EP0927033A1 - Retinoyloxy-alkylene butyrates (substitues) utiles pour le traitement du cancer et autres maladies proliferatives - Google Patents

Retinoyloxy-alkylene butyrates (substitues) utiles pour le traitement du cancer et autres maladies proliferatives

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Publication number
EP0927033A1
EP0927033A1 EP97932417A EP97932417A EP0927033A1 EP 0927033 A1 EP0927033 A1 EP 0927033A1 EP 97932417 A EP97932417 A EP 97932417A EP 97932417 A EP97932417 A EP 97932417A EP 0927033 A1 EP0927033 A1 EP 0927033A1
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EP
European Patent Office
Prior art keywords
compound
group
cells
agent
cancer
Prior art date
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EP97932417A
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German (de)
English (en)
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EP0927033A4 (fr
Inventor
Ada Rephaeli
Abraham Nudelman
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Bar Ilan University
General Federation of Labor Kupat Holim Health Insurance Inst of
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Bar Ilan University
General Federation of Labor Kupat Holim Health Insurance Inst of
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Priority claimed from US08/674,481 external-priority patent/US6040342A/en
Priority claimed from US08/883,219 external-priority patent/US6071923A/en
Application filed by Bar Ilan University, General Federation of Labor Kupat Holim Health Insurance Inst of filed Critical Bar Ilan University
Publication of EP0927033A4 publication Critical patent/EP0927033A4/xx
Publication of EP0927033A1 publication Critical patent/EP0927033A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/20—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by carboxyl groups or halides, anhydrides, or (thio)esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention is directed to retinoyloxy (substituted) alkylene butyrates and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising said compounds, and to methods of treating cancer and other proliferative diseases in a subject in need of such treatment.
  • the compounds of the invention are also useful in methods of inhibiting histone deacetylase, ameliorating wrinkles, treating or ameliorating dermatological disorders, inducing wound healing, treating cutaneous ulcers and treating gastrointestinal disorders.
  • cancer cells are characterized by a marked capacity to proliferate and a limited capacity to differentiate under normal homeostatic conditions, experimental evidence has demonstrated that neoplastic cells can be induced to differentiate, indicating that malignant processes can be altered or, at least partially, reversed.
  • the retinoids are a family of compounds consisting of vitamin A, retinoic acid (RA) and related derivatives. They play a pivotal role in normal development of endodermally- , mesodermally- and ectodermally-derived tissues. (Umesono K. et al . , Nature 336:262-265, 1989).
  • RA binds to the cytoplasmic RA-binding protein, whose role in mediating RA effects is unclear.
  • RA binds to the RA receptors (RAR- ⁇ , - ⁇ , - ⁇ ) .
  • the RAR/RA complex binds to a specific DNA sequence, as demonstrated by electrophoretic mobility shift (Rochette-Egly et al . , J. Cell. Biol . 115:535-545, 1991), leading to transcription of RA target genes.
  • RAR- ce has been shown to be involved with growth and differentiation of myeloid cells in vi tro .
  • RA was reported to induce differentiation and arrest proliferation in a wide spectrum of cancer cells in vi tro and in vivo, including patients with leukemia, myelodysplastic syndromes and solid tumors. For instance, Collins et al . Int. J. Cancer 25:213-218, 1980, have shown that the human promyelocytic leukemia cell line H -60 can be induced to differentiate by RA and express cellular and molecular characteristics of granulocytes . (Umesono e ⁇ al .
  • Emergence of differentiated features includes elevated protein kinase C and intracellular lysoso al activities. Strickland et al . , have shown that exposure of the teratocarcinoma cell line F9 to RA caused differentiation to visceral endoderm (Cell 15:393-403, 1978).
  • retinoids have achieved significant activity in the reversal of head and neck, skin, and cervical premalignancy and in prevention of second primary tumors associated with head and neck, skin and non-small lung cancer.
  • Lippman et al . J. Cell. Biochem. 22:1, 1995
  • chemoprevention activity of retinoids in aerodigestive tract carcinogenesis This was tested in the two-stage mouse lung carcinogenesis model described by Nishimo, J. Cell. Biochem. 22:231, 1995.
  • ATRA acute promyelocytic leukemia
  • ATRA is now considered to be a first line therapeutic agent for promyelocytic leukemias (Wright D.G., Blood 67:334-337, 1987) .
  • the achievement of remission induced by ATRA tends to be brief and may be explained by rapid clearance in patients resistant to ATRA (Muindi et al . Cancer Res. 52:2138-2142, 1992).
  • Adamson et al . reports that patients orally administrated ATRA had highly variable absorption of the drug (J. Natl. Can. Inst . , 85 (12) :993-996, 1993).
