U.S. patent application number 12/027552 was filed with the patent office on 2008-06-05 for materials and methods for treating hypercholesterolemia.
This patent application is currently assigned to ARYx Therapeutics, Inc.. Invention is credited to Pascal Druzgala, Jurg R. Pfister, Xiaoming Zhang.
Application Number | 20080132561 12/027552 |
Document ID | / |
Family ID | 30770990 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080132561 |
Kind Code |
A1 |
Druzgala; Pascal ; et
al. |
June 5, 2008 |
Materials and Methods for Treating Hypercholesterolemia
Abstract
The subject invention provides novel HMG-CoA-reductase
inhibitors. In a preferred embodiment, the HMG-CoA reductase
inhibitors of the subject invention can be deactivated to a primary
inactive metabolite by hydrolytic enzymes. Compounds of the present
invention can be advantageously used to treat patients suffering
hypercholesterolemia.
Inventors: |
Druzgala; Pascal; (Santa
Rosa, CA) ; Zhang; Xiaoming; (Campbell, CA) ;
Pfister; Jurg R.; (Los Altos, CA) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE, 32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
ARYx Therapeutics, Inc.
Fermont
CA
|
Family ID: |
30770990 |
Appl. No.: |
12/027552 |
Filed: |
February 7, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11220364 |
Sep 6, 2005 |
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12027552 |
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10624659 |
Jul 21, 2003 |
6951877 |
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11220364 |
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60397076 |
Jul 19, 2002 |
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Current U.S.
Class: |
514/419 |
Current CPC
Class: |
A61K 31/405 20130101;
A61P 9/00 20180101; C07C 69/675 20130101; C07C 2602/28 20170501;
C07D 209/12 20130101; C07D 209/24 20130101; A61P 3/06 20180101;
A61P 43/00 20180101; C07C 69/732 20130101; A61K 31/47 20130101;
C07D 307/80 20130101; C07D 213/55 20130101; C07D 207/34 20130101;
C07D 311/72 20130101; C07D 239/42 20130101; C07D 215/14 20130101;
A61K 31/505 20130101; C07C 69/708 20130101 |
Class at
Publication: |
514/419 |
International
Class: |
A61K 31/405 20060101
A61K031/405; A61P 9/00 20060101 A61P009/00 |
Claims
1-14. (canceled)
15. A method of inhibiting HMG-COA comprising administering a
therapeutically effective amount of a compound or salt to a patient
in need of such treatment, wherein the compound has the formula:
##STR00001## or pharmaceutically acceptable salts thereof, where n
is 1, 2, or 3; and where R is ##STR00002##
16. A method of inhibiting HMG-COA comprising administering a
therapeutically effective amount of a compound or salt to a patient
in need of such treatment, wherein the compound has the formula:
##STR00003## or pharmaceutically acceptable salts thereof, where n
is 0,1, 2, or 3; and where R is ##STR00004##
17. A method of lowering cholesterol levels comprising
administering a therapeutically effective amount of a compound or
salt to a patient in need of such treatment, wherein the compound
has the formula: ##STR00005## or pharmaceutically acceptable salts
thereof, where n is 1, 2, or 3; and where R is ##STR00006##
18. A method according to claim 17, wherein the patient is a
human.
19. A method of lowering cholesterol levels comprising
administering a therapeutically effective amount of a compound or
salt to a patient in need of such treatment, wherein the compound
has the formula: ##STR00007## or pharmaceutically acceptable salts
thereof, where n is 0, 1, 2, or 3; and where R is ##STR00008##
20. A method according to claim 19, wherein the patient is a
human.
