U.S. patent application number 17/307865 was filed with the patent office on 2022-03-31 for free base crystalline form of a complement component c5a receptor.
The applicant listed for this patent is CHEMOCENTRYX, INC.. Invention is credited to Antoni KRASINSKI, Rebecca M. LUI, Rajinder SINGH, Kwok YAU, Yibin ZENG, Penglie ZHANG.
Application Number | 20220096453 17/307865 |
Document ID | / |
Family ID | 1000006025985 |
Filed Date | 2022-03-31 |
United States Patent
Application |
20220096453 |
Kind Code |
A1 |
SINGH; Rajinder ; et
al. |
March 31, 2022 |
FREE BASE CRYSTALLINE FORM OF A COMPLEMENT COMPONENT C5a
RECEPTOR
Abstract
Provided herein is a free base crystalline form of a complement
component 5a receptor having the formula of Compound 1 ##STR00001##
Also provided herein are pharmaceutical compositions and methods of
treatment using the crystalline free base form of Compound 1
described herein.
Inventors: |
SINGH; Rajinder; (Belmont,
CA) ; YAU; Kwok; (Sunnyvale, CA) ; ZENG;
Yibin; (Foster City, CA) ; ZHANG; Penglie;
(Foster City, CA) ; LUI; Rebecca M.; (Mountain
View, CA) ; KRASINSKI; Antoni; (Sunnyvale,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CHEMOCENTRYX, INC. |
San Carlos |
CA |
US |
|
|
Family ID: |
1000006025985 |
Appl. No.: |
17/307865 |
Filed: |
May 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17091019 |
Nov 6, 2020 |
11026935 |
|
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17307865 |
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62932652 |
Nov 8, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/675 20130101;
C07B 2200/13 20130101; C07D 211/60 20130101; A61K 39/3955 20130101;
A61K 31/451 20130101 |
International
Class: |
A61K 31/451 20060101
A61K031/451; C07D 211/60 20060101 C07D211/60; A61K 31/675 20060101
A61K031/675; A61K 39/395 20060101 A61K039/395 |
Claims
1.-2. (canceled)
3. The method of claim 11, wherein the free base crystalline form
of Compound 1 is further characterized by XRPD peaks at 12.4, 15.2,
16.1, 24.4, and 24.7 degrees 2.theta. (.+-.0.2 degrees
2.theta.)
4. The method of claim 11, wherein the free base crystalline form
of Compound 1 is characterized by an X-ray powder diffraction
pattern substantially in accordance with FIG. 1.
5. The method of claim 11, wherein the free base crystalline form
of Compound 1 is further characterized by a differential scanning
calorimetry thermogram (DSC) comprising an endothermic peak at
around 216.degree. C.
6. The method of claim 11, wherein the free base crystalline form
of Compound 1 is further characterized by a melting point onset of
about 213.degree. C. as determined by differential scanning
calorimetry thermogram (DSC).
7. The method of claim 11, wherein the free base crystalline form
of Compound 1 is further characterized by a DSC substantially in
accordance with FIG. 2.
8.-10. (canceled)
11. A method for treating an individual suffering from or
susceptible to a disease or disorder involving pathologic
activation of C5a receptors, comprising administering to the
individual an effective amount of a free base crystalline form of
Compound 1 ##STR00006## characterized by an X-ray powder
diffraction (XRPD) pattern comprising peaks at 8.1, 8.4, 14.1,
16.9, and 19.0 degrees 2.theta. (.+-.0.2 degrees 2.theta.).
12. The method of claim 11, wherein the disease or disorder is an
inflammatory disease or disorder.
13. The method of claim 12, wherein the disease or disorder is
selected from the group consisting of neutropenia, sepsis, septic
shock, Alzheimer's disease, multiple sclerosis, stroke,
inflammatory bowel disease, age-related macular degeneration,
chronic obstructive pulmonary disorder, inflammation associated
with burns, lung injury, osteoarthritis, atopic dermatitis, chronic
urticaria, ischemia-reperfusion injury, acute respiratory distress
syndrome, systemic inflammatory response syndrome, multiple organ
dysfunction syndrome, tissue graft rejection, cancer and hyperacute
rejection of transplanted organs.
14. The method of claim 11, wherein the disease or disorder is a
cardiovascular or cerebrovascular disorder.
15. The method of claim 14, wherein the disease or disorder is
selected from the group consisting of myocardial infarction,
coronary thrombosis, vascular occlusion, post-surgical vascular
reocclusion, artherosclerosis, traumatic central nervous system
injury and ischemic heart disease.
16. The method of claim 11, wherein the disease or disorder is an
autoimmune disorder.
17. The method of claim 16, wherein the disease or disorder is
selected from the group consisting of rheumatoid arthritis, C3
glomerulopathy (C3G), hidradenitis suppurativa (HS), systemic lupus
erythematosus, Guillain-Barre syndrome, pancreatitis, lupus
nephritis, lupus glomerulonephritis, psoriasis, immunoglobulin A
(IgA) nephropathy, Crohn's disease, vasculitis, irritable bowel
syndrome, dermatomyositis, multiple sclerosis, bronchial asthma,
pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune
hemolytic and thrombocytopenic states, Goodpasture's syndrome,
immunovasculitis, tissue graft rejection and hyperacute rejection
of transplanted organs.
