JPH07501693A - Markfortin/parahaquaamide derivatives useful as antiparasitic agents - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Invention of mark fortein/parahaquamid derivatives useful as antiparasitic agents background Marcfortine is a known compound, Null of the Chemical Society Chemical Communications (J ournal of the Chemical 5ociety Che mical Communications), 1980.601-602 ( Mark Fortein A), and Tetrahedron Letters (Tetrahed) ron Letters), 1981.22.1977-1980 (Markoff olteins B and C) disclosed by Polonsky et al. It is. The compound is derived from Penicilli um roqueforti). The mark fortein is and Paraherquamide, which is a well-known compound, Structurally related. Parahaquamide is a tetrahedron letter (Te trahedron Letters), 1981.22.135-136 Also by Yamazaki et al., Journal of Antibiotics Journal of Antibiotics, 1991.44 ．． According to B. ranchflover et al. on pages 492-497. are disclosed. U.S. Patent Nos. 4.866.060 and 4.923.867 The issue is Markfortein A, which is useful for the treatment and prevention of parasitic diseases in animals. Discloses the use of B and C1 and certain derivatives.

Parahaquamide has the following structure/ has.

Markfortein A has the following structure: (Published on July 11, 1991) W091109961 describes Markhuo and Valahakuamide derivatives It is in. A further object of the invention is to describe methods for the preparation of these compounds. be. A still further object is the anti-inflammatory properties of said compounds in the treatment and prevention of parasitic diseases. The purpose is to describe its use as a pest control agent. A further object of the present invention is to In order to describe a composition for the treatment of parasitic diseases containing the specified compound as an active ingredient. Ru. Further objectives will become apparent from reading the description below.

Detailed description of the invention Compounds of the invention have formula I: [In the formula, n is 0 or 1° R14 and R14, are the same or different, hydrogen, hydroxy, C, -C , alkyl, CI-Csalcokyne, C, -C, alkenyl, C, -C, alke Nyl-C, -C6 alkoxy, C, -C, alkynyl-C, -C6 alkokino, C, -C, alkanoyloxy, polyC, -C, alkokino-C, -C, alco Quino, phenyl, phenyl-C, -C.

Alkyl, tri-CI-C, alkylinlyloxy, nophenylphosphoryloxy or R11* and R84, taken together. to form an epoxide or =CH2, provided that when n is 1, Ro and R1 Both 4b are hydrogen.

m is O or 1 (preferably O).

W is 0 or S.

When W is S, R1 is hydrogen, c, -c, alkyl, C, -Cs alkyl , benzyl, (optionally carboquine (-COOH), C, -C?alkano yl, carboCI-Cfalkoxy(-C(0)OCI-Ct alkyl(-C( 0) NR4Rs) may be I [t C2-C77 (0)Cx-C7alk), Cro-CHful7'7/yl(-C(0) Cro-C24 alkyl), (optionally carboquino, CrCv alkanoyl, Carbo C + - C t alkoxy, -N R 4 R s, amino carboni ) cycloC, -C. alkanoyl, alkanoyl xymethylene (-CHzOC(0)-Cz-Ct alkyl), (optionally halo Gen, C.-C. Alkyl, halo C, -C, alkyl, nitro, cyano and C Substituted with one or two groups selected from + - C 7 alkoxy ) penzoyloxymethylene (-CHIOC(0)phenyl), C,.

-024 alkenoyl (-〇(○)CrCzs alkenyl), (optionally ha) logen, CI-C4 alkyl, haloC. -C, alkyl, nitro, cyano and CI-C? Optionally substituted with one or two groups selected from alcoquines. b) Benzene sulfonyl (-SoIC H H 7 Any k), C1-0 4alkylaminocarboxylic acid (-CCO)NCC+-Cafurkyl)2), C, -C,furkyl7mi/thiocarbonyl(-〇(s)N(CI-C4alkyl)2 ), CI-C7 alkoxycarbonyl, (optionally halogen, C, -C, a alkyl, halo C,-C7 alkyl, nitro, fan and C,-C,alcoquine (optionally substituted with one or two groups selected from) fenoquine carbo Nyl, -C(0)NR' 4R', -P(=XXR2XR3), -SRs , - S O 2 N R s R 5th, 3rd or 4th position is 1CH2NR4R6 Substituted benzoyl or 2-tetrahydrofuran or pinoclo C8 -CIl alkanoyl: When W is 0. R. (a) Carboquine (-COOH), CI-C7 full 7'7/yl, CarboC. -C? Alcoquino (-C(0)OCI-C.alkyl), -NR. R,, Ami C2-Cfalcanoyl substituted with nocarbonyl (-C(0)NRIRs).

(b) If desired, carboquine, C, -C, alkanoyl, carboC, -C, alkanoyl Kokino, -N R + R s, optionally substituted with aminocarbonyl Kuro C. -C. Alkanoyl: (C) Alkanoyloxy/methylene (-CH20C(0)-C2-CtFlu! -R); (d) Halogen, C, -C, alkyl, halo C+ -C'+al Kill, Nitro, Cyano and C+-C? One selected from alcoquine or penzoyloxymethylene substituted with two groups (-CHzOC(0) (e) halogen, C, -C. Alkyl, halo C + - C t al 1 or 2 selected from cyano, nitro, cyano and CI-C7 alkoxy/ phenoxycarbonyl substituted with groups.

(f) -C(0)NR'4R's:(g)-P(=XXR2XR3 ); (h)-SR,: (+)C. +. -C24 alkanoyl (-C(0)CI.-C24 alkyl): (OCI.-CH alkenoyl (-C(0)CG-C23 alkenyl); or , (k) 2-tetrahydrofuran selected from the group consisting of.

R4 and R5 are the same or different, and are hydrogen, CI-Cv alkyl, ( Optionally halogen, C, -C4 alkyl, halo C + - C7 alkyl, 1 or 2 groups selected from nitro, cyano and C,-C,alkoxy optionally substituted with phenyl, or together with N, Forms a saturated or unsaturated heteroamine ring.

R°4 and R°5 are the same or different, C, -Ct alkyl, cyclo (Ca-Cg)alkyl, (optionally halogen, C+-C4alkyl Lu,! soc1-Cy alkyl, nitro, cyano and C. -C7 alcokino? phenyl, optionally substituted with one or two groups selected from or together with N, one selected from N10 or S as desired or forming a saturated heteroamine ring which may contain two additional petero atoms.

X is 0 or S: R2 and R3 are the same or different, C+-C7 alkyl, (as desired) )\rogen, C I- C 4 alkyl, halo C, -C, alkyl, nido Chewing anno and C + - C? 1 or 2 selected from Alcokino (optionally substituted with groups) phenyl, C, -C, alkoxy, thio (CI-C t) Alcoquine, fenoquino, thiophenoxy, IRt and R, are the same or are different and selected from hydrogen, C, -C, alkyl or together with N. Therefore, it is selected from l -NR7R, which forms a saturated heterocycle, or together with P. to form a 4- to 7-membered heterocycle.

R6 is C, -C, alkyl, haloC, -C7 alkyl, carboC. -C7 Al Koxy, -NR. R. , where R and RIO are the same or different, C, -C, alkyl or (optionally halo, lower alkyl, haloC, -C, alkyl) one or two groups selected from optionally substituted with) phenyl; R41 is hydrogen, halogen or C, -C, alkoxy.

R25 is hydrogen or halogen: R1@I is hydrogen, CI-C? alkyl, C2-C. Alkoxyalkyl, C2 -C, alkenyl, C2-C. Alkynyl or benzyl: carbon 24 and 25 The dashed line between the two represents a single or double bond.

The compounds of the present invention include pharmaceutically acceptable salts thereof as well as their 12a-N-oxy includes the code.

Another aspect of the present invention is 10, 10°'-(1.4-7 carbonylbiperazine)bis(6°,7°.8 °． 9'. 10'. ]] Published by 0'a-Hexahydro゛. 1° 4. 4. 12- pentamethyl)-[2°S-[2'. Alpha, 3°a Alpha, 9°a.

al)y. , 10 (2”’R book, 3°”aS book 9”’aS book.10”’aR*) 10'a, beta coco-spiro [4H. 8H-[1. 4] Oxepino [2 ．． 3-g Coin Dole-8,2° (3°H)-[IH. 4H-3a. 9ako ( Iminomethano) Nocropenota [b] Quinorijinko 9. 11' (IOH)- Dione-Cpd R120) and 10, 10”-(1.4-dioxo-2-butene)bis(6’, 7° ．． 8'. 9'. 10°. 10' a-hexahydro-1°B 1'. 4.4.12'-pentamethyl)-[2'S-[2'. alpha, 3 'a alpha, 9°a alpha.

10 (2”’ R*, 3°”aS 9”’aS book, 10°”aR book), 10 'a, beta]]-spiro[4H,8H-[1°4]dioxepino[2,3-g ] Indole-8,2° (3°H)-[IH,4H-3a,9a] (Iminome Tano) noclopenta[b] quinolidine 9.11” (IOH)-dione, C pd 1112T), which can be used in the same way as the compound of formula (1).

Another aspect of the present invention is the formula ■: [In the formula: m is 0 or 1 (preferably 0); Captives are hydrogen, Cl-Ct alkyl, chromoC, -C, alkyl, benzyl, (where If desired, carboquine (-COOH), C, -C7 alkanoyl, carboC, - C, alkokino (-C(0)QC, -Cfarkyl), -NR,R,, aminoca l CrCt alkali which may be substituted with carbonyl (-C(0)NR4Rs) Noyl (-C(0)Ct-C7 alkyl), C3゜-CO alkanoyl (-C( 0)Cl. -CZ<alkyl), (optionally carboquine, C+ -Ct alkyl) Kanoyl, carbo C+-Ct alkokino, -NR, R3, substituted with aminocarbonyl 1 Fukuro C3-Cs alkanoyl, alkanoyloxy J, which may be substituted with Tyrene (CH20C(0)-C2-Ctfurkyl), (desired 1m/'ro) Gen, C, -C4 alkyl, haloC+-Ct alkyl, nitro, cyano and C +　Optionally substituted with one or two groups selected from -C7 alkokyne 1 benzoyloxymethylene: z (-CHzOC(0) phenyl), Clo-C 24 Fluke/yl (-C(0)Co-C2s alkenyl), (optionally ha) rogene, C, -C, alkyl, halo C, -C, alkyl, nitro, cyano and Optionally substituted with one or two groups selected from C, -C, alkokino i) Benzenesulfonyl (-3OzCHz phenyl), Cr-C4 alkylamide Nocarbonyl (-C(0)N(Cl-C4alkyl)2), C, -C, alkyl Aminothiocarbonyl (-C(S)N(C,-C,alkyl)2), C,-C alkoxycarbonyl, (optionally halogen, C, -C, alkyl, haloC, 1 selected from -C, alkyl, nitro, cyano and Cl-Cv alcoquine (optionally substituted with one or two groups) phenoxycarbonyl, -C(0) NR'aR's, -P (=XXR1XRI), -8R,, -S O2N Ra Benzoyl, 2-tetra substituted with -CHtNR4Rs at R5, 3 or 4 position Hydrofuran, or bicycloCm-Cl! Alkanoyl; R4 and R5 are Same or different, hydrogen, C, -C, alkyl, (optionally halogen, C, - C, alkyl, halo C, -C7 alkyl, nitro, cyano and C, -C, alkyl optionally substituted with one or two groups selected from phenyl or or together with N to form a saturated or unsaturated heteroamine ring. Completion: R°4 and Ro are the same or different, C, -Cfarkyl, cyclo(Cs -Ca) alkyl, (optionally halogen, C, -C, alkyl, haloC+ - One selected from Ct alkyl, nitro, fan and Cl-Ct alkoxy or phenyl, optionally substituted with two groups, or Together with N, one or two additional pieces selected from N, O or S as desired. forming a saturated heteroamine ring containing an additional heteroatom: X is 0 or S: R2 and R3 are the same or different, CI-C7 alkyl, (optionally halo) Gen, Cl-Ca alkyl, halo C, -C7 alkyl, nitro, cyano and C r　Optionally substituted with one or two groups selected from -C7 alkoxy i) Phenyl, C, -C? Alkoxy, thio(Cr-Ct)alkoxy, pheno In this case, R1 and R@ are the same or different. selected from H, Cl-C7 alkyl, or together with N ) or together with P form 4 to 7 R8 is C, -C, alkyl, haloC+ -Ct alkyl , carbo C+ -Ct alkoxy, -N R* R+. , where Ro and R Is the IO the same or different, C+ -C? Alkyl, or (optionally halo, lower class alkyl, )\roC1-C7 alkyl, nitro, cyano, C+ -Ct alco phenyl optionally substituted with one or two groups selected from phenyl; RNA is hydrogen, halogen, or Cl-C7 alkoxy.

R25 is hydrogen or halogen.

R1□ is hydrogen, Cl-C7 alkyl, cl-c, alkoxyalkyl, C4- C8 alkenyl, C2-C, alkynyl or benol; carbon 24 and 25 The dashed line in between represents a single or double bond] 18-thiomark fortein or derivatives are provided.

Another aspect of the present invention is the formula ■・ [During the ceremony m is 0 or 1 (preferably 0).

R1 is hydrogen, CI-C7 alkyl, NocroC, -C, alkyl, benzyl, (Carboxy (-COOH), CI-C?alkanoyl, carbo-C as desired) I-C7 alkokyne (-C(0)OCI-C7 alkyl), -NR,R5, ami C2-C7 alkanoyl (-C (0) C2-C7 alkyl C,. -C24 alkanoyl (-C(0)C,.-C l alkyl), (optionally carboquine, CI-C?alkanoyl, carboC I-C7alcokyne, -NRaRs, substituted with aminocarbonyl ) CycloCs-Cm alkanoyl, alkanoyloxymethylene (-CHiOC(0)-Ct-Ct alkyl), (optional halogen, C I-C4 alkyl, halo C+-Ct alkyl, nitro, cyano and C (Optionally substituted with one or two groups selected from rCt alkoxy) Benzoyloxymethylene (-CHaOC(0)phenyl), C I 6-C H alkenoyl (-C(0)CrCu alkenyl), (optionally halogen, CI-C4 alkyl, halo C+-Ct alkyl, nitro, fan and Optionally substituted with one or two groups selected from C, -C, alkoxy b) Benzenesulfonyl (-SO2CHt phenyl), C + - C a rukylaminocarbonyl (-C(0)N(CI-C4alkyl),), C.I. -C ．． alkylaminothiocarbonyl ('C(S)N(Cl-C*alkyl)2), C, -C, alkoxycarbonyl, (optionally halogen, C, -C4 alkyl , halo C,-Ct alkyl, nitro, cyano and C,-C,alcokyne. fenoquine carbonyl, optionally substituted with one or two selected groups; -C(0)NR'4R'! , -P (=XXIhXRs), -SRS, -S O 2　N　R　<　R　5, 3t or 4th place goes to 1st conversion Sareta with 1CHiNR4Rs soyl, 2-tetrahydrofuran, or bicycloCI-CI2alkanoyl ; R4 and R5 are the same or different and are hydrogen, C. -C. Alkyl, (as desired More halogen, C, -C. Alkyl, halo C, -C, alkyl, nitro, cyano and C, -C? substituted with one or two groups selected from alkoxy phenyl, or together with N, saturated or Forms an unsaturated heteroamine ring: R'z and Ro, are the same or different, C+-Ct alkyl, (Cs-Cm)alkyl, (optionally halogen, C, -C.alkyl, C+-Ct alkyl, nitro, cyano and C+-Ct-alkyl optionally substituted with one or two groups selected from phenyl or or together with N, as desired from N, 0 or S. saturated heteroamines which may contain one or two additional heteroatoms Forms a ring: X is O or S: R and R3 are the same or different, C+-Ct alkyl, 1 desired Halogen, C + - C < alkyl, halo C, - C7 alkyl, nito 1 or 2 selected from B, Cyano and C + - Ct Alcoki/ optionally substituted with a group of) phenyl, C, -Ct alkokyne, thio (CI- C7) Alkoxy, phenoxy, thiophenoquine, -NRyRs f where, R 7 and R8 may be the same or different, and from H1C+-Ct alkyl (can be selected or together with N to form a saturated heterocycle) or together with P form a 4- to 7-membered heterocycle You can also do that.

R6 is auto-07 alkyl, halo C, -C, alkyl, carbo C1-Ct alkyl Kin, -NR,R,. , where R and R3° may be the same or different Often C, -C7 alkyl, or (optionally halo, lower alkyl, halo C, One or more selected from -C, alkyl, nitro, cyano, C, -C, alkokyne or optionally substituted with two groups) phenyl; R24 is hydrogen, halogen, or C,-C,alcokyne; R2S is hydrogen or is halogen.

R14 and R11 are the same or different, hydrogen, hydroxy, C, -C, a alkyl, C, -Cm alkokino, C, -C, alkenyl, C, -C, alkenyl -C, -C, alkokino, CI-Cm alkynyl-C, -C6 alkoxo, C, -C, alkanoyloxy, polyC, -C, alkoxy-C+ -Cs alkoxy -, phenyl, phenyl-C, -C, alkyl, tri-C, -C, alkylsilyl selected from: or R14, and R34, together form epoxide or =CH2. You can also do that.

R18, is hydrogen, C, -C, alkyl, c2-cs alkokinoalkyl, C, -C, alkenyl, C2-Cm alkynyl or benol: carbons 24 and 25 The dashed line between represents a single bond or a double bond] 18-thiopara-ahakuamide Derivatives are provided.

Another aspect of the present invention is the formula ■- [In the formula: m is 0 or 1 (preferably 0).

R1 is (a) Carboquine (-CooH), C, -Ctfurc/yl, CarboC, -C, Alcoquine (-C(0)OC+-Ctfur+ru), -NR4R1, Aminocarbo C! substituted with nyl (-C(0)NRtRs)! -c falcanoyl; (b) place optionally carboquino, CI-Ct alkanoyl, carboC,-C,alcoquine, -NR*Rs, NocroC, -C, alkanoyl substituted with aminocarbonyl; (C)7/L, force #/l, t+shimechire:z(-CH,QC(0)-C2-C ? (furkyl): (d) halogen, Cl-C4 alkyl, haloC, -C7 alkyl , nitro, cyano and CI-C? 1 or 2 selected from alcoquine Penzoyloxymethylene substituted with group (-CH20C(0)phenyl): ( e) Halogen, Cl-C4 alkyl, halo C1-C7 alkyl, nitro, cyano and one or two groups selected from C, -C, alkoxy Enoquinocarbonyl.

