NZ719457B2 - Tyrosine derivatives and compositions comprising them - Google Patents
Tyrosine derivatives and compositions comprising themInfo
- Publication number
- NZ719457B2 NZ719457B2 NZ719457A NZ71945714A NZ719457B2 NZ 719457 B2 NZ719457 B2 NZ 719457B2 NZ 719457 A NZ719457 A NZ 719457A NZ 71945714 A NZ71945714 A NZ 71945714A NZ 719457 B2 NZ719457 B2 NZ 719457B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- tyrosine
- amino
- propanoate
- solid particulate
- Prior art date
Links
- 150000003667 tyrosine derivatives Chemical class 0.000 title claims abstract description 44
- 239000000203 mixture Substances 0.000 title claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 41
- 239000011236 particulate material Substances 0.000 claims abstract description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- -1 2-chloro- 4 hydroxyphenyl Chemical group 0.000 claims description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 13
- VXYFARNRGZWHTJ-SBSPUUFOSA-N hydron;methyl (2R)-2-amino-3-(4-hydroxyphenyl)propanoate;chloride Chemical compound Cl.COC(=O)[C@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-SBSPUUFOSA-N 0.000 claims description 5
- JZKXXXDKRQWDET-UHFFFAOYSA-N 2-azaniumyl-3-(3-hydroxyphenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=CC(O)=C1 JZKXXXDKRQWDET-UHFFFAOYSA-N 0.000 claims description 2
- ACWBBAGYTKWBCD-ZETCQYMHSA-N 3-chloro-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(Cl)=C1 ACWBBAGYTKWBCD-ZETCQYMHSA-N 0.000 claims description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 2
- FBTSQILOGYXGMD-LURJTMIESA-N Nitrotyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C([N+]([O-])=O)=C1 FBTSQILOGYXGMD-LURJTMIESA-N 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- GITKQXFBNJTMRP-QRPNPIFTSA-N ethyl (2S)-2-amino-3-(4-hydroxy-3-nitrophenyl)propanoate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@H](N)CC1=CC=C(O)C([N+]([O-])=O)=C1 GITKQXFBNJTMRP-QRPNPIFTSA-N 0.000 claims description 2
- MWZPENIJLUWBSY-SECBINFHSA-N methyl (2R)-2-amino-3-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(O)C=C1 MWZPENIJLUWBSY-SECBINFHSA-N 0.000 claims description 2
- CICLCIIIUOCDBN-UHFFFAOYSA-N (4-hydroxyphenyl) propanoate Chemical compound CCC(=O)OC1=CC=C(O)C=C1 CICLCIIIUOCDBN-UHFFFAOYSA-N 0.000 claims 2
- NHTGHBARYWONDQ-UHFFFAOYSA-N D,L-α-methyl-Tyrosine Chemical compound OC(=O)C(N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-UHFFFAOYSA-N 0.000 claims 2
- OOTFAHIVGAQXOL-LBPRGKRZSA-N (2,5-dioxopyrrolidin-1-yl) (2S)-3-(4-hydroxy-3,5-diiodophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(CCC1=O)=O)C1=CC(I)=C(O)C(I)=C1 OOTFAHIVGAQXOL-LBPRGKRZSA-N 0.000 claims 1
- VCIPIPFJHGBKTL-SECBINFHSA-N (2R)-2-azaniumyl-2-(4-hydroxyphenyl)propanoate Chemical compound [O-]C(=O)[C@@]([NH3+])(C)C1=CC=C(O)C=C1 VCIPIPFJHGBKTL-SECBINFHSA-N 0.000 claims 1
- JZUZJVFERQWLNC-UHFFFAOYSA-N 2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxy-3-nitrophenyl)propanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)NC(C(=O)O)CC1=CC=C(O)C([N+]([O-])=O)=C1 JZUZJVFERQWLNC-UHFFFAOYSA-N 0.000 claims 1
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- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 1
- 229940120982 Tarceva Drugs 0.000 description 1
- 229940099419 Targretin Drugs 0.000 description 1
- 229940069905 Tasigna Drugs 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- 229940100411 Torisel Drugs 0.000 description 1
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 description 1
- 229960001727 Tretinoin Drugs 0.000 description 1
- 229940094060 Tykerb Drugs 0.000 description 1