18. The method of claim 11, wherein the disease or disorder is a
pathologic sequelae associated with the group consisting of
insulin-dependent diabetes, mellitus, lupus nephropathy, Heyman
nephritis, membranous nephritis, glomerulonephritis, contact
sensitivity responses, and inflammation resulting from contact of
blood with artificial surfaces.
19. The method of claim 11, wherein the disease or disorder is
selected from the group consisting of anti-neutrophil cytoplasmic
antibody associate (ANCA) vasculitis, C3 glomerulopathy,
hidradenitis suppurativa, and lupus nephritis.
20. The method of claim 11, wherein the disease or disorder is
anti-neutrophil cytoplasmic antibody associate (ANCA)
vasculitis.
21. The method of claim 11, wherein the disease or disorder is
granulomatosis with polyangiitis.
22. The method of claim 11, wherein the disease or disorder is
microscopic polyangiitis.
23. The method of claim 11, wherein the disease or disorder is C3
glomerulopathy.
24. The method of claim 11, wherein the disease or disorder is
hidradenitis suppurativa.
25. The method of claim 11, wherein the disease or disorder is
lupus nephritis.
26. The method of claim 11, further comprising administering to the
individual an effective amount of one or more additional
therapeutic agents.
27. The method of claim 26, wherein the one or more additional
therapeutic agent is rituximab.
28. The method of claim 26, wherein the one or more additional
therapeutic agent is cyclophosphamide.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of Ser. No. 17/091,019
filed Nov. 60, 2020 which application claims the benefit of
priority under 35 U.S.C .sctn. 119(e) to U.S. Provisional
Application Ser. No. 62/932,652 filed Nov. 8, 2019, the disclosures
of each are incorporated herein by reference in their entirety.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] NOT APPLICABLE
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK
[0003] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0004] The complement system plays a central role in the clearance
of immune complexes and in immune responses to infectious agents,
foreign antigens, virus infected cells and tumor cells.
Inappropriate or excessive activation of the complement system can
lead to harmful, and even potentially life-threatening consequences
due to severe inflammation and resulting tissue destruction. These
consequences are clinically manifested in various disorders
including septic shock; myocardial, as well as, intestinal
ischemia/reperfusion injury; graft rejection; organ failure;
nephritis; pathological inflammation; and autoimmune diseases.
[0005] The complement system is composed of a group of proteins
that are normally present in the serum in an inactive state.
Activation of the complement system encompasses mainly three
distinct pathways, i.e., the classical, the alternative, and the
lectin pathway (V. M. Holers, In Clinical Immunology: Principles
and Practice, ed. R. R. Rich, Mosby Press; 1996, 363-391): 1) The
classical pathway is a calcium/magnesium-dependent cascade, which
is normally activated by the formation of antigen-antibody
complexes. It can also be activated in an antibody-independent
manner by the binding of C-reactive protein, complexed with ligand,
and by many pathogens including gram-negative bacteria. 2) The
alternative pathway is a magnesium-dependent cascade which is
activated by deposition and activation of C3 on certain susceptible
surfaces (e.g. cell wall polysaccharides of yeast and bacteria, and
certain biopolymer materials). 3) The lectin pathway involves the
initial binding of mannose-binding lectin and the subsequent
activation of C2 and C4, which are common to the classical pathway
(Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992);
Suankratay, C. et al., J Immunol. 160: 3006-3013 (1998)).
[0006] The activation of the complement pathway generates
biologically active fragments of complement proteins, e.g. C3a, C4a
and C5a anaphylatoxins and C5b-9 membrane attack complexes (MAC),
all which mediate inflammatory responses by affecting leukocyte
chemotaxis; activating macrophages, neutrophils, platelets, mast
cells and endothelial cells; and increasing vascular permeability,
cytolysis and tissue injury.
[0007] Complement C5a is one of the most potent proinflammatory
mediators of the complement system. (The anaphylactic C5a peptide
is 100 times more potent, on a molar basis, in eliciting
inflammatory responses than C3a.) C5a is the activated form of C5
(190 kD, molecular weight). C5a is present in human serum at
approximately 80 .mu.g/ml (Kohler, P. F. et al., J Immunol. 99:
1211-1216 (1967)). It is composed of two polypeptide chains,
.alpha. and .beta., with approximate molecular weights of 115 kD
and 75 kD, respectively (Tack, B. F. et al., Biochemistry 18:
1490-1497 (1979)). Biosynthesized as a single-chain promolecule, C5
is enzymatically cleaved into a two-chain structure during
processing and secretion. After cleavage, the two chains are held
together by at least one disulfide bond as well as noncovalent
interactions (Ooi, Y. M. et al., J. Immunol. 124:
2494-2498(1980)).
[0008] Recent work has identified
(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4--
methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, Compound
1
##STR00002##
as useful for treating C5a mediated diseases. Despite this
identification, the efficient delivery of biologically relevant
amounts of Compound 1 remains challenging.
[0009] As such, there is a need to identify solid forms of Compound
1 that can improve important biological characteristics such as
solubility, dissolution rate, and bioavailability, without
sacrificing stability and potency. The present disclosure addresses
these needs and provides related advantages as well.
BRIEF SUMMARY OF THE INVENTION
[0010] Provided herein is a free base crystalline form of Compound
1, methods of using the same, and pharmaceutical compositions
prepared using a free base crystalline form of Compound 1.
[0011] In some aspects, provided herein is a free base crystalline
form of
(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4--
methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, Compound
1
##STR00003##
[0012] The free base crystalline form of Compound 1 can be
characterized using various techniques including, but not limited
to, X-ray powder diffraction (XRPD) and differential scanning
calorimetry (DSC). Relevant characterizing features from the listed
techniques are further described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of
the free base crystalline form described in Example 1.