  • maintenance of effective plasma concentrations and toxicity are problems associated with retinoid treatments (Adamson et al . , J. Natl. Cancer Inst. 85:993-996, 1993) .
  • Butyric acid (BA) is a non-toxic natural product. It is supplied to mammals from two main sources: 1) the diet, mainly from dairy fat, 2) as a major product of bacterial fermentation of unabsorbed carbohydrates in the colon, where it reaches mM concentrations (Cummings J.H., Gut 22:763-779, 1982; Leder A. et al . , Cell 5:319-322, 1975) .
  • BA has been known for nearly the last three decades to be a potent differentiating and antiproliferative agent in a wide spectra of neoplastic cells in vi tro (Prasad N.K., Life Sci . 27:1351-1358, 1980).
  • BA is reported to induce cellular and biochemical changes, e.g., in cell morphology, enzyme activity, receptor expression and cell -surface antigens (Nordenberg J. et al . , Exp. Cell Res. 162:77-85, 1986; Nordenberg J. et al . , Br. J. Cancer 56:493-497, 1987; and Fishman P.H. et al . , J. Biol . Chem. 254:4342-4344, 1979).
  • BA or its sodium salt sodium butyrate, SB
  • sodium butyrate sodium butyrate
  • BA or its sodium salt sodium butyrate, SB
  • butyric acid is inhibition of nuclear deacetylase (s) , resulting in hyper acetylation of histones H3 and H4 (Riggs M.G. , et al . , Nature 263:462-464, 1977).
  • Increased histone acetylation, following treatment with BA has been correlated with changes in transcriptional activity and the differentiated state of cells (Thorne A.W. et al . , Eur. J. Biochem. 193:701-713, 1990).
  • BA also exerts other nuclear actions, including modifications in the extent of phosphorylation (Boffa L.C.
  • BA is normally metabolized rapidly and has a very short half-life in vivo .
  • Apoptosis is the physiological mechanism for the elimination of cells in a controlled and timely manner.
  • Organisms maintain a delicate balance between cell proliferation and cell death, which when disrupted can tip the balance between cancer, in the case of over accumulation of cells, and degenerative diseases, in the case of premature cell losses.
  • inhibition of apoptosis can contribute to tumor growth and promote progression of neoplastic conditions.
  • RA might be useful in combination with other agents in the treatment of some leukemias.
  • treatment with either BA or RA alone or in combination will continue to have the problems of toxicity, as well as achieving and maintaining effective plasma concentrations.
  • R' is H or C x -C 6 alkyl
  • R' ' ' is R' or the hydrocarbon backbone of fatty acids, for affecting the reduction and reversal of photo aging and skin cancer.
  • This invention addresses this need and is thus directed to the compounds of Formula (I) which are retinoyloxy (substituted) alkylene butyrates and which are more potent than BA or RA alone or combined, to compositions comprising same and to methods of using same for the treatment of cancers and other proliferative diseases, for inhibiting histone deacetylase, for gastrointestinal disorders, for ameliorating wrinkles, for wound healing and for treatinbg dermatological disorders (in the case of the aryl-substituted compounds) .
  • None of the references discussed above teaches or suggests the compounds of Formula (I), pharmaceutical compositions containing same or the methods of using these compounds or compositions as anti- cancer and anti-proliferative agents.
  • one embodiment of the present invention is directed to the novel compounds having the Formula (I) :
  • Ret is selected from the group consisting of a retinoyl group, a therapeutically-active retinoid carbonyl group, a therapeutically-active carbonyl group represented by the formula
  • retinoids which are C20 or C22 des ethyl vinylogs of said groups, wherein Z is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group or a cyclohexenyl group, and said phenyl or naphthyl group can be substituted with from 0 to 5 substitutents selected from the group consisting of halo, hydroxy, alkyl, alkyoxy, amino, cyano or carbalkoxy, and wherein double bonds in the polyene chain of any of said groups can have a cis or trans configura ion; n is 0 or 1; and when n is 0, then
  • R is H or C x to C 5 alkyl, R x is ethyl, n-propyl or isopropyl, with the proviso that when Ret is 13 -cis-retinoyl and R ⁇ is n-propyl, then R cannot be H or C ⁇ to C b alkyl; or when n is 1, then
  • R is aryl or heteroaryl optionally substituted with halo, hydroxy, alkyl, alkoxy, amino, cyano, carbalkoxy, nitro, or trifluoromethyl,
  • Ret is trans.
  • ROBA trans- retinoyloxymethylbutyrate
  • the compounds of Formula II are retinoyloxy (p-chlorophenyl) methyl butyrates and the compounds of Formula III are the pharmaceutically- acceptable anion salts of 1-retinoyloxy-2- (3 - pyridyl) ethyl isobutyrate and its N-alkyl pyridinium salts.