- 229940099039 Velcade Drugs 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229960000237 Vorinostat Drugs 0.000 description 1
- 229940069559 Votrient Drugs 0.000 description 1
- 229940049068 Xalkori Drugs 0.000 description 1
- 229940036061 Zaltrap Drugs 0.000 description 1
- 229940034727 Zelboraf Drugs 0.000 description 1
- 229940061261 Zolinza Drugs 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007792 gaseous phase Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 231100000405 induce cancer Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- BPKBTKQFMPZVNO-SSDOTTSWSA-N methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=C(Cl)C=C(OC)C(O)=C1Cl BPKBTKQFMPZVNO-SSDOTTSWSA-N 0.000 description 1
- WOOVWLVXVNIALE-SSDOTTSWSA-N methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(OC)C(O)=C1Cl WOOVWLVXVNIALE-SSDOTTSWSA-N 0.000 description 1
- JRBGZVHYLIYGFT-SECBINFHSA-N methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC(Cl)=C(OC)C(OC)=C1 JRBGZVHYLIYGFT-SECBINFHSA-N 0.000 description 1
- KWTIOVPQMRSIJF-MRVPVSSYSA-N methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(O)C(Cl)=C1 KWTIOVPQMRSIJF-MRVPVSSYSA-N 0.000 description 1
- QUBSTZJVDZUTFR-SECBINFHSA-N methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate Chemical compound COC(=O)[C@H](N)CC1=CC=C(OC)C(Cl)=C1 QUBSTZJVDZUTFR-SECBINFHSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- WRFPVMFCRNYQNR-UHFFFAOYSA-N o-Tyrosine Chemical compound OC(=O)C(N)CC1=CC=CC=C1O WRFPVMFCRNYQNR-UHFFFAOYSA-N 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrugs Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- ZOPOQLDXFHBOIH-UHFFFAOYSA-N regorafenib hydrate Chemical compound O.C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 ZOPOQLDXFHBOIH-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000005490 tosylate group Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960002760 ziv-aflibercept Drugs 0.000 description 1
Abstract
Provided herein are methods comprising providing a tyrosine derivative and a solid particulate material (and, optionally, melanin) and applying force to said tyrosine derivative and said solid particulate material for a time and under conditions effective to impregnate at least one of said tyrosine derivative and said solid particulate material with the other of said tyrosine derivative and said solid particulate material. The invention also provides compositions comprising at least one of a tyrosine derivative impregnated with a solid particulate material and a solid particulate material impregnated with a tyrosine derivative. derivative and said solid particulate material with the other of said tyrosine derivative and said solid particulate material. The invention also provides compositions comprising at least one of a tyrosine derivative impregnated with a solid particulate material and a solid particulate material impregnated with a tyrosine derivative.
Description
TYROSINE DERIVATIVES AND COMPOSITIONS COMPRISING THEM
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of US. Ser. No. 14/062194, filed October 24,
2013 and provisional U.S. Ser. No. 61/894,279, filed October 22, 2013, the entire contents of
both are hereby incorporated by reference herein.
TECHNICAL FIELD
The present inventions relate generally to compositions and methods for
delivering pharmaceuticals.
BACKGROUND
To achieve an optimal therapeutic effect in humans or animals, various methods
and ses have been developed to administer pharmaceutical compounds. A number of
routes of administration have been ped for drug delivery including nasal, oral,
uscular, intravenous, anal, and vaginal. These routes have shown varying degrees of
success for different types of pharmaceuticals.
