U.S. patent application number 14/329191 was filed with the patent office on 2014-10-30 for lipid conjugates in the treatment of chronic rfhinosinusitis.
The applicant listed for this patent is YISSUM RESEARCH DEVELOPMENT COMPANY. Invention is credited to Saul YEDGAR.
Application Number | 20140323434 14/329191 |
Document ID | / |
Family ID | 48167222 |
Filed Date | 2014-10-30 |
United States Patent
Application |
20140323434 |
Kind Code |
A1 |
YEDGAR; Saul |
October 30, 2014 |
LIPID CONJUGATES IN THE TREATMENT OF CHRONIC RFHINOSINUSITIS
Abstract
This invention provides a method of treating, suppressing,
inhibiting, or preventing chronic rhinosinusitis in a subject
comprising the step of administering to a subject a compound
comprising a lipid or phospholipid moiety bond to a physiologically
acceptable monomer, dimer, oligomer, or polymer, and/or a
pharmaceutically acceptable salt or a pharmaceutical product
thereof. This invention also provides a method of treating,
suppressing, inhibiting, or preventing nasal polyps in a subject
comprising the step of administering to a subject a compound
comprising a lipid or phospholipid moiety bond to a physiologically
acceptable monomer, dimer, oligomer, or polymer, and/or a
pharmaceutically acceptable salt or a pharmaceutical product
thereof.
Inventors: |
YEDGAR; Saul; (Jerusalem,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
YISSUM RESEARCH DEVELOPMENT COMPANY |
Jerusalem |
|
IL |
|
|
Family ID: |
48167222 |
Appl. No.: |
14/329191 |
Filed: |
July 11, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13283020 |
Oct 27, 2011 |
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14329191 |
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11285375 |
Nov 23, 2005 |
8076312 |
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13283020 |
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PCT/IL05/01225 |
Nov 17, 2005 |
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11285375 |
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12463792 |
May 11, 2009 |
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13283020 |
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12997014 |
Dec 9, 2010 |
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PCT/US10/34317 |
May 11, 2010 |
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12463792 |
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61177083 |
May 11, 2009 |
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Current U.S.
Class: |
514/56 ; 514/54;
514/57 |
Current CPC
Class: |
A61K 31/717 20130101;
A61P 11/02 20180101; A61K 31/727 20130101; A61K 31/737 20130101;
A61K 31/728 20130101; A61K 31/685 20130101; A61K 47/61 20170801;
A61K 31/721 20130101; A61P 11/00 20180101; A61K 31/726 20130101;
A61K 47/544 20170801; A61P 29/00 20180101 |
Class at
Publication: |
514/56 ; 514/54;
514/57 |
International
Class: |
A61K 47/48 20060101
A61K047/48; A61K 31/737 20060101 A61K031/737; A61K 31/727 20060101
A61K031/727; A61K 31/728 20060101 A61K031/728; A61K 31/717 20060101
A61K031/717 |
Claims
1. A method of treating or preventing chronic rhinosinusitis in a
subject, comprising the step of administering to said subject a
compound represented by the structure of the general formula (A):
[L-Z--Y.quadrature..sub.nX n (A) wherein L is a lipid or a
phospholipid; Z is either nothing, ethanolamine, serine, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a polymer; and n is a number
from 1 to 1000.
2. The method according to claim 1, wherein X is a
polysaccharide.
3. The method according to claim 1, wherein L is
phosphatidylethanolamine.
4. The method according to claim 3, wherein said
phosphatidylethanolamine is dipalmitoyl
phosphatidylethanolamine.
5. The method according to claim 1, wherein said chronic
rhinosinusitis is chronic rhinosinusitis with polyps.
6. The method according to claim 1, wherein L is a phospholipid, Z
is nothing and-said compound is represented by the structure of the
general formula (I): ##STR00070## wherein R.sub.1 is a linear,
saturated, mono-unsaturated, or poly-unsaturated, alkyl chain
ranging in length from 2 to 30 carbon atoms; R.sub.2 is a linear,
saturated, mono-unsaturated, or poly-unsaturated, alkyl chain
ranging in length from 2 to 30 carbon atoms; Y is either nothing or
a spacer group ranging in length from 2 to 30 atoms; X is a
polymer; and n is a number from 1 to 1,000.
7. The method of claim 1, wherein said polymer has a molecular
weight of between 5 kD and 90 kD.
8. The method of claim 1, wherein said polymer has a molecular
weight of between 5 kD and 20 kD.
9. The method of claim 1, wherein n is a number from 2 to 500.
10. The method of claim 1, wherein the step of administering
comprises nasal administration.
11. A method of treating or preventing nasal polyps in a subject,
comprising the step of administering to said subject a compound
represented by the structure of the general formula (A):
[L-Z--Y.quadrature..sub.nX (A) wherein L is a lipid or a
phospholipid; Z is either nothing, ethanolamine, serine, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a polymer; and n is a number
from 1 to 1000.
12. The method according to claim 11, wherein X is a
polysaccharide.
13. The method according to claim 11, wherein L is a
phosphatidylethanolamine.
14. The method according to claim 13, wherein said
phosphatidylethanolamine is dipalmitoyl
phosphatidylethanolamine.
15. The method according to claim 11, wherein L is a phospholipid,
Z is nothing and said compound is represented by the structure of
the general formula (I): ##STR00071## wherein R.sub.1 is a linear,
saturated, mono-unsaturated, or poly-unsaturated, alkyl chain
ranging in length from 2 to 30 carbon atoms; R.sub.2 is a linear,
saturated, mono-unsaturated, or poly-unsaturated, alkyl chain
ranging in length from 2 to 30 carbon atoms; Y is either nothing or
a spacer group ranging in length from 2 to 30 atoms; X is a
polymer; and n is a number from 1 to 1,000.
16. The method of claim 11, wherein said polymer has a molecular
weight of between 5 kD and 90 kD
17. The method of claim 11, wherein said polymer has a molecular
weight of between 5 kD and 20 kD.
18. The method of claim 11, wherein n is a number from 2 to
500.
19. The method of claim 11, wherein the step of administering
comprises nasal administration.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 13/283,020, which is a
continuation-in-part of U.S. application Ser. No. 11/285,375, filed
Nov. 23, 2005, now U.S. Pat. No. 8,076,312, which is a
continuation-in-part of PCT International Application Number
PCT/IL2005/001225, filed Nov. 17, 2005. This application is also a
continuation-in-part of U.S. application Ser. No. 12/463,792, filed
May 11, 2009, and of U.S. application Ser. No. 12/997,014, filed
Dec. 9, 2010, which is a National Phase Application of PCT
International Application No. PCT/US10/34317, International Filing
Date May 11, 2010, claiming priority of U.S. Provisional
Application No. 61/177,083, filed May 11, 2009, which are all
hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention provides a method of treating, suppressing,
inhibiting, or preventing chronic rhinosinusitis in a subject
comprising the step of administering to a subject a compound
comprising a lipid or phospholipid moiety bond to a physiologically
acceptable monomer, dimer, oligomer, or polymer, and/or a
pharmaceutically acceptable salt or a pharmaceutical product
thereof. This invention also provides a method of treating,
suppressing, inhibiting, or preventing nasal polyps (NP) in a
subject comprising the step of administering to a subject a
compound comprising a lipid or phospholipid moiety bond to a
physiologically acceptable monomer, dimer, oligomer, or polymer,
and/or a pharmaceutically acceptable salt or a pharmaceutical
product thereof.
BACKGROUND OF THE INVENTION
[0003] Lipid-conjugates having a pharmacological activity of
inhibiting the enzyme phospholipase A2 (PLA2, EC 3.1.1.4) are known
in the prior art. Phospholipase A2 catalyzes the breakdown of
phospholipids at the sn-2 position to produce a fatty acid and a
lysophospholipid. The activity of this enzyme has been correlated
with various cell functions, particularly with the production of
lipid mediators such as eicosanoid production (prostaglandins,
thromboxanes and leukotrienes), platelet activating factor and
lysophospholipids.
[0004] Glycosaminoglycans (GAG) are macro-molecules that protect
the cell membrane from attacks or stimuli by a multitude of
extra-cellular agents such as: Free radicals (ROS), exogenous PLA2,
interleukins and other inflammatory mediators, allergens, growth
factors, and degrading enzymes or invasion-promoting enzymes (e.g.,
heparinase, collagenase, heparanase, hyaluronidase). GAG enrichment
assists in protecting cells from damage.
[0005] Since their inception, lipid-conjugates have been subjected
to intensive laboratory investigation in order to obtain a wider
scope of protection of cells and organisms from injurious agents
and pathogenic processes.
[0006] Chronic rhinosinusitis (CRS) is a chronic inflammatory
disease of the sinuses and upper airways.
[0007] CRS is now defined as a group of disorders characterized by
inflammation of the mucosa of the nose and paranasal sinuses of at
least 12 weeks duration. The group of CRS disorders annually
accounts as many as 22 million office visits and more than 500,000
emergency department visits in the U.S., according to some
estimates. Annual CRS-related healthcare expenditures may reach as
much as $3.5 billion.
[0008] Clinically, CRS is a heterogenous symptom complex, often
resistant to medical therapy that is typically characterized by two
or more of the following: mucopurulent drainage, nasal obstruction,
facial pain/pressure and hyposmia/anosmia. CRS is clinically
classified into CRS with nasal polyps (CRSwNP) and CRS without
nasal polyps (CRSsNP). Often, CRSwNP is associated with nasal
obstruction and smell loss, and CRSsNP is associated with facial
pain/pressure and headaches.
[0009] Chronic rhinosinusitis with nasal polyps is a multifactorial
disease, frequently associated with asthma and occasionally with
aspirin sensitivity. Chronic rhinosinusitis with nasal polyps has
mainly Th2 characteristics, with Eosinophilia and a typical
cytokine profile.
[0010] Staphylococcus Aureus Superantigens (SAS) may be involved in
the amplification of the inflammation and exacerbation of the
disease. S. Aureus is the most common microorganism isolated from
mucus adjacent to massive NP (60-70% of the cases), and IgE
specific to SAS is often found in NP tissue. In addition, S. Aureus
produce enterotoxins capable of acting on peripheral blood T
lymphocytes stimulating cytokine production.
SUMMARY OF THE INVENTION
[0011] In one embodiment, the invention provides for a method of
treating chronic rhinosinusitis in a subject comprising the step of
administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0012] In another embodiment, the invention provides a method of
preventing chronic rhinosinusitis in a subject, comprising the step
of administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0013] In another embodiment, the invention provides a method of
treating nasal polyps in a subject, comprising the step of
administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0014] In another embodiment, the invention provides a method of
preventing nasal polyps in a subject, comprising the step of
administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0015] In one embodiment, X in general formula (A) is a
polysaccharide. In one embodiment, the polysaccharide is
carboxymethylcellulose, while in another embodiment, the
polysaccharide is a glycosaminoglycan. In one embodiment, the
glycosaminoglycan is hyaluronic acid, while in another embodiment,
the glycosaminoglycan is heparin. In one embodiment L in general
formula (A) is phosphatidylethanolamine, which in one embodiment is
dipalmitoyl phosphatidylethanolamine.
BRIEF DESCRIPTION OF FIGURES
[0016] FIG. 1. Treatment of T cells from nasal polyps in vitro with
Staphylococcus Aureus Superantigens (SA) induced the release of
large amounts of IL-4, IL-5 and INF-.gamma. compared to untreated
nasal polyp T cells (NA).
[0017] FIG. 2. Addition of anti-IL-5 antibodies to T cells from
nasal polyps treated in vitro with Staphylococcus Aureus
Superantigens (SAS) suppressed IL-4 and INF-.gamma. release in
polyps with high levels of IL-5 (A and C), while having no effect
on IL-4 and INF-.gamma. release in polyps with low levels of IL-5
(B and D).
[0018] FIG. 3. Treatment of human nasal polyps with the PLA2
inhibitor HyPE, a compound of the present invention, suppressed the
release of Th2 and Th1 cytokines at a level comparable to (IL-5,
IL-13) or better than (Interferon-.chi.) that of dexamethasone.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The invention provides a novel method of use for
lipid-conjugates which display a wide-range combination of
cytoprotective pharmacological activities. These compounds can
alleviate airway obstruction in asthma, protect mucosal tissue in
gastrointestinal disease, suppress immune responses, alleviate
cutaneous hypersensitivity reactions, inhibit cell proliferation
associated with vascular injury and immunological responses,
inhibit cell migration associated with vascular and central nervous
system disease, attenuate oxidative damage to tissue proteins and
cell membranes, interfere with viral spread, reduce tissue
destroying enzyme activity, and reduce intracellular levels of
chemokines and cytokines. Thus these compounds are useful in the
treatment of a diversity of disease states, including asthma,
rhinitis, allergic rhinitis, chronic obstructive pulmonary disease,
obstructive respiratory disease, colitis, Crohn's disease, central
nervous system insult, multiple sclerosis, contact dermatitis,
psoriasis, cardiovascular disease, invasive medical procedures,
invasive cellular proliferative disorders, anti-oxidant therapy,
hemolytic syndromes, sepsis, acute respiratory distress syndrome,
tissue transplant rejection syndromes, autoimmune disease, viral
infection, and hypersensitivity conjunctivitis.
[0020] In one embodiment, the invention provides a method of
treating an obstructive respiratory disease in a subject comprising
the step of administering to said subject a compound represented by
the structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0021] In another embodiment, the invention provides a method of
preventing an obstructive respiratory disease in a subject,
comprising the step of administering to said subject a compound
represented by the structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0022] In another embodiment, the obstructive respiratory disease
is rhinosinusitis. In another embodiment, the obstructive
respiratory disease comprises a physical or anatomical obstruction,
which in one embodiment, is a nasal polyp. In another embodiment,
the obstructive respiratory disease is rhinitis. In another
embodiment, the obstructive respiratory disease is sinusitis. In
one embodiment, the obstructive respiratory disease is asthma. In
another embodiment, the obstructive respiratory disease is allergic
rhinitis. In another embodiment, the obstructive respiratory
disease is chronic obstructive pulmonary disorder. In another
embodiment, the obstructive respiratory disease is nasal
polyposis.
[0023] In one embodiment, the obstructive respiratory disease is
chronic. In another embodiment, the obstructive respiratory disease
is acute. In another embodiment, the obstructive respiratory
disease is seasonal.
[0024] In one embodiment, the invention provides a method of
treating chronic rhinosinusitis in a subject comprising the step of
administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y.quadrature..sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0025] In another embodiment, the invention provides a method of
preventing chronic rhinosinusitis in a subject, comprising the step
of administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y.quadrature..sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0026] In another embodiment, the invention provides a method of
treating nasal polyps in a subject, comprising the step of
administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0027] In another embodiment, the invention provides a method of
preventing nasal polyps in a subject, comprising the step of
administering to said subject a compound represented by the
structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000.
[0028] In one embodiment, X in general formula (A) is a
polysaccharide. In one embodiment, the polysaccharide is
carboxymethylcellulose, while in another embodiment, the
polysaccharide is a glycosaminoglycan. In one embodiment, the
glycosaminoglycan is hyaluronic acid, while in another embodiment,
the glycosaminoglycan is heparin. In one embodiment L in general
formula (A) is phosphatidylethanolamine, which in one embodiment is
dipalmitoyl phosphatidylethanolamine.
[0029] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for the preparation of a
composition to treat chronic rhinosinusitis.
[0030] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for the preparation of a
composition to prevent chronic rhinosinusitis.
[0031] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for the preparation of a
composition to treat nasal polyps.
[0032] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for the preparation of a
composition to prevent nasal polyps.
[0033] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for treating chronic
rhinosinusitis.
[0034] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for preventing chronic
rhinosinusitis.