(f)-C(0)NR'aR's: (g)-P(=XXRzXR1): (h)-3R6; (i) CIO-C24 alkanoyl (-C(0)CIo-Ct4 alkyl); ( j) CI. -C24alkenoyl (-C(0)Cs-Ctsalkenyl): also is (k) 2-tetrahydrofuran.

selected from the group consisting of; R4 and R6 are the same or different, hydrogen, C+-Ct alkyl, (optionally More halogen, C, -C, alkyl, halo C, -C, alkyl, nitro, cyano and C+ -Cv alkokino substituted with one or two groups selected from selected from phenyl, or saturated or saturated when combined with N. or may form an unsaturated heteroamine ring.

R″4 and R″5 are the same or different, CI-Ct alkyl, cyclo(Cs -Cm) alkyl, (optionally halogen, C, -C4 alkyl, haloC, - 1 selected from C7 alkyl, nitro, cyano and C+-Ct alkokino phenyl, optionally substituted with one or two groups, or When combined with N, one or more selected from N, O or S as desired It is also possible to form saturated heteroamine rings which may contain two additional heteroatoms. tree.

X is 0 or S: R2 and R8 may be the same or different and represent C, -C7 alkyl, ( Optionally halogen, C+ -C4 alkyl, /% C, -C7 alkyl, nitro 1 or 2 groups selected from B, /ano and C+ -Ct alkokino Optionally substituted 1 phenyl, C, -C, alkoxy/, thio (C, -C7) Alcoquine, fenoquine, thiophenoxy, -N R7Rs, R7 and R8 may be the same or different and is selected from H, C+ = Ct alkyl. or when combined with N, can also form a saturated heterocycle) or together with P form a 4- to 7-membered heterocycle You can also do that.

R6 is C1-C7 alkyl, halo C, -C7 alkyl, carbo C+ -C7 alkyl Lukokin, -N R, R + o 1 where Ro and RLO are the same or different C+ -C7 alkyl or (optionally halo, lower alkyl) , 110C, -CS alkyl, nitro, cyano, C, -C, alkokino (optionally substituted with 1 or 2 groups) phenyl RH is hydrogen, halogen or C,-C,alcoquine.

R25 is hydrogen or halogen.

R+s, Ha, hydrogen, CI-Ctfurkyl, C2-C@flucoquinofur+h, Ct -C@alkenyl, C, -C, alkynyl or benzyl.

The dashed line between carbons 24 and 25 represents a single or double bond]. 1 mark fortein or derivatives.

Another aspect of the invention is the formula V. [During the ceremony m is O or 1 (preferably O).

R. (a) Carboquino (-COOH), C, -C7 alkanoyl, carboC+ -C tA/lz: 11 kin (-C(0)OC+-Cyful+ru), -NR,R,,A C2-C, alkali substituted with minocarbonyl (-C(○)N R4Rs) Noyl: (b) optionally carboquino, C, -C, alkanoyl, carbo C, - C, alkokino, -NR4R,, cyclo optionally substituted with aminocarbonyl RoCs-Cm alkanoyl.

(c) Alkanoyl oxy7 methylene (-CHzOC(0)-Cz-Ct alkyl ).

(d) Halogen, C, -C, alkyl, haloC, -C, alkyl, nitro, /a substituted with 1 or 2@ groups selected from - and C+ -Cy alkokyne penzoyloxymethyleno (-CH20C(0)phenyl).

(e) Halogen, C, -C, alkyl, halo CI-C? alkyl, nitro, shea substituted with one or two groups selected from - and C, -C, alkoxy Phenoxycarbonyl.

(f) -C(0)NR' 4R's: (g) -P (=XXRxXRs) : (h)-3R,: (+)Cl. -C24 alkanoyl (-C(0) self.-C24 alkyl): (j ) C1°-C24 alkenoyl (-C(0)Co-Czs alkenyl): or , (k) 2-tetrahydrofuran: selected from the group consisting of: R4 and R3 may be the same or different, and represent halogen, C, -C, alkyl (Optional halogen, C, -C, alkyl, halo C1-C7 alkyl) , nitro, fan and one or two selected from C+-C7 Alcoki/ optionally substituted with phenyl, or together with N A saturated or unsaturated heteroamine ring can also be formed if R°4 and and R'5 may be the same or different <, Cl-C7 alkyl, /chloro(C s-Cm) alkyl, (optionally halogen, C, -C, alkyl, haloC+ selected from -C7 alkyl, nitro, /ano and C, -C, alkoxy phenyl (optionally substituted with one or two groups); or when combined with N, one selected from N, O or S as desired; or forming a saturated heteroamine ring which may contain two additional heteroatoms: O or S: R7 and R3 may be the same or different (, C, -C, alkyl, ( If desired, halogen, C, -C4 alkyl, halo C+ -Ct alkyl, nitro , Cyano and CI-C? Substituted with one or two groups selected from alkoxy phenyl, C, -C? Alcoquino, thio(C,-C,)al Koki/, phenoxy, thiophenoquino, -N Rt Ra t, where R7 and and R8 may be the same or different and are selected from H, Cl-C7 alkyl. or when combined with N, can also form a saturated heterocycle) When selected or together with P, forms a 4- to 7-membered heterocycle It is also possible: Rs is Cl-Ct7/L4, c+C, -C? 7/l le, cal BoC1-Ct fluoroxy, -NR,R,, where R9 and R1° are the same or CI-Ct alkyl or (optionally halo, lower alkyl) alkyl, halo C, -C7 alkyl, nitro, cyano, CI-C? Alkoxy phenyl, optionally substituted with one or two selected groups; R24 is hydrogen, halogen or C+-Ct alkoxy; RH is hydrogen or halogen.

R14, and R64, may be the same or different (, hydrogen, hydroxy , Cl-C6 alkyl, Cl-Cs flucoquino, Cl-Cs7/L'7'nyl, Cl-Cs7/L'kanyl-Cl-Ca7)Ii mycoquine Cl-Ca alkynyl -C, -C, alkoxy, Cl-Cs fluquinoyloxy, polyC, -C, alkoxy Coquin-C, -C, alkoxy, phenyl, phenyl-C, -C, alkyl, to C, -C, alkylsilyloxy, diphenylphosphoboryloxy and halo or when R14° and R14, are selected from It is also possible to form poxides or ═CH2: R18, is hydrogen, Cl-C Alkyl, Cx-Cm alkoxyalkyl, C2-C Hatake alkenyl, C, -C8 Alkynyl or penkale; the dashed line between carbons 24 and 25 indicates a single bond or [representing a heavy bond] is provided.

The carbon content of the various hydrocarbons containing the group refers to the minimum and maximum number of carbon atoms in the group. For example, the prefix C, -C, is represented by a prefix indicating from the integer "i" to the integer " j” represents the carbon atom content of carbon atoms. Gakushi, CI-C, alkyl is inclusive alkyl of 1 to 3 carbon atoms, or methyl, ethyl, propyl and and isopropyl.

In relation to the above, rcI-C7 alkyl" means 1 carbon atom in a straight or branched chain. It means to include from 7 to 7 alkyl groups, and represents an interchain double bond. darn Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, These include ee-butyl, tert-butyl, pentyl, hexyl, heptyl, and the like.

Chloro(C,-C,)alkyl includes a 3- to 8-membered alkyl ring. means. Examples of chloro(C3-Ca)alkyl groups are cyclopropyl, chlorobutyl Chlor, chloropentyl, cyclohexyl, chlorohebutyl, vinclo[2,2, 1] Heptyl, etc.

C,-C,alcoquine is a straight-chain or branched alcoquine having 1 to 8 carbon atoms; is meant to include groups. Examples of such C,-C,alcokyne groups are metquine , Nidoquino, Propoquine, Isopropoquine, Butoxy, 5ec-Butokino, Pen Doquin, hexoquin, heptoxy, etc.

C2-C,alkanoyl is straight or branched alkanoyl having 2 to 7 carbon atoms; It is meant to include the yl group. Examples of such C2-C7 alkanoyl groups are a Cetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl Including il etc.

Cl0-C24 alkanoyl (-〇(○)Co-Czs alkyl) is a carbon atom meant to include 10 to 24 straight or branched alkanoyl groups . An example of such a c+o-cz<alkanoyl group is decanoyl[-C(OXCH2 ), CH2F, lauroyl [-C(OXCH2)+. CH3], tridecanoy le[-C(○XCH2)IICH3, myristoyl[-C(OXCH2)+2 CH3], pentadecanoyl [-C(0)(CHz)+5CH3, balmite yl[-C(0)(CH2)14CH3], magaoyl[-C(OXCH2)+ 5cH3], Suf70il'ru [-C(OXCH2)IIcHa], Araki Toyl [-C(OXCHz)+5CH3], heneikoisanoyl [-C(OX CH2)19cH3], behenoyl [-C(OXCH2)2゜CH2F,) Cosanoyl [-〇(○)(CH2)21CH3], Tetracosanoyl [-C( 0)(CH2)22CH3] and the like.

C1-C24 alkenoyl (-〇(○)CG-C23 alkenyl) is a carbon atom It is meant to include 10 to 24 straight or branched chain unsaturated groups. Kaka Examples of C1°-C24 alkenoyl groups include undefluenoyl[-C(OX CH2)7CH: CHCH31, oleoyl [-C(0)(CH2), CH: CH(CH2), CH3co, linoloyl [-C(OXCHz)tcH+cH, CHLCH: CH(CHz)4CHs] and the like.

rc2-c, the term "alcokynealkyl" means 2 to 8 carbon atoms and an oxygen atom. Straight chain or branched lower alkyl group substituted with lower alkyl group containing 1 to 3 atoms Meant to include Lucoquin. Such C2-C, alkoxyalkyl group Examples are methoxymethyl, methquinethoxymethyl, methquinethoxymethyl Includes ethyl, ethoxyethyl and the like. As an example of C,-C,alkoxymethyl, Ethoquinomethyl, Ethoquinomethyl, Propoxymethyl, Butoxymethyl, Pento oxymethyl, butquin methyl, pentoxymethyl, hexoquin methyl and hepoxymethyl Toquinomethyl, as well as their isomers.

The term "alkanoyloxymethylene" means a straight or branched chain of 2 to 8 carbon atoms. Meant to include alkanoyloxy substituted methylenes containing branched chains.

Examples of such C2-cs alkanoyloxymethylene groups are acetoxymethyl, t Including ert-butoxymethyl, n-propoquinemethyl, valeroxymethyl, etc. Ru.

The term "substituted penzoyloxymethylene" means that the benzene ring is a lower alkyl , trifluoromethyl, C, -C, alkoxy, nitro, or cyano group and Benzoyloyl substituted with 0 to 3 substituents selected from halogen atoms It is meant to include the methyl group.

The term "substituted benzenesulfonyl" means that the benzene ring is lower alkyl, Fluoromethyl, C, -C? Alkoxy, nitro, or cyano groups and halogens benzenesulfonyl group substituted with 0 to 3 substituents selected from It means to include.

The word "halogen" refers to the halogen atoms fluorine, chlorine, bromine and iodine. It means to include.

The term "haloC,-C,alkyl" means a straight or branched chain of 1 to 7 carbon atoms. atoms, and halogen-substituted C1-C groups containing from 1 to 3 halogen atoms. It is meant to include alkyl groups. Examples of haloC,-C7 alkyl are fluoro Methyl, 2-bromoethyl, 3-chloropropyl, 5-iodopentyl, trif Including fluoromethyl and the like.

The term "rcrca alkenyl" refers to straight or branched chain carbon atoms of 2 to 8 carbon atoms. and includes a lower alkyl group containing one or two double bonds. means. Examples of such C, -C, alkenyl groups are allyl, 3-butenyl, 2. Contains 4-pentadienyl, hexenyl, etc.

The term "rci-Cm alkynyl" refers to linear or branched chain carbon atoms of 1 to 8 carbon atoms. an alkynyl group containing one or two carbon-carbon triple bonds; It means to include. Examples of such C2-C,alkynyl groups are propargyl , 2-butynyl, 2,4-pentacyinyl, hexynyl, etc.

[Alkoxycarbonyl j (-(=O)O-(CHz), -CrCt full: + Examples of ethoxycarbonyl, isopropoquine carbonyl, methoxy carbonyl, butquine carbonyl, hexoquinecarbonyl, and the like.

C+ -C? Alkanoyl is a straight-chain or branched alkyl group having 1 to 7 carbon atoms. is meant to include the ru group. Examples of CrCt alkanoyl are acetyl, pro- Contains pionyl, 1so-butyryl, valeryl, 5-methylhexanoyl, etc. .

An example of aminocarbonyl (-C(=O)NR4R,) is /methylaminocarbonyl , propylmethylaminocarbonyl, dibutylaminocarbonyl, isopropylene It includes lyaminocarbonyl, hexylaminocarbonyl, and the like.

An example of aminothiocarbonyl (-C(=S)NR4Rs) is dimethylaminothio Carbonyl, propylmethylaminothiocarbonyl, dibutylaminothiocarbo Nyl, isopentylaminothiocarbonyl, hexylaminothiocarbonyl, etc. include.

Examples of the atomic group -P(=X) (R2XR3) are noethylthiophosphoryl, phenyl Methoquinophosphonyl, 2-thioxo-1,3,2-dioxaphospholinanyl, N , N-trimethylmethocinophosphoramidyl, nophenylphosphinyl, etc. Ru.

Examples of -3R are 2,4-/nitrobenzenesulfenyl, dimethylaminosulfenyl, Phenyl, ethquinocarbonylsulfenyl, trichloromethylsulfenyl, Includes 4-morpholinosulfenyl and the like.

-S　O! Examples of N R4Rs are dimethylsulfamoyl, phenylmethylsulfamoyl Rufamoyl, 4-morpholinosulfamoyl, piperidinylsulfamoyl, etc. includes.

The term "phosphorus-containing heterocycle" refers to 1,3-dioxa-2-phosphorinane, 1-aza- 3-oxa-2-phosphorane, 1,3-diaza-2-phosphorane, 1-thia-3 -Oxa-2-phosphorane and the like.

-N　R4Rs, -NR', R'5 and -NR,Rs-related heteroamine ring As an example: 4~morpholine, 4-phenyl-1-piperazine, 4-(2-pyridinyl)-1-piperazine, 2,6-nomethyl-4-morpholine , 1-pyrrolinone, 4-methyl-1-piperazine, 4-phenyl-1,2,3,6-natrahydrobiridine, 4-phenylpiperidine hmm, ethyl broinate, tetrahydrofurylamine, 3-pyrroline, thiazolidine-4-carboxylic acid, thiomorpholine, N-methylbiperanone 1-methylhomopiperazine, 1-acetylpiperazine, With N-carpoethoxobiberane- "Pharmaceutically acceptable salts" means salts useful in the administration of compounds of the invention; Menlate, hydrochloride, hydropromide, hydroionod, sulfate , phosphate, acetate, propionate, lactate, maleate, male Includes tartrate, succinate, tartrate, etc. These salts are in the form of hydrates. Good too.

Preferred compounds of the invention are compounds of formula (similar to formulas ■, ■, ■ and V); [Here, R2i and R25 are hydrogen, RI8. is hydrogen, C, -C, alkyl C2-Clalcoquinoalkyl, C2-C, alkenyl or benzyl, carbon The dashed line between elements 24 and 25 indicates a double bond].

Examples of compounds of formula H of the invention include 18-thiomark fortei N A 1-acetoquinemethyl-18-thiomark fortein A1-shedokinophosphor Lyle-18-thiomark fortein A1-dimethylsulfamoyl-18-thi Omark fortein A1-7 R-loprovir carbonyl-18-thiomarcfortein Lutein A2-binculo[2,2,11heptanoyl-18-thiomarchol] Teine A1-(1-piperinyl)thiocarbonyl-1-sacunnoyl-18- Thiomark fortein A1-(4-morpholinosulfenyl)-18-thiomer -kfortein A1-(2,4-dinitrobenzenesulfenyl)-18-thi Omark Fortein A24-Propoquine-2 4. 2 5-dihydro-18 -thiomark fortein A1-(p-toluenesulfonyl)-18-thiomer Cupfortein A1-acetyl-18-thiomarkfortein A1-methyl- 18-thiomarc fortein A1-bennol-18-thiomarc fortein A1-Methylcarbamoyl-18-thiomark fortein A1-Methoquinoca Rubonyl-18-thiomertafortine A24,25-dihydro-18-thio MarkFortein B24-Methoquino-24.25-dihydro-18-thiomer Coufortein B1-(p-toluenesulfonyl)-18-thiomark forte inB1-ethyl-18-thiomark forteinB1-bennol-18-thio Mark fortein B18a-ethyl-18-thiomertafortein B18a -hen/ruu 18-thiomark fortein B18a-methquinoethquine methyl -18-thiomark fortein B18a-allyl-18-thiomark fortein inB18a-propargyl-18-thiomarkforteinB18a-ethyl -24-methoxy-24.25-dihydro-18-thiomark fortein B 1 18a-bis-ethyl-18-thiomark fortein B1, 18a-bis -bennol-18-thiomark fortein B1 8 a-ethyl-24-meth Quino-18-thiomark fortein B1 (2,4-dinitrobenzenesulfony )-18a-ethyl-24-methquin-24.

25-dihydro-18-thiomertafortine B18a-ethyl-24.25 Dihydro-18-thiomark fortein B24, 25 Dihydro-18-thi Omark fortein C1-(p-bromobenzenesulfonyl)-18-thiomer -Fortein C1-propionyl-18-thiomark fortein C1-propionyl-18-propionyl Lopyl-18-thiomertafortine C1-bentrue-18-thiomertafortine Lutein C18a-propyl-18-thiomarkfortein C18a-henz Leu-18-thiomark fortein C18a-methoxynoethoxymethyl-18- Thiomark Forteia C18-Allyl-18-Thiomark Fortein Cl8 a-propargyl-18-thiomark fortein C1,18a-bis-propylene Ru-18-thiomark fortein C1,18a-bis-benzyl-18-thio MarkFortein C18-ThiomarkFortein C 1-(4-carbethoxy-1,3-thiazolignin-3-yl)carbonyl- 18-thiomark fortein A 1-Valmitoyl-18-thiomark fortein A1-(4-morpholinocal (bonyl)-18-thiomark fortein as an example of the compound of formula (■) of the present invention There are the following:

18-thioparahaquamide 24.25-dihydro-18-thioparahaquamide 14-0-methyl-18- Thioparahaquamide 14-0-ethyl-18-thioparahaquaamide 14-O -butyl-18-thioparahaquamide 14-0-benzyl-18-thioparaha -Quamide 14-O-allyl-18-thioparahaquaamide 14-O-propal Gyl-18-thioparahaquamid 14-0-methquinmethyl-18-thiopara Herquamide 14-0-methoxy/-ethokino-18-thioparahaquamide 14 -0-methoxy-ethyoxy-methyl-18-thioparahaquaamide 17-methy -18-thioparahaquamide 17-methylene-18-thioparahaquaamide 1-N-(p-toluenesulfonyl)-18-thioparahaquaramide 24-meth Quin-24,25-/hydro-18-thioparahaquamide.

