JPS5933278A - Morpholinyldaunorubicin and morpholinyldoxorubicin derivatives and their analogue - 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 The present invention relates to morpholinyldaunorubicin and morpholinyldogisolpicin derivatives and analogs thereof.

The invention described herein has been approved by the United States Department of Health and Human Services (Dopar-t
(ment of heart)i and l(uma
National Institute of Diseases approval number CA
25711 and CA 32250.

The present invention is in the field of anthracycline chemistry, and more particularly relates to analogs of the anthracyclines doxorubicin and daunorubicin useful as antitumor agents.

US Pat. No. 3,159,01028, F. Arcamone, et al.
Doxorubicin (Adriamycin), described and claimed in , is perhaps the most useful new anticancer agent currently in use. Doxorubicin (along with daunorubicin) is a basic drug used in the treatment of a wide variety of solid tumors and leukemias. But unfortunately,
Many patients with these tumors fail to respond, and virtually no response in patients with several severe tumor types (colon cancer, melanoma).

In addition, in some patients, continued treatment with long-term therapy causes irreversible heart damage that leads to death. Thus, there is a particular need for analogues that provide better response rates, broader response spectra, or less anxiety. More effective and less toxic drugs are being widely sought, and this is a fundamental objective of the present invention. The most active novel analogues, as judged by the screening results of a widely used three-dose therapy (4-interval Q4d, 5,9.13) study against the murine leukemia P388, are the two lipophilic derivatives ( AD32 and N,
N-dibenzyldaunorubicin). These derivatives require significantly higher doses, and although DNA is believed to be the initial biological target of anthrazyclines, no interaction with DNA takes place in vitro. Most N-alkyl derivatives are active in antitumor screening against murine leukemia P388, but doxorubicin and daunorubicin are not significantly different. Also, some such derivatives are inert.

Much of the history and prior art of doxorubicin and its anthracycline analogues can be found in David W. Henry, Nicynis Symposium Series, page 30.
・Cancer chemotherapy.

American Chemical Society, pp. 15-57.
]'176 (David W, Henry, AC
See the Symposium sentence “Fudriamycin” (Ad
riamycin) and Federico F. Camone, Doginlupicin, published by Academic Press, 198
1 year, (Doxorubic Lee by Feder
ico Arcamone, Academic Pr
ess, 1981). AD32 is disclosed in US Pat. No. 4,035,565 (July 12, 1977).

5-iminodaunorubicin was released on August 22, 1978.
As shown in U.S. Patent No. 4,109,076 issued to David W. Henry and Gsrgi L. Tong,
This US patent is glazed over to the eyelid receiver of the present invention. Doxorubicin equivalents: Edwar, D. M. Acton, and Joe 9 L. Tong, Synthense. and·
Preliminary Antitumer Evaluation Op. 5-Iminodoxorubicin'', J. Mesoinnal Chem, Vol. 24, (p. i69, 1981)
uSyn also besisand preliminary
Antitumor Evaluation of
5-Iminodoxorubicin”, ,-J
, 4cljc-inQ S Lee-m,, 24669
(+!1F11) by Edward M, Ac
ton and georg.

L, Tong). 5-iminodaunorubicin had activity with reduced side effects, while 5-iminodoxorubicin showed high activity but required high doses.

November 7, 1981, Nidward M. Acton and Carol W9Mo
3'-deamino-3'-(4-morpholinyl)daunorubicin, which is disclosed in U.S. Pat. kidney.

have identical T/C values (P
Give 166 chi to 1 (]co) for 2S5.

This compound, its so-called products, and properties are also described in “Enhanced Antibiotics Properties of Enhanced Antibiotics” by Carol W. Mosher, Helen Wai Wu, Alan F. Fujiwara, and Nidward M. Acton.
3'-(4-morpholinyl) and 3'-(4-methoxy-1-piperidinyl) derivatives of 3
'-Deaminodaunorubicin 1. Jay Medicinal Chem.

Volume 25, 18-24 negative, 1982 (“Enhanco
dAnLitumor PropsrLiea ol'
3'-(4-Morpholi-nyl) an
d3'-(4-MeLboxy-1-Piper
idi-nyl) DerivaLives of
3' -Deaminodaunorbicin”ren” Isolation (廿-!) Ha Naka,,hi,pp-1s-24 (19
82) by Carol W, Mo5har, He
1sn Y Wu, A11an N.

Fujiwara and Edward M, Ac
ton).

A general reductive alkylation method for the synthesis of novel semisynthetic anthracycline derivatives was described by G.L.L.
Ng, H.W.W., T.H. Smith, and D.W. Henry, 6 Adriamycin Analogs 3. Synthesis Op. N-Alkylated Andhracyclines Quiz Enhanced.
“Efficacy and Reduce Cardiodoxicity”, J Medicinal Chem, Vol. 22, 9.
12-91.8, 1979 (“Adriamyoi
n Analogll.

3.5yntbesis orN-Alkylate
d AnthracyclinesWith Enha
nced Efricasy and Redt+eo
d Cardio-Toxicity'', J.
Medical Chom, 22. pp
, 912'-918 (1979) by G,
L., Tong, I., Y., Wu, T.

H, Sm1th arid D, W, Henry
)It is described in.

The gist of this prior art is described in particular detail in the literature.

A new group of daunorubicin and doxorubicin derivatives has been discovered. These compounds have the following formula: -CH20H mol, (i, i 9' in Cll0H-CI20H)
: X is 0 or N+i and s,! t; A is a cyano group (C
(N) or a hydrogen atom, provided that when X is 0, A is a cyano group). When A is a hydrogen atom, these compounds can also exist as acid addition salts.

These salts are an additional feature of this invention.

In another broad aspect, the invention provides derivatives of these compounds formed by one or more transformations that are effective techniques for the similar daunorubicin and doxorubicin. Such transformations include transformation of the R group, removal of the 4-position methoxy group, transformation of the 4'-carbon substituent, transformation of A, and substitution of the morpholinyl ring. The compounds encompassed by these various derivatizations are generally classified as morpholinyl derivatives or analogs of morpholinyl derivatives of daunorubicin and doxorubicin type substances and have the following formula l
: (wherein, R is 100-CH in the case of a simple daunorubicin derivative, or -CHoH-CH5: -Co-CH20H or -CHoH-CH,OH in the case of a simple doxorubicin derivative; hydroxyl group; CH2CH3, etc. an alkyl group having 1 to 3 carbon atoms; -CM, -OH or
A terminal hydroxyalkyl group having 1 to 3 carbon atoms such as -CH, -CH, -OH; for example, -Co-CHpOAo,
-Co-CH! -0Bz, -Co-CH, -0P
r.

-Co-CH2-OGL, -CI(OAc)-CH
2-OAc +, -CH(OBg)-CH! OBg.

-CI(OAc)CH, and -CH(OBz)C
-〇〇-CM, OH, -CHoH-, including acetate ester (-OAc), propionate ester (-0Pr), benzoate ester (-QBz), and glycolate ester (-0-Gt) such as H, CHtOH and -CHO
Esters and diesters of T(-CH, using organic acids having 2 to 7 carbon atoms; -CH(OCH,)-CH3゜-C
o-CH, 0-CH,, -Co-CH20-C2H,,
-Co-CH,OH, such as -Co-CH,OC,H,
-CHoI (-CH8 and -CHoH-CH, 1 of OH
or more hydroxyl group having 1 to 6 carbon atoms or an alkyl ether substituent; and -C(NOH)-CHs
.

-C(NNHBz) CH3, -C(lOcf(,)-
CH,, -C(NOH)-CH,OH.

-C(NOCH,) -CH,OH and -C(NNH
B z) -s CH, OH, etc. -Co-CH1 or
-Co-CH20H is a 13-ketoimine conductor; Y is usually a methoxy group (-0CH3), but may be a hydrogen atom, and X is =0 or =NH; R'
and R'' are each a hydrogen atom and the other is a hydroxyl group (that is, either R' or R'' is a hydroxyl group and the other is a hydrogen atom)
, both are hydrogen atoms, or R' is an 0-methoxy group and R'' is a hydrogen atom; A is a cyano group (-C:
N ) and a hydrogen atom, and when A is a hydrogen atom, these compounds can also exist as acid addition salts; 2 is an oxygen atom, an ylkyl group) or -CH,-, and Z is -C
Indicated by H, - or.

Synthesis of the compound of formula (1) The synthesis of this compound is carried out using known daunorubicin, doxorubicin and its or a suitable precursor thereof, in a mixed aqueous polar organic medium, and the reaction is carried out in the presence of a cyanopolohydride salt, such as an alkali metal cyanoborohydride. These compounds are related to the known anticancer drugs daunorubicin and doxorubicin (adriamycin), and are characterized by the isolation and purification of the target substance by methods known per se. These compounds appear to combine two advantageous and desired properties: high antitumor efficacy and low dosage requirements. Compared to the previously disclosed substances, the compound of Nikosai et al. thus guarantees a high efficacy in reducing side effects related to the administration site, such as psychotic effects.

In another aspect, the present invention also provides formulations containing these novel Chiang Sentai as well as methods of treating cancer in a mammal by administering such formulations to a mammal in need of treatment. .