[0035] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for treating nasal
polyps.
[0036] In another embodiment, the invention provides for the use of
a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer; and n is a number from 1 to 1000 for preventing nasal
polyps.
[0037] In one embodiment, compositions of the present invention may
be used to treat, suppress, inhibit or prevent rhinosinusitis. In
one embodiment, rhinosinusitis is an inflammation of the nasal
cavity and sinuses. In one embodiment, chronic rhinosinusitis (CRS)
is a chronic inflammatory disease of the sinuses and upper
airways.
[0038] In one embodiment, "chronic" rhinosinusitus lasts 12 weeks
or more. In another embodiment, CRS lasts more than 4 weeks. In
another embodiment, CRS lasts more than 6 weeks. In another
embodiment, CRS lasts more than 8 weeks. In another embodiment, CRS
lasts more than 10 weeks. In another embodiment, CRS lasts more
than 14 weeks. In another embodiment, CRS lasts more than 16 weeks.
In another embodiment, CRS lasts for months to years.
[0039] In one embodiment, CRS is initially caused by a stimulus,
such as an allergen, environmental stimulus, fungus, bacteria, or
virus. In one embodiment, the bacterial infection is Staphylococcus
Aureus. In one embodiment, the fungus or bacteria colonizes the
sinus in CRS thereby causing an aggressive inflammatory reaction.
In another embodiment, any of the stimuli described hereinabove
lead to an inflammatory reaction of CRS.
[0040] In one embodiment, compositions of the present invention may
be used to treat, suppress, inhibit or prevent a polyp, which in
one embodiment, is a nasal polyp. In one embodiment, a polyp is an
overgrowth of tissue from the surface of a body organ. In one
embodiment, a polyp may have a round, droplet, or irregular shape.
In one embodiment, compositions of the present invention may be
used to treat, suppress, inhibit or prevent nasal polyposis.
[0041] In another embodiment, the invention provides a method of
decreasing cytokine levels in a subject, comprising the step of
administering to said subject a compound of the present invention.
In another embodiment, the invention provides a method of returning
elevated cytokine levels to basal levels in a subject, comprising
the step of administering to said subject a compound of the present
invention. In another embodiment, the invention provides a method
of decreasing IL-13 levels in a subject, comprising the step of
administering to said subject a compound of the present invention.
In another embodiment, the invention provides a method of
decreasing IL-5 levels in a subject, comprising the step of
administering to said subject a compound of the present invention.
In another embodiment, the invention provides a method of
decreasing interferon-.gamma. levels in a subject, comprising the
step of administering to said subject a compound of the present
invention. In another embodiment, the invention provides a method
of reversing increased IL-13 levels in a subject, comprising the
step of administering to said subject a compound of the present
invention. In another embodiment, the invention provides a method
of reversing increased IL-5 levels in a subject, comprising the
step of administering to said subject a compound of the present
invention. In another embodiment, the invention provides a method
of reversing increased interferon-.gamma. levels in a subject,
comprising the step of administering to said subject a compound of
the present invention.
[0042] In one embodiment, X in general formula (A) is a
polysaccharide. In one embodiment, the polysaccharide is
carboxymethylcellulose, while in another embodiment, the
polysaccharide is a glycosaminoglycan. In one embodiment, the
glycosaminoglycan is hyaluronic acid, while in another embodiment,
the glycosaminoglycan is heparin. In one embodiment L in general
formula (A) is phosphatidylethanolamine, which in one embodiment is
dipalmitoyl phosphatidylethanolamine.
[0043] In one embodiment, "treating" or "preventing" refers to
delaying the onset of symptoms, reducing the severity of symptoms,
reducing the severity of an acute episode, reducing the number of
symptoms, reducing the incidence of disease-related symptoms,
reducing the latency of symptoms, ameliorating symptoms, reducing
secondary symptoms, reducing secondary infections, prolonging
patient survival, preventing relapse to a disease, decreasing the
number or frequency of relapse episodes, increasing latency between
symptomatic episodes, increasing time to sustained progression,
expediting remission, inducing remission, augmenting remission,
speeding recovery, or increasing efficacy of or decreasing
resistance to alternative therapeutics.
[0044] In one embodiment, symptoms are primary, while in another
embodiment, symptoms are secondary. In one embodiment, "primary"
refers to a symptom that is a direct result of infection with a
pathogen, while in one embodiment, "secondary" refers to a symptom
that is derived from or consequent to a primary cause.
[0045] In one embodiment, the invention provides a method of
treating a subject suffering from chronic rhinosinusitis,
comprising the step of administering to a subject a compound
comprising a lipid or phospholipid moiety bond to a physiologically
acceptable monomer, dimer, oligomer, or polymer, and/or a
pharmaceutically acceptable salt or a pharmaceutical product
thereof, in an amount effective to treat the subject suffering from
chronic rhinosinusitis. In another embodiment, the invention
provides a method of treating a subject suffering from chronic
rhinosinusitis, comprising the step of administering to a subject
any one of the compounds according to the invention, in an amount
effective to treat the subject suffering from an chronic
rhinosinusitis. In another embodiment, the chronic rhinosinusitis
is chronic rhinosinusitis with polyps.
[0046] In one embodiment, the invention provides a method of
treating a subject suffering from an obstructive respiratory
disease, comprising the step of administering to a subject a
compound comprising a lipid or phospholipid moiety bond to a
physiologically acceptable monomer, dimer, oligomer, or polymer,
and/or a pharmaceutically acceptable salt or a pharmaceutical
product thereof, in an amount effective to treat the subject
suffering from an obstructive respiratory disease. In another
embodiment, the invention provides a method of treating a subject
suffering from an obstructive respiratory disease, comprising the
step of administering to a subject any one of the compounds
according to the invention, in an amount effective to treat the
subject suffering from an obstructive respiratory disease. In
another embodiment, the obstructive respiratory disease is
asthma.
[0047] In one embodiment of the invention, the physiologically
acceptable monomer is either a salicylate, salicylic acid, aspirin,
a monosaccharide, lactobionic acid, maltose, an amino acid,
glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic
acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid,
didodecanoic acid, bile acid, cholic acid,
cholesterylhemmisuccinate; or wherein the physiologically
acceptable dimer or oligomer is a dipeptide, a disaccharide, a
trisaccharide, an oligopeptide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin sulfate, dermatin, dermatan sulfate,
dextran, or hyaluronic acid; or wherein the physiologically
acceptable polymer is a glycosaminoglycan, polygelin (`hemaccell`),
alginate, hydroxyethyl starch (hetastarch), polyethylene glycol,
polycarboxylated polyethylene glycol, chondroitin sulfate, keratin,
keratin sulfate, heparan sulfate, dermatin, dermatan sulfate,
carboxymethylcellulose, heparin, dextran, or hyaluronic acid. In
another embodiment, the physiologically acceptable polymer is
chondrotin sulfate. In another embodiment, the chondrotin sulfate
is chondrotin-6-sulfate, chondroitin-4-sulfate or a derivative
thereof. In another embodiment, the physiologically acceptable
polymer is hyaluronic acid.
[0048] In one embodiment of the invention, the lipid or
phospholipid moiety is either phosphatidic acid, an acyl glycerol,
monoacylglycerol, diacylglycerol, triacylglycerol, sphingosine,
sphingomyelin, chondroitin-4-sulphate, chondroitin-6-sulphate,
ceramide, phosphatidylethanolamine, phosphatidylserine,
phosphatidylcholine, phosphatidylinositol, or phosphatidylglycerol,
or an ether or alkyl phospholipid derivative thereof, and the
physiologically acceptable monomer or polymer moiety is either
aspirin, lactobionic acid, maltose, glutaric acid, polyethylene
glycol, carboxymethylcellulose, heparin, dextran, hemacell,
hetastarch, or hyaluronic acid. In another embodiment, the
phospholipid moiety is phosphatidylethanolamine.
[0049] In one embodiment, obstructive respiratory disease is a
disease of luminal passages in the lungs, marked by dyspnea,
tachypnea, or ausculatory or radiological signs of airway
obstruction. Obstructive respiratory disease comprises asthma,
acute pulmonary infections, acute respiratory distress syndrome,
chronic obstructive pulmonary disease, rhinitis, and allergic
rhinitis. In one embodiment, the pathophysiology is attributed to
obstruction of air flow due to constriction of airway lumen smooth
muscle and accumulation of infiltrates in and around the airway
lumen.
[0050] In one embodiment, asthma is a disease process wherein the
bronchi may be narrowed, making breathing difficult. In one
embodiment, symptoms comprise wheezing, difficulty breathing
(particularly exhaling air), tightness in the chest, or a
combination thereof. In one embodiment, factors which can
exacerbate asthma include rapid changes in temperature or humidity,
allergies, upper respiratory infections, exercise, stress, smoke
(e.g., cigarette), or a combination thereof.
[0051] In one embodiment, rhinitis comprises an inflammation of the
mucous membrane of the nose. In one embodiment, allergic rhinitis
is an inflammatory response in the nasal passages to an allergic
stimulus. In one embodiment, symptoms comprise nasal congestion,
sneezing, runny, itchy nose, or a combination thereof.
[0052] In one embodiment, chronic obstructive pulmonary disease is
a progressive disease process that most commonly results from
smoking. In one embodiment, chronic obstructive pulmonary disease
comprises difficulty breathing, wheezing, coughing, which may be a
chronic cough, or a combination thereof. In one embodiment, chronic
obstructive pulmonary disease may lead to health complications,
which in one embodiment, may comprise bronchitis, pneumonia, lung
cancer, or a combination thereof.
[0053] Cellular elaboration of cytokines and chemokines serve an
important regulatory function in health; however, when a
hyperactive response to stress or disease is triggered, these
compounds may present in excess and damage tissue, thereby pushing
the disease state toward further deterioration. Cytokine
overproduction is involved in numerous diseases, such as sepsis,
airway and lung injury, renal failure, transplant rejection, skin
injuries, intestine injuries, cancer development and metastasis,
central nervous sytem disorders, vaginal bacterial infection, and
more.
[0054] In one embodiment, the present invention offers methods for
the treatment of disease based upon administration of lipids
covalently conjugated through their polar head group to a
physiologically acceptable chemical moiety, which may be of high or
low molecular weight.
[0055] In one embodiment, the lipid compounds (Lipid-conjugates) of
the present invention are described by the general formula:
[phosphatidylethanolamine-Y]n-X
[phosphatidylserine-Y]n-X
[phosphatidylcholine-Y]n-X
[phosphatidylinositol-Y]n-X
[phosphatidylglycerol-Y]n-X
[phosphatidic acid-Y]n-X
[lyso-phospholipid-Y]n-X
[diacyl-glycerol-Y]n-X
[monoacyl-glycerol-Y]n-X
[sphingomyelin-Y]n-X
[sphingosine-Y]n-X
[ceramide-Y]n-X
wherein Y is either nothing or a spacer group ranging in length
from 2 to 30 atoms; and X is a physiologically acceptable monomer,
dimer, oligomer or polymer; and n, the number of lipid molecules
bound to X, is a number from 1 to 1000.
[0056] In one embodiment of this invention, n is a number from 1 to
1000. In another embodiment, n is a number from 1 to 500. In
another embodiment, n is a number from 2 to 500. In another
embodiment, n is a number from 2 to 1000. In another embodiment, n
is a number from 1 to 100. In another embodiment, n is a number
from 100 to 300. In another embodiment, n is a number from 300 to
500. In another embodiment, n is a number from 500 to 800.
[0057] In one embodiment, the lipid compounds of this invention,
known herein as lipid conjugates (Lipid-conjugates) are now
disclosed to possess a combination of multiple and potent
pharmacological effects in addition to the ability to inhibit the
extracellular form of the enzyme phospholipase A2. The set of
compounds comprising phosphatidylethanolamine covalently bound to a
physiologically acceptable monomer or polymer is referred to herein
as the PE-conjugates. Related derivatives, in which either
phosphatidylserine, phosphatidylcholine, phosphatidylinositol,
phosphatidic acid or phosphatidylglycerol are employed in lieu of
phosphatidylethanolamine as the lipid moiety provide equivalent
therapeutic results, based upon the biological experiments
described below for the Lipid-conjugates and the structural
similarities shared by these compounds. Other Lipid-conjugate
derivatives relevant to this invention are Lipid-conjugates wherein
at least one of the fatty acid groups of the lipid moieties at
position C1 or C2 of the glycerol backbone are substituted by a
long chain alkyl group attached in either ether or alkyl bonds,
rather than ester linkage.
[0058] As defined by the structural formulae provided herein for
the Lipid-conjugates, these compounds may contain between one to
one thousand lipid moieties bound to a single physiologically
acceptable polymer molecule.
[0059] Administration of the Lipid-conjugates in a diversity of
animal and cell models of disease invokes remarkable, and
unexpected, cytoprotective effects, which are useful in the
treatment of disease. They are able to stabilize biological
membranes; inhibit cell proliferation; suppress free radical
production; suppress nitric oxide production; reduce cell migration
across biological barriers; influence chemokine levels, including
MCP-1, ENA-78, Gro .alpha., and CX3C; affect gene transcription and
modify the expression of MHC antigens; bind directly to cell
membranes and change the water structure at the cell surface;
inhibit the uptake of oxidized lipoprotein; prevent airway smooth
muscle constriction; suppress neurotransmitter release; reduce
expression of tumor necrosis factor-.alpha. (TNF-.alpha.); modify
expression of transcription factors such as NF.kappa.B; inhibit
extracellular degradative enzymes, including collagenase,
heparinase, hyaluronidase, in addition to that of PLA2; and inhibit
viral infection of white cells. Thus the Lipid-conjugatesprovide
far-reaching cytoprotective effects to an organism suffering from a
disease wherein one or more of the presiding pathophysiological
mechanisms of tissue damage entails either oxidation insult giving
rise to membrane fragility; hyperproliferation behavior of cells
giving rise to stenotic plaque formation in vascular tissue,
angiogenesis and benign or malignant cancer disease, or psoriasis;
aberrant cell migration giving rise to brain injury or tumor cell
metastases; excessive expression of chemokines and cytokines
associated with central nervous system (CNS) insult, sepsis, ARDS,
or immunological disease; cell membrane damage giving rise to CNS
insult, CVS disease, or hemolysis; peroxidation of blood proteins
and cell membranes giving rise to atherosclerosis or reperfusion
injury; excessive nitric oxide production giving rise to CNS
insult, reperfusion injury, and septic shock; interaction with
major histocompatability antigens (MHC) associated with autoimmune
diseases and alloimmune syndromes, such as transplant
rejection.
[0060] In one embodiment of the present invention, the useful
pharmacological properties of the lipid or Lipid-conjugates may be
applied for clinical use, and disclosed herein as methods for
treatment of a disease. The biological basis of these methods may
be readily demonstrated by standard cellular and animal models of
disease as described below.
[0061] While pharmacological activity of the Lipid-conjugates
described herein may be due in part to the nature of the lipid
moiety, the multiple and diverse combination of pharmacological
properties observed for the Lipid-conjugates emerges from the
ability of the compound structure to act essentially as several
different drugs in one chemical entity. Thus, for example, internal
mucosal injury, as may occur in colitis or Crohn's disease, may be
attenuated by any one or all of the pharmaceutical activities of
immune suppression, anti-inflammation, anti-oxidation, nitric oxide
production, or membrane stabilization. Protection of blood vessels
from periluminal damage, as may occur in atherosclerosis, may
entail activity from anti-proliferative, anti-chemokine,
antioxidant, or antimigratory effects. Treatment or prevention of
chronic rhinosinusitis, nasal polyps, or obstructive respiratory
disease may involve any one of the many activities of the
Lipid-conjugates ranging from suppression of nitric oxide,
anti-chemokine, anti-proliferative, or membrane stabilization
effects.