Examples of compounds of formula (1) of the present invention include the following: 1-ethquinethiophosphor Lilumark forte A1-phenylmethokinophosphonyl-markforte in A1-cyclohexylcarbonyl lumamark fluortein A1-(1-piperi (dinyl)thiocarbonyl-markfortein A1-N-(4-carbuetquin -1,3-thiazolignin-3-yl)carbonyl-mark fortein A 1-Sakunnoyl Mark Fortin A1-(4-oxopentanoyl)-Ma -Mark fortein A1-dimethylaminoacetyl-mark fortein A1-N , N-dimethylsuccinamidoyl-markfortein A1-cyclopropylka rubonyl-18a-ethyl-markfortein B1-dimethylaminosulfe Nyl-18a-N-benzyl-markfortein B1-methocinocarbonyls Ruphenyl-18a-N-methoxyethoxymethyl-markfortein B 1-diphenylphosphinyl-18a-N-allyl-markfortein B1- (3-acetoxy)propionyl-18a-N-propargyl-markforte In B 1-(2,4-dichlorophenoxy)carbonyl-18a-N-ethyl-24- Methoxy-24,25-dihydro-markfortein B1-N-(2,4-di Nitrobenzenesulfenyl)-18a-N-ethyl-markfortein B 1-N-(p-bromobenzenesulfenyl)-mark fortein C1-acetate Toquinomethylmarkfortein C1-Schedquinthiophosphoryl-markfortein Lutein C1-phenylmethoxyphosphonyl-markfortein C1-cyclo Propylcarbonyl-mark fortein C1-cyclohequinylluponyluma -markfortein C1-(1-piperinyl)thiocarbonyl-markforte InC1-N-(4-carbuethoxy/-i,a-thiazolignin-3-yl)ka Rubonyl-Markfortein C 1-Sakunonoyrumakfortein C1-(4-morpholinosulfenyl) - Mark fortein C1 - Phenoquinocarbonylmata fortein C1 - (4-oxopentanoyl)-mark fortein C1-tumethylaminoacetyl Ru-mark fortein C1-N, N-dimethylsuccinamidoyl-mark fortein Lutein C1-valmitoyl-markfortein A, preferably 1 socrop lopyl carbonyl lumamark fluortein A1-phenoquine carbonyl-mark fluortein Fortein A1-Valmitoyl-MarkFortein A1-[[(4-Nitroph phenyl)oxy]carbonyl]-markfortein A1-(1-pipericinca (rubonyl)-markfortein A1-[[4-(etchincarbonyl)vipera Non-1-yl]carbonyl]-mark fortein A 1-[[4-(pencyl)piveranone-1-ylcocarbonyl comark fluor Teine A1-[[4-(1,3-benzodioxol-5-yl-methyl)bibe Ranon-1-yl]carbonyl]-markfortein A 1-[[4-(methyl)piveranon-1-yl]carbonyl]-Marcforte InA1-(1,3-one 1,3-one oxo-2H-isoindole-2 -il) -mark fortein A 1-[[4-(pyrinon-2-yl)piperazin-1-yl]carbonyl]-ma -Qufortein A 1-C[4-(phenyl)piperazin-1-yl]carbonyl 1-[[4-(c) lolocarbonyl)biperanon-1-yl]carbonylteine A 1-[[4-(phenyl)biperinone-1-yl]carbonyl]-markfor Teine A1-[[4-(dimethyl)pipery7-1-yl]carponyl comer Cufuortein A1-[[4-(5-chloropyridanone-3-yl)piperazine -1-yl] carponyl comark fortin A 1-[[4-(4-chlorophenyl)piperazin-1-yl]carbonyl]-mer -Qufortein A 1-[[4-()lichloroethquinyl)piperazin-1-yl]carbo Nil J-Mark Fortein A 1-[[4-(3-1-lifluoromethyl-thiadiazol-1-yl)pipera [din-1-yl]carponyl comark fortin A1-acetoquine methyl- Markfortein 1-(2,4-dinitrobenzenesulfenyl)-Markf Fortein A1-(4-morpholinosulfenyl)-MarkFortein A1- (trichloromethylsulfenyl)-markfortein A1-(methocynocal Bonylsulfenyl)-Markfortein A1-(benzenesulfenyl)- MarkFortein A1-(2-tetrahydrofuranyl)-MarkFortein A.

More preferably, 1-(4-morpholinocarbonyl)-mark fortein A or Or, 1-(4-morpholinocarbonyl)-markfortein AN-oxide.

Examples of compounds of formula V of the invention include:

1-acetoquine methyl-varahakuamido 1-one ethoxythiophosphorylupara Harquamide 1-phenylmethoxyphosphonyl-varahakuamide 1-noclob robyl carbonylrubalahar amide 1-cyclohequinolcarbonylrubalaher Quamid 1-(1-piperidinyl)thiocarbonyl-barahakuamide 1-N- (4-carbuetquin-1,3-thiazolignin-3-yl)carbonyl-bara Harquamide 1-Sakunnoirouparahaquamide 1-(4-morpholinosulfenyl)-parahaquamid 1-phenoki7carbo Niruparahaquamide 1-(4-oxopentanoyl)-varahakuamide 1 -dimethylaminoacetyl-varahakuamide 1-N,N-dimethylsatanami Doyle parahaquamide]-valmitoyl-parahaquamide 1-(4-morpholinocarbonyl)-barahakuamide.

Compounds of formula H are prepared in the following manner: Unexpectedly, Markfortein A , B and C1 or, as appropriate, their substitutions C-24, C-25, N-1 and N -18a derivatives are phosphorus trisulfide or, preferably, 2,4-bis(metquinphein) Nyl)-1,3-dithia-2,4-nephosphethane-2,4-disulfide - When treated with Etsson's reagent), It has been found that the corresponding 18-thio-derivatives are selectively provided. suitable for the reaction. C-24, C-25, N-1 and N-18a substitution marks fortein A, B and C derivatives (the disclosure of which is hereby incorporated by reference) are It can be easily produced by the method described in Patent No. 4923.867. The reaction is 1 Pyridine, colidine at a temperature of 0 to 180°C, preferably 80 to 140°C. (preferably) toluene, quinolene, dioxane, tetrahydrofuran, etc. Carry out in a suitable inert solvent.

Alternatively, the C-24, C-25 and N-1 derivatives are It can be produced from oltein. For example, a huge series of 18-thioma -Qufortein analogue is an N-18ali substituted 18-thiomerta It can be produced by alkylating or anorizing N-1 of the compound. These induction The body is treated with an excess of (preferably) potassium hydride at a temperature in the range of 0 to 50°C. , sodium hydride, butyllithium, potassium tert-butkind, etc. with a strong base such as 18 in excess of an aprotic solvent such as carbon, ether, benzene, etc. -Thiomark fortein ASN-188-substituted 18-thiomark fortein Add B or N-18a-substituted 18-thiomark fortino C, 0,25~ It can be easily produced by a series of treatments for 48 hours. A suitable alkylating agent is a Lucyl bromide, alkyl ioside, alkyl sulfonate, alkenyl iodine , alkynyl bromide, alkyne alkyl chloride, and the like. Appropriate a Sylating agents include acyl anhydrides, acyl chlorides, acyl bromides, and substituted benzenes. Zenesulfonyl chloride, substituted benzenesulfonyl anhydride, sulfenyl chloride chloride, isocyanate, carbamoyl chloride, chloroformate, etc. Contains.

A further series of derivatives include the C2 of 18-thiomark forteins A, B and C. It can be produced by modifying the 4-C25 double bond. 24°25 Nohydro analogs include alcohols such as methanol, ethanol, and propatool. A suitable solution of 18-thiomertafalutine in a similar solvent was heated in the presence of hydrogen gas in With catalysts such as aluminum, platinum, tris(triphenylphosphine)-chlororhodium, etc. It can be easily produced by stirring together. The product, i.e. 24.25-di Hydro-18-thiomertafortine analogs can be prepared using techniques known to those skilled in the art. Can be isolated and purified. Modification of other parts of the 18-thiomark fortein structure described above The decorating reaction was performed in 24.24 to produce the corresponding 24.25-dihydro analogue. Applicable to 25-dihydro 18-thiomark fortein analogs Please be careful. Repairing the C24-C25 double bond of 18-thiomark fortein Further analogues include dichloromethane, chloroform, carbon trichloride, etc. A solution of 18-thiomark fortein in a logenated solvent with 1 molar equivalent of bromine and -2 24, which can be easily produced by processing at 0 to 25°C for 0 to 8 hours. ．． 25 Can be produced via dibromide. This process is carried out by means known to those skilled in the art. The corresponding 24.25-dibromo24.25-dihydro- 18-thiomark fortein derivatives are provided. Bromine is salted in the process described above. Note that the 24,25-dichloro analog can be produced by substituting I want to be understood. 24.25-dibromo24.25-dihydro-18-thio as described above Markfortein analogs are useful intermediates for producing further derivatives. It is the body. Thus, alcoholic solvents such as methanol, ethanol, propatool, etc. The dibromide solution in the medium was added to 0.25 in the temperature range of 0 to 30℃ with a strong base such as -ene (DBU) After 24 hours of treatment, 24-alcohol is produced which can be isolated and purified using techniques known to those skilled in the art. coquine-25bromo-24,25onehydro-18-thiomark fortein a Get analog. These 24-alcoquine, 25-bromo derivatives are A solution of the compound in an aprotic organic solvent such as toluene, hexane, etc. Hydrogenation regardless of the addition of lanocal initiators such as sobutyronitrile (AIBN) 25 with tin hydride reducing agents such as tributyltin and triphenyltin hydride. Debromination by treatment at a temperature range of 120°C for 0.5 to 48 hours. can. This process can be performed using methods known to those skilled in the art to isolate and purify the corresponding 2 4-alcoquine-18-thiomark fortein derivative (R24=-lower membrane structure) alkoxy).

A general method for the production of N-oxides of heteroaromatic rings is described by A.R., Katoritsu et al. Key (A, R, Katritzky) and N.A.M., Lagowski (J, M. Chemistry of Heteroaromatic BIN-oxides (Che. mistry of the HeterocyclicN-○xides)J , 1971, Academic Press (Author) ORGANIC CHEMISTRY Volume 19-Mo It can be found in Part ■ of the Nograph Series). Typically, the N-oxy The compound is formed by reaction with a percarboxylic acid in a suitable solvent. Most appropriately, Since the reaction can usually be carried out at room temperature, an aromatic peracid in a non-polar solvent is used. suitable Suitable aromatic peracids include perbenzoic acid, monoaroic acid, chloroperbenzoic acid and perphthalic acid. Ru.

Compound 2) is produced by the following method.

Varahakuamide and its derivatives are combined with phosphorus trisulfide or, preferably, 2.4 -bis(methoquinophenyl)-1,3-dithia-2,4-diphosphethane-2, When treated with 4-disulfide (Rhoesson Test Straw), the corresponding 18-thio-induced selectively providing conductors; A suitable parahaquaamide derivative for this reaction is (The disclosure of which is hereby incorporated by reference) U.S. Patent No. 4.978.6 56 and 4.873°247 and the method described in WO91109961. Easier to manufacture. The reaction is carried out using pyridine, collidine, (preferably) toluene. 1 in a suitable inert solvent such as quinoa, dioxane, tetrahydrofuran, etc. It is carried out at a temperature of 0 to 180°C, preferably 80 to 140°C.

Alternatively, the C-24, C-25 and N-1 derivatives are 18-thioparahar Can be manufactured from quamid. For example, the vast series of 18-thioparahaquamy The analogue is N-1 of N-18affi-substituted 18-thioparahaquaamide. It can be produced by alkylating or anorizing. These derivatives are not 0 Aprotons such as tetrahydrofuran, ether, and benzene in a temperature range of 50°C. A solution of 18-thioparahaquamide in an organic solvent is (preferably) hydrated with potassium hydride. permeate, sodium hydride, butyl lithium, potassium tert-butokind, etc. 0.25 to 48 with the remainder of the strong base followed by a suitable alkylating or acylating agent. It can be easily manufactured by a series of treatments over a period of time. Suitable alkylating agents include alkylating agents. Lupromide, alkyl iosito, alkyl sulfonate, alkenyl iosito, Includes alkynyl bromides, alkokinoalkyl chlorides, and the like. suitable acyl The curing agent is acyl anhydride, acyl chloride, acyl bromide, substituted benzene chloride. sulfonyl, substituted benzenesulfonic anhydride, sulfenyl chloride, isocyanene These include salts, carbamoyl chlorides, chloroformates, and the like.

A further series of derivatives is based on the C24-C25 double bond of 18-thioparahaquamide. It can be generated by modifying the combination. The 24.25 dihydro analog is hydrogen In the presence of gas, in alcoholic solvents such as methanol, ethanol, propatool, etc. The appropriate 18-thioparahaqueamide solution was mixed with palladium, platinum, and tris(triphenylene). Nylphosphine) - can be easily produced by stirring with chlororhodium, etc. Ru.

The product, i.e. 24.25-dihydro-18-thioparahaquamid ana Logs can be isolated and purified using techniques known to those skilled in the art. 18-Thioparahaqua The reactions described above for modifying other parts of the mido structure include the corresponding 24.25-di 24.25-dihydro 18-thioparahar for producing hydro analogs Note that it is also applicable to quamid analogs. 18-Thioparahaque Additional C24-C25 double bond modified analogs of amides include dichloromethane, 18-thioparahaqueamide solution in halogenated solvents such as loloform, carbon tetrachloride, etc. The solution is treated with 1 molar equivalent of bromine at a temperature range of 20 to 25°C for 0.25 to 8 hours. It can be produced via 24.25 dibromide, which can be easily produced by processing. Ru. This process can be used to isolate and purify the corresponding 24. 25-dibromo24.25-dihydro-18-thiovarahacamide derivative provide. 24.25 dichloro analog replaces bromine with chlorine in the above reaction. Please note that it can be manufactured by changing. 24.25-jib mentioned above Lomo24.25-dihydro-18-thiovalahacamide analogs are further It is a useful intermediate for the production of derivatives. (Methanol, ethanol, A solution of dibromide in an alcoholic solvent such as Patul was prepared by adding 1,8-noazabicyclo[ A strong base such as 5,4,03 undec-7-ene (DBU) at 0 to 30°C. for 0.25 to 24 hours using techniques known to those skilled in the art. 24-alcoquino-25bromo-24,25dihydro-18-thi which can be isolated and purified Provides Obarahakuamide analogues.

These 24-alcoquino, 25-bromo derivatives are A solution of the compound in an aprotic organic solvent such as azobis-isobutyronitrile ( Regardless of the addition of a radical initiator such as AIBN), tributyl hydride tin hydride, such as triphenyltin hydride, at a temperature of 25 to 120°C. Debromination can be achieved by treatment at temperatures ranging from 0.5 to 48 hours. this pro The corresponding 24-alkoxy/ -18-thiobalahakuamide derivative (R21 = lower alkokene with -shell structure) provide.

A general method for the production of heteroaromatic ring N-oxides is described by A.R., Katlicki. - (A, R, Katritzky) and N.A.M., Labowski (J, Chemistry of Heteroaromatic ff1N-oxides (Che. mistry of the HeterocyclicN-Oxides)J , 1971, Academic Press (Author) Gani, Ri Chemistry (OI?GANICCIIEMISTRY), No. 19 Volume - Monograph Series (A 5 series of Monographs) , Part n. Typically, the N-oxide is prepared in a suitable solvent. It is produced by reaction with percarboxylic acid in Since the reaction can usually be carried out at room temperature, Most suitably aromatic peracids in non-polar solvents are used. Suitable aromatic peracids are Includes zoic acid, chlorofluoric acid, monozoic acid and perphthalic acid.

Compounds of formula It is produced by alkylating or acylating N-1 of B and C. child These derivatives can be used in aprotic organic solvents such as tetrahydrofuran, ether, and benzene. Mark fortein A or N-18a substituted mark fortein B or C solution (preferably) potassium hydride, sodium hydride, butyl lithium , an excess of a strong base such as potassium tert-butoxide, followed by appropriate alkylation. or acylating agent at 0 to 50°C for 0.25 to 48 hours. This makes it easy to manufacture. Suitable alkylating or acylating agents include alkaline Noyloxyalkyl bromide, aminosulfenyl chloride, phosphoryl chloride Lido, phosphonyl chloride, acyl anhydride, acyl chloride, acyl pro mido, substituted benzenesulfenyl chloride, carbamoyl chloride, substituted phenol Includes oxychloroformate, etc. Under these conditions, Mark Fortein\ and N-18a substitution mark fontin B and C and C24-C25 modification Once processed, the unmarked fortein can be isolated and purified using techniques known to those skilled in the art. 1-N-substituted analogs are provided.

Compounds of formula V can be prepared by alkylating or acylating N-1 of the varahakuamide. Manufactured by. These derivatives include tetrahydrofuran, ether, and benzene. A solution of parahaquamide in an aprotic organic solvent such as ) Potassium hydride, sodium hydride, butyl lithium, potassium tert-butyl with a strong base such as Tokind, followed by a suitable alkylating agent or acylating agent. It can be easily produced by a series of treatments at 50°C for 25 to 48 hours. suitable Suitable alkylating or acylating agents include alkanoyloxyalkyl bromides, Aminosulfenyl chloride, phosphoryl chloride, phosphonyl chloride, acyl anhydride, acyl chloride, acyl bromide, substituted benzenesulfenyl Includes chloride, carbamoyl chloride, substituted phenoxy/chloroformate, and the like.

Treatment of varahakuamide under these conditions results in ], -N-substituted analogs are provided.

A general method for the production of heteroaromatic ring N-oxides is described by A.R., Katlicki. - (A, R, Katritzky) and N.A.M., Labowski (J, Chemistry of Heteroaromatic Ring N-oxides (Che. mistry of the HeterocyclicN-Oxides)J , 1971, Academic Press (AcadeIlic Press ORGANIC CHEMISTRY, Volume 19- Monographs/Leeds (A 5eries of Monographs), It can be found in Part n. Typically, the N-oxide is Produced by reaction with percarboxylic acid.

