Phospholipid derivatives, process for preparation thereof and pharmaceutical composition of the same

Claim 2

A compound of the formula: wherein R 1 is alkoxy or alkenyloxy; R 2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio thiadiazolylthio, lower alkylsulfony: lower alkoxycarbonylamino or lower alkylureido A is lower alkylene optionally interrupted by a -NHCO- group; and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,0 or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups; provided that R 1 is alkoxy. having 15 or more carbon atoms when is a pyridyl group, and pharmaceutically acceptable salt thereof.

Claim 3

A compound of claim 1. wherein is saturated 5-7 membered heterocyclic group which may contain additional N, 0 or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy-(lower)alkyl groups.

Claim 4

A compound of claim 2, wherein R 1 is alkoxy; R 2 is lower alkoxy or ar(lower)alkoxy; A is lower alkylene; and is saturated 6 or 7 membered heterocyclic group which may contain additional N or 0 atom(s) and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, hydroxy and hydroxy(lower)alkyl groups.

Claim 5

A compound of claim 3, wherein R 2 is lower alkoxy.

Claim 6

A compound of claim 4, wherein is morpholino, piperazinyl, piperidino or homopiperazinyl which may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, hydroxy and hydroxy(lower)alkyl groups.

Claim 7

A compound of claim 5, which is (rac)-l-O-octadecyl-2-0-methyl-glycerol-3-[2-(N-methylmorpholinio)ethyl]-phosphate.

Claim 8

A compound of claim 5, which is (rac)-1-O-hexadecyl-2-0-methyl-glycerol-3-[2-(4-methyl-l-piperazinyl)-ethyl]phosphate.

Claim 9

A compound of claim 5, which is (rac)-1-O-octadecyl-2-O-methyl-glycerol-3-[2-(4-methyl-l-piperazinyl)ethyl]phosphate.

Claim 10

A compound of claim 3, wherein R 2 is ar(lower)alkoxy.

Claim 11

A compound of claim 9, which is (rac)-1-O-hexadecyl-2-0-benzyl-glycerol-3-[2-(4-methyl-l-piperazinyl)-ethyl]phosphate.

Claim 12

A compound of claim 1. wherein is unsaturated 5-7 membered heterocyclic group which may contain additional N, 0 or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups.

Claim 13

A compound of claim 11, wherein R is alkoxy having 15 or more carbon atoms or alkenyloxy; R 2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted by a -NHCO- group; and is unsaturated 5 or 6 membered heterocyclic group which may contain additional N or S atom(s) and may have 1 or 2 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, halogen, lower alkoxycarbonyl and hydroxy(lower)-alkyl groups.

Claim 14

A compound of claim 12, wherein R 1 is alkoxy having 15 or more carbon atoms.

Claim 15

A compound of claim 13, wherein R 2 is lower alkoxy.

Claim 16

A compound of claim 14, which is (rac)-1-O-octadecyl-2-O-methyl-glycerol-3-[2-(l-pyridinio)ethyl]phosphate.

Claim 17

A compound of claim 14, which is (rac)-1-O-octadecyl-2-O-methyl-3-[2-(3-methyl-1-pyridinio)ethyl]phosphate.

Claim 18

A compound of claim 14, which is (rac)-1-O-octadecyl-2-O-methyl-glycerol-3-[2-(1-pyridinioacetylamino)ethyl]phosphate.

Claim 19

A compound of claim 14, which is (rac)-1-0-octadecyl-2-0-methyl-glycerol-3-[2-(4-methyl-1-pyridinio)ethyl]phosphate.

Claim 20

A compound of claim 13, wherein R 2 is ar(lower)alkoxy.

Claim 21

A compound of claim 19, which is (rac)-l-0-hexadecyl-2-0-benzyl-glycerol-3-[2-(l-pyridinio)ethyl]phosphate.

Claim 22

A compound of claim 13, wherein R 2 is hydroxy.

Claim 23

A compound of claim 21, which is (rac)-1-O-octadecyl-glycerol-3-[2-(1-pyridinio)ethyl)-phosphate.

Claim 24

A compound of claim 13, wherein R 2 is thiadiazolylthio.

Claim 25

A compound of claim 23, which is (rac)-1-O-octadecyl-2-(1,3,4-thiadiazol-2-ylthio)-1,3-propanediol-3-[2-(1-pyridinio)ethyl]phasphate.