[0062] The use of a single chemical entity with potent
anti-oxidant, membrane-stabilizing, anti-proliferative,
anti-chemokine, anti-migratory, and anti-inflammatory activity
provides increased cytoprotection relative to the use of several
different agents each with a singular activity. The use of a single
agent having multiple activities over a combination or plurality of
different agents provides uniform delivery of an active molecule,
thereby simplifying issues of drug metabolism, toxicity and
delivery. The compounds of the present invention also exhibit
properties present only in the combined molecule, not in the
individual components.
[0063] In one embodiment, the compounds of the invention may be
used for acute treatment of temporary conditions, or may be
administered chronically, especially in the case of progressive,
recurrent, or degenerative disease. In one embodiment of the
invention, the concentrations of the compounds will depend on
various factors, including the nature of the condition to be
treated, the condition of the patient, the route of administration
and the individual tolerability of the compositions.
[0064] In another embodiment, the invention provides low-molecular
weight Lipid-conjugates, previously undisclosed and unknown to
possess pharmacological activity, of the general formula:
[Phosphatidylethanolamine-Y]n-X
[Phosphatidylserine-Y]n-X
[Phosphatidylcholine-Y]n-X
[Phosphatidylinositol-Y]n-X
[Phosphatidylglycerol-Y]n-X
[Phosphatidic acid-Y]n-X
[lyso-phospholipid-Y]n-X
[diacyl-glycerol-Y]n-X
[monoacyl-glycerol-Y]n-X
[sphingomyelin-Y]n-X
[sphingosine-Y]n-X
[ceramide-Y]n-X
wherein Y is either nothing or a spacer group ranging in length
from 2 to 30 atoms; and X is salicylate, salicylic acid, aspirin, a
monosaccharide, lactobionic acid, maltose, an amino acid, glycine,
carboxylic acid, acetic acid, butyric acid, dicarboxylic acid,
glutaric acid, succinic acid, fatty acid, dodecanoic acid,
didodecanoic acid, bile acid, cholic acid,
cholesterylhemmisuccinate, a dipeptide, a disaccharide, a
trisaccharide, an oligosaccharide, an oligopeptide, or a di- or
trisaccharide monomer unit of heparin, heparan sulfate, keratin,
keratan sulfate, chondroitin, chondoitin-6-sulfate,
chondroitin-4-sulfate, dermatin, dermatan sulfate, dextran, or
hyaluronic acid, a glycosaminoglycan, polygeline (`haemaccel`),
alginate, hydroxyethyl starch (hetastarch), polyethylene glycol,
polycarboxylated polyethylene glycol, chondroitin-6-sulfate,
chondroitin-4-sulfate, keratin, keratin sulfate, heparan sulfate,
dermatin, dermatan sulfate, carboxymethylcellulose, heparin,
dextran, or hyaluronic acid; and n, the number of lipid molecules
bound to X, is a number from 1 to 1000.
[0065] In one embodiment of this invention, n is a number from 1 to
1000. In another embodiment, n is a number from 1 to 500. In
another embodiment, n is a number from 1 to 100. In another
embodiment, n is a number from 100 to 300. In another embodiment, n
is a number from 300 to 500. In another embodiment, n is a number
from 500 to 800.
[0066] In another embodiment of the invention, these
Lipid-conjugate derivatives possess wide-spectrum pharmacological
activity and, as pharmaceutical agents administered to treat
disease, are considered analogous to the Lipid-conjugates comprised
from high molecular weight polymers. Other lipid-conjugate
derivatives relevant to this invention are glycerolipid moieties in
which at least one of the two long chain alkyl groups in position
C1 and C2 of the glycerol backbone are attached in ether or alkyl
bonds, rather than ester linkage.
[0067] The present invention is further illustrated in the
following examples of the therapeutic Lipid-conjugate compounds,
their chemical preparation, their anti-disease activity, and
methods of use as pharmaceutical compositions in the treatment of
disease.
Compounds
[0068] In the methods, according to embodiments of the invention,
the Lipid-conjugates administered to the subject are comprised from
at least one lipid moiety covalently bound through an atom of the
polar head group to a monomer or polymeric moiety (referred to
herein as the conjugated moiety) of either low or high molecular
weight. When desired, an optional bridging moiety can be used to
link the Lipid-conjugates moiety to the monomer or polymeric
moiety. The conjugated moiety may be a low molecular weight
carboxylic acid, dicarboxylic acid, fatty acid, dicarboxylic fatty
acid, acetyl salicylic acid, cholic acid, cholesterylhemisuccinate,
or mono- or di-saccharide, an amino acid or dipeptide, an
oligopeptide, a glycoprotein mixture, a di- or trisaccharide
monomer unit of a glycosaminoglycan such as a repeating unit of
heparin, heparan sulfate, hyaluronic acid, chondrotin-sulfate,
dermatan, keratan sulfate, or a higher molecular weight peptide or
oligopeptide, a polysaccharide, polyglycan, protein,
glycosaminoglycan, or a glycoprotein mixture. From a composition
aspect, phospholipid-conjugates of high molecular weight, and
associated analogues, are the subject of U.S. Pat. No. 5,064,817,
as well as the publications cited herein.
[0069] In one embodiment of the invention, when the conjugated
carrier moiety is a polymer, the ratio of lipid moieties covalently
bound may range from one to one thousand lipid residues per polymer
molecule, depending upon the nature of the polymer and the reaction
conditions employed. For example, the relative quantities of the
starting materials, or the extent of the reaction time, may be
modified in order to obtain Lipid-conjugate products with either
high or low ratios of lipid residues per polymer, as desired.
[0070] The term "moiety" means a chemical entity otherwise
corresponding to a chemical compound, which has a valence satisfied
by a covalent bond.
[0071] Examples of polymers which can be employed as the conjugated
moiety for producing Lipid-conjugates for use in the methods of
this invention may be physiologically acceptable polymers,
including water-dispersible or -soluble polymers of various
molecular weights and diverse chemical types, mainly natural and
synthestic polymers, such as glycosaminoglycans, hyaluronic acid,
heparin, heparin sulfate, chondrotin sulfate, chondrotin-6-sulfate,
chondroitin-4-sulfate, keratin sulfate, dermatin, sulfate, plasma
expanders, including polygeline ("Haemaccel", degraded gelatin
polypeptide crosslinked via urea bridges, produced by "Behring"),
"hydroxyethylstarch" (Htastarch, HES) and extrans, food and drug
additives, soluble cellulose derivatives (e.g., methylcellulose,
carboxymethylcellulose), polyaminoacids, hydrocarbon polymers
(e.g., polyethylene), polystyrenes, polyesters, polyamides,
polyethylene oxides (e.g., polyethyleneglycols,
polycarboxyethyleneglycol), polyvinnylpyrrolidones,
polysaccharides, alginates, assimilable gums (e.g., xanthan gum),
peptides, injectable blood proteins (e.g., serum albumin),
cyclodextrin, and derivatives thereof.
[0072] Examples of monomers, dimers, and oligomers which can be
employed as the conjugated moiety for producing Lipid-conjugates
for use in the methods of the invention may be mono- or
disaccharides, carboxylic acid, dicarboxylic acid, fatty acid,
dicarboxylic fatty acid, acetyl salicylic acid, cholic acid,
cholesterylhemisuccinate, and di- and trisaccharide unit monomers
of glycosaminoglycans including heparin, heparan sulfate,
hyaluronic acid, chondrotin, chondroitin-6-sulfate,
chondroitin-4-sulfate, dermatin, dermatan sulfate, keratin, keratan
sulfate, or dextran.
[0073] In some cases, according to embodiments of the invention,
the monomer or polymer chosen for preparation of the
Lipid-conjugate may in itself have select biological properties.
For example, both heparin and hyaluronic acid are materials with
known physiological functions. In the present invention, however,
the Lipid-conjugates formed from these substances as starting
materials display a new and wider set of pharmaceutical activities
than would be predicted from administration of either heparin or
hyaluronic acid which have not been bound by covalent linkage to a
phospholipid. It can be shown, by standard comparative experiments
as described below, that phosphatidylethanolamine (PE) linked to
carboxymethylcellulose (referred to as CMPE, CMC-Peor CME), to
hyaluronic acid (referred to as HYPE, HyPE, and Hyal-PE), to
heparin (referred to as HEPPE, HepPE, HePPE, Hepa-PE), to
chondroitine sulfate A (referred to as CSAPE, CsaPE, CsAPE), to
Polygeline (haemaccel) (referred to HemPE, HEMPE), or to
hydroxyethylstarch (referred to as HesPE, HESPE), are far superior
in terms of potency and range of useful pharmaceutical activity to
the free conjugates (the polymers above and the like). In fact,
these latter substances are, in general, not considered useful in
methods for treatment of most of the diseases described herein, and
for those particular cases wherein their use is medically
prescribed, such as ischemic vascular disease, the concentrations
for their use as drugs are are several orders of magnitude higher.
Thus, the combination of a phospholipid such as
phosphatidylethanolamine, or related phospholipids which differ
with regard to the polar head group, such as phosphatidylserine
(PS), phosphatidylcholine (PC), phosphatidylinositol (PI), and
phosphatidylglycerol (PG), results in the formation of a compound
which has novel pharmacological properties when compared to the
starting materials alone.
[0074] The biologically active lipid conjugates described herein
can have a wide range of molecular weight, e.g., above 50,000 (up
to a few hundred thousands) when it is desirable to retain the
Lipid conjugate in the vascular system and below 50,000 when
targeting to extravascular systems is desirable. The sole
limitation on the molecular weight and the chemical structure of
the conjugated moiety is that it does not result in a
Lipid-conjugate devoid of the desired biological activity, or lead
to chemical or physiological instability to the extent that the
Lipid-conjugate is rendered useless as a drug in the method of use
described herein.
[0075] In one embodiment, the compound according to the invention
is represented by the structure of the general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer, wherein X is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between L, Z, Y and X is either an amide
or an esteric bond.
[0076] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(I):
##STR00001##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; and X is either a physiologically acceptable
monomer, dimer, oligomer or a physiologically acceptable polymer,
wherein X is a glycosaminoglycan; and n is a number from 1 to
1,000; wherein if Y is nothing the phosphatidylethanolamine is
directly linked to X via an amide bond and if Y is a spacer, the
spacer is directly linked to X via an amide or an esteric bond and
to the phosphatidylethanolamine via an amide bond.
[0077] Preferred compounds for use in the methods of the invention
comprise one of the following as the conjugated moiety X: acetate,
butyrate, glutarate, succinate, dodecanoate, didodecanoate,
maltose, lactobionic acid, dextran, alginate, aspirin, cholate,
cholesterylhemisuccinate, carboxymethyl-cellulose, heparin,
hyaluronic acid, polygeline (haemaccel), polyethyleneglycol, and
polycarboxylated polyethylene glycol. The polymers used as starting
material to prepare the PE-conjugates may vary in molecular weight
from 1 to 2,000 kDa.
[0078] Examples of phosphatidylethanolamine (PE) moieties are
analogues of the phospholipid in which the chain length of the two
fatty acid groups attached to the glycerol backbone of the
phospholipid varies from 2-30 carbon atoms length, and in which
these fatty acids chains contain saturated and/or unsaturated
carbon atoms. In lieu of fatty acid chains, alkyl chains attached
directly or via an ether linkage to the glycerol backbone of the
phospholipid are included as analogues of PE. According to the
present invention, a most preferred PE moiety is
dipalmitoylphosphatidy-ethanolamine.
[0079] Phosphatidyl-ethanolamine and its analogues may be from
various sources, including natural, synthetic, and semisynthetic
derivatives and their isomers.
[0080] Phospholipids which can be employed in lieu of the PE moiety
are N-methyl-PE derivatives and their analogues, linked through the
amino group of the N-methyl-PE by a covalent bond; N,N-dimethyl-PE
derivatives and their analogues linked through the amino group of
the N,N-dimethyl-PE by a covalent bond, phosphatidylserine (PS) and
its analogues, such as palmitoyl-stearoyl-PS, natural PS from
various sources, semisynthetic PSs, synthetic, natural and
artifactual PSs and their isomers. Other phospholipids useful as
conjugated moieties in this invention are phosphatidylcholine (PC),
phosphatidylinositol (PI), phosphatidic acid and
phosphoatidylglycerol (PG), as well as derivatives thereof
comprising either phospholipids, lysophospholipids, phosphatidyic
acid, sphingomyelins, lysosphingomyelins, ceramide, and
sphingosine.
[0081] For PE-conjugates and PS-conjugates, the phospholipid is
linked to the conjugated monomer or polymer moiety through the
nitrogen atom of the phospholipid polar head group, either directly
or via a spacer group. For PC, PI, and PG conjugates, the
phospholipid is linked to the conjugated monomer or polymer moiety
through either the nitrogen or one of the oxygen atoms of the polar
head group, either directly or via a spacer group.
[0082] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(II):
##STR00002##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is a physiologically acceptable monomer, dimer,
oligomer or polymer wherein x is a glycosaminoglycan; and n is a
number from 1 to 1000; wherein if Y is nothing the
phosphatidylserine is directly linked to X via an amide bond and if
Y is a spacer, the spacer is directly linked to X via an amide or
an esteric bond and to the phosphatidylserine via an amide
bond.
[0083] In another embodiment, the compound according to the
invention be [phosphatidylserine-Y]n--X, wherein Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms, X
is a physiologically acceptable monomer, dimer, oligomer or polymer
wherein x is a glycosaminoglycan, and n is a number from 1 to 1000,
wherein the phosphatidylserine may be bonded to Y or to X, if Y is
nothing, via the COO.sup.- moiety of the phosphatidylserine.
[0084] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(III):
##STR00003##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phosphatidyl, Z, Y and
X is either an amide or anesteric bond.
[0085] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(IV)
##STR00004##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond.
[0086] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(V):
##STR00005##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond.
[0087] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(VI):
##STR00006##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond.
[0088] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(VII):
##STR00007##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond.
[0089] In one embodiment of the invention, phosphatidylcholine
(PC), Phosphatidylinositol (PI), phosphatidic acid (PA), wherein Z
is nothing, and Phosphatidylglycerol (PG) conjugates are herein
defined as compounds of the general formula (III).
[0090] In one embodiment of the invention Y is nothing. Non
limiting examples of suitable divalent groups forming the optional
bridging group (spacer) Y, according to embodiments of the
invention, are straight or branched chain alkylene, e.g., of 2 or
more, preferably 4 to 30 carbon atoms, --CO-alkylene-CO,
--NH-alkylene--NH--, --CO-alkylene--NH--,
--NH-alkylene--NHCO-alkylene--NH--, an amino acid, cycloalkylene,
wherein alkylene in each instance, is straight or branched chain
and contains 2 or more, preferably 2 to 30 atoms in the chain,
--(--O--CH(CH.sub.3)CH.sub.2--).sub.x-- wherein x is an integer of
1 or more.
[0091] According to embodiments of the invention, in addition to
the traditional phospholipid structure, related derivatives for use
in this invention are phospholipids modified at the C1 or C2
position to contain an ether or alkyl bond instead of an ester
bond. In one embodiment of the invention, the alkyl phospholipid
derivatives and ether phospholipid derivatives are exemplified
herein.
[0092] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(VIII):
##STR00008##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the phospholipid, Z, Y and X is
either an amide or an esteric bond.
[0093] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(IX):
##STR00009##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phospholipid, Z, Y and
X is either an amide or an esteric bond.
[0094] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(IXa):
##STR00010##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phospholipid, Z, Y and
X is either an amide or an esteric bond.
[0095] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(IXb):
##STR00011##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phospholipid, Z, Y and
X is either an amide or an esteric bond.
[0096] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(X):
##STR00012##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the ceramide phosphoryl, Z, Y and
X is either an amide or an esteric bond.