  • the compounds of the present invention have greater efficacy as proliferation inhibitors and differentiating agents than either BA or RA alone or a combination of BA plus RA.
  • compositions comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically effective carrier or diluent.
  • a further embodiment of the present invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a combination a compound of Formula (I) with other anti-cancer or anti- neoplastic agents together with a pharmaceutically effective carrier or diluent.
  • Another embodiment of the present invention is directed to methods of treating, preventing or ameliorating cancer and other proliferative disorders which comprise administering a therapeutically effective amount of a compound of Formula (I) to a subject suffering from such disorders and to methods of enhancing the actions of other known pharmaceutical agents, including antiproliferative, differentiating or oncostatic agents.
  • the pharmaceutical agents of the invention for the above method include, but are not limited to, cytokines, interleukins, anti-cancer agents, chemotherapeutic agents, antibodies, conjugated antibodies, immune stimulants, antibiotics, hormone antagonists, and growth stimulants.
  • the compounds of the invention can be administered prior to, after or concurrently with any of the agents.
  • Yet another aspect of the invention is directed to a method of inhibiting histone deacetylase in cells by administering a compound of Formula I to said cells.
  • a still further embodiment of the invention is directed to a method of ameliorating wrinkles, inducing wound healing, treating cutaneous ulcers or treating a gastrointestinal disorder by administrating a therapeutically-effective amount of a compound of Formula (I) to a subject in need of such treatment.
  • the cutaneous ulcers which can be treated in accordance with the methods of the invention include leg and decubitus ulcers, stasis ulcers, diabetic ulcers and atherosclerotic ulcers.
  • the compounds are useful in treating abrasions, incisions, burns, and other wounds.
  • Gastrointestinal orders treatable by the methods of the invention include colitis, inflammatory bowel disease, Crohn's disease and ulcerative colitis.
  • Another embodiment of the invention is directed to a method of treating or ameliorating dermatological disorders by administrating a compound of Formula (I) wherein n is 1 to a subject in need of such treatment.
  • dermatological disorders include psoriasis, acne and the like.
  • the compounds are administered in topical preparations .
  • the methods of the present invention are particularly useful for treating, preventing or ameliorating the effects of cancer and other proliferative disorders by acting as anti-proliferative or differentiating agents in subjects afflicted with such anomalies.
  • disorders include but are not limited to leukemias, such as acute promyelocytic leukemia, acute yeloid leukemia, and acute myelomonocytic leukemia; other myelodysplastic syndromes, multiple myeloma such as but not limited to breast carcinomas, cervical cancers, melanomas, colon cancers, Kaposi's sarcoma, ovarian cancers, pancreatic cancers, hepatocarcinomas, prostate cancers, squamous carcinomas, renal cell carcinoma, other dermatologic malignancies, teratocarcinomas, T-cell lymphomas, lung tumors, gliomas, neuroblastomas, peripheral neuroectodermal tumors, rhabdomyosarcomas, and prostate tumors and other
  • compounds of Formula (I) have anti- proliferative effects on non-cancerous cells as well, and may be of use to treat benign tumors and other proliferative disorders such as psoriasis.
  • Preferred is the method for treating or ameliorating leukemia, squamous cell carcinoma and neuroblastoma .
  • Fig. 1 illustrates the effect of all- trans retinoids on cell differentiation in human HL-60 cells. DETAILED DESCRIPTION OF THE INVENTION
  • the compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. Many geometric isomers of olefins and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention.
  • stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
  • alkyl includes both branched- and straight-chain, saturated or unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the alkyl groups of the invention have up to 7 carbon atoms, and preferably 1 to 5 carbon atoms or 1 to 7 carbon atoms .
  • aryl is intended to mean any stable 5- to 7-membered monocyclic or bicyclic or 7- to
  • 14-membered bicyclic or tricyclic carbon ring containing at least one aromatic ring, for example, phenyl, naphthyl, indanyl and the like.
  • heteroaryl is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is aromatic, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N (nitrogen) , O (oxygen) and S (sulphur) and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached to its pendant group at any heteroato or carbon atom which results in a stable structure.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if he resulting compound is stable.
  • heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl , pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl .
  • a therapeutically active retinoid is a compound that exhibits a biological action similar to retinoic acid (i.e., similar to vitamin A acid) .
  • retinoids include those compounds, synthetic or natural, which have one or more of the therapeutic activities known for retinoic acid. Such activities include but are not limited to binding to and activating retinoic acid receptors, treating and preventing cancer and other proliferative disorders, acting as differentiating agents or anti-proliferatives agents and anti-tumor activity.
