USRE27384E - Acylated mitosbnbs - Google Patents

Acylated mitosbnbs Download PDF

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USRE27384E
USRE27384E US27384DE USRE27384E US RE27384 E USRE27384 E US RE27384E US 27384D E US27384D E US 27384DE US RE27384 E USRE27384 E US RE27384E
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • ABSTRACT OF THE DISCLOSURE Acylated mitosenes having the formula OCOR compound. They are useful antibacterial agents.
  • the present invention relates to novel derivatives of mitomycin and, more especially, to compounds produced by reductive acylation of mitomycin.
  • mitomycin A and mitomycin Bcompounds having anti-tumor potency as well as antibacterial activity weree isolated by Hata et al. from a culture medium of Streptomyces caespitosis. Subsequently, Wakaki et al. isolated mitomycin C from a culture medium of the same microorganism. It is known that mitomycin C, which also has anti-tumor and antibacterial activities, is one of the most potent of the known anti-tumor substances. However, its clinical utilization is restricted because of its relatively high toxicity. Thus, as is pointed out on page 687 of The Merck Index, Seventh Edition (1960), published by Merck and Co., Inc., Rahway, NJ mitomycin C has been used primarily against far advanced malignancies.
  • the present invention realizes this desideratum by embodying novel acylated mitosenes which are useful inter alia for the purposes for which, e.g., mitomycin C is used and in essentially the same way, but with the elimination of the aspect of undue, and thereby sometimes prejudical, toxicity.
  • novel compounds IV (mitosenes) of the present tvention are prepared by the reductive acylation of the )rresponding compounds of Formulae I, II and III.
  • a compound E the Formula I, II or IH is concurrently subjected to re action of an acylating agent and a chemical reducing gent in pyridine or is subjected to catalytic hydrogenaon in solution in a mixture of an acylating agent and yridine, reductive acylation takes place in accordance ith the following schemes:
  • the reductive acylation according to the pres- 1t invention involves the splitting of the azirrdine ring t the cases of starting compounds I and II.
  • the acylating agent is preferably an acid anhydride or an acid halide, corresponding to the acyl group to be introduced.
  • Preferred in this regard according to the invention are acetic anhydride and acetyl chloride, whereby the acetyl group is introduced into the molecule.
  • Chemical reducing agents are the so-called moderate reducing agents such as sodium hydrosulfite, although preference is given to zinc in this regard.
  • moderate reducing agents such as sodium hydrosulfite
  • reaction schemes are preferably carried out in a solvent medium, such as pyridine.
  • reaction is allowed to proceed until one mole of hydrogen has been adsorbed per mole of starting compound.
  • FIG. 1 shows the infrared absorption spectrum of the product of the reductive acetylation of 1 hydroxy-Z- amino-7-hydroxy-mitosene (cf. Example 1);
  • FIG. 2 shows the infra-red absorption spectrum of the product of the reductive acetylation of 1 hydroxy-Z- methyl-amino-7-methoxy-mitosene (cf. Example 2).
  • 500 parts by weight of l-hydroxy-2-amino-7-hydroxymitosene are dissolved in 10 parts by volume of acetic anhydride and 10 parts by volume of pyridine, to which 500 parts by weight of zinc powder have been added.
  • the mixture is vigorously agitated in ice.
  • the resultant colorless solution is filtered to remove zinc.