The present invention provides iminodaunorubicin, molporinyl derivatives of iminodoxorubicin and pharmaceutically acceptable salts thereof, and cyanomolporinyl %8L'; , the compounds of this 0 are shown in Table 1.
〃-Morporinyl)-5-iminodaunorubicin and its pharmaceutically acceptable salts NIT HCFIOII-CH113'-deami, 3'-(4''-morpholinyl)-13-dihydro-5-iminodaunorubicin and its Pharmaceutically acceptable salt NT-+ HC0-CH20H3'-deami/-3
'-(,i''-morpholinyl)-5-iminodoxorubicin and the pharmaceutically acceptable salt NHI (CHOIi-CI(20113'-deami/
-3'-(4''-morpholinyl)-13-dihydro-
5-Iminodoxorubicin and pharmaceutically acceptable OCN Co-CH,3'-deamino~3'-(3
″-cyano-4″-mol-j-linyl)dannorpicin OCN CHOH-CH,3'-defmi/-3
'-(3''-Schiff/-4''-morpholinyl)-13-
Dihydrodaunorubicin OCN Co-CH20H3'-deamino-3'-
(3″-Cyano4″- Bicine O CN CHOH-CTT20H 3′-
Deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodoxorubicinNH CN Co-CH33'-deamino-3'
- (3″-cyano-4″-molporinyl)-5-iminodaunorubicin NH CN CHOH-CH, 3′-deamino-3′-(3″-cyano-4″-molporinyl)
-13-dihydro-5-iminodaunorubicin NH CN Co-Cl,, OH 3'-
Deamino-3'-(3''-cyano-4''morpholinyl)-5-iminodoxorubicinNH CN CHOIf-CH,OH 3'-
Deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydro-5-iminodoxorubicin Among these substances, five are preferred because they have excellent activity as antitumor agents. These are: 3'-deamino-3'-(3"-cyano-4"-doxorubicin 3'-deamino-3'-(3"-cyano-4"-morpholinyl)=13-dihydrodoxorubicin 3'-deamino-3 '-(3''-cyano-4''-morpholinyl)daunorubicin 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodaunorubicin and 3'-deamino-3'-(,' 4″-morpholinyl)-
5-Iminodoxorubicin. Of these five substances, the first being the most preferred, the first four compounds of the invention listed in Table 1 are the free bases shown in the same table. Alternatively, pharmaceutically acceptable acid addition salts of these bases may be used.

The acid addition salts include water and water-alkanol or water-
It has the advantage of being soluble in aqueous mixed solvents such as alkanediols.

Specific examples of these mixed bath media include water-propylene glycol, water-ethanol, water-ethylene glycol,
Examples include saline, proprietary injectable aqueous media, and the like. However, these free bases can be used in organic solvents with low migration such as chloroform-methylene chloride and chloroform-methanol mixed solutions.

1, which are soluble, may be used as a liquid.

The above salts are acid addition products of the free base and a pharmaceutically acceptable acid. “Pharmaceutically acceptable acids are those that are non-toxic and commonly used in pharmaceutical products.
Inorganic acids such as phosphoric acid; carboxylic acids such as acetic acid, glycolic acid, maleic acid, malic acid, ochinlinchoic acid, tartaric acid, citric acid and salicylic acid; and organic sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid. Examples include organic acids such as. Alternatively, mixtures of two or more acids may be used, such as a mixture of three or more free bases and one or more acids.

Hydrochloric acid and hydrogen bromide Fg'2 salt addition are preferred because they provide easy and rapid solubility.

As previously mentioned, these compounds may exist as conductors,3 and these inducers are formed to increase the solubility of the compounds or to alter other physical properties of the compounds.

Synthesis of Some Preferred Compounds of the Invention These compounds are synthesized according to the following general methods. , commercially available daunorubicin or doxorubicin (as an acid salt) under reductive algylation conditions 2, 2/
-oxydiasecualdehyde, resulting in a mixed product containing four basic components. In the case of daunorubicin, these components are: 3'-deamino-3'-(4''-morpholinyl)daunorubicin, 3'-deamino-3'-(s''-morpholinyl)-13
-dihydrodaunorubicin, 3'-deamino-3'-(3''-cyano-4''-morpholinyl)daunorubicin and 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodaunorubicin. .

In the case of doxorubicin, the reaction products are 3'-deamino-3'-(4"-morpholinyl)doxorubicin, 3'-deamino-3'-(4"-morpholinyl)-+3
-dihydrodoxorubicin, 3'-deamino-3'-(3''-cyano-4''-morpholinyl)doxorubicin and '3'-deamino-3'-(31-cyano-.1''-morpholinyl)-1:>- Contains dihydrodoxorubicin.

2.2'-Oggin diacetaldehyde was prepared according to the method of Field et al., Belgian Patent No. 655,436 J:
2, 2r-Ogishidiacetal, Rdehydobis (diethyl acetal), -, Carbohydrate Research,! Volume 7, 299
Page, 1968 (Barry, et al, (1:
arltohydrateR08earcl+, 7.
299 (19fi 8 )) and Greenpelg et al., Carbohydrate Research.

Volume 35, page 195, 1974 (Greenberg
, etal, (nee a, r-bo-o, q+7-d
, raLe l'(eg-oarQ+, 35. +
95 (1974)), the reductive alkylation of 1,4-anhydroerythritol can be carried out using alkali metal cyanoborohydrides such as lithium or potassium noanoborobide.
・In the presence of a reducing agent such as idlide, generally about 1.117
This can be carried out using a mixed aqueous polar inorganic medium such as water-acetonitrile or a dialdehyde of 1111% in 18%. This is a 11ZIi+2 easy reaction and can typically be completed within 1 hour at room temperature. Synthetic algylation--as shown in the examples and described in U.S. Pat. No. 4,3 above.
QI, 2.77 So and J. Med., Vol. 25, pp. 18-24, 1982 (J, Med
icinal C1+e+n,, 25, pp
18-24 (1982)).

Preparation of the mixed reaction product may be carried out by any method that provides the desired isolation and separation.

Acid extraction of the reaction product is effective in separating acid-extractable cyano group-substituted substances from acid-insoluble cyano group-substituted substances. The pair of substances obtained can then be separated into individual compounds by various chromatographic methods such as thin layer chromatography, column chromatography, or thin layer high performance liquid chromatography.

The 5-imino compound can be easily and directly synthesized from the isolated 5-oxo compound using the method disclosed in the above-mentioned J. Med. Medicinal Chem, Vol. 24, p. 669, 1981. In this method, the 5-ogiso material is contacted with cold excess alcoholic ammonia for about 0.5 to about 100 hours at a suitable temperature of 5°C to -25°C. In the case of 3′-theamino-3′-(4″-morpholinyl)doxorubicin and 3′-deamino-3′-(3″-cyano-4″-morpholinyl)doxorubicin, the 14th carbon position was Protecting groups that are unstable to certain weak acids can also be used.For widespread use in pharmaceutical chemistry, the methoxytrityl group is the preferred protecting group. be.

: 3'-deamino-3'-(4"-morpholinyl)doxorubicin or 3'-deamino-3'-(3"-cyano-4"-lyolinyl)doxorubicin was added to excess p-anisylchlorodiphenylmethante at around room temperature. A trityl group can be introduced by treatment. After the reaction with ammonia is completed, it can be returned to 14-water 1'[12R,'; by contacting with an acid such as acetic acid or a cold trifluoroacetic acid water bath solution. can.

In addition to derivatives and analogs, the present invention provides derivatives and analogs of the 12 basic compounds mentioned above.
These derivatives include one or more of the following variants of the basic compound.

Any one or more hydroxyl groups represented by a, R can be present as esters of organic acids having 2 to 7 carbon atoms, including alkanoic acids, oxyalkanoic acids, hydroxyalkanoic acids and benzoic acids. This conversion results in an R group as shown in Table 2.
OCH.

-CH(OCOCR,)-CH2-0-COCH.

-CH(OCOCH,)-CI-120H-CH(OC
OCH,)-Ck(.

Propio7p -Co-CH, -0, -CO
CJ%.

-CH(0COC2H,)-CH, -0-COC2H.

-CI(OCOC,H,)-CH.

Glycol (4'? -Co-CTC, -0-
COCH,0H-CI (0COCH20i()-CH
, -0COCH2011-cl[ococ)y, 0H
)-CH5benzoin i'a -Co-(!:H,”-
0-COC6H.

-CTr(0COC1lH,)-CH, -0COC6H
.

-CH(0COC,H,)-CH.

Hooc-cI((oc2It,),, atp-G
The more complex acid ate of o-CH2-0-COCH(QC2H,,)2.

Arcamone et al., J Medicinal Chem Vol. 17, p. 335, 1974 (Arcamona at al.
JoMedicinal Chem,, 17, 3
35 (1974)) and Mara+ et al., Helgie Patent No. 848,219 (May 10, 1977). The compounds of the present invention can be easily converted into the corresponding ester derivatives by the chemical reaction method.

The l or more hydroxyl groups represented by b, R can also be present as ethers, especially alkyl ethers having 1 to 6 carbon atoms or aryl ethers having about 6 to 7 carbon atoms. Representative "ether" R units are shown in Table 3.

Table 3 Ether R Methyl ether/l/ -Co-CH, -0CH
3-C) [(OH) -CH2-0CH.

Ethyl x -a/l/ -CO-CH2-0C
2H.

-CH(OH)-C)% -QC2H.

Butyl ether-Co-CH2QC,H.

Phenyl ether -Co-CH2-0-C,H.

-CH(OH)-CH2-QC6H.

Such as doxorubicin 14-Nisdel Masi et al., Pharmaco Nido Sci, Vol. 34, p. 9071
979 (Maai, fit al, 11 Fa
rmaco.

Ed, Sci., Li, 907 (1979)) and can be used as a starting material for the reductive alkylation process of the present invention.

It is possible to convert the substituent at the 4' carbon position of C. Chem.

Volume 22, page 121, 1979 (Ca5sinell
i, J.

Medicine, 22, 1
21 (1979))'), Ki-ni.

It can be transformed into a bright compound. λ7. ! 114'j position 4
Due to other known structural variations at the '-position, the 4'-
Deoxy (no OH) and 4'-epi (over OH) derivatives [Suarato et al., Carbohydrate Lys.