  • Ret of Formula (I) is a retinoid carbonyl group of a therapeutically-active retinoid.
  • Ret includes compounds of the formula
  • retinoids contemplated by the invention can be found in U.S. Patent Nos. 4,476,056; 4,105,681; 4,215,215; 4,054,589 and
  • Retinoids include both cis and trans forms having therapeutic activity.
  • Preferred retinoids include those having a 9-cis double bond, a 13-cis double bond or a 13 -trans double bond.
  • substituted means that one or more hydrogens on the designated atom are replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • the substituted aryl and heteroaryl groups of the invention have one or more hydrogen atoms replaced with a halo, hydroxy, alkyl, alkoxy, amino, cyano, carboxy carbalkoxy, nitro or trifluoromethyl group.
  • a halo group is a halogen, and includes fluoro, chloro, bromo and iodo groups .
  • alkoxy refers to an alkyl group having at least one oxygen substitutent .
  • carbalkoxy refers to groups of the formula -R-C(0)0- where R is an alkyl group .
  • vinyllogs are desmethyl retinoyl groups having 1 or 2 additional vinyl groups relative to retinoic acid.
  • such compounds include 2,6,6, -trimethyl-1- (10' -carboxy-deca-1 ' ,3',5',7',9'- pentaenyl) cyclohex-1-ene and 2 , 6 , 6 -trimethyl-1- (12 ' - carboxy-dodeca-1' , 3 ' , 5' , 7' , 9' , 11' -hexaenyl) cyclohex-1- ene .
  • the vinylogs of this invention can be prepared from a retinoyl group, any therapeutically active retinoid carboxyl group, or any group of the formula
  • therapeutically-effective amount refers to that amount necessary to administer to a host to treat, prevent or ameliorate cancer, or other proliferative disorder, wherein that amount can further be an amount effective to inhibit histone deacetylase in the cells of a patient; to achieve an anti-tumor effect; to induce differentiation and/or inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells; to aid in the chemoprevention of cancer; to achieve an anti-wrinkling effect; to treat or ameliorate psoriasis; to promote wound healing or to treat a gastrointestinal disorder.
  • Therapeutically-effective amounts can be readily determined by one of ordinary skill in the art.
  • pharmaceutically acceptable salts and prodrugs refer to derivatives of the disclosed compounds that are modified by making acid or base salts, or by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo in relation to the parent compounds.
  • examples 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 carboxylic acids; acetyl, formyl and benzoyl derivatives of amines; and the like.
  • compositions of the compounds of the invention are prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences , 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety.
  • the "pharmaceutical agents" for use in the methods of the invention related to the coadministration of compounds of Formula I include but are not limited to anticancer agents as well as differentiating agents.
  • the pharmaceutical agent is a cytokine, an interleukin, an anti-cancer agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, a hormone antagonist or a growth stimulant.
  • the pharmaceutical agent is a cytotoxic agent. Cytotoxic agents include antiviral nucleoside antibiotics such as ganciclovir, acyclovir, and famciclovir. Cytotoxic agents also include radiation therapy.
  • chemotherapeutic agents include but are not limited to alkylating agents, purine and pyrimidine analogs, vinca and vinca-like alkaloids, etoposide and etoposide-like drugs, corticosteroids, nitrosoureas, antimetabolites, platinum-based cytotoxic drugs, hormonal antagonists, anti-androgens and antiestrogens .
  • the "cytokines” for use herein include but are not limited to interferon, preferably , ⁇ or ⁇ interferon, as well as IL-2, IL-3, G-CSF, GM-CSF and EPO.
  • an “immune stimulant” is a substance such as C. parvum or sarcolectin which stimulates a humoral or cellular component of the immune system.
  • chemotherapeutic agents of the invention include but are not limited to tamoxifen, doxorubicin, L- asparaginase, dacarbazine, amsacrine, procarbazine, hexamethylmelamine, mitoxantrone and gemcitabine.
  • the compounds provided by the present invention are prepared generally by any method known in the art. Preparation of the compounds of the invention is illustrated by the following non- limiting example.
  • the compounds of the invention can be made by reacting the acid form of the retinoid (e.g., Ret-OH) with a reagent of the formula
  • Y is a leaving group such as halogen, methanesulfonate or p-toulenesulfonate and Ret
  • A, R and R 1 are as defined herein.
  • the base is a trialkylamine, pyridine, an alkali metal carbonate or other suitable base.
  • the reaction is carried out in the presence or absence of an inert solvent .