  • the filtrate is concentrated under reduced pressure (1 mm. Hg) and the residue is dissolved in ethyl acetate, followed by shaking the solution in water.
  • the ethyl acetate solution is then dehydrated with Glaubers salt, after which it is subjected to silica gel chromatography.
  • the main fraction is first eluted with acetone-ethyl acetate (2:1). 350 parts by weight of colorless pillar-shaped crystals are obtained by concentrating the eluate under reduced pressure.
  • N 0A0 6A0 NAc 500 parts by weight of la-methyl-7-methoxy-aziridinomitosene are dissolved in 10 parts by volume of acetic anhydride and 100 parts by volume of pyridine.
  • 30 parts by weight of palladium-carbon (containing by weight of palladium) are suspended in the resultant solution, and gaseous hydrogen is bubbled through at room temperature (about 20 to about 35 C.).
  • gaseous hydrogen is bubbled through at room temperature (about 20 to about 35 C.).
  • the reaction mixture is filtered to remove the catalyst.
  • the filtrate is concentrated under reduced pressure and purified by silica gel chromatography after the manner described in Example 1. 170 parts by weight of colorless needles are obtained.
  • the Vaseline may be replaced by any other suitable and desired base, e.g. a vanishing cream base.
  • the l-hydroxy- 7-hydroxy-mitosene can be replaced by any other of the compounds IV of this inventon with like effect.
  • Example 5 Powder form reductively acetylated 1a-methy1-7-methoxy-aziridino-mitosene, i.e. the compound of the formula HaCOCO- ooocn,
  • a process for the production of a compound of the ormula ?COR I N -0ooa nooo rlr-oon Z 'herein X" is a member selected from the group conisting of -OCH and -NHCOR, and R is a member elected from the group consisting of H and CH and is a member selected from the group consisting of H nd CH which comprises subjecting the corresponding ompound of the formula CHzOC ONE! CHzO 0 ONE:
  • X is a member selected from the group consting of CH O and NH Y is a member selected tom the group consisting of OH and OCH and i is as precedingly defined, to reductive acylation with member selected from the group consisting of (RCO) O nd RCO.hal, where hal stands for a halogen atom and is as precedingly defined, in the presence of a reducing gent.
  • reducig agent is a non-catalytic reducing agent.
  • reducig agent is a catalytic hydrogen
  • I N 000R R000 N-COR 'herein X" is a member selected from the group conisting of -OCH -NHCOR and OCOR, R is a member selected from the group consisting of H and CH and Z is a member selected from the group consisting of H and CH which comprises subjecting the corresponding compound of the formula I X, I CHzO C ONH: s 1
  • a jjsz wherein X is a member selected from the group consisting of OCH NI-I and OH, and Z is as precedingly defined, to reductive acylation with a member selected from the group consisting of (R'CO) O and RCO-hal, where hal stands for a halogen atom and R is as precedingly defined, in the presence of a reducing agent.
  • X is a member selected from the group consisting of OCH NHCOR and OCOR
  • R is a member selected from the group consisting of H and CH
  • Z is a member selected from the group consisting of H and CH which comprises subjecting the corresponding compound of the formula wherein X is a member selected from the group consisting of OCH NH: and OH, and Z is as precedingly defined, to reductive acylation with a member selected from the group consisting of (RCO) O and RCO.hal, where hal stands for a halogen atom and R is as precedingly defined, in the presence of a reducing agent.
  • a process according to claim 10 wherein the reducing agent is a noncatalytic reducing agent.