Volume 98, 1981
, (:albohydriLaR6893, c Otsu (1
981)) :] is obtained. These compounds can be easily converted to the corresponding compounds of the invention by reductive alkylation methods.

d. 1-demethoxy analogues of doxorubicin and daunorubicin (without CH, O in the A-base of the aglycone)
It can be easily done [Alcamonera, Kiya,
Sir Test Revotes, Volume 60, Page 829, 19
1976 (Arcamone, at at, Canc
er Te5t Rpts,.

60.829 pages (1976)) and West German Patent No. 2,65
2゜391 (May 26, 177)], and can also be converted into the compounds of the present invention.

e, the carbonyl group (g) of the R unit of daunorubicin and doxorubicin, the ketone as oxime, and the typical ketoimines R are shown in the table.

Table 4 Ketoimine R -〇(NOH)-CH,0H -C(NOH)-CI(.

-C(N0CH5) -CH,OH -〇(NOCH,)-CH5 -C(NNHCOC6)(5)-CH,0H-C(NN
HCOC,H,)-CH3-〇 (NNHCONH2)CH20H-C(NNHC
These 13-ketoimine R substances such as ONH, )-CH3 can be easily converted to the compounds of the present invention by reductive alkylation as described above.

The f,R unit can be simplified by removing the carbonyl group and become the simple hydroxyl R unit shown in Table 5.

Table 5 Pure ROH CH20H -C2H,OH These daunorubicin and doxorubicin substances are described by Panoo et al., German Patent No. 2757057 (
(July 7, 1978) and Penff et al., J. Antibiotics, Vol. 30, p. 764, 1977 (P.
enco, et al., J.Antjbiotia
s, 30 Neer 64 (1977)) and are converted to the compounds of the invention by reductive alkylation I.

g, 2-C”-f/piperidi/ (Z-CH,) and U
2-cyano-4-methoxypiperidino (Z=CHO
CH3) (Formula n): These piperidino derivatives of daunorubicin and doxorubicin are described in US patents.

0 CH.

The corresponding 2-cyano-1-piperidinyl derivatives are obtained by converting the above compound to the N-oxide with metachloroperbenzoic acid in dichloromethane solution and then rearranging the N-oxide with trifluoroacetic anhydride in the presence of cyanide ions. (
It can be synthesized by the following methods.

z=-cH, or -CH0CH3 2, in place of 2,2-oxybisacetaldehyde.
2'-thiobisacetaldehyde [〇-CHCH2
5CH2Cl=O, Carbohydrate Lith.

Volume 110, page 195, 1982

Wholesale,,U,195(1fl+82'))
When the conventional algylation process of the present invention is carried out on daunorubicin, except that is made weakly acidic (pl+ 5 instead of 1+7.2), the thiomorpholino derivative of daunorubicin (A=H, formula I) is obtained. . Although this product requires a high dose (50η/ instead of 8q/Kr?), it has activity against murine leukemia p388 (T/C=
169%) is comparable to doxorubicin (T/c-160%). Similarly, when this reaction is applied to doxorubicin, thiomorpholino derivatives of doxorubicin are formed. To remove the thiomorpholino derivatives, these remain in the organic layer after extraction as water-soluble acid salts with an aqueous acid solution. The neutral <1-parabolic fraction of reaction r) contains 3-cyano-1-corresponding to daunorubicin and doxorubicin.
Contains a thio-4-morpholinyl fatty conductor (A=CN).

All of the above disclosures regarding conductor visiting methods are hereby embodied by the literature.

The invention is further illustrated by the following examples, which are presented to illustrate the invention and are not intended to limit the scope of the invention.

Example 1 Synthesis, isolation and identification of β'-deamino-3'-(3"-cyano-4"-morpholinyl)daunorubicin A, Mosiya et al., GIA Medicinal Chem.

25, pp. 18-24, 1982 (Mo5lier,
at al.

-J, Medicinal Che, m,, 25
．． pp] 8-24 (1982)).
Following the synthetic method of hydroxide salt, 3'-deamino-3
1-(4'J-morpholinyl)daunorubicin, 3'-
Deamino-3'-(r-morpholinyl)-13-dihydrodaunorubicin, 3'-deamino-3'-(3''-cyano-4''-morpholinyl)daunorubicin and 3'-
A sum reaction product containing deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodaunorubicin was synthesized. This crude material was extracted with cIxct, as indicated, to transfer the four basic products into the CI■C1, phase. O, OIN IC
The two basic morpholino products were removed by exhaustive extraction of the CIC4 phase with 4 as described in the literature.

This neutral product-rich CfIC1, was washed with Na HCOs solution, then dried and evaporated. Sample 4:1
CHCl, dissolved in CH30H, Waters
Injected onto a high performance liquid chromatography column with Ra
Eluted with 5J pH 4 citrate buffer: CH3CN eluent at 2 go/min. one substance (usually 19 of the total
~24ch) eluted at 6.1-68 minutes, while the other material (typically 26-27ch) eluted at 11.9 minutes. UV
Detected at 254 n+n. According to this, 6.
The substance from 1 to 68 minutes is 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodaunorubicin, and the substance from 1t9 is 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodaunorubicin.
:<'-(3''-cyano-4''-morpholinyl)daunorubicin.

B. On a larger scale, 5.412 solid by-products were dissolved in 9: ] CHCl3- CH,OH500-.

This solution was heated to 001N IC7 (3X 100 me),
H,0(I x 100Ine) and dilute NaHCO,
(I x 100 ml). The organic layer was dried and evaporated to dryness, and the residue was vacuum dried at room temperature with 0.1 ram Hy to give a glassy residue 5,1 Of. In addition,
The aqueous layer was also saved.

C9 Glassy residue from B above 5.09 r to 4:1 CF
I, CL, dissolved in -CH,OH50-. While stirring this bath solution, 30 ml of CH3CN was added dropwise.

The resulting suspension solution was evaporated to dryness to obtain 4: solid residue. This residue was ground with CJI3CN 200- in the dark.

This insoluble solid was collected and again subjected to CT (sCN 100 m
I ground it with l. The two liquid phases contained the desired product -C. When these are evaporated, a semi-solid residue 2,
23! i' was obtained.

D. The semi-solid residue of C above was dissolved in CH2C425rnl and washed with c3c, cffi 200-325m7
:L IJ) Ma l 1-inckro+i
Filled with 5ilic ARCC-7 silica gel:
s, ] crrr (lA diameter) x 59 m column. The column was eluted with CH2CL2 (500me), then CM2C4,-CH,OH (99:1
．． 1500d; 98: 2°1000nr1.
','! 1 7 ° ','=
, 1. 5 0 (Ime: 9
t) eluted at 2 10,500 J). After collecting 2550 mg of the initial eluate (I C+ n1 fraction, followed by TLC), 190 ml of fractions! Evaporation of gave product 0482. This initial component was determined by comparative high performance liquid chromatography and thin layer chromatography to be identical to a substance later identified as 3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin. Met. .

E. Sample 0352 of the above substance was further treated with two C1 (2Ct, -CH,OH2
It was first purified using a 9:1 developing solution. The central zone containing 65% of the sample weight used was cut, eluted, filtered and evaporated to dryness.

F. The product of E above is mixed with an equal amount of other purified material recovered from the middle part by chromatography, and 200-4
1.1 cm filled with 00 mesh silica gel
Final purification using a (OD)X27m column yielded 0.18 r of product. This column is CH2CL□-E
LQAc (so: 20.30 mg: 6
0: 40°30m/; 40: 60. 3omt
;2o :so, 30+d), then ELOA
o (175-).

After collecting 162 ml of initial eluate (2 ml fractions, tracked by TLC), 88 ml of both aliquots! were collected and evaporated to give the product 0,15S'.

Elemental analysis of this pure substance revealed that its structure was
It was confirmed to be 3'-deamino-3'-(3''-cyano-4''-morpholinyl) daunorubicin as well as NMRX UV, IR and mass spectrometry at 360 MHz.

This product was confirmed to exist as a mixture of diastereomers by HPLC and 360M) NMR analysis. Waters Radial-
2 ml with 0.05 MX m4 of citrate buffer-CH,CN (60:40) using a PakC-18 column.
HPLC run at 1/min showed two closely spaced peaks (9,6 min and 102 min) with a ratio of 53:44. The 360 MHz NMR spectrum of this material shows 6-Of(, 1l-OH, 1-H, 2-H, 3-H
, 1'-H, 7-H, 9-OH, 10A-H, 14-H
8 and 6-■.

Two protons resonated.

360 Ml(z NMRCDC1, δ13.99.1
3.98 (2s, 6-0H).

13.25.13.24 (2s, 1l-OH), 8
．． 02.8.00 (2d, 1-H).

7.79.7.77 (2t, 2-H), 7.40.
7.38 (2d, 3-H), 5.59°5.56 (
2d, 1'-H'l, 5.29.5.26 (2b
s, 7-H), 4.47.

*4.34(28,9-0H), 4.08([1,OC
R, ), 3.97-4.07 (m.

2″B-H, 5′-H), 3.92 (also, J
=12Hz 3"-H), 3.74(m, 2"
A-H, 6″El-H), 3.68 (δ8.4′H)
, 3.58 (t.

J=12Hz, 6″A-H), 3.20(d, J=19
Hz, 10B-H').

2.91, 2.90 (2d, J=19Hz, l0A-H
), 2.75-2.95 (m.

3'-11), 2.68 (rn, 5"-Hz
), 2.43.2.42 (2g, 14 H3).

2.35 (m, 8B-H), 2.13 (m, 8A
-H), 1.70-2.0(m, 2'-H,),
1.8fi*(8,4'-01-I, H20),
1.37.1.36 (2d.