  • a solvent is, for example, acetone, benzene, toluene, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, chloroform, dioxan or 1, 2-dichloroethane. Additional methods and details for synthesis of the compounds of this invention are provided in Nudelman et al . , J . Med . Chem . 35:687-694, 1992.
  • the compounds of the present invention are generally useful in the treatment of indications including cancer and other proliferative disorders, as differentiating agents or antiproliferative agents and in the chemoprevention of cancer.
  • the activity of compounds useful as differentiating agents can be measured using standard methodology of the nitro-blue tetrazolium reduction assay (e.g., Rabizadeh et al . , FEBS Lett. 328:225-229, 1993; Chomienne et al . , Leuk . Res . 10:631, 1986; and Breitman et al . in Methods for Serum-free Culture of Neuronal and Lymphoid Cells, Alan R. Liss, NY, p. 215-236, 1984 which are hereby incorporated by reference in their entirety) and as described below.
  • This in vi tro assay has been deemed to be predictive and in fact correlative with in vivo efficacy (Castaigne et al . , Blood 76:1704-1709, 1990) .
  • Another assay which is predictive of differentiating activity is the morphological examination for the presence of Auer rods and/or specific differentiation cell surface antigens in cells collected from treatment groups, as described in Chomienne et al . , (Blood 76:1710- 1717, 1990 which is hereby incorporated by reference in its entirety) and as described below.
  • the compounds of the present invention also have anti-proliferative and anti-tumor activity.
  • the anti- proliferation activity of compounds of the present invention are determined by methods generally known to those skilled in the art.
  • Two generally-accepted assays for measuring viability and anti-proliferative activity are the trypan blue exclusion test and incorporation of tritiated thymidine, also as described by Chomienne, et al .
  • Human promyelocytic leukemia Cells (HL-60) , Human Pancreatic Carcinoma Cells (PaCa-2) and Human Breast Adenocarcinoma, pleural effusion, Cells (MCF-7) can be cultured as follows. Cells are grown in RPMI media with 10% FCS, supplemented with 2 mM glutamine and incubated at 37°C in a humidified 5% C0 2 incubator. Viability is determined by trypan blue exclusion. Cells are exposed to butyric acid or retinoic acid or a compound of the invention and cultures are harvested at various time points following treatment.
  • NBT Nitro-Blue Tetrazolium Assay: Cell differentiation is evaluated by NBT reduction activity as follows. Cell cultures containing 0.1% NBT are stimulated with 400 nM of 12-0-tetradecanoyl-phorbol- 13-acetate (P.A.) . The cells are incubated for 30 min at 37°C and examined microscopically by scoring at least 200 cells. The capacity for cells to reduce NBT is assessed as the percentage of cells containing intracellular reduced black formazan deposits and corrected for viability.
  • P.A. 12-0-tetradecanoyl-phorbol- 13-acetate
  • Human promyelocytic cell line HL-60 are grown for 4 days in the presence of 0.25 ⁇ M of RA, or a retinoyloxy (substituted) alkylene butyrate of the invention.
  • the compounds are synthesized as described above.
  • Cell differentiation is measured by the NBT assay described above .
  • Cell surface antigen immunotyping are conducted using dual-color fluorescence of cells gated according to size.
  • the expression of a panel of antigens from early myeloid (CD33) to late myeloid is determined as described in Warrell, Jr. et al . , New En l . J. Med. 324:1385-1392, 1992, which is incorporated by reference herein in its entirety.
  • RNA analysis is conducted by guanidinium thiocyanate phenol/chloroform extraction as described by Rabizadeh et al . , FEBS Lett. 328 (3 ): 225-229 , 1993, and probed with human complementary DNA (cDNA) for RAR- ⁇ as described by Miller et al . , J. Natl. Cancer Inst . 82:1932-1933, 1990, which are incorporated by reference herein in their entireties.
  • cDNA human complementary DNA
  • Genomic DNA is prepared and completely digested for three hours with EcoRl or HindiII (2-3 U per microgram DNA). DNA is then size fractionated on 0.8% agarose gel, denatured, renatured, neutralized and blotted onto a nitrocellulose filter. The filter is then hybridized to a 640-base pair EcoRl-Sstl cut RAR- ⁇ cDNA and washed stringently at 55 °C. Autoradiograms are obtained after exposure at -70°C to Kodak-XAR film with use of an intensifying screen.
  • Apoptosis can be evaluated by DNA fragmentation, visible changes in nuclear structure and immunocytochemical analysis of Bel -2 expression.
  • DNA fragmentation is monitored by the appearance of a DNA ladder on an agarose gel.
  • Cellular DNA is isolated by the method of Martin et al . , J. Immunol . , 145:1859- 1867, 1990. Briefly, cells are washed twice with PBS and centrifuged at 1200 rpm at room temperature for 5 in.
