REFERENTIA~ EXAMPLE 1.
Preparation of 2-hydroxyimino-2-deoxo-K~-7367A:
~ A-7367A (1.3 g) and 500 mg of hydroxylamine hydrochloride were dissolved in 20 ml of methanol, and 0.3 ml of pyridine was added, followed by stirring the mixture at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. When the concentrate was purified by silica gel column chro-matography [eluent: benzene-2thyl acetate (20:1)], 950 mg ~ '.
2 ~ S.' ~J t~
of a final product (a mixture of a syn-isomer and an anti-isomer) was obtained.
H-NMR: (CDC13, TMS) ~
0.94(3H, t, J=7Hz, 6'-CH3) 1.38, 1.42(total 3H, d, J=7Hz, 4-CH3) 1.78, 1.96(total 3H, s, l-CH3) 4.80, 5.38(total lH, q, J=7Hz,-3-CH) Preparation of 2-methoxyimino-2-deoxo-KA-7367A:
The procedure in EXAMPI,E 1 was followed except using 70 mg of KA-7367A and 50 mg of o-methylhydroxyl-amine hydrochloride were treated as in EXAMæLE 1 to obtain 50 mg of a final product (an anti-isomer, contain-ing a very small amount of a syn-isomer).
; 15 lH-NMR: (CDC13, TMS) o 0.91(3H, t, J=7Hz, 6'-CH3) 1.35(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 3.85(3H, s, CH3-O) 4.78(1H, q, J=7Hæ, 3-CH) Preparation of 2-(2-ethoxy-ethoxyimino)-2-di-oxo-KA-7367A:
The procedure in EXAMPLE' 1 was followed except using 40 mg of KA-7367A and 40 ml of o-ethoxyethyl-hy-droxylamine to obtain 25 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.92~3H, t, J=7Hz, 6'-CH3) 1.21(3H, t, J=7Hz, CH3-CH2-) 1.35, 1.38(total 3H, d, J=7Hz, 4-CH3 1.74, 1.93(total 3H, s, l-CH3) 3.54(2H, g, J=7Hz, CH3-CH2-) 3.66~2H, q, J=4Hz, -CH2-CH2-) 4.20(2H, d, J=4Hz, -CH2-CH2-) 4.78, 5~38(total lH, q, J=7Hz, 3-CH) : .~- ,.; .-: , ;' :: .
;"~
-" 2 ~
Preparation of 2-carboxymethoxyimino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 100 mg of KA-7367A and 70 mg of aminoxyacetic acid hydrochloride, and the reaction product was purified by silica gel column chromatography [eluent: chloroform-methanol (20:1)3 to obtain 50 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.91(3H, t, J=7Hz, 6'-CH3) 1.36(3H, d, J=7Hz, 4-CH3) 1.98(3H, s, l-CH3) 4.62(2H, S, -O-CH2-COOH) - 4.77(1H, q, J=7Hz, 3-CH) EXAMPI.E 5 Preparation of 2-(1-carboxy-1-ethylmethoxy-imino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 100 mg of KA-7367A and 85 mg of aminoxyisobutyric acid hydrocnloride. When the reaction product was purifi-ed by silica gel column chromatography ~eluent: chloro-form-methanol (20:1)], 57 mg of a final product was afforded.
lH-NMR: (CDC13, TMS) o 0.91(3H, t, J~7Hz, 6'-CH3) 1~37(3H, d, J=7Hz, 4-CH3) 1.50, 1.52(each 3H, s, -0-C) I
1.97(3H, s, l-CH3) 4.77(1H, q, J=7Hz, 3-CH3) 3 o EXAMPLE 6 Preparation of 2-(3-carboxy-2-propenyloxy-imino)-2-deoxo-KA-7367A:
J., . : : :
'i ' . ~
The procedure in EXAMPLE 1 was followed except using 34 mg of KA-7367A and 26 mg of 4-aminoxycrotonic acid hydrochloride. When the reaction product was puri-fied by silica gel column chromatography [eluent: chloro-form-methanol (15:1)], 28 mg of a final product was afforded.
H-NMR: ( CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-C~3) 1.36(3H, d, J=7Hz, 4-CM3) 1.72, 1.95(total 3H, s, l-CH3) 7.10(lH, m, -CH=CH-COOH) Preparation of 2-(3-carboxy-2-chloro-n-propoxy-imino)-2~deoxo-RA-7367A:
The procedure in EXAMPLE 1 was followed except ; using 31 mg of KA-7367A and 29 mg of 4-aminoxy-3-chloro-butyric acid to provide 32 mg of a final product~
1H - NMR: ( CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.71, 1.90(total 3H, s, -CH2-COOH) Preparation of 2-(4-dimethylamino-n-butoxy-imino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except 25 using 40 mg of KA-7367A and 62 mg of o-(4-dimethylamino-butyl)-hydroxylamine dihydrochloride to provide 12 mg of a final product.
H-WMR: (CDC13, TMS)C~
0.91~3H, t, J=7Hz, 6'-CH3) 1.36, 1.38(total 3H, each d, J=7Hz, 4-CH3) 1.87, 2.01(total 3H, each s, l-CH3) 2~63, 2.67(total 6H, each s, -N
.
' :. .
;:
2~2~
-- 19 -- .
Preparation of ~-~p-carboxybenzyloxyimino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 20 mg of KA-7367A and 21 mg of o-(p-carboxybenzyl)-hydroxylamine hydrochloride to obtain 30 mg of a final product~
H-NMR: (CDC13, TMS)~
0.91(3H, t, J=7~z, 6'-CH3) 1.35, 1.41(total 3H, each d, J=7Hz, 4-CH3) 1.75, 1.97(total 3H, each s, l-C~3) 5.15(2H, s, -CH2 ~ ) 7.42, 8.07(each 2H, d, J=8.5Hz, aromatic H) Preparation of 2-(2,6-dichlorobenzyloxyimino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 50 mg of KA-7367A and 50 mg of o-(2,6-dichloro-ben~yl)-hydroxylamine hydrochloricle to afford 55 mg of a final product.
~-NMR: (CDC13, TMS ) ~
0.92t3H, t, J=7Hz, 6'-CEI3) 1.35, 1.41(total 3H, eac:h d, J=7Hz, 4-CH3) 1.70, 1.96(total 3H, each s, l-CH3) ; 25 5.13(2H, s, -O-CH2 ~ ) ; 7.2-7.4(3H, m, aromatic H) Preparation of 2-(alpha-2,4-dichlorophenylcar-boxymethoxyimino)-2-deoxo-KA-7367A:
- 30 The procedure in EXAMPLE 1 was followed except using 40 mg of KA-7367A and 55 mg of aminoxy-(2,4-di-chlorophenyl)-acetic acid hydrochloride to obtain 79 mg - :. . , ~ -, ' ' :
-"~ 2-~f~ hfJ '.,' "^"
of a final product.
H-NMR: ~CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.74, 1.76S 1.95, 1.96~total 3H, each s, l-CH3) 4 73, 4.75, 5.25, 5.32(total lH, each 1I J=7Hæ, 3-CH) 7.21(lH, m, aromatic H) 7.41(2H, m, aromatic H) Preparation of 2-(4-benzoyl-1-piperazinoethoxy-imino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using lU0 mg of KA-7367A and 100 mg of o-(4-benzoyl-1-piperzinoethyl)-hydroxylamine to provide 51 mg of a final product EI-NMR: (CDC13, TMS) ~
0 91(3H, t, J=7Hz, 6'-CH3) 1.35t3H, d, J=7Hz, 4-CH3) 1.99(3H, s, l-CH3) 2.22(2H, q, 3'-CH2-) 2.61(4H, t, piperazine ring 2,6-CI12) 4.19(4H, t, piperazine ring 3,5-CH2) 4.77(1H, q, J=7Hz, 3-CH-) 6.9-7.1(2H, m. aromatic H) EXAMPLES 13 to 23 ~ The procedure in EXAMP~E 2 was repeated except ; using a suitable o-substituted hydroxylamine instead of methoxyamine to obtain a compound of formula:
N-O-Y-Z
~\~\
CH3 N ¦ C 3 .
- ~ ' -- - -' ;`~
t,) Example Y Z
. ..
13 -CH2 -C~2 ~ H
CH3 E~
-CH2--C~-16 -CH2- ~) 17 single bond ,.
18 .. ~3Cl 19 .. ~
.. -~-Cl 21 --C~2-CH2-- --N
2 3 --CH2--CH2-- ..
:~
.
Preparation of 2-acetoxyimino-2-deoxo-KA-7367A:
2-Hydroxyimino 2-deoxo-KA-7367A (40 mg) obtain-ed in EXAMPI~E 1 and 100 mg of pyridine were dissolved in 6 ml of methylene chloride, and 100 mg of acetic anhydr-ide was added dropwise, followed by stirring the mixture at room temperature for 1 hour. To the reaction solution was added 30 ml of methylene chloride, and the mixture was washed wiih water, dried and concentrated under reduced pressure. When the concentrate was purified by silica gel column chromatography [eluent: benzene-acetic acid (20:1)], there resulted 26 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.41(3H r d, J=7Hz, 4-CH3) 2.05(3Hr s, l-CH3) 2.18(3H, s, CO-CH3) 4.91(lH, q, J=7Hz, 3-CH3) Preparation of 2-benzoyloxyimino-2~deoxo-KA-7367A:
The procedure in EXAMPLE 24 was repeated except using 120 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 100 mg oE benzoyl chloride to provide 110 mg of a final product H-~MR: tCDC13, TMS) ~
0~91~3H, t, J=7Hz, 6'-CH3) 1.47(3H, d, J=7Hz, 4-CH3) 2.20(lH, q, J=7Hz, 3-CH) ~
R~ and R2 are the same or different and each is a hydrogen atom, an alkyl group :: . : : . ~ :
2 ~
with 1 to 3 carbon atoms, a phenyl group or an am1no group.
~6) Compound of ~ormula ~I) wherein A is --N N-, Y is a linear alkylene group with 1 to 4 carbon atoms, and Z is a hydrogen atom.
Typical examples of the compound in this inven-tion are as follows.
2-Hydroxyimino-2-deoxo-KA-7367A, 2-Methoxyimino-2-deoxo-KA-7367A, 2-(~-Ethoxy-ethoxyimino)-2-deoxo-KA-7367A, 2-Carboxymethoxyimino-2-deoxo-KA-7367A, 2-(1~Carboxy-l-methylethoxyimino)-2-deoxo-KA-7367A, 2-Acetoxyimino-2-deoxo-KA-7367A, 2-Benzoyloxyimino-2-deoxo-KA-7367A, 2-(p-Chlorobenzoyloxyimino)-2-deoxo-KA-7367A, 2-Semicarbazono-2-deoxo-KA-7367A, 2-Thiosemicarbazono-2-deoxo-~A-7367A, 2-Acetylhydrazono-2~-deoxo-KA-7367A, 2-(1-Imidazolylacetylhydrazono)-2-deoxo-KA-7367A, 2-(3-Pyridylacetylhydrazono)-2-deoxo KA~7367A, 2-(2,4-Dichlorophenylacetylhydrazono)-2-deoxo-KA-7367A, 2-(alpha-Naphthylacetylhydrazono)-2-deoxo-KA-7367A, 2-(4-Acetylpiperazinyl-acetylhydrazono)-2-3~ deoxo~KA-7367A, 2-[4-(2,6-Dichlorophenylacetyl)-l-piperazinyl-acetylhydrazono]-2-deoxo-KA-7637A, 2-[(2,6-Difluorophenyl)acetylhydrazono]-2-deoxo-KA-7367A, 2-[2,6-Dimethoxyphenyl~acetylhydrazono]-2-deoxo-KA-7367A, :
2 ~ 2 ~
2-~2-Furylcarbonylhydrazono)-2-deoxo-KA-7367A, 2-Thenoylhydrazono-2-deoxo-KA-7367A, 2-Isonicotinoylhydrazono-2-deoxo-KA-7367A, 2-Nicotinoylhydrazono-2-deoxo-KA-7367A, 2-(p-Chlorophenylacetylhydrazono)-2-deoxo-KA-7367A, 2-~2,4'-Dichlorodiphenylacetylhydrazono)-2-deoxo-KA-7367A, and 2-(2,4-dichlorodiphenylacetylhydrazono)-2-deoxo-KA-7367A
Basic products of the compound in this inven-tion may take a form of acid addition salts. Examples of an acids capable of forming such acid addition salts are inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, earbonic aeid and nitric aeid; and organie aeids such as acetie aeid, fumaric acid, malie aeid, citric acid, mandelic aeid, sueeinie aeid, p-toluenesulfonie acid and methanesulfonic acid. Pharmaceutieally, veterinarily, agrieulturally or horticulturaly permissible substances may also selectively be used depending on the use of the compound in this invention~
Aeid produets of the eompound in this invention may take a form of salts such as alkali metal salts, e.g.
sodium salts and potassium salts, alkaline earth metal salts, e.g. calcium salts and quaternary ammonil~ salts.