J=6.4Hz, 6-H,) *I) 20 replaceable mass spectrum [as trimethylsilyl (TMS) visiting conductor],
n176910 [M (TM b 'J, ), 8
95 [M (TMb) 4 M o :], 8
83 [M (TMS), -HCN], 838 [M
(TMS), L 823 [M(TMS).

-Me), 811[:M(TMS)3HCN″l+
The mass spectrum at 70 aV showed a fundamental peak (HCN) at m1027.

Example 2 Isolation of 3'-theamino-3'(3-cyano-4-morpholinyl)-13-dihydrodaunorubicin Example 1
3'-deamino-3'-(3''-cyano-4''-morpholinyl)daunorubicin and 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-
The mixture of 13-dihydrodaunorubicin was chromatographed to give a series of fractions. Eluent 3460mJ
After collection, 430 ml of both portions containing 12.5% of the original charge and essentially a single compound were collected and evaporated. Both of these compounds are 3'-deamino-3'-
It was confirmed by HPI-C to be identical to (3″-cyano-4″-morpholinyl)-13-dihydrodaunorubicin.

This material was purified by the method set forth in Example 1, E and F, producing substantially pure 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydrodaunorubicin. It was refined into

Example 3 Isolation of 3'-deamino-3'-(4"-morpholinyl)daunorubicin and: 3'-deamino-3'-(4"-morpholinyl)-13-dihydrodaunorubicin in A and B of Example 1 3'-deamino-3'-(
A 001N HCl layer containing 3'-theamino-3'-(4'-morpholinyl)-13-dihydrodaunorubicin was removed.

This aqueous layer contained approximately 40% of the fill material. This aqueous layer was then shown above. 3'-theamino-3'-(
4''-morpholinyl)daunorubicin and 3'-deamino-3'-(4''-morpholinyl)-13-dihydrodaunorubicin were separated as isolated compounds.

Example 4 3′-deamino-3′-(3″-cyano-4″-morpholinyl)doxorubicin and 3′-deamino-3′(3
Synthesis and isolation of 'l-cyano-4"-morpholinyl)-13-dihydrodoxorubicin A, by a method analogous to the reaction described in G.I. Mesoinnal Chem, Vol. 25, cooled in a water bath at 15-20°C. In ml of H2O7S, the following formula: 6,
25? To a stirred solution of (60,0 mmol) of 1,4-anhydroerythritol was added 6.421/(30,0 mmol) of sodium metaperiodate.

The resulting clear solution was stirred at room temperature for 17 hours.

A precipitate was formed when the ... of the solution was adjusted to 4.0-7.3 with Na)(Co3 and then diluted with 75 tnt of CH,ON under stirring. The mixture was stirred and then diluted with N
aBH.

CN O, 126f! (2,0 mmol) of C)(,0N-T(,05-) was added to the mixture. Doxorubicin dihydrochlor I
J)”1 containing 1.16 f (2゜Ommol):
1 of CM, CN-H,030- was added. After 10 min, the reaction mixture was diluted with dilute NaHC0,50- and 50 d of C
Extracted with HCl three times. This crude extract contains 3′-deamino-3′-(4”-morpholinyl)doxorubicin, 3
'-Deamino-3'-(4''-morpholinyl)-13-
Dihydrodoxorubicin, 3'-theamino-3'-(3
It contained "-cyano-4"-morpholinyl)doxorubicin and 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydrodoxorubicin. The extracts were combined and extracted with 0.1N acetic acid (5X25d), then with H,O, dilute NaICO8 and Na
Washed with C1 saturated aqueous solution.

The acidic aqueous layer was saved. Nav b the chloroform layer
Dry with O4, filter through Celite diatomaceous earth, and concentrate to remove the residue. This residue was dissolved in CHCL, 25- and the solvent was re-evaporated under vacuum at room temperature to give a dark red foamy glass material.

day, the foamy glass sample of A above was dissolved in CH3CN,
Injected into a Waters Radial-Pak C-18 high performance liquid chromatography column, pi(4,
0,0,05M citrate buffer-CH,CN (55:
45), it was eluted in 2/7 minutes. Compound eluates were examined at 254 nm.

3′-deamino-3′-(3″-cyano-4″) in 23 minutes
3'-Deamino-3'-(3''-
[P
Separated by LC.

0.3'-deamino-3'-(3''-cyano-4''-morpholinyl)doxorubicin and 3'-deamino-3'
The isolation of -(3''-cyano-4''-molporinyl)-13-dihydrodoxorubicin was repeated sequentially as follows.

Sample of the foamy glass substance of A above (1,424f/CH
,C1,1,5- and washed with CH2Cl,2
A 15X 35.5 cm column of 00-400 mesh Blo-8il A silica gel was used. This column was CH2C/-.

(50++d), then CH2Cl, -CH
,OH(9'): 1,150mg;98:2,15
0+++g;97:3.300+nj;95:
5,100+! and 90:10°300m/). After collecting 445 ml of the initial eluate, fraction 80
tnl is evaporated to produce -C product 02]7? I got it. Purified product obtained from earlier synthesis of this material 0.0
The mixture was dissolved in 21 nl of CH2C, diluted with 10 ml of Cfl30H, and evaporated to dryness. This IA? 9 mash f with 5 mg of CH, OH, 3'-deamino-3'-(3"-cyano-4"-morpholinyl) doxorubicin 0.218 r fmfc.

HiJLC and 400 MI(z NMR analysis confirmed that the product is a mixture of diastereomers. Waters Radial
HPLC analysis was performed using -Pak C-18 in 0.05 M,...4 citrate buffer -CHaCN (65:35) at a rate of 2-/min.
closely spaced peaks (14.4 minutes and 15.7 minutes)
showed that. 400 M of this substance) (in the z spectrum, 1-H, 2-H, 3-H, 1'-H, 7-H, 14
-H,,9-OH,OCH,.

10 A-H and 6'-H, two protons resonated.

400MHz NMRCDC1, δ 14.02 (8,
6-0H).

(13,26(a, 11-0H), 8.05.8.0
4(2d, 1-1(), 7.80°7.79(2L
, 2-11), 7.41. '7.40 (2d, 3
”-H), 5.61.5.57 (2d, 1'-H)
, 5.34.5.30 (2m, 7-H), 4.7
9.4.78 (2a, 14-H2'), 4.54.
4.42 (2 also 9-0H), 4.11.4.10 (2
a, OCH3), 4.05(m, 5'-H),
3.97 (m, 2″B-H.

3″-H, 6″B-H), 3.71(m, 4′-H
, 6"A-H), a, 5s (t.

2″A-H), 3.30(d, J-19Hz, l
0B-H), 3.07.3.06 (2d, l0A-
H), 3.03 (m, 3'-H), 2.69 (m
, 5”H2).

2.38 (m, 8B H), 2.22 (m,
8 A--) (), 1.84 (m, 2' H2)
.

1.61 (8, HzO'), 1.4 O, 1,39
(2d, J = 6.5Hz, 6' Hs 'l.

UV-Vis(CH30H)nlaX 234nm
(640,100).

252 (27,700), 289 (9,420), 47
8 (13,1100).

495 (12,900), 530 (7,19 (N, mass spectrum [as trimethylsilyl (TMS) derivative]).

rn/e 899M (TMS) 4 HCN.

CIN Calculated value C321■34N2012・2H2056,97
5,684,15 Actual value 57.07
5.37 4.17 Furthermore, by elution from the above column, 3
'-Deamino-3'-(3"-cyano-41-morpholinyl)-13-dihydrodoxorubicin was obtained.

UV-Vis (CHρ old max 234nm (g 3
7,400).

252 (2B, 0Ofl), 289 (9,390),
475 (12,700).

496 (12,800'), 530 (7,410), mass spectrum [trimethylsilyl (as TMS'l derivative), m/e 985M (TMS), -CH,,
973M(TMS), -HCNCIN Calculated value C,,l(,6N, 0.2・I t/2H20
57,575,894,20 actual measurement value
57.35 5.94 3.82 Example 5 Isolation A of 3'-deamino-3'-(411-morpholinyl)doxorubicin and 3'-deamino-3'-(4''-morpholinyl)-13-dihydrodoxorubicin The acidic aqueous phase obtained in Example 4 A was made basic with NaHCOs and extracted with CHCt.
Wash with saturated solution of CL, Na! Dry with S04 and Ce
Filtered through 1ite®, concentrated and dried to give 0.8289 g of a red foam. This substance is
HPLC, 90MHz NMR, 300MI (z NM
R,UV-Vis spectroscopy and mass spectroscopy revealed that the two major components, 3'-deamino-3'-(4''-morpholinyl)doxorubicin 3'
It was shown that it contained -deamino-3'-(4"-morpholinyl)-13-dihydrodoxorubicin.

B. The foamed glass prepared in A above was collected at 0.98 F. This material was dissolved in CH2C4,3- and silica gel 2
．． Chromatography was performed using a 2X33cIn column. The column was eluted with c4ct, (50ml) and then CH,C6,-CH,OH (99:1.3
00mj:98:2,300mt;97:3,900
- and 90: 10. 7ootILe). After collecting the initial eluate 1170-, both portions 490-
- was separated and evaporated to give a residue. This residue contained 45% of the loaded sample and was determined by HPLC to be nearly pure (99%) 3'-deamino-3'-(4''-morpholinyl)doxorubicin.

90 MHK NMRCDC1, δ 13.88 (a'
, 6-0H), 13.07(s, 1l-OI()
, 7.90 (d, J=8Hz, 1-H'), 7
．． 72 (also, J-8Hz, 2-H), 7.38 (d
, J=8Hz, 3-H), 5.51(ba, 1
'-H), 5.20 (1+s, 7-H), 4.
75 (g, 14-H2), 4.68 (a, 90H
), 4.07 (8, OCH3), 3.98 (m
, 5'-H), 3.67 (m.

