WO2008044095A1 - Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate - Google Patents

Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate Download PDF

Info

Publication number
WO2008044095A1
WO2008044095A1 PCT/IB2006/053741 IB2006053741W WO2008044095A1 WO 2008044095 A1 WO2008044095 A1 WO 2008044095A1 IB 2006053741 W IB2006053741 W IB 2006053741W WO 2008044095 A1 WO2008044095 A1 WO 2008044095A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
oxicams
residues
compounds
methyl
Prior art date
Application number
PCT/IB2006/053741
Other languages
French (fr)
Inventor
Chongxi Yu
Lina Xu
Original Assignee
Techfields Biochem Co. Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2009531929A priority Critical patent/JP5378221B2/en
Priority to PCT/IB2006/053741 priority patent/WO2008044095A1/en
Priority to CN200680056073A priority patent/CN101522692A/en
Priority to EP06809572.8A priority patent/EP2084165B1/en
Application filed by Techfields Biochem Co. Ltd filed Critical Techfields Biochem Co. Ltd
Publication of WO2008044095A1 publication Critical patent/WO2008044095A1/en
Priority to US12/351,804 priority patent/US20090238763A1/en
Priority to US12/397,308 priority patent/US20090221703A1/en
Priority to US15/379,866 priority patent/US11135153B2/en
Priority to US15/402,618 priority patent/US9872846B2/en
Priority to US15/402,575 priority patent/US20170209585A1/en
Priority to US16/421,735 priority patent/US20210353579A1/en
Priority to US17/493,321 priority patent/US20220096370A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/10Anti-acne agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • A61P27/06Antiglaucoma agents or miotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/16Otologicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D279/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/021,2-Thiazines; Hydrogenated 1,2-thiazines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems

Definitions

  • the present invention relates to the preparations of positively charged and water- soluble pro-drugs of oxicams and related compounds, and their medicinal use in treating any oxicams-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of oxicams and related compounds. These pro-drugs can be administered orally or transdermally.
  • Piroxicam, sudoxiam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinnoxicam, meloxicam, and related compounds are members of enolic acid class of 4-hydroxy-l,2-benzothiazine carboxamides with anti-inflammatory and analgesic properties.
  • the first member of this class, piroxicam was introduced in the United States in 1982 as Feldene(Pfizer).
  • Oxicams are the leading analgesic and antipyretic drugs. They are used to relieve symptoms of rheumatoid arthritis, osteoarthritis and for fever.
  • Other agents of oxicams are disclosed in U.S. Pat. Nos. 3,787,324, 3,822,258, 4,180,662 and 4,376,768.
  • testosteronyl- 4-dimethylaminobutyrate.HCl (TSBH), which has a lipophilic portion and a tertiary amine groups that exists in the protonated form at physiological pH. They found that the prodrug diffuses through human skin -60 times faster than does the drug itself [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993).
  • Piroxicam sudoxiam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinnoxicam, meloxicam, and related compounds are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and for relief of fever.
  • This invention relates to the preparation of novel positively charged pro-drugs of oxicams and related compounds and their use medicinally.
  • the pro-drugs of oxicams and related compounds have the general formula (1) 'Structure 1'.
  • R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, CH , C H , CF or C F ; A " represents Cl “ , Br " , F " ,
  • R represents ary or heteroaryl system, they include, but are not limited to:
  • X and X represent H, F, Cl, Br, I, CF , C 2 F 5 , SO CF , SO CH , NO , CN, alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms.
  • X 1 and X 2 represent H, F, Cl, Br, I, CF 3 , C 3 F 5 , SO 2 CF 3 , SO 2 CH 3 , NO 2 , alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms.
  • All R, -(CH 2 ) n -, groups are branched or straight chains and may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
  • the goal of this invention is to avoid the side effects of oxicams and related compounds by increasing their solubility in gastric juice and moisture of skin and their penetration rate through the membrane and skin barrier which will make them ad- ministrable transdermally (topical application).