The eompound in this invention ean be produced by, for example, reacting the antifungal product KA-7367A
~: O
of formula A wherein X is -C- with a compound represent-ed by formula H2N-A-Y-Z (II) wherein A, Y and Z have the above meanings, or its salt, and converting the resulting compound of formula (I) into a salt if required.
,. : :,, ' ' ~,-, . :
"3 ~ 3 The reaction between the KA-7367~ product and the compound of formula (II) or its salt can usually be carried out in a suitable solvent and optionally in the presence of a base at a temperature of about -10C to a reflux temperature of a solvent, preferably about 5C to about 100C. Examples of the solvent include alcohols such as methanol, ethanol and isopropanol; halogenated hydrocarbons such as chloroform and methylene chloride;
hydrocarbons such as benzene, toluene, xylene and cyclo-hexane; and ethers such as ether, dioxane and tetra-hydrofurane.
Examples of the base that can optionally be used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; and orgnaic bases such as triethylamine, pyridine and 4-methylaminopyridine. These bases can be usually 0.1 to 100 equivalents, especially 1 to 10 equi-valents per mol of the KA-7367A product.
The proportion of the compound of formula (II) or its salt relative to the RA-7367 product is not strictly limited but can be variecl depending on -the type, etc. of the compound of formula (]I). The compound of formula (II) or its salt is usually 1 to 10 mols~ pre-ferably 2 to 5 mols per ~ol of the KA-7367 product.
The resulting compound of formula (I) can be converted into the acid addition salt, if required, by the ~eaction with the aforesaid acid.
Isolation and purification of the finai com-pound can be carried out by methods known per se, e.g.
chromatography (e.g. silica gel chromatography and silica gel preparative thin layer chromatography), extraction, distillation and crystallization.
The KA-7367A product used as a starting mate-rial in the above process is a known product descri~ed in European Patent Laid-open Specification No. 282,001.
J ~
Examples of the compound of formula (II) in-clude hydroxylamine (NH2OH), o-alkyl-substituted-hydroxylamine (NH2-O-Y-Z), o-acyl-substituted-hydroxylamine (NH2-OCO-Y-Z), semicarbazide ~Rl ~Rl (MH2-NHCO-N ), thiosemicarbazide (NH2-N~CS-N ), hydrazine (NH2-NH2), acyl-substituted hydrazine ( ~ -NHCO-Y-Z) and N-amino-N'-substituted pipera~ine (NH2-N N-y_z).
The compound of formula (I) in this invention : 10 has high antifungal activity, and exhibits excellent antifungal activity to fungi that infect warm-blooded animals including human, such as Candida, Cryptococcus, Aspergillus, Trichophyton, etc. and fungi that infect agricultural and horticultural crops and fruit trees, such as Piricularia, Botrytis, Saccharomyces, Septoria, etc.
The minimum inhibitory concentrations (~g/ml), relative to test fungi, oE some of the typical compounds in this invention produced in Examples to be described later were measured, and the results are tabulated below.
2 ~ 2 ~
Table 1 Minimum inhibitory concentration (~g/ml)*
Test Compound Test fungi Example No.) Candida Cystococcus Trichophyton Trichophyton albicans neoformans men~agrophytes rubrus 1 12.5 25 12.5 3.1 3 25 50 25 6.25 4 12.5 25 12.5 3.1 12.5 25 12.5 3.1 ~4 25 50 12.5 6.25 12.5 3.1 27 100 100 12.5 6.25 34 3.1 3.1 3.1 1.6 3.1 6.25 6.25 3.1 43 106 3.1 6.25 3.1 47 6.25 50 25 12.5 48 1.6 6.25 3.1 1.6 ~9 1.6 6.25 3.1 1.6 52 3.1 12.5 6.25 3.1 53 3.1 12.5 6.25 3.1 54 3.1 12.5 6.25 3.1 61 0.8 6.25 3.1 1.6 62 1.6 12~5 6.25 3.1 67 1.~ 6.25 3.1 3.1 68 3.2 6.25 6.25 6.25 12.5 71 6.25 12~5 6.25 6.25 74 1.6 6.25 ~.25 3.1 78 0.8 6.25 3.1 3.1 79 _ 1.6 6.25 3.1 1.6 , - ., ~ .
2 ~ J r;J "
*The minimum inhibitory concentrations were measured by an agar dilution method using a Sabouraud's dextrose medium in accordance with a standard method of Nippon Ragaku Ryoho Gakkai tChemical Therapy Academy).
The compound in this invention is low in tox-icity. For example; acute toxicities LD50 to mice of the compounds in Examples 1 and 4 to be described later are both more than 100 mg/kg (intravenous administration).
It has been confirmed that when KA-7367A is left to stand in serum at 37C for 4 hours and then subjected to measurement by thin layer chromatography and biological verification using Candida albicans, it is almost decomposed, whereas the compounds in this inven-tion are little decomposed.
As stated above, the compounds in this inven-tion have excellent antifungal activity to fungi that infect warm-blooded animals including humans and fungi that infect agricultural and horticllltural crops and fruit trees, and are useful as antifungal agents for medical, veterinary, agricultural and horticultural usages.
The compounds or their salts in this invention, when used as antifungal agents, can be prepared in dosage forms suited for various usag~s. For example, when the compounds or their salts in this invention are used as medicines or veterinary drugs (animal drugs), it is possible that adjuvants such as a vehicle, a binder, a lubricantr a disintegrator, a coating, an emulsifier, a suspending agent, a solvent, a stabilizer~ an absorption aid, an ointment base, etc. can properly be added thereto and they are prepared into dosage forms for oral admini-stration, adminîstration by injection, subcutaneous injection and external use.
Examples of the preparations for oral admini-stration are granules, tablets, sugar coated tablets~capsules~ pills, liquid preparations, emulsions and .:
.
C~ 2~``3 suspensions. Examples of the preparations for admini-stration by injection are preparations for intravenous injection, subcutaneous injection and instillation.
Examples of the preparations for intrarectal administra-tion are suppositories and soft elastic capsules. Ex-amples of the preparations for external use are oint-ments, lotions, liniments and creams. Dosage forms such as eye drops, ear drops, etc. are also available.
The compounds or their salts in this invention, when used as agricultural and horticultural antifungal agents, can take dosage forms such as liquid prepara-tions, emulsions, granules, powders, dusts and pastes.
The dose of the compound in this invention, when administered to the warm-blooded animals including humans, can vary over a wide range depending on types, conditions, weights and sexes of animals being admini-stered, doctor's judgement, etc. Generally, it is about 0.1 to about 500 mg/kg~weight per day, and the compound can be administered either once or in divided portions a day.
When the compound in this invention is used as an agricultural and horticultural agent, it can be appli-ed to a habitat area of fungi as an agent for soil treat-ment, an agent for treatment of stems and leaves, etc.
25 Its dose can be e.g. about 0.005 to about 5 kg/ha.
PREFE~ABLE EMBODIMENTS IN WORKING INVE~TION
The following Referential Examples, Examples and Preparation Examples illustrate this invention more speci~ically.
Streptomyces sp. KC-7367 strain (FERM BP-1277) grown in a potato dextrose agar slant culture medium was inoculated in a liquid culture medium having a composi-tion of 1 % of a soluble starch, 1 % of glucose, 1 % of a 35 soybean powder, 0.5 % of a corn steep liquor, 0.05 % of magnesium sulfate heptahydrate, 0.3 % of calcium carbon-.
. ' ' ate and 0.0005 ~ of cobalt chloride hexahydrate, said liquid culture medium being adjusted to pH of 7.5. It was cultivated at 28C for 2 days to form a seed liquid culture medium.
' 5 Ten liters of a liquid culture medium having a composition of 1 % of a soluble starch, 0.5 ~ of poly-peptone S, 0.2 % of a yeast extract, 0.05 % of magnesium sulfate heptahydrate, 000005 ~ of cobalt chloride hexa-hydrate and 0.2 % of a cotton seed oil, said liquid culture medium being adjusted to pH of 7.5, was charged in a 30-liter jar fermenter. One hundred milliliters of the above seed liquid culture medium was inoculated in said culture medium, and cultivated at a cultivation temperature of 28C and an aeration rate of 5 liters/min with 300 rpm for 2 days.
After the cultivation was over, the liquid culture was filtered and 40 liters of the filtrate was adsorbed on Diaion HP-20 column (6 x 70 cm). After this column was washed with a small amount of a 50 % ethanol solution, elution was conducted with methanol. Fractions having antifungal activity to Cand:ida albicans were gathered and concentrated to dryne~ss under reduced pres-sure. The residue was dissolved in 200 ml of ethyl acetate, and the solution was washed with 100 ml of a 5 %
2s sodium bicarbonate aqueous solution, 100 ml of 0.02 N
hydrochloric acid and then 100 ml of water.
An ethyl acetate layer was concentrated to dryness under reduced pressure, and the residue was dissolved in a small amount of methanol and purified by gel chromatography using Toyopearl TSKHW-40 tcolumn: 2 x 90 cm, eluent: methanol~. Active fractions were gathered, concentrated under reduced pressure and developed by preparative thin layer chromatography [eluent: benzene-ethyl acetate (10:1)] using silicagel 60F254 (Merck).
Active fractions of RfO.53 (KA-7367A) and RfO.22 (KA-7367B) were gathered and eluted with ethyl acetate. The ~ ~ .
: , - , . .:
:
~ ~ ~.J ~ ) 2 2 eluate was concentrated under reduced pressure, and the residue was dissolved in methanol. This was purified by gel chromatography (column: 1.5 x 90 cm, eluent: meth-anol) using Sephadex L~-20. ~ctive fractions were gather-ed and concentrated under reduced pressure. There re-sulted 30 mg of KA-7367A and 3 mg of KA-7367B as color-less oils.
KA-7367B (78 mg~ was dissolved in 3 ml of methylene chloride, and 37 mg of pyridinium trifluoro-acetate and 243 mg of pyridinium dichromate were added, followed by stirring the mixture at room temperature.
Five hours later, 247 mg of pyridinium chromate was added, and the mixture was further stirred at room tem-perature for 15 hours. To the reac~ion solution wasadded 20 ml of diethyl ether, and impurities were removed by suction filtration using celite, followed by concen-trating the filtrate under reduced pressure. As a result, 101 mg of a crude oil was obtained. When the crude oil was purified by silica gel chromatography [eluent: benz-ene-ethyl acetate t50:1)], 19 mg of a colorless oil was provided.
Physicochemical and biological properties of said oil agreed with those of KA-7367A obtained in ~5 REFERENTIA~ EXAMPLE 1.
Preparation of 2-hydroxyimino-2-deoxo-K~-7367A:
~ A-7367A (1.3 g) and 500 mg of hydroxylamine hydrochloride were dissolved in 20 ml of methanol, and 0.3 ml of pyridine was added, followed by stirring the mixture at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. When the concentrate was purified by silica gel column chro-matography [eluent: benzene-2thyl acetate (20:1)], 950 mg ~ '.
2 ~ S.' ~J t~
of a final product (a mixture of a syn-isomer and an anti-isomer) was obtained.
H-NMR: (CDC13, TMS) ~
0.94(3H, t, J=7Hz, 6'-CH3) 1.38, 1.42(total 3H, d, J=7Hz, 4-CH3) 1.78, 1.96(total 3H, s, l-CH3) 4.80, 5.38(total lH, q, J=7Hz,-3-CH) Preparation of 2-methoxyimino-2-deoxo-KA-7367A:
The procedure in EXAMPI,E 1 was followed except using 70 mg of KA-7367A and 50 mg of o-methylhydroxyl-amine hydrochloride were treated as in EXAMæLE 1 to obtain 50 mg of a final product (an anti-isomer, contain-ing a very small amount of a syn-isomer).
; 15 lH-NMR: (CDC13, TMS) o 0.91(3H, t, J=7Hz, 6'-CH3) 1.35(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 3.85(3H, s, CH3-O) 4.78(1H, q, J=7Hæ, 3-CH) Preparation of 2-(2-ethoxy-ethoxyimino)-2-di-oxo-KA-7367A:
The procedure in EXAMPLE' 1 was followed except using 40 mg of KA-7367A and 40 ml of o-ethoxyethyl-hy-droxylamine to obtain 25 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.92~3H, t, J=7Hz, 6'-CH3) 1.21(3H, t, J=7Hz, CH3-CH2-) 1.35, 1.38(total 3H, d, J=7Hz, 4-CH3 1.74, 1.93(total 3H, s, l-CH3) 3.54(2H, g, J=7Hz, CH3-CH2-) 3.66~2H, q, J=4Hz, -CH2-CH2-) 4.20(2H, d, J=4Hz, -CH2-CH2-) 4.78, 5~38(total lH, q, J=7Hz, 3-CH) : .~- ,.; .-: , ;' :: .
