WO2019197015A1

WO2019197015A1 - Composition comprising 4-phenylbutyric acid derivatives & opioids

Info

Publication number: WO2019197015A1
Application number: PCT/EP2018/059032
Authority: WO
Inventors: Peter Truog
Original assignee: Peter Truog
Priority date: 2018-04-09
Filing date: 2018-04-09
Publication date: 2019-10-17
Also published as: TW201943687A

Abstract

The present invention relates to a pharmaceutical composition comprising 4-phenylbutyric acid derivatives according to the independent claims and further comprising an opioid of the methadone group for use in the treatment of cancer.

Description

Composition comprising 4-Phenylbutyric acid derivatives & opioids

The present invention relates to a pharmaceutical composition comprising 4-phenylbutyric acid derivatives according to the in dependent claims and further comprising an opioid of the metha done group for use in the treatment of cancer.

4-phenylbutyric acid is a well-known compound that is marketed in form of its sodium salt as a drug in the United States and the European Union. Sodium 4-phenylbutyrate is an orphan drug for the treatment of urea cycle disorders. In addition, 4- phenylbutyric acid sodium salt has also been described in pa tents and in the scientific literature for a number of medical uses. These uses encompass a variety of illnesses, such as be nign prostatic hyperplasia, cancer, HIV, kidney failure and tha lassemia. For example, , EP 2 599 767 A1 describes a number of 4-phenylbutric acid derivatives for use in cancer therapy and other pharmaceutical applications. However, efficacy of the drug is limited to the treatment of rather small tumors and has shown no efficacy in the treatment of melanomas.

It has further been suggested in the state of the art that opi oids capable of inhibiting cancer cell proliferation be used for treatment of resistant cancer patients (EP2149372). More specif ic, it has been suggested that opioids pertaining to the group of methadone be used for treatment of resistant cancer patients (EP230900) . However, these drugs have been applied only to a range of cancer cells as are known today (occurring e.g. in leu kemia, breast cancer, glioblastoma, etc) . In particular, the drug has proven effective for the treatment of non-solid can cers, such as haematological malignancies affecting blood, bone marrow and lymph nodes. The types of cancer potentially treata- ble by opioid medication include lymphoblastic leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, chronic lymphocyt ic leukaemia and all pro-forms of leukaemia, hairy cell leukae mia, Hodgkin's disease, Non-Hodgkin lymphoma and multiple myelo ma (EP2149372, [0026] and [0031]).

It is a problem underlying the present invention to improve the efficacy of 4-phenylbutric acid derivatives as pharmaceutical agent in the treatment of cancer. It is, in particular, an ob ject of the present invention to provide a pharmaceutical compo sition improving the efficacy of 4-phenylbutric acid derivatives in the treatment of solid cancers with metastases.

This problem is solved with a pharmaceutical composition accord ing to the independent claim.

The present invention refers to a composition comprising a phar maceutically active amount of 4-phenylbutyric acid derivative of Formula 1,

Formula 1 wherein Y is selected from 0 or ¾; Ri is selected from N¾ or H; R2 is a radical of an amino acid, a salicylic acid, a 4- phenylbutyric acid, a catechol, or a derivative of any of the aforementioned; and n is selected from 0, 1, 2, 3, 4, 5, 6, 7,

8, 9, or 10, for use in the treatment of inflammatory diseases. In Formula 1, when Y is selected as 0, C=Y corresponds to a car bonyl group (C=0) and when Y is selected as ¾, C=Y corresponds to a methylene group (CH₂₎ .

The composition further comprises an opioid of the methadone group. An opioid is a chemical heterogeneous group of natural, synthetic or semi-synthetic substances, working agonistic or an tagonistic which all can bind to the opioid receptors, prefera bly to the m opioid receptor. The group of opioids includes nat ural opiates such as alkaloids like morphine, dihydrocodein, co deine and thebaine, as well as semi-synthetic opiates, derived from the natural opiates (e.g. hydromorphone, hydrocodone, ox ycodone, oxymorphone, desomorphine, diacetylmorphine (Heroin) , nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmor- phine) , or fully synthetic opioids, such as fentanyl, pethidine and methadone, tramadol or propoxyphene. It also includes endog enous opioid peptides, which may be produced naturally in the body as endorphins, dynorphins or enkephalins but which can also be synthesized.

According to the invention, the opioid is a member of the metha done group, comprising D-/L-methadone, levomethadone, levacetyl- methadol and piritramide. All these opioids can be used as salts, for example as dissolved salts. The racemic form of D-/L- methadone is preferably provided in form of a hydrochloride.