[0097] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XI):
##STR00013##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is a physiologically acceptable monomer, dimer,
oligomer or polymer, wherein x is a glycosaminoglycan; and n is a
number from 1 to 1000; wherein if Y is nothing the sphingosyl is
directly linked to X via an amide bond and if Y is a spacer, the
spacer is directly linked to X and to the sphingosyl via an amide
bond and to X via an amide or an esteric bond.
[0098] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XII):
##STR00014##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; L is ceramide; Z is either nothing, ethanolamine, serine,
inositol, choline, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the ceramide, Z, Y and X is either an amide or an
esteric bond.
[0099] In another embodiment, the compound according to the
invention is represented by the is structure of the general formula
(XIII):
##STR00015##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, choline, phosphate, inositol, or
glycerol; Y is either nothing or a spacer group ranging in length
from 2 to 30 atoms; X is a physiologically acceptable monomer,
dimer, oligomer or polymer, wherein x is a glycosaminoglycan; and n
is a number from 1 to 1000; wherein any bond between the
diglyceryl, Z, Y and X is either an amide or an esteric bond.
[0100] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XIV):
##STR00016##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the glycerolipid, Z, Y and X is either an amide or an
esteric bond.
[0101] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XV):
##STR00017##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the glycerolipid, Z, Y and X is either an amide or an
esteric bond.
[0102] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XVI):
##STR00018##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the lipid, Z, Y and X is either an amide or an esteric
bond.
[0103] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XVII):
##STR00019##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the lipid, Z, Y and X is either an amide or an esteric
bond.
[0104] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XVIII):
##STR00020##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond.
[0105] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XIX):
##STR00021##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond.
[0106] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XX):
##STR00022##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond.
[0107] In another embodiment, the compound according to the
invention is represented by the structure of the general formula
(XXI):
##STR00023##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond.
[0108] In one embodiment of the invention, the glycosaminoglycan
may be, inter alia, hyaluronic acid, heparin, heparan sulfate,
chondrotin sulfate, keratin, keratan sulfate, dermatan sulfate or a
derivative thereof.
[0109] In another embodiment, the glycosaminoglycan is di- and
trisaccharide unit monomers of glycosaminoglycans. In another
embodiment, the chondroitin sulfate may be, inter alia,
chondroitin-6-sulfate, chondroitin-4-sulfate or a derivative
thereof
[0110] In one embodiment of the invention, the sugar rings of the
glycosaminoglycan are intact.
[0111] In another embodiment, intact refers to closed. In another
embodiment, intact refers to natural. In another embodiment, intact
refers to unbroken.
[0112] In one embodiment of the invention, the structure of the
lipid or phospholipids in any compound according to the invention
is intact. In another embodiment, the natural structure of the
lipid or phospholipids in any compound according to the invention
is maintained.
[0113] In one embodiment, the compounds according to the invention
are biodegradable.
[0114] In one embodiment, the compound according to the invention
is a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is phosphatidyl; Z is ethanolamine, wherein L and Z are
chemically bonded resulting in phosphatidylethanolamine; Y is
nothing; X is hyaluronic acid; and n is a number from 1 to 1000;
wherein any bond between the phosphatidylethanolamine and the
hyaluronic acid is an amide bond.
[0115] In one embodiment, the compound according to the invention
is a compound represented by the structure of the general formula
(A):
[L-Z--Y .sub.nX (A)
wherein L is phosphatidyl; Z is ethanolamine, wherein L and Z are
chemically bonded resulting in phosphatidylethanolamine; Y is
nothing; X is chondroitin sulfate; and n is a number from 1 to
1000; wherein any bond between the phosphatidylethanolamine and the
chondroitin sulfate is an amide bond.
[0116] In another embodiment, the invention provides a method of
treating a subject suffering from asthma, comprising the step of
administering to a subject any one of the compounds according to
the invention, or any combination thereof, in an amount effective
to treat the subject suffering from asthma. In another embodiment,
the compounds according to the invention include, inter alia, the
compounds represented by the structures of the general formulae:
(A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IXa),
(IXb), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), (XX), (XXI), (XXII) or any combination thereof. In
another embodiment, the invention provides a method of preventing
asthma in a subject.
[0117] In another embodiment, the invention provides a method of
treating a subject suffering from rhinitis, comprising the step of
administering to a subject any one of the compounds according to
the invention, or any combination thereof, in an amount effective
to treat the subject suffering from rhinitis. In another
embodiment, the compounds according to the invention include, inter
alia, the compounds represented by the structures of the general
formulae: (A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII),
(IX), (IXa), (IXb), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI),
(XVII), (XVIII), (XIX), (XX), (XXI), (XXII) or any combination
thereof. In another embodiment, the invention provides a method of
preventing rhinitis in a subject.
[0118] In another embodiment, the invention provides a method of
treating a subject suffering from allergic rhinitis, comprising the
step of administering to a subject any one of the compounds
according to the invention, or any combination thereof, in an
amount effective to treat the subject suffering from allergic
rhinitis. In another embodiment, the compounds according to the
invention include, inter alia, the compounds represented by the
structures of the general formulae: (A), (I), (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX), (IXa), (IXb), (X), (XI), (XII),
(XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI),
(XXII) or any combination thereof. In another embodiment, the
invention provides a method of preventing allergic rhinitis in a
subject.
[0119] In another embodiment, the invention provides a method of
treating a subject suffering from chronic obstructive pulmonary
disease, comprising the step of administering to a subject any one
of the compounds according to the invention, or any combination
thereof, in an amount effective to treat the subject suffering from
chronic obstructive pulmonary disease. In another embodiment, the
compounds according to the invention include, inter alia, the
compounds represented by the structures of the general formulae:
(A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IXa),
(IXb), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), (XX), (XXI), (XXII) or any combination thereof. In
another embodiment, the invention provides a method of preventing
chronic obstructive pulmonary disease in a subject.
[0120] In another embodiment, the invention provides a method of
treating a subject suffering from an obstructive respiratory
disease, comprising the step of administering to a subject any one
of the compounds according to the invention, or any combination
thereof, in an amount effective to treat the subject suffering from
an obstructive respiratory disease. In another embodiment, the
compounds according to the invention include, inter alia, the
compounds represented by the structures of the general formulae:
(A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (IXa),
(IXb), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),
(XVIII), (XIX), (XX), (XXI), (XXII) or any combination thereof. In
another embodiment, the obstructive respiratory disease is asthma.
In another embodiment, the obstructive respiratory disease is
rhinitis. In another embodiment, the obstructive respiratory
disease is allergic rhinitis. In another embodiment, the
obstructive respiratory disease is chronic obstructive pulmonary
disease. In another embodiment, the invention provides a method of
preventing asthma, rhinitis, allergic rhinitis, chronic obstructive
pulmonary disease, obstructive respiratory disease, or a
combination thereof, in a subject.
[0121] Illustrative of preferred Lipid-conjugates for use in the
methods according to embodiments of this invention are those in
which the lipid/phospholipid moiety is linked directly or
indirectly through a bridging moiety listed below.
TABLE-US-00001 phospho- lipid spacer polymer (m.w.) abbreviation PE
Dicarboxylic Polygeline (haemaccel) HeMPE; HemPE acid + (4-40 kDa)
Diamine PE None Carboxymethylcellulose CMPE; CMC- (20-500 kDa) PE
PE None Hyaluronic acid HYPE (HyPE) (2-2000 kDa) PE Dipalmitoic
Hyaluronic acid HYPE- acid (2-2000 kDa) dipalmitoyl PE None
Polyethylene glycol PE Y Hydroxyethylstarch HESPE; HesPE PE
Dicarboxylic Dextran DexPE acid + (1-2,000 kDa) Diamine PE None
Dextran DexPE (1-2,000 kDa) PE None Albumin PE None Alginate
(2-2000 kDa) PE None Polyaminoacid PE None Lactobionic acid PE None
Acetylsalicylate PE None Cholesteryl- hemmisuccinate PE None
Maltose PE Y None Cholic acid PE None Polycarboxylated polyethylene
glycol PE None Heparin HEPPE; HEPE; (0.5-110 kDa) HepPE
Dimyristoyl- Y Variable DMPE PE Dimyristoyl- Y Hyaluronic acid
HyDMPE PE PS Y Polygeline (haemaccel) PS Y Heparin PS Y Hyaluronic
acid PC Y Polygeline (haemaccel) PC Y Heparin PC Y Hyaluronic acid
PI Y Polygeline (haemaccel) PI Y Heparin PI Y Hyaluronic acid PG Y
Polygeline (haemaccel) PG Y Heparin PE Y Chondoitin sulfates CSPE
PE Y Polygeline (haemaccel) PG Y Hyaluronic acid
[0122] In one embodiment of the invention, the compounds
administered are HyPE, CSAPE, CMPE, HemPE, HesPE, DexPE and As-PE
and pharmaceutically acceptable salts thereof, in combination with
a physiologically acceptable carrier or solvent. These polymers,
when chosen as the conjugated moiety, may vary in molecular weights
from 200 to 2,000,000 Daltons. Various molecular weight species
have been shown to have the desired biological efficacy, as shown
in the section below.
[0123] In addition to the compounds of the Examples, further
illustrative compounds of this invention are set forth in the
section below.
Novel Compounds
[0124] Low molecular weight Lipid-conjugates, in which the
conjugated moiety (X) is a monomer such as a salicylate, a bile
acid, or cholesterylhemmisuccinate, or a di- or trisaccaharide unit
monomer of a polyglycosoaminoglycan such as heparin, heparan
sulfate, chondrotin-6-sulfate, chondroitin-4-sulfate, hyaluronic
acid, keratin, keratan sulfate, dermatin, or dermatan sulfate, have
not been described before. According to embodiments of the
invention, these new compounds display a similar biological
activity profile as demonstrated below for the other
Lipid-conjugates and have the general formula
[Phosphatidylethanolamine-Y].sub.n--X
[Phosphatidylserine-Y].sub.n--X
[Phosphatidylcholine-Y].sub.n--X
[Phosphatidylinositol-Y].sub.n--X
[Phosphatidylglycerol-Y].sub.n--X
[Phosphatidic acid-Y].sub.n--X
[lyso-phospholipid-Y].sub.n--X
[diacyl-glycerol-Y].sub.n--X
[monoacyl-glycerol-Y].sub.n--X
[sphingomyelin-Y].sub.n--X
[sphingosine-Y].sub.n--X
[ceramide-Y].sub.n--X
wherein Y is either nothing or a spacer group ranging in length
from 2 to 30 atoms; X is a mono- or disaccharide, carboxylated
disaccharide, mono- or dicarboxylic acids, a salicylate, salicylic
acid, aspirin, lactobionic acid, maltose, an amino acid, glycine,
acetic acid, butyric acid, dicarboxylic acid, glutaric acid,
succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile
acid, cholic acid, cholesterylhemmisuccinate, a di- or tripeptide,
an oligopeptide, a trisacharide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin,
dermatan sulfate, dextran, hyaluronic acid or glycosaminoglycan;
and n is the number of lipid moiety molecules bound to a molecule
of X wherein n is a number from 1 to 100. In another embodiment,
the glycosaminoglycan is a polymer (X) of disaccharide units. In
another embodiment, the number of the disaccharide units in the
polymer is m. In another embodiment, m is a number from 2-10,000.
In another embodiment, m is a number from 2-500. In another
embodiment, m is a number from 2-1000. In another embodiment, m is
a number from 50-500. In another embodiment, m is a number from
2-2000. In another embodiment, m is a number from 500-2000. In
another embodiment, m is a number from 1000-2000. In another
embodiment, m is a number from 2000-5000. In another embodiment, m
is a number from 3000-7000. In another embodiment, m is a number
from 5000-10,000. In another embodiment, a disaccharide unit of a
glycosaminoglycan may be bound to one lipid or phospholipid moiety.
In another embodiment, each disaccharide unit of the
glycosaminoglycan may be bound to zero or one lipid or phospholipid
moieties. In another embodiment, the lipid or phospholipid moieties
are bound to the --COOH group of the disaccharide unit. In another
embodiment, the bond between the lipid or phospholipid moiety and
the disaccharide unit is an amide bond.
[0125] In one embodiment, this invention provides lipid-GAG
conjugate or phospholipid-GAG conjugate of this invention, and
methods of use thereof, wherein said conjugate represented by the
structures of the general formulae (A), (I), (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX), (IXa), (IXb), (X), (Xa), (XI),
(XII), (XIIa), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX),
(XX), (XXI), and (XXII). In another embodiment, the average
molecular weight of said GAG is between 5 kD to 90 kD. In another
embodiment, the average molecular weight of said GAG is between 5
kD to 60 kD. In another embodiment, the average molecular weight of
said GAG is between 5 kD to 40 kD. In another embodiment, the
average molecular weight of said GAG is between 5 kD to 15 kD. In
another embodiment, the average molecular weight of said GAG is
between 5 kD to 20 kD. In another embodiment, the lipid-GAG
conjugate is a phospholipid-GAG conjugate
[0126] In one embodiment of this invention, low molecular weight
phosphatidylethanolamine (PE)-conjugates are defined hereinabove as
the compounds of formula (I) wherein:
R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is a mono- or disaccharide, carboxylated
disaccharide, mono- or dicarboxylic acids, a salicylate, salicylic
acid, aspirin, lactobionic acid, maltose, an amino acid, glycine,
acetic acid, butyric acid, dicarboxylic acid, glutaric acid,
succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile
acid, cholic acid, cholesterylhemmisuccinate, a di- or tripeptide,
an oligopeptide, a trisacharide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin,
dermatan sulfate, dextran, hyaluronic acid or glycosaminoglycan;
and n is the number of lipid moity molecules bound to a molecule of
X wherein n is a number from 1 to 1000.
[0127] In another embodiment, the molecular weight of said
glycosaminoglycan is between 5 kD and 20 kD. In another embodiment,
n is a number between 1 to 100. In another embodiment, said
glycosaminoglycan is between 5 kD and 20 kD and n is between 1 to
100.
[0128] In one embodiment of this invention, low molecular weight
phosphatidylserine (PS)-conjugates are defined hereinabove as the
compounds of formula (II) wherein:
R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is a mono- or disaccharide, carboxylated
disaccharide, mono- or dicarboxylic acids, a salicylate, salicylic
acid, aspirin, lactobionic acid, maltose, an amino acid, glycine,
acetic acid, butyric acid, dicarboxylic acid, glutaric acid,
succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile
acid, cholic acid, cholesterylhemmisuccinate, a di- or tripeptide,
an oligopeptide, a trisaccharide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin,
dermatan sulfate, dextran, hyaluronic acid or glycosaminoglycan;
and n is the number of lipid moiety molecules bound to a molecule
of X wherein n is a number from 1 to 1000.
[0129] In another embodiment, the molecular weight of said
glycosaminoglycan is between 5 kD and 20 kD. In another embodiment,
n is a number between 1 to 100. In another embodiment, said
glycosaminoglycan is between 5 kD and 20 kD and n is between 1 to
100.
[0130] In one embodiment of this invention, Phosphatidylcholine
(PC), Phosphatidylinositol (PI), and Phosphatidylglycerol (PG)
conjugates are hereinabove defined as the compounds of formula
(III) wherein:
R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a mono- or disaccharide, carboxylated disaccharide,
mono- or dicarboxylic acids, a salicylate, salicylic acid, aspirin,
lactobionic acid, maltose, an amino acid, glycine, acetic acid,
butyric acid, dicarboxylic acid, glutaric acid, succinic acid,
fatty acid, dodecanoic acid, didodecanoic acid, bile acid, cholic
acid, cholesterylhemmisuccinate, a di- or tripeptide, an
oligopeptide, a trisaccharide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin,
dermatan sulfate, dextran, hyaluronic acid or glycosaminoglycan;
and n is the number of lipid moiety molecules bound to a molecule
of X wherein n is a number from 1 to 1000.