It is generally very expensive to p new drug molecules and then bring
them to market. There also have been numerous older drugs that initially showed e but
proved to be too toxic and/or unstable to use as medications. The use of alternative delivery
techniques holds the potential to increase safety and/or efficacy for these and other drugs. The
costs associated with developing such techniques are lly much lower than those associated
with identifying and developing a completely novel drug.
There remains a need for drug delivery techniques having relatively broad
applicability.
SUMNLARY
The t invention provides compositions and s for delivering solid
particulate materials, ularly solid particulate materials comprising one or more
pharmaceutically active ingredient such as those associated with the treatment of cancer. In
n embodiments, the invention provides s comprising ing a tyrosine derivative
and a solid particulate material (and, optionally, melanin) and applying force to said tyrosine
derivative and said solid particulate material for a time and under conditions effective to
impregnate at least one of said tyrosine derivative and said solid particulate material with the
other of said tyrosine derivative and said solid particulate material. In other embodiments, the
invention provides compositions comprising at least one of a tyrosine derivative impregnated
with a solid ulate material and a solid particulate material impregnated with a tyrosine
derivative. Such composition optionally can also include melanin. According to the present
invention, such compositions are administered to a patient in need thereof. In other
embodiments, the ion provides compositions comprising a tyrosine derivative, melanin,
and a solid particulate material.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
The present subject matter may be tood more readily by reference to the
following ed description which forms a part of this disclosure. It is to be understood that
this invention is not limited to the specific products, methods, conditions or ters described
and/or shown herein, and that the ology used herein is for the e of describing
particular embodiments by way of example only and is not intended to be ng of the claimed
invention.
Unless otherwise defined herein, scientific and technical terms used in
connection with the present application shall have the meanings that are commonly understood
by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms
shall include pluralities and plural terms shall include the singular.
As ed above and throughout the disclosure, the following terms and
abbreviations, unless otherwise ted, shall be understood to have the following meanings.
In the present disclosure the ar forms “a,” “an,” and “the” include the
plural reference, and reference to a particular numerical value includes at least that particular
value, unless the context clearly indicates otherwise. Thus, for example, a nce to “a
compound” is a reference to one or more of such compounds and equivalents thereof known to
those d in the art, and so forth. The term “plurality”, as used herein, means more than one.
When a range of values is expressed, another embodiment incudes from the one particular and/or
to the other particular value. Similarly, when values are expressed as approximations, by use of
the antecedent “about,” it is understood that the ular value forms another ment. All
ranges are inclusive and combinable.
3’ CC 3’ LC
As used herein, the terms “component, composition, composition of
compounds,99 “compound,” “drug,55 66pharmacologically active agent,77 (4active agent,”
“therapeutic,” “therapy,” “treatment,” or “medicament” are used interchangeably herein to refer
to a compound or compounds or composition of matter which, when administered to a t
(human or animal) induces a desired pharmacological and/or physiologic effect by local and/or
systemic .
As used , the terms “treatment” or “therapy” (as well as different forms
thereof) e preventative (e.g., lactic), ve or palliative treatment. As used
herein, the term “treating” includes ating or reducing at least one adverse or negative effect
or symptom of a condition, disease or er. This ion, e or disorder can be
cancer.
As employed above and throughout the disclosure the term “effective amount”
refers to an amount effective, at dosages, and for periods of time necessary, to achieve the
desired result with respect to the treatment of the relevant disorder, condition, or side effect. It
will be appreciated that the effective amount of components of the present invention will vary
from patient to patient not only with respect to the particular compound, component or
composition selected, the route of administration, and the ability of the components to elicit a
desired result in the individual, but also with respect to factors such as the disease state or
severity of the condition to be alleviated, hormone levels, age, sex, weight of the individual, the
state of being of the patient, and the severity of the pathological condition being treated,
concurrent medication or special diets then being followed by the particular patient, and other
factors which those skilled in the art will recognize, with the appropriate dosage being at the
discretion of the attending physician. Dosage regimes may be adjusted to provide improved
therapeutic response. An ive amount is also one in which any toxic or detrimental effects
of the components are outweighed by the therapeutically beneficial effects.
aceutically acceptable” refers to those compounds, materials,
compositions, and/or dosage forms which are, within the scope of sound medical judgment,
suitable for contact with the s of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications commensurate with a reasonable
benefit/risk ratio.