;"~
-" 2 ~
Preparation of 2-carboxymethoxyimino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 100 mg of KA-7367A and 70 mg of aminoxyacetic acid hydrochloride, and the reaction product was purified by silica gel column chromatography [eluent: chloroform-methanol (20:1)3 to obtain 50 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.91(3H, t, J=7Hz, 6'-CH3) 1.36(3H, d, J=7Hz, 4-CH3) 1.98(3H, s, l-CH3) 4.62(2H, S, -O-CH2-COOH) - 4.77(1H, q, J=7Hz, 3-CH) EXAMPI.E 5 Preparation of 2-(1-carboxy-1-ethylmethoxy-imino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 100 mg of KA-7367A and 85 mg of aminoxyisobutyric acid hydrocnloride. When the reaction product was purifi-ed by silica gel column chromatography ~eluent: chloro-form-methanol (20:1)], 57 mg of a final product was afforded.
lH-NMR: (CDC13, TMS) o 0.91(3H, t, J~7Hz, 6'-CH3) 1~37(3H, d, J=7Hz, 4-CH3) 1.50, 1.52(each 3H, s, -0-C) I
1.97(3H, s, l-CH3) 4.77(1H, q, J=7Hz, 3-CH3) 3 o EXAMPLE 6 Preparation of 2-(3-carboxy-2-propenyloxy-imino)-2-deoxo-KA-7367A:
J., . : : :
'i ' . ~
The procedure in EXAMPLE 1 was followed except using 34 mg of KA-7367A and 26 mg of 4-aminoxycrotonic acid hydrochloride. When the reaction product was puri-fied by silica gel column chromatography [eluent: chloro-form-methanol (15:1)], 28 mg of a final product was afforded.
H-NMR: ( CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-C~3) 1.36(3H, d, J=7Hz, 4-CM3) 1.72, 1.95(total 3H, s, l-CH3) 7.10(lH, m, -CH=CH-COOH) Preparation of 2-(3-carboxy-2-chloro-n-propoxy-imino)-2~deoxo-RA-7367A:
The procedure in EXAMPLE 1 was followed except ; using 31 mg of KA-7367A and 29 mg of 4-aminoxy-3-chloro-butyric acid to provide 32 mg of a final product~
1H - NMR: ( CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.71, 1.90(total 3H, s, -CH2-COOH) Preparation of 2-(4-dimethylamino-n-butoxy-imino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except 25 using 40 mg of KA-7367A and 62 mg of o-(4-dimethylamino-butyl)-hydroxylamine dihydrochloride to provide 12 mg of a final product.
H-WMR: (CDC13, TMS)C~
0.91~3H, t, J=7Hz, 6'-CH3) 1.36, 1.38(total 3H, each d, J=7Hz, 4-CH3) 1.87, 2.01(total 3H, each s, l-CH3) 2~63, 2.67(total 6H, each s, -N
.
' :. .
;:
2~2~
-- 19 -- .
Preparation of ~-~p-carboxybenzyloxyimino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 20 mg of KA-7367A and 21 mg of o-(p-carboxybenzyl)-hydroxylamine hydrochloride to obtain 30 mg of a final product~
H-NMR: (CDC13, TMS)~
0.91(3H, t, J=7~z, 6'-CH3) 1.35, 1.41(total 3H, each d, J=7Hz, 4-CH3) 1.75, 1.97(total 3H, each s, l-C~3) 5.15(2H, s, -CH2 ~ ) 7.42, 8.07(each 2H, d, J=8.5Hz, aromatic H) Preparation of 2-(2,6-dichlorobenzyloxyimino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using 50 mg of KA-7367A and 50 mg of o-(2,6-dichloro-ben~yl)-hydroxylamine hydrochloricle to afford 55 mg of a final product.
~-NMR: (CDC13, TMS ) ~
0.92t3H, t, J=7Hz, 6'-CEI3) 1.35, 1.41(total 3H, eac:h d, J=7Hz, 4-CH3) 1.70, 1.96(total 3H, each s, l-CH3) ; 25 5.13(2H, s, -O-CH2 ~ ) ; 7.2-7.4(3H, m, aromatic H) Preparation of 2-(alpha-2,4-dichlorophenylcar-boxymethoxyimino)-2-deoxo-KA-7367A:
- 30 The procedure in EXAMPLE 1 was followed except using 40 mg of KA-7367A and 55 mg of aminoxy-(2,4-di-chlorophenyl)-acetic acid hydrochloride to obtain 79 mg - :. . , ~ -, ' ' :
-"~ 2-~f~ hfJ '.,' "^"
of a final product.
H-NMR: ~CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.74, 1.76S 1.95, 1.96~total 3H, each s, l-CH3) 4 73, 4.75, 5.25, 5.32(total lH, each 1I J=7Hæ, 3-CH) 7.21(lH, m, aromatic H) 7.41(2H, m, aromatic H) Preparation of 2-(4-benzoyl-1-piperazinoethoxy-imino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 1 was followed except using lU0 mg of KA-7367A and 100 mg of o-(4-benzoyl-1-piperzinoethyl)-hydroxylamine to provide 51 mg of a final product EI-NMR: (CDC13, TMS) ~
0 91(3H, t, J=7Hz, 6'-CH3) 1.35t3H, d, J=7Hz, 4-CH3) 1.99(3H, s, l-CH3) 2.22(2H, q, 3'-CH2-) 2.61(4H, t, piperazine ring 2,6-CI12) 4.19(4H, t, piperazine ring 3,5-CH2) 4.77(1H, q, J=7Hz, 3-CH-) 6.9-7.1(2H, m. aromatic H) EXAMPLES 13 to 23 ~ The procedure in EXAMP~E 2 was repeated except ; using a suitable o-substituted hydroxylamine instead of methoxyamine to obtain a compound of formula:
N-O-Y-Z
~\~\
CH3 N ¦ C 3 .
- ~ ' -- - -' ;`~
t,) Example Y Z
. ..
13 -CH2 -C~2 ~ H
CH3 E~
-CH2--C~-16 -CH2- ~) 17 single bond ,.
18 .. ~3Cl 19 .. ~
.. -~-Cl 21 --C~2-CH2-- --N
2 3 --CH2--CH2-- ..
:~
.
Preparation of 2-acetoxyimino-2-deoxo-KA-7367A:
2-Hydroxyimino 2-deoxo-KA-7367A (40 mg) obtain-ed in EXAMPI~E 1 and 100 mg of pyridine were dissolved in 6 ml of methylene chloride, and 100 mg of acetic anhydr-ide was added dropwise, followed by stirring the mixture at room temperature for 1 hour. To the reaction solution was added 30 ml of methylene chloride, and the mixture was washed wiih water, dried and concentrated under reduced pressure. When the concentrate was purified by silica gel column chromatography [eluent: benzene-acetic acid (20:1)], there resulted 26 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.41(3H r d, J=7Hz, 4-CH3) 2.05(3Hr s, l-CH3) 2.18(3H, s, CO-CH3) 4.91(lH, q, J=7Hz, 3-CH3) Preparation of 2-benzoyloxyimino-2~deoxo-KA-7367A:
The procedure in EXAMPLE 24 was repeated except using 120 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 100 mg oE benzoyl chloride to provide 110 mg of a final product H-~MR: tCDC13, TMS) ~
0~91~3H, t, J=7Hz, 6'-CH3) 1.47(3H, d, J=7Hz, 4-CH3) 2.20(lH, q, J=7Hz, 3-CH) ~
7.45t2H, m, aromatic H) -7.58(1H, m, aromatic H) 8.05t2H, m, aromatic H) Preparation of 2-to-chlorobenzoyloxyimino)-2-deoxo-KA-7367A-~ .
, . -,~
' , `? 2 ~
The procedure in EXAMPLE 24 was repeated except using 60 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 60 mg of o-chlorobenzoyl chloride to afford 65 mg of a final product.
' 5 H-NMR: (CDC13, TMS) 0.92(3H, t, J=7Hz, 6'-CH
1.48(3H, d, J=7Hz, 4-CH3) 2.18(3H, s, CO-CH3) 5.03(lH, q, J=7Hz, 3-CH) 7.30-7.50(total 3H, m, aromatic H) 7.83(1H, M, aromatic H) Preparation of 2-(p-chlorobenzoyloxyimino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 24 was repeated except using 60 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 60 mg of p-chlorobenzoyl chloride to afford 65 mg of a final product.
lH-NMR: (CDC13, TMS)~
O.9Z(3H, t, J=7Hz, 6'-CH3) 1.48(3H, d, J=7Hz, 4-CH3) 2.18~3H, s, C0-CH3) 5.03(1H, q, J=7Hz, 3-CH) 7.42(2H, m, aromatic H) 7.98(2H, m, aromatic H) ; EXAMPLE 28 Preparation of 2-~2,6-dichlorobenzoylimino)-2-deoxo-KA-7367A:
The procedure in EXAMPEE 24 was repeated except using 60 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 70 mg of 2~6-dichlorobenzoyl chloride to provide 70 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hz, 4-CH3) 2.16~3H, s, CO-CH3) 5.05(lH, q, J-7Hz, 3-CH) 7.32-7.40(total 3H, m, aromatic H) EXAMPLES 29 to 33 The procedure in EXAMPLE 25 was repeated except using the other acid halide than benzoyl chloride to obtain a compound of formula:
N-O-CO-Y-Z
/\/\~ \
CH3 N ¦ CH3 Example Z
I
32 single bond Cl 33 ll ~ C1 :
Cl ~, ,.
' ' ; , :' ~ . , , - . ' ' 2 ~
Preparation of 2-semicarbazono-2-deoxo-KA-7367A:
KA-7367A (40 mg) and 23 mg of semicarbazide hydrochloride were dissolved in 5 ml of methanol, and 0.1 ml of pyridine was added, followed by stirring the mix-ture at room temperature for 1 hour. The reaction solu-tion was concentrated under reduced pressure, and the residue was extrac~ed with ethyl acetate. The extract was washed with water and con centrated under reduced pressure. When the residue was purified by silica gel column chrGmatography [eluent: chloroform-methanol S30:1)], 20 m~ of a final product was obtained.
lH-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.35(3H, d, J=7Hz, 4-CH3) 1.90(3H, s, l-CH3) 4.80(1H, q, J=7Hz, 3-CH) Preparation of 2-thiosemicarbaæono-2-deoxo-K~-7367A:
KA-7367A ~40 mg) and 35 mg of thiosemicarbazide were dissolved in 5 ml of methanol, and stirred at room temperature for 16 hours. the reaction mixture was treated as in EXAMPLE 34 to obtain 20 mg of a final product.
H-NMR: ~CDC13, TMS~ S
0.92(3H, t, J=7Hz, 6'-CH3) 1.38t3H, d, J=7Hz, 4-CH3) 1.97(3H, s, l-CH3) 4077(1H, q, J=7Hz, 3-CH) EXAMPLES 36 to 40 The procedure in EXAMPLE 34 or 35 was repeated except using 4-N-substituted semicarbazide or thiosemi-carbazide to obtain a compound of formula:
:
.
:
-~Rl ~
N-A-N
~, / " ~ / ~ 2 CH3 N ¦ CH3 (I) Example A Rl R2 37 -NHCO- .. -H
38 .l n H3 39 .. ~ -H
-NHCS- .. -H
Preparation of 2-hydrazono-2-deoxo-KA-7367A:
KA-7367A (25 mg) was dissolved in 2.5 ml of methanol, and 1 ml of a 0.2 mol hydrazine-methanol solu-tion was added under ice cooling. The mixture was left to stand at room temperature for 2 hours. The reaction solution was concentrated to dryness and purified by preparative thin layer chromatography (carrier: silica gel, solvent: ethyl acetate) to obtain 5 mg of a final product.
uv: A Cm30H , 231nm H-NMR: (CDC13, TMS) 0.92(3H, t, J=7Hz, 6'-CH3 1.36(3H, d, J=7Hz, 4-CH3) 1.83t3H, s, l-CH3) 2.39(2H, t, J=7Hz, 3'-CH) 6.96-6.98(2H, m, -CH=CH-) .
,, :
Preparation of 2-(4-methyl-1-piperazinoimino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367 and 23 mg of N-amino-N'-methyl-piperazine hydrochloride to obtain 8 mg of a final pro-duct.
H-NMR: tCDC13, TMS)g 0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 2.01(3H, s, l-CH3) 2.29~3H, s, N-CH3) 2.56(4H, t, J=5Hz, -NCH2x2) 2.76, 2.98(each 2H, t, J=5Hz, -NCH2x2) 4.65(1H, q, J=7Hz, 3-CH) 6.96(2H, m, -CH=CH-) Preparation of 2-acetylhydrazono-2-deoxo KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 10 mg of KA-7367 and 3.4 mg of acetylhydrazine to provide 10 mg of a final product~
H-NMR: tCDC13, TMS)S
0.92(3H, t, J=7Hz, 6'-CH3) 1.38t3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 2.25(3H, s, N-COCH3) 4.80(1H, q, J=7Hz, 3-CH) 6.96(2H, m, -CH=CH-) Preparation of 2-chloroacetylhydrazono-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 20 mg of chloroacetylhydraz-. ' : ,' "
.
ine to a~ford 13 mg of a final product.