21. A method of preventing coronary artery disease by lowering low
density lipoprotein (LDL) levels, the method comprising
administering a therapeutically effective amount of a compound or
salt to a patient in need of such treatment, wherein the compound
has the formula: ##STR00009## or pharmaceutically acceptable salts
thereof, where n is 1, 2, or 3; and where R is ##STR00010##
22. A method of preventing coronary artery disease by lowering low
density lipoprotein (LDL) levels, the method comprising
administering a therapeutically effective amount of a compound or
salt of claim 1 to a patient in need of such treatment, wherein the
compound has the formula: ##STR00011## or pharmaceutically
acceptable salts thereof, where n is 0, 1, 2, or 3; and where R is
##STR00012##
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/397,076, filed Jul. 19, 2002.
BACKGROUND OF INVENTION
[0002] Elevated levels of low-density lipoprotein (LDL)-cholesterol
has been recognized as the most important risk factor for Coronary
Artery Disease (CAD). The most effective method of LDL-cholesterol
lowering is the administration of inhibitors of HMG-CoA reductase
(statins), a rate-limiting key enzyme of the cholesterol synthesis
pathway. Since the discovery of compactin and lovastatin, both of
which were compounds of microbial origin, primary and secondary
preventive measures have been established in several statin trials
to help prevent future events of CAD by lowering LDL-cholesterol
levels. To date, pravastatin, lovastatin, simvastatin, fluvastatin,
cerivastatin and atorvastatin have been used in clinical
practice.
[0003] Several landmark studies demonstrate that primary and
secondary prevention strategies with lipid-lowering therapies
provide significant reductions in cardiovascular morbidity and
mortality. The Helsinki Heart Study demonstrated the benefit of
lipid lowering in asymptomatic, middle-aged men with primary
hypercholesterolemia. Treatment with gemfibrozil increased HDL
cholesterol and lowered LDL, cholesterol; this improved lipid
profile was associated with a significant 34% reduction in CHD risk
over the 5-year follow-up period.
[0004] The Scandinavian Simvastatin Survival Study (4S) and the
Cholesterol and RecurrentEvents (CARE) trial demonstrated the
benefit of lipid lowering with statins in patients with established
CAD. In 4S, simvastatin treatment reduced LDL cholesterol by 35%
and increased HDL cholesterol by 8%. This was associated with
significant 30% and 42% reductions in all-cause and coronary
mortality risk, respectively, and a 34% reduction in major coronary
events over the mean 5.4-year follow-up period. In the CARE study,
pravastatin significantly reduced risk for fatal coronary events or
nonfatal MI by 24% over a 5-year period. Taken together, these
studies demonstrate that a reduction in LDL cholesterol of
approximately 25%-35% significantly reduces risk for cardiovascular
morbidity and mortality in patients with or without established
CAD.
[0005] Several recent studies using quantitative coronary
angiography demonstrate that lipid lowering slows progression of
coronary atherosclerosis in CAD patients. In the Lipoprotein and
Coronary Atherosclerosis Study (LCAS), fluvastatin was administered
to patients with angiographic CAD who had baseline LDL cholesterol
levels of 115-190 mg/dL. Fluvastatin reduced LDL cholesterol by 24%
and significantly reduced progression of coronary atherosclerosis
over the 2.5-year follow-up period. In the Pravastatin Limitation
of Atherosclerosis in the Coronary Artery (PLAC I) study,
pravastatin was administered to CAD patients with baseline LDL
cholesterol levels of 130-190 mg/dL. Pravastatin significantly
reduced LDL cholesterol by 28% and atherosclerotic progression by
40% over the 3-year follow-up. As coronary atherosclerosis
progresses, interventional procedures, such as balloon angioplasty,
must be performed to reduce cardiac risk. Therefore, the
Atorvastatin Versus Revascularization Treatments (AVERT) study was
designed to ascertain if aggressive lipid lowering with
atorvastatin can be used as an alternative to angioplasty or other
catheter-based revascularization procedures in patients with
significant CAD. The primary end point in this ongoing 18-month,
open-label trial is the incidence of ischemic events.