[0014] FIG. 2 shows the differential scanning calorimetry (DSC)
thermogram of the free base crystalline form of Compound 1.
DETAILED DESCRIPTION OF THE INVENTION
I. General
[0015] The present disclosure provides a free base crystalline form
of Compound 1. This form is suitable for preparing pharmaceutical
compositions including oral solid dosage forms such as tablet,
capsule, softgel, oral liquid dosage forms such as solutions and
suspensions, topical dosage forms such as semisolids, ointments,
pastes, creams and gels, inhalation dosage forms, and parenteral
dosage forms such as IV, IM and SC; but not limited to the
above-mentioned dosage forms.
II. Definitions
[0016] The terms "about" and "around," as used herein to modify a
numerical value, indicate a close range around that explicit value.
If "X" were the value, "about X" or "around X" would indicate a
value from 0.9X to 1.1X, and more preferably, a value from 0.95X to
1.05X. Any reference to "about X" or "around X" specifically
indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X,
1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" and "around
X" are intended to teach and provide written description support
for a claim limitation of, e.g., "0.98X."
[0017] "Compound 1" is a chemical compound having an IUPAC name of
(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4--
methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, and the
structure shown below:
##STR00004##
[0018] "Substantially free" refers to an amount of 10% or less of
another form, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less of
another form.
[0019] The term "treating" or "treatment" encompasses both
disease-modifying treatment and symptomatic treatment, either of
which may be prophylactic (i.e., before the onset of symptoms, in
order to prevent, delay or reduce the severity of symptoms) or
therapeutic (i.e., after the onset of symptoms, in order to reduce
the severity and/or duration of symptoms).
[0020] As used herein, a condition is considered "responsive to C5a
receptor modulation" if modulation of C5a receptor activity results
in the reduction of inappropriate activity of a C5a receptor.
[0021] The term "individual" refers to mammals, which includes
primates (especially humans), domesticated companion animals (such
as dogs, cats, horses, and the like) and livestock (such as cattle,
pigs, sheep, and the like), with dosages as described herein. In
some embodiments, the term "individual" refers to a human.
III. Detailed Description of Embodiments
[0022] A. Free Base Crystalline Form of Compound 1
[0023] In some aspects, provided herein is a free base crystalline
form Compound 1
##STR00005##
which is substantially free of other forms of Compound 1.
[0024] In some embodiments, the free base crystalline form of
Compound 1 is characterized by an X-ray powder diffraction pattern
comprising peaks at 8.1, 8.4, 14.1, 16.9, and 19.0 degrees 2.theta.
(.+-.0.2 degrees 2.theta.). In some embodiments, the free base
crystalline form of Compound 1 is further characterized by an X-ray
powder diffraction pattern comprising peaks at 12.4, 15.2, 16.1,
24.4, and 24.7 degrees 2.theta. (.+-.0.2 degrees 2.theta.). In some
embodiments, the free base crystalline form of Compound 1 is
characterized by an X-ray powder diffraction pattern substantially
in accordance with FIG. 2.
[0025] Differential scanning calorimetry (DSC) can also be used to
characterize the free base crystalline form of Compound 1. In some
embodiments, the free base crystalline form of Compound 1 is
characterized by a differential scanning calorimetry thermogram
(DSC) comprising an endothermic peak at around 216.degree. C. In
some embodiments, the free base crystalline form of Compound 1 is
characterized by a melting point onset of about 213.degree. C. as
determined by differential scanning calorimetry thermogram (DSC).
In some embodiments, the free base crystalline form of Compound 1
is characterized by a differential scanning calorimetry (DSC)
thermogram substantially in accordance with FIG. 2.
[0026] B. Methods of Making a Free Base Crystalline Form of
Compound 1
[0027] Compound 1 can be prepared as described previously. See, for
example, WO2010/075257, the contents of each are incorporated by
reference in their entirety for all purposes.
[0028] The free base crystalline form described herein can be
prepared as described in the provided Examples. It is understood
that there may be more than one crystallization method that will
yield the described free base crystalline form.
[0029] C. Pharmaceutical Compositions
[0030] Provided herein are pharmaceutical compositions comprising a
free base crystalline form of Compound 1 or liquid pharmaceutical
compositions prepared using the free base crystalline form of
Compound 1. Pharmaceutical compositions will include one or more
pharmaceutically acceptable excipients.
[0031] The pharmaceutical compositions containing the free base
crystalline form of Compound 1 may be in a form suitable for oral
use, for example, as tablets, troches, lozenges, liquid
formulations, aqueous or oily suspensions, dispersible powders or
granules, emulsions and self emulsifications as described in U.S.
Patent Application 2002-0012680, hard or soft capsules, syrups,
elixirs, solutions, buccal patch, oral gel, chewing gum, chewable
tablets, effervescent powder and effervescent tablets. Compositions
intended for oral use may be prepared according to any method known
to the art for the manufacture of pharmaceutical compositions and
such compositions may contain one or more agents selected from the
group consisting of sweetening agents, flavoring agents, coloring
agents, antioxidants and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the free base crystalline form of Compound 1 in admixture
with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as cellulose, silicon dioxide,
aluminum oxide, calcium carbonate, sodium carbonate, glucose,
mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example PVP, cellulose, PEG,
starch, gelatin or acacia, and lubricating agents, for example
magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated, enterically or otherwise, by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated by the techniques described in the U.S. Pat.
Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to form
osmotic therapeutic tablets for control release.
[0032] Formulations for oral use may also be presented as hard
gelatin capsules wherein the free base crystalline form of Compound
1 is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules
wherein the free base crystalline form of Compound 1 is mixed with
water or an oil medium, for example peanut oil, liquid paraffin, or
olive oil. Additionally, emulsions can be prepared with a non-water
miscible ingredient such as oils and stabilized with surfactants
such as mono-diglycerides, PEG esters and the like.
[0033] Aqueous suspensions for oral use contain the free base
crystalline form of Compound 1 in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such
excipients are suspending agents, for example sodium
carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, hydroxy-propylcellulose, sodium
alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring
phosphatide, for example lecithin, or condensation products of an
alkylene oxide with fatty acids, for example polyoxy-ethylene
stearate, or condensation products of ethylene oxide with long
chain aliphatic alcohols, for example heptadecaethyleneoxycetanol,
or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene
sorbitol monooleate, or condensation products of ethylene oxide
with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate as well as
other poloxamers (e.g. Poloxamer F-68). The aqueous suspensions may
also contain one or more preservatives, for example ethyl, or
n-propyl, p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0034] Accordingly, provided herein is aqueous suspension
comprising the free base crystalline form of Compound 1 and at
least one excipient. In some embodiments, the at least one
excipient is at least one suspending agent and/or at least one
wetting agent as described above.
[0035] Oily suspensions for oral use may be formulated by
suspending the free base crystalline form of Compound 1 in a
vegetable oil, for example arachis oil, olive oil, sesame oil or
coconut oil, or in a mineral oil such as liquid paraffin. The oily
suspensions may contain a thickening agent, for example beeswax,
hard paraffin or cetyl alcohol. Sweetening agents such as those set
forth above, and flavoring agents may be added to provide a
palatable oral preparation. These compositions may be preserved by
the addition of an anti-oxidant such as ascorbic acid.
[0036] The pharmaceutical compositions may be in the form of a
sterile injectable or infusable aqueous or oleagenous solution or
suspension. This solution or suspension may be formulated according
to the known art using those suitable dispersing or wetting agents
and suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butane diol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution, isotonic sodium chloride solution, isotonic
aqueous buffer solutions, as well as mixtures of saline, a
disintegrating agent such as PEG (e.g. PEG 200, PEG 400, PEG 800,
etc), and nonionic surfactants such as Tween80. In addition,
sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed including synthetic mono- or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables and infusables. Compositions for injectable or
infusable administration optionally include a local anesthetic such
as lignocaine to ease pain at the site of the injection.
Ingredients can be supplied pre-mixed or supplied separately, with
mixing of the ingredients occurring shortly before use. In some
embodiments, mixing shortly before use is desirable to take
advantage of the high initial solubility of the free base
crystalline form of Compound 1 in certain liquid formulation
mixtures.
[0037] Injectable or infusible compositions includes, but is not
limited to, intravenous administration, intramuscular
administration as well as subcutaneous or intrasternal injection.
Accordingly, in some embodiments, provided herein is an injectable
or infusible solution comprising Compound 1 and at least one
wetting agent or solvent, wherein the intravenous pharmaceutical
composition is prepared using the free base crystalline form of
Compound 1 described herein. In some embodiments, the injectable or
infusible solution is prepared for intravenous administration. In
some embodiments, the injectable or infusible solution is prepared
for intramuscular administration. In some embodiments, the
injectable or infusible solution is prepared for subcutaneous
injection. In some embodiments, the injectable or infusible
solution is prepared for intrasternal injection. In some
embodiments, the at least one wetting agent or solvent in the
injectable or infusible pharmaceutical composition includes saline,
a disintegrating agent, and nonionic surfactant.
[0038] Injectable or infusible compositions can be prepared at any
time that is convenient for the medical practitioner or user; this
includes shortly before use or well in advance of use. In some
embodiments, the composition is prepared shortly before use.
Shortly before use includes 0-24 hours before use, 0-10 hours
before use, 0-5 hours before use, or 0-1 hours before use. In some
embodiments, the injectable or infusible composition is prepared
0-5 hours before use. Well in advance typically refers to one or
more days before use. Accordingly, also provided herein are methods
of preparing injectable or infusible solution. The method
including, dissolving the free base crystalline form of Compound 1
with the at least one wetting agent or solvent to prepare an
injectable or infusible solution; and administering the injectable
or infusible solution to a subject in need thereof.
[0039] Dispersible powders and granules suitable for preparation of
an aqueous oral formulations or oral suspensions by the addition of
water provide the free base crystalline form of Compound 1 in
admixture with a dispersing or wetting agent, suspending agent and
one or more preservatives. Suitable dispersing or wetting agents
and suspending agents are exemplified by those already mentioned
above. Additional excipients, for example sweetening, flavoring and
coloring agents, may also be present.
[0040] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0041] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and
surfactants.