Since the reaction is usually carried out at room temperature, it is most suitably carried out using an aromatic peracid in a non-polar solvent. Ru. Suitable aromatic peracids include perbenzoic acid, chloroperbenzoic acid and perphthalic acid. Contains.

Preparation of starting materials Varahakuamide was prepared using standard fermentation and isolation techniques from Benithulium sp. Penjcilium Sp,) TMI 332995 and/or Sirium Challenge MF 5123 (Penicilliu IIcharl essf) (ATCC 20841). The isolation is No. 4,873,247 and 4, all of which are hereby incorporated by reference. ．． 978.656 and European Patent Application No. 390532, European Patent Application No. 3 No. 01742 and WO91109961.

Preparation of starting materials N-18a substitution mark fontin B and C and C24-C25 modified mer Kufuortein (the disclosure of which is hereby incorporated by reference) It can be easily produced by the method described in Japanese Patent No. 4.923.867.

Markfortine A, B and C are already known Roqufortine (roqufortine). Beni/Rium Roqueforti (Penicill) standard fermentation and isolation as a fungal metabolite of Isolate using techniques. Isolation, analysis and structural characterization of Markfortein A Regarding gender, P. Olonsky et al., General of the Chemica Le Society Chemical Communion 　the Chemical　5ociety　ChemicalCommun cations), 1980, pp. 601-602. markoff The isolation and analysis and structural characterization of olteins B and C were described by Polonsky (P. olonsky et al., Tetrahedron Letters Letters), 1981.22, pages 1977-1980.

Alternatively, more preferably Markforteins A and C are Penicillium UC7780 (Upjohn Co., Kalamazoo, Michigan) Culture Collection a:z (IJpjohn Culture Co11e tion) strain number tlc7780). This strain is It was isolated from soil samples collected in a) United States Department of Agriculture, Patent Culture Collection B (U, S, D apartment of agriculture patent cult urecollection) and given the accession number NRRL 18887. It is being In order to further investigate the characteristics of the bacterium, Ai Jeong and Pinto (1, Jo hn Pitt), “The Genus Penicillium” ium) J, Academic Press, London (Academic Press A taxonomic study was carried out according to the methods and materials described in Test was carried out. The spores and hyphal surfaces were prepared using D. ietz, A, and Matthew+s, J), Applied Microba Iorono (Appl.

Microbiology), 18: 694-696 (1969) The specimens were examined using a scanning electron microscope according to the following procedures. Intact conidiophores are grown in a sliding culture. - After that, visualize with an optical microscope [Ae H Varnish, Onions (A, H, Smith's Introduction to Industrial Mycology (Smith's I ntrodction to Industrial Mycology) J, Jo>Whely & Sons, 2, - York (J ohn Wiel y and 5ons, New York), pp. 301-302 (1979)] Glass bedding dishes containing glass peas, microscope slide glasses and covers – Sterilize the glasses. Slide a small block of potato dextrose agar. Place on a mat and inoculate four sides with bacterial culture.

Place the coverslip onto the inoculated agar block and add sterile water to maintain humidity.

The chamber is incubated for 6 days at 24°C. Take out the cover glass and - Prepared by placing drops of Lactophenol Cotton Blue dye solution.

Benitulium sp. UC7780 (NRRL) 18887) are as follows: Morphology - Biaxially branched peninlus (two branch points between conidium and stalk). These branches ( Metho) supports the structure that carries the phialides or conidia. Conidiophore (approximately 35 μm) terminated in a whorl of 2 to 5 (10-14 μm) methos. centre The diarides are present in two to five whorls (7 μm) (ancient Girinyawai). It was in the form of an ampoule (like Nnoya). Conidia are smooth and spheroidal (2 μm) and typically looked like long columns. The side walls of the stipe are smooth. It was clear.

The cultures were grown on malt extract agar (MEA) and 25% nitric acid, respectively, with a diameter of 6 cm. Czapek yeast agar (CYA) with glycerol agar (025N) Three Petri dishes were inoculated. The inoculation was carried out in a semi-solid suspension (0.05% Tween 80 0.2% agar, 5ml). Testing the conidial inoculation loop Add to tube and mix. Loop the suspension in a pattern of 3 locations per plate. Inoculated. A needle was used to puncture and inoculate 5 cm plates. incubate One method is to add MEA and 025N to a CYA plate at 24°C. One is CYA plate at 37°C and 6cm CYA plate at 5°C. .

After 7 days, colony diameter, hue and other characteristics are recorded and listed in Table ■. Ja Gaimo dextrose agar (PDA, Difco) Or, on the contrary, deep red colonies are proliferating.

Sexual stage was not recorded. This in cultured bacteria (NRRL 18887) The result is a key to the subgenus of Penicillium Key. It is what it is. Among Benithulium keys, only the peninrus type has seeds distributed. Determine the subgenus. This species, even though its peninlus is biaxially branched, - Some distinct from the subgenus Biverticillium Has characteristics. Several species grew to a diameter of lQmm on glycerol nitrate agar medium in 7 days. Consistently forms larger colonies. The metho seems to be longer than the phialide. and in two to five whorls. These characteristics are that this beniturium The species (NRRL 18887) was placed in the subgenus F urcatum. Place it.

The following description can be used for the production of Markfortein and its derivatives. This is a demonstration of Benithulium sp. UC7780 (NRRL18887) strain. deer However, the present invention also includes mutants of the above microorganisms. For example, these mutants can be obtained by natural selection or ionizing radiation such as ultraviolet irradiation, or It can be produced by mutagenic factors including chemical mutagens such as guanidine, and this process is also standard. within the scope of the invention.

This specification covers, for example, joining, transaction, and Species produced by genetic techniques well known to those skilled in the art, such as genetic engineering techniques. It is desirable and intended to encompass inter- and intraspecific genetic recombinants.

Benithurium species UC7780 (NRRL 18887) is a well-known Penicillium It can be cultured under aerobic conditions using methods commonly used in the field of culturing strains of the genus. Wear.

As a medium component, any Penicillium (known nutritional substances can be used). Can also be done. For example, glucose, glycerol, malt as assimilable carbon sources ester, dextrin, starch, lactose, sugar, molasses, soybean oil, Preferably glucose and glycerol are used, such as cotton seed oil. , soybean meal, peanut meal, and coconut seed oil as sources of assimilable nitrogen. , Fitzschmir, Corn soaking liquid (corn 5teep 1iquo r), peptone, rice, bran, meat extract, yeast, yeast extract, sodium nitrate , ammonium nitrate, ammonium sulfate, etc. can be used. And chloride Adding inorganic salts to the medium, such as sodium, phosphate, calcium carbonate, etc. Can be done. If necessary, trace amounts of metal salts can also be added. In addition, trace amounts if necessary of heavy metals can be added.

Specifically, Benithurium spp. (NRRL 18887) is cultivated under aerobic conditions. For example, solid-state culture, culture under aeration and agitation, and conventional aerobic culture such as agricultural culture. Cultivation methods can be conveniently used. For example, zinc, magnesium, manga Trace metals such as cobalt, iron, etc. are not emitted because we supply reverse osmosis grade water. should be added to the fermentation medium.

For culturing with aeration and agitation, it is appropriate to use silicone oil, for example. Antifoaming agents such as , vegetable oil, and surfactants can be used.

The pH of the medium is usually in the range of 3 to 9, preferably in the neutral range or neutral range. The culture temperature is usually 20 to 30°C, particularly preferably about 21°C.

Cultivation is typically carried out for 20 to 24 hours, during which marked fortein A substantially accumulates in the medium. 0 hours, preferably 48 to 168 hours, and after incubation mark fortein A is isolated and recovered from cultured meat juice by an appropriate method that combines various methods. can. Extraction with organic solvents such as ether, ethyl acetate or chloroform For example, dissolve in a polar solvent such as acetone and alcohol and dissolve in petroleum ether or or activated carbon or silica gel adsorption column chromatography with a non-polar solvent such as hexane. Raffy to remove impurities (Fhurmana, Pharmacia, USA) Co.

Ltd.) “Sephadex” column available from It can be extracted by gel filtration.

MarkFortein B contains assimilable carbon and nitrogen sources under aerobic conditions. Biotransformation using microorganisms in an aqueous nutrient medium It can be produced from Markfortein A by tion).

The present invention applies to NR, RL 1368.1393 or 3655 and ATCC8 688a (an apparently discovered entity). Kuninno 1 Mela (Cu Also provided are biologically pure cultures of the genus Nnninghaiella.

From NRRL 1368.1393 or 3655 and ATCC8688a Cunningha lambda (Cunningha) was identified as a species selected from the group The production method of Markfortein B using bacteria of M. nella) fli is It consists of adding oltein A to the metabolic medium of the microorganism.

The term “bioconversion” refers to the use of microorganisms and/or isolated and partially purified enzymes in refers to the conversion of a given substrate into a useful product [H.G., D.B. Davis, H.G. et al., Biotransformation in Organic Chemistry (Biotra nsformations 1nPreparative Organic C hemistry) J Academy'yri Press, New Yori (Acad eIlicPress, N, Y, ), 1989, p. The word means to carry out the process of metabolism. The definition of metabolism is given by A.L. and Le. Ninon +- (L, A, Lehninger), [Principle of Biochemistry (Principle of Biochemistry)] lesof Biochemistry) J, Worth Bubbles, Nini Yo (Worth Publ, New York), 1982, p. 333. I can put it out.

Adding Markfortein A to the growth medium of the microorganism using the new method of the present invention Mark fortein B is produced by this. Improve the effectiveness of this conversion In order to (Cunninghanella echinulata 5ubsp, el Preferred is the genus Kuninhamella, which includes S. egans (-)) NRRL 1368.

Cunninghamella Blakesleyana (+) (Cunninghamella bl akesleeana (+)) AT CC8688a, Kunin/\Mela E Quinulata Subsp. 7-Zoo x Legance (Cunninghamella) echinulata subsp, elegans) N RRL 1393 , Cunninghamella echinu lata) NRRL 3655: The NRRL 3655 strain is particularly preferred.

Cunnhamera echinulata subspanes elegans (-) (Cunn inghamella echinulata 5ubsp, elegans ( −))) subculture was established in the Northern Region under the terms of the Budapest Treaty. Research Center, AIRNIS, US Department of Agriculture and Forestry: Peoria, IL, USA. Country (Northern Region Re5erch Center, AR S: U, S, Dept, of A4riculture: Peor ia, I1linois, U@S A) To the permanent collection Deposited. Its accession number is NRRL1368. Kuninhamera echinula Data Subspense Elegance (-XCunninghamella ec hinulata 5ubsp, elegans←)) subculture, Under the terms of the Treaty of Dapest, the American Type Culture Collection, Kubil, Maryland, USA (American Type Culture Co11ection.

Deposited in the Permanent Collection of Rockville, MD, USA) . Its accession number is ATCC8688b. Kuninhamera Blakesley Ana (+) (Cunnjnghamella breaksleeana (+) ) subculture was classified as an American type culture under the terms of the Treaty of Budapest. American Collection, Rockville, Maryland, USA Type Culture Co11ection, Rockville, Deposited in the Permanent Collection of MD, USA). its accession number is ATCC8688a.

Cunnihamera echinulata subspecies elegans (-) (Cunni nghamella echinulata 5ubsp, elegans (- )) subculture was established in the Northern Region under the terms of the Budapest Treaty. Search Center, AIRNIS, U.S. Department of Agriculture, Peoria, IL, USA. (Northern Region Re5erch Center, A RS ; U, S, Dept, of Agrjculture; Peor ia, I1linois, tS A) Deposited in the Permanent Collection. Its accession number is NRRL 1393 It is. Kuninhamera echinulata subspecies elegans (-) (C unningha+mella echinulata 5ubsp, eleg The ans (-)) subculture was also brought under the terms of the Budapest Treaty. Ip Culture Collection, Rockville, Maryland, USA (Ame rican Type Curture Co11ection, Rockv ille.

Deposited in the Permanent Collection of MD, USA). Its accession number is A It is TCC10028b.

Cυmlngha■ella echinula Under the terms of the Budapest Treaty, the subculture of Search Center, AIRNIS, US Department of Agriculture and Forestry: Peoria, IL, USA. (Northern Region Research Center, A RS ; U, S, Dept, of Agriculture; Peori a, I 1l Amashishishimantou B Deposited in the Permanent Collection of USA). Its accession number is NRRL It is 3655.

When these microorganisms are used in the method of the present invention, mark fortein A can be converted to mark fortein A. - Qufortein B is produced.

In the presence of Mark Fortino A, Kuni Nhamera echinulata subspecies elegans (-XCunning amellaechinulata 5ubsp, elegans(-))NR RL 1368, Cunningham Bragasleyana (+X Cunningham ella brakesleeana (+)) AT CC8688a, Kuni Nhamera echinulata subspecies elegans (-) (Cunning hamella echinulata 5ubsp, elegans(-)) NRRL 1393 or Cunningham echinulata When fermenting ella echinulata) N RRL 3655, Markfu Generate oltein B. Typically, microorganisms provide carbon sources and protein-like substances Fermented in a medium containing quality. Preferred carbon sources are glucose, brown sugar, and Knowledge, glycerol, starch, corn starch, lactose, dextrin , molasses, etc. Preferred nitrogen sources include cotton seed flour, corn steeping liquid, and fermented Mother, self-dissolving brewer's yeast and milk solids, soybean meal, cottonwood meal, Cornmeal, milk nonnos (milk 5olids), casein pancreas Distiller's 5olids ), animal peptone liquid, meat and bone fragments (5cr apts) etc. Advantageously, a combination of these carbon and nitrogen sources can be used. Trace metals are detected in tap water and unpurified components as culture medium components. For example, zinc, magnesium, manganese, cobalt, iron, etc. There is no need to add.

Mark fortein B is produced at a temperature of 23 to 32°C, preferably at which the microorganism can proliferate. or at any temperature of about 28°C. Normally, mark fortein A After about 1 to 4 days, preferably about 2 days after addition to the growth medium, the highest mark foliage is achieved. Production of lutein B is obtained. Normally, fermented meat juices are slightly acidic to basic ( pH remains at 5.8-9.0). The final pH is determined in part by the presence of buffer, It depends in part on the initial pH of the medium, if any. Before sterilization, conveniently , the pH is adjusted to 6.5 to 7.5, preferably 7.2.

When growing bacteria in shake flasks or large vessels and tanks, use Markfu To avoid significant delays in oltein B production and associated inefficiencies in equipment utilization, It is preferred to use the vegetative form of the microorganism for inoculation rather than the spore form. Therefore , in an aqueous nutrient medium by inoculating this medium with a portion from soil or slanted medium. It is desirable to create a vegetative inoculum. Thus, active vegetative contact in young children Once the seed is obtained, the bacteria are aseptically transferred to another shake flask or tank. microorganisms The medium in which the vegetative inoculum is produced should be It may be the same as or different from that used in the production of bottle B.

It can be used to isolate and purify mark fortein A from fermented meat juice, for example. Chromatographic adsorption followed by elution with a suitable solvent, column chromatography chromatography, partition chromatography, and solvent crystallization and their combinations. Depending on the setting, various techniques can be used.

In a preferred recovery process, Markfortein B is extracted from the entire brew. be done. To perform the initial purification, preferably a column chromatograph on silica gel. Use roughy technique. The final purification of Markfortein B is carried out by chromatography. - and crystallization from organic solvents.

Method A further illustrates the bioconversion process of the titled invention.

The compounds of the present invention have unexpectedly been shown to be effective against numerous parasitic diseases in humans, animals and plants. Excellent resistance against internal and external parasites, especially worms and arthropods that cause It is a parasite activator.

Parasitic diseases can be caused by endoparasites or ectoparasites. internal parasites is either an organ (such as the stomach, lungs, heart, intestines, etc.) or simply a subcutaneous host. It is a parasite that occurs inside the body. Ectoparasites live on the external surface of the host body, but It is a parasite that sucks nutrients from

Endoparasitic disease, commonly known as phlegmiasis, is an infection of the host by a parasite known as phlegmiasis. This is caused by Capillary worm disease affects pigs, sheep, horses, orchids, goats, dogs, and cats. and an epidemic and severe global economic problem caused by infection of livestock such as poultry. be. Many of these infections are caused by nematodes and nematodes that cause diseases in various animal species around the world. caused by a group of parasites expressed as These diseases are often It is often severe and can lead to death in infected animals. The most common infecting animals listed above Common nematode genera include Haemonchus, Trichostrongylus ( Tricostrongylus), Ostertagia , Nematodirus, Cooperi a), Ascaris (A 5caris), Bunostomum (B unostom) ull), Oesophagostomum, Chape Chabertia, Trichuris, Stro / S trongylus, Trichonema , Djctyocaulus, Capillaria H1aria), Heterakis, Tokinokara (Toxo) cara), Ascaridia (, 5caridia), Oxyalis (Oxyu) ris), AncylostoIla, Rannonaria (U ncinaria), Toxascaris and Balascaris It is a squirrel (Parascaris). Many parasites are species-specific (-host only) most have a preferred site of infection in animals. Thus, Haemonchus and Ostertagi a) primarily infects the stomach, whereas neomatodilus (Neo+atodilus) rus) and Cooperia mostly attack the intestines. other Parasites prefer to live in the heart, eyes, lungs, blood vessels, etc., while parasites live under the skin. There are some too. Mizushi disease can cause weakness, weight loss, anemia, intestinal disorders, malnutrition and damage to other organs. Vine causing disturbance. If these diseases are left untreated, the animal will die. It is possible.

External parasites such as ticks, mites, lice, stable flies, horn flies, black flies, fleas, etc. Infectious diseases caused by arthropods are also a serious problem. Infection with these parasites causes Blood loss, skin lesions occur, and can interfere with normal eating habits and cause weight loss .

These infected animals are susceptible to serious diseases such as potentially fatal encephalitis, anaplasmosis, and swinepox. It can also be used as a communicator.

Infection with the first species of parasite weakens the animal, which then becomes susceptible to infection with the second species. The animal can be infected with several parasites at the same time to make it more susceptible to infection. . Thus, compounds with a broad spectrum of activity are particularly useful in the treatment of these diseases. It is advantageous for medical treatment. The compounds of the present invention unexpectedly exhibit high resistance to these parasites. In addition, Dirofilaria has activity in dogs. ia), and Nematospiroides in the occidental ides), Syphacia, and Uno. jawed insects and migratory dipterous insects such as Hypoderma sp. Gastrophilus in the larva of the eye and in the horse It also has high activity against.