  • These novel pro-drugs have two structural features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the protonated form (hydrophilic part) at physiological pH. Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich, et al., J. Pharm. Sci., 82, 227(1993)].
  • the positively charged amino groups largely increase the solubility of the drugs.
  • Oxicams and related compounds have a very low solubility in gastric juice or the moisture of skin.
  • these new pro-drugs When these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately.
  • the positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane.
  • the local concentration of the outside of the membrane will be very high and will facilitate the passage of these prodrugs from a region of high concentration to a region of low concentration.
  • the hydrophilic part When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension.
  • the pH of the stomach is 1-3, so the negative charge on the phosphate head group of the membrane of the gastric mucosa is bonded with proton (H + ).
  • the positive charges of these prodrugs cannot bond to phosphate head group of the gastric mucosa. Thus, prodrugs will not damage the stomach.
  • the receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm.
  • the cumulative amounts of these prodrugs and their parent drugs penetrating the skin versus time were determined by a specific high-performance liquid chromatography method.
  • the donor consisted of a 20% solution of these compounds in 1 mL of isopropanol applied to a 10 cm on the backs of the hairless mice.
  • Plasma levels of drugs were determined by a specific high-performance liquid chromatography method.
  • Figure 2 show that the peak levels of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl, N-
  • pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments.
  • the in vivo rates of penetration of other pro-drugs of the general 'Structure I' are close to that of
  • mice [11] The acute toxicity of the prodrugs was investigated.
  • the LD orally in mice are:
  • prodrugs are less toxic than the parent drugs. [12] A good prodrug should go back to the parent drug in plasma.
  • the prodrugs in this invention can be rapidly cleaved by the enzymes in human plasma in vitro. More than
  • Antipyretic activity Rats received a sterilized E. coli suspension as a pyrogen.
  • the control group is group A. 2 hours later,
  • prodrugs can also be used to treat psoriasis, acne, sunburn or other skin disorders due to inhibition of the cyclooxygenase activity and very high skin penetration rate. They may useful for treating skin, lung, breast, and other cancers.
  • the present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for administration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration.
  • the new active compounds of the general 'Structure 1' can be combined with vitamins such as A, B, C or E or beta-carotene, or other pharmaceuticals, such as beta-carotene, Caffeine , pseudoephedrine, azapirone, folic acid, etc., for treating any oxicams- treatable conditions in humans or animals.
  • 'Structure 1' or a composition comprising of at least one compound of the general 'Structure 1', as an active ingredient can be used for treating any oxicams-treatable conditions in humans or animals.
  • These systems can be a bandage or a patch comprising of one active substance-containing matrix layer and an impermeable backing layer.
  • the most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of oxicams and related compounds.
  • These systems can be worn on the wrist, ankle, arm, leg, or any part of body.
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from oxicams and related compounds, by reaction with compounds of the general formula (2) 'Structure 2' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O- (Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- (Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol- l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, et al.
  • coupling reagents such as N,N'-Dicyclohexylcarbodiimide, N, N
  • the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from oxicams and related compounds, by reaction with compounds of the general formula (3) 'Structure 3'.
  • pro-drugs of oxicams and related compounds have a lipophilic portion and a hydrophilic portion (the amine groups that exist in the protonated form at physiological pH).
  • the positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new prodrugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. Second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration.
  • the pro-drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of oxicams and related compounds, most notably GI disturbances such as dyspepsia, gas- troduodenal bleeding, gastric ulcerations, and gastritis.
  • Another great benefit of the transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
  • Piroxicam H, 20% suspension
  • sudoxiam I, 20% suspension
  • lornoxicam J, 20% suspension
  • tenoxicam K, 20% suspension
  • lomoxicam L, 20% suspension
  • isoxicam M, 20% suspension
  • the vehicle was pH 7.4 phosphate buffer (0.2 M).