1H-NMR: ( CDCl 3, TMS ) ~
0.93(3H, t, J=7Hz, 6'-CH3) 1.38(3H, d, J=7Hz, 4-CH3) 1.92(3H~ s, l-CH3) 4.47(2H, s, rl-cH2) 4.77(1H, q, J=7Hz, 3-CH) 6.97(2H, m, -CH=CH-) EX~MPLE 45 Preparation of 2-trimethylamînoacetylhydraz-ono-2-deo~o-KA-7367A chloride:
Tbe procedure in EXAMPLE 41 was repeated except using 100 mg of KA-7367A and 60 mg of trimethylamino-acetylhydrazine chloride to afford 115 mg of a final product~
1H-NMR: (CDCl3, TMS) ~
0.92( 3H, t, Ja7Hz, 6'- CH3) 1.38~3H, a, J=7Hz, 4-CH3) 1.19(3H, 5~ 1-CH3) 3.50(9H, s, NCH3) 4.90(2H, s, CO-CH2-N) 6.93(2H, m, _CH=CH_) EXAMPLE ~6 Preparation of 2-benzoylhydrazono-2-deoxo-RA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 27 m~ of benzoylhydrazine to provide 56 mg of a final product.
lH-NMR ~CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 2.02(3H, s, l-CH3) 6.97(2Hr m, -CH=CH-) 7.45(3H, m, aromatic H) 7.83(3H, m, aromatic H) ' '' f ~
Preparation of 2-(1-imidazolylacetylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 21 mg of l-imidazolylacetyl-hydrazine to provide 13 mg of a final prodllct.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.40(3H, d, J=7Hz, 4-CH3) 1.89t3H, s, l-CH3) 5.40(2H, s, CO-CH2-N) 6.9-7.1(4H, m~ -CH=CH- and imidazole ring H-4 5) 7.53(1H, s, imidazole ring H-2) Preparation of 2-(3-pyridylacetylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 35 mg of 3-pyridylacetylhy-drazine to provide 62 mg of a fina]L product.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J-7Hz, 4-CH3) 1.88(3H, s, l-CH3) 3.96(2H, s, CO-CH3) 7.26(1H, dd, J=8HzF pyrizine ring H-5) 7.69(1H, td, J=8Hz, 2Hz, pyrizine ring H-4) 8.50(1H, dd, J=5Hz, 2Hz, pyrizine ring H-6) 8.57(1H, d, J=2Hz, pyrizine ring H-2) EXA~LE 49 Preparation of 2-(2,4-dichlorophenylacetyl-hydrazono)-2-deoxo-KA~7367A:
The procedure in EXAMPLE 41 was repeated except using 20 mg of KA-7367A and 22 mg of 2,4-dichlorophenyl-- ~ : , :::
i 2 ~ ~
acetylhydrazine to obtain 36 mg of a final product.
1H - NMR (CDC13~ TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.38(3H, d, J=7Hz, 4-CH3) 1.87(3H, s, l-CH3) 4.05(2H, s, CO-CH2) 7.1-7.3(2H, m, aromatic H) 7.38(1HI m, aromatic H) Preparation of 2-t3,4-dichlorophenylacetylhy-drazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 32 mg of 3,4-dichlorophenyl acetylhydra2ine to provide 59 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 3.87, 3.91(total 2H, q, CO-CH2) 7.16(1H, dd, J=8EIz, 5Hz, 2Hz, aromatic H) 7.36(lH, td, J=8Hz, 5Hz, aromatic H) 7.44~1H, dd, J=2Hz, aromatic H) Preparation of 2-(2,6~dichlorophenylacetyl-hydrazono)-2-deoxo-RA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 33 mg of 2,6-dichlorophenyl-acetylhydrazine to provide 59 mg of a final product.
lH-NMR (CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.40{3H, d, J=7Hz, 4~CH
1.86(3H, s, l-CH3) 4.32(2H/ s, CO-CH2) 7.15(1H, dd, J=9Hz, 7Hz, aromatic H) 7.3~(2H, m, aromatic H) Preparation of 2-(alpha-naphthylacetylhydraz-ono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 28 mg of alpha-naphthyl-acetylhydrazine to provide 43 mg of a final product.
H-NMR: (CDC13, TMS)~
0.89(3H, t, J=7Hz, 6'-CH3) 1.38(3H, d, J=7Hz, 4-CH3) 1.78(3H, s, l-CH3) 7.45~4H, m, aromatic H) 7.8(2H, m, aromatic H) 8.08(1H, m, aromatic H) Preparation of 2-(4-acetylpiperazinyl-acetyl-hydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 58 mg of 4-acetylpiperazinyl-acetylhydrazine to obtain 58 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.93(3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hz, 4-CH3) 1.96(3H, s, l-CH3) 2.11(3~, s, CO-CH3) 3.23(2H, s, N-CH2-CO) 2.62(4H, m, aromatic H) 3.53(2H, m, aromatic H) 3.67(2H, m, aromatic H) Preparation of ~-t4-(2,6-dichlorophenylacetyl)-l-piperazinylacetylhydrazino]-2-deoxo-KA-7367A:
The procedure in EXAMPL~ 41 was repeated except using 40 mg of KA-7367A and 68 mg of 4-(2,6-diphenyl-acetyl)-l-piperazinylacetylhydrazine to obtain 80 mg of a : ~.
, ' .~ ~ ' .
final product.
H-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hzl 4-CH3) 1.96(3H, s, l-CH3) 2.64~4H, mr aromatic H) 3.58(2H, m, aromatic H) 3.72(2H, m, aromatic H) 3.78(2H, s, ~O-CH2-N) 7.25(2H, m, aromatic H) 7.42(1H, mF aromatic H3 Preparation of 2-(2,4-dichlorophenoxyacetyl-hydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 33 mg oE 2,4-dichlorophenoxy-acetylhydrazine to provide 35 mg of a final product.
H~NMR: (CDC13 r TMS ) S
0.92(3H, t, J=7Hz, 6'-CH3) 1.43(3H, d, J=7Hz, 4-CH3) 2.04(3M, s, l-CH3) 4.65(2H, s, CO-CH2-N) 6.86(lH, d, J=9Hz, aromatic H) 7 . 2 6 S lH ~ ad r J=3Hz, aromatic H ) 7.43(1~, d, J=3Hz, aromatic H) Preparation of 2-t(N-methyl-N-alpha-naphthyl-methylamino)-acetylhydrazino~-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except 30 using 60 mg of KA-7367A and 79 mg of (N-methyl-N-alpha-naphthylmethylamino)-acetylhydrazine to afford 73 mg of a r?
final product.
H-NMR: ( CDCl 3, TMS ) ~
0.92~3H, t, J=7Hz, 6'-CH3) 1.28(3H, d, J-7~z, 4-CH3) ` 5 1.53(3H, s, l-CH3) 2.48(3H, s, N-CH3) 3.2Ç(2H, s, N-CH2-naphthyl) 4.03(2H, s, CO-CH2-N) 7.4-7.6(4H, m, aromatic H) 7.85(2H, m, aromatic H) 8.2(1H, m, aromatic H) Preparation of 2-lp-(N-methyl-N-alpha-naphthyl-methylaminomethyl)benzoylhydrazono]-2-deoxo-KA-7367A: -The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 70 mg of p-~N-methyl-N-alpha-naphthylmethylaminomethyl)benzoylhydrazine to obtain 14 mg of a final product.
lH-NMR: (CDC13, TMS ) ~
0.91~3H, t, J=7Hz~ 6'-CH3) 1.98(3H, s, l-CH3) 2.20(3H, s, N-CH) 3.61(2H, s, -N-CH2 ~ ) 3.95(2H, s, N-CH2 ~ ) ~ .
7.35-7.55(6H, m, aromatic H) 7.75-7.9(4H; aromatic H) 8.3(1H, m, aromatic H) Preparation of 2-(2,6-dichlorobenzoylhydraz-ono)-2-deoxo~KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 31 mg of 2,6-dichlorobenzoyl-, .
.
.. ~ . , :.
.~ .. .
, . ~ : . .
hydrazine to obtain 40 mg of a final product.
H-NMR: (CDC13, TMS~ ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.14(3H, d, J=7Hz, 4-CH3) 1.99(3H, s, 1-CH3) 7.25-7.35(3H, m, aromatic H) Preparation of 2-~(2,6-dichlorophenyl)pro-pionylhydrazono]-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 35 mg of (2,6-dichloro-phenyl)propionylhydraæine to afford 36 mg of a final product.
lH-NMR: (CDC13, TMS) S
0.92(3H, t, J=7Hz, 6'-CH3) 1.34(3H, d, J=7Hz, 4-CH3) 1.89(3H, s, l-CH3) 2.88(2H, m, CO-CH2-CH2) 3.28(2H, m, CO-CH2-CH2) 7.09~1H, dd, J=9Hz, arom~tic H) 7.3~2H, m, aromatic H) Preparation of 2-~(2,6-d:ichlorophenyl)butyryl-hydrazono]-2-deoxo-K~-7367A:
The procedure in EXAMPLE 41 was repeated except using 20 mg of RA-7367A and 25 mg of (2,6-dichloro-phenyl)butyrylhydrazine to afford 19 mg of a final pro-duct.
lH-NMR: tCDC13, TMS) ~
0.92(3H, tr J=7Hz, 6'-CH3) 1.36~3H, d, J=7Hz, 4-CH3) 1.89~3H~ s, l-CH3) 1.97(2H, ~, J=8Hz, CO-CH2-CH2-CH2-) 2.76(2H, t, J=8Hz, CO-CH2-CH2-CH2-) 3.00(2H, m, CO-CH2-CH2-CH2-) ~ ~ ~.J ~ 'J ~J ~'`
7.07(1H, dd, J=9Hz, 7Hz r aromatic H) 7.3(2H, m, aromatic H) Preparation of 2-[(2,6-difluorophenyl)acetyl-hydrazono]-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 65 mg of XA-7367A and 61 mg of (2,6-difluoro-phenyl)acetylhydrazine to obtain 73 mg of a final pro-duct.
lH-NMR: (CDC13, TMS)~
O.91t3H, t, J=7Hz, 6'-CH3) 1.37(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 4.42(2H, s, CO-CH2 ~ ) 6.9-7.3(5H, m, -CH=CH-, aromatic H) Preparation of 2-[(2,6-dimethoxyphenyl)acetyl-hydrazono]-2-deoxo-KA-7367A: -The procedure in EXAMPLE 41 was repeated except using 14 mg of KA-7367A and 15 mg of (2,6-dimethoxy-phenyl)acetylhydrazine to obtain 8 m of a final product.
H-NMR: tCDC13, TMS)S
0.91(3H, t, J=7Hz, 6'-CH3) 1.33, 1.38~total 3H, t, J=7Hz r 4 - CH3 ) 1.72, 1.86(total 3H, s, l-CH3) 3.77, 3.85ttotal 6H, s~ OCH3) 6.5-6.6(2H, m, aromatic H) 7.2(lH, m, aromatic H) Preparation of 2-(2,6-dinitrophenylhydrazono)-2-deoxo-KA~7367A:
The procedure in EXAMPLE 41 was repeatea except using 50 mg of KA-7367A and 50 mg of 2,6-dinitrophenyl-.
2 ~
hydrazine to obtain 71 mg of a final product.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.47(3H, d, J=7Hz, 4-CH3) 2.12(3H, s, l-CH3) 7.90(lH, m, aromatic H) 8.28(1H, m, aromatic H) 9.09(1H, m, aromatic H) Preparation of 2-methoxycarbonylhydrazono-2-de-oxo-KA-7367A:
The proce~ure in EXAMPLE 41 was repeated except using ~0 mg of KA-7367A and 9.1 mg of methyl carbazinate to afford 13 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.37(3H, d, J=7Hz, 4-CH3) 1.89(3H, s, l-CH3) 3.82~3H, s, OCH3) 4.89(lH, 1, J=7Hz, 3-CH3) Preparation of 2-sulfophenylhydrazono-2-deoxo-KA-7367A monosodium salt:
The procedure in EXAMPLE 41 was repeated except 25 using 100 mg of KA-7367A and 106 mg of monosodium p-hy-drazonobenzenesulfonate to afford 196 mg o~ a final product.