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Abstract

ACYLATED MITOSENES HAVING THE FORMULA

1-(R-OOC-),2-(R-CO-N(-Z)-),5-(R-OOC-),6-(H3C-),7-X",

8-(R-OOC-)-1,2-DIHYDRO-3H-PYRROLO(1,2-A)INDOLE

WHEREIN X" IS OCH3, NHCOR OR OCOR, R IS H OR CH3 AND Z IS H OR CH3. THESE COMPOUNDS ARE PRODUCED BY THE REDUCTIVE ACYLATION OF THE CORRESPONDING MITOSENE COMPOUND. THEY ARE USEFUL ANTIBACTERIAL AGENTS.

Description

June 13, 1972 MASANAQ MATSUl ETAL RG. 27,384
AOYLATED IITOSENES Original Filed Nov. 8. 1965 FIG BYLU/LMM $0 741 4! ATTORNEYS United States Patent 27,384 ACYLATED MITOSENES Masano Matsui and Yasuhiro Yamada, Tokyo, Keizo Uzu, Shizuoka, and Tadashi Hirata and Shigetoshi Wakaki, Tokyo, Japan, assignors to Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan Original No. 3,429,894, dated Feb. 25, 1969, Ser. No. 511,018, Nov. 8, 1965. Application for reissue Dec. 31, 1969, Ser. No. 889,760
Claims priority, application Japan, Nov. 7, 1964, 39/ 62 806 Int. Cl. c 14 27/80 us. (:1. 260-3263 12 Claims Matter enclosed in heavy brackets II] appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.
ABSTRACT OF THE DISCLOSURE Acylated mitosenes having the formula OCOR compound. They are useful antibacterial agents.
The present invention relates to novel derivatives of mitomycin and, more especially, to compounds produced by reductive acylation of mitomycin.
In 1956, mitomycin A and mitomycin Bcompounds having anti-tumor potency as well as antibacterial activitywere isolated by Hata et al. from a culture medium of Streptomyces caespitosis. Subsequently, Wakaki et al. isolated mitomycin C from a culture medium of the same microorganism. It is known that mitomycin C, which also has anti-tumor and antibacterial activities, is one of the most potent of the known anti-tumor substances. However, its clinical utilization is restricted because of its relatively high toxicity. Thus, as is pointed out on page 687 of The Merck Index, Seventh Edition (1960), published by Merck and Co., Inc., Rahway, NJ mitomycin C has been used primarily against far advanced malignancies.
It is a desideratum in this art to embody new therapeutically useful compounds which retain the advantages of the mitomycins, particularly those of mitomycin C, e.g. possess the antibacterial potencies thereof, but are free of the disadvantage thereof, namely, are of such reduced toxicity as effectively to broaden the possibilities of use thereof.
The present invention realizes this desideratum by embodying novel acylated mitosenes which are useful inter alia for the purposes for which, e.g., mitomycin C is used and in essentially the same way, but with the elimination of the aspect of undue, and thereby sometimes prejudical, toxicity.
The chemical structure of the mitomycins is as shown by the formula:
| C1120 C ONH:
wherein X, Y and Z have the following significances:
Mitomyeln A B C 01130 NH:
H0 onto OH: H
The following mitomycin derivatives are also known:
X OHIO 0 ONE,
N 6 NZ I) and X H20 ONE;
H30 N 0R BIT-B Z (III) --o (1) Pd-O. H2 (2) Aeration 01120 0 ONE:
| C1120 C ONH,
Y 1G I Z i 0.1N H01 0 ll CHzO C ONH:
X HaCU H N OH O NHZ The novel compounds IV (mitosenes) of the present tvention are prepared by the reductive acylation of the )rresponding compounds of Formulae I, II and III.
When according to the present invention, a compound E the Formula I, II or IH is concurrently subjected to re action of an acylating agent and a chemical reducing gent in pyridine or is subjected to catalytic hydrogenaon in solution in a mixture of an acylating agent and yridine, reductive acylation takes place in accordance ith the following schemes:
" cmoconn:
(IV) OCOR CHzOCONHz X" CH20CONH T Iooon:
N-C OR OCOR I =RCO O or RC Ohal RCO herein ==H or or NH;
I'=CH O, NH, or 0H j"=OCH NHCOR or OCOR =OH or OCH al=halogen (Cl, Br)
Note that the reductive acylation according to the pres- 1t invention involves the splitting of the azirrdine ring t the cases of starting compounds I and II.
The acylating agent is preferably an acid anhydride or an acid halide, corresponding to the acyl group to be introduced. Preferred in this regard according to the invention are acetic anhydride and acetyl chloride, whereby the acetyl group is introduced into the molecule.