[0006] The statins, in general are well tolerated during long-term
use as evidenced by results from the major outcomes studies. The
most serious adverse event associated with statins is myopathy,
which occurs in 0.2% or less of treated patients. Myopathy is
characterized by myalgia, muscle tenderness and weakness, and
marked elevation in creatine phosphokinase to 10 or more times the
upper limits of normal (ULN). In rare cases, myopathy may progress
to rhabdomyolysis with acute renal failure. Risk for myopathy and
rhabdomyolysis is increased by concomitant use of statins with
gemfibrozil, cyclosporine, erythromycin, niacin, or azole
antifungal agents. In approximately 1%-2% of patients, statins
cause persistent elevations in liver function enzymes that are 3
times greater than the ULN. The incidence of elevated liver enzymes
increases with higher statin doses. For example, during clinical
trials with atorvastatin, elevated liver enzymes were found in 0.2%
of patients receiving doses of 10 or 20 mg, 0.6% of those receiving
40 mg, and 2.3% of those receiving 80 mg. In general, a reduction
in dose or discontinuation of statin treatment results in the
return of liver enzymes to baseline levels.
[0007] While all statins have been associated with very rare
reports of rhabdomyolysis, cases of fatal rhabdomyolysis in
association with the use of cerivastatin have been reported
significantly more frequently than for other approved statins.
Fatal rhabdomyolysis reports with cerivastatin have been reported
most frequently when used at higher doses, when used in elderly
patients, and particularly, when used in combination with
gemfibrozil (LOPID and generics), another lipid lowering drug. FDA
has received reports of 31 U.S. deaths due to severe rhabdomyolysis
associated with use of cerivastatin, 12 of which involved
concomitant gemfibrozil use.
[0008] The rare rhabdomyolysis is presumed to be the result of
higher level of systemic exposure of statins. Therefore
HMG-CoA-reductase inhibitors with high first-pass metabolism and/or
short plasma half-life would be desirable, since they will have
limited systemic exposure and more predictable metabolic
profile.
BRIEF SUMMARY
[0009] The subject invention provides new and advantageous
materials and methods for treating hypercholesterolemia. The
compositions and therapeutic methods of the subject invention can
be used to effectively and safely reduce cholesterol levels.
Specifically exemplified herein are novel inhibitors of HMG-CoA
reductase. The use of these compounds helps to prevent Coronary
Artery Disease (CAD) by lowering LDL cholesterol levels.
[0010] The compounds of the subject invention are particularly
advantageous because of their favorable metabolic profile.
Specifically, these compounds are readily metabolized by hydrolytic
enzymes. Thus, these compounds which have a highly predictable
pharmokinetic profile are particularly advantageous because they
reduce systemic exposure to the active drug.
[0011] The present invention also provides methods of treatment
which involve administering an effective amount of a compound of
the present invention to a person in need of such treatment.
BRIEF DESCRIPTION OF DRAWINGS
[0012] FIG. 1A-1F shows the structures of various compounds
currently used for lowering cholesterol levels.
[0013] FIG. 2A-2N shows specific compounds of the subject
invention.
[0014] FIG. 3A-3N shows specific compounds of the subject
invention.
[0015] FIGS. 4-6 provide examples of synthesis procedures which can
be used to produce compounds of the subject invention. FIG. 4(a)
NaH, BuLi, cinnamaldehyde (b) NaBH.sub.4, triethylborane (c)
Acetone dimethylacetal, H.sup.+ (d) OsO.sub.4/NaIO.sub.4. FIG. 5(a)
NaBH.sub.4 (b) RCOCl/Triethylamine (c) H.sub.2, Pd/C, then H.sup.+.
FIG. 6(a) PDC/DMF (b) ROH/DCC (c) H.sub.2, Pd/C, then H.sup.+.
DETAILED DISCLOSURE
[0016] The subject invention provides novel HMG-CoA-reductase
inhibitors. In a preferred embodiment, the HMG-CoA reductase
inhibitors of the subject invention can be deactivated to a primary
inactive metabolite by hydrolytic enzymes. Compounds of the present
invention can be advantageously used to treat individuals suffering
hypercholesterolemia. The compounds of the subject invention are
particularly advantageous because they have more predictable
pharmacokinetics and reduced systemic exposure of the drugs.