Within the present invention, the disclosed compounds may be prepared in the
form of pharmaceutically acceptable salts. aceutically acceptable salts” refer to
_ 3 _
derivatives of the disclosed compounds wherein the parent compound is modified by making
acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts
of acidic residues such as ylic acids; and the like. The pharmaceutically acceptable salts
e the conventional xic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non—toxic inorganic or organic acids. For example, such
conventional non—toxic salts include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, ic, phosphoric, nitric and the like; and the salts ed from
organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,
ascorbic, , maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2—
acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, , isethionic,
and the like. These physiologically able salts are prepared by methods known in the art,
e. g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or
neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an
amine.
Compounds described herein can be prepared in alternate forms. For example,
addition salt. Often such
many amino—containing compounds can be used or prepared as an acid
salts improve isolation and handling properties of the compound. For example, ing on the
reagents, reaction ions and the like, compounds as described herein can be used or
prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all
chiral and racemic forms, e, es, solvates, and acid salt hydrates, are also
contemplated to be within the scope of the present invention.
Certain acidic or basic compounds of the present invention may exist as
zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are
contemplated to be within the scope of the present invention. It is well known in the art that
compounds containing both amino and carboxy groups often exist in equilibrium with their
zwitterionic forms. Thus, any of the compounds described herein that contain, for example, both
amino and y groups, also include reference to their corresponding zwitterions.
The term “stereoisomers” refers to compounds that have identical chemical
constitution, but differ as regards the arrangement of the atoms or groups in space. The term
“enantiomers” refers to stereoisomers that are mirror images of each other that are non—
superimposable.
The term “administering” means either directly administering a compound or
composition of the present invention, or administering a prodrug, derivative or analog which will
form an equivalent amount of the active compound or substance within the body.
The terms “subject,” “individual,” and “patient” are used hangeably
herein, and refer to an animal, for example a human, to whom treatment, including prophylactic
treatment, with the pharmaceutical composition according to the present invention, is provided.
The term “subject” as used herein refers to human and non—human animals. The terms “non-
human animals” and uman mammals” are used interchangeably herein and include all
vertebrates, e.g., mammals, such as non—human primates, (particularly higher primates), sheep,
dog, rodent, (e.g. mouse or rat), guinea pig, goat, pig, cat, rabbits, cows, horses and non—
mammals such as reptiles, amphibians, chickens, and turkeys.
The term itor” as used herein includes compounds that inhibit the
expression or activity of a protein, polypeptide or enzyme and does not necessarily mean
complete tion of expression and/or activity. Rather, the inhibition includes inhibition of
the expression and/or activity of a protein, ptide or enzyme to an extent, and for a time,
sufficient to produce the d effect.
The term “promoter” as used herein includes compounds that promote the
expression or activity of a protein, polypeptide or enzyme and does not necessarily mean
complete promotion of expression and/or activity. Rather, the promotion includes promotion of
the expression and/or activity of a protein, ptide or enzyme to an extent, and for a time,
sufficient to produce the desired effect.
Representative therapeutic ent methods include those in which the cancer
is non—small cell lung cancer, ovarian cancer, breast cancer, cervical cancer, pancreatic cancer,
stomach cancer, brain cancer, spinal cancer, liver cancer, bone cancer, osteosarcoma, lymphoid
cancer, thyroid , te cancer, breast cancer, ovarian cancer, cervical , or
testicular cancer. In other embodiments, the cancer is leukemia or lymphoma.