}H-NMR: ~CDC13, TMS)~
0.92(3H, t~ J=7Hz J 6'-CH3) 1.32(3H, d, J=7Hz, 4-CH3) 1.64(3H, s, l-CH3) 7.73(2H, m, aromatic H) 7.95~2H, m, aromatic H) Preparation of 2-phenylacetylhydrazono-2-de-oxo-KA-7367A:
` ' , ;' '" ': ~
The procedure in EXAMPLE 41 was repeated except using 50 mg of KA-7367A and 38 mg of phenylacetylhydraz-ine to afford 55 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1~40(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, 1-CH3) 3.96(2H, s, -CO-CH2 ~ ) 6.9 7.2(5H, m, aromatic H) EXAMæLE 67 Preparation of 2-(2-furylcarbonylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 30 mg of 2-furylcarbonylhy-drazine to obtain 37 mg of a final productO
H-NMR: (CDC13, TMS)S
0.92(3H, t, J=7Hz, 6'-CH3) 1.46(3H, d, J=7Hz, 4-CH3) 1.98(3H, s, l-CH3) 7.0-7.2(3H, m, aromatic H) Preparation of 2-thenoylhydrazono-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except 25 using 40 mg of KA-7367A and 35 mg of thenoylhydrazine to obtain 30 mg of a final product.
1~ - NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 5'-CH3) 1.48(3H, d, J=7Hz, 4-CH3) 30 2.00(3H, s, l-CH3) 7.02-7012(3H, m, aromatic H) Preparation of 2-thiocarbonohydrazono-2-deoxo-KA-7367A:
.
. , , ~ ::
~ ~ s~
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 40 mg of thiocarbonohydrazide to obtain 38 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.93(3H, t, J=7Hz, 6'-CH3) 1.37(3H, d, J=7Hz, 4-CH3) 1.95(3H, s, l-CH3) 2.23(2H, 1, J=7Hz, 3'-CH3) 4~75tlH, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -CH=CH~) Preparation of 2-isonicotinoylhydrazono-2-de-oxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 100 mg of KA-7367A and 112 mg of isonicotinoylhy-drazine to obtain 119 mg of a final product.
H-NMR: ~CDC13, TMS)~
0.93(3H, t, J=7Hzl 6'-CH3) 1.54(3H, d, J=7Hz, 4-CH
2.24(3H, s, l-CH3) 5.22(1H, q, J=7Hz, 3-CH) 6.9-7.1t2H, m, -CH=CH-) 7.67(2H, m, aromatic H) 8.74(2H, m, aromatic ~) Preparation of 2-nicotinoylhydrazono-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 200 mg of KA-7367A and 200 mg of nicotinoylhydraz-ine to afford 206 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.93(3Hr t, J=7Hz, 6'-CH3) 1~53(3H, a, J=7Hz, 4-CH3) 2.24(3H, s, l-CH3) 5.22(1H, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -C~=CH-~
,, , , . :
., , . , , , :.
, ~
J iJ ~
7.45(1H, dd, J=5Hz, 7Hz, aromatic H) 8.18(1H, dt, J=2Hz, 2Hz, 8Hzt aromatic H) 8.67(1H, dd, J=2Hz, 5Hz, aromatic H) 9.06(lH, br.s, aromatic H) EXAMPI.E 72 Preparation of 2-(o-chlorophenylacetylhydraz-ono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 50 mg of KA-7367~ and 48 mg of o-chlorophenyl-acetylhydrazine to afford 64 mg of a final product.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 1.83(3H, s, l-CH3) lS 2.23(2H, q, 3'-CH2) 4.11(2H, s, CO-CH2 ~ ) 4.83(1H, q, J=7Hz, 3-CH) Preparation of 2-(m-chlorophenylacetylhydraz-ono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated excep-t using 25 mg of KA-7367A and 24 mg of m-chlorophenyl-acetylhydrazine to afford 27 mg of a final product.
lH-NMR: (CDC13, TMS) ~
2S 0.92t3H, t, J=7Hz, 6'-CH3) 1.40t3H, d, ~=7Hz, 4-CH3) 1.38~3H, s, l-CH3) 2.23(2H, q, 3'-CH2) 3.93(2H, s, CO-CH2 ~ ) 4.82(1H, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -CH=CH-) EXAMPI,E 74 Preparation of 2-(p-chlorophenylacetylhydraz-ono)-2-deoxo-KA-7367A: .
~:
`J~
The procedure in EXAMPLE 41 was repeated except using 25 mg of KA-7367A and 24 mg of p-chlorophenyl-acetylhydrazine to afford 30 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 1.87(3H, s, l-CH3) 2.23(2H, q, 3'-CH2) 3.93(2H, s, CO-CH2 ~ ) 4.90(1H, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -CH=C~-) EX~MPLE 75 Preparation of 2-[alpha-(1-imidazolyl)-p-chlorophenylacetylhydrazono]-2-deoxo-KA-7367A:
The procedure in EX~MPLE 41 was repeated except using 150 mg of KA-7367A and 178 mg of alpha-(l-imidazol-yl)-p-chlorophenylacetylhydrazine to obtain 180 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.93(3H, t, J=7Hz, 6'-CH3) 1.28, 1.29(total 3H, d, J=7Hz, 4-CH3) 1.90, l.91(total 3H, s, l-CH3) 2.21, 2.23(total 2H, 3' CH2) 4.68, 4.71(total lH, qr 3-CH) 6.80tlH, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-talpha-(2-oxo-1-pyridyl)-p-chlorophenylacetylhydrazono]-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 85 mg of KA-7367A and 96 mg of alpha-(2-oxo-1-pyridyl)-p-chlorophenylacetylhydrazine to obtain 45 mg of :
., ~ :
a final product.
1~-NMR (cDcl3t TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.18, 1.14(total 3H, d, J=7Hz, 4-CH3) 1.82, 1.85(total 3H, s, 1-CH3) 2~21(2H, q, 3'-CH2) 4.64, 4.66(total lH, q, J=7Hz, 3-CH~
6.8-7.0(2H, m, -CH=CH-) Preparation of 2 ~p-chlorocinnamoylhydrazono)-2-deoxo-KA-7367A:
The procedure in EX~MPLE 41 was repeated except using 150 mg of KA-7367A and 983 mg of p-chlorocinnamoyl-hydrazine to obtain 80 ~g of a final product.
lH-NMR: (CDC13, TMS) ~
0.92t3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hz, 4-CH3) 2.01(3H, s~ l-CH3) 2.22(2H, q, 3~-CH2) 4.00(1H, q, J=7Hz, 3-CH) 6.0-7.1(2H, m, -CH=CH-) Preparation of 2-12,4'-dichlorodiphenylacetyl-hydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 85 mg of KA-7367A and 104 mg of 2,4'-dichlorodi-phenylacetylhydrazine to obtain 58 mg of a final product.
H-NMR: ~CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.24(3H, d, J=7Hz, 4-CH3) 1.77(3H, s, 1-CH3) 2.22(2H, q, 3'-CH2) 4.78(1H, q, J=7Hz, 3-CH) 6.31(1H, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) ,~
.
: .
f~ J S''' '.J
Preparation of 2-(2,4-dichlorodiphenylacetyl-hydrazono)-2-dioxo-KA-7367A:
The procedure in EXA~LE 41 was repeated except using 120 mg of KA-7367A and 151 mg of 2,4-dichloro-phenylacetylhydrazine to afford 161 mg of a final pro-duct H-NMR: (CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-OEI3) 1.23, 1.27t3H, d, J=7Hz, 4-CH3) 1.77(3H, s, l-CH3) 2.22t2H, q, 3'-CH2) 4.70, 4.73(1H, q, J=7Hz, 3-CH) 5.31(1H, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-diphenylacetylhydrazono-2-de-oxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 60 mg of diphenylacetylhy-drazine to afford 70 mg of a final product.
H-NMR: (CDC13, TMS) 0.92(3H, t, J=7Hz, 6'-CH
1.31~3H, d, J=7Hz, 4-CH3) 1.82(3H, s, l-CH
2.23(2H, q, 3'-CH2) 4.77(lH, q, J=7Hz, 3-CH) 6.00(1H, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-tbis(2,4-dichlorophenyl)-acetylhydrazono]-2-deoxo-KA~7367A:
The procedure in EXAMPI.E 41 was repeated except using 20 mg of KA-7367A and 40 mg of bis(2,4-dichloro-phenyl)-acetylhydrazine to afford 19 mg of a final pro-' , 2 fi 2 ?. ~
duct.
1H_NMR ( CDCl 3, TMS) ~
0.92(3H, t, J=7HZ, 6~-CH3) 1.23(3H, a, J=7HZ, 4-CH3) 1.78t3H, S, 1-CH3) 2.23(2H, q, 3'-CH2) 4.66(1H, q, J=7Hz, 3-CH) 6.49(1H, s, aromatic H) 6.8-7~0( 2H, m, -CH=CH-) Preparation of 2-(2,4,4'-trichlorodiphenyl-acetylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 43 mg of 2,4,4'-trichlorodi-phenylacetylhydrazine to afford 23 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.25, 1.29(total 3H, d, ~=7Hz, 4-CH3) 1.82(3H, s, 1 CH3) 2.21, 2.23(~H, q, 3'-CH2) 4.72, 4.73(1H, q, J=7Hz, 3-CH) 6.23(1H, s, aromatic H) 6.9-7.1(2H, m, -CM=CH-) Prparation of 2-methoxycarbonylhydra~ono 2-de-oxo-KA-7367A:
The procedure in EXAM2LE 41 was repeated except using 100 mg of KA-7367A and 60 mg of methoxycarbonyl-ethylhydrazine to obtain 37 mg of a final product.
H-NMR: ~CDC13, TMS) S
0.92(3H, t, J=7Hz, 6'-CH3) 1.33(3H, d, J=7Hz, 4-CH3) 1.78(3H, s, l-CH3) 2.22(2H, q, 3'-CH2) 2.59(2H, t, J=6Hz, NCH2CH2CO) 3.45(2H, t, J=6Hz, NCH2CH2CO) 3.70(3H, s, OCH3) .::
r;
~ 44 ~
4.76(1H~ q, 3-CH) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-[2-(p-chlorophenyl)-2-methoxy-carhonylethylhydrazono]-2-aeoxo-KA-7367A:
The procedure in EXAMPLE 41 ~as repeated except using 100 mg of KA 7367A and 70 mg of 2-(p-chloro-phenyl)-2-methoxyethylhydrazine to obtain 75 mg of a final product.
lH-NMR: (CDCl~, TMS)S
0.92(3H, t, J=7Hz, 6'-CH3) 1.35(3H, d, J=7Hz, 4 CH3) 1.62(3H, s, l-CH3) 2.22(2H, q, 3'-CH2) 3.3-3~8(3~, m, -CH2-CH-) 3.66(3H, s, OCH3) 4.70(1H, q, 3-CH) 6.9-7.1(2H, m, -CH=CH-) 7.1-7.3(4H, m, aromatic E~) PREPARATION EXAME'LE 1 (Capsules for administration to humans) Compound in EXAMPI.E 4 500 g Microcrystal cellulose 90 Talc 30 The above components were uniformly mixed in a usual manner and the mixture was filled in 1000 No. O
capsules.
(Cream for administration to humans) 30 Compound in EXAMPLE 3 2.0 g White soft paraffin 25.0 Stearyl alcohol 25.0 Propylene glycol 12.0 Sodium lauryl sulfate 1.5 35 Ethyl p-hydroxybenzoate 0.5 Deionized water 34.0 ~ - ' 2 ~ r; f~
The above components were uniformly mixed in a usual manner and the mixture was formed into a cream.
(Emulsifiable concentrate for agricultural and horticultural use) Compound in EXAMPLE 43250 g Epoxidized vegetable oil 25 Mixture of alkylaryl sulfonate, polyglycol ether and aliphatic alcohol 100 Dimethylformamide 50 Xylene 575 The above components were uniformly mixed in a usuall manner and the mi~ture was formed into an emulsi-fiable concentrate. This is diluted with water into an 15 emulsion.
INDUSTRIAL AVAILABILITY
The compounds in this invention are excellent in antifungal activity to fungi t.hat infect warm-blooded animals including humans and agricultural and horticul-tural crops and in stability, and are useful as agentsfor prevention, treat ment or therapy of infectious diseases caused by these fungi or control of plant diseases caused by these fungi.
' ' ' "`-'" :'~ ' :. :::~
,
, . -,~
' , `? 2 ~
The procedure in EXAMPLE 24 was repeated except using 60 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 60 mg of o-chlorobenzoyl chloride to afford 65 mg of a final product.