[0017] As used herein, the term "individual(s)" refers to a mammal
to which is administered a compound or composition of the present
invention. The mammal may be, for example a mouse, rat, pig, horse,
rabbit, goat, pig, cow, cat, dog, or human. In a preferred
embodiment, the individual is a human.
[0018] Lovastatin, pravastain, simvastatin, atorvastatin,
cerivastatin and fluvastatin are widely used for treating
hypercholesterolemia (FIG. 1A-1F). The present invention provides
novel statin analogues that are preferentially metabolized by
endogenous hydrolytic enzymes (FIG. 2A-2N and FIG. 3A-3N). The
novel compounds are bioactive molecules having antilipidemic
properties and which undergo deactivation to primary inactive
metabolites by hydrolytic enzymes. FIGS. 4-6 provide examples of
synthesis procedures which can be used to produce compounds in the
subject invention.
[0019] Adverse drug-drug interactions (DDI), elevation of liver
function test (LFT) values, and QT prolongation leading to torsades
de pointes (TDP) are three major reasons why drug candidates fail
to obtain FDA approval. All these causes are, to some extent,
metabolism-based. A drug that has two metabolic pathways, one
oxidative and one non-oxidative, built into its structure is highly
desirable in the pharmaceutical industry. An alternate,
non-oxidative metabolic pathway provides the treated subject with
an alternative drug detoxification pathway (an escape route) when
one of the oxidative metabolic pathways becomes saturated or
non-functional. While a dual metabolic pathway is necessary in
order to provide an escape metabolic route, other features are
needed to obtain drugs that are safe regarding DDI, TDP, and LFT
elevations.
[0020] In addition to having two metabolic pathways, the drug
should have a rapid metabolic clearance (short metabolic half-life)
so that blood levels of unbound drug do not rise to dangerous
levels in cases of DDI at the protein level. Also, if the metabolic
half-life of the drug is too long, then the CYP450 system again
becomes the main elimination pathway, thus defeating the original
purpose of the design. In order to avoid high peak concentrations
and rapidly declining blood levels when administered, such a drug
should also be administered using a delivery system that produces
constant and controllable blood levels over time.
[0021] The compounds of this invention have one or more of the
following characteristics or properties:
[0022] 1. Compounds of the invention are metabolized both by CYP450
and by a non-oxidative metabolic enzyme or system of enzymes;
[0023] 2. Compounds of the invention have a short (up to four (4)
hours) non-oxidative metabolic half-life;
[0024] 3. Oral bioavailability of the compounds is consistent with
oral administration using standard pharmaceutical oral
formulations; however, the compounds, and compositions thereof, can
also be administered using any delivery system that produces
constant and controllable blood levels over time;
[0025] 4. Compounds according to the invention contain a
hydrolysable bond that can be cleaved non-oxidatively by hydrolytic
enzymes;
[0026] 5. Compounds of the invention can be made using standard
techniques of small-scale and large-scale chemical synthesis;
[0027] 6. The primary metabolites of compounds of this invention
results from the non-oxidative metabolism of the compounds;
[0028] 7. The primary metabolites, regardless of the solubility
properties of the parent drug, is, or are, soluble in water at
physiological pH and have, as compared to the parent compound, a
significantly reduced pharmacological activity;
[0029] 8. The primary metabolites, regardless of the
electrophysiological properties of the parent drug, has, or have,
negligible inhibitory activity at the IK.sub.R (HERG) channel at
normal therapeutic concentration of the parent drug in plasma
(e.g., the concentration of the metabolite must be at least five
times higher than the normal therapeutic concentration of the
parent compound before activity at the IK.sub.R channel is
observed);
[0030] 9. Compounds of the invention, as well as the metabolites
thereof, do not cause metabolic DDI when co-administered with other
drugs;
[0031] 10. Compounds of the invention, as well as metabolites
thereof, do not elevate LFT values when administered alone.