This compound is effective against internal and external parasites that cause parasitic diseases in humans. is also useful. An example of an internal parasite that infects humans is ankylostoma (A ncylostoma), Necator, Ascaris arjs), S strongyloides, Turin early Trichinella, Capillaria, Trichinella Trichuris, Enterobius, etc. including gastrointestinal parasites. Other internal parasites that infect humans are the blood or other organs. is found in An example of such a parasite is the filamentous parasite Wucheria. , Brugia, Onchocerca, etc. Intestinal parasites S strongylides and Trichinae There is an extraintestinal stage of Trichinella. Endoparasites that infect humans Insects include arthropods such as ticks, sun flies, mites, and lice; For humans, infection with these parasites can result in the transmission of serious and even fatal diseases.

The compound has manual activity against these internal and external parasites, and is additionally active against humans. It is also active against unpleasant jawed insects and other dipteran pests. This compound 0.05 to 20 mg/kg animal body weight when administered orally or parenterally administered at a dosage ratio of

This compound is used in Blatella sp. La species (Tineolasp, ), Attagen ous sp, Musca domesticus (Musca d common household pests such as the housefly Against Invicta ((Solenopsis I nvicta)) It is also valid even if

The compound further comprises alkylthiosiphon species ((Acyrthiosiphons). Agricultural hazards such as P. p. insects and stored grains such as Tribolium sp. Also against insect pests that attack plants and immature stages of insects that live in plant tissues. Useful. The compound is useful as a nematicide for controlling agriculturally important soil nematodes. It is also useful.

When used as an antiparasitic agent in animals, the compound may be administered either orally or by injection. It can be administered internally or topically as a liquid infusion or noyanbu.

For oral administration, the compound may be in capsule, tablet or dip pill form or It can be administered by mixing it into the animal's feed. The capsules, tablets and liquid pills The drug contains starch, talc, magnesium stearate or dicalcium phosphate The active ingredient is combined with a suitable carrier vehicle such as. These single Dosage forms include diluents, fillers, disintegrating agents, suspending agents and/or single admixtures or with suitable finely divided inert ingredients including a binder such that a suspension is obtained. Prepared by thoroughly mixing the active ingredients. Inert ingredients are those that do not react with the compound and are It is non-toxic to treated animals. Suitable inactive ingredients include starch, lactose, Includes talc, magnesium stearate, vegetable gums and oils, etc. this Their formulation depends on the size and species of the animal being treated and the symptoms and type of infection. (variable amounts of active and inactive ingredients) can contain. The active ingredient can be added by simply mixing or compounding the compound with the feed. It can also be administered by adding the compound to the feed by applying it to the surface of the feed. Ma Alternatively, the ingredients are mixed with an inert carrier and the resulting composition is then mixed with the feed. or can be given directly to animals. A suitable inert carrier is corn. Includes meal, citrus meal, yeast residue, soy flour, dried grains, etc. Applicable The active ingredient is such that the final composition contains 0.001 to 5.0% by weight of active ingredient. These inert carriers are ground, stirred, crushed or agitated until thoroughly mixed. will be combined.

The compound may also be administered via injection, a formulation consisting of the active ingredient dissolved in an inert liquid carrier. It can be administered parenterally. Injections may be intramuscular or intragastric. ++1nal), intratracheal or subcutaneous It can be done with The injectable composition comprises the active ingredients mixed with a suitable inert liquid carrier. I understand. Acceptable liquid carriers include peanut oil, cottonseed oil, vegetable oils such as sesame oil, turketal, glycerol Includes organic solvents such as formals and the like. Alternatively, aqueous parenteral formulations may also be used. I can be there. The vegetable oil is a preferred liquid carrier. The formulation should be The active ingredient is carried in a liquid such that the liquid contains 0.005 to 20% by weight of active ingredient. Prepared by dissolving or suspending in the body.

Topical administration of the compound may be achieved by using a liquid containing the compound as an aqueous solution or suspension. It is possible through the use of soaks or shampoos. These prescriptions are generally Like tonite! It will contain a clouding agent and will usually also contain an antifoaming agent.

Formulations containing from 0.005% to 20% by weight of active ingredient are acceptable. preferred place The latter contains 0.5 to 5% by weight of the compound.

The compound may be used in animals such as sheep, horses, dogs, cats, goats, pigs, and poultry. Mainly used as an antiparasitic agent for the treatment and/or prevention of mange disease in domestic animals. Useful. These are caused by external parasites such as ticks, mites, lice, fleas, etc. It is also useful for the prevention and treatment of parasitic infections in these animals. These are human It is also effective in treating parasitic infections. In the treatment of such infectious diseases, the present invention Compounds may be used individually or in combination with other unrelated antiparasitic agents or antiparasitic agents. They can be used together. The dosage of the compound required for best results is species and size, type of infection and severity of symptoms, method of administration and use Depends on several factors, such as the compound. The compound is generally administered orally to animals. At dosage levels of 0.005 to 50 mg/kg of body weight, either as a single dose or every few days. Good results can be obtained by administering the drug several times. A single dose of one of the compounds usually produces a maximum effect, but to resist reinfection or to abnormally persistent parasite species. can be administered repeatedly. Techniques for administering these compounds to animals Known to those skilled in the medical field.

The compounds of the invention are useful for resisting agricultural pests that attack fields or stored crops. It can also be used for In such applications, the compound may be sprayed, airborne, etc. Applied as a spray, suspension, etc. to growing plants or harvested grain. In this method Techniques for applying these compounds are known to those skilled in the agricultural arts.

The following examples are provided to more fully understand the invention; This is not to be construed as limiting the invention.

Example 1 Production and isolation node fermentation process of Markfortein A Seed fermentation was carried out using Penicillium species preserved in liquid nitrogen. sp, ) UC7780 (NRRL 18887) isolated strain agar p Inoculate using the following methods.

Thaw three stoppers and use as inoculum. G5-7 is a combination of glucose and - Dar's Protein, Brocter & Gamble Co., Memphis, Tennessee; United States (Traders Protein, Procter & Gamble 0ilseed Products Co, , Memp ■ Kanto B TN, tJSA)'s "Pharma+1edia) J Naru" Consisting of Kotton node powder (which is a trademarked solid). Additive-free tap water to culture medium component water The medium was adjusted to pH 7.2 with aqueous ammonia hydroxide. 10% of the medium 00m1 Bladeless closed system frass: I (unbaffled closed sy Pour 300 ml of Elff agent into stem flasks and incubate for 30 minutes at 121°C. Sterilize by tococlaving. Without each blade containing 300ml of G5-7 medium In a closed flask, add Benicilliu species (Penicilliu++ sp,) UC. Inoculate three agar plugs of 7780 (NRRL 18887) and Stir at -22°C and 25 rpm for 36 hours.

Second seed fermentation step.

The grown seed culture is used as an inoculum to the second medium at a 0.3% seed ratio.

The second medium was prepared in reverse osmosis grade water 11 (CPC International Inc.). .

P, C, I international)'s "Cerelose" 25 g of glucose-hydrate (a solid with the trademark J), (rPharmamedia (Pharmamedia) cotton powder 5 g1 Magnesium chloride hexahydrate 329.8 mg.

Manganese sulfate hydrate 11.4mg, iron sulfate heptahydrate 3.2mg, molybdic acid Sodium trihydrate 1.8 mg, calcium chloride dihydrate 367.6 mg, chloride Sodium 84.2 mg, potassium chloride 5.8 mg, zinc sulfate heptahydrate 0.1 m g, cobalt chloride hexahydrate 0.1 mg, copper sulfate pentahydrate 3.1 mg and (rS AG-471Aniform (S AG-471Aniform) J trademark 05 ml of silicone antifoam (solid). Sufficient for No. 27-do medium 2001 Hydrate the media components with sufficient 1901 reverse osmosis grade water in a 2501 fermenter. do.

After formulation, the medium was adjusted to pH 7.2 with ammonium hydroxide and then Sterilize the substrate at 121° C. for 30 minutes. Two clusters containing the grown first seed culture bacteria Closed-system flask: + (closed-system flask) at 0.3% Used as an injection source at a low ratio. The second node cultured bacteria was heated to 22°C with aeration of 125 sl (back pressure of 5 p). Incubate for 36 hours at sig, 250rp+*.

Manufacturing fermentation process: The production fermentation medium consisted of 50 g of beet molasses per 11 hours of reverse osmosis grade water, Menhaden 5elect 16 g of Fish Meal (a solid trademarked as Fish Meal) J, (r Yeast Extract Log, Chloride Mag Ne/Rum hexahydrate 329.8 mg.

Manganese sulfate-hydrate 11.4 mg, iron sulfate heptahydrate 3.29 mg, molybdenum sodium acid dihydrate 1.8 mg, calcium chloride dihydrate 367.5 mg, salt sodium chloride 84.2 mg, potassium chloride 5.8 mg, zinc sulfate heptahydrate 0.1 mg, cobalt chloride hexahydrate 1 mg, copper sulfate pentahydrate 3.1 mg, and (S AG-471 Antifoam (SAG-471 Antifoam) J trademark 0.5 ml of silicone antifoam (solid).

Add enough medium components to the medium 50001 to a sufficient amount of 47001 in the 50001 fermenter. Hydrate with reverse osmosis grade water. After formulation, the pH of the medium is adjusted to potassium hydroxide. The medium is then sterilized at 121° C. for 30 minutes. grow up The second node culture was used as the inoculum at a 10% node ratio. Culture bacteria at 22℃ with aeration. 2. Ink coating for 96 hours at 500 sl+i, 5 psig back pressure, 25 Orpm to

Isolation of mark fortein A Collect 49001 fermentation volumes through a high shear mixer into a collection vessel. after that Add 4% vt, /v diatomaceous earth and 1/2 volume methylene chloride. Next The collected solution is then filtered using a filter press. The filter cake was mixed with 10% salt by volume. Wash twice with methylene chloride.

The obtained filtrate is decanted to remove the water (aqueous) layer. Then, The remaining product-rich methylene chloride layer is concentrated to a volume of 441 g. Then, the corresponding Pour the concentrate into 20% concentrated volume (91) of methylene chloride and diatomaceous earth on the filter. Finish using.

In order to separate mark fortein A from other components of the finished concentrate of 531/ Further purification is performed by silica gel chromatography and crystallization.

Before chromatography, divide the finished concentrate into approximately four equal volumes. Ru. Each aliquot was prepared with 25 Kg (bed volume 591) of dry silica gel and freshly prepared. Chromatography on a 9" diameter column packed with loaded column , 10% acetone in methylene chloride 1201, 20% acetone in methylene chloride 1201, 30% acetone in methylene chloride 1201, 40% in methylene chloride % acetone 1601, and acetone 1301, 30% and 40% elution. The effluent is collected in 201 fractions. The eluate is diluted with eluate, e.g. 6% isopropylene in methylene chloride. Whatman LK6 in a solvent system consisting of Patur and 3% ammonium hydroxide. D　F　(Whatman　L　K　6　D　F　) Nlica gel plate is developed. and monitor with TLC. (A small amount of Markforte co-chromatographs with D. Both parts of Markfortein A (containing InD) are crystallized from acetone. suitable The relevant fractions (40-1001) are concentrated under reduced pressure to a volume of approximately 51. Then the Transfer the solution (or light slurry) to a rotary evaporator and concentrate under reduced pressure. Continue. During the concentration, 11 aliquots were added in several portions until the methylene chloride was completely replaced. Add setone. The resulting acetone slurry (approx. II volume) was frozen overnight and - Collect crystals of Quafortein A and wash them with a small amount of cold acetone in several portions. Dry under vacuum. Such crystals are contaminated with a few percent of mark fortein D. You may be doing it. Repeated methylene chloride/acetone (chloride as described) Recrystallization from methylene substitution) provides pure Markfortein A. Ru.

Example IA Production and Isolation of Mark Fortein A and C First Round Fermentation Process degree Nodal fermentation was performed using Benicilliu species (Penicilliu + *) preserved in liquid nitrogen. sp, ) UC7780 (NRRL 18887) isolate using an agar plug. . Thaw the three stoppers and use them as an inoculum for 100 ml of G5-7 mode medium. . G5-7 contains glucose and (Traders Protein, Brocter & Gi Traders Protein, Inc., Memphis, TN, USA (Traders Protein , Procter & Gamble 0ilseedProducts C o, , Memphis, Ding N, USA) trademarked “Pharmamedia” solid state. ) Conotondo powder added to tap water at a concentration of 25 g/I each Become. After formulation, the pH of G5-7 is adjusted to 7.2 with ammonium hydroxide. 5 Pour 100ml of the medium into a 00m bladeless fermentation flask and autoclave for 30 minutes. process. Inoculated with sterile G5-7 as above and incubated at 25 Q rpm and 23°C. Shake for 35 to 58 hours.

Manufacturing fermentation process (shake flask) The grown node culture was used as an inoculum for sterilized production media at a 1% node ratio. There is. The production medium contains 45 g of glucose per tap water of II. Sheffield Products, Norwich, New York, USA (Sheffield Products.

Norvich, N.Y., U.S.A.) "Pebtonized Milk =... - Triendo (Peptonized Milk Nutrient) J quotient 25 g of enzymatically decomposed casein (as a labeled solid), (Difco Laboratories, Det. Royt Michigan (Difco Laboratories).

Detroit, M+) rBACT○ yeast extract code: 01 Consisting of 2.5 g of yeast extract h (solid) under the trademark 27J. Like a prescription , the pH of the production medium is adjusted to 7.0 using potassium hydroxide. Next, this culture Pour 100ml of the fermentation mixture into a 500ml bladeless fermentation flask and auto-cook for 30 minutes. Reve processing.

Sterile production medium was inoculated as above and incubated at 250 rpII for 7 to 14 hours at 21°C. Stir for days.

Manufacturing fermentation process (Labrafern tanks) The grown / -do culture is used as an inoculum in a sterile production medium at a 0.5% nodal ratio.

The production medium is as described above. After adjusting the pH to 70 using potassium hydroxide 121 Labruff Arm Tank with Brunswick Scientific New Brunswick 5 scientific Co., Inc. , )) This medium 101 is autoclaved for 90 minutes. The tank is 0. Inoculate at 5% node ratio and stir at 500 rpm and 20° C. for 5 to 9 days. air The flow rate is maintained between 10 and 151/min.

Mark Fortino, and isolation of C.

The whole fermented juice (351) was softened at low speed in a large commercial Waring Brengu; Blend equal volumes of methylene chloride. The mixture was frozen and stored overnight, then Then, it is centrifuged to break the emulsion. The resulting transparent methylene chloride layer Pull up and evaporate under reduced pressure. Concentrated solution of residue 11 (37.4 g) in methylene chloride The solution was applied to a column of Norica gel (1, Kg) slurried in methylene chloride. vinegar. The column was washed with increasing concentrations of acetone (10%, 20%) in methylene chloride. %, 30%, 40%, and 50% acetone). Monitor the fractions by TLC. ter, distill off appropriate fractions, recrystallize from acetone, and obtain mark fortein. A and mark fortein C are obtained.

Example IB Preparation and isolation of mark forteins A and C.

/-Fermentation process: / - fermentation was carried out using Penicillium species preserved in liquid nitrogen. sp, ) IJC7780 (NRRL 18887) isolated strain using an agar plug. Seed. Thaw the three stoppers and use them as an inoculum for 100 ml of G5-7 mode medium. Ru. G5-7 contains glucose and (Traders Protein, Brocter & Gamble Inc., Memphis, Tenn., USA (Traders Protei) n, Procter & Gamble 0ilseedProducts Co., Memphis, T.N., U.S.A.)'s "Pharmamedia" 25g/I powder of Kottonnode (trademark solid) was added to tap water at a concentration of 25g/I. Consists of added ingredients. Prescription 1. Adjust the pH of G5-7 to 7.0 with ammonium hydroxide. Adjust to 2. 500 m') Pour 100 ml of the medium into a fermentation flask without AWi. Autoclave for 30 minutes. Inoculated as above into mG5-7 medium, Shake at 250 rpm for 35 to 58 hours.

Manufacturing fermentation process (Mx flask)・ The grown node culture is used as an inoculum in the production medium at a 1% node ratio. Made by The culture medium consists of 20 g of glucose 1 15 ml of glycerol (11 g of tap water) - Dar's Protein, Brocter & Gamble Co., Memphis, Tenn. United States (Traders Protein, Procter & Gamble 0ilseed Products Co.

MeIIphis, TN, U.S.A.) “Pharmamedia (Ph armamedia) J solid powder), die Consisting of 10 g of Summir and 3 g of dipotassium hydrogen phosphate. After formulation, production medium The pH of the solution is adjusted to 6.8 using potassium hydroxide. Next, 100ml of second medium Pour volume I into a 500 ml bladeless fermentation flask and autoclave for 30 minutes. Ru. Inoculate the sterile production medium as above and grow at 250 rpm and 21°C for 7-14 days. Intermittent.

Production fermentation method (Labruff arm tank).

The grown node culture was used as an inoculum in a sterile production medium at a 0.5% node ratio. There is. The production medium is as described above. Adjust the pH to 7.0 using potassium hydroxide. After adjusting, I put a new Brunswick Scientist on the 121 Labruff arm tank. CNev Brunswick 5cientific Co. This medium 101 is autoclaved for 90 minutes in a microcomputer, Inc., )). The tongue The mixture was inoculated with 0.5% seed ratio and stirred at 500 rpm and 20° C. for 5 to 9 days.

The air flow rate is maintained between 10 and 15 minutes.

Isolation of mark forteins A and C: The whole fermentation juice (351) was Soften at low speed in a ring blender and then mix with an equal volume of methylene chloride do. The mixture was frozen and stored overnight, then centrifuged to break up the suspension. Attach it separately. The resulting transparent methylene chloride layer is pulled up and distilled off under reduced pressure. chloride A concentrated solution of the residue (37.4 g) in methylene was prepared using a glue gel (I) in methylene chloride. Kg) Apply to a column packed with slurry. The column was slowly placed in methylene chloride. With increasing concentrations of acetone (10%, 20%, 30%, 40% and 50% acetone) t). The fractions were monitored by TLC, and both appropriate fractions were distilled off and acetone was added. Mark forteins A and C are obtained by recrystallization from .

