# US 8,999,960 B2 · Oxidized thiophospholipid compounds and uses thereof

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- Number: US 8,999,960 B2
- Document ID: US8999960B2
- Status: Granted
- Kind: B2
- Application number: 13/122,766
- Filed: 2009-10-01
- Published: 2011-08-11
- Granted: 2015-04-07
- Earliest claimed: 2008-10-08
- Assignees: Vascular Biogenics Ltd.
- Applicants: Eyal Breitbart; Eti Kovalevski-Ishai; Erez Feige; Itzhak Mendel; Zeev Ziniuk; Gideon Halperin
- Inventors: Eyal Breitbart; Eti Kovalevski-Ishai; Erez Feige; Itzhak Mendel; Zeev Ziniuk; Gideon Halperin
- Web page: https://patentgrep.com/patent/US8999960B2

## CPC

- C07F 9/10: Phosphatides, e.g. lecithin
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel oxidized thiophospholipids are provided herein, as well as methods for producing same, and uses thereof in treating or preventing an inflammation associated with endogenous oxidized lipids and related conditions. Exemplary oxidized thiophospholipid according to embodiments described herein have the formula: wherein X1, X2, A1, A2, B′, B″, D′ and D″ are as described herein.

## Claims

### Claim 1

A compound having formula III:
wherein:
each of A1 and A2 is independently selected from the group consisting of CR″R′″, C═O and C═S;
each of B′ and B″ is independently selected from the group consisting of sulfur and oxygen;
each of D′ and D″ is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, phosphonate and thiophosphonate; and
each of X1 and X2 is independently a saturated or unsaturated hydrocarbon having the general formula II:
wherein:
m is an integer of 3-26; and
Z is selected from the group consisting of:
wherein:
W is selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, whereby each of said nitrogen and phosphorus is substituted by at least one substituent selected from the group consisting of hydrogen, lone pair electrons, alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo;
R′ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; and
at least one Z is not hydrogen;
and wherein:
each of R″ and R′″ and each of Ra, R′a, Rb, R′b, to Rm−1, R′m−1, Rm and R′m is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkylnyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, thiophosphonate, phosphate, thiophosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, or, alternatively, at least two of Ra, R′a, Rb, R′b, to Rm−1, R′m−1, Rm and R′m form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring,
or a pharmaceutically acceptable salt, a hydrate or a solvate thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein at least one of A1 and A2 is CR″R′″.

### Claim 3 (depends on 2)

The compound of claim 2, wherein A2 is CR″R′″.

### Claim 4 (depends on 2)

The compound of claim 2, wherein each of A1 and A2 is CR″R′″.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X2 comprises a Z different than hydrogen.

### Claim 6 (depends on 5)

The compound of claim 5, wherein said Z is selected from the group consisting of
and

### Claim 7 (depends on 6)

The compound of claim 6, wherein W is oxygen and each R′ is independently selected from the group consisting of hydrogen and alkyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein:
B′ and B″ are each oxygen;
D″ is hydrogen;
D′ is selected from the group consisting of 2-aminoethyl and N,N,N-trimethyl-2-aminoethyl; and
each of X1 and X2 is a saturated hydrocarbon having the general formula II:
wherein:
m is an integer of 3-15; and
Z is selected from the group consisting of:
H and
wherein:
W is oxygen; and
at least one Z is not hydrogen; and
each of R′, Ra, Ra, Rb, R′b, to Rm−1, R′m−1, Rm and R′m is hydrogen.

### Claim 9

A compound being 1-hexadecyl-2-(4-carboxyl)butyl-sn-glycero-3-thiophosphorylcholine, and having formula IV:
or a pharmaceutically acceptable salt thereof.

### Claim 10

A compound being 1-hexadecyl-2-(4-carboxyl)butyl-sn-glycero-3-O-thiophosphorylethanolamine, and having formula V:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, being 1-hexadecyl-2-(4-carboxyl)butyl-glycero-3-thiophosphorylcholine, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, being 1-hexadecyl-2-(4-carboxyl)butyl-glycero-3-O-thiophosphorylethanolamine, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising, as an active ingredient, the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13, packaged in a material and identified in print, in or on said packaging material, for use in the treatment or prevention of an inflammation.