[0131] In another embodiment, the molecular weight of said
glycosaminoglycan is between 5 kD and 20 kD. In another embodiment,
n is a number between 1 to 100. In another embodiment, said
glycosaminoglycan is between 5 kD and 20 kD and n is between 1 to
100.
[0132] Examples of suitable divalent groups forming the optional
bridging group Y are straight- or branched-chain alkylene, e.g., of
2 or more, preferably 4 to 18 carbon atoms, --CO-alkylene-CO,
--NH-alkylene--NH--, --CO-alkylene--NH--, cycloalkylene, wherein
alkylene in each instance, is straight or branched chain and
contains 2 or more, preferably 2 to 18 carbon atoms in the chain,
--(--O--CH(CH.sub.3)CH.sub.2--).sub.x-- wherein x is an integer of
1 or more.
[0133] In another embodiment, in addition to the traditional
phospholipid structure, related derivatives for use in this
invention are phospholipids modified at the C1 or C2 position to
contain an ether or alkyl bond instead of an ester bond. These
derivatives are exemplified hereinabove by the general formulae
(VIII) and (IX) wherein:
R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, ethanolamine, serine, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a mono- or disaccharide,
carboxylated disaccharide, mono- or dicarboxylic acids, a
salicylate, salicylic acid, aspirin, lactobionic acid, maltose, an
amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid,
glutaric acid, succinic acid, fatty acid, dodecanoic acid,
didodecanoic acid, bile acid, cholic acid,
cholesterylhemmisuccinate, a di- or tripeptide, an oligopeptide, a
trisaccharide, or a di- or trisaccharide monomer unit of heparin,
heparan sulfate, keratin, keratan sulfate, chondroitin,
chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin, dermatan
sulfate, dextran, hyaluronic acid or glycosaminoglycan; and n is
the number of lipid moity molecules bound to a molecule of X
wherein n is a number from 1 to 1000.
[0134] In another embodiment, the molecular weight of said
glycosaminoglycan is between 5 kD and 20 kD. In another embodiment,
n is a number between 1 to 100. In another embodiment, said
glycosaminoglycan is between 5 kD and 20 kD and n is between 1 to
100.
[0135] In another embodiment, related low molecular weight
derivatives for use in this invention are exemplified hereinabove
by the general formulae (X), (XI) and (XII) wherein:
R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, ethanolamine, serine, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a mono- or disaccharide,
carboxylated disaccharide, mono- or dicarboxylic acids, a
salicylate, salicylic acid, aspirin, lactobionic acid, maltose, an
amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid,
glutaric acid, succinic acid, fatty acid, dodecanoic acid, is
didodecanoic acid, bile acid, cholic acid,
cholesterylhemmisuccinate, a di- or tripeptide, an oligopeptide, a
trisaccharide, or a di- or trisaccharide monomer unit of heparin,
heparan sulfate, keratin, keratan sulfate, chondroitin,
chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin, dermatan
sulfate, dextran, hyaluronic acid or glycosaminoglycan; and n is
the number of lipid moiety molecules bound to a molecule of X
wherein n is a number from 1 to 1000.
[0136] In another embodiment, the molecular weight of said
glycosaminoglycan is between 5 kD and 20 kD. In another embodiment,
n is a number between 1 to 100. In another embodiment, said
glycosaminoglycan is between 5 kD and 20 kD and n is between 1 to
100.
[0137] In another embodiment, related low molecular weight
derivatives for use in this invention are exemplified hereinabove
by the general formulae (XIII) wherein:
R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, choline, phosphate, inositol, or
glycerol; Y is either nothing or a spacer group ranging in length
from 2 to 30 atoms; X is a mono- or disaccharide, carboxylated
disaccharide, mono- or dicarboxylic acids, a salicylate, salicylic
acid, aspirin, lactobionic acid, maltose, an amino acid, glycine,
acetic acid, butyric acid, dicarboxylic acid, glutaric acid,
succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile
acid, cholic acid, cholesterylhemmisuccinate, a di- or tripeptide,
an oligopeptide, a trisaccharide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin,
dermatan sulfate, dextran, hyaluronic acid or glycosaminoglycan;
and n is the number of lipid moiety molecules bound to a molecule
of X wherein n is a number from 1 to 1000.
[0138] In another embodiment, the molecular weight of said
glycosaminoglycan is between 5 kD and 20 kD. In another embodiment,
n is a number between 1 to 100. In another embodiment, said
glycosaminoglycan is between 5 kD and 20 kD and n is between 1 to
100.
[0139] In another embodiment, related low molecular weight
derivatives according to the invention may be exemplified herein by
any of the general formulae (A), (I)-(XXI) wherein:
[0140] In one embodiment of the invention, X is covalently
conjugated to a lipid. In another embodiment, x is covalently
conjugated to a lipid via an amide bond. In another embodiment, x
is covalently conjugated to a lipid via an esteric bond. In another
embodiment, the lipid is phosphatidylethanolamine. In another
embodiment, the GAG may be, inter alia, chondroitin sulfate. In
another embodiment, the conjugate is biodegradable. In another
embodiment, the glycosaminoglycan is between 5 kD and 20 kD.
[0141] In one embodiment, the invention provides glycosaminoglycans
(GAG) compound covalently conjugated to a lipid to obtain a
compound having preferred therapeutic properties. In another
embodiment, the GAG compound is covalently conjugated to a lipid
via an amide bond. In another embodiment, the GAG compound is
covalently conjugated to a lipid via an esteric bond. In another
embodiment, the lipid may be, inter alia, phosphatidylethanolamine.
In another embodiment, the GAG may be, inter alia, chondroitin
sulfate. In another embodiment, the conjugate is biodegradable. In
another embodiment, the glycosaminoglycan is between 5 kD and 20
kD.
[0142] In one embodiment, this invention is directed to low
molecular weight lipid-polymer conjugate comprising a GAG wherein
the average molecular weight of said GAG is between 5 kd to 90 kd.
In another embodiment, the average molecular weight of said GAG is
between 5 kD to 60 kD. In another embodiment, the average molecular
weight of said GAG is between 5 kD to 40 kD. In another embodiment,
the average molecular weight of said GAG is between 5 kD to 15 kD.
In another embodiment, the average molecular weight of said GAG is
between 5 kD to 20 kD. In another embodiment, the average molecular
weight of said GAG is between 5 kD to 25 kD.
[0143] Cell surface GAG play a key role in protecting cells from
diverse damaging agents and processes, such as reactive oxygen
species and free radicals, endotoxins, cytokines, invasion
promoting enzymes, and agents that induce and/or facilitate
degradation of extracellular matrix and basal membrane, cell
invasiveness, white cell extravasation and infiltration,
chemotaxis, and others. In addition, cell surface GAG protect cells
from bacterial, viral and parasite infection, and their stripping
exposes the cell to interaction and subsequent internalization of
the microorganism. Enrichment of cell surface GAG would thus assist
in protection of the cell from injurious processes. Thus, In one
embodiment of the invention, PLA2 inhibitos were conjugated to GAGs
or GAG-mimicking molecules. In another embodiment, these
Lipid-conjugates, provides wide-range protection from diverse
injurious processes, and are effective in amelioration of diseases
that requires cell protection from injurous biochemical
medistors.
[0144] In another embodiment, GAG-mimicking molecule may be, inter
alia, a negatively charged molecule. In another embodiment,
GAG-mimicking molecule may be, inter alia, a salicilate derivative.
In another embodiment, GAG-mimicking molecule may be, inter alia, a
dicarboxylic acid.
Preparation of Compounds
[0145] The preparation of some high molecular weight
Lipid-conjugates is the subject of U.S. Pat. No. 5,064,817, which
is incorporated herein by reference. These synthetic methods are
reiterated below and are considered to be applicable as well to the
preparation of low molecular, i.e. Lipid-conjugates comprising
monomers and dimers as the conjugated moiety, with modifications in
the procedure as readily evident to one skilled in the art.
[0146] When the starting compound chosen for the conjugated moiety
has a substituent which is or can be rendered reactive to a
substituent on the starting Lipid compound, the conjugated carrier
moiety may be linked directly to lipid molecule(s) to produce the a
Lipid-conjugate. When it does not, a bifunctional linking starting
material can be used to link the two molecules indirectly.
[0147] Lipid-conjugates are prepared by linking a polar conjugate,
e.g., a monomer or polymer, directly or indirectly to a PL moiety
according to the general reaction schemes delineated in U.S. Pat.
No. 5,064,817 and according to US Publication 2011-0130555.
[0148] For example, with acylated PE used as precursor for the PE
conjugate, various lengths of dicarboxylic acids can be used as
spacers. These acids can be linked to natural, semi-synthetic or
synthetic PE.
[0149] For example, PE can be linked to aminodextran indirectly as
delineated in U.S. Pat. No. 5,064,817 and US Publication
2011-0130555.
[0150] Polymers with carboxylic groups, such as polyamino acids,
carboxymethyl cellulose or polymers to which fatty acids have been
linked, can be linked directly to PE according to the scheme
delineated in U.S. Pat. No. 5,064,817.
[0151] It is to be understood that these examples are given by way
of illustration only and are not to be construed as limiting the
invention either in spirit of in scope, as many modifications both
in reagents and methods could be possible to those skilled in the
art. Based on the wide spectrum of pharmacological properties
exhibited by Lipid-conjugates, it is likely that compounds covered
by Formula I-XXI, in addition to those explicitly described above,
have the same valuable biological activities demonstrate to be
useful in the methods of treating disease described below.
[0152] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (A):
[L-Z--Y .sub.nX (A)
wherein L is a lipid or a phospholipid; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer, wherein X is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between L, Z, Y and X is either an amide
or an esteric bond, including, inter alia, the steps of:
conjugating L to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, L is conjugated directly to Y, if Y is nothing, Z
is conjugated directly to X, and if Y and Z are nothing, L is
conjugated directly to X, thereby preparing a compound represented
by the structure of the general formula (A).
[0153] In another embodiment, the invention provides a process for
the preparation of a compound represented by the structure of the
general formula (I):
##STR00024##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is either a physiologically acceptable monomer,
dimer, oligomer or a physiologically acceptable polymer, wherein X
is a glycosaminoglycan; and n is a number from 1 to 1,000; wherein
if Y is nothing the phosphatidylethanolamine is directly linked to
X via an amide bond and if Y is a spacer, the spacer is directly
linked to X via an amide or an esteric bond and to the
phosphatidylethanolamine via an amide bond, including, inter alia,
the steps of: conjugating the phosphatidylethanolamine to Y; and
conjugating Y to X; if Y is nothing, the phosphatidylethanolamine
is conjugated directly to X, thereby preparing a compound
represented by the structure of the general formula (I).
[0154] In one embodiment of the invention, the
phosphatidylethanolamine is the chemical moiety represented by the
structure of:
##STR00025##
wherein R.sub.1 and R.sub.2 are defined herein.
[0155] In another embodiment, the invention provides a process for
the preparation of a compound represented by the structure of the
general formula (II):
##STR00026##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is a physiologically acceptable monomer, dimer,
oligomer or polymer wherein x is a glycosaminoglycan; and n is a
number from 1 to 1000; wherein if Y is nothing the
phosphatidylserine is directly linked to X via an amide bond and if
Y is a spacer, the spacer is directly linked to X via an amide or
an esteric bond and to the phosphatidylserine via an amide bond,
including, inter alia, the steps of: conjugating the
phosphatidylserine to Y; conjugating Y to X; if Y is nothing, the
phosphatidylserine is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(II).
[0156] In one embodiment of the invention, the phosphatidylserine
is the chemical moiety represented by the structure of:
##STR00027##
wherein R.sub.1 and R.sub.2 are defined herein.
[0157] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (III):
##STR00028##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phosphatidyl, Z, Y and
X is either an amide or anesteric bond, including, inter alia, the
steps of: conjugating the phosphatidyl to Z; conjugating Z to Y;
conjugating Y to X; wherein if Z is nothing, the phosphatidyl is
conjugated directly to Y, if Y is nothing, Z is conjugated directly
to X, and if Y and Z are nothing, the phosphatidyl is conjugated
directly to X, thereby preparing a compound represented by the
structure of the general formula (III).
[0158] In one embodiment of the invention, the phosphatidyl may be
the chemical moiety represented by the structure of:
##STR00029##
wherein R.sub.1 and R.sub.2 are defined herein.
[0159] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (IV):
##STR00030##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
phospholipid to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, the phospholipid is conjugated directly to Y, if Y
is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the phospholipid is conjugated directly to X, thereby
preparing a compound represented by the structure of the general
formula (IV).
[0160] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00031##
wherein R.sub.1 and R.sub.2 are defined herein.
[0161] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (V):
##STR00032##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
phospholipid to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, the phospholipid is conjugated directly to Y, if Y
is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the phospholipid is conjugated directly to X, thereby
preparing a compound represented by the structure of the general
formula (V).
[0162] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00033##
wherein R.sub.1 and R.sub.2 are defined herein.
[0163] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (VI):
##STR00034##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
phospholipid to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, the phospholipid is conjugated directly to Y, if Y
is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the phospholipid is conjugated directly to X, thereby
preparing a compound represented by the structure of the general
formula (VI).
[0164] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00035##
wherein R.sub.1 and R.sub.2 are defined herein.
[0165] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (VII):
##STR00036##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, inositol,
choline, or glycerol; Y is either nothing or a spacer group ranging
in length from 2 to 30 atoms; X is a physiologically acceptable
monomer, dimer, oligomer, or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the phospholipid, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
phospholipid to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, the phospholipid is conjugated directly to Y, if Y
is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the phospholipid is conjugated directly to X, thereby
preparing a compound represented by the structure of the general
formula (VII).
[0166] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00037##
wherein R.sub.1 and R.sub.2 are defined herein.
[0167] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (VIII):
##STR00038##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing,
ethanolamine, serine, inositol, choline, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer, or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the phospholipid, Z, Y and X is
either an amide or an esteric bond, including, inter alia, the
steps of: conjugating the phospholipid to Z; conjugating Z to Y;
conjugating Y to X; wherein if Z is nothing, the phospholipid is
conjugated directly to Y, if Y is nothing, Z is conjugated directly
to X, and if Y and Z are nothing, the phospholipid is conjugated
directly to X, thereby preparing a compound represented by the
structure of the general formula (VIII).
[0168] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00039##
wherein R.sub.1 and R.sub.2 are defined herein.
[0169] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (IX):
##STR00040##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phospholipid, Z, Y and
X is either an amide or an esteric bond, including, inter alia, the
steps of: conjugating the phospholipid to Z; conjugating Z to Y;
conjugating Y to X; wherein if Z is nothing, the phospholipid is
conjugated directly to Y, if Y is nothing, Z is conjugated directly
to X, and if Y and Z are nothing, the phospholipid is conjugated
directly to X, thereby preparing a compound represented by the
structure of the general formula (IX).
[0170] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00041##
wherein R.sub.1 and R.sub.2 are defined herein.
[0171] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (IXa):
##STR00042##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phospholipid, Z, Y and
X is either an amide or an esteric bond, including, inter alia, the
steps of: conjugating the phospholipid to Z; conjugating Z to Y;
conjugating Y to X; wherein if Z is nothing, the phospholipid is
conjugated directly to Y, if Y is nothing, Z is conjugated directly
to X, and if Y and Z are nothing, the phospholipid is conjugated
directly to X, thereby preparing a compound represented by the
structure of the general formula (IXa).
[0172] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00043##
wherein R.sub.1 and R.sub.2 are defined herein.
