Lipid derivatives, their production and use

Claim 2

A compound of the formula: ##STR41## wherein R 1 is C 10-30 alkyl or a group of the formula: R.sup.5 NHCO-- in which R 5 is C 10-30 alkyl; R 2 is hydrogen, C 1-5 alkoxy, phenyl-C 1-5 alkoxy, C 1-5 alkanoyloxy, benzoyloxy, phenoxycarbonyloxy, C 1-5 alkoxycarbonyloxy, a group of the formula: ##STR42## in which W is oxygen or sulfur, and R 6 and R 7 are independently hydrogen or C 1-5 alkyl or both, taken together with the adjacent nitrogen atom, are 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, and 4-perhydrothiazepinyl, amino, C 1-5 alkanoylamino, benzoylamino, optionally oxo substituted 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, 4-perhydrothiozepinyl, or optionally oxo substituted 2-isoindolinyl; R 3 is a chemical binding or C 1-18 alkylene unsubstituted or substituted by C 1-4 alkoxycarbonyl or carboxylato; R 4 is hydrogen, C 1-6 alkyl or phenyl-C 1-6 alkyl; X is O, S or a group of the formula: ##STR43## in which R 8 is hydrogen, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkyl, C 1-5 alkanoyl, benzoyl, phenoxycarbonyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, (aziridin-1-yl)carbonyl, (azetidin-1-y)carbonyl, (pyrrolidin-1-yl)-carbonyl, piperidinocarbonyl, (perhydroazepin-1-yl)-carbonyl, (piperazin-1-yl)carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl; Y is O, S or a group of the formula: ##STR44## in which R 9 is hydrogen, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkyl, C 1-5 alkanoyl, benzoyl, phenoxycarbonyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, (aziridin-1-yl)carbonyl, azetidin-1-yl)carbonyl, (pyrrolidin-1-yl)carbonyl, piperidinocarbonyl, (perhydroazepin-1-yl)carbonyl, (piperazin-1-yl)carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl; and R 8 and R 9 or R 4 and R 9 may form C 1-4 alkenylene or alkylene unsubstituted or substituted by oxo; Z is imino, optionally C 1-4 alkoxycarbonyl substituted C 1-6 alkylimino, phenyl-C 1-6 alkylimino or iminio substituted by optionally C 1-4 alkoxycarbonyl or carboxylato substituted C 1-6 alkyl or phenyl-C 1-6 alkyl or a pharmaceutically acceptable salt thereof or a salt thereof with a pharmaceuticaly acceptable anion when Z has a quaternary nitrogen atom.

Claim 3

A compound according to claim 1, wherein R 1 is C 14-20 alkyl or C 14-20 alkyl-NHCO--.

Claim 4

A compound according to claim 1, wherein R 1 is C 14-18 alkyl or C 14-18 alkyl-NHCO--.

Claim 5

A compound according to claim 1, wherein R 1 is C 15-18 alkyl or C 15-18 alkyl-NHCO--.

Claim 6

A compound according to claim 1, wherein R 1 is C 16-18 alkyl or C 16-18 alkyl-NHCO--.

Claim 7

A compound according to claim 1, wherein R 1 is octadecyl or octadecylcarbamoyl.

Claim 8

a compound according to claim 1, wherein R 1 is octadecylcarbamoyl.

Claim 9

A compound according to claim 1, wherein R 2 is C 1-5 alkoxy, phenyl-C 1-5 alkoxy, C 1-5 alkanoyloxy, C 1-5 alkoxycarbonyloxy, mono- or di-C 1-5 alkylcarbamoyloxy, C 1-5 alkanoylamino, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, 4-perhydrothiazepinyl or phthalimido.

Claim 10

A compound according to claim 1, wherein R 2 is C 1-5 alkoxy.

Claim 11

A compound according to claim 1, wherein R 2 is methoxy.

Claim 12

A compound according to claim 1, wherein R 3 is C 1-8 alkylene.

Claim 13

A compound according to claim 1, wherein R 3 is methylene, ethylene or trimethylene.

Claim 14

A compound according to claim 1, wherein R 3 is methylene or ethylene.

Claim 15

A compound according to claim 1, wherein R 4 is hydrogen or C 1-6 alkyl.

Claim 16

A compound according to claim 1, wherein R 4 is hydrogen, methyl or ethyl.

Claim 17

A compound according to claim 1, wherein X is O, imino or C 1-5 alkanoylimino.

Claim 18

A compound according to claim 1, wherein X is O.

Claim 19

A compound according to claim 1, wherein Y is O or a group of the formula: ##STR45## in which R 9 is hydrogen, C 1-5 alkyl, C 1-5 alkanoyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, or 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl and 4-perhydrothiazepinyl.

