Toyo Jozo Kabushiki Kaisha

Asahi Kasei Kogyo Kabushiki Kaisha

Toyo Jozo Company, Ltd.

Tatsuro Fujiwara

Hideo Sakakibara

Takao Hirano

Eiichi Honda

Susumu Watanabe

Tetsuo Matsuda

Hideyuki Watanabe

Osamu Okegawa

Satoshi Shuto

Hiromichi Itoh

Toshiyuki Watanabe

Kazuyo Ohta

Takumi Obara

Satoshi Omura

Masao Yaso

Yuji Kogami

Asako Watanabe

Tomoko Yashiro

Takehiro Koshio

Compounds of the formula ##STR1## wherein R.sub.1 and R.sub.2 are each C.sub.16-18 long-chain aliphatic acyl and are the same or different; and pharmacologically acceptable salts thereof are disclosed. These novel compounds are effective against 5-FU-resistant tumor cells, have low toxicity, and are not inactivated by nucleoside phosphorylase in vivo.

5'-trifluoromethyl-2'-deoxy-uridine phospholipid compounds

A compound of the formula ##STR1## wherein A is adenine-9-yl and X is halogen, Preferably iodine, or a pharmaceutically acceptable salt thereof. It is a novel derivative of neplanocin A and has almost the same level of cytotoxic activity. However, it is not inactivated by the action of adenosine deaminase. It is produced by replacing a hydroxyl at position-6' in neplanocin A or 2', 3'-O-protected neplanocin A with halogen by use of a halogenating agent, and when hydroxyl at position-2' or -3' is protected, removing the protective group thereof.

6'-deoxy-6'-halo-neplanocin A and its production

9-Dihydro-9-O-alkyldesmycosin derivatives and their salts are disclosed. The 9-dihydro-9-O-alkyldesmycosin derivatives are represented by the following formula (I), ##STR1## --wherein X represents an --O-- mycinose or a di-lower alkylamino group, R.sup.1 represents a hydrogen atom or a lower alkanoyl group, R.sup.2 represents a lower alkyl group, a cycloalkyl-lower group, or phenyl-lower alkyl group which may have a substituent, and R.sup.3 represents a hydrogen atom or a hydroxyl group. The compounds and the salts are useful as an antimicrobial agent. Unlike known desmycosin derivatives, the compounds give a high blood concentration by oral administration.

9-dihydro-9-O-alkyldesmycosin derivatives

4'-deoxy-3'-demethoxy-3'-methylene-desmycosin derivatives of the formula ##STR1## wherein R.sub.1 is hydrogen, acyl or substituted carbamoyl,

4'-Deoxy-3'-demethoxy-3'-methylenedesmycosin derivatives and synthetic

Compounds of the formula ##STR1## wherein R.sub.1 is lower alkyl, lower alkoxycarbonyl-lower alkyl, phenyl, phenyl substituted by one or more lower alkyl or halogen, phenyl-lower alkyl optionally substituted in its side chain by lower alkyl or lower alkoxycarbonyl, thienylmethyl or thiazolyl, R.sub.2 is hydrogen or lower alkyl, or ##STR2## constitutes a 3-7-membered nitrogen-containing heterocyclic ring in which R.sub.1 and R.sub.2 are connected, R.sub.3 is hydrogen or hydroxyl, and X is oxygen or sulfur, or a non-toxic salt thereof. These compounds have stronger antibacterial activity as compared with known clinically used macrolide antibiotics such as erythromycin, oleandomycin, josamycin and leucomycin, and also have strong antibacterial activity against all macrolide antibiotic-resistant strains such as macrolide-resistant A group strains (clinical isolates or erythromycin, oleandomycin and 16-membered macrolide antibiotic resistant strains). These compounds are also stable in vivo and hence may be used for treatment of infectious diseases and also are useful for feed additives and growth stimulants.

23-O-substituted carbamoyl-23-demycinosyldesmycosin

Novel 3-O-acyl-4'-deoxydesmycosin derivatives of the formula ##STR1## wherein R.sub.1 is lower alkyl, phenyl, substituted phenyl, phenyl-lower alkyl or substituted phenyl-lower alkyl, R.sub.2 is hydrogen or --CHO and R.sub.3 is hydrogen or hydroxyl, or a non-toxic salt thereof, can be produced by acylating the hydroxyl group at position-3 of the corresponding intermediate while protecting the hydroxyl at position-2' or positions-2' and -4' with acetyl, and then removing the protective group or groups. These derivatives have antibiotic utility against Gram positive and Gram negative bacteria.