  • the pellets are resuspended at 2xl0 7 cells/mL in lysing buffer (10 mM EDTA, 50 mM Tris, pH 8) containing 0.5% (w/v) N-laurylsarcosine and 0.5 mg/mL proteinase K and incubated for 1 h at 50°C, Heat-treated Rnase is added to a concentration of 0.25 mg/mL and incubation at 50°C continued for 1 h.
  • the crude DNA preparations are extracted with buffered phenol followed by two chloroform: isoamyl alcohol (24:1) extractions.
  • DNA preparation are brought to 2.5 volumes in 10 mM Tris, pH 8, 1 mM EDTA (TE buffer) and precipitated for 24 hours in 2 volumes of ethanol at -70°C.
  • the DNA precipitates are recovered by centrifugation, air dried, resuspended in TE buffer, and stored at 4°C. DNA concentration is calculated by determining the OD at 260 nm.
  • Electrophoresis of DNA is carried out in 1% agarose gels containing 1 ⁇ g ethidium bromide as described (Martin et al . ) .
  • Gels contain size markers ( xl74 DNA Haelll digest, 11 fragments ranging from 72-1353 bp) .
  • stained gels are viewed by transillumination with UV light (302 nm) and photographed through a DS34 Polaroid direct screen instant camera using Polaroid 667 (3000 ASA) film.
  • Cytospins are prepared from HL- 60 cells treated with BA, RA, or with one of the compounds of the invention. Untreated cells are used as a control. Cells are fixed with 100% ethanol for 10 min . Acridine orange (1.2 mg/mL in 0.13 M Na 2 HP0 4 , 0.35 M citric acid and l ⁇ M Na 2 EDTA, pH 6.5) is applied to the fixed cells for 30 min. At least 3 fields containing about 250 cells are examined and counted under an Olympus BH-2 fluorescence microscope. The fields are photographed with an Olympus camera using Agfa film (ASA 1000) .
  • ASA 1000 Agfa film
  • Immunological detection of Bcl-2 is performed on untreated HL-60 cells or HL-60 cells treated with BA, RA or one of the compounds of RN-1 to RN-4. Cytospins are prepared and the cells are fixed with ethanol. Fixed cells are reacted overnight at 4°C with the primary monoclonal antibody anti-Bcl-2 (Dako) at a dilution of 1:50. Staining is completed using Strep A-B Universal Kit (DPC, Sigma) according to manufacturer's instructions. Microscopy and photography are performed as in the preceding paragraph except that the film is ASA 200. Identically-treated cells which received no primary antibody serve as non-specific binding controls.
  • Compounds of the present invention can be examined for their ability to increase the life span of animals bearing B16 melanomas, Lewis lung carcinomas and myelomonocytic leukemias as described in Nudelman et al . , J. Med. Chem. 35:687-694, 1992, or Rephaeli et al . , Int. J. Cancer 49:66-72, 1991, which are incorporated by reference herein in their entireties.
  • mice are injected with WEHI cells and drug or control solution is administered the following day.
  • the life span of the treated animals is compared to that of untreated animals.
  • the efficacy of compounds of the present invention on primary tumors is tested in subcutaneously implanted lung carcinoma or B16 melanoma by measuring the mass of the tumor at the site of implantation every two weeks in control and drug-treated animals.
  • Chemoprevention activity of the compounds of the invention is determined in the two-stage mouse carcinogenesis model of Nishimo et al . (supra) .
  • Xenografts Colon adenocarcinoma (human HCT-15 cells) , mammary adenocarcinoma (human MX-1 cells) and melanoma (murine B16) xenografts are made by implanting the respective cells subcutaneously into athymic mice. Treatment with control solution or a compound of Formula (I) begins when tumors are approximately 100 mg. Anti-tumor activity is assessed by the delay in tumor growth.
  • Compounds of Formula (I) can be measured in a biological sample by any method known to those skilled in the art of pharmacology, clinical chemistry or the like. Such methods for measuring compounds of Formula (I) are standard methods and include, but are not limited to high performance liquid chromatography (HPLC) , gas chromatography (GC) , gas chromatography mass spectroscopy (GC-MS) , radioimmunoassay (RIA) , and others.
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • GC-MS gas chromatography mass spectroscopy
  • RIA radioimmunoassay
  • the compounds of the present invention are administered to treat cancer or other proliferating disorders by any means that produces contact of the active agent with the agent's site of action in the body of a subject. They are administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions of the invention can be adapted for oral, parenteral, transdermal or transmucosal administration, and may be in unit dosage form, as is well known to those skilled in the pharmaceutical art.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques.