[0173] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (IXb):
##STR00044##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, ethanolamine, serine, inositol, choline, or glycerol; Y is
either nothing or a spacer group ranging in length from 2 to 30
atoms; X is a physiologically acceptable monomer, dimer, oligomer,
or polymer, wherein x is a glycosaminoglycan; and n is a number
from 1 to 1000; wherein any bond between the phospholipid, Z, Y and
X is either an amide or an esteric bond, including, inter alia, the
steps of: conjugating the phospholipid to Z; conjugating Z to Y;
conjugating Y to X; wherein if Z is nothing, the phospholipid is
conjugated directly to Y, if Y is nothing, Z is conjugated directly
to X, and if Y and Z are nothing, the phospholipid is conjugated
directly to X, thereby preparing a compound represented by the
structure of the general formula (IXb).
[0174] In one embodiment of the invention, the phospholipid may be
the chemical moiety represented by the structure of:
##STR00045##
wherein R.sub.1 and R.sub.2 are defined herein.
[0175] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (X):
##STR00046##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing ethanolamine,
serine, inositol, choline, or glycerol; Y is either nothing or a
spacer group ranging in length from 2 to 30 atoms; X is a
physiologically acceptable monomer, dimer, oligomer, or polymer,
wherein x is a glycosaminoglycan; and n is a number from 1 to 1000;
wherein any bond between the ceramide phosphoryl, Z, Y and X is
either an amide or an esteric bond, including, inter alia, the
steps of: conjugating the ceramide phosphoryl to Z; conjugating Z
to Y; conjugating Y to X; wherein if Z is nothing, the ceramide
phosphoryl is conjugated directly to Y, if Y is nothing, Z is
conjugated directly to X, and if Y and Z are nothing, the ceramide
phosphoryl is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(X).
[0176] In one embodiment of the invention, the ceramide phosphoryl
may be the chemical moiety represented by the structure of:
##STR00047##
wherein R.sub.1 and R.sub.2 are defined herein.
[0177] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XI):
##STR00048##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Y is either nothing or a spacer group ranging in length from
2 to 30 atoms; X is a physiologically acceptable monomer, dimer,
oligomer or polymer, wherein x is a glycosaminoglycan; and n is a
number from 1 to 1000; wherein if Y is nothing the sphingosyl is
directly linked to X via an amide bond and if Y is a spacer, the
spacer is directly linked to X and to the sphingosyl via an amide
bond and to X via an amide or an esteric bond, including, inter
alia, the steps of: conjugating the sphingosyl to Y; conjugating Y
to X; wherein if Y is nothing, the sphingosyl is conjugated
directly to X, thereby preparing a compound represented by the
structure of the general formula (XI).
[0178] In one embodiment of the invention, the sphingosyl may be
the chemical moiety represented by the structure of:
##STR00049##
wherein R.sub.1 is defined herein.
[0179] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XII):
##STR00050##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; L is ceramide; Z is either nothing, ethanolamine, serine,
inositol, choline, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the ceramide, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
ceramide to Z; conjugating Z to Y; conjugating Y to X; wherein if Z
is nothing, the ceramide is conjugated directly to Y, if Y is
nothing, Z is conjugated directly to X, and if Y and Z are nothing,
the ceramide is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(XII).
[0180] In one embodiment of the invention, the ceramide may be the
chemical moiety represented by the structure of:
##STR00051##
wherein R.sub.1 and R.sub.2 are defined herein.
[0181] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XIII):
##STR00052##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; Z is either nothing, choline, phosphate, inositol, or
glycerol; Y is either nothing or a spacer group ranging in length
from 2 to 30 atoms; X is a physiologically acceptable monomer,
dimer, oligomer or polymer, wherein x is a glycosaminoglycan; and n
is a number from 1 to 1000; wherein any bond between the
diglyceryl, Z, Y and X is either an amide or an esteric bond,
including, inter alia, the steps of: conjugating the diglyceryl to
Z; conjugating Z to Y; conjugating Y to X; wherein if Z is nothing,
the diglyceryl is conjugated directly to Y, if Y is nothing, Z is
conjugated directly to X, and if Y and Z are nothing, the
diglyceryl is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(XIII).
[0182] In one embodiment of the invention, the diglyceryl may be
the chemical moiety represented by the structure of:
##STR00053##
wherein R.sub.1 and R.sub.2 are defined herein.
[0183] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XIV):
##STR00054##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the glycerolipid, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
glycerolipid to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, the glycerolipid is conjugated directly to Y, if Y
is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the glycerolipid is conjugated directly to X, thereby
preparing a compound represented by the structure of the general
formula (XIV).
[0184] In one embodiment of the invention, the glycerolipid may be
the chemical moiety represented by the structure of:
##STR00055##
wherein R.sub.1 and R.sub.2 are defined herein.
[0185] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XV):
##STR00056##
wherein R.sub.1 is a linear, saturated, mono-unsaturated, or
poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon
atoms; R.sub.2 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the glycerolipid, Z, Y and X is either an amide or an
esteric bond, including, inter alia, the steps of: conjugating the
glycerolipid to Z; conjugating Z to Y; conjugating Y to X; wherein
if Z is nothing, the glycerolipid is conjugated directly to Y, if Y
is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the glycerolipid is conjugated directly to X, thereby
preparing a compound represented by the structure of the general
formula (XV).
[0186] In one embodiment of the invention, the glycerolipid may be
the chemical moiety represented by the structure of:
##STR00057##
wherein R.sub.1 and R.sub.2 are defined herein.
[0187] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XVI):
##STR00058##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the lipid, Z, Y and X is either an amide or an esteric
bond, including, inter alia, the steps of: conjugating the lipid to
Z; conjugating Z to Y; conjugating Y to X; wherein if Z is nothing,
the lipid is conjugated directly to Y, if Y is nothing, Z is
conjugated directly to X, and if Y and Z are nothing, the lipid is
conjugated directly to X, thereby preparing a compound represented
by the structure of the general formula (XVI).
[0188] In one embodiment of the invention, the lipid may be the
chemical moiety represented by the structure of:
##STR00059##
wherein R.sub.1 and R.sub.2 are defined herein.
[0189] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XVII):
##STR00060##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; Z is either nothing, choline,
phosphate, inositol, or glycerol; Y is either nothing or a spacer
group ranging in length from 2 to 30 atoms; X is a physiologically
acceptable monomer, dimer, oligomer or polymer, wherein x is a
glycosaminoglycan; and n is a number from 1 to 1000; wherein any
bond between the lipid, Z, Y and X is either an amide or an esteric
bond, including, inter alia, the steps of: conjugating the lipid to
Z; conjugating Z to Y; conjugating Y to X; wherein if Z is nothing,
the lipid is conjugated directly to Y, if Y is nothing, Z is
conjugated directly to X, and if Y and Z are nothing, the lipid is
conjugated directly to X, thereby preparing a compound represented
by the structure of the general formula (XVII).
[0190] In one embodiment of the invention, the lipid may be the
chemical moiety represented by the structure of:
##STR00061##
wherein R.sub.1 and R.sub.2 are defined herein.
[0191] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XVIII):
##STR00062##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond, including, inter alia, the steps of:
conjugating the lipid to Z; conjugating Z to Y; conjugating Y to X;
wherein if Z is nothing, the lipid is conjugated directly to Y, if
Y is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the lipid is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(XVIII).
[0192] In one embodiment of the invention, the lipid may be the
chemical moiety represented by the structure of:
##STR00063##
wherein R.sub.1 and R.sub.2 are defined herein.
[0193] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XIX):
##STR00064##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond, including, inter alia, the steps of:
conjugating the lipid to Z; conjugating Z to Y; conjugating Y to X;
wherein if Z is nothing, the lipid is conjugated directly to Y, if
Y is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the lipid is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(XIX).
[0194] In one embodiment of the invention, the lipid may be the
chemical moiety represented by the structure of:
##STR00065##
wherein R.sub.1 and R.sub.2 are defined herein.
[0195] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XX):
##STR00066##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond, including, inter alia, the steps of:
conjugating the lipid to Z; conjugating Z to Y; conjugating Y to X;
wherein if Z is nothing, the lipid is conjugated directly to Y, if
Y is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the lipid is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(XX).
[0196] In one embodiment of the invention, the lipid may be the
chemical moiety represented by the structure of:
##STR00067##
wherein R.sub.1 and R.sub.2 are defined herein.
[0197] In one embodiment, the invention provides a process for the
preparation of a compound represented by the structure of the
general formula (XXI):
##STR00068##
wherein R.sub.1 is either hydrogen or a linear, saturated,
mono-unsaturated, or poly-unsaturated, alkyl chain ranging in
length from 2 to 30 carbon atoms; R.sub.2 is either hydrogen or a
linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl
chain ranging in length from 2 to 30 carbon atoms; Z is either
nothing, choline, phosphate, inositol, or glycerol; Y is either
nothing or a spacer group ranging in length from 2 to 30 atoms; X
is a physiologically acceptable monomer, dimer, oligomer or
polymer, wherein x is a glycosaminoglycan; and n is a number from 1
to 1000; wherein any bond between the lipid, Z, Y and X is either
an amide or an esteric bond, including, inter alia, the steps of:
conjugating the lipid to Z; conjugating Z to Y; conjugating Y to X;
wherein if Z is nothing, the lipid is conjugated directly to Y, if
Y is nothing, Z is conjugated directly to X, and if Y and Z are
nothing, the lipid is conjugated directly to X, thereby preparing a
compound represented by the structure of the general formula
(XXI).
[0198] In one embodiment of the invention, the lipid may be the
chemical moiety represented by the structure of:
##STR00069##
wherein R.sub.1 and R.sub.2 are defined herein.
[0199] In another embodiment, the conjugating according to the
invention may be performed by eliminating a water molecule, thereby
forming amide or esteric bonds. In another embodiment, the
conjugating may be performed in the presence of a detergent. In
another embodiment, the conjugating may be induced by ultrasonic
radiation.
[0200] In another embodiment, any conjugation process according to
the invention may be performed by eliminating a water molecule,
thereby forming amide or esteric bonds. In another embodiment, any
conjugation process according to the invention may be performed in
the presence of a detergent. In another embodiment, any conjugation
process according to the invention may be induced by ultrasonic
radiation.
[0201] In another embodiment, any compound according to the
invention may be prepared by a conjugation process performed by
eliminating a water molecule, thereby forming amide or esteric
bonds. In another embodiment, any compound according to the
invention may be prepared by a conjugation process in the presence
of a detergent. In another embodiment, any compound according to
the invention may be prepared by a conjugation process induced by
ultrasonic radiation.
[0202] In one embodiment of the invention, the conjugation of the
phosphatidylethanolamine and chondroitin sulfate is performed in
the presence of a detergent. In another embodiment a detergent may
be, inter alia, DDAB. Of course any other appropriate detergent may
be used.
[0203] In one embodiment of the invention, the conjugation of the
phosphatidylethanolamine and hyaluronic acid is induced by
sonication.
Methods of Treating Disease Based on PL Conjugates
[0204] In one embodiment of the invention, the Lipid-conjugates
described herein can be used to treat disease, through exerting at
least one of their many pharmacological activities, among which are
amelioration, or prevention, of tissue injury arising in the course
of pathological disease states by stabilizing cell membranes;
limiting oxidative damage to cell and blood components; limiting
cell proliferation, cell extravasation and (tumor) cell migratory
behavior; suppressing immune responses; or attenuating
physiological reactions to stress, as expressed in elevated
chemokine levels. The medicinal properties of these compounds are
readily exemplified in using animal models of the particular
disease in which it is desired to use the drug. The patients to
whom the lipid or PL conjugates should be administered are those
that are experiencing symptoms of disease or who are at risk of
contracting the disease or experiencing a recurrent episode or
exacerbation of the disease. The efficacy of these compounds in
cellular and animal models of disease are described below in The
Examples.
[0205] The combination of lipids, such as, but not limited to
phosphatidylethanolamine and phosphatidylserine, with additional
monomer or polymer moieties, is thus a practical route to the
production of new drugs for medical purposes, provided that the
resultant chemical composition displays the desired range of
pharmacological properties. In the cases described herein, the
diversity of biological activities and the effectiveness in disease
exhibited by the compounds far exceed the properties anticipated by
use of the starting materials themselves, when administered alone
or in combination. However, it is likely that the PL conjugate
compounds, alone or in combination, will prove to be valuable drugs
when adapted to methods of disease treatment other to those
conditions specifically described herein.
[0206] In one embodiment, the invention provides a method of
treating a subject afflicted with a disease related to chronic
rhinosinutis, nasal polyps.
[0207] In one embodiment, the invention provides a method of
treating a subject suffering from chronic rhinosinutis, including,
inter alia, the step of administering to a subject an effective
amount of a lipid or phospholipid moiety bonded to a
physiologically acceptable monomer, dimer, oligomer, or
polymer.
[0208] In one embodiment, the invention provides a method of
preventing chronic rhinosinutis in a subject, including, inter
alia, the step of administering to a subject an effective amount of
a lipid or phospholipid moiety bonded to a physiologically
acceptable monomer, dimer, oligomer, or polymer.
[0209] In one embodiment, the invention provides a method of
treating a subject suffering from nasal polyps, including, inter
alia, the step of administering to a subject an effective amount of
a lipid or phospholipid moiety bonded to a physiologically
acceptable monomer, dimer, oligomer, or polymer.
[0210] In one embodiment, the invention provides a method of
preventing nasal polyps in a subject, including, inter alia, the
step of administering to a subject an effective amount of a lipid
or phospholipid moiety bonded to a physiologically acceptable
monomer, dimer, oligomer, or polymer.
[0211] In one embodiment, the invention provides a use of a lipid
or phospholipid moiety bonded to a physiologically acceptable
monomer, dimer, oligomer, or polymer, in the preparation of a
pharmaceutical composition for treating a subject suffering from
chronic rhinosinutis.
[0212] In one embodiment, the invention provides a use of a lipid
or phospholipid moiety bonded to a physiologically acceptable
monomer, dimer, oligomer, or polymer, in the preparation of a
pharmaceutical composition for preventing chronic rhinosinutis in a
subject.
[0213] In one embodiment, the invention provides a use of a lipid
or phospholipid moiety bonded to a physiologically acceptable
monomer, dimer, oligomer, or polymer, in the preparation of a
pharmaceutical composition for treating a subject suffering from
nasal polyps.
[0214] In one embodiment, the invention provides a use of a lipid
or phospholipid moiety bonded to a physiologically acceptable
monomer, dimer, oligomer, or polymer, in the preparation of a
pharmaceutical composition for preventing nasal polyps in a
subject.
[0215] In one embodiment of the invention, the treatment requires
controlling the expression, production, and activity of
phospholipase enzymes. In another embodiment, the treatment
requires controlling the production and/or action of lipid
mediators. In another embodiment, the treatment requires
amelioration of damage to glycosaminoglycans (GAG) and
proteoglycans. In another embodiment, the treatment requires
controlling the production and action of oxidants, oxygen radicals
and nitric oxide. In another embodiment, the treatment requires
anti-oxidant therapy. In another embodiment, the treatment requires
anti-endotoxin therapy. In another embodiment, the treatment
requires controlling the expression, production or action of
cytokines, chemokines, adhesion molecules or interleukines. In
another embodiment, the treatment requires protection of
lipoproteins from damaging agents. In another embodiment, the
treatment requires controlling the proliferation of cells. In
another embodiment, the treatment requires controlling of
angiogenesis and organ vascularization. In another embodiment, the
treatment requires inhibition of invasion-promoting enzymes. In
another embodiment, the treatment requires controlling of cell
invasion. In another embodiment, the invading cells are white blood
cells. In another embodiment, the invading cells are cancer cells.
