EP0187702A1 — N-(omega,omega-1-dialkoxy)- and N-(omega,omega-1-…

Claim 1

Independent Claim 99 words

A compound of the formula or an optical isomer thereof wherein R 1 and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; R 3 , R 4 and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl of 7 to 11 carbons, or when two or three of R 3 , R 4 , and R 5 are taken together form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion.

Claim 2

Dependent Claim 99 words

A compound of the formula or an optical isomer thereof wherein R 1 and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; R 3 , R 4 and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl of 7 to 11 carbons, or when two or three of R 3 , R 4 , and R 5 are taken together form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion.

Claim 3

Dependent Claim 44 words

A compound according to claim 1 wherein R 1 and R 2 are the same and are alkenyl of 10 to 20 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl and n is 1 to 4.

Claim 4

Dependent Claim 41 words

A compound according to claim 2 selected from (+) N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl-N,N-trimethylammonium chloride or an optical isomer thereof; (+) N-(2,3-di-(4-(Z)-decenyloxy))-prop-1-yl-1-trimethylammonium chloride or an optical isomer thereof; (+) N-(3,4-di-(9-(Z)-octadecenyloxy))-but-l-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; and (+) N-(5,6-di-(9-(Z)-octadecenyloxy))-hex-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof.

Claim 5

Dependent Claim 49 words

A compound according to claim 1 wherein R l and R 2 are the same and are alkyl of 10 to 20 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl, n is 1 to 4 and X is a halide ion.

Claim 6

Dependent Claim 20 words

A compound according to claim 4 selected from (+) N-(2,3-di-hexadecyloxy)prop-l-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; and (+) N-(2,3-di-octadecyloxy)prop-1-yl-N,N,N-trimethylammonium chloride.

Claim 7

Dependent Claim 56 words

A compound according to claim I wherein R 1 is' alkyl or alkenyl of 14 to 22 carbon atoms; R 2 is alkyl or alkenyl of 6 to 14 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl; n is 1 to 4 and X is a halide ion.

Claim 8

Dependent Claim 20 words

A compound according to claim 6 selected from (+) N-(2-hexadecyloxy-3-decyloxy)-prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; and (+) N-(2-hexadecyloxy-3-decyloxy)-prop-1-yl-N,N-dimethylamine hydrochloride.

Claim 9

Dependent Claim 55 words

A liposome formulation which comprises 0.05 to 10% by weight of a drug, 1 to 20% surfactant component by weight of which a compound of formula I of any one of the preceding claims comprises 1 to 100% of this surfactant component, and an aqueous solution in a quantity sufficient to make 100% by volume.

Claim 10

Dependent Claim 56 words

A pharmaceutical formulation which comprises 0.05 to 10% by weight of a drug, 1 to 20% surfactant component by weight of which a compound of formula I of any one of claims 1 to 7 comprises 1 to 100% of this surfactant component, and an aqueous solution in a quantity sufficient to make 100% by volume.

Claim 11

Dependent Claim 29 words

The formulation of claim 9 wherein said drug is 9-(1,3-dihydroxy-2-propoxymethyl)quanine dipalmitate, 6a,9a-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide (fluocinolone acetonide), 6a,9a-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide-21-acetate (fluocinonide), 1-[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyll imidazole nitrate (butaconazole nitrate), beta-interferon, gamma- interferon, 6-0-stearoyl-N-acetylmuramyl-L-a-aminobutyryl-D-isoglutamine or a herpes antigen.

Claim 12

Dependent Claim 27 words

A formulation according to claim 9 or claim 10 wherein said drug comprises 1 to 5% and formula I comprises 50% or more of the surfactant component.

Claim 13

Dependent Claim 60 words

A formulation according to claim 9, 10 or 11 having a compound of formula I wherein R 1 and R 2 are the same and are alkyl or alkenyl of 10 to 20 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl, n is 1 to 4 and X is a halide ion.

Claim 14

Dependent Claim 43 words

A formulation according to claim 12 having a compound of formula I which is selected from ( + ) N-(2,3-di-hexadecyloxy)-prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; (+) N-(2,3-di-octadecyloxy)-prop-1-yl-N',N,N-trimethylammonium chloride or an optical isomer thereof; and (+) N-t2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof.

Claim 15

Dependent Claim 62 words

A formulation according to claim 9, 10 or 11 having a compound of formula I wherein R l and R 2 are the same and are alkyl of 10 to 20 carbon atoms, or alkenyl of 10 to 20 carbon atoms and R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl and n is 1 to 4.

Claim 16

Dependent Claim 61 words

A formulation according to claim 9, 10 or 11 wherein R l is alkyl or alkenyl of 14 to 22 carbon atoms and R 2 is a different alkyl group of 6 to 14 carbon atoms; R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl; n is 1 to 4; and X is a halide ion.