[0042] The compounds of the present invention may also be
administered in the form of suppositories for rectal administration
of the drug. These compositions can be prepared by mixing the free
base crystalline form of Compound 1 with a suitable non-irritating
excipient which is solid at ordinary temperatures but liquid at the
rectal temperature and will therefore melt in the rectum to release
the drug. Such materials include cocoa butter and polyethylene
glycols. Additionally, the compounds can be administered via ocular
delivery by means of solutions or ointments. Still further,
transdermal delivery of the subject compounds can be accomplished
by means of iontophoretic patches and the like. For topical use,
creams, ointments, jellies, solutions or suspensions, etc.,
containing the compounds of the present invention are employed. As
used herein, topical application is also meant to include the use
of mouth washes and gargles.
[0043] The compounds of this invention may also be coupled a
carrier that is a suitable polymers as targetable drug carriers.
Such polymers can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxy-propyl-methacrylamide-phenol,
polyhydroxyethyl-aspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds of the invention may be coupled to a
carrier that is a class of biodegradable polymers useful in
achieving controlled release of a drug, for example polylactic
acid, polyglycolic acid, copolymers of polylactic and polyglycolic
acid, polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates
and cross linked or amphipathic block copolymers of hydrogels.
Polymers and semipermeable polymer matrices may be formed into
shaped articles, such as valves, stents, tubing, prostheses and the
like. In one embodiment of the invention, the compound of the
invention is coupled to a polymer or semipermeable polymer matrix
that is formed as a stent or stent-graft device.
[0044] D. Methods of Treatment
[0045] Also provided herein are methods of treating individuals
suffering from conditions that are responsive to C5a receptor
modulation.
[0046] In some aspects provided herein are methods of treating an
individual suffering from or susceptible to a disease or disorder
involving pathologic activation of C5a receptors, comprising
administering to the individual an effective amount of a free base
crystalline form of Compound 1 or a pharmaceutical formulation
including Compound 1 as described herein.
[0047] In some embodiments, the free base crystalline form of
Compound 1 described herein is used for treating patients suffering
from conditions that are responsive to C5a receptor modulation.
Conditions that can be Treated by C5a Modulation:
[0048] Autoimmune disorders--e.g., Rheumatoid arthritis, systemic
lupus erythematosus, Guillain-Barre syndrome, pancreatitis, C3
glomerulopathy (C3G), hidradenitis suppurativa (HS), lupus
nephritis, lupus glomerulonephritis, immunoglobulin A (IgA)
nephropathy, psoriasis, Crohn's disease, vasculitis, irritable
bowel syndrome, dermatomyositis, multiple sclerosis, bronchial
asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis,
autoimmune hemolytic and thrombocytopenic states, Goodpasture's
syndrome (and associated glomerulonephritis and pulmonary
hemorrhage), immunovasculitis, tissue graft rejection, hyperacute
rejection of transplanted organs; and the like.
[0049] Inflammatory disorders and related conditions--e.g.,
Neutropenia, sepsis, septic shock, Alzheimer's disease, multiple
sclerosis, stroke, inflammatory bowel disease (IBD), age-related
macular degeneration (AMD, both wet and dry forms), inflammation
associated with severe burns, lung injury, and ischemia-reperfusion
injury, osteoarthritis, as well as acute (adult) respiratory
distress syndrome (ARDS), chronic pulmonary obstructive disorder
(COPD), systemic inflammatory response syndrome (SIRS), atopic
dermatitis, psoriasis, chronic urticaria and multiple organ
dysfunction syndrome (MODS). Also included are pathologic sequellae
associated with insulin-dependent diabetes mellitus (including
diabetic retinopathy), lupus nephropathy, Heyman nephritis,
membranous nephritis and other forms of glomerulonephritis, contact
sensitivity responses, and inflammation resulting from contact of
blood with artificial surfaces that can cause complement
activation, as occurs, for example, during extracorporeal
circulation of blood (e.g., during hemodialysis or via a heart-lung
machine, for example, in association with vascular surgery such as
coronary artery bypass grafting or heart valve replacement), or in
association with contact with other artificial vessel or container
surfaces (e.g., ventricular assist devices, artificial heart
machines, transfusion tubing, blood storage bags, plasmapheresis,
plateletpheresis, and the like). Also included are diseases related
to ischemia/reperfusion injury, such as those resulting from
transplants, including solid organ transplant, and syndromes such
as ischemic reperfusion injury, ischemic colitis and cardiac
ischemia. The free base crystalline form of Compound 1 described
herein may also be useful in the treatment of age-related macular
degeneration (Hageman et al, P.N.A.S.102: 7227-7232, 2005).
[0050] Cardiovascular and Cerebrovascular Disorders--e.g.,
myocardial infarction, coronary thrombosis, vascular occlusion,
post-surgical vascular reocclusion, atherosclerosis, traumatic
central nervous system injury, and ischemic heart disease. In one
embodiment, an effective amount of a free base crystalline form of
Compound 1 described herein may be administered to a patient at
risk for myocardial infarction or thrombosis (i.e., a patient who
has one or more recognized risk factor for myocardial infarction or
thrombosis, such as, but not limited to, obesity, smoking, high
blood pressure, hypercholesterolemia, previous or genetic history
of myocardial infarction or thrombosis) in order reduce the risk of
myocardial infarction or thrombosis.