In certain embodiments, the invention provides s comprising providing a
tyrosine derivative and a solid particulate material and applying force to said tyrosine derivative
and said solid particulate material for a time and under conditions effective to impregnate at least
one of said tyrosine derivative and said solid particulate material with the other of said tyrosine
derivative and said solid particulate material. In other embodiments, the invention provides a
ition comprising at least one of a tyrosine derivative impregnated with a solid particulate
material and a solid ulate material impregnated with a tyrosine derivative. In other
embodiments, the invention provides methods comprising providing a tyrosine derivative,
_ 5 _
melanin, and a solid ulate material; applying force to said tyrosine derivative, said melanin,
and said solid particulate material for a time; and administering said tyrosine tive, n,
and said solid particulate material to a t in need thereof.
The tyrosine derivative can be capable of existing in isomeric forms.
Specifically, the tyrosine derivative can be in its L-form or in its D—form. The tyrosine derivative
can also be in racemic form.
Representative tyrosine derivatives include one or more of methyl (2R)
amino—3 —(2—chloro-4 hydroxyphenyl) propanoate, sine ethyl ester hydrochloride, methyl
(2R) amino—3-(2,6-dichloro-3,4—dimethoxyphenyl) propanoate H-D-Tyr(TBU)—allyl ester HCl,
methyl (2R)—2—amino—3—(3-chloro—4,5-dimethoxyphenyl) propanoate, methyl (2R)-2—amino-3—(2-
chloro—3—hydroxy—4—methoxyphenyl) propanoate, methyl (2R)—2—amino—3—(4—[(2—chloro
henyl) methoxy] phenyl) propanoate, methyl (2R)—2— 3—(2—chloro—3,4—
dimethoxyphenyl) propanoate, methyl (2R)—2—amino—3—(3—chloro—5—fluoro—4—hydroxyphenyl)
oate, diethyl 2—(acetylamino)—2-(4-[(2—chloro—6—fluorobenzyl) oxy] benzyl malonate,
methyl (2R)—2—amino—3—(3 —chloro—4—methoxyphenyl) propanoate, methyl (2R)—2—amino—3—(3—
chloro—4—hydroxy—5—methoxyphenyl) oate, methyl (2R)—2—amino—3—(2,6— dichloro—3—
hydroxy—4—methoxyphenyl) propanoate, methyl (2R)—2—amino-3—(3 —chloro—4—hydroxyphenyl)
propanoate, H—DL-tyr—OME HCl, diiodo—tyr—OME HCl, H—D—3,5—diiodo-tyr—OME HCl,
H—D—tyr—OME HCl, D—tyrosine methyl ester hydrochloride, D—tyrosine-ome HCl, methyl D—
tyrosinate hydrochloride, H—D-tyr—OMe0HCl, D—tyrosine methyl ester HCl, H—D—Tyr—OMe—HCl,
(2R)—2—amino—3—(4—hydroxyphenyl) propionic acid, (2R)—2—amino—3—(4—hydroxyphenyl) methyl
ester hloride, methyl (2R)—2—amino—3—(4—hydroxyphenyl) propanoate hydrochloride,
methyl (2R)—2—azanyl—3—(4—hydroxyphenyl) propanoate hydrochloride, 3—chloro—L—tyrosine, 3—
nitro—L—tyrosine, 3—nitro—L—tyrosine ethyl ester hydrochloride, DL—m—tyrosine, DL-o—tyrosine,
Boc—Tyr (3,5—12)—OSu, Fmoc-tyr(3 OH, (x—methyl—L—tyrosine, (x-methyl—D—tyrosine, and 0t-
methyl—DL—tyrosine. In certain embodiments of the invention, the tyrosine derivative is 0t-
methyl-L-tyrosine. In other embodiments the tyrosine derivative is (x—methyl—D-tyrosine.
In suitable embodiments of the invention, the solid particulate material is
soluble in water. In other suitable embodiments of the ion, the solid particulate material is
not soluble in water.