In another embodiment, the treatment requires controlling of white
cell activation, adhesion or extravasation. In another embodiment,
the treatment requires amelioration of ischemia or reperfusion
injury. In another embodiment, the treatment requires inhibition of
lymphocyte activation. In another embodiment, the treatment
requires protection of blood brain barrier. In another embodiment,
the treatment requires control of neurotransmitter production and
action. In another embodiment, the treatment requires controlling
of blood vessel and airway contraction. In another embodiment, the
treatment requires extracorporeal tissue preservation.
[0216] In one embodiment of the invention, the lipid mediator is a
glycerolipid. In another embodiment, the lipid mediator is a
phospholipid. In another embodiment, the lipid mediator is
sphingolipid. In another embodiment, the lipid mediator is a
sphingosine. In another embodiment, the lipid mediator is ceramide.
In another embodiment, the lipid mediator is a fatty acid. In
another embodiment, the fatty acid is arachidonic acid. In another
embodiment, the lipid mediator is an arachidonic acid-derived
eicosanoid. In another embodiment, the lipid mediator is a platelet
activating factor (PAF). In another embodiment, the lipid mediator
is a lysophospholipid.
[0217] In one embodiment of the invention, the damaging agent is a
phospholipase. In another embodiment, the damaging agent is a
reactive oxygen species (ROS). In another embodiment, the damaging
agent is a free radical. In another embodiment, the damaging agent
is a lysophospholipid. In another embodiment, the damaging agent is
a fatty acid or a derivative thereof. In another embodiment, the
damaging agent is hydrogen peroxide. In another embodiment, the
damaging agent is a phospholipid. In another embodiment, the
damaging agent is an oxidant. In another embodiment, the damaging
agent is a cationic protein. In another embodiment, the damaging
agent is a streptolysin. In another embodiment, the damaging agent
is a protease. In another embodiment, the damaging agent is a
hemolysin. In another embodiment, the damaging agent is a
sialidase.
[0218] In one embodiment of the invention, the invasion-promoting
enzyme is collagenase. In another embodiment, the
invasion-promoting enzyme is matrix-metaloproteinase (MMP). In
another embodiment, the invasion-promoting enzyme is heparinase. In
another embodiment, the invasion-promoting enzyme is heparanase. In
another embodiment, the invasion-promoting enzyme is hyaluronidase.
In another embodiment, the invasion-promoting enzyme is gelatinase.
In another embodiment, the invasion-promoting enzyme is
chondroitinase. In another embodiment, the invasion-promoting
enzyme is dermatanase. In another embodiment, the
invasion-promoting enzyme is keratanase. In another embodiment, the
invasion-promoting enzyme is protease. In another embodiment, the
invasion-promoting enzyme is lyase. In another embodiment, the
invasion-promoting enzyme is hydrolase. In another embodiment, the
invasion-promoting enzyme is a glycosaminoglycan degrading enzyme.
In another embodiment, the invasion-promoting enzyme is a
proteoglycan degrading enzyme.
[0219] In one embodiment of the invention, the physiologically
acceptable monomer is salicylate. In another embodiment, the
physiologically acceptable monomer is salicylic acid. In another
embodiment, the physiologically acceptable monomer is aspirin. In
another embodiment, the physiologically acceptable monomer is a
monosaccharide. In another embodiment, the physiologically
acceptable monomer is lactobionic acid. In another embodiment, the
physiologically acceptable monomer is glucoronic acid. In another
embodiment, the physiologically acceptable monomer is maltose. In
another embodiment, the physiologically acceptable monomer is an
amino acid. In another embodiment, the physiologically acceptable
monomer is glycine. In another embodiment, the physiologically
acceptable monomer is a carboxylic acid. In another embodiment, the
physiologically acceptable monomer is an acetic acid. In another
embodiment, the physiologically acceptable monomer is a butyric
acid. In another embodiment, the physiologically acceptable monomer
is a dicarboxylic acid. In another embodiment, the physiologically
acceptable monomer is a glutaric acid. In another embodiment, the
physiologically acceptable monomer is succinic acid. In another
embodiment, the physiologically acceptable monomer is a fatty acid.
In another embodiment, the physiologically acceptable monomer is
dodecanoic acid. In another embodiment, the physiologically
acceptable monomer is didodecanoic acid. In another embodiment, the
physiologically acceptable monomer is bile acid. In another
embodiment, the physiologically acceptable monomer is cholic acid.
In another embodiment, the physiologically acceptable monomer is
cholesterylhemmisuccinate.
[0220] In one embodiment of the invention, the physiologically
acceptable dimer or oligomer is physiologically acceptable dimer or
oligomer is a dipeptide. In another embodiment, the physiologically
acceptable dimer or oligomer is a disaccharide. In another
embodiment, the physiologically acceptable dimer or oligomer is a
trisaccharide. In another embodiment, the physiologically
acceptable dimer or oligomer is an oligosaccharide. In another
embodiment, the physiologically acceptable dimer or oligomer is an
oligopeptide. In another embodiment, the physiologically acceptable
dimer or oligomer is a di- or trisaccharide monomer unit of
glycosaminoglcans. In another embodiment, the physiologically
acceptable dimer or oligomer is hyaluronic acid. In another
embodiment, the physiologically acceptable dimer or oligomer is
heparin. In another embodiment, the physiologically acceptable
dimer or oligomer is heparan sulfate. In another embodiment, the
physiologically acceptable dimer or oligomer is keratin. In another
embodiment, the physiologically acceptable dimer or oligomer is
keratan sulfate. In another embodiment, the physiologically
acceptable dimer or oligomer is chondroitin. In another embodiment,
the chondroitin is chondoitin sulfate. In another embodiment, the
chondroitin is chondoitin-4-sulfate. In another embodiment, the
chondroitin is chondoitin-6-sulfate. In another embodiment, the
physiologically acceptable dimer or oligomer is dermatin. In
another embodiment, the physiologically acceptable dimer or
oligomer is dermatan sulfate. In another embodiment, the
physiologically acceptable dimer or oligomer is dextran. In another
embodiment, the physiologically acceptable dimer or oligomer is
polygeline (`Haemaccel`). In another embodiment, the
physiologically acceptable dimer or oligomer is alginate. In
another embodiment, the physiologically acceptable dimer or
oligomer is hydroxyethyl starch (Hetastarch). In another
embodiment, the physiologically acceptable dimer or oligomer is
ethylene glycol. In another embodiment, the physiologically
acceptable dimer or oligomer is carboxylated ethylene glycol.
[0221] In one embodiment of the invention, the physiologically
acceptable polymer is a glycosaminoglycan. In another embodiment,
the physiologically acceptable polymer is hyaluronic acid. In
another embodiment, the physiologically acceptable polymer is
heparin. In another embodiment, the physiologically acceptable
polymer is heparan sulfate. In another embodiment, the
physiologically acceptable polymer is chondroitin. In another
embodiment, the chondroitin is chondoitin-4-sulfate. In another
embodiment, the chondroitin is chondoitin-6-sulfate. In another
embodiment, the physiologically acceptable polymer is keratin. In
another embodiment, the physiologically acceptable polymer is
keratan sulfate. In another embodiment, the physiologically
acceptable polymer is dermatin. In another embodiment, the
physiologically acceptable polymer is dermatan sulfate. In another
embodiment, the physiologically acceptable polymer is
carboxymethylcellulose. In another embodiment, the physiologically
acceptable polymer is dextran. In another embodiment, the
physiologically acceptable polymer is polygeline (`Haemaccel`). In
another embodiment, the physiologically acceptable polymer is
alginate. In another embodiment, the physiologically acceptable
polymer is hydroxyethyl starch (`Hetastarch`). In another
embodiment, the physiologically acceptable polymer is polyethylene
glycol. In another embodiment, the physiologically acceptable
polymer is polycarboxylated polyethylene glycol.
[0222] In one embodiment of the invention, the lipid or
phospholipid moiety is phosphatidic acid. In another embodiment,
lipid or phospholipid moiety is an acyl glycerol. In another
embodiment, lipid or phospholipid moiety is monoacylglycerol. In
another embodiment, lipid or phospholipid moiety is diacylglycerol.
In another embodiment, lipid or phospholipid moiety is
triacylglycerol. In another embodiment, lipid or phospholipid
moiety is sphingosine. In another embodiment, lipid or phospholipid
moiety is sphingomyelin. In another embodiment, lipid or
phospholipid moiety is ceramide. In another embodiment, lipid or
phospholipid moiety is phosphatidylethanolamine. In another
embodiment, lipid or phospholipid moiety is phosphatidylserine. In
another embodiment, lipid or phospholipid moiety is
phosphatidylcholine. In another embodiment, lipid or phospholipid
moiety is phosphatidylinositol. In another embodiment, lipid or
phospholipid moiety is phosphatidylglycerol. In another embodiment,
lipid or phospholipid moiety is an ether or alkyl phospholipid
derivative thereof
[0223] In one embodiment, the invention provides a method of
treating a subject afflicted with a disease, wherein the treatment
of the disease requires controlling phospholipase A2 activities;
controlling the production and/or action of lipid mediators, such
as eicosanoids, platelet activating factor (PAF) and
lyso-phospholipids; amelioration of damage to cell surface
glycosaminoglycans (GAG) and proteoglycans; controlling the
production of oxygen radicals and nitric oxide; protection of
cells, tissues, and plasma lipoproteins from damaging agents, such
as reactive oxygen species (ROS) and phospholipases; anti-oxidant
therapy; anti-endotoxin therapy; controlling of cytokine, chemokine
and interleukine production; controlling the proliferation of
cells, including smooth muscle cells, endothelial cells and skin
fibroblasts; controlling of angiogenesis and organ vascularization;
inhibition of invasion-promoting enzymes, such as collagenase,
heparinase, heparanase and hyaluronidase; controlling of cell
invasion; controlling of white cell activation, adhesion and
extravasation; amelioration of ischemia/reperfusion injury,
inhibition of lymphocyte activation; controlling of blood vessel
and airway contraction; protection of blood brain barrier;
controlling of neurotransmitter (e.g., dopamine) production and
action (e.g., acethylcholine); extracorporeal tissue preservation
or any combination thereof
[0224] In one embodiment of the invention, the term "controlling"
refers to inhibiting the production and action of the above
mentioned factors in order to maintain their activity at the normal
basal level and suppress their activation in pathological
conditions.
[0225] In one embodiment of the invention, the physiologically
acceptable monomer is either a salicylate, salicylic acid, aspirin,
a monosaccharide, lactobionic acid, maltose, an amino acid,
glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic
acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid,
didodecanoic acid, bile acid, cholic acid,
cholesterylhemmisuccinate; or wherein the physiologically
acceptable dimer or oligomer is a dipeptide, a disaccharide, a
trisaccharide, an oligopeptide, or a di- or trisaccharide monomer
unit of heparin, heparan sulfate, keratin, keratan sulfate,
chondroitin, chondoitin-6-sulfate, chondroitin-4-sulfate, dermatin,
dermatan sulfate, dextran, or hyaluronic acid; or wherein the
physiologically acceptable polymer is a glycosaminoglycan,
polygelin (`haemaccel`), alginate, hydroxyethyl starch
(hetastarch), polyethylene glycol, polycarboxylated polyethylene
glycol, chondroitin-6-sulfate, chondroitin-4-sulfate, keratin,
keratin sulfate, heparan sulfate, dermatin, dermatan sulfate,
carboxymethylcellulose, heparin, dextran, or hyaluronic acid.
[0226] In one embodiment of the invention, the lipid moiety is
either phosphatidic acid, an acyl glycerol, monoacylglycerol,
diacylglycerol, triacylglycerol, sphingosine, sphingomyelin,
chondroitin-4-sulphate, chondroitin-6-sulphate, ceramide,
phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine,
phosphatidylinositol, or phosphatidylglycerol, or an ether or alkyl
phospholipid derivative thereof, and the physiologically acceptable
monomer or polymer moiety is either aspirin, lactobionic acid,
maltose, glutaric acid, polyethylene glycol,
carboxymethylcellulose, heparin, dextran, hemacell, hetastarch, or
hyaluronic acid.
[0227] In one embodiment, the present invention provides for use of
a lipid moiety bonded to a physiologically acceptable monomer,
dimer, oligomer, or polymer, in the preparation of a pharmaceutical
composition for treating a subject afflicted with chronic
rhinosinusitis, nasal polyps, asthma, allergic rhinitis, chronic
obstructive pulmonary disease, obstructive respiratory disease,
colitis, Crohn's disease, central nervous system insult, multiple
sclerosis, contact dermatitis, psoriasis, cardiovascular disease,
including prophylaxis for invasive procedures, invasive cellular
proliferative disorders, anti-oxidant therapy, hemolytic syndromes,
sepsis, acute respiratory distress syndrome, tissue transplant
rejection syndromes, autoimmune disease, viral infection, and
hypersensitivity conjunctivitis.
[0228] In one embodiment, the present invention provides use of a
pharmaceutical composition according to the present invention for
treating a subject afflicted with chronic rhinosinusitis, nasal
polyps, asthma, allergic rhinitis, chronic obstructive pulmonary
disease, obstructive respiratory disease, colitis, Crohn's disease,
central nervous system insult, multiple sclerosis, contact
dermatitis, psoriasis, cardiovascular disease, including
prophylaxis for invasive procedures, invasive cellular
proliferative disorders, anti-oxidant therapy, hemolytic syndromes,
sepsis, acute respiratory distress syndrome, tissue transplant
rejection syndromes, autoimmune disease, viral infection, or
hypersensitivity conjunctivitis, wherein the composition is
prepared for administration by topical, oral, nasal, aerosol,
intravenous, intraocular, intra-arterial, subcutaneous, or
suppository routes.
[0229] In one embodiment, the invention provides a method of
treating a subject suffering from a disease involving the
production and/or action of lipid mediators and/or impairment of
glycosaminoglycan (GAG) functioning.
[0230] In one embodiment of the invention, the physiologically
acceptable monomer may be, inter alia, a salicylate, salicylic
acid, aspirin, a monosaccharide, lactobionic acid, glucoronic acid,
maltose, amino acid, glycine, carboxylic acid, acetic acid, butyric
acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid,
dodecanoic acid, didodecanoic acid, bile acid, cholic acid,
cholesterylhemmisuccinate, or wherein the physiologically
acceptable dimer or oligomer may be, inter alia, a dipeptide, a
disaccharide, a trisaccharide, an oligosaccharide, an oligopeptide,
or a di- or trisaccharide monomer unit of glycosaminoglcans,
hyaluronic acid, heparin, heparan sulfate, keratin, keratan
sulfate, chondroitin, chondroitin sulfate,chondroitin-4-sulfate,
chondoitin-6-sulfate, dermatin, dermatan sulfate, dextran,
polygeline, alginate, hydroxyethyl starch, ethylene glycol, or
carboxylated ethylene glycol, or wherein the physiologically
acceptable polymer may be, inter alia, a glycosaminoglycan,
hyaluronic acid, heparin, heparan sulfate, chondroitin, chondroitin
sulfate, keratin, keratan sulfate, dermatin, dermatan sulfate,
carboxymethylcellulose, dextran, polygeline, alginate, hydroxyethyl
starch, polyethylene glycol or polycarboxylated polyethylene
glycol.
[0231] In another embodiment, the physiologically acceptable
polymer may be, inter alia, hyaluronic acid.
[0232] In another embodiment, the physiologically acceptable
polymer may be, inter alia, chondroitin sulfate.
[0233] In one embodiment of the invention, the lipid or
phospholipid moiety may be, inter alia, phosphatidic acid, an acyl
glycerol, monoacylglycerol, diacylglycerol, triacylglycerol,
sphingosine, sphingomyelin, ceramide, phosphatidylethanolamine,
phosphatidylserine, phosphatidylcholine, phosphatidylinositol,
phosphatidylglycerol, or an ether or alkyl phospholipid derivative
thereof
[0234] In another embodiment, the phospholipid moiety may be, inter
alia, phosphatidylethanolamine.