Claim 26

A compound of claim 13, wherein R 2 is lower alkoxycarbonylamino.

Claim 27

26 . A compound of claim 25 , which is (rac)-l-O-octadecyl-2-ethoxycarbonylamino-1,3-propanediol-3-[2-(l-pyridinio)ethyl]phosphate.

Claim 28

A process for preparing a compound of the formula: wherein R 1 is alkoxy or alkenyloxy; R 2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio,thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrrupted by a -NHCO- group ; and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)-alkyl groups; provided that R 1 is alkoxy having 15 or more carbon atoms when is a pyridyl group, and pharmaceutically acceptable salt thereof, which comprises (1) by reacting a compound of the formula: wherein R 1 , R 2 and A are each as defined above, and X 1 is an acid residue, or its salt with a compound of the formula: wherein is as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 2 0 A and are each as defined above or its salt, or (2) by reacting a compound of the formula: wherein R 1 , R 2 and A are each as defined above, _and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,0 or S atom(s), and may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups, or its salt with a compound of the formula: X 2 -R 3 (IV) wherein R 3 is lower alkyl, and X 2 is an acid residue, to provide a compound of the formula: wherein R 1 , R Z , A, R 3 and are each as defined above, or its salt, or (3) by subjecting a compound of the formula: wherein R 1 , A and are each as defined above, and R 4 is a protective group of hydroxy, or its salt to an elimination reaction of the protective group to provide a compound of the formula: wherein R 1 , A and are each as defined above, or its salt, or (4) by reacting a compound of the formula: wherein R 1 , R 2 and A are each as defined above, or its salt with a compound of the formula: wherein is as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 2 , A and are each as defined above, or its salt.

Claim 29

A process for preparing a compound of the formula: wherein R 1 is alkoxy or alkenyloxy; R 2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio,thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrrupted by a -NHCO- group ; and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,O or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)-alkyl groups; provided that R 1 is alkoxy having 15 or more carbon atoms when is a pyridyl group, and pharmaceutically acceptable salt thereof, which comprises (1) by reacting a compound of the formula: wherein R 1 , R 2 and A are each as defined above, and X 1 is an acid residue, or its salt with a compound of the formula: wherein is as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 2 0 A and are each as defined above or its salt, or (2) by reacting a compound of the formula: wherein R 1 , R 2 and A are each as defined above, _and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,0 or S atom(s), and may have 1 to 2 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups, or its salt with a compound of the formula: X 2 -R 3 (IV) wherein R 3 is lower alkyl, and X 2 is an acid residue, to provide a compound of the formula: wherein R 1 , R Z , A, R 3 and are each as defined above, or its salt, or (3) by subjecting a compound of the formula: wherein R 1 , A and are each as defined above, and R 4 is a protective group of hydroxy, or its salt to an elimination reaction of the protective group to provide a compound of the formula: wherein R 1 , A and are each as defined above, or its salt, or (4) by reacting a compound of the formula: wherein R 1 , R 2 and A are each as defined above, or its salt with a compound of the formula: wherein is as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 2 , A and are each as defined above, or its salt.

Claim 30

A pharmaceutical composition comprising an effective amount of a compound of the formula: wherein R 1 is alkoxy or alkenyloxy; R 2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio,thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted hv a -NHCO- group; and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,0 or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups; provided that R 1 is alkoxy having 15 or more carbon atoms when is a pyridyl group, or pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.

Claim 31

A pharmaceutical composition comprising an effective amount of a compound of the formula: wherein R 1 is alkoxy or alkenyloxy; R 2 is hydrogen, halogen, hydroxy, lower alkoxy, ar(lower)alkoxy, aryloxy, lower alkylthio, arylthio,thiadiazolylthio, lower alkylsulfonyl, lower alkoxycarbonylamino or lower alkylureido; A is lower alkylene optionally interrupted hv a -NHCO- group; and is unsaturated or saturated 5-7 membered heterocyclic group which may contain additional N,0 or S atom(s), and may have 1 to 3 substituent(s) selected from the group consisting of lower alkyl, lower alkylamino, lower alkoxy, halogen, hydroxy, carboxy, lower alkoxycarbonyl and hydroxy(lower)alkyl groups; provided that R 1 is alkoxy having 15 or more carbon atoms when is a pyridyl group, or pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.