  • a daily dosage of active ingredient is expected to be about 0.001 to 500 milligrams per kilogram (mg/kg) of body weight, with the preferred dose being 0.01-50 mg/kg.
  • Dosage forms contain from about 1 mg to about 1 g of active ingredient per unit.
  • the active ingredient is ordinarily present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally in solid or semi-solid dosage forms, such as for example hard or soft-gelatin capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, disperse powders or granules, emulsions, and aqueous or oily suspensions. It can also be administered parenterally, in sterile liquid dosage forms. Other dosage forms are possible, such as but not limited to, administered transdermally, via a patch mechanism or ointment.
  • compositions intended for oral use are prepared according to any methods known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets .
  • excipients include, for example, inert diluents, such as calcium phosphate, calcium carbonate, sodium carbonate, sodium phosphate, or lactose; granulating disintegrating agents, for example, maize starch or alginic acid; binding agents, such as starch, gelatin, or acacia; and lubricating agents, for example, magnesium stearate, stearic acids or talc.
  • Compressed tablets are uncoated or sugar coated or film coated by known techniques to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration and adsorption in the gastrointestinal tract.
  • Hard gelatin capsules or liquid filled soft gelatin capsules contain the active ingredient and inert powdered or liquid carriers, such as, but not limited to calcium carbonate, calcium phosphate, kaolin, lactose, lecithin starch, cellulose derivatives, magnesium stearate, stearic acid, arachis oil, liquid paraffin, olive oil, pharmaceutically-accepted synthetic oils and other diluents suitable for the manufacture of capsules. Both tablets and capsules can be manufactured as sustained release-products to provide for continuous release of medication over a period of hours.
  • inert powdered or liquid carriers such as, but not limited to calcium carbonate, calcium phosphate, kaolin, lactose, lecithin starch, cellulose derivatives, magnesium stearate, stearic acid, arachis oil, liquid paraffin, olive oil, pharmaceutically-accepted synthetic oils and other diluents suitable for the manufacture of capsules.
  • Both tablets and capsules can be manufactured as sustained release-products to
  • Aqueous suspensions contain the active compound in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone , gum tragacanth, and gum acacia; dispersing or wetting agents, such as a naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, for example of polyoxyethylene stearate, or a condensation products of ethylene oxide with long chain aliphatic alcohols, e.g., heptadecaethyleneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with partial esters derived from fatty acids
  • the aqueous suspensions can also contain one or more preservatives, for example ethyl, n-propyl, or p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.
  • Disperse powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents, can also be present.
  • Syrups and elixirs are formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous suspension.
  • This suspension is formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3 -butane diol.
  • water a suitable oil, saline, aqueous dextrose (glucose) , polysorbate and related sugar solutions, emulsions, such as Intralipid ® (Cutter Laboratories, Inc., Berkley CA) and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Antioxidizing agents such as but not limited to sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also useful.
  • parenteral solutions can contain preservatives, such as but not limited to benzalkonium chloride, methyl- or propyl- paraben, and chlorobutanol .
  • compositions of the present invention also include compositions for delivery across cutaneous or mucosal epithelia including transdermal, intranasal, sublingual, buccal, and rectal administration.
  • Such compositions can be part of a transdermal device, patch, topical formulation, gel, etc., with appropriate excipients.
  • the compounds of the present invention are useful compounded with a penetration-enhancing agent such as 1-n- dodecylazacyclopentan-2-one or the other penetration- enhancing agents disclosed in U.S. Patent Nos. 3,991,203 and 4,122,170 which are hereby incorporated by reference in their entirety to describe penetration-enhancing agents which can be included in the transdermal or intranasal compositions of this invention.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 0.1-50 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, lecithin, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 0.1-50 milligrams of the active ingredient.
  • the capsules are washed and dried.
  • Triethylamine (1.2 eq) was added dropwise to a solution of 13-cis-retinoic acid (300 mg, 1 mmol) and 1- chloro-1- (4 -chlorophenyl) methyl butyrate (1 eq) in dry DMF (lmL) .
  • the 1-chloro-1- (4 -chlorophenyl) methyl butyrate was prepared from butyroyl chloride and p- chlorobenzaldehyde according to Rasmussen et al . (1967) J. Am. Chem. Soc . 89:5439. The solution was stirred at 70°C for several hours.
  • Table 1 show that compounds of the invention cause HL-60 cells to differentiate in a dose dependent manner, with an increase of 81% differentiated cells. This increase is much greater than any increase seen by BA alone or RA alone .
  • Human promyelocytic cell line HL-60 was grown for 4 days in the presence of 0.25 ⁇ M of RA, ROBA (RN-1) , retinoyloxymethylpropionate (RN-2) , retinoyloxymethylisobutyrate (RN-3) or retinoyloxymethylpivalate (RN-4) .