Claim 17

Dependent Claim 66 words

A process for the preparation of a compound of any one of claims 1 to 7 which comprises reacting a compound of the formula wherein R 1 and R 2 are as defined above and each R group is defined as R 3 , R 4 , and R 5 are defined above, with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 18

Dependent Claim 186 words

A process for preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; none or one of R 3 , R 4 and R 5 is hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons and two or three of R 3 , R 4 , and R 5 are taken together to form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion, which comprises (a) reacting a compound of the formula wherein R 1 and R 2 are as defined above and Y is a halide or p-toluene sulfonyl group with the appropriate hydrocarbon selected from quinuclidine, oyrrolidine, piperidine, or morpholine, optionally followed by (b) reacting the product of step (a) wherein two of R 3 , R 4 , and R 5 are taken together to form pyrrolidino, oiperidino, or morpholino with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 19

Dependent Claim 186 words

A process for preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; none or one of R 3 , R 4 and R 5 is hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons and two or three of R 3 , R 4 , and R 5 are taken together to form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion, which comprises (a) reacting a compound of the formula wherein R 1 and R 2 are as defined above and Y is a halide or p-toluene sulfonyl group with the appropriate hydrocarbon selected from quinuclidine, oyrrolidine, piperidine, or morpholine, optionally followed by (b) reacting the product of step (a) wherein two of R 3 , R 4 , and R 5 are taken together to form pyrrolidino, oiperidino, or morpholino with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 20

Dependent Claim 71 words

A compound of the formula or an optical isomer thereof wherein R 1 and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; each R is the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons or two R groups are taken together to form pyrrolidino, piperidino, or morpholino.

Claim 21

Dependent Claim 71 words

A compound of the formula or an optical isomer thereof wherein R 1 and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; each R is the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons or two R groups are taken together to form pyrrolidino, piperidino, or morpholino.

Claim 22

Dependent Claim 156 words

A process for the preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; R 3 , R 4 and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl of 7 to 11 carbons or when two or three of R 3 , R 4 , and R 5 are taken together to form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion, which comprises reacting a compound of the formula wherein R 1 and R 2 are as defined above and each R group is defined as R 3 , R 4 , and R 5 are defined above, with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 23

Dependent Claim 156 words

A process for the preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; R 3 , R 4 and R 5 are the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, aralkyl of 7 to 11 carbons or when two or three of R 3 , R 4 , and R 5 are taken together to form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion, which comprises reacting a compound of the formula wherein R 1 and R 2 are as defined above and each R group is defined as R 3 , R 4 , and R 5 are defined above, with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 24

Dependent Claim 188 words

A process for preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; none or one of R 3 , R 4 and R 5 is hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons and two or three of R 3 , R 4 , and R 5 are taken together to form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion, which comprises (a) reacting a compound of the formula wherein R l and R 2 are as defined above and Y is a halide or p-toluene sulfonyl group with the appropriate hydrocarbon selected from quinuclidine, pyrrolidine, piperidine, or morpholine, optionally followed by (b) reacting the product of step (a) wherein two of R 3 , R 4 , and R 5 are taken together to form pyrrolidino, pi p eridino, or morpholino with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 25

Dependent Claim 188 words

A process for preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; none or one of R 3 , R 4 and R 5 is hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons and two or three of R 3 , R 4 , and R 5 are taken together to form quinuclidino, pyrrolidino, piperidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion, which comprises (a) reacting a compound of the formula wherein R l and R 2 are as defined above and Y is a halide or p-toluene sulfonyl group with the appropriate hydrocarbon selected from quinuclidine, pyrrolidine, piperidine, or morpholine, optionally followed by (b) reacting the product of step (a) wherein two of R 3 , R 4 , and R 5 are taken together to form pyrrolidino, pi p eridino, or morpholino with an alkyl or aralkyl chloride to form a compound of formula I.

Claim 26

Dependent Claim 77 words

A process for the preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; each R is the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons or two R groups are taken together to form pyrrolidino, piperidino, or morpholino.

Claim 27

Dependent Claim 77 words

A process for the preparation of a compound of the formula or an optical isomer thereof wherein R l and R 2 are the same or different and are an alkyl or alkenyl group of 6 to 22 carbons; each R is the same or different and are hydrogen, alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbons or two R groups are taken together to form pyrrolidino, piperidino, or morpholino.

Claim 28

Dependent Claim 47 words

A process according to claim 1 or claim 3 wherein R l and R 2 are the same and are alkenyl of 10 to 20 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl and n is 1 to 4.