4'-11,2"-H2,6"-Ht), 3.09
(d, J=19) (Z, 10B-H”l.

2.83 (d, J=19Hz, 10A-H), 2
．． 80-3.20(m, 3'-I().

2.50-3.00(bs, 4'-OH, 14-0
H), 1.95-2.65 (m, 8-, H2,3"
-H2, 5"-112), 1.80(rri, 2'
H2), 1.38 (tl.

J = 6.511z, 6' - H,), p to mass x
Tor[)IJ methylsil+)yl (TMS) v5i form], m/e 973M (TMS)B.

901M (TMS).

Suspend the free base in H2O and add 0. IN HCl-
Acidified to 14.4. The resulting solution was lyophilized and the product was dissolved in CH,OH and precipitated with 10 volumes of ether to give the hydrochloride.

CHCL N Calculated value -C3,H35NO,・HCt・2H,054,
275,885,172,04 actual measurement value
54, O85, 354, 782, 00UV-Vis
(CM, QH) m11x 234nm (ε39,0
00), 252 (26,300), 290 (8,9
90'l, 480 (12,600), 495 (12
,50,0), 530(6,700).

After collecting both fractions 190-, fraction 160-me was collected. Both parts of this latter were evaporated to form pure (97%) 3'-
It was found to contain 19.5 hours of filler material as deamino-3'-(4"-morpholinyl)-13-dihydrodogisorubicin.

300MHz NMRCDCL, 8 13.9B, 1
3.96 (2s, 6-0H), 13.34.13.
32 (2g, 1l-OH), 8.03(d, 1-
H).

7.79 (t, 2-H), 7.40 (d, 3-H
), 5.56 (ba, 1'-H).

5.29 (ba, 7-) (), 4.64.4.59
(2s, 9-0H), 4.09 (8°OCR,)
, 4.03(m, 5'-H), 3.82-4.
05(m, 4'-H, 13-H), 3.68 (
m, 2″-H!, 6″-bird, 14B-H), 3
．． 54 (ba.

14A-H'), 3.30 (rrl, 10B-H)
, 2.98 (bs, OH), 2.87 (1) [1, OH
), 2.77 (m, 10A-H,3'-H)
, 2.30-2.70 (Jn, 8B H, 3
1H2, 5″H2), 1.99 (m, 8A
H), 1.78(m, 2'-1(2), 1.
4], (d, 6'-H,'), mass spec l
- #r) Limethylsilyl (TMS) as a rust conductor
mZe 975M (TMS), .

Example 6 3'-deamino-3'-(4''-morpholinyl)-5-
Synthesis of iminodoxorubicin A, dry pyridine 5 m7! 0.99 (l) of P-anisylchlorodiphenylmethane was added to the 3'-deamino-3'-(4"-morpholinyl) doxorubicin solution prepared as shown in Example 5 of The reaction was allowed to take place at room temperature for about 2 days.The solution was cooled in ice water.
CI, OH0,5- was added. The mixture was stirred for 2 hours, added to dilute NaHC0.50me and extracted with CH2C4. The extract was concentrated to give a gummy residue. The gummy residue was dissolved in toluene, concentrated, dissolved in CH,C4 and precipitated by slow addition of petroleum ether at 35-65<0>C.

This precipitate was collected, redissolved in CH2C62, and 2:
Petroleum ether of 1: 14-0-P-ayucyldiphenylmethyl-3'-theamino-3'-(4"-
Morpholinyl) doxorubicin (I) was obtained.

This material was identified by 90 MHz NMR in CDC1.

B, 14-0-p-anisyldifhenylmethyl-3'-
A solution of 0.532 r of deamino-3'-(4''-molporinyl)doxorubicin in CH,Ct, 10- was added to 30 mZ of OHsOH saturated with ammonia at 0°C. The mixture was stirred at 0°C for 1 hour, then 3 ℃ for 27 hours. The solvent in the reaction product was evaporated. The residue was dissolved in 4:1 CH, CL, -CH, OH and concentrated. It was refluxed twice and the solid c4ct, filtered through Celite, concentrated and diluted with 1:2 C
Dissolved in H,CL, -CH,OH, concentrated again and dried to give a purple residue 0.52j' (97%).

C1 The residue of B above was dissolved in CH, C1,2-, and 1.5
It was applied to ×40 secondary silica gel column, CH, Ct, (5
0 ml), then CH2C4-CH,OH (9
9:1.

150m7! : 98:2.150m6 : 97:
3.500m; 95:5,100 Go: 93 Near,
100td; and 90:10°200-). Following 565 ml of eluate, fraction 335- was separated, filtered and evaporated to yield 59.9 ml of sample as a single substance. This knowledge is based on 90MHz NMR, 14-0
-p-anisyldiphenylmethyl-3'-deamino-3
'=(4''-morpholinyl)-5 iminodoxorubicin was confirmed.

D. A 0.341r sample of the product from C above was dissolved in 80% acetic acid 20- and the solution was then stirred in the dark for 7 hours. This solution was then diluted with 50-m water and CHC
Extracted three times with l3. The aqueous layer contained the desired product, which was lyophilized in the dark to give a solid of 0.2949. Dissolved in IN acetic acid. The oil was washed with CHC/=, basified with NaHCO, and extracted with cHct. The target substance transferred to the organic layer was washed, dried, filtered, and concentrated to obtain a residue. This residue was dissolved in CHCl, -C%H (1:10),
Concentration and drying yielded 0.228f of 3'-deamino-3'-(4"-morpholinyl)-5-iminodoxorubicin. This material was identified by 300 M) (zNMR and elemental analysis.

Example 7 Preparation of Acid Addition Salt The free base product of Example 6 was suspended in 20 ml of water. This mixture was stirred and 0. IN HCl 3.2- was slowly added to...4.5. This suspended solid gradually dissolved. This solution was lyophilized in the dark and HPLC
According to 97% purity acid addition salt, 3'-deamino-
3'-(4''-morpholinyl)-5-iminodoxorubicin hydrochloride was obtained.

CHCl-N Calculated value C3, H,, N20. ,・IC/-2H,05
4,356,035,174,09 actual measurement value
54,20 5.96 4,33 4.03
Example 8 3′-deamino-3′-(4″-molporinyl)-5-
Preparation and isolation of imino-13-dihydrodoxorubicin A, 3'-deamino-3'-(4LJ-
Morpholinyl)-13-dihydrodoquinrubicin o, 1
CH s6ym solution saturated with ammonia at 0 °C,
Added to 0H201d. The mixture was stirred for 1 hour, then left at 3° C. for 27 hours and concentrated. The residual product was converted into CH2
It was dissolved in C4-CHsOH (4:1) and squeezed three times to completely remove ammonia. The obtained residue, 2
W x 20 on x 20 on silica gel plate C
It was prepared by thin layer chromatography using HCl, -CH,OH (9:1) developing solution. Substantially pure 3'-deamino-37-(4'/-morpholinyl)-
The band containing 5-imino-13-dihydrodoxorubicin was separated, eluted, and the eluate was dried to +300M
Free base product confirmed by H7NMH 0.139
I got f.

B. The free base of A above was converted into the hydrochloride salt by the method of Example 7. According to HPLC analysis, its hydrochloride salt is 97-9
It had a purity of 8.

C) I C1N Calculated value C31H38N2011・HCl・2H,05
4,196,315,164,08 actual measurement value
54.17 5,95 4.88.3.87
Example 9 Six cycles of 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-5-iminodaunorubicin 3'-deamino-a'-(3"-cyano-4"-morpholinyl)
CH2Cl containing 0.0311 daunorubicin.

1.0 z-m/ of the solution was added to 5 portions of methanol saturated with ammonia at 0°C. The mixture was stirred for 30 minutes and then left at 3°C for 45 minutes. The reaction product was evaporated to dryness to obtain a residue. This residue was dissolved in 19:1 CHCl
, -CH30H5nrt and enzymatically condensed. This operation was repeated 1-times. This residue was dissolved in CHCl, -CH30
Dissolved in H, 2 g X 20 rrnX 20 cr
9:1 CHCl3-
It was developed using CH30H. The main band was eluted and analyzed. According to mass spectrometry analysis, the compound is 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-
It was confirmed that it was 5-iminodaunorubicin.

Example 10 Instead of 3'-deamino-3'-(4''-morpholinyl)doxorubicin, 3'-deamino-3'-(3''-cyano-4''-morpholinyl) synthesized in Example 4 was used as a raw material. ) Doxorubicin was used to repeat the synthesis of Example 6. The blocking-amination-blocking isolation series of Example 6 was performed to give the final product 3'-theamino-3' (3/l- Cyano-4〃-morpholinyl)-5-
Iminodoxorubicin was obtained.

More specifically, the synthesis was as follows.

A, 3'-deamino- synthesized as shown in Example 4
A dry pyridine solution containing 0.241 F of 3′-(3″-cyano-4″-morpholinyl)doxorubicin was added with p
0.5872 of -anisylchlorodiphenylmethane was added. The solution was stirred at room temperature in the dark for 44 hours. The reaction mixture was cooled, diluted with CI(, OI(0,5-), stirred at room temperature for 3 hours, then treated with 50 ml of dilute NaHCO
K added, CH! Extracted with ct. The extract was concentrated, the residue was dissolved in 3 ml of CH2Cl, and precipitated by slow addition of 40-diethyl ether.
0.333f (97%) of 4-0-P-anisyldiphenylmethyl-3'-deamino-3'-(3''-cyano-4''dimorpholinyl)doxorubicin was obtained.