### Claim 15 (depends on 13)

The pharmaceutical composition of claim 13, packaged in a packaging material and identified in print, in or on said packaging material, for decreasing of a level of a cytokine selected from the group consisting of interleukin-12 and interleukin 23.

### Claim 16 (depends on 1)

A method of treating or preventing an inflammation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, thereby treating or preventing the inflammation in said subject.

### Claim 17 (depends on 1)

A method of decreasing a level of a cytokine selected from the group consisting of interleukin-12 and interleukin 23 in a subject, the method comprising administering to the subject an effective amount of a compound of claim 1.

### Claim 18 (depends on 14)

The composition of claim 14, wherein said inflammation is associated with a disease or disorder selected from the group consisting of an idiopathic inflammatory disease or disorder, a chronic inflammatory disease or disorder, an acute inflammatory disease or disorder, an autoimmune disease or disorder, an infectious disease or disorder, an inflammatory malignant disease or disorder, an inflammatory transplantation-related disease or disorder, an inflammatory degenerative disease or disorder, a disease or disorder associated with a hypersensitivity, an inflammatory cardiovascular disease or disorder, an inflammatory cerebrovascular disease or disorder, a peripheral vascular disease or disorder, an inflammatory glandular disease or disorder, an inflammatory gastrointestinal disease or disorder, an inflammatory cutaneous disease or disorder, an inflammatory hepatic disease or disorder, an inflammatory neurological disease or disorder, an inflammatory musculo-skeletal disease or disorder, an inflammatory renal disease or disorder, an inflammatory reproductive disease or disorder, an inflammatory systemic disease or disorder, an inflammatory connective tissue disease or disorder, an inflammatory tumor, necrosis, an inflammatory implant-related disease or disorder, an inflammatory aging process, an immunodeficiency disease or disorder and an inflammatory pulmonary disease or disorder.

### Claim 19 (depends on 16)

The method of claim 16, wherein said inflammation is associated with a disease or disorder selected from the group consisting of an idiopathic inflammatory disease or disorder, a chronic inflammatory disease or disorder, an acute inflammatory disease or disorder, an autoimmune disease or disorder, an infectious disease or disorder, an inflammatory malignant disease or disorder, an inflammatory transplantation-related disease or disorder, an inflammatory degenerative disease or disorder, a disease or disorder associated with a hypersensitivity, an inflammatory cardiovascular disease or disorder, an inflammatory cerebrovascular disease or disorder, a peripheral vascular disease or disorder, an inflammatory glandular disease or disorder, an inflammatory gastrointestinal disease or disorder, an inflammatory cutaneous disease or disorder, an inflammatory hepatic disease or disorder, an inflammatory neurological disease or disorder, an inflammatory musculo-skeletal disease or disorder, an inflammatory renal disease or disorder, an inflammatory reproductive disease or disorder, an inflammatory systemic disease or disorder, an inflammatory connective tissue disease or disorder, an inflammatory tumor, necrosis, an inflammatory implant-related disease or disorder, an inflammatory aging process, an immunodeficiency disease or disorder and an inflammatory pulmonary disease or disorder.