' 5 H-NMR: (CDC13, TMS) 0.92(3H, t, J=7Hz, 6'-CH
1.48(3H, d, J=7Hz, 4-CH3) 2.18(3H, s, CO-CH3) 5.03(lH, q, J=7Hz, 3-CH) 7.30-7.50(total 3H, m, aromatic H) 7.83(1H, M, aromatic H) Preparation of 2-(p-chlorobenzoyloxyimino)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 24 was repeated except using 60 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 60 mg of p-chlorobenzoyl chloride to afford 65 mg of a final product.
lH-NMR: (CDC13, TMS)~
O.9Z(3H, t, J=7Hz, 6'-CH3) 1.48(3H, d, J=7Hz, 4-CH3) 2.18~3H, s, C0-CH3) 5.03(1H, q, J=7Hz, 3-CH) 7.42(2H, m, aromatic H) 7.98(2H, m, aromatic H) ; EXAMPLE 28 Preparation of 2-~2,6-dichlorobenzoylimino)-2-deoxo-KA-7367A:
The procedure in EXAMPEE 24 was repeated except using 60 mg of 2-hydroxyimino-2-deoxo-KA-7367A and 70 mg of 2~6-dichlorobenzoyl chloride to provide 70 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hz, 4-CH3) 2.16~3H, s, CO-CH3) 5.05(lH, q, J-7Hz, 3-CH) 7.32-7.40(total 3H, m, aromatic H) EXAMPLES 29 to 33 The procedure in EXAMPLE 25 was repeated except using the other acid halide than benzoyl chloride to obtain a compound of formula:
N-O-CO-Y-Z
/\/\~ \
CH3 N ¦ CH3 Example Z
I
32 single bond Cl 33 ll ~ C1 :
Cl ~, ,.
' ' ; , :' ~ . , , - . ' ' 2 ~
Preparation of 2-semicarbazono-2-deoxo-KA-7367A:
KA-7367A (40 mg) and 23 mg of semicarbazide hydrochloride were dissolved in 5 ml of methanol, and 0.1 ml of pyridine was added, followed by stirring the mix-ture at room temperature for 1 hour. The reaction solu-tion was concentrated under reduced pressure, and the residue was extrac~ed with ethyl acetate. The extract was washed with water and con centrated under reduced pressure. When the residue was purified by silica gel column chrGmatography [eluent: chloroform-methanol S30:1)], 20 m~ of a final product was obtained.
lH-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.35(3H, d, J=7Hz, 4-CH3) 1.90(3H, s, l-CH3) 4.80(1H, q, J=7Hz, 3-CH) Preparation of 2-thiosemicarbaæono-2-deoxo-K~-7367A:
KA-7367A ~40 mg) and 35 mg of thiosemicarbazide were dissolved in 5 ml of methanol, and stirred at room temperature for 16 hours. the reaction mixture was treated as in EXAMPLE 34 to obtain 20 mg of a final product.
H-NMR: ~CDC13, TMS~ S
0.92(3H, t, J=7Hz, 6'-CH3) 1.38t3H, d, J=7Hz, 4-CH3) 1.97(3H, s, l-CH3) 4077(1H, q, J=7Hz, 3-CH) EXAMPLES 36 to 40 The procedure in EXAMPLE 34 or 35 was repeated except using 4-N-substituted semicarbazide or thiosemi-carbazide to obtain a compound of formula:
:
.
:
-~Rl ~
N-A-N
~, / " ~ / ~ 2 CH3 N ¦ CH3 (I) Example A Rl R2 37 -NHCO- .. -H
38 .l n H3 39 .. ~ -H
-NHCS- .. -H
Preparation of 2-hydrazono-2-deoxo-KA-7367A:
KA-7367A (25 mg) was dissolved in 2.5 ml of methanol, and 1 ml of a 0.2 mol hydrazine-methanol solu-tion was added under ice cooling. The mixture was left to stand at room temperature for 2 hours. The reaction solution was concentrated to dryness and purified by preparative thin layer chromatography (carrier: silica gel, solvent: ethyl acetate) to obtain 5 mg of a final product.
uv: A Cm30H , 231nm H-NMR: (CDC13, TMS) 0.92(3H, t, J=7Hz, 6'-CH3 1.36(3H, d, J=7Hz, 4-CH3) 1.83t3H, s, l-CH3) 2.39(2H, t, J=7Hz, 3'-CH) 6.96-6.98(2H, m, -CH=CH-) .
,, :
Preparation of 2-(4-methyl-1-piperazinoimino-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367 and 23 mg of N-amino-N'-methyl-piperazine hydrochloride to obtain 8 mg of a final pro-duct.
H-NMR: tCDC13, TMS)g 0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 2.01(3H, s, l-CH3) 2.29~3H, s, N-CH3) 2.56(4H, t, J=5Hz, -NCH2x2) 2.76, 2.98(each 2H, t, J=5Hz, -NCH2x2) 4.65(1H, q, J=7Hz, 3-CH) 6.96(2H, m, -CH=CH-) Preparation of 2-acetylhydrazono-2-deoxo KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 10 mg of KA-7367 and 3.4 mg of acetylhydrazine to provide 10 mg of a final product~
H-NMR: tCDC13, TMS)S
0.92(3H, t, J=7Hz, 6'-CH3) 1.38t3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 2.25(3H, s, N-COCH3) 4.80(1H, q, J=7Hz, 3-CH) 6.96(2H, m, -CH=CH-) Preparation of 2-chloroacetylhydrazono-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 20 mg of chloroacetylhydraz-. ' : ,' "
.
ine to a~ford 13 mg of a final product.
1H-NMR: ( CDCl 3, TMS ) ~
0.93(3H, t, J=7Hz, 6'-CH3) 1.38(3H, d, J=7Hz, 4-CH3) 1.92(3H~ s, l-CH3) 4.47(2H, s, rl-cH2) 4.77(1H, q, J=7Hz, 3-CH) 6.97(2H, m, -CH=CH-) EX~MPLE 45 Preparation of 2-trimethylamînoacetylhydraz-ono-2-deo~o-KA-7367A chloride:
Tbe procedure in EXAMPLE 41 was repeated except using 100 mg of KA-7367A and 60 mg of trimethylamino-acetylhydrazine chloride to afford 115 mg of a final product~
1H-NMR: (CDCl3, TMS) ~
0.92( 3H, t, Ja7Hz, 6'- CH3) 1.38~3H, a, J=7Hz, 4-CH3) 1.19(3H, 5~ 1-CH3) 3.50(9H, s, NCH3) 4.90(2H, s, CO-CH2-N) 6.93(2H, m, _CH=CH_) EXAMPLE ~6 Preparation of 2-benzoylhydrazono-2-deoxo-RA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 27 m~ of benzoylhydrazine to provide 56 mg of a final product.
lH-NMR ~CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 2.02(3H, s, l-CH3) 6.97(2Hr m, -CH=CH-) 7.45(3H, m, aromatic H) 7.83(3H, m, aromatic H) ' '' f ~
Preparation of 2-(1-imidazolylacetylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 21 mg of l-imidazolylacetyl-hydrazine to provide 13 mg of a final prodllct.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.40(3H, d, J=7Hz, 4-CH3) 1.89t3H, s, l-CH3) 5.40(2H, s, CO-CH2-N) 6.9-7.1(4H, m~ -CH=CH- and imidazole ring H-4 5) 7.53(1H, s, imidazole ring H-2) Preparation of 2-(3-pyridylacetylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 35 mg of 3-pyridylacetylhy-drazine to provide 62 mg of a fina]L product.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J-7Hz, 4-CH3) 1.88(3H, s, l-CH3) 3.96(2H, s, CO-CH3) 7.26(1H, dd, J=8HzF pyrizine ring H-5) 7.69(1H, td, J=8Hz, 2Hz, pyrizine ring H-4) 8.50(1H, dd, J=5Hz, 2Hz, pyrizine ring H-6) 8.57(1H, d, J=2Hz, pyrizine ring H-2) EXA~LE 49 Preparation of 2-(2,4-dichlorophenylacetyl-hydrazono)-2-deoxo-KA~7367A:
The procedure in EXAMPLE 41 was repeated except using 20 mg of KA-7367A and 22 mg of 2,4-dichlorophenyl-- ~ : , :::
i 2 ~ ~
acetylhydrazine to obtain 36 mg of a final product.
1H - NMR (CDC13~ TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.38(3H, d, J=7Hz, 4-CH3) 1.87(3H, s, l-CH3) 4.05(2H, s, CO-CH2) 7.1-7.3(2H, m, aromatic H) 7.38(1HI m, aromatic H) Preparation of 2-t3,4-dichlorophenylacetylhy-drazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 32 mg of 3,4-dichlorophenyl acetylhydra2ine to provide 59 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 3.87, 3.91(total 2H, q, CO-CH2) 7.16(1H, dd, J=8EIz, 5Hz, 2Hz, aromatic H) 7.36(lH, td, J=8Hz, 5Hz, aromatic H) 7.44~1H, dd, J=2Hz, aromatic H) Preparation of 2-(2,6~dichlorophenylacetyl-hydrazono)-2-deoxo-RA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 33 mg of 2,6-dichlorophenyl-acetylhydrazine to provide 59 mg of a final product.
lH-NMR (CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-CH3) 1.40{3H, d, J=7Hz, 4~CH
1.86(3H, s, l-CH3) 4.32(2H/ s, CO-CH2) 7.15(1H, dd, J=9Hz, 7Hz, aromatic H) 7.3~(2H, m, aromatic H) Preparation of 2-(alpha-naphthylacetylhydraz-ono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 28 mg of alpha-naphthyl-acetylhydrazine to provide 43 mg of a final product.
H-NMR: (CDC13, TMS)~
0.89(3H, t, J=7Hz, 6'-CH3) 1.38(3H, d, J=7Hz, 4-CH3) 1.78(3H, s, l-CH3) 7.45~4H, m, aromatic H) 7.8(2H, m, aromatic H) 8.08(1H, m, aromatic H) Preparation of 2-(4-acetylpiperazinyl-acetyl-hydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 58 mg of 4-acetylpiperazinyl-acetylhydrazine to obtain 58 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.93(3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hz, 4-CH3) 1.96(3H, s, l-CH3) 2.11(3~, s, CO-CH3) 3.23(2H, s, N-CH2-CO) 2.62(4H, m, aromatic H) 3.53(2H, m, aromatic H) 3.67(2H, m, aromatic H) Preparation of ~-t4-(2,6-dichlorophenylacetyl)-l-piperazinylacetylhydrazino]-2-deoxo-KA-7367A:
The procedure in EXAMPL~ 41 was repeated except using 40 mg of KA-7367A and 68 mg of 4-(2,6-diphenyl-acetyl)-l-piperazinylacetylhydrazine to obtain 80 mg of a : ~.
, ' .~ ~ ' .
final product.
H-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hzl 4-CH3) 1.96(3H, s, l-CH3) 2.64~4H, mr aromatic H) 3.58(2H, m, aromatic H) 3.72(2H, m, aromatic H) 3.78(2H, s, ~O-CH2-N) 7.25(2H, m, aromatic H) 7.42(1H, mF aromatic H3 Preparation of 2-(2,4-dichlorophenoxyacetyl-hydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 33 mg oE 2,4-dichlorophenoxy-acetylhydrazine to provide 35 mg of a final product.
H~NMR: (CDC13 r TMS ) S
0.92(3H, t, J=7Hz, 6'-CH3) 1.43(3H, d, J=7Hz, 4-CH3) 2.04(3M, s, l-CH3) 4.65(2H, s, CO-CH2-N) 6.86(lH, d, J=9Hz, aromatic H) 7 . 2 6 S lH ~ ad r J=3Hz, aromatic H ) 7.43(1~, d, J=3Hz, aromatic H) Preparation of 2-t(N-methyl-N-alpha-naphthyl-methylamino)-acetylhydrazino~-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except 30 using 60 mg of KA-7367A and 79 mg of (N-methyl-N-alpha-naphthylmethylamino)-acetylhydrazine to afford 73 mg of a r?
final product.
H-NMR: ( CDCl 3, TMS ) ~
0.92~3H, t, J=7Hz, 6'-CH3) 1.28(3H, d, J-7~z, 4-CH3) ` 5 1.53(3H, s, l-CH3) 2.48(3H, s, N-CH3) 3.2Ç(2H, s, N-CH2-naphthyl) 4.03(2H, s, CO-CH2-N) 7.4-7.6(4H, m, aromatic H) 7.85(2H, m, aromatic H) 8.2(1H, m, aromatic H) Preparation of 2-lp-(N-methyl-N-alpha-naphthyl-methylaminomethyl)benzoylhydrazono]-2-deoxo-KA-7367A: -The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 70 mg of p-~N-methyl-N-alpha-naphthylmethylaminomethyl)benzoylhydrazine to obtain 14 mg of a final product.
lH-NMR: (CDC13, TMS ) ~
0.91~3H, t, J=7Hz~ 6'-CH3) 1.98(3H, s, l-CH3) 2.20(3H, s, N-CH) 3.61(2H, s, -N-CH2 ~ ) 3.95(2H, s, N-CH2 ~ ) ~ .