Example 2 18-thiomark fortein A (compound #2) in 5 ml toluene Markfortein A 30mg and 2.4-bis(methquinophenyl)-1 ,3-dithia-2,4-nophosphethane-2,4-disulfide (Rhoethosone) Reflux the reagent (Lawesson's reagent) solution for 18 hours under nitrogen. do. The mixture is cooled and the solvent is distilled off under reduced pressure. The residue is treated with silica gel. 10% acetate in methylene chloride 18-thiomark A with a melting point of 258-260° C. is obtained using C. as eluent.

FAB-MS 494 (M4+H) The following is the conventional method of Example 2, but using the appropriate Markfortein starting material. The following compounds are manufactured as other 18-thiomark fortein compounds. do 1-Methyl-18-thiomark fortein A1-benzyl-18-thiomark fortein A1-ethyl-18-thiomark fortein B1-benzyl-1 8-thiomark fortein B18a-ethyl-18-thiomark fortein B18a-benzyl-18-thiomark fortein B18a-methquine ethoxy methyl-18-thiomark fortein B18a-allyl-18-thiomark Fortein B18a-propargyl-18-thiomark fortein B1,1 8a-bis-ethyl-18-thiomark fortein B1.188-bis-ben True 18-thiomark fortein B18a-ethyl-24-methquin-18 - Thiomark Fortein B18 - Thiomark Fortein B (Compound #2A) FAB-MS 480 (M4+H) 18a-ethyl-24,25 dihydro-18-thiomark fortein B1-propylene Lopyl-18-thiomark fortein C1-bentrue 18-thiomark fortein Lutein Cl8a-propyl-18-thiomark fortein Cl8a-bendi Le-18-thiomark fortein Cl8a-methquinethoquinomethyl-18- Thiomark fortein 018B-allyl-18-thiomark fortein Cl 8a-propargyl-18-thiomark fortein C1,188-bis-pro Pyr-18-thiomark fortein C1,18a-bis-benzyl-18-thi Omark Fortein C18-Thiomark Fortein C 1-Valmitoyl-18-thiomark fortein A1-decanoyl-18-thi Omark fortein A1-decanoyl-18-thiomark fortein B implementation Example 3 24.25 Nhydro 18-thiomark fortein A methanol 1 m 15 mg of 5% carbon palladium and 18-thiomark fortein A (3 A mixed solution consisting of 0mg, 0.06mmol) was vigorously heated for 45 minutes under a hydrogen atmosphere. Stir thoroughly. The reaction solution was filtered through Celite, and the filtrate was evaporated under vacuum. evaporate to the bottom. Perform preparative chromatography on the residue using a 0.5 mm gel plate. and eluted with 3% methanol in methylene chloride to give 24.25-dihydro 1 8-thiomark fortein A is obtained.

Example 4 24.25-dibromo-24,25-onehydro18-thiomarcof Altein A Bromine solution (04 ml of 12M solution, 0.048 mmol) in lyoform A solution of 18-thiomark fortein A cooled in a water bath in 2 ml of chloroform. (20 mg, 0.04 mmol) dropwise. Pour the resulting yellow solution into the chamber. Stir at room temperature for 15 minutes and then evaporate under nitrogen atmosphere. Q, 5mm thick 2% methane in methylene chloride was subjected to preparative chromatography on Kagel plates. Elute with 24.25-dibromo-24,25-dihydro-18-thiomer. - Obtain Kufornine A.

Example 524-Methoquino 24.25-dihydro 18-thiomark fortein Bromine solution in roroform (0,12M solution Q, 5 ml, O0072mmo l) in 2 ml of chloroform (in a water bath) of cooled 18-thiomark fortei. Add dropwise to Solution B (28 mg, 0.06 mmol). generated yellow The color solution was stirred at room temperature for 10 minutes, then at 0°C for 20 minutes and heated under nitrogen atmosphere. Distilled under the water. The yellow solid residue was dissolved in 2 ml of methanol and then 1. Total diazapinoclo[5,4,0]undec-7-ene (DBU, 0.015ml ．． 0.10 mmo+) is added. The solution was stirred at room temperature for 90 minutes, then Distill into the sky. 1. Transfer the residue to a preparative layer chromatogram on a Qmm glue gel plate. 24-Method and eluted with 2% methanol in methylene chloride. Quin-25-bromo-24゜25-7hydro-18-thiomark fortein B get. The thus obtained 24-medokino 25-bromo-24,25-dihydro -18-thiomark fortein B was dissolved in 2 ml of dry toluene, and then Add tributyltin hydride (0.12 ml 0.45 mmol I). Applicable The solution is stirred at 100° C. for 16 hours and then evaporated under vacuum. The residue was 2.0 Methyl chloride was subjected to preparative layer chromatography on a mm silica gel plate. 24-methquine-24,25-dihydro-1 8-thiomark fortein B is obtained.

Example 624-Propoxy 24.25-dihydro-18-thiomark fortei N A The above 24-methoxy24.25-dihydro-18-thiomark fortein B ( The propatool in the method of Example 5) was replaced with methanol, and the modification method was changed to 1. Apply 20 mg of 8-thiomark fortein A to obtain an oily residue. The crude product Q, subjected to preparative layer chromatography on a 5 mm silica gel plate, Elute with 2% methanol in methylene chloride, 24-propoxy-24,25-di Hydro-18-thiomark fortein A is obtained.

Example 7 1-(dimethylcarbamoyl)-18-thiomark fortein A hydrogen (50 mg of 25% oily dispersion) in 1 ml of dry tetrahydrofuran. Added to 18-thiomark fortein A solution (15 mg, 0.030 mmol I) add The solution was stirred at room temperature for 2 hours and then dimethylcarbamoyl chloride (0 ,028m1.0.30mmo+). The mixture was stirred at room temperature for 18 hours. and then 5% aqueous sodium bicarbonate solution (1 ml) and methylene chloride (1 ml). ) to distribute between. Once the layers are separated, the aqueous layer is extracted with methylene chloride (2 ml). If The combined extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. the residue was subjected to preparative layer chromatography on a silica gel plate in hexane. Elute with 25% acetone of 1-(dimethylcarbamoyl)-18-thiomark. Obtain Fortein A.

The following is the conventional method of Example 7, but using the appropriate Markfortein starting material. The following compounds are manufactured as other 18-thiomark fortein compounds. do 1-acetoxymethyl-18-thiomark fortein A1-jethoxyphospho Lyle-18-thiomark fortein A1-cyclopropylcarbonyl-18- Thiomarc fortein A1-methylsulfamoyl-18-thiomarcfortein Lutein A1-(1-piperidinyl)thiocarbonyl-18-thiomarchol Tein A1-Sarannoyl-18-thiomark fortein A1-(2,4-di Nitrobenzenesulfenyl)-18-thiomark fortein A1-(4-mo rufolinosulfenyl)-18-thiomark fortein A1-(p-toluene sulfonyl)-18-thiomark fortein A1-acetyl-18-thiomer Coufortein A1-methquine carbonyl-18-thiomark fortein A1 -1)-toluenesulfonyl)-18a-thiomark fortein B1-(2, 4-Dinitrobenzenesulfonyl)-18a-ethyl-24-methquine-24° 25-dihydro 1-(bromobenzenesulfonyl)-18-thiomark fortein C1-p lopinoyl-18-thiomarkfortein C1-(4-carbuetquin-1, 3-Thiazidinin-3-yl)carbonyl-18-thiomark fortein A Example 8 1-bentrue 18-thiomarcfortin A potassium hydride (25 % oil dispersion) in 1 ml of dry tetrahydrofuran. Add to fortein compound (15 mg, 0.030 mmo I). The melt The solution was stirred at room temperature for 2 hours, then pennlubromide (0.025 ml, 0.2 1 mmol). The mixture was stirred at room temperature for 3 hours and diluted with methylene chloride (2 m Extract the aqueous layer with l). The combined extracts were then diluted with water (1 ml) and methyl chloride. (1 ml). Once the layers are separated, remove the aqueous layer with methylene chloride (2 ml). Extract. The combined extracts were dried over magnesium sulfate, filtered and evaporated under vacuum. do. The residue was subjected to preparative layer chromatography on a 1.0 mm Linkel plate. and eluted with 3% methanol in methylene chloride to obtain IN-benzyl-18-thi. O-mark fortein A is obtained.

The following is the conventional method of Example 8, but using the appropriate Markfortein starting material. The following 18-thiomark fortein compound: 1.18a-bis-ethyl-1 8-thiomark fortein B: 1-allyl-18-thiomark fortein A ;1-methquinmethyl-18-thiomark fortein A;1-propargyl- 18-thiomark fortein A: 1-benzyl-18a-dithylthiomark Fortein B; is produced.

Example 9 Haemonchus contorcus tus) / Trichostrongylus coluburiformis (Trichostr. ongylus colubriformfs)/gerbil assay (J) ird assay): There are two types of this in vivo assay. H. contorcus (H, can toru s) and T. colubriformis (anthelmintics - susceptible or slightly resistant worms can be used) It uses rats. At first, G, A, Congee (G, A, Conder) et al., Journal of Parasitology (J, Parasi tol, ), 76, pp. 168-170 (1990). It will be evaluated only for H, contorus, but in the supplementary exam G.A., Cong.G., A.

Conder) et al., Journal of Parasitology (J, Parasf) tol, ), 77.621-623 (1991). activity against both species. The activity is shown in Table 1 onwards.

Example 10 The following is the usual method of Example 2, but suitable parahaquaamide/thioparahaque Using the amide starting material, the following other 18-thioparahaqueamide compounds 18-thi Oparahaquamid 1-Methyl-18-thioparahaquaamide 1-ethyl-18-thioparahaqua mido-1-bencyl-18-thiobalahakuamido-1-valmitoyl-18-thio Parahaquamide 1-decanoyl-18-thioparahaquaamide is prepared.

Example 10a The following is the usual method of Example 7, but with a suitable parahercamide/thioparahar Using the quamid starting material, the following other 18-thioparahaquamid compounds: 1- Acetoxymethyl-18-thiomark fortein 1-jethoxyphosphoryl- 18-thioparahaquamid 1-cyclopropylcarbonyl-18-thioparaha -quamid 1-dimethylsulfur 7moyl-18-thioparahaquaamide 1-(1 -piperidinyl)thiocarbonyl-18-thioparahakuamide 1-sakunonoy 18-thioparahaquamid 1-(2,4-dinitrobenzenesulfenyl )-18-thioparahaquamid 1-(4-morpholinosulfenyl)-18- Thioparahaquamide 1-(p-toluenesulfonyl)-18-thioparahaque Amide 1-acetyl-18-thioparahaquaamide 1-methoxycarbonyl-1 8-Thioparahaquamide is produced.

Example 11 The following is the conventional method of Example 8, but using the appropriate parahaquamid starting material: Other 18-thioparahaquaamide compounds: 1.18a-bis-ethyl-1 8-thioparahaquamide: 1-allyl-18-thioparahaquamide.

1-Methoxymethyl-18-thioparahaquamide.

1-propargyl-18-thioparahaquamide; 1-benzyl-188-ethyl 18-thioparahaquamide is prepared.

Example 121-pyrrolidinylcarbonyl-mark fortein ASCpd #12 Potassium hydride (50 mg of 25% oil dispersion) in 1 ml of dry tetrahydrofuran Add to MarkFortein A solution (15 mg, 0.0.30 mmol I) in Ru. The solution was stirred at room temperature for 2 hours and then diluted with pyrrolidinylcarbonyl chloride (40 mg, 0.30 mmol). The mixture was stirred at room temperature for 18 hours, then and partitioned between aqueous sodium bicarbonate (1 ml) and methylene chloride (1 ml). do. Once the layers are separated, extract the aqueous layer with methylene chloride (2 ml). combined draw The output is dried over magnesium sulfate, filtered and evaporated. The residue was washed with silica gel. eluted with 25% acetone in hexane. 1-pyrrolidinylcarbonyl-mark fortein A is obtained. 'HNMR (CDC11) 60, 83 (s, 3H), 1.20s, 3H), 1.41 (s , 3H), 1.45 (s, 3H), 1.3-2.4 (+a, 17H), 2. 38 (d, IH), 2.6-28 (■, 2H), 2.84 (d.

IH), 3.00 (s, 3H), 3.4-3.6 (L4H), 3.72 (d, LH), 4.85 (d.

IH), 6.41 (d, IH), 6.84 (s, 2H) or less are Example 1 2, but using the appropriate mark fortein starting material and carbonyl chloride. Other marks fortein compounds below.

1-Shedkin phosphoryl-mark fortein A1-cyclopropylcarbony Lumark Fortein A is manufactured.

Cpd#12A'HNMR (CDCIs) 60.82 (s, 3H), 1.0 5 (s, 3H), 1.44 (2s, 6H), 0.9-1.7 (in, 8H), 1.7-3.0 (s, IIH), 3.14 (s, 3H), 3.80 (d, IH) , 4.84 (d, LH), 6.28 (d, LH), 6.88 (s, 2H) 1-(1-piperidinyl)thiocarbonyl-markfortein A1-saku7no Ilumark fortein Al-phenoquine carbonyl-mark fortein A SCpd112B'HNMR (CDCl5) 60.83 (s, 3H), 1.0 9 (s, 3H), 1.3-1.5 (m, IH), 1.42 (S, 3H), 1. 4 6 (s, 3H), 1.5-3.0 (Sono, 1 3H), 3.14 (s, 3H ), 3.70 (d, IH), 4.83 (d, IH), 6.27 (d, LH), 6.90 (s.

2H), 7.2-7.5 (m, 5H) 1-(2,4-dichlorophenoquinecarbonyl)-188-allylumer pho 1-(4-oxopentanoyl)-18a-methyl-markfortein C1-valmitoyl-mark fortein A, Cpd#12CFAB-MS 7 16 (M3+H) 1-(4-nitrophenoxycarbonyl)-mark fortein A, Cpd#1 2D'HNMR (CDCls) δ0.90 (s, 3H), 1.09 (s, 3H) , 1.3-1.5 (m, IH), 1.44 (s, 3H), 1.47 (s, 3H), 1.5-2.9 (m, 13H), 3,14 (s, 3H), 3.70 (d, IH), 4.86 (d, IH), 6.23 (d, IH), 693 (AB,, 2H), 7.48 (d, 2H), 8.32 (d, 2H) 1-(1 -Piperidine carbonyl)-MarkFortein A, Cpd#12FFAB-M S 589 (M'+H): HRMS m/Z (M'+H, C34H44N40 S1H1) Calculated value 589.3390, measured value 589.33981-[[4-(E carbonyl) piperazin-1-yl] carbonyl comber tafoltin A, Cpd112G FAB-MS662(M”+H)+684(M’+Na):HRMSm/z(M '+HSC3゜H47N　s　□+H+), calculated value 662.3553, actual value 662.35691-[[4-(bennol)piperazin-1-yl]carbonyl ]-Mark Fortein A1Cpd#12H 'HNMR (300mH2SCDCI3) + 0.80 (s, 3H), 1.26 (s, 3H), 1.41 (s, 3H), 1.45 (s, 3H), 1.2-2.9 (m, H), 2.98 (s, 3H), 3.4-3.8 (m, 8H), 6.41 ( d, IH), 6.84 (s, 2H), 7.2-7.5 (m.

5H). FAB-MS680 (M”+H): 702 (M”+Na) 1-[[ 4-(1,3-Benzoneoxol-5-ylmethyl)piperazin-1-yl ]Carponyl Comark Fortin ASCpd# 121'HNMR (300 mHz, CDCI3): 0.80 (s, 3H), 1.00-2.60 (m, 1 5H), 1.2 (s, 3H), 1.41 (s, 3H), 1.45 (s, 3H) , 2.63 (t.

IH), 2.84 (d, LH), 2.98 (s, 3H), 3.45-3.80 (m, 8H), 485 (d, IH), 5.95 (s, 2H), 6.41 (d, IH), 6.70-6.90 (m, 5H) FAB-MS 724 (M”+H) 1-[[4-(methyl)piperazin-1-yl]carbonyl]-Marcforte In A, cpd# 12 J 'HNMR (300mHz, CDCl5): 0.82 (s, 3H), 1.2 6 (s, 3H), 1.40-2.72 (m, 20H), 1.41 (s, 3H), 1.44 (s, 3H), 2.82 (d.

LH), 2.99 (s, 3H), 3.40-3.81 (+g, 5H), 4.8 5 (d, LH), 6.41 (d, IH), 6.84 (s, 2H).　FAB-M S 604 (M”+H); HRMS s/z (M’+H, Cs 4 H4 sNsOs+H+), calculated value 604.3499, actual value 604゜1 -(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) - Mark Fortein A, Cpd #12K FAB-MS 665 (M4+H) 1-[[4-(pyridin-2-yl)piperazin-1-ylcocarbonyl]-ma -Qufortein A, Cpd#12L 'HNMR (300mHz, CDCIs): 0.84 (s, 3H), 1.10 ~2.30 (m, 12H), 1.41 (s, 3H), 1.44 (s, 3H), 2 ．． 40 (d, 2H), 2.67 (t.

2H), 2.85 (d, IH), 3. OO(s, 3H), 3.45-3.8 5 (m, 9H), 4.85 (cl, IH), 6.40 (d, IH), 6.60~ 6.70 (m, 2H), 6.85 (s, 2H), 7, 52 (t, LH), 8.15-8.22 (m, IH) FAB-MS 667 (M'+H) 1-[[4 -(phenyl)piperazin-1-yl]carbonyl]-markfortein A1 Cpd#12M 'HNMR (300mHz, CDC13) + 0.84 (S, 3H), 1.20 ~2.50 (m, 11 H), 1.22 (s, 3H), 1.42 (s, 3H) ), 1.45 (s, 3H), 2.67 (t, IH), 2.85 (d, IH), 3. OO (s, 3H), 3.10-3.91 (Peng, 9H), 4.85 (d, IH), 6.40 (d, LH), 6.85 (s, 2H), 6.90-7. OO (++, 3H), 725-7.38 (Satoru, 2H) 1-[[4-(chlorocarbonyl)piperazin-1-yl]carbonyl]-mer Coufortein A, Cpd#12N 'HNMR (300 mHz, CDCl5) + 0.74 (s, 3H), 1.18 (s, 3H), 1, 30-2.65 (m, 20H), 2.74 (d, IH) , 2.80s, 3H), 3.48-3.90 (m, 8H), 4.30 (d, L H), 6.32 (d, IH), 6.80 (s, 2H).

FAB-MS 652 (M4+H) 10.10°'-(1,4-nocarbonylbiperanone)bis(6°, 7°, 8° , 9', 10'.

10'a-hexahydro-1', 1°, 4.4.12'-pentamethyl)- [2°S-[2'.