As defined for the purpose of this invention "composition" is to be understood as a single dose of all constituents or a kit of parts of two or more separate elements, which are to be adminis tered to the patient either concomitantly or sequentially.

A "pharmaceutical composition" means a pharmaceutical prepara tion comprising a therapeutically effective amount of a 4- phenylbutyric acid derivative of Formula 1 and any of the opi- oids or opioid mimetics as defined according to the invention, which are to be administered to the patient either concomitantly or sequentially. The above mentioned 4-phenylbutyric acid deriv atives are preferably combined with methadone.

Surprisingly, the efficacy of the composition comprising a 4- phenylbutyric acid derivative is enhanced through co

administration of the opioid even though a 4-phenylbutyric acid derivative does not have the same effect as a conventional chemotherapeutical agent.

Conventional chemotherapeutical agents used in oncology include cytotoxic and cytostatic agents, which kill the cancer cells or reduce and/or stop their growth or proliferation. The modes of action of these anticancer drugs can vary; examples are anti metabolites (e.g. cytarabine, methotrexate, mercaptopurine or clofarabine) , DNA cross-linking agents (e.g. cisplatine and its derivates) , DNA intercalating substances (e.g. doxorubicin), Topoisomerase poisons (e.g. etoposide) , kinase inhibitors (e.g. cetuximab) , steroids (e.g. dexamethasone) or mitotic inhibitors (e.g. vincristine).

4-Phenylbutyric acid derivatives, however, do not interact with a specific cell proliferation or growth mechanism. The suitabil ity is not limited to certain peripheral processes. The exact mechanism of operation of 4-phenylbutyric acid derivatives still remains elusive. However, compounds are suitable for the treat ment of a range of medical conditions and, in particular, types of cancer. 4-phenylbutyric acid derivatives are physiologically well tolerated and, thus far, no recidivism in patients treated with a composition according to claim 1 has been observed. It is an advantage of the composition according to claim 1 that it can successfully be applied in the treatment of cancer in volving large solid tumors or melanomas. The cancer can further be applied in the treatment of solid cancers where metastases are present.

In an above-described 4-phenylbutyric acid derivative, R2 can be selected from any of the following structures:

When Y is ¾, R2 can also have the following structures:

In the above formulas, R3 can be H or can be selected from any of the following structures:

And R4 can be H or a radical of an amino acid, a salicylic acid, a 4-phenylbutyric acid, a catechol, or a derivative of any of the aforementioned.

On the other hand, R2 can be selected from any of the following structures :

Notably, a 4-phenylbutyric acid derivative according to the pre sent invention can be selected from any of the following struc- tures :

The above-mentioned 4-phenylbutric acid derivatives may be em ployed as a single stereoisomer or as a mixture of stereoiso mers. Such stereoisomers can be enantiomers or diastereomers . The compounds may be used as a racemate. However, preferably they are used in enantiomerically pure form. Furthermore, the 4- phenylbutric acid derivatives may be employed in form of the free acid, the free base, or as a salt. 4-phenylbutric acid derivatives of Formula 1 are physiologically well tolerated.

The pharmaceutical composition according to claim 1 can be of any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults. It can be produced by standard procedures known to those skilled in the art. The composition may vary depending on the route of admin istration .

A composition or compositions of the present invention may for example be administered partially in combination with conven tional injectable liquid carriers, such as water or suitable al cohols. Conventional pharmaceutical recipients for injection, such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions. Such medica ments or pharmaceutical formulations may for example injected intramuscularly, intraperitoneal or intravenously.

A composition or compositions according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carrier or ex cipient, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubri cants, and acceptable wetting agents. The compositions may take any convenient form, such as tablets, pellets, granule, cap sules, lozenges, aqueous or oily solutions, suspensions, emul sions or dry powdered forms suitable for reconstitution with wa ter or other suitable liquid media before use. The multiparticu late forms, such as pellets or granules, may be filled into a capsule, compressed into tablets or suspended in a suitable liq uid. Furthermore, suitable controlled release formulations and methods for their preparations are known from the prior art.

A composition or compositions according to the present invention may also comprise enteric coating, so that their dissolution is depended on the pH value. Due to said coating, the medicament may pass the stomach unresolved and the 4-phenylbutric acid de rivatives of Formula 1 are liberated in the intestinal tract. Preferably, the enteric coating is soluble at the pH value of 5.0-7.5. Suitable materials and methods for the preparation are known in the art.