Chemical reducing agents are the so-called moderate reducing agents such as sodium hydrosulfite, although preference is given to zinc in this regard. In the catalytic reduction alternative, use can be made of any of the conventional hydrogenating catalysts such as platinum oxide, rhodium oxide, Raney nickel and the like, but palladiumon-carbon is preferred.
The reactions shown on the foregoing reaction schemes are preferably carried out in a solvent medium, such as pyridine.
Where hydrogen is the reducing agent, the reaction is allowed to proceed until one mole of hydrogen has been adsorbed per mole of starting compound.
Work-up of the reaction mixture is as illustrated in the exemplary embodiments, infra.
On the accompanying sheet of drawing:
FIG. 1 shows the infrared absorption spectrum of the product of the reductive acetylation of 1 hydroxy-Z- amino-7-hydroxy-mitosene (cf. Example 1); and
FIG. 2 shows the infra-red absorption spectrum of the product of the reductive acetylation of 1 hydroxy-Z- methyl-amino-7-methoxy-mitosene (cf. Example 2).
The following examples set forth, by way of illustration, but not of limitation, presently preferred typical em bodiments of the invention. In these examples, parts by weight bear the same relation to parts by volume as do grams to milliliters.
Example 1 (CHsC 0) O pyridine zinc (L ke .AcO- CEzOCONHz I N 0A0 0A2 I NHAe (Ao=CH;C O)
500 parts by weight of l-hydroxy-2-amino-7-hydroxymitosene are dissolved in 10 parts by volume of acetic anhydride and 10 parts by volume of pyridine, to which 500 parts by weight of zinc powder have been added. The mixture is vigorously agitated in ice. The resultant colorless solution is filtered to remove zinc. The filtrate is concentrated under reduced pressure (1 mm. Hg) and the residue is dissolved in ethyl acetate, followed by shaking the solution in water. The ethyl acetate solution is then dehydrated with Glaubers salt, after which it is subjected to silica gel chromatography. The main fraction is first eluted with acetone-ethyl acetate (2:1). 350 parts by weight of colorless pillar-shaped crystals are obtained by concentrating the eluate under reduced pressure.
Analysis.C H O 'N 5C24H27O11N3Z Theoretical: C, 54.03; H, 5.10; N, 7.88. Found: C, 53.76; H, 5.02; N, 7.75.
The infra-red absorption spectrum observed in Nujol is as shown in FIG. 1.
Example 2 OHqO C O NH:
HsCO
HaC
N-OH;
P d-C HI (CHBCOMO pyridine 0 H20 0 0 NH;
N 0A0 6A0 NAc 500 parts by weight of la-methyl-7-methoxy-aziridinomitosene are dissolved in 10 parts by volume of acetic anhydride and 100 parts by volume of pyridine. 30 parts by weight of palladium-carbon (containing by weight of palladium) are suspended in the resultant solution, and gaseous hydrogen is bubbled through at room temperature (about 20 to about 35 C.). When 1 mole of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure and purified by silica gel chromatography after the manner described in Example 1. 170 parts by weight of colorless needles are obtained.
Analysis.-C H O' N Theoretical: C, 55.48; H, 5.67; N, 8.09. Found: C, 55.20; H, 5.60; N, 8.20.
The infra-red absorption spectrum observed in Nujol is as shown in FIG. 2.
Example 3 H CHzO C ONH:
P d-C H2 (CHaCO) 2O pyridine I CHzO C ONH: l I H3O I N OAe (lAe -NAc Staphylococcus aureus Sarcina lutea Bacillus subtilis Salmonella typhi Shigella fiexneri Klebsiella pneumoniae Proteus vulgaris Escherichia coli Bacillus pyocyaneus Vibrio comma Mycobacterium tuberculosis Streptococcus haemolyticus Streptococcus faecalis Diplococcus pneumoniae Corynebacterium diphtheriae One gram of reductively acetylated l-hydroxy-Z-amino- 7-hydroxymitosene U-om0oomn Iooocm Nnoocm soon,
is homogeneously incorporated into about 500 grams of an ointment base (Vaseline). Repeated application of the thus-prepared ointment to topical infections due to Staphylococcus aureus exhibits a curative effect.
The Vaseline may be replaced by any other suitable and desired base, e.g. a vanishing cream base. The l-hydroxy- 7-hydroxy-mitosene can be replaced by any other of the compounds IV of this inventon with like effect.
Example 5 Powder form reductively acetylated 1a-methy1-7-methoxy-aziridino-mitosene, i.e. the compound of the formula HaCOCO- ooocn,
H10 0- TCHQO C ONH:
N W'OCOCHI 'NMe 00 on;
scattered lightly, but uniformly, over raw fish is found to inhibit putrefaction of the latter so that it remains fresh for a prolonged period of time. Any of the other compounds IV of this invention, similarly employed, exhibits a like action.