Al) y,, 3’a, alpha 4, 9°a alpha,, 10 (2°”R book, 3” 'aS book 9'''aS book + 10'''aR book), 10°a beta]]-nopro[4H ,8H-[1,41dioxebino[2,3-g1 indole-8,2°(3°H )-[I H, 4H-3a, 9a] (iminomethano)cyclopenta[b]quino Linonko 9,11° (IOH)-dione, Cpd#120FAB-MS 11 093 (+H) 1-[[4-(phenyl)piperinone-1-ylcocarbonyl comark fluor Tein A1CpH2P 'HNMR (300mHz, CDCIs): 0.76 (s, 3H), 1.10 ~2.30 (+, 13H), 1.14 (s, 3H), 1.35 (s, 3H), 1.38 (s, 3H), 2.33 (d.

LH), 2.52-3.00 (m, 8H), 3. OO~3.20 (m, I H), 3.50-3, 75 (m, 2H), 4.05 (d, IH), 4. 33 (d, LH), 4.79 (dd, IH), 6, 35 (dd, IH ) 6.78 (s, 2H), 7.10-7.30 (m, 5H). FAB-M S665 (M-+H) 1-[[4-(dimethyl)piperinon-1-yl]carbonyl]-mertaphor Tin A1Cpd#12Q 'HNMR (300mHz, CDCl3): 0.75 (s, 3H), 0.90~ 1.95 (+a, 13H), 0.92 (s, 3H), 0.96 (s, 3H), 1 ．． 14 (s, 3H), 1.34 (s.

3H), 1.37 (s, 3H), 2.08 (d, IH), 2.20 (br s,, IH), 2.33 (d.

IH), 2.60 (t, 2H), 2.77 (d, IH), 2.92 (s, 3H), 345-3.75 (++, 4H), 4.77 (d, IH), 6.33 ( d, xH), 6.77 (s, 2H). FAB-MS617 (M゛+H) 1-[[4-(5-chloropyridazin-3-yl)piperazin-1-yl]cal Bonyl]-MarkFortein A, Cpd#12R 'HNMR (300mHz, CDCIs): 0.83 (s, 3H), 1.20 ~2.30 (m, 11H), 1.22 (s, 3H), 1.42 (s, 3H), 1 ．． 44 (s, 3H), 2.45 (d.

IH), 2.65 (t, 2H), 2.83 (s, 1.H), 2.99 ( s, 3H), 3.60-3.85 (m, 8H), 4.86 (d, LH), 6.40 (d, IH), 6.86 (s, 2H), 6.92 (d.

LH), 7.29(d, IH).

FAB-MS 702 (M”+H) 1-[[4-(4-chlorophenyl)piperazin-1-yl]carbonyl]-ma -Kfortein ASCpd#128 'HNMR (300mHz, CDCIs): 0.84 (s, 3H), 1.2 0-2.30 (■79H), 1.26 (s, 3H), 1.42 (s, 3H), 1 ．． 45 (s, 3H), 2.40 (d.

IH), 2.60-2.75 (m, 2H), 2.85 (d, IH), 3. O O (s, 3H), 3.15-330 (誼, 4H), 3.49 (d, IH), 3 ．． 52-3.84 (■, 5H), 4.85 (d.

IH), 6.39 (d, IH), 680-6.90 (m, 4H), 7.23 (d, 2H).

10.10°'-(1,4-dioxo-2-butene)bis(6', 7', 8 ’, 9’, 10°, 10゛a-hexahit o-1’, 1°, 4.4.12 °-pentamethyl)-[2°S-[2', alpha.

3°a al) y,,9’a,alpha,,10(2”’R*,3°”aS book 9” ’aS*, 10”’aRs, IQ’abeta] coursepio[4H,8H- [1,4]dioxepino[2,3-g1 indole-8,2'(3°H)-[L H,4H-3a,9a](iminomethano)cyclopenta[b]quinolidine 9 , 11° (IOH)-dione, Cpd#12TFAB-MS 11035 (" H) 1-[[4-(1-lichloroethquinyl)piperazin-1-yl]cal Bonyl]-MarkFortein ASCpd #12U’HNMR (300 mHz, CDCl5): 0.75 (s, 3H), 1.1-1.85 (m.

8H), 1.15 (s, 3H), 1.34 (s, 3H), 1.34 (s, 3H) , 1.92 (d, IH), 200-2.40 (m, 2H), 2.34 (d, IH ), 2.55 (t, 2H), 2.76 (d.

IH), 2.91 (s, 3H), 342-3.75 (t 8H), 465-4. 77 (m, 2H), 4.79 (d, LH), 6.33 (d, LH), 6.79 (s, 2H). FAB-MS 764 (M+H): HRMS m/Z (M”+ H, CHH44ClsNsO7+H+), calculated value 764.2384, measured value 76 4.23661-[[4-(3-trifluoromethyl-thiadiazole-1-y ) piperazin-1-yl]carbonyl]-mark fortein A, Cpd#1 2V NMR (300mHz, CDCl5) + 0.83 (s, 3H), 1.26 (s, 3H), 1.30-2.30 (m, 11H), ], 42 (s, 3H) , 1.45 (s, 3H), 2.42 (d.

IH), 2.55-2.72 (a, 2H), 2.84 (d, IH), 2.99 (s, 3H), 3.60-3.90 (m, 8H), 4.87 (d, IH), 6 ．． 30 (d, IH), 6.88 (s, 2H).

FAB-MS 742 (M"+H); HRMS m/z (M”+HSC3sH+zFsNtS1+H+), calculated value 74 2.2998, actual value 742.3038 Example 13 1-acetoquine methyl-mark fortein A, Cpd #13 hydrogenation Sodium (47 mg of 60% oily dispersion) in 1 ml of dry tetrahydrofuran Add to Markfortein A solution (850 mg, 1.78 mmol I). Applicable The solution was stirred at room temperature for 3 hours, then bromomethyl acetate (280 mg.

1.82 mmol) is added. The mixture was stirred at room temperature for 4 hours and then further stirred. Bromomethyl acetate (280 mg, 1.82 mmol I) is added to the solution. the mixture The solution was stirred at room temperature for 8 hours, then added with 5% sodium bicarbonate (1 ml) and dichloromethane. Partition between tyrene (1 ml). Once the layers are separated, remove the aqueous layer with methylene chloride (2 ml). Extract.

The combined extracts are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The remainder The residue was subjected to column chromatography on a silica gel plate using methylene chloride. 1-acetoquine methyl-mer was eluted first with 5% and then 10% acetone. Coufortein A is obtained as a colorless oil 'HNMR (CDCIa) δ 0.7 5 (3H, s), 1.08 (3H, s), 1.43 (3H, s), 1.45 (3 H,s), 2.05 (3H.

S), 3.12 (3H, s), 4.86 (IH, d, J=8), 5.85 (IH , d, J=8), 5.96 (IH, d, J=8), 6.26 (LH, d, J=8) ), 6.77 (L H, d, J ~ 7), 6.86 (IH, d, J = 7).

The following is the conventional method of Example 13, but with the appropriate Markfortein starting material. Other marked fortein compounds used: 1-t-butyriuki/methyl-mer Cupfortein A1-benzoyloxymethyl-markfortein A1-acetate Toxymethyl-188-benzyl-markfortein B1-3,4-dichloro Produce benzoyloxy-mark fortein C.

Implementation fl'1l14 1-(2,4-dinitrobenzenesulfenyl)-mark Fortein ASCpcl#14 (180 mg, 1.50 mmo+, 35% minerals) in THF (6 ml) at 5°C. Markfortein A (75 mg, 15 mmol), followed by 2,4-dinitrobenzene-sulfenyl chloride (73 mg.

0.30 mmol). The reaction mixture was then stirred at 5°C for 3 hours. Ru.

After dilution with water and extraction with chloroform, the crude product was separated into 1 mm lysogel fractions. Chromatographed on a thin layer plate for chromatography with a 30% acetone solution in methylene chloride. t, 1-(2,4-dinitrobenzenesulfenyl)-mark fortein A (90 mg, 89.1%) was obtained as a yellow solid, melting point 155-160 °C (dec). Ru. IHNMR (CDCl3) 60.86-0.97 (m, 3H), 1.13 ~1.45 (m, 15H), 1.56 ~ 1.78 (m, 5H), 1.86 (m, LH), 2.00 (m, LH), 2.15 (d.

IH), 2.30 (m, LH), 2.45 (d, IH), 2.67 (b d, IH), 2.79 (d.

LH), 2.97 (m, LH), 3.08 (s, 3H), 3.74 (d, IH ), 4.76 (b d.

1, H), 5.85 (d, IH), 6.87 (a, or), 6.97 (d, L H), 7.28 (m.

05H), 7.62 (m, 0.5H), 8.36 (d d, 1.H), 9.1 6(d, IH).

The following is the conventional method of Example 14, but with the appropriate Markfortein starting material. Other marked fortein compounds used: 1-(4-morpholinosulfenyl ) - Mark Fortein ASCpd# 14 AFAB-MS +m/e, 59 5(M”+H)1-(trichloromethylsulfenyl)-markfortein A , Cpd#14BFAB-MS; m/e, 626.628.630 (M'+H ) 1-(Methquincarbonylsulfenyl)-MarkFortein ASCpd# 14C) FAB-MS; m/e, 568 (M'+H) 1-(benzenesulfe m/e, Cpd# 14DFAB-MS; 586(M'+H) 1-trichloromethylsulfenyl-18a-ethyl-mer Coufortein B1-ethoxycarbonylsulfenyl-18a-methyl-mer Manufacture Coufortein C.

Example 15 1-(4-morpholinecarbonyl)-markfortein AN-O Xido, Cpd#15 1-(4-morpholinecarbonyl)-mark fortein A (Cpd# 12 E, 15 mg) of 3-chloroberoroxy7benzoic acid in methylene chloride (2 ml) (15 mg) for 10 minutes at 0°C. The mixture was diluted with 5% sodium bicarbonate IJO (2 ml) and methylene chloride (2 ml). Once the layers separate, drain the aqueous layer with chloride solution. Extract with tyrene (2 ml). The combined extracts were dried with magnesium sulfate and filtered. and evaporate under reduced pressure.

The residue was subjected to chromatography using a 0.5 mm Norimeter litho preparative thin layer plate. , eluting with 10% methanol in methylene chloride gave the title compound (10 mg) as a solid. get as. FAB-MS: 670 (M゛+H) Example 16 1-(2- Tetrahydrofuranyl)-MarkFortein A, Cpd#Tetrahydrofuran Mark fortein A (60 mg) solution in 5 ml 1 dicarbonyl/imidazo (50 mg). The mixture was heated to reflux and hydrogenated under 120 m g). The resulting mixture was stirred under reflux for 1 hour, the precipitate was filtered off, and the filtrate Concentrate. The residue was chromatographed on a silica plate with methyl chloride Elution with 25% acetone in water gives the title compound (30 mg) as a solid.

HRMS (F, A B); m/e (M”+H, C32H41N s O, +H), calculated value 548.3124, actual value 548.3086 Example 1 7 1-(4-morpholcarponyl)-mark fortein A, Cpd#2E (25 ml, distilled from sodium metal and benzophenone) Markfortein A (1 g, 2.1 mmol) in Dorofuran and hydrogenated carbon Lithium (35 wt%, 0.5 g, 4.4 mmol) was incubated under nitrogen at room temperature for 5 hours. Stir.

Morpholine carbonyl chloride (1 ml, 8.4 mmol) was then added via the syringe. Add via After stirring for 3 hours at room temperature, the cloudy reaction mixture was cooled in an ice-water bath. and quench the reaction by dropwise addition of cold saturated potassium carbonate solution (5 ml). Next The mixture was then diluted with water (75 ml) and dissolved in dichloromethane (775 ml). Extract to.

The organic layer is dried over magnesium sulfate, filtered and concentrated to obtain an oil-containing compound. .

Subjected to silica gel chromatography (2% to 5% methanol/dichloromethane) 1-morpholinecarbonyl-mark fortein A is obtained. (Chromatron Silica gel chromatography on (4% methanol/nochloromethane) (4% methanol/nochloromethane) % methanol/chloromethane) is 1-morphonecarbonyl-markforte This is an excellent method for purifying InA. )'HNMR (300MHz, CDCIa) δ 0.81 (s, 3H), 1, 21 (s, 3H), 1.19-1.94 (m, 8H), 1.41 (s, 3H), 145 (S, 3H), 1.98 (d, IH), 2.08-2.28 (m, 2H), 2.40 (d, IH), 2.62 (t, 2 H), 2.82 (6, 11 (), 2.99 (s, 3H), 3.50-3.86 ( m.

8H), 4.86 (d, IH), 6.41 (d, IH), 6.85 (s, 2H) . FAB-MS591 (M”+H): HRM S M/Z (M”+ H, C33H42N 4Ch 10H+), calculated value 591.3182, actual value 591 ．． 3200° Example] 8 The following is the conventional method of Example 12, but using an excessive parahaquaamide compound. Other parahaquamide compounds: 1-/ethoquinophosphoryl Amide 1-Cyclopropylcarbonyl Rubarahaquaamide 1-(1-Piperidini ) Thiocarbonyl-barahakuamide 1-Zaku/noyl-barahakuamide 1-(4-carbuethoquino-1,3-thiacylinonin-3-yl)carbonyl Balano＼-Quamide 1-phenoxycarbonyl-varahakuamide 1-pyrrolidinylcarbonyl-p Rahakuamide 1-piperidinylcarbonyl-Rahaquaamide 1-(4-mol (holin carbonyl)-barahakuamide is prepared.

Example 19 The following is the conventional method of Example 13, but using the appropriate parahaquamide starting material. Other parahaquaamide compounds as follows: 1-t-butyryloxymethyl-baraha -Quamide 1-penzoyloxymethyl-Parahaquaamide 1-acetoquinmethythyl Ru-18a-varahakuamide 1-3,4-dichloropenzoyloxy-paraha - Manufacture quamid.

Example 20 The following is the conventional method of Example 14, but using the appropriate parahaquamide starting material. The following other parahaquaamide compounds: 1-(2,4-dinitrobenzene sulfur) 1-(4-morpholinosulfenyl)-varahak Amide 1-trichloromethylsulfenyl-18a-ethyl-barahakuamide 1-Ethoxycarbonylsulfenyl-18a-methyl-barahakuamide 1- Valmitoyl-barahakuamide is produced.

Cunninghamera echinulata subspense elegans amellaechinulata 5ubsp, elegansX-) NR RL 1368, Cunningha + ae lla brakesleeana) (+) A T T C8688a, Ku Ninhamera echinulata subspense elegans (Cunningha) wlla echinulata subsp, elegans) (-) NRR L 1393, Cunninghamellae chinulata) NRRL 3655, (preserved in liquid nitrogen rLN2J ) NRRL 1368 or 1393, ATCC 8688a or preferably, NRRL 3655 in a 500ml wide-mouth shake flask with a 100ml capacity Aseptically transfer to 5-7 medium (sterile condition). G5-7 is Celerose and Pharma 25 g/] of each media was added to tap water. p of the medium The pH of H is adjusted to 7.2 using ammonium hydroxide. Autoclave the medium. Sterilize in the oven for 30 minutes. 125 to 300 (preferably 25 0rp■), 21-30°C, preferably about 28°C for 24-72 hours (preferably Shake for about 48-72 hours). Approximately 1 to 5% of this fermented product is used as inoculation for the bioconversion process. ratio (preferably about 5% ratio).

B. Bioconversion process Approximately 1 to 5 % ratio (preferably about 5% ratio) and seed fermentation for 48-72 hours. inoculate G5-7 was incubated at 25 rpm and 28° C. for 24 to 48 hours. At this time , 10 to 1 mark fortein A dissolved in dimethylformamide (DMF) 2 mg/flask, preferably per fermentation, 10 mg 10.4 ml DMF/1 Add to the fermentor in the range of 00ml flask. Contains mark fortein A Fermentation continues as above (24-72 hours).

100 cells containing <100 ml fermentate as described in the bioconversion protocol. The contents of the flask were shaken at 28°C for 24-72 hours, then filtered with further DMF (fluorescence). Mark fortein A (frame size: 0.2 ml per lasco, total 20 ml) 0.010 g per flask, total Ig), and each was mixed with dichloromethane ( 100 ml). Combine the contents and blend in a Waring Brenzy for 5 minutes. Stir. Centrifuge this mixture and decant the resulting aqueous layer. . The organic layer is collected, dried (sodium sulfate), filtered and concentrated. Formation of crude mixture solid extract ratio of 50 to 125:1 ) is separated by continuous column chromatography using silica gel. Giclo 2-5% methanol in lomethane or 15-60% acetate in dichloromethane Elute the column on the other hand. Mark Forte from these chromatographic separations InB is separated. HRMS (FAB); m/e, 77 ounds, 464.25 63; Calculated value of CzyHs3N30n+H+, 464°2549° Optionally, MarkFortein B can be crystallized from methylene chloride/acetone. I can do it. For example, a methylene chloride solution of Mark Fortein B is Dilute with some acetone during concentration until a slurry of Tin B remains.

Continuation of front page (51) Int, C1,6 identification symbol Internal office reference number C07F 9/6561 9155-4H//(C12P 17/18 C12R1:80) (31) Priority claim number: 796,948 (32) Priority date: November 2, 1991 2nd (33) Priority claim country: United States (US) (31) Priority claim number 797,736 (32) Priority date November 2, 1991 2nd (33) Priority claim country: United States (US) FI (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, SE), 0A (BF, BJ, CF, CG, CI, CN・f, GA, GN, ML, MR, SN, TD, TG), AU, BB, BG, BR, CA, C3, FI, HU.