In other embodiments of the invention, the solid particulate material is or
comprises a pharmaceutically active ingredient. That pharmaceutically active ingredient can
have therapeutic activity in the treatment of cancer. A representative solid particulate material is
or comprises at least one of a selective estrogen receptor modulator, an aromatase inhibitor, a
_ 6 _
WO 61288
signal transduction inhibitor, a drug that modifies the function of ns that regulate gene
expression and other ar functions, a drug that induces cancer cells to o apoptosis,
and a drug that eres with angiogenesis. Specifically, the pharmaceutically active
ingredient is one or more of FDA—approved cancer drugs that include selective estrogen receptor
modulators such as tamoxifen, toremifene (Fareston®), and fulvestrant (Faslodex®); aromatase
tors such as anastrozole (Arimidex®), exemestane (Aromasin®), and letrozole (Femara®);
signal transduction tors such as ib mesylate ec®), dasatinib (Sprycel®),
nilotinib (Tasigna®), bosutinib (Bosulif®), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib
(Tarceva®), temsirolimus (Torisel®), everolimus (Afinitor®), vandetanib (Caprelsa®),
vemurafenib (Zelboraf®), and crizotinib (Xalkori®); drugs that modify the function of proteins
that regulate gene expression and other cellular functions, such as vorinostat (Zolinza®),
romidepsin (Istodax®), bexarotene (Targretin®), alitretinoin (Panretin®), tretinoin (Vesanoid®);
drugs that induce cancer cells to undergo apoptosis, such as bortezomib (Velcade®), carfilzomib
(KyprolisTM), and pralatrexate (Folotyn®); and drugs that interfere with angiogenesis, such as
sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), regorafenib (Stivarga®), and
cabozantinib (CometriqTM). Additional cancer drugs amenable to the present invention include
denileukin diftitox (Ontak®), ziv-aflibercept (Zaltrap®), cisplatin, cisplatinum, (cis—
diamminedichloroplatinum(ll)), latin, latin, benzyl ocyanate, acetylcholine,
and dihydrotestosterone (DHT). It should be appreciated, however, that other drugs that exist in
particulate form may be amenable to processing in accordance with the present invention.
In another embodiment of the invention, the methods comprise providing a
tyrosine derivative and a solid particulate material, ng force to said tyrosine derivative and
said solid particulate material for a time and under conditions effective to achieve said
impregnation, and adding en peroxide to said tyrosine derivative and said solid particulate
material before or (preferably) after applying said force.
The forces applied to the tyrosine derivative and the solid particulate material
(and, ally, the melanin) need not be applied by any particular means. In certain
embodiments of the invention, the force is d by contacting said tyrosine derivative and said
particulate material with at least one ceramic member, such as with a mortar and pestle.
Preferred methods and devices, in which the force applied is rative force, are disclosed in
the patent application entitled Speed Centrifugal Mixing Devices and Methods of Use,”
filed on October 22, 2013 and given US. Patent Application number 14/059,837. When force is
applied, the softer of the substances typically will be impregnated by the other(s). It should be
appreciated, however, that the potential exists for the softer of two particulates to effect
_ 7 _
WO 61288
impregnation. In this regard, nation according to the present invention can involve, but
does not require, a portion of one type of particulate extending into a portion of another type of
ulate. For example, one type of particulate can be impregnated by another by fully
surrounding or partially surrounding it. Thus, impregnation according to the present invention is
ed where at least two different type of particulates are sufficiently conjoined that they
exhibit the physical ties of a single type of particulate when exposed to normal material
handling procedures such as sieving and pouring.
The compositions prepared in accordance with the present invention preferably
are administered to a patient in need thereof. entative routes of administration include
oral, nasal, subcutaneous, intravenous, uscular, transdermal, vaginal, rectal or in any
combination f. Nasal routes of administration can be especially useful because the blood
brain barrier is st in the posterior portion of the nasal cavity. This can be a preferred route
of administration for treatments for, for example, brain and spinal cancers. The pharmaceutically
active ingredient preferably is administered using the same dosages and dosing schedule that is
ise applicable for a given indication, although it is believed that administration with a
tyrosine derivative in accordance with the present invention will permit the use of a lower dosage
to achieve the same eff1cacy.