What we claim is:
1. A compound of the formula ocon x" CH OCONH:
, f 000R ROCO III-COR 2 wherein X" is a member selected from the group consisting of OCH NHCOR and OCOR, R is a member selected from the group consisting of H and methvl and Z i a member selected from the group consisting of H and 3. The compound of the formula ooooni mool-oniocoun,
| N 000011, HaCOCO N-COCH:
4. A process for the production of a compound of the ormula ?COR I N -0ooa nooo rlr-oon Z 'herein X" is a member selected from the group conisting of -OCH and -NHCOR, and R is a member elected from the group consisting of H and CH and is a member selected from the group consisting of H nd CH which comprises subjecting the corresponding ompound of the formula CHzOC ONE! CHzO 0 ONE:
herein X is a member selected from the group consting of CH O and NH Y is a member selected tom the group consisting of OH and OCH and i is as precedingly defined, to reductive acylation with member selected from the group consisting of (RCO) O nd RCO.hal, where hal stands for a halogen atom and is as precedingly defined, in the presence of a reducing gent.
5. A process according to claim 4 wherein the reducig agent is a non-catalytic reducing agent.
6. A process according to claim 4 wherein the reducig agent is a catalytic hydrogen.
7. A process for the production of a compound of 1c formula Jooa x" CHzOCONH;
I N 000R R000 N-COR 'herein X" is a member selected from the group conisting of -OCH -NHCOR and OCOR, R is a member selected from the group consisting of H and CH and Z is a member selected from the group consisting of H and CH which comprises subjecting the corresponding compound of the formula I X, I CHzO C ONH: s 1
A jjsz wherein X is a member selected from the group consisting of OCH NI-I and OH, and Z is as precedingly defined, to reductive acylation with a member selected from the group consisting of (R'CO) O and RCO-hal, where hal stands for a halogen atom and R is as precedingly defined, in the presence of a reducing agent.
8. A process according to claim 7 wherein the reducing agent is a non-catalytic reducing agent.
9. A process according to claim 7 wherein the reducing agent is a catalytic hydrogen.
10. A process for the production of a compound of the formula won x omoooNm Hac \N 000R R000 L III-COR wherein X" is a member selected from the group consisting of OCH NHCOR and OCOR, R is a member selected from the group consisting of H and CH and Z is a member selected from the group consisting of H and CH which comprises subjecting the corresponding compound of the formula wherein X is a member selected from the group consisting of OCH NH: and OH, and Z is as precedingly defined, to reductive acylation with a member selected from the group consisting of (RCO) O and RCO.hal, where hal stands for a halogen atom and R is as precedingly defined, in the presence of a reducing agent.
11. A process according to claim 10 wherein the reducing agent is a noncatalytic reducing agent.
-12. A process according to claim 10 wherein the reducing agent is a catalytic hydrogen.
References Cited The following references, cited by the Examiner, are of record in patented the of this patent or the original patent.
UNITED STATES PATENTS 3,332,944 7/ 1967' Cosulich et a1 260-3263 ALEX MAZEL, Primary Examiner I OSE TOVAR, Assistant Examiner US. "Cl. X.R. 424-274
US27384D 1964-11-07 1969-12-31 Acylated mitosbnbs Expired USRE27384E (en)

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BR (1) BR6574623D0 (en)
CH (1) CH465613A (en)
DE (1) DE1570046A1 (en)
DK (1) DK115115B (en)
FR (2) FR1550958A (en)
GB (1) GB1091096A (en)
NL (1) NL6514382A (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5523411A (en) * 1994-03-14 1996-06-04 Rutgers University Synthesis of mitomycin and its analogs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5523411A (en) * 1994-03-14 1996-06-04 Rutgers University Synthesis of mitomycin and its analogs

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FR1550958A (en) 1968-12-27
SE305217B (en) 1968-10-21
NL6514382A (en) 1966-05-09
FR5204M (en) 1967-06-26
NO119275B (en) 1970-04-27
DE1570046A1 (en) 1970-02-12
GB1091096A (en) 1967-11-15
DK115115B (en) 1969-09-08
CH465613A (en) 1968-11-30
BE671904A (en) 1966-03-01

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