3-O-acyl-4'-deoxydesmycosin derivatives

A compound of the formula ##STR1## wherein R.sub.1 is hydrogen, --COOR.sub.11 or ##STR2## R.sub.11 is optionally substituted lower alkyl, R.sub.12 is optionally substituted hydrocarbon, heterocyclic or heterocyclic-lower alkyl, R.sub.13 is hydrogen or lower alkyl, or R.sub.12 and R.sub.13 together constitute a heterocyclic ring together with the attached nitrogen atom, and R.sub.2 is hydrogen or hydroxyl, or a pharmaceutically-acceptable salt thereof, has stronger antibacterial activity against Gram-positive bacteria than does tylosin. It is produced by deformylation, or by oxidizing a formyl at position-14, or by amidating the latter compound.

14-de(hydroxymethyl)-mycaminosyltylonolide derivatives

Novel 23-demycinosyldesmycosin derivatives are disclosed of the formula ##STR1## wherein A is oxygen or sulfur, R.sub.1 is optionally substituted phenyl or ##STR2## group, in which R.sub.3 is optionally substituted phenyl and R.sub.4 and R.sub.5 are the same or different and are hydrogen, lower alkyl or optionally substituted phenyl, and R.sub.2 is hydrogen or hydroxyl. The compounds or non-toxic salts thereof are useful as antibiotics.

23-Demycinosyldesmycosin derivatives

Compounds of the formula ##STR1## wherein R.sub.1 is optionally substituted phenyl, thienyl, 2-amino-4-thiazolyl or 2-chloroacetamido-4-thiazolyl; A is lower alkylene, lower alkenylene, or lower alkylene substituted by lower alkyl, amino, lower alkoxyimino or phenyl-Z-group wherein Z is a single bond or --S-- or --SO.sub.2 --, but when R.sub.1 is 2-amino-4-thiazolyl or 2-chloroacetamido-4-thiazolyl then A is lower alkylene substituted by lower alkoxyimino; R.sub.2 is hydrogen or hydroxyl; X is oxygen or sulfur and n=0 or 1, or a non-toxic salt thereof. These compounds have a stronger antibacterial activity against Gram positive bacteria as compared with known macrolide antibiotics such as erythromycin and tylosin, and also have an equivalent level of antibacterial activity against Gram negative bacteria as compared with that of erythromycin, and hence may be useful for clinical use. These compounds are also useful for feed additives and growth stimulants.

23-O-Acyl-23-demycinosyldesmycosin derivatives

A compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen or hydroxy and at least one of R.sub.1 and R.sub.2 is hydrogen, or a pharmaceutically acceptable salt thereof, has strong antimicrobial and antibacterial activity..

Deoxydesmycosin

A compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen or hydroxyl and at least one of R.sub.1 and R.sub.2 is hydrogen, or a pharmaceutically acceptable salt thereof, has antibacterial activity against Gram positive bacteria and against macrolide-resistant A group bacteria.

19-Deformyl-deoxy-desmycosin

Deformyltylosin derivatives of the formula ##STR1## wherein A is ##STR2## --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --, R.sub.1 is hydrogen, lower alkanoyl or aryl-lower alkanoyl, X.sub.1 and X.sub.2 are hydrogen or are connected to form a valence bond, Y.sub.1 and Y.sub.2 are hydrogen or are connected to form a valence bond, Q.sub.1 is hydrogen or methyl, Q.sub.2 is hydrogen or ##STR3## R.sub.2 is hydrogen or lower alkanoyl, R is hydrogen or ##STR4## R.sub.3 is hydrogen or C.sub.2-5 alkanoyl, and R.sub.4 is hydrogen or C.sub.2-6 alkanoyl, and when R.sub.3 is not hydrogen, then R.sub.4 is not hydrogen, or a pharmaceutically acceptable salt thereof, have strong antibacterial activities as compared to the known antibiotic tylosin, and also have enhanced antibacterial activities against all macrolide antibiotic-resistant strains such as A, B and C group strains, and have higher blood levels as compared with tylosin.

Deformyltylosin derivatives

Derivatives of antibiotic tylosin of the formula ##STR1## wherein R.sub.1 is hydrogen or lower alkanoyl, A.sub.1 and A.sub.2 are groups of which one is R.sub.2 and the other is R.sub.3, and R.sub.2 and R.sub.3 are C.sub.2-6 alkanoyl, or a physiologically acceptable salt thereof, have enhanced antibacterial activity against macrolide antibiotic-resistant strains.

Derivatives of antibiotic tylosin

3'-acylated macrolide antibiotics of the formula ##STR1## wherein R.sub.1 is hydrogen or C.sub.2-3 alkanoyl, R.sub.2 is hydrogen or C.sub.2-4 alkanoyl, at least one of R.sub.1 and R.sub.2 being hydrogen, and one of R' and R' being R.sub.3 and the other R.sub.4, R.sub.3 being C.sub.2-6 alkanoyl and R.sub.4 being C.sub.2-5 alkanoyl, or a pharmaceutically acceptable salt thereof.

Growing community of inventors

Shizuoka, Japan

Tatsuro Fujiwara