In certain ments of the invention, the step of administering said tyrosine
derivative and said solid particulate material (and, optionally, melanin) to a patient in need
thereof can include applying an electromagnetic field to said patient. The electromagnetic field
can be from radio waves, microwaves, infrared light, visible light, ultraviolet light, x—rays or
of operation, it is
gamma rays. While not intending to be bound by any particular mechanism
ed that the application of the electromagnetic field can be used to increase the efficacy of
one or more pharmaceutically active ingredient as, for example, by causing it and/or an
accompanying molecule to enter a gaseous phase.
It will be iated by those skilled in the art that various modifications and
alterations of the invention can be made without ing from the broad scope of the appended
claims. Some of these have been discussed above and others will be apparent to those skilled in
the art.
rs\vzs\AppData\Roaming\iManage\Work\Recent\35249338NZ Tyrosine derivatives and compositions comprising them\clean copy - 35249338(21092734.1).docx-1/19/2021
Claims (1)
1. A method comprising: providing a tyrosine derivative and a solid particulate material; and applying accelerative force to said tyrosine tive and said solid particulate al to cause at least one of said tyrosine derivative and said solid particulate material to fully surround or lly nd the other of said ne derivative and said solid particulate material; wherein the tyrosine derivative is one or more of methyl (2R)amino(2-chloro- 4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R) amino- 3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-Tyr(TBU)-allyl ester HCl, methyl (2R)amino(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)amino(2- chlorohydroxymethoxyphenyl) propanoate, methyl (2R)amino(4-[(2-chloro fluorophenyl) methoxy] phenyl) propanoate, methyl (2R) amino(2-chloro-3,4- dimethoxyphenyl) propanoate, methyl (2R)amino(3-chlorofluoro hydroxyphenyl) propanoate, diethyl 2-(acetylamino)(4-[(2-chlorofluorobenzyl) oxy] benzyl te, methyl (2R)amino(3-chloromethoxyphenyl) propanoate, methyl (2R)amino(3-chlorohydroxymethoxyphenyl) propanoate, methyl (2R) amino(2,6- dichlorohydroxymethoxyphenyl) oate, methyl (2R)amino orohydroxyphenyl) propanoate, yr-OME HCl, H-3,5-diiodo-tyr-OME HCl, H-D-3,5-diiodo-tyr-OME HCl, r-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, H-D-tyr- OMe•HCl, D-tyrosine methyl ester HCl, H-D-Tyr-OMe-HCl, (2R)amino(4- hydroxyphenyl) propionic acid, (2R)amino(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)amino(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)azanyl(4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-otyrosine , Boc-Tyr (3,5-I2)-OSu, Fmoc-tyr(3-NO2)-OH, α-methyl-L-tyrosine, α-methyl-D- tyrosine, and α-methyl-DL-tyrosine. C:\Users\vzs\AppData\Roaming\iManage\Work\Recent\35249338NZ Tyrosine derivatives and compositions comprising them\clean copy - 35249338(21092734.1).docx-
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361894279P | 2013-10-22 | 2013-10-22 | |
US61/894,279 | 2013-10-22 | ||
US14/062,194 | 2013-10-24 | ||
US14/062,194 US9585841B2 (en) | 2013-10-22 | 2013-10-24 | Tyrosine derivatives and compositions comprising them |
PCT/US2014/061527 WO2015061288A1 (en) | 2013-10-22 | 2014-10-21 | Tyrosine derivatives and compositions comprising them |
Publications (2)
Publication Number | Publication Date |
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NZ719457A NZ719457A (en) | 2021-02-26 |
NZ719457B2 true NZ719457B2 (en) | 2021-05-27 |
Family
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