[0051] Diseases of Vasculitis--Vasculitic diseases are
characterized by inflammation of the vessels. Infiltration of
leukocytes leads to destruction of the vessel walls, and the
complement pathway is believed to play a major role in initiating
leukocyte migration as well as the resultant damage manifested at
the site of inflammation (Vasculitis, Second Edition, Edited by
Ball and Bridges, Oxford University Press, pp 47-53, 2008). The
free base crystalline form of Compound 1 described herein can be
used to treat vasculitis, including anti-neutrophil cytoplasmic
antibody associate vasculitis (or ANCA-associated vasculitis, which
includes microscopic polyangiitis, eosinophilic granulomatosis with
polyangitis, and granulomatosis with polyangiitis, which is also
known as Wegener's disease), Churg-Strauss syndrome,
Henoch-Schonlein purpura, polyateritis nodosa, Rapidly Progressive
Glomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis
(GCA), Behcet's disease and Takayasu's arteritis (TAK).
[0052] HIV infection and AIDS--the free base crystalline form of
Compound 1 described herein may be used to inhibit HIV infection,
delay AIDS progression or decrease the severity of symptoms or HIV
infection and AIDS.
[0053] Neurodegenerative disorders and related diseases--Within
further embodiments, the free base crystalline form of Compound 1
described herein may be used to treat Alzheimer's disease, multiple
sclerosis, and cognitive function decline associated with
cardiopulmonary bypass surgery and related procedures.
[0054] Cancers--The free base crystalline form of Compound 1
described herein are also useful for the treatment of cancers and
precancerous conditions in a subject. Specific cancers that can be
treated include, but are not limited to, sarcomas, carcinomas, and
mixed tumors. Exemplary conditions that may be treated according to
the present invention include fibrosarcomas, liposarcomas,
chondrosarcomas, osteogenic sarcomas, angiosarcomas,
lymphangiosarcomas, synoviomas, mesotheliomas, meningiomas,
leukemias, lymphomas, leiomyosarcomas, rhabdomyosarcomas, squamous
cell carcinomas, basal cell carcinomas, adenocarcinomas, papillary
carcinomas, cystadenocarcinomas, bronchogenic carcinomas,
melanomas, renal cell carcinomas, hepatocellular carcinomas,
transitional cell carcinomas, choriocarcinomas, seminomas,
embryonal carcinomas, wilm's tumors, pleomorphic adenomas, liver
cell papillomas, renal tubular adenomas, cystadenomas, papillomas,
adenomas, leiomyomas, rhabdomyomas, hemangiomas, lymphangiomas,
osteomas, chondromas, lipomas and fibromas.
[0055] In some embodiments, the free base crystalline form of
Compound 1 described herein can be used for the treatment of
diseases selected from the group consisting of sepsis (and
associated disorders), COPD, rheumatoid arthritis, lupus nephritis
and multiple sclerosis.
[0056] In some embodiments, the free base crystalline form of
Compound 1 described herein can be used for the treatment of
diseases selected from the group consisting of anti-neutrophil
cytoplasmic antibody associate (ANCA) vasculitis, C3
glomerulopathy, hidradenitis suppurativa, and lupus nephritis.
[0057] Treatment methods provided herein include, in general,
administration to a patient an effective amount of a free base
crystalline form of Compound 1. Suitable patients include those
patients suffering from or susceptible to (i.e., prophylactic
treatment) a disorder or disease identified herein. Typical
patients for treatment as described herein include mammals,
particularly primates, especially humans. Other suitable patients
include domesticated companion animals such as a dog, cat, horse,
and the like, or a livestock animal such as cattle, pig, sheep and
the like.
[0058] In general, treatment methods provided herein comprise
administering to a patient an effective amount of the free base
crystalline form of Compound 1 described herein. The exact
formulation, route of administration and dosage for the
pharmaceutical compositions of the present invention can be chosen
by the individual physician in view of the patient's condition.
(See e.g., Fingl et al. 1975, in "The Pharmacological Basis of
Therapeutics", which is hereby incorporated herein by reference in
its entirety, with particular reference to Ch. 1, p. 1). In some
embodiments, the free base crystalline form of Compound 1 described
herein is administered to a patient (e.g., a human) orally. In some
embodiments, the free base crystalline form of Compound 1 described
herein is administered to a patient (e.g., a human) intravenously,
intramuscularly, or via subcutaneous or intrasternal injection. The
effective amount may be an amount sufficient to modulate C5a
receptor activity and/or an amount sufficient to reduce or
alleviate the symptoms presented by the patient. Preferably, the
amount administered is sufficient to yield a plasma concentration
of the compound (or its active metabolite, if the compound is a
pro-drug) high enough to detectably inhibit white blood cell (e.g.,
neutrophil) chemotaxis in vitro.
[0059] For treatment of most disorders via oral administration, a
person of skill in the art may determine the appropriate frequency
of administration. In some embodiments, a frequency of
administration of 4 times daily or less is preferred. In some
embodiments, a dosage regimen of 2 times daily is used. In some
embodiments, once daily administration is used. The patient may be
administered a free base crystalline form of Compound 1 in a fed or
fasted state. In some embodiments, the patient takes the free base
crystalline form Compound 1 with food. In some embodiments, the
patient takes the free base crystalline form of Compound 1 without
food.
[0060] For treatment of most disorders via intravenous,
intramuscular administration or via subcutaneous or intrasternal
injection, a person of skill in the art may determine the
appropriate frequency of administration. In some embodiments, the
frequency of administration is about once every two weeks. In some
embodiments, the frequency of administration is about once every
week. In some embodiments, the frequency of administration is about
three times a week. In some embodiments, the frequency of
administration is about 2 to 5 times a week. In some embodiments,
the frequency of administration is about once every other day. In
some embodiments, the frequency of administration is about once a
day.