JP, KP, KR, LK, MG, MN, MW, No, PL, R○, RU, SD, U.A., U.S. (72) Inventor: Whaley, Howard A. 490 Michigan, USA 02, Portage, Stone Plutsk 5619 (72) Inventor Nelson, Steven Jay Michigan, USA 4 9034 Flymax, 654 South 42nd Street Number 0 (72) Inventor Marshall, Vincent Bi 49, Michigan, USA 006, 203 Paisley Court, Kalamazoo

Claims (1)

[Claims] 1. Formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula: n is 0 or 1: R14a and R14b are the same or different, hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl , C1-C6 alkeni -C1-C6 alkoxy, C1-C6 alkynyl-C1-C6 alkoxy, C1-C6 alkinoyloxy, poly-C1-C6 alkoxy-C1-C6 alkoxy cy, phenyl, phenyl-C1-C6 alkyl, tri-C1-C6 alkylsilyl selected from fluoroxy, diphenylphosphoryloxy and halogen. or R14a and R14b together form an epoxide or =CH2, provided that when n is 1, R14a and R14b are both hydrogen; m is 0 or 1; W is O or S; W is S , R1 is hydrogen, C1-C7 alkyl, cycloC3-C6 alkyl benzyl, (optionally carboxy (-COOH), C1-C7 alkanoyl carbo C1-C7 alkoxy (-C(O)OC1-C7 alkyl), -NR4R5, aminocarbonyl (-C(O)NR4R5)) C2-C7 alkanoyl (-C(O ) C2-C7 alkyl), C10-C24 a Lucanoyl (-C(O)C10-C24 alkyl), (optionally substituted with carboxy (-COOH), C1-C7 alkanoyl, carboC1-C7 alkoxy, -NR4R5, aminocarbonyl) cycloC3- C6 arcano yl, alkanoyloxymethylene (-CH2OC(O)-C2-C7 alkyl), (optionally halogen, C1-C4 alkyl, haloC1-C7 alkyl, benzoyloxymethylene (-CH2OC(O)phenylene, optionally substituted with one or two groups selected from tro, cyano and C1-C7 alkoxy) ), C10-C24 alkenoyl (-C(O)C9-C23 alkenyl), {optionally one selected from halogen, C1-C4 alkyl, haloC1-C7 alkyl, nitro, cyano and C1-C7 alkoxy, or substituted with two groups Benzenesulfonyl (-SO2CH2phenyl), C1-C4 alkylaminocarbonyl (-C(O)N(C1-C4 alkyl)2), C1-C4 alkylaminothiocarbonyl (-C(S)N (C1-C4 alkyl)2), C1-C7 alkoxycarbonyl, {optionally halogen, C1-C4 alkyl Halo, C1-C7 alkyl, nitro, ano and C1-C7 alkoxy phenoxycarbonyl, which may be substituted with one or two groups selected from -C(O)NR'4R'5, -P(=X)(R2)(R3), -SR6, -SO2NR4R5, the 3rd or 4th position is -CH2NR4R5, 2-tetrahydrof benzoyl substituted with ran or bicycloC8-C12 alkanoyl; when W is O; R1 is (a) carboxy (-COOH), C1-C7 alkanoyl, carboC1-C7 alkoxy (-C(O)OC1- C7 alkyl), -NR4R5, aminocarbo C2-C7 alkanoyl substituted with nyl (-C(O)NR4R5); (b) cycloC3-C8 alkyl optionally substituted with carboxy, C1-C7 alkanoyl, carboC1-C7 alkoxy, -NR4R5, aminocarbonyl; Kanoyl; (c) alkanoyloxymethylene (-CH20C(O)-C2-C7 alkyl); (d) 1 selected from halogen, C1-C4 alkyl, haloC1-C7 alkyl, nitro, cyano and C1-C7 alkoxy substituted with one or two groups benzoyloxymethylene (-CH2OC(O)phenyl); (e) halogen phenoxycarbonyl substituted with one or two groups selected from C1-C4 alkyl, haloC1-C7 alkyl, nitro, cyano and C1-C7 alkoxy (f) -C(O)NR'4R'5; (g) -P(=X)(R2)(R3); (h) -SR8; (i) C10-C24 alkanoyl (-C(O ) C10-C24 alkyl); (j) C10-C24 alkenoyl (-C(O)C9-C23 alkenyl); (k) R4 and R5 are the same or different and are selected from hydrogen, C1-C7 alkyl, (optionally halogen, C1-C4 alkyl, haloC1-C7 alkyl, nitro, cyano and C1-C7 alkoxy) phenyl (optionally substituted with one or two groups) or, when taken together with N, can also form a saturated or unsaturated heteroamine ring; R'4 and R' 5 is the same or different and is one selected from C1-C7 alkyl, cyclo(C3-C8) alkyl, (optionally halogen, C1-C4 alkyl, haloC1-C7 alkyl, nitro, cyano and C1-C7 alkoxy) or substituted with two groups selected from phenyl (which may be present) or when combined with N, optionally containing one or two additional heteroatoms selected from N, O or S. It is also possible to form a saturated or unsaturated heteroamine ring which may have; or S; R2 and R3 are the same or different, C1-C7 alkyl, (optionally halo); phenyl, C1-C7 alkoxy, thio( C1-C7) Alkoxy, phenoxy R7 and R8 are the same or different and are selected from H, C1-C7 alkyl, or when taken together with N can form a saturated heterocycle) or be with P. may also form a 4- to 7-membered heterocycle; R6 is C1-C7 alkyl, halo C1-C7 alkyl, carbo C1-C7 alkyl; koxy, -NR9R10, where R9 and R10 are the same or different and are C1-C7 alkyl or (optionally halo, lower alkyl, haloC1-C7 alkyl) R24 is hydrogen, halogen or C1-C7 alkoxy; R25 is hydrogen or halogen ; R18a is hydrogen, C1-C7 alkyl, C2-C8 alkoxyalkyl, C2-C8 alkenyl, C2-C8 alkynyl or benzyl; and 25] and pharmaceutically acceptable salts and hydrates thereof. 2. 2. The compound according to claim 1, wherein m is 0. 3. Claims in which R24 and R25 are hydrogen: R18a is hydrogen, C1-C7 alkyl, C1-C8 alkoxymethyl, C2-C8 alkenyl or benzyl; the dashed line indicates a single or double bond between carbons 24 and 25 Compound according to 2. 4. 2. A compound according to claim 1, wherein W is S and n is 0. 5. m is 0; R24 and R25 are hydrogen; R18a is hydrogen, C1-C7 alkyl, C1-C8 alkoxymethyl, C2-C8 alkenyl or benzyl; the broken line represents the single bond between carbons 24 and 25 or 5. The compound according to claim 4, which exhibits a double bond. 6.18-thiomark fortin A; 1-acetoxymethyl-18-thiomer Cupfortine A; 1-diethoxyphosphoryl-18-thiomarkfortine A; 1-dimethylsulfamoyl-18-thiomarkfortine A; 1-dimethylsulfamoyl-18-thiomarkfortine A; lopropylcarbonyl-18-thiomark fortin A; 1-(1-piperidi 1-(2,4-dinitrobenzenesulfenyl)thiocarbonyl-18-thiomark fortin A; 1-succinoyl-18-thiomark fortin A; 1-(4-morpholinosulfenyl)-1 8-thiomark fortin A; 24-proboxy-24,25-dihydro-1 8-thiomark fortin A; 1- (p-Toluenesulfonyl)-18-thiomarkfortine A; 1-acetyl-18-thiomarkfortine A; 1-methyl-18-thiomarkfortine A; 1-benzyl-18-thiomarkfortine A; Fortin A; 1-dimethylcarbamoyl-18-thiomark fortin A; 1-methoxycarbonyl-18-thiomark fortin A; 18-thiomark fortin B; 24,25-dihydro-18-thiomark fortin B; 24-methoxy-2 4,25-dihydro-18-thiomark fortin B; 1-(p-toluene 1-acetyl-18-thiomer Coufortine B; 1-ethyl-18-thiomarkfortine B; 1-bendi Ru-18-thiomark fortin B; 18a-ethyl-18-thiomark fortin B; lutein B; 18a-benzyl-18-thiomark fortin B; 18a-mer Toxyethoxymethyl-18-thiomark fortin B; 18a-allyl-1 8-thiomark fortin B; 18a-propargyl-18-thiomark fortin B; lutein B; 18a-ethyl-24-methoxy-24,25-dihydro-18-thiomark fortin B; 18ethyl-18-benzyl-18-thiomark fortin B; 18a-ethyl -24-methoxy-18-thiomark fortin B; 1-(2,4-dinito lobenzenesulfonyl)-18a-ethyl-24-methquin-24,25-dihy Dro-18-thiomark fortin B; 18a-ethyl-24,25 dihydro-18-thiomark fortin B; 18-thiomark fortin C; 24.25 dihydro-18-thiomark fortin C; 1- (p-bromoben 1-propyl-18-thiomark fortin C; 1-benzyl-18-thiomark fortin C; 18a- Propyl-18-thiomarcfortin C; 18a-benzyl-18-thiomark fortin C; 18a-methoxyethoxymethyl-18-thiomark fortin C; 18a-allyl-18-thiomark fortin C; 18a- propargyl-18-p Lopyl-18-benzyl-18-thiomarc fortin C; 1-(4-carbuethoxy-1,3-thiazolidinin-3-yl)carbonyl-18-thiomarc fortin A; 1-palmitoyl-18-thiomarc Fortin A; or 1-(4-mol 6. A compound according to claim 5 selected from holinocarbonyl)-18-thiomark fortin A. 7. 2. The compound according to claim 1, wherein W is S and n is 1. 8. m is 0; R24 and R25 are hydrogen; R18a is hydrogen, C1-C7 alkyl, C1-C8 alkoxymethyl, C2-C9 alkenyl or 8. A compound according to claim 7, wherein the dashed line indicates the double bond between carbons 24 and 25. 9. 9. The compound according to claim 8, wherein R14a and R14b are both hydrogen. 10. 9. The compound according to claim 8, wherein R14a is methyl and R14b is hydroxy. 11.18-thioparahaquamide 24,25-dihydro-18-thioparahaquamide 14-O-methyl-18- thioparahaquamide 14-O-ethyl-18-thioparahaquamide 14-O -butyl- 18-thioparahaquamid 14-O-benzyl-18-thioparaha -Quamide 14-O-allyl-18-thioparahaquaamide 14-O-bropal Gyl-18-thioparahaquamid 14-O-methoxymethyl-18-thioparahaquaamide 14-O-methoxy-ethoxy-18-thioparahaquaamide 14 -O-methoxy-ethoxy-methyl-18-thioparahaquaamide 17 -Methyl -18-thioparahakuamide 17-methylene-18-thioparahakuamide 1 -N-(p-toluenesulfonyl)-18-thioparahakuamide 24-methoxy 9. A compound according to claim 8, selected from cy-24,25-dihydro-18-thioparahaquamide. 12. 2. The compound according to claim 1, wherein W is O and n is 0. 13. m is 0; R24 and R25 are hydrogen; R18a is hydrogen, C1-C7 alkyl, C1-C8 alkoxymethyl, C2-C8 alkenyl or 13. The dashed line indicates the double bond between carbons 24 and 25. Compounds listed. 14.1-(1-piperidinyl)thiocarbonyl-markfortin C; 1-(1-piperidinyl)thiocarbonyl-markfortin A; 1-(2,4-dichlorophenoxy)carbonyl-18a-N-ethyl- 24-methoxy-24,25-dihydro-markfortine B; 1-(2,4-dichlorophenoxy carbonyl)-18a-allyl-markfortine B; 1-(2,4-dinitrobenzenesulfenyl)-mark Fortin A; 1-(3-acetoxy)propionyl-18a-N-bropargyl-markforte B; 1-(4-carbuethoxy-1,3-thiazolidin-3-yl)carbonyl-ma -markfortin A; 1-(4-morpholinosulfenyl)-markfortin C; 1-(4-ox sobutyryl)-18a-methyl-markfortine C; 1-(4-oxopene 1-(4-oxopentanoyl)-mark fortin A; 1-(4-oxopentanoyl)-mark fortin C; 1-3,4-dichloronzoyloxy-mark fortin C; 1-acetoxymethyl mark fortin C; 1- Acetoxymethyl-18a -benzyl-markfortin B; 1-benzoyloxymethyl-markfortin lutein A; 1-cyclohexylcarbonyl-markfortin A; 1-cyclo lohexylcarbonyl-markfortin C; 1-cyclopropylcarbonyl-markfortin A; 1-cyclopropylcarbonyl-18a-ethyl-ma -kfortin B; 1-cyclopropylcarbonyl-markfortin C; 1-diethoxyphosphoryl-markfortin A; 1-diethoxythiophospho Lil-Marc Forte A; 1-diethoxythiophosphoryl-Marc Forte In C; 1-dimethylaminoacetyl-markfortin C; 1-dimethylaminoacetyl Minoacetyl-markfortin A; 1-dimethylaminosulfenyl-18 a-N-benzyl-markfortin B; 1-diphenylphosphinyl-18 a-N-allyl-markfortin B; 1-ethoxycarbonyl sulfate Phenyl-18a-methyl-markfortine C; 1-ethoxycarbonylsulfenyl 1-N-(2,4-dinitrobenzenesulfenyl)-18a-N-ethyl-M -Qufortin B; 1-N-(4-carbuethoxy-1,3-thiazolidinin-3-yl)carbony Lumark Fortin C; 1-N-(4-carbuethoxy-1,3-thiazolidinin-3-yl)carbony Ru-mark fortin A; 1-N-(p-bromobenzenesulfenyl)-mark fortin C; 1-N,N-dimethylsuccinamidoyl-mark fortin A; 1-N,N-dimethy rusaxinamidoyl-markfortin C; 1-phenoxycarbonyl-mer Markfortin C; 1-phenylmethoxyphosphonyl-markfortin A; 1-phenylmethoxyphosphonyl-markfortin C; 1-succinoyl-markfortin A; 1-succinoyl-markfortin C; 1-t-butyl 13. selected from tyryloxymethyl-Marcfortine A; or 1-trichloromethylsulfenyl-18a-ethyl-Marcfortine B. Compounds listed. 15. Preferably, 1-cyclopropylcarbonyl-markfortine A1-phenoxycarbonyl Marc Fortin A1-Palmitoyl-Marc Fortin A1-[[(4-nitrophenyl)oxy]carbonyl]-Marc Fortin A1-(1-piperidinecarbonyl)-Marc Fortin A1-[[4-(Ethoxy) Calbo 1-[[4-(benzyl)piperazin-1-yl]carbonyl]-markfortine A 1-[[4-(1,3-benzodio xol-5-yl-methyl)piperazin-1-yl]carbonyl]-markfortin A1-[[4-(methyl)pipera din-1-yl]carbonyl]-Marcfortine A 1-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-Marcfortine A 1-[[4-(pyridine) -2-yl)piperazin-1-yl]carbonyl]-ma -Fortin A 1-[[4-(phenyl]piperazin-1-yl]carbonyl]-markFortin A 1-[[4-(chlorocarbonyl)piperazin-1-yl]carbonyl-Mark Fortin A 1-[[ 4-(phenyl)piperidin-1-yl]carbonyl]-markfortine A 1-[[4-(phenyl)(dimethyl)piperidin-1-yl]carbonyl]-markfortine A 1-[[4-( 5-chloropyridazin-3-yl)piperazin-1-yl]cal 1-[[4-(4-chlorophenyl)piperazin-1-yl]carbonyl]-markfortin A -Qufortin A 1-[[4-(trichloroethoxycarbonyl)piperazin-1-yl]carbo Nyl]-Marcfortine A 1-[[4-(3-trifluoromethyl-thiadiazol-1-yl)piperazi MarkFortin A1-(2,4-dinitrobenzenesulfenyl)-MarkFortin A1-(4-morpholinosulfenyl)-MarkFortin A1-(trichloromethylsulfenyl)-markfortin A1-(methoxyca (rubonylsulfenyl) - Mark Fortin A1 - (benzenesulfenyl) - Mark Fortin A1 - (2-tetrahydrofuranyl) - Mark Fortin 2. A compound according to claim 1, selected from A1-(4-morpholinocarbonyl)-markfortine A or 1-(4-morpholinocarbonyl)-markfortine AN-oxide. 16.1-Diethoxyphosphoryl-parahaquamid 1-cyclopropylcarbo Nyl-parahaquamid 1-(1-piperidinyl)thiocarboel-parahaquaamide 1-succinoyl-parahaquamid 1-(4-carbethoxy-1,3-thiazolidinin-3-yl)carbonyl-parahaquamid 1-phenoxycarbonyl -parahaquamid 1-pyrrolidinylcarbonyl-para Rahakuamide 1-t-butyryloxymethyl-parahaquamid 1-benzoy parahaquamide 1-(2,4-dinitrobenzenesulfenyl)-parahaquaamide 1-(4-morpholinos) phenyl)-parahaquamid 1-trichloromethylsulfenyl-18a-ethyl-parahaquamid 1-ethoxycarbonylsulfenyl-18a-methy parahaquamide 1-palmitoyl-parahaquamide 1-piperidinylcarbonyl-parahaquamide 1-(4-morpholinecarbonyl 2. A compound according to claim 1, wherein the compound is selected from the group consisting of 17. A method for treating or preventing helminth and arthropod infections in domesticated animals, comprising treating the domesticated animal with an effective amount of a compound according to claim 1. 18. A method for treating insects or soil pests on plants, which comprises treating plants or the soil in which they grow with an effective amount of the compound according to claim 1. 19. A composition effective for the treatment and prevention of helminths or arthropods in domestic animals, comprising an inert carrier and a compound according to claim 1. 20. Insect or soil damage to plants comprising an inert carrier and a compound according to claim 1. Composition effective in preventing and treating insects. 21. Biologically pure culture of Penicillium sp. NRRL18887. 22. An aqueous nutrient medium containing a source of carbon assimilation and a source of nitrogen assimilation under aerobic conditions. A method for producing a compound with the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ using underground microorganisms. 23. 23. The method according to claim 22, wherein the microorganism is Cunninghamella species or a mutant thereof. 24. The strain is NRRL1368, NRRL1393, NRRL3655 or 23. The method of claim 22, wherein is selected from the group consisting of ATCC 8688a. 25.10,10''-(1,4-dicarbonylpiperazine)bis(6',7',8',9',10',10'a-hexahydro-1',1',4,4, 12'-pentanotyl)-[2'S-[2', alpha. ．． 3'a, alpha. ．． 9′ a, alpha. ．． 10 (2'''R*.3'''aS*9'''aS*, 10'''aR*), 10'a. beta. ]]-spiro[4H,8H-[1,4]dio xepino[2,3-g]indole-8,2'(3'H)-[1H,4H-3a,9a](iminomethano)cyclopenta[b]quinolidine]-9,11'(10H)-dione; or 10,10''-(1,4-dioxo-2-butene)bis(6',7',8',9',10',10'a-hexahydro-1,1',4,4, 12'-pentamethyl)-[2'S-[2', alpha. ．． 3'a. Alf A. ．． 9'a. alpha. ．． 10 (2'''R*, 3'''aS*9'''aS*, 10'''aR*), 10'a. beta. ]]-spiro[4H,8H-[1,4]dioxepino[2,3-g]indole-8,2'(3'H)-[1H, 4H-3a,9a](iminomethano)cyclopenta[b] quinolidine]-9,1 1'(10H)-dione.