NZ719457B2 - Tyrosine derivatives and compositions comprising them - Google Patents

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)

What is Claimed:

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-