[0032] In some embodiments, the subject invention provides
compounds having any two of the above-identified characteristics or
properties. Other embodiments provide for compounds having at least
any three of the above-identified properties or characteristics. In
another embodiment, the compounds, and compositions thereof, have
any combination of at least four of the above-identified
characteristics or properties. Another embodiment provides
compounds have any combination of five to 10 of the
above-identified characteristics or properties. In a preferred
embodiment the compounds of the invention have all ten
characteristics or properties.
[0033] In various embodiments, the primary metabolites of the
inventive compounds, regardless of the electrophysiological
properties of the parent drug, has, or have, negligible inhibitory
activity at the IK.sub.R (HERG) channel at normal therapeutic
concentrations of the drug in plasma. In other words, the
concentration of the metabolite must be at least five times higher
than the normal therapeutic concentration of the parent compound
before activity at the IK.sub.R channel is observed. Preferably,
the concentration of the metabolite must be at least ten times
higher than the normal therapeutic concentration of the parent
compound before activity at the IK.sub.R channel is observed.
[0034] Compounds according to the invention are, primarily,
metabolized by endogenous hydrolytic enzymes via hydrolysable bonds
engineered into their structures. The primary metabolites resulting
from this metabolic pathway are water soluble and do not have, or
show a reduced incidence of, DDI when administered with other
medications (drugs). Non-limiting examples of hydrolysable bonds
that can be incorporated into compounds according to the invention
include amide, ester, carbonate, phosphate, sulfate, urea,
urethane, glycoside, or other bonds that can be cleaved by
hydrolases.
[0035] Additional modifications of the compounds disclosed herein
can readily be made by those skilled in the art. Thus, analogs and
salts of the exemplified compounds are within the scope of the
subject invention. With a knowledge of the compounds of the subject
invention skilled chemists can use known procedures to synthesize
these compounds from available substrates. As used in this
application, the term "analogs" refers to compounds which are
substantially the same as another compound but which may have been
modified by, for example, adding additional side groups. The term
"analogs" as used in this application also may refer to compounds
which are substantially the same as another compound but which have
atomic or molecular substitutions at certain locations in the
compound.
[0036] The subject invention further pertains to enantiomerically
isolated compounds, and compositions comprising the compounds, for
inhibition of HMG-CoA-reductase. The isolated enantiomeric forms of
the compounds of the invention are substantially free from one
another (i.e., in enantiomeric excess). In other words, the "R"
forms of the compounds are substantially free from the "S" forms of
the compounds and are, thus, in enantiomeric excess of the "S"
forms. Conversely, "S" forms of the compounds are substantially
free of "R" forms of the compounds and are, thus, in enantiomeric
excess of the "R" forms. In one embodiment of the invention, the
isolated enantiomeric compounds are at least about in 80%
enantiomeric excess. In a preferred embodiment, the compounds are
in at least about 90% enantiomeric excess. In a more preferred
embodiment, the compounds are in at least about 95% enantiomeric
excess. In an even more preferred embodiment, the compounds are in
at least about 97.5% enantiomeric excess. In a most preferred
embodiment, the compounds are in at least 99% enantiomeric
excess.
[0037] A further aspect of the subject invention pertains to the
breakdown products which are produced when the therapeutic
compounds of the subject invention are acted upon by hydrolytic
enzymes, such as esterases. The presence of these breakdown
products in urine or serum can be used to monitor the rate of
clearance of the therapeutic compound from a patient.
[0038] The compounds of this invention have therapeutic properties
similar to those of the unmodified parent compounds. Accordingly,
dosage rates and routes of administration of the disclosed
compounds are similar to those already used in the art and known to
the skilled artisan (see, for example, Physicians' Desk Reference.
54.sup.th Ed., Medical Economics Company, Montvale, N.J.,
2000).