90 Ml(z NMRCDC65δ 13.84(s
, 6-0H), 12.99(s, 1l-OH),
? , 82(d, 1-H'l, 6.70-7.75
(m, 2-H.

3-H,)rityl-aryl), 5.42(bs,
1'-H), 5.08(bs, 7-H>, 4
．． 45 (be, Rei 14-H2), 4.19 (β, 9-
OH”l.

4.00 (s, 0CR5), 3.79 (a,
OCH3), 3.30-4.15 (bow 4'-fl,
5'-〇, 2''-H2, 3''-H, 6''-H2),
1.60-3.10(m, 2'-H2,8-H,,
5"-H2,10-H,,3'-H), 1.13(d
, 6'-H,).

B, 48 ml of CH2C 14-0-11-ayucyldiphenylmethyl-3'-deamino-3'-(3''-cyano-4''-morpholinyl)doquinrubicin o, 369
yi, 1 c■2ct, 8 ml of solution was added to C1 (sOH25+J) saturated with ammonia at 0°C.
The mixture was stirred at 0°C for 1 hour and then left at 3°C for 26 hours.

The reaction mixture was evaporated to completely remove ammonia, yielding 0.376 t of a purple residue.

C, CH2C41.5tnt of the residue of the above B was 1.5X
Applied to a 28 m (200-400 mesh) silica gel column and eluted with CH2C4 (50 m), then CH2C
4,-CH30H (99:1,200mg: 98:
2.300m1: 97:3゜100td: 95
:5,100- and QO: 10.200mg). First elution i - min 1 after collecting 360 ηrl
25me was evaporated to give 14-o-p-'y nisyl diphenylmethyl-3'-deamino-3'-(3''-cyano-
4″-morpholinyl)-5-iminodoxorubicin 0.
2039 was obtained.

D. Cool the 0.1585' residue sample of C above to 0 °C;
It was cooled on ice and dissolved in IJ fluoroacetic acid 8-.

The solution was stirred at 0° C. for 2 minutes and then poured into 100 g of ice water. The mixed aqueous solution was extracted with CHC4 (4X 10ml) and the combined extracts were diluted with dilute NaHCOs and Hlo
The residue was washed with Na, dried with So, filtered through (:elite) and evaporated.
Dissolved in H3OH (4:1)3- and stirred the solution,
25 ml of ether was added dropwise. The resulting precipitate was collected to obtain 0.0939 of 3'-deamino-3'-(3''-cyano-4''-morpholinyl)-5-iminodoxorubicin.

HPLC and 300 MHl NMR analysis confirmed that the material was a mixture of diastereomers, 0.05 M, p! on a Watera Radial-Pak C-18 column. 14 citrate buffer -
HPLC analysis using CH30H (40:60) revealed peaks at 18.4 minutes and 25.0 minutes with a ratio of 69:31. The 300M)iz spectrum of this product shows I-)T, 2-H, 3-H, 1'-H
，? -H,14-H2,9-OH,OCH3,10A-
Two H,6'-H3 protons resonated.

300 M) (z NMRCDC25δ 15.61
(s, 11-0ff).

13.74 (d, 6-0H), 9.27 (d, N
H), 8.21.8.19 (2d.

1-M), ? , 73.7.72 (2L, 2-H),
7.33.7.32 (2d, 3-H).

5.77, 5.72 (2d, 1'-H), 5.4
1.5.38 (2m, 7-H), , 1.7Q.

4.77 (211,14I(2), 4.72.4.6
6 (2g, 90)t), J, 15°4.14<28
．． OCR, ), 4.04 (m, 5'-11),
3.97(m, 3″i[.

2"B-H), 3.75(m, 6"-H2, 4'-
H), 3.59 (tn, 2″A H).

3.23 (d, l0B-H), 3.03 (m, I
OA-fT, 3'-1t), 2.72(m, 5
”-H,), 2.33 (m, 8B-H), 2.1
4(m, 8A-H'l.

1.85 (m, 2'-112), 1.38.1.
37 (2d, 6'-H3).

UV-Via (CH30H) max 221nm
(g: 41.0flO).

252 (32,900), 307 (7,110),
520ah (9,11(N.

551 (17,4001,592 (20, 7 (10)
, DCI-MS mle63B (M+H), 611 (
M1H-HCN)N Calculated value C, 2H8, NsO,, -H2058,625,
696,41 Actual value 58,79
5.47 6.30 Example 11 3'-deamino-3'-(4''-morpholinyl)-13
The preparation of Example 8 was repeated four times using equimolar amounts of other starting materials in place of dihydrodoxorubicin. In the first case, 3'-deamino-3'-(3
"-cyano-4"-morpholinyl)-13-dihydrodoxorubicin was used as the raw material, and 3'-
Deamino-3'-(3''-cyano-4#-morpholinyl)-5-imino-13-dihydrodoxorubicin was obtained. In the second case, 3'-deamino-3'-(4''-morpholinyl)-5-imino-13-dihydrodoxorubicin was obtained. Using daunorubicin as raw material, 3'-deamino-3'-(4''-morpholinyl)-5-iminodaunorubicin was obtained as the final product. In the third case, 3'-deamino-3'-(4 ″-Morporinyl)-
Using 13-dihydrodaunorubicin as a raw material, 3'-deamino-3'-(4"-morpholinyl)-5-imino-13-dihydrodaunorubicin was obtained as the final product. In the fourth case, 3'- deamino-3'-(3″
-cyano-4"-morpholinyl)-13-dihydrodaunorubicin is used as the raw material, and 3'-deamino-3'-(3"-cyano-4"-morpholinyl) is used as the final material.
-5-imino-13-dihydrodaunorubicin was obtained.

Example 12 Examples 1-11 were prepared using derivatized doxorubicin and daunorubicin, synthesized as described herein, in the range designated ``Derivatives and Analogs'' in place of doxorubicin or daunorubicin as starting materials. The synthesis was repeated. By repeating these steps, corresponding derivatives and analogs of the compounds of the present invention were obtained.

Compounds of the invention are useful as antitumor agents in mammalian animals. This effect is demonstrated by in vivo and in vitro studies. Chemotherapy Revolutions, National Cancer Institute, Volume 3,
No. 2, Bart 3゜September 1972 ((::aBc-o
5-(:, -Q4n+os+-e, y, a-py-f
1. e p O! C8・-National Canc
er In5LiLuLe, 3, m2. Pa
In an in vivo study conducted according to the protocol described in rt 3° Saptam I Jar, 1972), lymphocytic leukemia P-388II! Water was inoculated intraperitoneally into healthy mice. The inoculated mice were then continuously administered various indulgent compounds of the invention on days 5, 9, and 13.

(2) Other mice were not administered and other mice received daunorubicin or doxorubicin, 3'-deamino-3'-(4"-morpholinyl) daunorubicin or U.S. Pat. No. 4:401,277. 3'-deamino-3
'-(4''-molporinyl)-13-dihydrodaunorubicin or 3'-deamino-3'-(4-methoxy-1-piperidinyl)daunorubicin or its derivatives as shown in U.S. No. 1-4,314. (154). 13-dihydro equivalent] 7k.

The average survival period of the treated mice was measured and compared with the average survival period of mice inoculated with leukemic ascites but not treated with the test compound.

stomach! The calculated data is shown in the fiA table below. This data shows that the survival of treated mice is 1 compared to the survival of control 1.
υ] divided by 1 to 100 and 1', then the %T/C value and (7
It is expressed as Also shown in Table A is the administration side of the divine compound that was observed to yield the best improved survival.

Table A-41-morpholinyl) Daunorbiny 332304
197 0.4 0.012 0.0
023'-deamino-3'-(3''-/ano4''-morpholinyl)-13-dihydrodacnorpi/7 332.305
143 0.1 0.019 0.0
023′-deamino-3′-(3”-77)-41-
Morpholinyl) Dokinlupi7y 357,70
4 1g7 0.075 0.003 0
．． 0005γ-deamino-3′-(3″-cyano-4″-morpholinyl)-13-dihydrodoxorubicin 360,291
150 0.2 0.02+
0.003031-Deamino-3'-(4''-morpholinyl)-13-dihydro-5-inodoxolpinno 355.465
161 50 )+00 2
4 Comparison Example: Daunorbishiy 82J51 130
8 0.66 0.33 Doxorubi //
123.127 160 8 1.5
0.58 Blue N80141 U.S. National Institute of Health and Welfare National Institute of Health and Welfare's National Institute of Health and Human Services 7/T Approval Number Table A (Continued)
! 66 0.2 0.76 0.103'
-Deamino-3'-(4''-morpholinyl)-13-dihydro/rubinone 327,45
0 132 0.2 2.2 0.
673'-theamino~31- (4+1-me1quino1
″-piperinonyl)daunorbi//334,353 199 6.25 0
．． 63 0.123'-Deamino-3'-(4
-methquin-1-piperidinyl)-13-daunorubicin 334°35
4 199 12.5 0,58 0
．． 08 These results demonstrate that the compound of the invention q17) 7) <low optimal dosing! # indicates that it has excellent antitumor effects in vivo. Compound NSC357704 exhibited an optimal dose that was approximately 150 times lower than that required for the base compound. The material of the invention exhibited significantly lower optimal dosages than daunorubicin and doxorubicin. This promises to provide effective antitumor agents with substantially reduced toxicity.

3′-deamino-3′-(3″-cyano-4″-morpholinyl)daunorubicin and 3′-theamino-3′=(
In vitro testing of 3''-cyano-4''-molporinyl)-13-dihidirhodaunorubicin also showed increased activity of this family of compounds. G. Tong, T. R. Black, D. W. Henry et al., J. Mesoinnal Chem., vol. 19, p. 395, 1976 (G, Tong, W.