7.35-7.55(6H, m, aromatic H) 7.75-7.9(4H; aromatic H) 8.3(1H, m, aromatic H) Preparation of 2-(2,6-dichlorobenzoylhydraz-ono)-2-deoxo~KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 31 mg of 2,6-dichlorobenzoyl-, .
.
.. ~ . , :.
.~ .. .
, . ~ : . .
hydrazine to obtain 40 mg of a final product.
H-NMR: (CDC13, TMS~ ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.14(3H, d, J=7Hz, 4-CH3) 1.99(3H, s, 1-CH3) 7.25-7.35(3H, m, aromatic H) Preparation of 2-~(2,6-dichlorophenyl)pro-pionylhydrazono]-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 30 mg of KA-7367A and 35 mg of (2,6-dichloro-phenyl)propionylhydraæine to afford 36 mg of a final product.
lH-NMR: (CDC13, TMS) S
0.92(3H, t, J=7Hz, 6'-CH3) 1.34(3H, d, J=7Hz, 4-CH3) 1.89(3H, s, l-CH3) 2.88(2H, m, CO-CH2-CH2) 3.28(2H, m, CO-CH2-CH2) 7.09~1H, dd, J=9Hz, arom~tic H) 7.3~2H, m, aromatic H) Preparation of 2-~(2,6-d:ichlorophenyl)butyryl-hydrazono]-2-deoxo-K~-7367A:
The procedure in EXAMPLE 41 was repeated except using 20 mg of RA-7367A and 25 mg of (2,6-dichloro-phenyl)butyrylhydrazine to afford 19 mg of a final pro-duct.
lH-NMR: tCDC13, TMS) ~
0.92(3H, tr J=7Hz, 6'-CH3) 1.36~3H, d, J=7Hz, 4-CH3) 1.89~3H~ s, l-CH3) 1.97(2H, ~, J=8Hz, CO-CH2-CH2-CH2-) 2.76(2H, t, J=8Hz, CO-CH2-CH2-CH2-) 3.00(2H, m, CO-CH2-CH2-CH2-) ~ ~ ~.J ~ 'J ~J ~'`
7.07(1H, dd, J=9Hz, 7Hz r aromatic H) 7.3(2H, m, aromatic H) Preparation of 2-[(2,6-difluorophenyl)acetyl-hydrazono]-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 65 mg of XA-7367A and 61 mg of (2,6-difluoro-phenyl)acetylhydrazine to obtain 73 mg of a final pro-duct.
lH-NMR: (CDC13, TMS)~
O.91t3H, t, J=7Hz, 6'-CH3) 1.37(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, l-CH3) 4.42(2H, s, CO-CH2 ~ ) 6.9-7.3(5H, m, -CH=CH-, aromatic H) Preparation of 2-[(2,6-dimethoxyphenyl)acetyl-hydrazono]-2-deoxo-KA-7367A: -The procedure in EXAMPLE 41 was repeated except using 14 mg of KA-7367A and 15 mg of (2,6-dimethoxy-phenyl)acetylhydrazine to obtain 8 m of a final product.
H-NMR: tCDC13, TMS)S
0.91(3H, t, J=7Hz, 6'-CH3) 1.33, 1.38~total 3H, t, J=7Hz r 4 - CH3 ) 1.72, 1.86(total 3H, s, l-CH3) 3.77, 3.85ttotal 6H, s~ OCH3) 6.5-6.6(2H, m, aromatic H) 7.2(lH, m, aromatic H) Preparation of 2-(2,6-dinitrophenylhydrazono)-2-deoxo-KA~7367A:
The procedure in EXAMPLE 41 was repeatea except using 50 mg of KA-7367A and 50 mg of 2,6-dinitrophenyl-.
2 ~
hydrazine to obtain 71 mg of a final product.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.47(3H, d, J=7Hz, 4-CH3) 2.12(3H, s, l-CH3) 7.90(lH, m, aromatic H) 8.28(1H, m, aromatic H) 9.09(1H, m, aromatic H) Preparation of 2-methoxycarbonylhydrazono-2-de-oxo-KA-7367A:
The proce~ure in EXAMPLE 41 was repeated except using ~0 mg of KA-7367A and 9.1 mg of methyl carbazinate to afford 13 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.37(3H, d, J=7Hz, 4-CH3) 1.89(3H, s, l-CH3) 3.82~3H, s, OCH3) 4.89(lH, 1, J=7Hz, 3-CH3) Preparation of 2-sulfophenylhydrazono-2-deoxo-KA-7367A monosodium salt:
The procedure in EXAMPLE 41 was repeated except 25 using 100 mg of KA-7367A and 106 mg of monosodium p-hy-drazonobenzenesulfonate to afford 196 mg o~ a final product.
}H-NMR: ~CDC13, TMS)~
0.92(3H, t~ J=7Hz J 6'-CH3) 1.32(3H, d, J=7Hz, 4-CH3) 1.64(3H, s, l-CH3) 7.73(2H, m, aromatic H) 7.95~2H, m, aromatic H) Preparation of 2-phenylacetylhydrazono-2-de-oxo-KA-7367A:
` ' , ;' '" ': ~
The procedure in EXAMPLE 41 was repeated except using 50 mg of KA-7367A and 38 mg of phenylacetylhydraz-ine to afford 55 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1~40(3H, d, J=7Hz, 4-CH3) 1.88(3H, s, 1-CH3) 3.96(2H, s, -CO-CH2 ~ ) 6.9 7.2(5H, m, aromatic H) EXAMæLE 67 Preparation of 2-(2-furylcarbonylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 40 mg of KA-7367A and 30 mg of 2-furylcarbonylhy-drazine to obtain 37 mg of a final productO
H-NMR: (CDC13, TMS)S
0.92(3H, t, J=7Hz, 6'-CH3) 1.46(3H, d, J=7Hz, 4-CH3) 1.98(3H, s, l-CH3) 7.0-7.2(3H, m, aromatic H) Preparation of 2-thenoylhydrazono-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except 25 using 40 mg of KA-7367A and 35 mg of thenoylhydrazine to obtain 30 mg of a final product.
1~ - NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 5'-CH3) 1.48(3H, d, J=7Hz, 4-CH3) 30 2.00(3H, s, l-CH3) 7.02-7012(3H, m, aromatic H) Preparation of 2-thiocarbonohydrazono-2-deoxo-KA-7367A:
.
. , , ~ ::
~ ~ s~
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 40 mg of thiocarbonohydrazide to obtain 38 mg of a final product.
lH-NMR: (CDC13, TMS) ~
0.93(3H, t, J=7Hz, 6'-CH3) 1.37(3H, d, J=7Hz, 4-CH3) 1.95(3H, s, l-CH3) 2.23(2H, 1, J=7Hz, 3'-CH3) 4~75tlH, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -CH=CH~) Preparation of 2-isonicotinoylhydrazono-2-de-oxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 100 mg of KA-7367A and 112 mg of isonicotinoylhy-drazine to obtain 119 mg of a final product.
H-NMR: ~CDC13, TMS)~
0.93(3H, t, J=7Hzl 6'-CH3) 1.54(3H, d, J=7Hz, 4-CH
2.24(3H, s, l-CH3) 5.22(1H, q, J=7Hz, 3-CH) 6.9-7.1t2H, m, -CH=CH-) 7.67(2H, m, aromatic H) 8.74(2H, m, aromatic ~) Preparation of 2-nicotinoylhydrazono-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 200 mg of KA-7367A and 200 mg of nicotinoylhydraz-ine to afford 206 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.93(3Hr t, J=7Hz, 6'-CH3) 1~53(3H, a, J=7Hz, 4-CH3) 2.24(3H, s, l-CH3) 5.22(1H, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -C~=CH-~
,, , , . :
., , . , , , :.
, ~
J iJ ~
7.45(1H, dd, J=5Hz, 7Hz, aromatic H) 8.18(1H, dt, J=2Hz, 2Hz, 8Hzt aromatic H) 8.67(1H, dd, J=2Hz, 5Hz, aromatic H) 9.06(lH, br.s, aromatic H) EXAMPI.E 72 Preparation of 2-(o-chlorophenylacetylhydraz-ono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 50 mg of KA-7367~ and 48 mg of o-chlorophenyl-acetylhydrazine to afford 64 mg of a final product.
H-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 1.83(3H, s, l-CH3) lS 2.23(2H, q, 3'-CH2) 4.11(2H, s, CO-CH2 ~ ) 4.83(1H, q, J=7Hz, 3-CH) Preparation of 2-(m-chlorophenylacetylhydraz-ono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated excep-t using 25 mg of KA-7367A and 24 mg of m-chlorophenyl-acetylhydrazine to afford 27 mg of a final product.
lH-NMR: (CDC13, TMS) ~
2S 0.92t3H, t, J=7Hz, 6'-CH3) 1.40t3H, d, ~=7Hz, 4-CH3) 1.38~3H, s, l-CH3) 2.23(2H, q, 3'-CH2) 3.93(2H, s, CO-CH2 ~ ) 4.82(1H, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -CH=CH-) EXAMPI,E 74 Preparation of 2-(p-chlorophenylacetylhydraz-ono)-2-deoxo-KA-7367A: .
~:
`J~
The procedure in EXAMPLE 41 was repeated except using 25 mg of KA-7367A and 24 mg of p-chlorophenyl-acetylhydrazine to afford 30 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.92(3H, t, J=7Hz, 6'-CH3) 1.39(3H, d, J=7Hz, 4-CH3) 1.87(3H, s, l-CH3) 2.23(2H, q, 3'-CH2) 3.93(2H, s, CO-CH2 ~ ) 4.90(1H, q, J=7Hz, 3-CH) 6.9-7.1(2H, m, -CH=C~-) EX~MPLE 75 Preparation of 2-[alpha-(1-imidazolyl)-p-chlorophenylacetylhydrazono]-2-deoxo-KA-7367A:
The procedure in EX~MPLE 41 was repeated except using 150 mg of KA-7367A and 178 mg of alpha-(l-imidazol-yl)-p-chlorophenylacetylhydrazine to obtain 180 mg of a final product.
lH-NMR: (CDC13, TMS)~
0.93(3H, t, J=7Hz, 6'-CH3) 1.28, 1.29(total 3H, d, J=7Hz, 4-CH3) 1.90, l.91(total 3H, s, l-CH3) 2.21, 2.23(total 2H, 3' CH2) 4.68, 4.71(total lH, qr 3-CH) 6.80tlH, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-talpha-(2-oxo-1-pyridyl)-p-chlorophenylacetylhydrazono]-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 85 mg of KA-7367A and 96 mg of alpha-(2-oxo-1-pyridyl)-p-chlorophenylacetylhydrazine to obtain 45 mg of :
., ~ :
a final product.
1~-NMR (cDcl3t TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.18, 1.14(total 3H, d, J=7Hz, 4-CH3) 1.82, 1.85(total 3H, s, 1-CH3) 2~21(2H, q, 3'-CH2) 4.64, 4.66(total lH, q, J=7Hz, 3-CH~
6.8-7.0(2H, m, -CH=CH-) Preparation of 2 ~p-chlorocinnamoylhydrazono)-2-deoxo-KA-7367A:
The procedure in EX~MPLE 41 was repeated except using 150 mg of KA-7367A and 983 mg of p-chlorocinnamoyl-hydrazine to obtain 80 ~g of a final product.
lH-NMR: (CDC13, TMS) ~
0.92t3H, t, J=7Hz, 6'-CH3) 1.42(3H, d, J=7Hz, 4-CH3) 2.01(3H, s~ l-CH3) 2.22(2H, q, 3~-CH2) 4.00(1H, q, J=7Hz, 3-CH) 6.0-7.1(2H, m, -CH=CH-) Preparation of 2-12,4'-dichlorodiphenylacetyl-hydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 85 mg of KA-7367A and 104 mg of 2,4'-dichlorodi-phenylacetylhydrazine to obtain 58 mg of a final product.
H-NMR: ~CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.24(3H, d, J=7Hz, 4-CH3) 1.77(3H, s, 1-CH3) 2.22(2H, q, 3'-CH2) 4.78(1H, q, J=7Hz, 3-CH) 6.31(1H, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) ,~
.
: .
f~ J S''' '.J
Preparation of 2-(2,4-dichlorodiphenylacetyl-hydrazono)-2-dioxo-KA-7367A:
The procedure in EXA~LE 41 was repeated except using 120 mg of KA-7367A and 151 mg of 2,4-dichloro-phenylacetylhydrazine to afford 161 mg of a final pro-duct H-NMR: (CDC13, TMS) ~
0.91(3H, t, J=7Hz, 6'-OEI3) 1.23, 1.27t3H, d, J=7Hz, 4-CH3) 1.77(3H, s, l-CH3) 2.22t2H, q, 3'-CH2) 4.70, 4.73(1H, q, J=7Hz, 3-CH) 5.31(1H, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-diphenylacetylhydrazono-2-de-oxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 60 mg of diphenylacetylhy-drazine to afford 70 mg of a final product.