Dosages and Routes of Administration
[0235] The methods of this invention can be adapted to use of the
therapeutic compositions comprising Lipid-conjugates in admixture
with conventional excipients, i.e. pharmaceutically acceptable
organic or inorganic carrier substances suitable for parenteral,
enteral (e.g., oral) or topical application which do not
deleteriously react with the active compounds. Suitable
pharmaceutically acceptable carriers include but are not limited to
water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl
alcohols, polyethylene glycols, gelatine, carbohydrates such as
lactose, amylose or starch, magnesium stearate, talc, silicic acid,
viscous paraffin, white paraffin, glycerol, alginates, hyaluronic
acid, collagen, perfume oil, fatty acid monoglycerides and
diglycerides, pentaerythritol fatty acid esters, hydroxy
methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceutical
preparations can be sterilized and if desired mixed with auxiliary
agents, e.g., lubricants, preservatives, stabilizers, wetting
agents, emulsifiers, salts for influencing osmotic pressure,
buffers, coloring, flavoring and/or aromatic substances and the
like which do not deleteriously react with the active compounds.
They can also be combined where desired with other active agents,
e.g., vitamins.
[0236] In one embodiment, the invention provides a pharmaceutical
composition for treating a subject suffering from chronic
rhinosinutis, including a lipid or phospholipid moiety bonded to a
physiologically acceptable monomer, dimer, oligomer, or polymer;
and a pharmaceutically acceptable carrier or excipient.
[0237] In another embodiment, the invention provides a
pharmaceutical composition for preventing chronic rhinosinutis in a
subject, including a lipid or phospholipid moiety bonded to a
physiologically acceptable monomer, dimer, oligomer, or polymer;
and a pharmaceutically acceptable carrier or excipient.
[0238] In another embodiment, the invention provides a
pharmaceutical composition for treating a subject suffering from
nasal polyps, including a lipid or phospholipid moiety bonded to a
physiologically acceptable monomer, dimer, oligomer, or polymer;
and a pharmaceutically acceptable carrier or excipient.
[0239] In another embodiment, the invention provides a
pharmaceutical composition for preventing nasal polyps in a
subject, including a lipid or phospholipid moiety bonded to a
physiologically acceptable monomer, dimer, oligomer, or polymer;
and a pharmaceutically acceptable carrier or excipient.
[0240] In another embodiment, the invention provides a
pharmaceutical composition for treating a subject suffering from
chronic rhinosinutis, including a lipid or phospholipid moiety
bonded to a physiologically acceptable carrier or excipient.
[0241] In another embodiment, the invention provides a
pharmaceutical composition for preventing chronic rhinosinutis in a
subject, including any one of the compounds according to the
invention or any combination thereof; and a pharmaceutically
acceptable carrier or excipient.
[0242] In another embodiment, the invention provides a
pharmaceutical composition for treating a subject suffering from
nasal polyps, including any one of the compounds according to the
invention or any combination thereof; and a pharmaceutically
acceptable carrier or excipient. In another embodiment, the
invention provides a pharmaceutical composition for preventing
nasal polyps in a subject, including any one of the compounds
according to the invention or any combination thereof; and a
pharmaceutically acceptable carrier or excipient.
[0243] In another embodiment, the compounds according to the
invention include, inter alia, the compounds represented by the
structures of the general formulae: (A), (I), (II), (III), (IV),
(V), (VI), (VII), (VIII), (IX), (IXa), (IXb), (X), (XI), (XII),
(XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI),
(XXII) or any combination thereof.
[0244] While the examples provided herein describe use of the PL
conjugates in subcutaneous, intraperitoneal or topical
administration, the success described affords good evidence to
suppose that other routes of administration, or combinations with
other pharmaceutical preparations, would be at least as successful.
The route of administration (e.g., topical, parenteral, enteral,
intravenous, vaginal, inhalation, nasal aspiration (spray),
supository or oral) and the dosage regimen will be determined by
skilled clinicians, based on factors such as exact nature of the
condition being treated, the severity of the condition, the age and
general physical condition of the patient, and so on.
[0245] In general, the doses utilized for the above described
purposes will vary, but will be in an effective amount to exert the
desired anti-disease effect. As used herein, the term
"pharmaceutically effective amount" refers to an amount of a
compound of formulae A and I-XXI which will produce the desired
alleviation in symptoms or signs of disease in a patient. The doses
utilized for any of the above-described purposes will generally be
from 1 to about 1000 milligrams per kilogram of body weight
(mg/kg), administered one to four times per day, or by continuous
IV infusion. When the compositions are dosed topically, they will
generally be in a concentration range of from 0.1 to about 10% w/v,
administered 1-4 times per day.
[0246] As used herein, the term "pharmaceutically acceptable
carrier" refers to any formulation which is safe, and provides the
appropriate delivery for the desired route of administration of an
effective amount of at least one compound of the present invention.
As such, all of the above-described formulations of the present
invention are hereby referred to as "pharmaceutically acceptable
carriers." This term refers to as well the use of buffered
formulations wherein the pH is maintained at a particular desired
value, ranging from pH 4.0 to pH 9.0, in accordance with the
stability of the compounds and route of administration.
[0247] For parenteral application, particularly suitable are
injectable, sterile solutions, preferably oily or aqueous
solutions, as well as suspensions, emulsions, or implants,
including suppositories. Ampoules are convenient unit dosages.
[0248] For application by inhalation, particularly for treatment of
airway obstruction or congestion, solutions or suspensions of the
compounds mixed and aerosolized or nebulized in the presence of the
appropriate carrier.
[0249] For topical application, particularly for the treatment of
skin diseases such as contact dermatitis or psoriasis, admixture of
the compounds with conventional creams or delayed release patches
is acceptable.
[0250] For enteral application, particularly suitable are tablets,
dragees, liquids, drops, suppositories, or capsules. A syrup,
elixir, or the like can be used when a sweetened vehicle is
employed. When indicated, suppositories or enema formulations may
be the recommended route of administration.
[0251] Sustained or directed release compositions can be
formulated, e.g., liposomes or those wherein the active compound is
protected with differentially degradable coatings, e.g., by
microencapsulation, multiple coatings, etc. It is also possible to
freeze-dry the new compounds and use the lyophilisates obtained,
for example, for the preparation of products for injection.
[0252] Thus, the present invention provides for use of the
Lipid-conjugates in various dosage forms suitable for aerosol,
rectal, vaginal, conjunctival, intravenous, intra-arterial, and
sublingual routes of administration.
[0253] It will be appreciated that the actual preferred amounts of
active compound in a specific case will vary according to the
specific compound being utilized, the particular compositions
formulated, the mode of application, and the particular situs and
organism being treated. Dosages for a given host can be determined
using conventional considerations, e.g., by customary comparison of
the differential activities of the subject compounds and of a known
agent, e.g., by means of an appropriate, conventional
pharmacological protocol.
[0254] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0255] The main abbreviations used in the application are:
[0256] HA=hyaluronic acid
[0257] HYPE=dipalmitoyl-phosphatidyl-ethanolamine (PE) conjugated
to HA (also referred to as HyPE, Hya;PE)
[0258] CSA=chondroitin sulfate A
[0259] CSAPE=PE conjugated to CSA (also referred to as CsAPE,
CsAPE)
[0260] CMC=carboxymethyl cellulose
[0261] CMPE=PE conjugated to CMC
[0262] HEPPE=PE conjugated to heparin (also referred to as HepPE,
HePPE)
[0263] DEXPE=PE conjugated to dextran
[0264] AsPE=PE conjugates to aspirin
[0265] HemPE=PE conjugated to Polygeline (haemaccel)
[0266] HyDMPE=dimyristoyl PE linked to HA.
[0267] Examples demonstrating the utility of lipid-conjugates in
preventing and treating disease are presented in PCT/US05/06591
filed 2 Mar. 2005, U.S. application Ser. No. 10/989,606 filed 17
Nov. 2004 and U.S. application Ser. No. 10/989,607 filed 17 Nov.
2004, which are incorporated herein by reference in their
entirety.
Example 1
Hype Decreased Cytokine Levels in Nasal Polyps from Patients With
Chronic Rhinosinusitis
[0268] In vitro, treatment of T cells from nasal polyps with
Staphylococcus Aureus Superantigens (SAS) induced the release of
large amounts of IL-4, IL-5 and INF-.gamma. (FIG. 1), while
addition of anti-IL-5 suppressed IL-4 and INF-.gamma. release in
polyps with high amount of IL-5 (FIG. 2). Blocking the eosinophilic
inflammation by anti-IL5 reduced TH1 and TH2 mediated reaction in
the polyps. Similarly, in vivo studies showed that a single iv
infusion of 3 mg/kg or 1 mg/kg of a humanized anti-human IL-5
monoclonal antibody in 24 patients with bilateral NP was safe,
reduced eosinophil number and concentration of ECP in blood, and
improived NP clinical scores in 50% of the patents receiving
treatment (Gebaert et al. J Allergy Clin Immunol. 2006 November;
118(5):1133-41). Patients with high levels of basal IL-5 were more
likely to be responsive to treatment with anti-IL-5 antibody.
[0269] Some findings link nasal polyp development and aggravation
with the presence of specific immunologic response to SAS.
[0270] Nasal polyps were obtained from patients who underwent
Endoscopic Sinus Surgery (ESS) for chronic rhinosinusitis with
nasal polyps (CRSwNP) at Tel Aviv Medical Center. Tissue was
enzymatically digested, cells were filtered, and some were
stimulated in vitro with SA (SA). Some groups of cells received
either no treatment (NA), Hyaluronic acid-phosphtidylethanolamine
(HyPE) or dexamethasone (DEXA). IL-5, IL-13, and Interferon-.chi.
levels were measured by ELISA.
[0271] Treatment of human nasal polyps with PLA2 inhibitor
suppressed the release of Th2 and Th1 cytokines at a level
comparable to (IL-5, IL-13) or better than (Interferon-.chi.) that
of dexamethasone (FIG. 3).
Example 2
Toxicity Tests
[0272] Experiment 2:
[0273] The following compounds were tested: HyPE, CMPE, CSAPE and
HepPE. The compounds were injected IP at one dose of 1000, 500 or
200 mg/Kg body weight. Toxicity was evaluated after one week, by
mortality, body weight, hematocrit, blood count (red and white
cells), and visual examination of internal organs after sacrifice.
These were compared to control, untreated mice. Each dose was
applied to a group of three mice. No significant change in the
above criteria was induced by treatment with these compounds,
except for the HepPE, which induced hemorrhage.
[0274] The non-toxicity of the Lipid conjugates is demonstrated in
Table 2.1 and Table 2.2, depicting the results obtained for HyPE in
acute (2.1) and long-term (2.2) toxicity tests.
TABLE-US-00002 TABLE 2.1 Acute toxicity Dose of HyPE (mg/ kg body
RBC .times. WBC .times. Hemat- weight) Body weight (g) 10.sup.6
10.sup.3 ocrit % 0.0 21.9 .+-. 0.2 22.6 .+-. 0.3 10.7 .+-. 0.4 9.3
.+-. 0.3 45.0 .+-. 0.5 (control) 250 22.1 .+-. 0.4 23.1 .+-. 0.6
11.4 .+-. 0.1 7.7 .+-. 0.2 43.3 .+-. 0.7 500 21.4 .+-. 0.3 22.3
.+-. 0.4 11.5 .+-. 0.3 8.1 .+-. 1.3 44.7 .+-. 2.3 1000 21.7 .+-.
0.2 22.1 .+-. 0.2 10.9 .+-. 0.4 7.4 .+-. 0.6 40.3 .+-. 0.7 RBC =
red blood cells. WBC = white blood cells. Each datum is mean .+-.
SEM.
[0275] For long-term toxicity test of HyPE, a group of 6 mice
received a dose of 100 mg HyPE/Kg body weight, injected IP 3 times
a week for 30 weeks (total of 180 mg to a mouse of 20 g). Toxicity
was evaluated as for Table 4.1. No mortality, and no significant
change in the above criteria was induced by this treatment,
compared to normal untreated mice (see Table 4.1), as depicted in
Table 2.
TABLE-US-00003 TABLE 2.2 Results at week 30: Body weight RBC
.times. WBC .times. (g) 10.sup.6 10.sup.3 Hematocrit % Control 39.5
.+-. 3.1 10.9 .+-. 0.8 9.3 .+-. 0.6 45.0 .+-. 0.8 (untreated) rats
HyPE-injected 39.0 .+-. 2.7 11.7 .+-. 0.7 8.1 .+-. 15 43.4 .+-. 4.9
rats
Example 3
Synthesis Procedures
[0276] The procedures below are examples for synthesis of specific
variants of the lipid-conjugates, and can be modified according to
the desirable compositions (e.g., changing the molar ratio between
the lipid/phospholipid and the GAG, or the GAG size).
[0277] Synthesis of low molecular weight lipid-GAG conjugates are
prepared according to US publication 2011-0130555 which is
incorporated herein by reference.
I. HyPE=phosphatidyl-ethanolamine (PE)-linked hyaluronic acid. A.
Truncating hyaluronic acid (HA): [0278] Dissolve 20 g of HA in 12 L
water, add 200 mg FeSO.sub.4.7H.sub.2O dissolved in 20 ml water,
add 400 ml H.sub.2O.sub.2 (30%), stir for 1.5 h. Filter through 30
kD Filtron, Lyophilize. Yield: 16 g truncated HA. B. Conjugation
with PE (adjusted for 1 g):
Prepare:
[0279] 1.10 g HA dissolved in 500 ml MES buffer, 0.1M, pH=6.5
[0280] 2. 1.0 g PE dissolved in 500 ml t-BuOH with 100 ml
H.sub.2O.
Mix the two solutions, add 1 g HOBT and 10 g EDC. Sonicate the
mixture in an ultrasonic bath for 3 h. Remove access free PE (and
EDC and HOBT) by extraction into organic phase (by addition of
chloroform and methanol to obtain a ratio of C/M/H.sub.20:1/1/1).
Separate the aqueous phase by a separation funnel. Repeat this step
twice. For final cleaning from reagents, filter through a Filtron
membrane (30 kD), and lyophilize. Yield: about 8 g. II.
CSAPE=PE-linked chondroitin sulfate A (CSA):
Prepare:
[0281] 1.10 g CSA dissolved in 1.2 L MES buffer, 0.1M, pH=6.5
[0282] 2. 1 g PE dissolved in 120 ml chloroform/methanol:1/1. Add
15 ml of a detergent (DDAB).
Mix 1 with 2, while stirring, add 1 g HOBT and 10 g EDC, continue
stiffing thoroughly for a day at least. Remove access free PE (and
EDC and HOBT) by extraction into organic phase (by addition of
chloroform and methanol to obtain a ratio of
Chloroform/MeOH/EtOH/H.sub.20: 1/1/0.75/1). Separate the aqueous
phase by a separation funnel. Repeat this step twice. Filter
through a Filtron membrane (30 kD), and lyophilize. To remove DDAB
traces, dissolve 1 g of dry product in 100 ml water and 100 ml
MeOH, and clean by ion exchanger using IR120 resin. Dialyse (to
remove MeOH) and lyophilize. Yield: about 8 g.
[0283] Unexpected results showed that the sonication applied in the
HyPE synthesis, is an better substitute for the detergent in mixing
the aqueous and lipid phases. Using sonication techniques
simplifies the synthesis and improves the purification of the
product.
[0284] It will be appreciated by persons skilled in the art that
the present invention is not limited by what has been particularly
shown and described herein above and that numerous modifications,
all of which fall within the scope of the present invention, exist.
Rather, the scope of the invention is defined by the claims which
follow:
* * * * *