W, Lae, D, R, Blnck, D, W.
Henry, J.-He4-jc-i-nal C
1+am, 19.395 (1976)) in L1210 cells.
When these compounds were tested as A-synthesis inhibitors, they were effective at doses 600 times lower than before 4 days of daunorubicin, doxorubicin or the previous %'1 analogue.

These compounds also have a much greater inhibitory effect on RNA synthesis than on DNA synthesis (1!El), o
A ratio of DN input/RNA=1 (1:11) was observed. Such ratios belong to the second class of anthrazyclines, which have improved therapeutic properties.
0 pages, 1978 (S, T, Crooka, eL
al.

Mo1. Pl+armaco1. , 14.290(
1978)). These data are
As shown in Table 1, Q'+ A Table (D data shows increased antitumor efficacy with morpholino structure and further increased efficacy with cyanomorpholino structure, symbolizing the activity by this class of compounds. are doing.

In order to demonstrate the biological effects of the compounds of the invention, 9)
: The test was conducted. The test of Jl et al. was carried out substantially according to the method of Cancer Chemotherapy Laboratories, 1972, previously described.
Leukemia and B-16N! , was an in vivo study in mice for melanoma. Intraperitoneal (
ip), intravenous (i) and oral (po) administration.The results are shown in Table 8.

746 The compounds of the present invention and salts thereof may be administered by any available route, including oral, parenteral (intravenous, intraperitoneal, subcutaneous, intramuscular). Parenteral administration, particularly intravenous administration, has historically been the mode of choice and is preferred. For example, in the treatment of lower test #), the compound of the present invention is sufficient to effectively ameliorate leukemia or cancer of the form of cancer. A dose of the compound in the range of about 0.0010 to about 25 y/Kg per day is sufficient to treat leukemia. The upper limit of the administration needle is the height up to which sexual side effects appear, and is determined by trial and error depending on the animal to be tested.

Generally, the dosage of the compounds of the present invention will be lower than that required for the base compound (e.g., ~8 o',
.

Food administration once every 4σ for 2 to 7 days is effective, while shorter dosing intervals, i.e., within 1 day, can be used as well.

To facilitate administration, the compounds of the invention and their salts can also be administered in the form of pharmaceutical compositions, in particular in single dosage form. It is more common to administer the compound in combination with a pharmaceutically acceptable carrier which is dilute and facilitates handling. The term "pharmaceutically acceptable" means that the carrier (as well as the resulting composition) is sterile and non-toxic.

For oral administration, the 411 concentrate or diluent may be solid, semi-solid or liquid and acts as an excipient or vehicle for the drug as described in pharmaceutical texts. For parenteral administration, the compounds are dissolved or suspended in suitable injectable liquid vehicles known in the art.

In preparing these dosage forms, any accepted technique for formulating water-soluble (for salts) and water-insoluble (for free bases) formulations may be employed.

For example, an injectable substance can be formulated as follows.

Mixture A: Eaves e '43 F! L;<j< q Q-"Onion" person-9
17 Examples as suspendable powder], 2.3.4°5.6.9 or lO compound 3 Sodium citrate 5.7 Sodium carboxymethyl cellulose (IJf viscosity) 2 ．．
0 Barahydroquine, -methyl fragrant 1
5 parahydro A/benzoic acid 1 pill
Sterile Suspension of O210〃L Nida M) in an Aqueous Medium for Injection Water Formulation APA Example 4
23'-deamino-3'-(3''-cyano4''-storium citrate 5,
7 Carboxymethyl cellulose sodium (low viscosity)
2.0 Methyl barahydrobenzoate
1.5 Propyl barahydrobenzoate
021, 0- Water for injection formulation B: Water for injection is a sterile solution of the U system my Compound of Example 7 4 Sodium citrate 57 Sodium carboxymethyl cellulose (low viscosity) 20 units Menal hydroxybenzoic acid 1.5 units Propyl hydroxybenzoate
(), 210- Similarly to water for injection, tablets for oral administration can be formulated as follows.

Preparation 8-C: Tablet formulation Compound of Example 7 (Ray 1 50 Lactose 91 Cornstarch (dried) 51.Fi gelanan 2.5 Magnenium stearate 1.0 Powderize the compound of Example 7 and sieve) +'i+ 1/, then mix well lactose and corn starch (7. Pass both through a sieve.

Stir the mixed powder and gelatin in water (7, heating 1,
The gelatin warm solution prepared by forming 1% (1%~'/'''ti + 71'i) was used to form a lump. This lump was passed through a sieve (7 and granulated., i' The granules that had risen were dried at 40°C.

The dried granules were passed through a sieve and granulated again, and the remaining starch and magnesium stearate were added and thoroughly mixed.

The granules were compressed to prepare tablets of each weight.

Capsules can be formulated as follows.

Formulation D: Capsule combination! Compound of Example 8 10 Lactose 190 Formulation D': Capsule Formulation! 3'-Deamino-3'-(3''-cyano-4''-morpholinyl)doxorubicin of Example 4(C) 1 Lactose 199 The compound of Example 8 or 4(c) and lactose were passed through a sieve to obtain the After the powder was thoroughly mixed, it was filled into hard gelatin capsules of suitable size. Each capsule contains 200 da of mixed powder.

・Kyo 1496122 Inventor Nidward Matsukintrash Acton 281 Arlington Way, Menlo Park, California 94025, United States of America Shift correction t4j Showa, 1958: +8, 11+-, 1 'I, l,, ri'l Director-General Kazuo Wakasugi Tono 1, Shen 1 Indication Showa Fu 58 Q' Patent Toj11 No. 13039
0 +328 Name of the invention Morpholinyl daunorubicin and morpholinyl doxorubicin derivatives and analogs thereof: 3. Ura 11: Relationship with the person responsible for the patent application: f+, Niss R.I. International (
With Mr.) 5. Sleeves! I:, Instruction 11 I] Spontaneous (3, Number of inventions increasing due to Ura Masa) Amended as per the appendix of the first section of the request.

■6 Column for detailed description of the invention (1) Akira #11 (': No. 2407 and 111 “(
)-Methoquine group” is corrected to “Methoxy group” Z.

(2) r 1-1/2 +1 on page 56, second line from the bottom
．． (river r 1.5)1. OJ and correction-r.

(3) p. 78 of the same page, unpublished r(4) 3'-buamino 3'
-(4"-morpholinyl)-13-dihydrodoquinrubicin (Claim 5 of U.S. Pat. No. 4.3 (No. 11,277)
)"4・r(413'-Aamino3'-(4"-
Morporinyl) Taunorubicin (US 1. + 乍Amend #4 to Claim 26UK of No. 4,301,277) J.

Patent blue water jjjt14 [De
C.O.

-(X)-CII, OH, -C11011-CLI. O
ll, hydroxyl group, carbon IC! Alkyl group having 11 to 3 carbon atoms, terminal hydroxyargyl group having 1 to 3 carbon atoms, -CO-
1□0F1. -CIK)H-Cn2on and -CIJO
tJ - C113 organic acid Nisdel and diester with 2 to 7 carbon atoms, 11 kJ (hydroxy acid with iz or more), (carbon 7
:Numbers 1 to 6 of Argyl or Oriri-Rue f/l->)
re: teLt exchange f,: -CO-CIJ, 0
11, - C1-10H-Q (20H people-CH0J
4-CH, and -CO-CH, and -COCIJ2
selected from -13-ketoimine derivatives of 0H; Y1
is a hydrogen atom or a methoxy group; is a methoxy group and It'' is a hydrogen atom; A&: is a hydrogen atom or a cyano group, but when X is = 0, A is a cyano group; Z is oxygen and all/ is the number of carbon atoms 1-3
A compound having the basic structure of [ selected from ] which is an alkyl group) and which is a group).

(In the formula, l is C(')-CI[,,C)I(-)H-
CH3,C0-CH,OH and 1ON-CIJ20H
, X is 0 and N1- (selected from f+, A is C
selected from N and hydrogen atoms, provided that when X is 0, A
), icN) is 4492'+:i'jlj.

Special V1-Serious! The compound described in Section 2 of Il'1.

(4) The following formula: A compound having the structure of the hepta-drug Bl' (the second term n-bi branch of the desired range).

(In the formula, R has the same meaning as the second term of the patent claim! [λ tetrasaccharide 2nd term) +! The compound according to item 2 of the scope of the invention.

(6) 3'-deamino-3'-(3"-cyano-
4”-morpholini) daunorubicin.

(7) 3'-deamino-3'-(3"-cyano-4
“-morpholinyl)-113-dihydrodaunorubicin.

(8) 3'-deamino-3/ -(3/-cyano-
4“-morpholinyl) doxorubicin.

(9) 3'-deamino-3/-(a//-cyano-4"-molporinyl)-13-dihydrodoxorubicin.

(Hl) 3'-deamino-3'-(4"-morpholinyl)-5-iminodoxorubicin and its pharmaceutically acceptable, No. 1 to 1.

(n) A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable diluent or carrier.

(2) An antitumor pharmaceutical composition comprising a compound according to claims 2 to 5 or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable carrier.

(13) 3'-Theamino-3'-(3"-cyano-4"-molporinyl) daunorubicin is effective! :3'
An anti-inflammatory formulation composition.

(14) An antitumor pharmaceutical composition effectively containing 3'-deamino-3'-(3''-cyano-4''-molporinyl)-13-dihydrodaunorubicin.

(15) a'-deamino-3'-(3''-cyano-
A pharmaceutical composition with antitumor properties that effectively sutures 4"-morpholinyl) doxorubicin.

(16) An antitumor pharmaceutical composition comprising an effective amount of 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydrodoxorubicin.

(17) Anti-I containing 3'-deamino-3'-(4"-molporinyl)-5-iminodoxorubicin
Mt 7t4 pharmaceutical composition.