Typically, the composition comprising 4-phenylbutyric acid de rivatives of Formula 1 according to the present invention con tains 1-60% by weight of one or more 4-phenylbutric acid deriva tives of Formula 1 and 40-99% by weight of one or more auxiliary substances .

Typically, the composition comprising an opioid according to the present invention contains 7.5 mg methadone.

4-phenylbutric acid derivatives of Formula 1 may also be at min istered topically or via a suppository.

The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth .

The daily dosage of 4-phenylbutyric acid derivative of Formula 1 for humans is in the range of 10 mg to 2 '000 mg of active sub stance (4-phenylbutric acid derivatives of Formula 1), to be ad ministered during one or several intakes per day. Preferably, the daily dosage for humans is in the range of 100 mg to 500 mg of active substance (4-phenylbutric acid derivatives of Formula 1) to be administered during one or several intakes per day.

Even more preferably, the daily dosage for humans is in the range of 300 mg to 400 mg of active substances (4-phenylbutric acid derivatives of Formula 1) to be administered in two intakes per day. The daily dosage of the opioid for humans is in the range of 5- 25 mg of active substance, to be administered during one or sev eral intakes per day. Preferably, the daily dosage for humans is in the range of 10-20 mg of active substance to be administered during one or several intakes per day. Even more preferably, the daily dosage for humans is in the range of 14-16 mg of active substances to be administered in two intakes per day.

Further advantages and aspects of the present invention become apparent from the description of the following examples.

The following examples refer to the in vivo biological activity of N- (4-phenylbutanoyl) -D-alanine (4-PB) in co-administration with methadone. However, there is not intent to restrict the scope of the present invention in any manner. Other embodiments will be evident to a person skilled in the art through the for going detailed description.

Example 1: In vivo activity of the composition comprising 4-PB and methadone

A male patient suffering from a renal carcinoma with multiple lung metastases was subject to nephrectomy. Subsequently, treat ment with 4-PB (200 mg orally, b.i.d.) in combination with meth adone (1% g/v, 10 drops b.i.d orally) was prescribed. After con tinued administration of the composition for three months, the patient's lung metastases were stable, no new metastases were observed and the patient was clinically free of symptoms

Example 2: In vivo activity of the composition comprising 4-PB and methadone A male patient suffering from multifocal adenocarcinoma of paro- tis with bone, lung, lymphatic and hepatic metastases was sub ject to adjuvant x-ray and chemotherapy (cis-platin) . The condi tion also involved pathological fractures of spine, rips and ac- etabulum. 3.5 years after therapy, multiple spinal, lymphatic and pulmonary recurrences were observed. Ventral spondylodesis was performed and treatment with 4-PB started. After a temporary increase of CA72-4, therapy with 4-PB in combination with metha done was initiated. CA72-4 values decreased from 554 to 4 within six months. At the end of the treatment, patient was found in good shape, apart from pain in the hip.

Claims

1. A pharmaceutical composition comprising

- a 4-Phenylbutyric acid derivative of Formula 1,

Formula 1

wherein

Y is selected from 0 or ¾;

Ri is selected from N¾ or H;

R2 is a radical of an amino acid, a salicylic acid, a 4-phenylbutyric acid, a catechol, or a derivative of any of the aforementioned; and

n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and further comprising

- an opioid of the methadone group;

for use in the treatment of cancer.

2. A pharmaceutical composition according to claim 1 for use in the treatment of cancer, wherein the cancer involves a sol id tumor, in particular a carcinoma or a melanoma, in par ticular in the treatment of a solid cancer with metastases.

3. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of cancer, wherein R2 is selected from any of the following structures

or and R is H or selected from any of the following structures

and R is H or a radical of an amino acid, a salicylic acid, a 4-phenylbutyric acid, a catechol, or a derivative of any of the aforementioned.

4. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of cancer, wherein Y is H2, R2 is

and R3 is H or selected from any of the following structures

5. A pharmaceutical composition according to claim 1 to 2 for use in the treatment of cancer, wherein R2 is selected from any of the following structures

6. A pharmaceutical composition according to claim 3 for use in the treatment of cancer, wherein the 4-Phenylbutyric acid derivative is selected from any of the following structures

N- (4-phenylbutanoyl) -D-alanine (4-PB)

7. A pharmaceutical composition according to claim 5 for use in the treatment of cancer, wherein the 4-Phenylbutyric acid derivative is selected from any of the following structures