[0039] The compounds of the subject invention can be formulated
according to known methods for preparing pharmaceutically useful
compositions. Formulations are described in detail in a number of
sources, which are well known and readily available to those
skilled in the art. For example, Remington's Pharmaceutical Science
by E. W. Martin describes formulation, which can be used in
connection with the subject invention. In general, the compositions
of the subject invention are formulated such that an effective
amount of the bioactive compound(s) are present in the
composition.
[0040] In accordance with the subject invention, pharmaceutical
compositions are provided which comprise, as an active ingredient,
an effective amount of one or more of the compounds and one or more
non-toxic, pharmaceutically acceptable carriers or diluents.
[0041] Compounds of the present invention may be formulated as
solutions or suspensions, in the form of tablets, capsules (each
including timed release and sustained release formulations), pills,
oils, powders, granules, elixers, tinctures, suspensions, syrups,
emulsions, microemulsions, or with excipients. Likewise, they may
also be administered by any conventional route, for example in
intravenous (both bolus and infusion), intraperitoneal,
intraocularly, subcutaneous, intramuscular form, enterally,
preferably orally (e.g., in the form of tablets or capsules), or in
a nasal, buccal, transdermal, or a suppository form, using well
known formulations to those of ordinary skill in the pharmaceutical
arts.
[0042] In addition, the compounds of the present invention can also
be administered in the form of liposomes or the like.
Disintegrators include, without limitation, delivery systems such
as small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
[0043] For oral administration in the form of a tablet or capsule,
the active drug component can be combined with an oral, non-toxic
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents and coloring
agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes and the like. Lubricants used in these
dosage forms include, for example, sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride, starch, methyl cellulose, agar, bentonite, zanthan gum,
and the like.
[0044] The dosage regimen for the compounds of the present
invention is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of
the patient; the severity of the condition to be treated; the route
of administration; the renal and hepatic function of the patient;
and the particular compound or salt thereof employed. An ordinarily
skilled physician or veterinarian can readily determine and
prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0045] In general, satisfactory results in animals are indicated to
be obtained at a daily dosage of from about 0.1 to about 200 mg,
preferably from about 0.1 to about 5 mg/kg animal body weight. In
larger mammals, for example humans, an indicated daily dosage is in
the range from about 0.5 to about 100 mg, preferably from about 1
to about 50 mg of an agent of the invention conveniently
administered, for example, in divided doses up to four times a day
or in sustained release form.
[0046] Injected intravenous, subcutaneous or intramuscular dosages
of the compounds of the present invention, when used for the
indicated effects, will range between about 0.001 to 1.0 mg/kg.
Furthermore, preferred compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal routes, using those forms
of transdermal skin patches well known to those of ordinary skill
in that art. To be administered in the form of a transdermal
delivery system, the dosage administration can be continuous rather
than intermittent throughout the dosage regimen. Transdermal
delivery can also be achieved using approaches known to those
skilled in the art.
[0047] The subject invention further provides methods of
synthesizing the unique and advantageous therapeutic compounds of
the subject invention. Particularly, methods of producing less
toxic therapeutic agents comprising introducing ester groups into
therapeutic agents are taught. The ester linkage may be introduced
into the compound at a site which is convenient in the
manufacturing process for the compounds of the invention. Various
exemplary synthetic routes for the preparation of the compounds of
the subject invention are described. Additionally, the sensitivity
of the ester linkage may be manipulated by the addition of side
groups which hinder or promote the hydrolytic activity of the
hydrolases or esterases responsible for cleaving the drug at the
ester locus. Methods of adding such side groups, as well as the
side groups themselves, are well known to the skilled artisan and
can be readily carried out utilizing the guidance provided
herein.
[0048] All patents, patent applications, provisional applications,
and publications referred to or cited herein are incorporated by
reference in their entirety to the extent they are not inconsistent
with the explicit teachings of this specification.
[0049] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application.
* * * * *