  • Figure 2 Total plasma levels of drugs after topical application of 1 ml of
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues;
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues;
  • R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues;
  • R represents H, CH , C H , CF or C F ;
  • R represents ary or heteroaryl system as indicated in the claim 1.
  • Ar represents ary or heteroaryl rings as indicated in the claim 1.
  • X represents halogen, or p- toluenesulphonyl
  • the pro-drugs of the general formula (1) 'Structure 1' are superior to oxicams and related compounds. They can be used medicinally in treating any oxicams and related compounds-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by inhalation to a host. They can be used for treating breast cancer, colorestal cancer, pancreatic cancer, skin cancer, and any other cancers and for treating psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The novel positively charged pro-drugs of oxicams and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin ~100 times faster than do oxicams and related compounds. It takes 1-2 hours for oxicams and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about ~50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any oxicams-treatable conditions in humans or animals. Second, the prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of oxicams. Controlled transdermal administration systems of the prodrugs enable oxicams and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of oxicams and related compounds. Another great benefit of the transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Description

Description
POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF OXICAMS AND RELATED COMPOUNDS WITH VERY HIGH
SKIN PENETRATION RATE
Technical Field
[1] The present invention relates to the preparations of positively charged and water- soluble pro-drugs of oxicams and related compounds, and their medicinal use in treating any oxicams-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of oxicams and related compounds. These pro-drugs can be administered orally or transdermally.
Background Art
[2] Piroxicam, sudoxiam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinnoxicam, meloxicam, and related compounds are members of enolic acid class of 4-hydroxy-l,2-benzothiazine carboxamides with anti-inflammatory and analgesic properties. The first member of this class, piroxicam, was introduced in the United States in 1982 as Feldene(Pfizer). Oxicams are the leading analgesic and antipyretic drugs. They are used to relieve symptoms of rheumatoid arthritis, osteoarthritis and for fever. Other agents of oxicams are disclosed in U.S. Pat. Nos. 3,787,324, 3,822,258, 4,180,662 and 4,376,768.
[3] Unfortunately, a number of side effects are associated with the use of oxicams and related compounds, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. These levels are often much higher than would be necessary if it were possible to accurately target the particular site of pain or injury. Fishman and many others (Van Engelen et al. U.S. Pat. No. 6,416,772; Macrides et al. U.S. Pat. No. 6,346,278; Kirby et al. U.S. Pat. No. 6,444,234, Roentsch, et al., U.S. Pat. No. 5,654,337, Park, et al., U.S. Pat. No. 6,190,690, Pearson et al. U.S. Pat. No. 6,528,040, and Botknecht et al. U.S. Pat. No. 5,885,597) have tried to develop a delivery system for transdermal application by formulation. It is very difficult, however, to deliver therapeutically effective plasma levels of these kind drugs into the host by formulation, due to the slow skin penetration rate. Susan Milosovich, et al. designed and prepared testosteronyl- 4-dimethylaminobutyrate.HCl (TSBH), which has a lipophilic portion and a tertiary amine groups that exists in the protonated form at physiological pH. They found that the prodrug diffuses through human skin -60 times faster than does the drug itself [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993).
Disclosure of Invention
Technical Problem
[4] Piroxicam, sudoxiam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinnoxicam, meloxicam, and related compounds are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and for relief of fever.
[5] Unfortunately, a number of side effects are associated with the use of oxicams and related compounds, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis.
Technical Solution
[6] This invention relates to the preparation of novel positively charged pro-drugs of oxicams and related compounds and their use medicinally. The pro-drugs of oxicams and related compounds have the general formula (1) 'Structure 1'.