(18) The following formula: [In the formula, L is -('0-(3.
.

-CO-C112011, -1 (for 111-CIII,
hydroxyl group, alkyl group having 1 to 3 carbon atoms, 1 terminal hydroxyl gamma group having 1 to 3 carbon atoms, -CO-CH12011,
-CIIOH-CH2011 and -C1l (for -CIJ
, organic harsh esters having 2 to 7 carbon atoms and Diesdel, ttJ, 'tt1 or more hydroxyl groups having 1 to 7 carbon atoms
It ? with the alkyl or aryl ether group of 6? A -CO-CIIノ)II, -Cll0)J
-cII2on and -(MMl-CH.

, ) and -CO-C1l, and -COC, (]-I
Yd is a hydrogen atom or a methoxy group; X is -O or 1=N11;
It' and It''tj, - atom with hydroxyl on all sides, or both of them are hydrogen atoms, or t and It' are methoxy and hydrogen atoms. A is a hydrogen atom or a cyan group, but when the input is = (), A is a cyan group; However, Z is selected] In the method for producing I+! of a compound having the structure i;
Known daunorubicin, doxorubicin and (in the formula, 1
4. l, +t'', x and Y have the same meaning and meaning as the previous h (:), (1-j) clear C' and its analogs 1. and the following formula:
/CH2-C1(O \C112-(130 [1-1], Z rl oxygen atom, Iowa IJI child, -C
1l,-.

A mixture having the structure of 11 and 11 its favorable precursors is reacted 1x in an organic medium, and the reaction of 7 is to form an alkali gold 1. autocyanoborohydride. A manufacturing method characterized in that the presence of a cyanoborohydride base such as 1) is isolated and isolated by a method known per se.

(19) The following formula: (wherein IJ-, 1-Co-C11s, -CfJ(,
M(-C1l, .

-C(')-CII, ofIB, He-cII01-4
-CIJ is mixed with a compound having the structure of the following formula: /(J, Cll0 \C1l, Cll0 or a suitable precursor thereof in an aqueous polar organic medium, and the reaction produces compounds such as alkali metal cyanoborohydrides. The production method was carried out in the presence of a cyanoholohydride salt, and the target substance was isolated by a known method.

(2(1)) In a method for forming foils of a compound having the following formula: doxorubicin or its usual base is added to a mixed aqueous polar organic compound in the presence of an alkali metal cyanoborohydride such as sodium or potassium cyanoborohydride. 2 in the medium,
A production method which involves reacting 2'-oxydiacetaldehyde or 2'-oxydiacetaldehyde with a compound generated on the spot, and isolating and purifying the target substance according to chemical and physical methods known per se.

(21) Separation of the crude reaction product obtained in a morpholino enclosure into neutral and basic fractions (7. Both neutral fractions were purified by chromatography) to obtain pure Compounds described in Part 20 of the Scope of Wahose Seikyu to Obtain Products (
1v) manufacturing method.

(22) The following formula: (In the formula, 1 is also &: t-C0-C118, -CIIOjl
-C)], .

-CO-CI, (River and -CIK) 11- C) 120
11, A is selected from CN and a hydrogen atom as IA) In the method for producing a compound having the structure of the following formula: - If a hydroxyl group is present, the 14-hydroxyl group is preferably protected by a protecting group labile to weak acids and then reacted with excess alcoholic ammonia at a temperature between -25°C and +25°C. u1: Next, after cleaving the protecting group that is unstable to weak acids, the target substance is isolated and purified by a known method.

Claims (1)

[Claims] /],) The following formula. [Wherein, R is -Co-(Ji3.-CI(OH-CH
,. -Co-CH20H, -CHoH-CHtOH, hydroxyl group, alkyl group having 1 to 3 carbon atoms, terminal hydroxyalkyl group having 1 to 3 carbon atoms, -Co-CH,OH, -CHo)I
-C)i□OH and -C)IoH-CH, carbon number 2 ~
7 organic acid esters and diesters, one or more hydroxyl groups substituted with alkyl or aryl ether groups having 1 to 6 carbon atoms -Co-CH20H, -CHO) (
-CH20H and -CHoH-CH. and -Co-C1 (and -1 of -COCH20H
3-Ketoimine visiting conductor; Y is a hydrogen atom or a methoxy group; or, R' is an 0-methoxy group and Rn is a hydrogen atom; A is a hydrogen atom or a cyano group, provided that when X is -O, A is a cyano group;
2 is an oxygen atom, an alkyl group with a sulfur atom 3),
However, 2 is -CH. A compound that has the structure of (2) The following formula. (In the formula, R is Co-CH3, CHOH-CH,, Co-
CH20H and Cl-1014-CI'120H, X is selected from 0 and NH force, A is selected from CN and hydrogen nuclear λ; however, when
A compound according to claim 1, which has the structure (N). (3) A characteristic having the structure of the following formula: (4) The compound according to claim 2, which has the structure of the following formula: (5) The compound according to claim 2, which has a structure of the following formula: (wherein R has the same meaning as in claim 2). (6) 3'-deamino-3'-(3'l-cyano-
4″-morpholinyl) daunorubicin. (7) 3′-deamino-3′-(3″-cyano-4
″-morpholinyl)-13-dihydrodaunorubicin. (8) 3′-deamino-3′-(3″-cyano-4
″-morpholinyl) doxorubicin. (9) 3′-deamino-3′-(3″-/ano4″-morpholinyl-13-dihydrodaunorubicin. (10) 3′-theamino-3′-(c′-morpholinyl)- □5-Iminodoxorubicin and its pharmaceutically acceptable salts. (11) The compound according to claim 1 or its pharmaceutically acceptable salt mixed with a pharmaceutically acceptable diluent or phase. A pharmaceutical composition comprising an acceptable salt. (12) An antitumor formulation comprising a compound of claims 2 to 5 or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable carrier. Composition. (13) 3'-deamino-3'-(3''-cyano-4''
- An antitumor pharmaceutical composition comprising an effective amount of (morpholinyl) daunorubicin. (14) 3'-theamino-3'-(3''-thia) to 4''
An antitumor pharmaceutical composition comprising an effective amount of -morpholinyl)-13-dihydrodaunorubicin. (15) 3'-deamino-3'-(3''-cyano-4''
- An antitumor pharmaceutical composition containing effective t1 of doxorubicin (molporinyl). (16) 3'-deamino-3'-(3''-cyano-
An antitumor pharmaceutical composition comprising an effective amount of (1'5 3'-deamino-3'-(4〃-morpholinyl)-5-iminodoxorubicin). Antitumor pharmaceutical composition. (18) Following formula: [wherein R is -Co-CH3,-CHoH-CI (,,
-Co-CH,OH. -CHOH-CH20H, hydroxyl group, alkyl group having 1 to 3 carbon atoms, terminal hydroxyalkyl group having 1 to 3 carbon atoms, -
Co, -CH20H, -C)IOH-CH,OH and -
CHoH-CH, organic acid esters and diesters having 2 to 7 carbon atoms, one or more water rJ1 groups having 1 to 7 carbon atoms
-C substituted with argyl or ether group of 6
o-CH20H. -CHoH-CH20H and -CHoH-C)I, and -Co-CH. and -13-ketoimine derivative of -COCH20f; Y is a hydrogen atom or a methoxy group;
X is -0 or -NH, and R' and R〃, one is a hydrogen atom and the other is a hydroxyl group, or both are hydrogen atoms,
Alternatively, R' is a 0-methoxy group and R'' is a hydrogen atom; the hydrogen atom of A is a cyano group, provided that X =
When O, A is a cyano group; 2 is an oxygen atom, a sulfur atom, -CH2-, and -8H; (where Rm is an alkyl having 1 to 3 carbon atoms A is a cyan group) structure] In the method for producing a compound having the following formula, known daunorubicin, doxorubicin and the following formula. H2 (wherein R, R', R'', X and Y have the same meanings as above), the following formula: The desired substance is reacted with a compound having the structure - or a suitable precursor thereof in a mixed aqueous polar organic medium, and the reaction is carried out in the presence of a cyanoborohydride salt such as an alkali metal cyanoborohydride. is isolated and purified by a method known per se. (19) The following formula (wherein R is -Co-CI(,,-CHoH-C)(
,. -Co-CH,OH and -CHoH-CH20H) In a method for producing a compound having a structure of the following formula: (wherein R has the same meaning as above), a compound having a structure of the following formula: or a suitable precursor thereof in a mixed aqueous polar organic medium, the reaction is carried out in the presence of a cyanoborohydride, such as an alkali metal cyanoborohydride, and the target substance is produced by a known method. isolated,
Manufacturing method 4, characterized by refining (20) the following formula. In a method for preparing a compound having the structure of
, 2'-oxydiacetaldehyde or a compound generated in situ, and producing the target substance according to a chemical-physical method known per se. . (21) The crude reaction product obtained after "morpholino compound closure" is separated into neutral and basic fractions, and the neutral fraction is purified by chromatography to obtain a pure product. A method for producing the compound OV) in Item 20 of Scope 11. (22) The following formula: (wherein I7 is -Co-CI, -CHoH-C
H3゜-Co-CH20H and -CH(M-CH20H
A is selected from CN and Konoha atoms) +11! In the method for producing a compound that is irritating to ¥, a compound having the structure of the following formula: (in the formula, i (6) has the same meaning as above) is prepared when a 14-hydroxyl group is present, preferably the 14-hydroxyl group. - Hydroxyl group is unstable to weak acids, i
-25°C to +25°C after 1.7% protection by φ group
After reacting with an excess of alcoholic ammonia and then cleaving the protecting group which is unstable to weak acids, the target substance is isolated and nitrified by known methods. A manufacturing method that makes it % similar.