Claim 20

A compound according to claim 1, wherein Y is C 1-5 alkanoylimino.

Claim 21

A compound according to claim 1, wherein Y is acetylimino.

Claim 22

A compound according to claim 1, wherein ##STR46## is a group of the formula: ##STR47##

Claim 23

A compound according to claim 1, wherein Z is di-C 1-6 alkyliminio.

Claim 24

A compound according to claim 1, wherein Z is dimethyliminio.

Claim 25

A compound according to claim 1, wherein Z--R 4 is trimethylammonio.

Claim 26

A compound according to claim 1, wherein Z--R 4 is an optionally C 1-6 alkyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl, carboxylato-C 1-6 alkyl or phenyl-C 1-6 alkyl substituted azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, pyrrolinyl, pyrazolinyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, pyridazinyl, pyrimidyl, pyradinyl, imidazolyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, quinolinyl, isoquinolinyl, perhydroindolyl or perhydroisoquinolinyl group being unsubstituted or substituted by optionally hydroxy or amino substituted C 1-4 alkyl, hydroxy, amino, imino, mono- or di-C 1-4 alkylamino, carbamoyl, ureido, carboxy, carboxylato or C 1-4 alkoxycarbonyl.

Claim 27

A compound according to claim 1, wherein Z--R 4 is an optionally C 1-6 alkyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl, carboxylato-C 1-6 alkyl or phenyl-C 1-6 alkyl substituted morpholinyl, pyrrolidinyl, piperidinyl, imidazolyl, pyridyl or thiazolyl group being unsubstituted or substituted by optionally hydroxy or amino substituted C 1-4 alkyl, hydroxy, amino, imino, mono- or di-C 1-4 alkylamino, carbamoyl, ureido, carboxy, carboxylato or C 1-4 alkoxycarbonyl.

Claim 28

A compound according to claim 1, wherein Z--R 4 is an optionally C 1-6 alkyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl, carboxylato-C 1-6 alkyl or phenyl-C 1-6 alkyl substituted pyridyl or thiazolyl group being unsubstituted or substituted imido by optionally hydroxy or amino substituted C 1-4 alkyl, hydroxy, amino, imino, mono- or di-C 1-4 alkylamino, carbamoyl, ureido, carboxyl, carboxylato or C 1-4 alkoxycarbonyl.

Claim 29

A compound according to claim 1, wherein Z--R 4 is pyridyl or thiazolyl.

Claim 30

A compound according to claim 1, wherein Z--R 4 is 2-pyridyl, thiazol-2-yl or thiazol-4-yl.

Claim 31

A compound according to claim 1, wherein Z--R 4 is an optionally C 1-6 alkyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl, carboxylato-C 1-6 alkyl or phenyl-C 1-6 alkyl substituted imidazolio, pyridinio, oxazolio, thiazolio, pyridazinio, pyrimidinio, pyradinio, quinolinio, isoquinolinio, morpholinio, piperidinio, piperazinio or pyrrolidinio group being unsubstituted or substituted by optionally hydroxy or amino substituted C 1-4 alkyl, hydroxy, amino, imino, mono- or di-C 1-4 alkylamino, carbamoyl, ureido, carboxy, carboxylato or C 1-4 alkoxycarbonyl.

Claim 32

A compound according to claim 1, wherein Z--R 4 is an optionally C 1-6 alkyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl, carboxylato-C 1-6 alkyl or phenyl-C 1-6 alkyl substituted morpholinio, pyrrolidinio, piperidinio, imidazolio, pyridinio or thiazolio group being unsubstituted or substituted by optionally hydroxy or amino substituted C 1-4 alkyl, hydroxy, amino, imino, mono- or di-C 1-4 alkylamino, carbamoyl, ureido, carboxy, carboxylato or C 1-4 alkoxycarbonyl.

Claim 33

A compound according to claim 1, wherein Z--R 4 is an optionally, C 1-6 alkyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl, carboxylato-C 1-6 alkyl or phenyl-C 1-6 alkyl substituted pyridinio or thiazolio group being unsubstituted or substituted by optionally hydroxy or amino substituted C 1-4 alkyl, hydroxy, amino, imino, mono- or di-C 1-4 alkylamino, carbamoyl, ureido, carboxy, carboxylato or C 1-4 alkoxycarbonyl.

Claim 34

A compound according to claim 1, wherein Z--R 4 is pyridinio-1-yl or thiazolio-3-yl.

Claim 35

A compound according to claim 1, wherein Z--R 4 is 1-(C 1-6 alkyl)pyridinio-2-yl.

Claim 36

A compound according to claim 1, wherein Z--R 4 is 1-ethylpyridinio-2-yl.

Claim 37

A compound according to claim 1, wherein Z--R 4 is 3-(C 1-6 alkyl)thiazolio-2-yl.

Claim 38

A compound according to claim 1, wherein Z--R 4 is 3-ethylthiazolio-2-yl.

Claim 39

A compound according to claim 1, wherein Z--R 4 is 3-(C 1-6 alkyl)thiazolio-4-yl.

Claim 40

A compound according to claim 1, wherein Z--R 4 is 3-ethylthiazolio-4-yl.

Claim 41

A compound according to claim 1, which is 3-O-[N-acetyl-N-(N-methylpyridinio-2-yl)methyl]carbamoyl-2-O-methyl-1-O-octadecylcarbamoylglycerol chloride.

Claim 42

A compound according to claim 1, which is 1-[(2-methoxy-3-octadecylcarbamoyloxy)propyl]-3-(2-thiazolioethyl)hydantoin chloride.

Claim 43

A compound according to claim 1, which is N-[2-{1-(3-octadecylcarbamoyloxy-2-methoxyproyyl)uracil-3-yl}ethyl]N,N,N-trimethylammonium chloride.

Claim 44

A compound according to claim 1, which is 1-ethyl-2-[N-acetyl-N-(3-octadecylcarbamoyloxy-2-methoxypropyloxy)carbonylamino]methylpyridinium halide.

Claim 45

A compound according to claim 1, which is 2-[N-acetyl-N-(3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl)amino]methyl-3-methylthiazolium halide.

Claim 46

A compound according to claim 1, which is 2-[N-acetyl-N-(3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl)amino]methyl-3-ethylthiazolium halide.

Claim 47

A compound according to claim 1, which is 2-[N-(3-octadecylcarbamoyloxy-2-ethoxypropyloxycarbonyl)amino]methyl-N-ethylpyridinium halide.

Claim 48

A compound according to claim 1, which is 4-[N-acetyl-N-(3-octadecylcarbamoyloxy-2-methoxypropoxycarbonyl)amino]methyl-3-ethylthiazolium halide.

Claim 49

A compound according to claim 43, wherein halide is chloride.

Claim 50

A compound according to claim 44, wherein halide is iodide.

Claim 51

A compound according to claim 45, wherein halide is iodide.

Claim 52

A compound according to claim 46, wherein halide is iodide.

Claim 53

A compound according to claim 47, wherein halide is iodide.

Claim 54

A compound according to claim 1, wherein R 2 is hydrogen, hydroxy, C 1-5 alkoxy, phenyl-C 1-5 alkoxy, C 1-5 alkanoyloxy, benzoyloxy, C 1-5 alkoxycarbonyloxy, C 1-5 alkanoylamino, benzoylamino or a group of the formula: ##STR48## in which W is oxygen or sulfur, and R 6 and R 7 are independently hydrogen or C 1-5 alkyl, or both, taken together with the adjacent nitrogen atom, are 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl and 4-perhydrothiazepinyl; R 3 is C 1-8 alkylene; one of X and Y is oxygen or sulfur and the other is imino, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkylimino, C 1-5 alkanoylimino; Z--R 4 is amino, mono- or di-C 1-6 alkylamino or tri-C 1-6 alkylammonio.

Claim 55

A compound according to claim 1, wherein R 3 is C 1-8 alkylene and Z is imino, C 1-6 alkylimino, phenyl-C 1-6 alkylimino or iminio substituted by C 1-6 alkyl or phenyl-C 1-6 alkyl.

Claim 56

A pharmaceutical composition suitable for inhibiting activities of platelet activating factor which comprises, as an active ingredient, an effective amount of a compound of the formula: ##STR49## wherein R 1 is C 10-30 alkyl or a group of the formula: R.sup.5 NHCO-- in which R 5 is C 10-30 alkyl; R 2 is hydrogen, hydroxy, C 1-5 alkoxy, phenyl-C 1-5 alkoxy, C 1-5 alkanoyloxy, benzoyloxy, phenoxycarbonyloxy, C 1-5 alkoxycarbonyloxy, a group of the formula: ##STR50## in which W is oxygen or sulfur, and R 6 and R 7 are independently hydrogen or C 1-5 alkyl or both, taken together with the adjacent nitrogen atom are 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, 4-perhydrothiazepinyl, amino, C 1-5 alkanoylamino, benzoylamino, optionally oxo substituted 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazephinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, 4-perhydrothiazepinyl, or optionally oxo substituted 2-isoindolinyl; R 3 is a chemical binding or C 1-18 alkylene unsubstituted or substituted by C 1-4 alkoxycarbonyl or carboxylato; R 4 is hydrogen, C 1-6 alkyl or phenyl-C 1-6 alkyl; X is O, S or a group of the formula: ##STR51## in which R 8 is hydrogen, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkyl, C 1-5 alkanoyl, benzoyl, phenoxycarbonyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, (aziridin-1-yl)carbonyl, (azetidin-1-y)carbonyl, (pyrrolidin-1-yl)-carbonyl, piperidinocarbonyl, (perhydroazepin-1-yl)-carbonyl, (piperazin-1-yl)carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl; Y is O, S or a group of the formula: ##STR52## in which R 9 is hydrogen, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkyl, C 1-5 alkanoyl, benzoyl, phenoxycarbonyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, (aziridin-1-yl)carbonyl, (azetindin-1-yl)carbonyl, (pyrrolidin-1-yl)carbonyl, piperidinocarbonyl, (perhydroazepin-1-yl)carbonyl, (piperazin-1-yl)carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl; and R 8 and R 9 or R 4 and R 9 may form C 1-4 alkenylene or alkylene unsubstituted or substituted by oxo; Z is imino, optionally C 1-4 alkoxycarbonyl substituted C 1-6 alkylimino, phenyl-C 1-6 alkylimino or iminio substituted by optionally C 1-4 alkoxycarbonyl or carboxylato substituted C 1-6 alkyl or phenyl-C 1-6 alkyl or a pharmaceutically acceptable salt thereof or a salt thereof with a pharmaceuticaly acceptable anion when Z has a quaternary nitrogen atom, and a pharmaceutically acceptable carrier, excipient or diluent therefor.

Claim 57

A pharmaceutical composition suitable for inhibiting activities of platelet activating factor which comprises, as an active ingredient, an effective amount of a compound of the formula: ##STR49## wherein R 1 is C 10-30 alkyl or a group of the formula: R.sup.5 NHCO-- in which R 5 is C 10-30 alkyl; R 2 is hydrogen, hydroxy, C 1-5 alkoxy, phenyl-C 1-5 alkoxy, C 1-5 alkanoyloxy, benzoyloxy, phenoxycarbonyloxy, C 1-5 alkoxycarbonyloxy, a group of the formula: ##STR50## in which W is oxygen or sulfur, and R 6 and R 7 are independently hydrogen or C 1-5 alkyl or both, taken together with the adjacent nitrogen atom are 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, 4-perhydrothiazepinyl, amino, C 1-5 alkanoylamino, benzoylamino, optionally oxo substituted 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydroazephinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-perhydrodiazepinyl, 4-perhydrooxazepinyl, 4-perhydrothiazepinyl, or optionally oxo substituted 2-isoindolinyl; R 3 is a chemical binding or C 1-18 alkylene unsubstituted or substituted by C 1-4 alkoxycarbonyl or carboxylato; R 4 is hydrogen, C 1-6 alkyl or phenyl-C 1-6 alkyl; X is O, S or a group of the formula: ##STR51## in which R 8 is hydrogen, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkyl, C 1-5 alkanoyl, benzoyl, phenoxycarbonyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, (aziridin-1-yl)carbonyl, (azetidin-1-y)carbonyl, (pyrrolidin-1-yl)-carbonyl, piperidinocarbonyl, (perhydroazepin-1-yl)-carbonyl, (piperazin-1-yl)carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl; Y is O, S or a group of the formula: ##STR52## in which R 9 is hydrogen, optionally carboxy or C 1-5 alkoxycarbonyl substituted C 1-5 alkyl, C 1-5 alkanoyl, benzoyl, phenoxycarbonyl, C 1-5 alkoxycarbonyl, carbamoyl, mono- or di-C 1-5 alkylcarbamoyl, (aziridin-1-yl)carbonyl, (azetindin-1-yl)carbonyl, (pyrrolidin-1-yl)carbonyl, piperidinocarbonyl, (perhydroazepin-1-yl)carbonyl, (piperazin-1-yl)carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl; and R 8 and R 9 or R 4 and R 9 may form C 1-4 alkenylene or alkylene unsubstituted or substituted by oxo; Z is imino, optionally C 1-4 alkoxycarbonyl substituted C 1-6 alkylimino, phenyl-C 1-6 alkylimino or iminio substituted by optionally C 1-4 alkoxycarbonyl or carboxylato substituted C 1-6 alkyl or phenyl-C 1-6 alkyl or a pharmaceutically acceptable salt thereof or a salt thereof with a pharmaceuticaly acceptable anion when Z has a quaternary nitrogen atom, and a pharmaceutically acceptable carrier, excipient or diluent therefor.

Claim 62

A method according to claim 57, wherein R 1 is a group of the formula: R.sup.5 NHCO-- in which R 5 is C 10-30 alkyl; R 2 is C 1-5 alkoxy, R 3 is methylene; X is O; Y is a group of the formula: ##STR61## in which R 9 is C 1-5 alkanoyl.