[0061] It will be understood, however, that the specific dose level
and treatment regimen for any particular patient will depend upon a
variety of factors including the age, body weight, general health,
sex, diet, time of administration, route of administration, rate of
excretion, drug combination (i.e., other drugs being administered
to the patient) and the severity of the particular disease
undergoing therapy, as well as the judgment of the prescribing
medical practitioner. In general, the use of the minimum dose
sufficient to provide effective therapy is preferred. Patients may
generally be monitored for therapeutic effectiveness using medical
or veterinary criteria suitable for the condition being treated or
prevented.
[0062] Dosage levels of the order of from about 0.1 mg to about 140
mg per kilogram of body weight per day are useful in the treatment
or preventions of conditions involving pathogenic C5a activity
(about 0.5 mg to about 7 g per human patient per day). The amount
of the free base crystalline form of Compound 1 that may be
combined with the carrier materials to produce a single dosage form
will vary depending upon the host treated and the particular mode
of administration. Dosage unit forms will generally contain between
from about 1 mg to about 500 mg of the free base crystalline form
of Compound 1. When administered orally, transdermally,
intravaneously, or subcutaneously, it is preferred that sufficient
amount of the free base crystalline form of Compound 1 be
administered to achieve a serum concentration of 5 ng
(nanograms)/mL-10 .mu.g (micrograms)/mL serum, more preferably
sufficient compound to achieve a serum concentration of 20 ng-1
.mu.g/ml serum should be administered, most preferably sufficient
compound to achieve a serum concentration of 50 ng/ml-200 ng/ml
serum should be administered. For direct injection into the
synovium (for the treatment of arthritis) sufficient amounts of the
free base crystalline form of Compound 1 should be administered to
achieve a local concentration of approximately 1 micromolar.
[0063] E. Combination Therapy
[0064] The presently disclosed methods may include combination
therapy with one or more additional therapeutic agents that are
used in the treatment, prevention, suppression or amelioration of
the diseases or conditions involving pathologic activation of C5a
receptors. Such one or more additional therapeutic agents may be
administered, by a route and in an amount commonly used therefor,
contemporaneously or sequentially with the free base crystalline
form of Compound 1. When the free base crystalline form of Compound
1 is used contemporaneously with the additional therapeutic agent,
a pharmaceutical composition containing such other drugs in
addition to the free base crystalline form of Compound 1 is
preferred. Accordingly, the pharmaceutical compositions of the
present disclosure include those that also contain one or more
other active ingredients or therapeutic agents, in addition to the
free base crystalline form of Compound 1.
[0065] Examples of the one or more additional therapeutic agents
are corticosteroids, steroids, immunosuppressants, Immunoglobulin G
agonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte function
antigen-3 receptor antagonists, Interleukin-2 ligands,
Interleukin-1 beta ligand inhibitors, IL-2 receptor alpha subunit
inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5
antagonists, Alpha 1 antitrypsin stimulators, Cannabinoid receptor
antagonists, Histone deacetylase inhibitors, AKT protein kinase
inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK
tyrosine kinase inhibitors, TNF alpha ligand inhibitors, Hemoglobin
modulators, TNF antagonists, proteasome inhibitors, CD3 modulators,
Hsp 70 family inhibitors, Immunoglobulin agonists, CD30
antagonists, tubulin antagonists, Sphingosine-1-phosphate
receptor-1 agonists, connective tissue growth factor ligand
inhibitors, caspase inhibitors, adrenocorticotrophic hormone
ligands, Btk tyrosine kinase inhibitors, Complement Cis
subcomponent inhibitors, Erythropoietin receptor agonists,
B-lymphocyte stimulator ligand inhibitors, Cyclin-dependent
kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators,
mTOR inhibitors, Elongation factor 2 inhibitors, Cell adhesion
molecule inhibitors, Factor XIII agonists, Calcineurin inhibitors,
Immunoglobulin G1 agonists, Inosine monophosphate dehydrogenase
inhibitors, Complement Cis subcomponent inhibitors, Thymidine
kinase modulators, Cytotoxic T-lymphocyte protein-4 modulators,
Angiotensin II receptor antagonists, Angiotensin II receptor
modulators, TNF superfamily receptor 12A antagonists, CD52
antagonists, Adenosine deaminase inhibitors, T-cell differentiation
antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase
inhibitors, Syk tyrosine kinase inhibitors, Interferon type I
receptor antagonists, Interferon alpha ligand inhibitors,
Macrophage migration inhibitory factor inhibitors, Integrin
alpha-V/beta-6 antagonists, Cysteine protease stimulators, p38 MAP
kinase inhibitors, TP53 gene inhibitors, Shiga like toxin I
inhibitors, Fucosyltransferase 6 stimulators, Interleukin 22
ligands, IRS1 gene inhibitors, Protein kinase C stimulators,
Protein kinase C alpha inhibitors, CD74 antagonists, Immunoglobulin
gamma Fc receptor IIB antagonists, T-cell antigen CD7 inhibitors,
CD95 antagonists, N acetylmannosamine kinase stimulators,
Cardiotrophin-1 ligands, Leukocyte elastase inhibitors, CD40 ligand
receptor antagonists, CD40 ligand modulators, IL-17 antagonists,
TLR-2 antagonists, Mannan-binding lectin serine protease-2 (MASP-2)
inhibitors, Factor B inhibitors, Factor D inhibitors, C3aR
modulators, C5aR2 modulators, T cell receptor antagonists, PD-1
inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors,
LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors,
adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors,
antagonists of the chemokine receptors, especially CXCR1, CXCR2,
CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7,
CCR9, CX3CR1 and CXCR6, and combinations thereof.