Figure imgf000004_0001
Structure 1 Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2, 3, 4, 5,
6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, CH , C H , CF or C F ; A" represents Cl", Br", F",
I", AcO", citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ; R represents ary or heteroaryl system, they include, but are not limited to:
Figure imgf000005_0001
Wherein, X and X represent H, F, Cl, Br, I, CF , C 2 F 5 , SO CF , SO CH , NO , CN, alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms.
represents ary or heteroaryl system, they include, but are not limited to
Figure imgf000005_0002
Figure imgf000005_0003
Figure imgf000006_0001
Wherein, X1 and X2 represent H, F, Cl, Br, I, CF3, C3F5, SO2CF3, SO2CH3 , NO2, alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms. All R, -(CH 2 ) n -, groups are branched or straight chains and may include C, H, O, S, or N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.
[7] Drug absorption, whether from the gastrointestinal tract or other sites, requires the passage of the drug in a molecular form across the barrier membrane. The drug must first dissolve, and if the drug possesses the desirable biopharmaceutical properties, it will pass from a region of high concentration to a region of low concentration across the membrane and into the blood or general circulation. All biological membranes contain lipids as major constituents. The molecules that play the dominant roles in membrane formation all have phosphate-containing highly polar head groups, and, in most cases, two highly hydrophobic hydrocarbon tails. Membranes are bilayers, with the hydrophilic head groups facing outward into the aqueous regions on either side. Very hydrophilic drugs cannot pass the hydrophobic layer of membrane and very hydrophobic drugs will stay in the hydrophobic layer as part of the membrane due to their similarities and cannot enter the cytosol on the inside efficiently.
[8] The goal of this invention is to avoid the side effects of oxicams and related compounds by increasing their solubility in gastric juice and moisture of skin and their penetration rate through the membrane and skin barrier which will make them ad- ministrable transdermally (topical application). These novel pro-drugs have two structural features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the protonated form (hydrophilic part) at physiological pH. Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich, et al., J. Pharm. Sci., 82, 227(1993)]. The positively charged amino groups largely increase the solubility of the drugs. The solubility of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl, N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ 'T-dithia-S-azabicycloK^Olnona-SJO-dien-S-one.HCl, 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H- 1 ,2-benzothiazine-3-carboxamide- 1 , 1 -dioxide.HCl, Piroxicam, sudoxiam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam in water are >300 mg, >300 mg, >300 mg, >300 mg, >300 mg, >300 mg, >300 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, and <0.1 mg/ml, In many instances, the lowest or rate-limiting step in the sequence is the dissolution of the drug. Oxicams and related compounds have a very low solubility in gastric juice or the moisture of skin. When these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately. The positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration of the outside of the membrane will be very high and will facilitate the passage of these prodrugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension. The pH of the stomach is 1-3, so the negative charge on the phosphate head group of the membrane of the gastric mucosa is bonded with proton (H+). The positive charges of these prodrugs cannot bond to phosphate head group of the gastric mucosa. Thus, prodrugs will not damage the stomach. The penetration rates of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl, N-
(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1 -dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ 'T-dithia-S-azabicycloK^Olnona-SJO-dien-S-one.HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N - [5-Methyl-3-isoxolyl-2H- 1 ,2-benzothiazine-3-carboxamide 1 , 1 -dioxide] .HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H- 1 ^-benzothiazine-S-carboxamide- 1 , 1 -dioxide.HCl, Piroxicam, sudoxiam, lornoxicam, tenoxicam, lomoxicam, isoxicam, meloxicam, and related compounds through human skin were measured in vitro by using modified Franz cells, which were isolated from human skin tissue (360-400 μm thick) of the anterior and posterior thigh areas. The receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm. The cumulative amounts of these prodrugs and their parent drugs penetrating the skin versus time were determined by a specific high-performance liquid chromatography method. The results using a donor consisting of either a 20% solution of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl, N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1 -dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ67-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl, 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl, and 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide- 1,1 -dioxide.HCl or a 20% suspension of Piroxicam, sudoxiam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam in 2mL of pH 7.4 phosphate buffer (0.2M) are shown in Figure 1. Apparent flux values of 1.7 mg, 1.5 mg, 1.6 mg, 1.8 mg, 1.7 mg, 1.8 mg, 1.9 mg, 0.001 mg, 0.001 mg, 0.001 mg, 0.001 mg, 0.001 mg, 0.001 mg, and 0.001 mg/cm2/h were calculated for