  • the compounds were synthesized as described in Example 1 or by appropriate modification of Example 1.
  • Cell differentiation was measured by the NBT assay described above .
  • the results of two separate experiments show that ROBA, RN-2 and RN-3 significantly increased the percentage of differentiated cells in the culture relative to RA or RN-4 (Fig. 1) .
  • Table 3 shows that the average percent differentiated cells for ROBA was 73% whereas the average percent differentiated cells for RN-4 was 17%. This difference is substantial and unexpected.

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Abstract

L'invention concerne de nouveaux composés de rétinoyloxy-alkylène butyrate (substitué) et des compositions pharmaceutiques contenant lesdits composés, ainsi que des méthodes permettant de traiter, de prévenir le cancer ou de soulager les symptômes du cancer et d'autres maladies prolifératives chez un sujet ayant besoin d'un tel traitement. La méthode consiste à administrer à un patient ces composés, leurs sels ou leurs promédicaments pharmaceutiquement acceptables. Les composés de l'invention sont également utiles dans des méthodes permettant d'inhiber l'histone déacétylase, d'atténuer les rides, de traiter ou de soulager les troubles dermatologiques, de favoriser la cicatrisation, de traiter les ulcères cutanés et les troubles gastro-intestinaux.
EP97932417A 1996-07-02 1997-07-01 Retinoyloxy-alkylene butyrates (substitues) utiles pour le traitement du cancer et autres maladies proliferatives Withdrawn EP0927033A1 (fr)

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US674481 1996-07-02
US08/674,481 US6040342A (en) 1994-09-16 1996-07-02 Retinoyloxy (alkyl-substituted) methyl butyrates useful for the treatment of cancer and other proliferative diseases
US08/883,219 US6071923A (en) 1994-09-16 1997-06-26 Retinoyloxy aryl-substituted alkylene butyrates useful for the treatment of cancer and other proliferative diseases
PCT/US1997/011452 WO1998000127A1 (fr) 1996-07-02 1997-07-01 Retinoyloxy-alkylene butyrates (substitues) utiles pour le traitement du cancer et autres maladies proliferatives
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US6110970A (en) * 1997-03-11 2000-08-29 Beacon Laboratories, Inc. Nitrogen-containing oxyalkylene esters and uses thereof
US6124495A (en) * 1997-03-11 2000-09-26 Beacon Laboratories, Inc. Unsaturated oxyalkylene esters and uses thereof
US5939455A (en) * 1997-03-11 1999-08-17 Beacon Laboratories, Inc. Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives
JP2002511432A (ja) * 1998-04-15 2002-04-16 レキシジェン ファーマシューティカルズ コーポレイション 新脈管形成インヒビターの同時投与による抗体−サイトカイン融合タンパク質媒介性免疫応答の増強
AU758851B2 (en) * 1998-04-17 2003-04-03 Lexigen Pharmaceuticals Corporation Enhancement of antibody-cytokine fusion protein mediated immune responses by co-administration with prostaglandin inhibitor
US6720445B2 (en) 2000-12-21 2004-04-13 Beacon Laboratories, Inc. Acetyloxymethyl esters and methods for using the same
WO2002079415A2 (fr) 2001-03-30 2002-10-10 Lexigen Pharmaceuticals Corp. Reduction de l'immunogenicite de proteines de fusion
SE0101702D0 (sv) 2001-05-15 2001-05-15 Ardenia Investments Ltd Novel potentiating compounds
US8946295B2 (en) * 2002-07-25 2015-02-03 Sunny Pharmtech Inc. Histone hyperacetylating agents for promoting wound healing and preventing scar formation
EP1491188A1 (fr) * 2003-06-25 2004-12-29 G2M Cancer Drugs AG Utilisation topique de l'acide valproique pour traiter des maladies de la peau
EP1702069A2 (fr) 2004-01-05 2006-09-20 EMD Lexigen Research Center Corp. Interleukine-12 ciblee sur la fibronectine oncofoetale
KR20130050395A (ko) * 2004-03-26 2013-05-15 디에스엠 아이피 어셋츠 비.브이. 히스톤 데아세틸라제(ｈｄａｃ) 저해제를 레티노이드와 함께 포함하는 조성물
CN101263121A (zh) 2005-07-14 2008-09-10 塔克达圣地亚哥公司 组蛋白脱乙酰基酶抑制剂
EA201171259A1 (ru) 2009-04-22 2012-05-30 Мерк Патент Гмбх Антительные гибридные белки с модифицированными сайтами связывания fcrn

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