[0066] In some embodiments, the additional therapeutic agent used
in the therapeutic methods herein, is selected from the group
consisting of obinutuzumab, rituximab, ocrelizumab, tositumomab,
obinutuzumab, ibritumomab, cyclophosphamide, prednisone,
hydrocortisone, hydrocortisone acetate, cortisone acetate,
tixocortol pivalate, prednisolone, methylprednisolone,
triamcinolone acetonide, triamcinolone alcohol, mometasone,
amcinonide, budesonide, desonide, fluocinonide, fluocinolone
acetonide, halcinonide, betamethasone, betamethasone sodium
phosphate, dexamethasone, dexamethasone sodium phosphate,
fluocortolone, hydrocortisone-17-valerate, halometasone,
alclometasone dipropionate, beclomethasone, betamethasone valerate,
betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate,
clobetasol-17-propionate, fluocortolone caproate, fluocortolone
pivalate, fluprednidene acetate, hydrocortisone-17-butyrate,
hydrocortisone-17-aceponate, hydrocortisone-17-buteprate,
ciclesonide and prednicarbate, GB-0998, immuglo, begelomab,
alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab,
inolimomab, beperminogene perplasmid, sirukumab, tocilizumab,
clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine,
nilotinib, imatinib, tofacitinib, momelotinib, peficitinib,
itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib,
bortezomib, muromonab, otelixizumab, gusperimus, brentuximab
vedotin, Ponesimod, KRP-203, FG-3019, emricasan, corticotropin,
ibrutinib, cinryze, conestat, methoxy polyethylene glycol-epoetin
beta, belimumab, blisibimod, atacicept, seliciclib, neihulizumab,
everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab,
catridecacog, ciclosporin, tacrolimus, voclosporin, voclosporin,
canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept,
belatacept, olmesartan medoxomil, sparsentan, TXA-127, BIIB-023,
alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide,
PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab,
BAX-069, BG-00011, losmapimod, QPI-1002, ShigamAbs, TZ-101, F-652,
reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin,
sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74,
cardiotrophin-1, tiprelestat, ASKP-1240, BMS-986004, HPH-116,
KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, Thymoglobulin,
laquinimod, remestemcel-L, Equine antithymocyte immunoglobulin,
Stempeucel, LIV-Gamma, Octagam 10%, t2c-001, 99mTc-sestamibi,
Clairyg, Prosorba, pomalidomide, laquinimod, teplizumab, FCRx,
solnatide, foralumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU,
irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001, saratin,
anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100,
LT-1951, OMS721, ALN-CC5, ACH-4471, AMY-101, Acthar gel, and
CD4+CD25+ regulatory T-cells, MEDI7814, P32, P59, pembrolizumab,
nivolumab, atezolizumab, avelumab, durvalumab, CCX354, CCX721,
CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282,
CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and
combinations thereof.
IV. Examples
[0067] The following examples are provided to help illustrate the
described invention and are not intended to limit the scope of what
the inventors regard as their invention.
Example 1: Preparing a Crystalline Form of Compound 1
[0068] Crude Compound 1 was prepared essentially as described in WO
2016/053890.
[0069] A crystalline form of Compound 1 was prepared by dissolving
18 g of crude Compound 1 in 50 mL acetone with heating at
40.degree. C. (a concentration of about -0.36 g/mL). The warm
solution was passed through a 10 .mu.m polyethylene filter. The
solution was then loaded into rotary evaporator at 30.degree. C.
bath temperature and 180 rpm rotational speed. The solid collected
was dried further in a 45.degree. C. oven for 1 hour. The XRPD data
of the crystalline form is shown in FIG. 1, and the table of peaks
measured are listed in Table 1, below.
TABLE-US-00001 TABLE 1 Significant Peaks of Free Base Crystalline
Form of Compound 1 Significant Peaks 2-theta (deg) 8.06 20.28 8.40
21.32 8.88 22.36 10.20 22.60 10.72 23.14 12.35 23.46 13.44 24.42
14.10 24.66 15.21 25.05 16.05 25.48 16.20 26.20 16.92 26.44 17.28
27.18 17.64 27.60 18.58 28.70 19.00 29.28 19.44 29.60
Example 2: Differential Scanning Calorimetry (DSC) and Thermal
Gravimetic Analysis (TGA) of the Free Base Crystalline Form of
Compound 1
[0070] To evaluate the physical characteristics of the free base
crystalline form of Compound 1, differential scanning calorimetry
data was collected. Differential scanning calorimeter model DSC25
from TA Instruments.about. Waters LLC was used. Sample was weighed
into a standard aluminum pan and sealed by a standard aluminum lid
with pinhole. The measurement was completed by using 10.degree.
C./min scanning rate, under a nitrogen purge. The DSC analysis
determined that the free base crystalline form exhibits a melting
(on set) of .about.213.degree. C. and a endothermic peak at around
216.degree. C. A plot of the DSC thermogram is shown in FIG. 2.
[0071] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, one of skill in the art will appreciate that
certain changes and modifications may be practiced within the scope
of the appended claims. In addition, each reference provided herein
is incorporated by reference in its entirety to the same extent as
if each reference was individually incorporated by reference. Where
a conflict exists between the instant application and a reference
provided herein, the instant application shall dominate.
* * * * *