H-NMR: (CDC13, TMS) 0.92(3H, t, J=7Hz, 6'-CH
1.31~3H, d, J=7Hz, 4-CH3) 1.82(3H, s, l-CH
2.23(2H, q, 3'-CH2) 4.77(lH, q, J=7Hz, 3-CH) 6.00(1H, s, aromatic H) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-tbis(2,4-dichlorophenyl)-acetylhydrazono]-2-deoxo-KA~7367A:
The procedure in EXAMPI.E 41 was repeated except using 20 mg of KA-7367A and 40 mg of bis(2,4-dichloro-phenyl)-acetylhydrazine to afford 19 mg of a final pro-' , 2 fi 2 ?. ~
duct.
1H_NMR ( CDCl 3, TMS) ~
0.92(3H, t, J=7HZ, 6~-CH3) 1.23(3H, a, J=7HZ, 4-CH3) 1.78t3H, S, 1-CH3) 2.23(2H, q, 3'-CH2) 4.66(1H, q, J=7Hz, 3-CH) 6.49(1H, s, aromatic H) 6.8-7~0( 2H, m, -CH=CH-) Preparation of 2-(2,4,4'-trichlorodiphenyl-acetylhydrazono)-2-deoxo-KA-7367A:
The procedure in EXAMPLE 41 was repeated except using 60 mg of KA-7367A and 43 mg of 2,4,4'-trichlorodi-phenylacetylhydrazine to afford 23 mg of a final product.
H-NMR: (CDC13, TMS) ~
0.92(3H, t, J=7Hz, 6'-CH3) 1.25, 1.29(total 3H, d, ~=7Hz, 4-CH3) 1.82(3H, s, 1 CH3) 2.21, 2.23(~H, q, 3'-CH2) 4.72, 4.73(1H, q, J=7Hz, 3-CH) 6.23(1H, s, aromatic H) 6.9-7.1(2H, m, -CM=CH-) Prparation of 2-methoxycarbonylhydra~ono 2-de-oxo-KA-7367A:
The procedure in EXAM2LE 41 was repeated except using 100 mg of KA-7367A and 60 mg of methoxycarbonyl-ethylhydrazine to obtain 37 mg of a final product.
H-NMR: ~CDC13, TMS) S
0.92(3H, t, J=7Hz, 6'-CH3) 1.33(3H, d, J=7Hz, 4-CH3) 1.78(3H, s, l-CH3) 2.22(2H, q, 3'-CH2) 2.59(2H, t, J=6Hz, NCH2CH2CO) 3.45(2H, t, J=6Hz, NCH2CH2CO) 3.70(3H, s, OCH3) .::
r;
~ 44 ~
4.76(1H~ q, 3-CH) 6.9-7.1(2H, m, -CH=CH-) Preparation of 2-[2-(p-chlorophenyl)-2-methoxy-carhonylethylhydrazono]-2-aeoxo-KA-7367A:
The procedure in EXAMPLE 41 ~as repeated except using 100 mg of KA 7367A and 70 mg of 2-(p-chloro-phenyl)-2-methoxyethylhydrazine to obtain 75 mg of a final product.
lH-NMR: (CDCl~, TMS)S
0.92(3H, t, J=7Hz, 6'-CH3) 1.35(3H, d, J=7Hz, 4 CH3) 1.62(3H, s, l-CH3) 2.22(2H, q, 3'-CH2) 3.3-3~8(3~, m, -CH2-CH-) 3.66(3H, s, OCH3) 4.70(1H, q, 3-CH) 6.9-7.1(2H, m, -CH=CH-) 7.1-7.3(4H, m, aromatic E~) PREPARATION EXAME'LE 1 (Capsules for administration to humans) Compound in EXAMPI.E 4 500 g Microcrystal cellulose 90 Talc 30 The above components were uniformly mixed in a usual manner and the mixture was filled in 1000 No. O
capsules.
(Cream for administration to humans) 30 Compound in EXAMPLE 3 2.0 g White soft paraffin 25.0 Stearyl alcohol 25.0 Propylene glycol 12.0 Sodium lauryl sulfate 1.5 35 Ethyl p-hydroxybenzoate 0.5 Deionized water 34.0 ~ - ' 2 ~ r; f~
The above components were uniformly mixed in a usual manner and the mixture was formed into a cream.
(Emulsifiable concentrate for agricultural and horticultural use) Compound in EXAMPLE 43250 g Epoxidized vegetable oil 25 Mixture of alkylaryl sulfonate, polyglycol ether and aliphatic alcohol 100 Dimethylformamide 50 Xylene 575 The above components were uniformly mixed in a usuall manner and the mi~ture was formed into an emulsi-fiable concentrate. This is diluted with water into an 15 emulsion.
INDUSTRIAL AVAILABILITY
The compounds in this invention are excellent in antifungal activity to fungi t.hat infect warm-blooded animals including humans and agricultural and horticul-tural crops and in stability, and are useful as agentsfor prevention, treat ment or therapy of infectious diseases caused by these fungi or control of plant diseases caused by these fungi.
' ' ' "`-'" :'~ ' :. :::~
,
Claims (13)
1. An azoxy compound represented by formula (I) wherein A denotes -0-, -OCO-, -NH-, -NHCO-, -HNCS- or , Y denotes a single bond or a linear or branched alkylene group with 1 to 6 carbon atoms or a linear or branched alkenylene group with 2 to 6 carbon atoms, and said alkylene or alkenylene group may optionally be substituted by a halogen atom, a phenyl group or a halophenyl group, Z denotes a hydrogen atom, an alkoxy group with 1 to 5 carbon atoms, a carboxyl group, an alkoxycarbonyl group with 2 to 6 carbon atoms, a phenyl group that may optionally have 1 to 3 substituents selected from a halogen atom, an alkoxy group with 1 to 5 carbon atoms, a car-boxyl group, a nitro group, a sulfonyl group and a N-methyl-N-alpha-naphthylmethylamino-methyl group, a phenoxy group in which a benz-ene ring may optionally be substituted by 1 to 3 halogen atoms, a naphthyl group, a cyano group, a pyridyl group, an oxopyridyl group, a imidazolyl group, a furyl group, a thienyl group or a group of formula or -N N-R3 R1 and R2 are the same or different and each denotes a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, a phenyl group, a naphthyl group, a phenylalkyl group with 7 to 10 carbon atoms, a naphthylalkyl group with 11 to 14 carbon atoms or an amino group, and R3 denotes an alkyl group with 1 to 3 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, a benzoyl group or an alkanoyl group with 2 to 6 carbon atoms that may optionally be substituted by a phenyl group or a halophenyl group, provided when A is the group of formula , Z is a hydrogen atom, and its salt.
2. The compound of claim 1 wherein A is -O-, Y is a single bond, or a linear or branched alkylene group with 1 to 4 carbon atoms or a linear alkenylene group with 2 to 4 carbon atoms that may obtionally be substituted by 1 to 3 halogen atoms or halophenyl groups, Z is a hydrogen atom, an alkoxy group with 1 to
3 carbon atoms, a carbonyl group, a phenyl group that may optionally have 1 to 2 substitu-ents selected from a halogen atom and a carbox-yl group, a cyano group or a group of formula or R1 and R2 are the same or different and each is an alkyl group with 1 to 3 carbon atoms, and R3 is a benzoyl group.
3. The compound of claim 1 wherein A is -OCO-, Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms, and Z is a hyarogen atom, an alkoxy group with 1 to 3 carbon atoms or a phenyl group that may optionally be substituted by 1 to 3 halogen atoms.
3. The compound of claim 1 wherein A is -OCO-, Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms, and Z is a hyarogen atom, an alkoxy group with 1 to 3 carbon atoms or a phenyl group that may optionally be substituted by 1 to 3 halogen atoms.
4. The compound of claim 1 wherein A is -NH-, Y is a single bond or a linear alkylene group with 1 to 4 carbon atoms that may optionally be substituted by a phenyl group or a halophenyl group, and Z is a hydrogen atom, an alkoxycarbonyl group with 2 to 4 carbon atoms or a phenyl group that may optionally be substituted by a sulfonyl group.
5. The compound of claim 1 wherein A is -NHCO-, Y is a single bond or a linear alkylene or alkenylene group with 1 to 4 carbon atoms that may optionally be substituted by 1 to 3 halogen atoms, phenyl groups or halophenyl groups, Z is a hydrogen atom, an alkoxy group with 1 to 3 carbon atoms, a phenyl group that may option-ally have 1 to 2 substituents selected from a halogen atom, an alkoxy group with 1 to 3 carbon atoms, a nitro group and a N-methyl-N-alpha-naphthylmethylaminomethyl group, a phenoxy group in which a benzene ring may optionally be substituted with 1 to 2 halogen atoms, a naphthyl group, a pyridyl group, an oxopyridyl group, an imidazolyl group, a furyl group, a thienyl group or a group of formula or R1 and R2 are the same or different and each is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, a phenyl group or a naphthylalkyl group with 11 to 12 carbon atoms, and R3 is an alkoxy group with 1 to 3 carbon atoms or an alkanoyl group with 2 to 4 carbon atoms that may optionally be substituted by a halo-phenyl group.
6. The compound of claim 1 wherein A is -NHCS-, Y is a single bond, Z is , and R1 and R2 are the same or different and each is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, a phenyl group or an amino group.
7. The compound of claim 1 wherein A is , Y is a linear alkylene group with 1 to 4 carbon atoms, and Z is a hydrogen atom.
8. The compound of claim 1 which is selected from 2-hydroxyimino-2-deoxo-KA-7367A, 2-methoxyimino-2-deoxo-KA-7367A, 2-(2-ethoxy-ethoxyimino)-2-deoxo-KA-7367A, 2-carboxymethoxyimino-2-deoxo-KA-7367A, 2-(1-carboxy-1-methylethoxyimino)-2-deoxo-KA-7367A, 2-acetoxyimino-2-deoxo-KA-7367A, 2-benzoyloxyimino-2-deoxo-KA-7367A, 2-(p-chlorobenzoyloxyimino)-2-deoxo-KA-7367A, 2-semicarbazono-2-deoxo-KA-7367A, 2-thiosemicarbazono-2-deoxo-KA-7367A, 2-acetylhydrazono-2-deoxo-KA-7367A, 2-(1-imidazolylacetylhydrazono)-2-deoxo-KA-7367A, 2-(3-pyridylacetylhydrazono)-2-deoxo-KA-7367A, 2-(2,4-dichlorophenylacetylhydrazono)-2-deoxo-KA-7367A, 2-(alpha-naphthylacetylhydrazono)-2-deoxo-KA-7367A, 2-(4-acetylplperazinyl-acetylhydrazono)-2-deoxo-KA-7367A, 2-[4-(2,6-dichlorophenylacetyl)-1-piperazinyl-acetylhydrazono]-2-deoxo-KA-7637A, 2-[(2,6-difluorophenyl)acetylhydrazono]-2-deoxo-KA-7367A, 2-[2,6-dimethoxyphenyl)acetylhydrazono]-2-deoxo-KA-7367A, 2-(2-furylcarbonylhydrazono)-2-deoxo-KA-7367A, 2-thenoylhydrazono-2-deoxo-KA-7367A, 2-isonicotinoylhydrazono-2-deoxo-KA-7367A, 2-nicotinoylhydrazono-2-deoxo-KA-7367A, 2-(p-chlorophenylacetylhydrazono)-2-deoxo-KA-7367A, 2-(2,4'-dichlorodiphenylacetylhydrazono)-2-deoxo-KA-7367A, and 2-(2,4-dichlorodiphenylacetylhydrazono)-2-deoxo-KA-7367A.
9. A process for producing the compound of formula (I) or its salt, which comprises reacting KA-7367A pro duct represented by formula with a compound represented by formula H2N-A-Y-Z (II) or its salt and if required, converting the product into a salt.
10. An antifungal agent containing the compound of formula (I) or its salt recited in claim 1.
11. An antifungal composition comprising an anti-fungally effective amount of the compound of formula (I) or its salt recited in claim 1 and an adjuvant.
12. The antifungal agent of claim 10 which is used for prevention, treatment or therapy of infectious di-seases by fungi of warm-blooded animals including humans.
13. The antifungal agent of claim 10 which is used as an agricultural and horticultural agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002028220A CA2028220A1 (en) | 1988-10-22 | 1990-10-22 | Azoxy compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26527588 | 1988-10-22 | ||
| CA002028220A CA2028220A1 (en) | 1988-10-22 | 1990-10-22 | Azoxy compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2028220A1 true CA2028220A1 (en) | 1992-04-23 |
Family
ID=25674349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002028220A Abandoned CA2028220A1 (en) | 1988-10-22 | 1990-10-22 | Azoxy compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2028220A1 (en) |
-
1990
- 1990-10-22 CA CA002028220A patent/CA2028220A1/en not_active Abandoned
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |