Glycerol derivatives

Claim 2

A glycerol derivative of the general formula: [wherein A represents an oxygen atom or a carbonyloxy group (i.e. -0-CO-, in which the carbonyl group should be attached to a group R 3 and the oxa group should be attached to the carbon atom at the third position of the glycerol skeleton), R represents an alkyl group of 6 to 22 carbon atoms, or an alkyl group of 2 to 5 carbon atoms being substituted by a phenyl group, R 2 represents an azido group (-N 3 group), an amino group (-NH 2 group) or a group of the general formula: -NHCOR 5 , -NHCOOR 5 or -NHCONHR 5 , in which R 5 represents an alkyl group of 1 to 10 carbon atoms or a phenyl group, with the proviso that, when A represents a carbonyloxy group, R 2 does not represent an amino group, R represents an alkylene group of 1 to 12 carbon atoms and R 4 represents an amino group, or a group of the general formula: -NHCOR 6 , -NHR 7 , -N(R 7 ) 2 or (R 7 )3 · , in which R represents an alkyl group of 1 to 6 carbon atoms or a phenyl group, R represents an alkyl group of 1 to 8 carbon atoms, with the proviso that, when R 4 represents a group of the formula: -N(R 7 ) 2 or -N(R 7 ) 3 ·Y, two or more of R may be same or different to each other, and Y represents an anion of an acid], or non-toxic acid addition salts thereof.

Claim 3

A glycerol derivative according to claim 1 which is: (2RS)-l-0-hexyl-2-dehydroxy-2-azido-3-0-[8-(N,N-dimethyl amino)-octyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-azido-3-0-[4-(N,N-di- methylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydraxy-2-azido-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-azido-3-0-[5-(N,N-di- methylamino)pentyl]glycerol, (2RS)-1-0-hexadeayl-2-dehydroxy-2-azido-3-0-[5-(N,N-di- methylamino)pentyl]glycerol. (2RS)-1-0-hexadecyl-2-dehydroxy-2-azido-3-0-[5-(N,N,N-trimethyl- ammonio)pentyl]glycerol iodide, (2RS)-l-0-hexadecyl-2-dehydroxy-2-azido-3-0-[7-(N,N-dimethyl- amino)heptyl]glycerol or (2RS)-1-0-hexadecyl-2-dehydroxy-2-azido-3-0-[7-(N,N-diethyl- amino)heptyl]glycerol.

Claim 4

A glycerol derivative according to claim 1 which is: (2RS)-1-0-hexyl-2-dehydroxy-2-amino-3-0-[8-(N,N-dimethylamino)-octyl]glycerol, (2RS)-l-0-hexadecyl-2-dehydroxy-2-amino-3-0-[4-(N,N-dimethyl- amino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-amino-3-0-[4-(N,N,N-trimethyl- ammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-amino-3-0-[5-(N,N-dimethyl- amino)pentyl]glycerol, (2RS)-l-0-hexadecyl-2-dehydroxy-2-amino-3-0-[5-(N,N,N-trimethyl- ammonio)pentyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-amino-3-0-[7-(N,N-dimethyl- amino)heptyl]glycerol or (2RS)-l-0-hexadecyl-2-dehydroxy-2-amino-3-0-[7-(N,N-diethyl- amino)heptyl]glycerol.

Claim 5

A glycerol derivative according to claim 1 which is: (2RS)-l-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[5-(N,N-dimethylamino)pentyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[7-(N,N, - dimethylamino)heptyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-benzoylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol iodide, (2RS )-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-l-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol iodide, (2RS)-l-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[7-(N,N-dimethylamino)heptyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-acetylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[4-N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-butyrylamino-3-0-[4-(N, N, N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol or (2RS)-l-0-hexadecyl-2-dehydroxy-2-hexanoylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide.

Claim 6

A glycerol derivative according to claim 1 which is: (2RS)-1-0-hexyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[8-(N,N-dimethylamino)octyl]glycerol, (2RS)-1-0-hexyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-l-0-hexadecyl-2-dehydroxy-2-phenoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[7-(N,N-dimethylamino)heptyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-methoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-l-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[5-(N,N-dimethylamino)pentyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-ethoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)pentyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-l-0-hexadecyl-2-dehydroxy-2-butoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[4-(N,N,N-triethylammonio)butyl]glycerol mesylate, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[5- (N,N,N-trimethylammonio)pentyl]glycerol bromide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-4-[6-(N,N,N-trimethylammonio)hexyl]glycerol bromide, (2RS)-1-4-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol bromide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[7-(N,N-diethylamino)heptyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[7-(N,N-diethyl-N-methylammonio)heptyl]glycerol iodide, (2RS)-l-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octyl]glycerol bromide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[9-(N,N,N-trimethylammonio)nonyl]glycerol bromide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[10-(N,N,N-trimethylammonio)decyl]glycerol bromide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[4-(N,N,N-trimethylammonio)butyryl]glycerol bromide, (2RS)-l-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[5-(N,N,N-trimethylammonio)valeryl]glycerol bromide, (2RS)-l-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[6-(N,N,N-trimethylammonio)hexanoyl]glyderol bromide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[7-(N,N,N-trimethylammonio)heptanoyl]glycerol mesylate or (2RS)-l-0-hexadecyl-2-dehydroxy-2-isobutoxycarbonylamino-3-0-[8-(N,N,N-trimethylammonio)octanoyl]glycerol mesylate.

Claim 7

A glycerol derivatives according to claim 1. which is: (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[4-(N,N-dimethylamino)butyl)glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-phenylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-methlureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-methylureido}-3-0-[7-(N,N-dimethylamino)heptyl] glycerol, (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-methylureido)-3-0-[7-(N,N,N-trimethylammonio)heptyl]glycerol iodide, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-0-[4-(N,N-dimethylamino)butyl]glycerol, (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-propylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide or (2RS)-1-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[4-(N,N-dimethylamino)butyl]glycerol or (2RS)-l-0-hexadecyl-2-dehydroxy-2-(N'-butylureido)-3-0-[4-(N,N,N-trimethylammonio)butyl]glycerol iodide.

Claim 8

A process for the preparation of glycerol derivatives as claimed in claim 1 and conforming to the general formula: (wherein the various symbols are as defined in claim 1) which comprises: (i) reaction of a compound of the general formula: (wherein R 4a represents a group of the general formula: -NHCOR 6 , -N(R 7 ) 2 or (R 7 ) 3 · , in which the various symbols are as defined in claim 1, T represents an alkylsulfonyl group, having 1 to 4 carbon atoms in the alkyl group, or a substituted or unsubstituted arylsulfonyl group, and the other symbols are as defined in claim 1) with sodium azide, (ii) reduction of an azido group of a compound of the general formula: (wherein the various symbols are as hereinbefore defined) into ai amino group. (iii) reaction of a compound of the general formula: (wherein the various symbols are as hereinbefore defined) with ar acyl halide of the general formula: (wherein X 1 represents a halogen atom and R 5 is as defined in claim 1) or with an acid anhydride of the general formula: (wherein R 5 is as hereinbefore defined),

Claim 9

(iv) reaction of a compound of the general formula IA-12 hereinbefore depicted with an ester of haloformic acid of the general formula: (wherein X 2 represents a halogen atom and R5 is as hereinbefore defined),

Claim 10

(iv) reaction of a compound of the general formula IA-12 hereinbefore depicted with an ester of haloformic acid of the general formula: (wherein X 2 represents a halogen atom and R5 is as hereinbefore defined),

Claim 11

(v) reaction of a compound of the general formula IA-12 hereinbefore depicted with an isocyanate of the general formula: (wherein R 5 is as hereinbefore defined),

Claim 12

(v) reaction of a compound of the general formula IA-12 hereinbefore depicted with an isocyanate of the general formula: (wherein R 5 is as hereinbefore defined),

Claim 13

(vi) elimination of tert-butoxycarbonyl group of a compound of the general formula: (wherein boc represents tert-butoxycarbonyl group, R represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms and the other symbols are as hereinbefore defined),

Claim 14

(vi) elimination of tert-butoxycarbonyl group of a compound of the general formula: (wherein boc represents tert-butoxycarbonyl group, R represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms and the other symbols are as hereinbefore defined),

Claim 15

(vii) reaction of a compound of the general formula: (wherein R represents a halogen atom or a group of the formula: -OT, in which T represents an alkylsulfonyl group, having to 4 carbon atoms in the alkyl group, or a substituted unsubstituted arylsulfonyl group, and the other symbols are a hereinbefore defined) with a compound of the general formula: (wherein R 7 is as hereinbefore defined) and, if desired, subjecting methods for salt-exchange,

Claim 16

(vii) reaction of a compound of the general formula: (wherein R represents a halogen atom or a group of the formula: -OT, in which T represents an alkylsulfonyl group, having to 4 carbon atoms in the alkyl group, or a substituted unsubstituted arylsulfonyl group, and the other symbols are a hereinbefore defined) with a compound of the general formula: (wherein R 7 is as hereinbefore defined) and, if desired, subjecting methods for salt-exchange,

Claim 17

(viii) reaction of a compound of the general formula XXXII hereinbefore depicted with a compound of the general formula: (wherein R 7 is as hereinbefore defined),

Claim 18

(viii) reaction of a compound of the general formula XXXII hereinbefore depicted with a compound of the general formula: (wherein R 7 is as hereinbefore defined),

Claim 19

(ix) reaction of a compound of the general formula XXXII hereinbefore depicted with a compound of the general formula: (wherein R 7 is as hereinbefore defined),

Claim 20

(ix) reaction of a compound of the general formula XXXII hereinbefore depicted with a compound of the general formula: (wherein R 7 is as hereinbefore defined),

Claim 21

(x) reaction of a compound of the general formula; (wherein R 2a represents an azido group, an amino group or a group of the general formula: -NHCONHR , in which R 5 is as hereinbefore defined, and the other symbols are as hereinbefore defined) with phthalimide and then reacting the resulting compound with hydrazine,

Claim 22

(x) reaction of a compound of the general formula; (wherein R 2a represents an azido group, an amino group or a group of the general formula: -NHCONHR , in which R 5 is as hereinbefore defined, and the other symbols are as hereinbefore defined) with phthalimide and then reacting the resulting compound with hydrazine,

Claim 23

(xi) reaction of a compound of the general formula; (wherein R 2b represents a group of the general formula: -NHCOR 5 or -NHCOOR , in which R 5 is as hereinbefore defined, and the other symbols are as hereinbefore defined) with sodium azide and then reducing an azido group of the resulting compound into an amino group,

Claim 24

(xi) reaction of a compound of the general formula; (wherein R 2b represents a group of the general formula: -NHCOR 5 or -NHCOOR , in which R 5 is as hereinbefore defined, and the other symbols are as hereinbefore defined) with sodium azide and then reducing an azido group of the resulting compound into an amino group,

Claim 25

(xii) acylation of a compound of the general formula: (wherein R 2c represents an azido group or a group of the general formula: -NHCOR 5 , -NHCOOR 5 or -NHCONH 5 , in which R 5 is as hereinbefore defined, and the other symbols are as hereinbefore defined), or

Claim 26

(xii) acylation of a compound of the general formula: (wherein R 2c represents an azido group or a group of the general formula: -NHCOR 5 , -NHCOOR 5 or -NHCONH 5 , in which R 5 is as hereinbefore defined, and the other symbols are as hereinbefore defined), or

Claim 27

(xiii) elimination of a tert-butoxycarbonyl group of a compound of the general formula: (wherein the various symbols are as hereinbefore defined).

Claim 28

(xiii) elimination of a tert-butoxycarbonyl group of a compound of the general formula: (wherein the various symbols are as hereinbefore defined).

Claim 29

.8. A process for the preparation of glycerol derivatives as claimed in claim I and conforming to the general formula: (wherein the various symbols are as defined in claim 7) which comprises: (i) reaction of a compound of the general formula: (wherein the various symbols are as defined in claim 7) with a compound of the general formula XXX depicted in claim 7, and, if desired, subjecting methods for salt-exchange, (ii) esterification of a compound of the general formula: (wherein the various symbols are as hereinbefore defined) with an acid of the general formula: (wherein R 3 and R 7 are as hereinbefore defined) or a reactive derivative thereof,

Claim 30

(iii) elimination of tert-butoxycarbonyl group of a compound of the general formula: (wherein R 8 and boc are as defined in claim 7 and the other symbols are as hereinbefore defined), or

Claim 31

(iv) acylation of a compound of the general formula: (wherein the various symbols are as hereinbefore defined),

Claim 32

(iv) acylation of a compound of the general formula: (wherein the various symbols are as hereinbefore defined),

Claim 33

A process for the preparation of glycerol derivatives as claimed in claim 1 and conforming to the general formula: (wherein X represents a halogen atom, R 2c is as defined in claim 7 and the other symbols are as defined in claim 1) which comprises reaction of a compound of the general formula: (wherein the various symbols are as hereinbefore defined) with an alkyl halide.

Claim 34

A platelet aggregation inhibiting, anti-asthmatic, anti-allergic, anti-inflammatory, hypotensive or anti-tumour pharmaceutical composition which comprises, as active ingredient, an effective amount of at least one compound of the general formula I depicted in claim I, wherein the various symbols are as defined in claim 1, or a non-toxic acid addition salt thereof, together with a pharmaceutical carrier or coating.

Claim 35

A method of inhibiting platelet aggregation, or for the prevention and treatment of asthma, allergy, inflammation, hypertension and tumour which comprises the oral or parenteral administration of an effective amount of a compound as claimed in claim 1,. wherein the various symbols are as defined in claim 1, or a non-toxic acid addition salt thereof.