### Claim 20 (depends on 1)

A method of introducing a thiophosphate moiety into a compound so as to produce the compound of claim 1, the method comprising:
reacting a thiophosphorus-containing compound having a second reactive group and a third reactive group with a compound having the general formula VI:
wherein:
n is an integer of 1-6, whereas if n=1, Cn, Rn and R′n are absent, and C1 is attached to Bn;
each of B1, B2, to Bn−1 and Bn is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon, whereby each of said nitrogen, phosphorus and silicon is substituted by at least one substituent selected from the group consisting of hydrogen, lone pair electrons, alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo;
each of A1, A2, to An−1 is independently selected from the group consisting of CR″R′″, C═O and C═S; and
each of X1, X2, to Xn−1 is independently a saturated or unsaturated hydrocarbon having the general formula II:
wherein:
m is an integer of 1-26; and
Z is selected from the group consisting of:
H,
and a pre-oxidized moiety,
whereas:
W is selected from the group consisting of oxygen, sulfur, nitrogen and phosphorus, whereby each of said nitrogen and phosphorus is substituted by at least one substituent selected from the group consisting of hydrogen, lone pair electrons, alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo;
R′ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; and
at least one Z is not hydrogen;
and wherein:
each of R1, R′1, R2, to Rn−1, Rn, R′n, each of R″ and R′″ and each of Ra, R′a, Rb, R′b, to Rm−1, R′m−1, Rm and R′m is independently selected from the group consisting of hydrogen, a bond, alkyl, alkenyl, alkylnyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, thiophosphonate, phosphate, thiophosphate, phosphinyl, sulfonyl, sulfinyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, or, alternatively, at least two of R1, R′1, R2, to Rn−1, Rn and R′n and/or at least two of Ra, R′a, Rb, R′b, to Rm−1, R′m−1, Rm and R′m form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring; and
each of C1, C2, to Cn−1, Cn, and each of Ca, Cb, to Cm−1 and Cm is a chiral or non-chiral carbon atom, whereby each chiral carbon atom has a S-configuration and/or a R-configuration,
or a pharmaceutically acceptable salt, a hydrate or a solvate thereof,
said second reactive group being capable of reacting with said Bn, to thereby provide a compound having a reactive thiophosphorus-containing group attached to said Bn; and
converting said reactive thiophosphorus-containing group to said thiophosphate moiety, thereby producing the compound of claim 1,
wherein when Z in said Formula VI is said pre-oxidized moiety, the method further comprises oxidizing said pre-oxidized moiety.

### Claim 21 (depends on 20)

The method of claim 20, wherein Bn is selected from the group consisting of oxygen and sulfur.

### Claim 22 (depends on 20)

The method of claim 20, wherein said pre-oxidized moiety is an unsaturated alkyl.

### Claim 23 (depends on 20)

The method of claim 20, wherein said thiophosphorus-containing compound is PSCl3.

### Claim 24 (depends on 20)

The method of claim 20, wherein said reacting is performed in the presence of a base.

### Claim 25 (depends on 24)

The method of claim 24, wherein said base is a tertiary amine.

### Claim 26 (depends on 23)

The method of claim 23, wherein said reactive thiophosphorus-containing group is a dichlorothiophosphate group.

### Claim 27 (depends on 20)

The method of claim 20, wherein said compound having the general formula VI has said saturated or unsaturated hydrocarbon having the general formula II attached thereto via an ether bond.

### Claim 28 (depends on 20)

The method of claim 20, wherein said thiophosphate moiety is thiophosphoric acid and said converting comprises hydrolyzing said reactive thiophosphorus-containing group.

### Claim 29 (depends on 20)

The method of claim 20, wherein said thiophosphate moiety comprises an alkylamino group and said converting comprises reacting said reactive thiophosphorus-containing moiety with a derivative of an aminoalkyl, said derivative being capable of reacting with said reactive thiophosphorus-containing group.

### Claim 30 (depends on 6)

The compound of claim 6, wherein said Z is

### Claim 31 (depends on 1)

The compound of claim 1, wherein B′ and B″ are each oxygen.

### Claim 32 (depends on 1)

The compound of claim 1, wherein D″ is hydrogen.

### Claim 33 (depends on 1)

The compound of claim 1, wherein D′ is amino-substituted alkyl.

### Claim 34 (depends on 1)

The compound of claim 1, wherein D′ is selected from the group consisting of 2-aminoethyl and N,N,N-trimethyl-2-aminoethyl.

### Claim 35 (depends on 1)

The compound of claim 1, wherein:
B′ and B″ are each oxygen;
D″ is hydrogen; and
D′ is selected from the group consisting of 2-aminoethyl and N,N,N-trimethyl-2-aminoethyl.