Claim 29

Dependent Claim 45 words

A process according to claim 4 wherein a compound selected from (+) N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl-N,N-trimethylammonium chloride or an optical isomer thereof; (±) N-(2,3-di-(4-(Z)-decenyloxy)),-prop-1-yl-1-trimethylammonium chloride or an optical isomer thereof; (+) N-(3,4-di-(9-(Z)-octadecenyloxy))-but-l-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; and (+)N-(5,6-di-(9-(-(Z))-octadecenyloxy))-hex-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof, is prepared.

Claim 30

Dependent Claim 52 words

A process according to claim 1 or claim 3 wherein R 1 and R 2 are the same and are alkyl of 10 to 20 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl, n is 1 to 4 and X is a halide ion.

Claim 31

Dependent Claim 25 words

A compound according to claim 6 wherein a compound selected from (+) N-(2,3-di-hexadecyloxy)prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; and (+) N-(2,3-di-octadecyloxy)prop-1-yl-N,N,N-trimethylammonium chloride is prepared.

Claim 32

Dependent Claim 59 words

A process according to claim 1 or claim 3 wherein R 1 is alkyl or alkenyl of 14 to 22 carbon atoms; R 2 is alkyl or alkenyl of 6 to 14 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl; n is 1 to 4 and X is a halide ion.

Claim 33

Dependent Claim 27 words

A process according to claim 8 wherein a compound selected from (+) N-(2-hexadecyloxy-3-decyloxy)-prop-1-yl-N,N,N-tri- . methylammonium chloride or an optical isomer thereof; and (+) N-(2-hexadecyloxy-3-decyloxy)-prop-1-yl-N,N-dimethylamine hydrochloride is prepared.

Claim 34

Dependent Claim 75 words

Use of a compound of formula I as defined in any one of the preceding claims in the manufacture of a liposome formulation which comprises 0.05 to 10% by weight of a drug, 1 to 20% surfactant component by weight of which a compound of formula I of any one of the preceding claims comprises 1 to 100% of this surfactant component, and an aqueous solution in a quantity sufficient to make 100% by volume.

Claim 35

Dependent Claim 77 words

Use of a compound of formula I as defined in any one of claims 1 to 9 in the manufacture of a pharmaceutical formulation which comprises 0.05 to 10% by weight of a drug, 1 to 20% surfactant component by weight of which a compound of formula I of any one of claims 1 to 7 comprises 1 to 100% of this surfactant component, and an aqueous solution in a quantity sufficient to make 100% by volume.

Claim 36

Dependent Claim 30 words

A process according to claim 11 wherein said drug is 9-(1,3-dihydroxy-2-propoxymethyl)quanine dipalmitate, 6a,9a-difluoro-ll6,16a,17a,21-tetrahydroxy-pregna-l,4-diene-3,20-dione-16,17-acetonide (fluocinolone acetonide), 6a,9a-difluoro-11β,16α,17α,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide-21-acetate (fluocinonide), 1-[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl] imidazole nitrate (butaconazole nitrate), beta-interferon, gamma- interferon, 6-0-stearoyl-N-acetylmuramyl-L-a-aminobutyryl-D-isoglutamine or a herpes antigen.

Claim 37

Dependent Claim 27 words

A process according to claim 11 or claim 12 wherein said drug comprises 1 to 5% and formula I comprises 50% or more of the surfactant component.

Claim 38

Dependent Claim 60 words

A process according to claim 11, 12 or 13 wherein in the compound of formula I, R l and R 2 are the same and are alkyl or alkenyl of 10 to 20 carbon atoms, R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl, n is 1 to 4 and X is a halide ion.

Claim 39

Dependent Claim 40 words

A process according to claim 14 wherein the compound of formula I is selected from (+) N-(2,3-di-hexadecyloxy)-prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; (+) N-(2,3-di-octadecyloxy)-prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof; and (+) N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride or an optical isomer thereof.

Claim 40

Dependent Claim 63 words

A process according to claim 11, 12 or 13 wherein in the compound of formula I R l and R 2 are the same and are alkyl of 10 to 20 carbon atoms, or alkenyl of 10 to 20 , carbon atoms and R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl and n is 1 to 4.

Claim 41

Dependent Claim 67 words

A process according to claim 11, 12 or 13 wherein in the compound of formula I R l is alkyl or alkenyl of 14 to 22 carbon atoms and R 2 is a different alkyl group of 6 to 14 carbon atoms; R 3 , R 4 , and R 5 are hydrogen, methyl or ethyl; n is 1 to 4; and X is a halide ion.

N-(omega,omega-1-dialkoxy)- and N-(omega,omega-1-dialkenoxy)-alk-1-yl-N,N,N-trisubstituted ammonium surfactants, their preparation and pharmaceutical formulations containing them

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