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl, N-
(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1 -dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ 'T-dithia-S-azabicycloK^Olnona-SJO-dien-S-one.HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N -
[5-Methyl-3-isoxolyl-2H- 1 ,2-benzothiazine-3-carboxamide 1 , 1 -dioxide] .HCl, and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2- thiazolyl)-2H- 1 ,2-benzothiazine-3-carboxamide- 1 , 1 -dioxide.HCl , Piroxicam, sudoxiam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam. The results suggest that the positive charge on the dialkyaminoethyl group has a very important role in the passage of the drug across the membrane or skin barrier. Other prodrugs of the general 'Structure 1' have very high penetration rates and are very close to that of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl. [9] The in vivo rates of penetration of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl, N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1 -dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ 'T-dithia-S-azabicycloK^Olnona-SJO-dien-S-one.HCl, 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H- 1 ,2-benzothiazine-3-carboxamide- 1 , 1 -dioxide.HCl, Piroxicam, sudoxiam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam through the skin of intact hairless mice were compared. The donor consisted of a 20% solution of these compounds in 1 mL of isopropanol applied to a 10 cm on the backs of the hairless mice. Plasma levels of drugs were determined by a specific high-performance liquid chromatography method. The results (Figure 2) show that the peak levels of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1 -dioxide.HCl, N-
(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1 -dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ ^-dithia-S-azabicycloK^OJnona-SJO-dien-S-one.HCl, 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-l,l-dioxide.HCl were reached in -50 minutes after application of the donor systems.
[10] It takes 1-2 hours for oxicams and related compounds to reach their peak plasma level when they are taken orally. The peak plasma levels were -0.005 mg/ml for piroxicam, and sudoxiam and -0.5 mg/ml for
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl, N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1-dioxide.HCl,
8-chloro-(4-N,N-dimethylaminobutyiyloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ67-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl, 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl, 4- N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2- thiazolyl)-2H- 1 ,2-benzothiazine-3-carboxamide- 1 , 1 -dioxide.HCl (approximately 100 times difference). -0.5 mg/ml of acetaminophen and acetaminosalol in plasma is more than -50 times higher than plasma level for effective analgesia and effective antiinflammatory activity. This is a very exciting result. It will be very easy and fast to deliver therapeutically effective plasma level of oxicams into the host by administration of these prodrugs transdermally. These results suggest that the pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments. The in vivo rates of penetration of other pro-drugs of the general 'Structure I' are close to that of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl.
[11] The acute toxicity of the prodrugs was investigated. The LD orally in mice are:
550 mg/kg, 670 mg/kg, 580 mg/kg, 500 mg/kg, 610 mg/kg, 570 mg/kg, and 590 mg/ kg, and 360 mg/kg for 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl, N-
(2-thiazoyl)-4-N,N-dimethylaminobutyiyloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l
,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1-dioxide.HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ67-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl, 4-
N,N-dimethylaminobutyryloxy -2-methyl-N -
[5-Methyl-3-isoxolyl-2H- 1 ,2-benzothiazine-3-carboxamide 1 , 1 -dioxide] .HCl, 4-
N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide- 1,1 -dioxide.HCl and piroxicam. The prodrugs are less toxic than the parent drugs. [12] A good prodrug should go back to the parent drug in plasma. The prodrugs in this invention can be rapidly cleaved by the enzymes in human plasma in vitro. More than
90% of the pro-drugs are changed back to their parent drugs in a few minutes. Due to the pro-drugs having a much better absorption rate, the prodrugs will have more strength than their parent drugs at the same dosage. Oxicams demonstrated analgesic and antipyretic activity. The analgetic and antipyretic activities of these prodrugs were tested using piroxicam as a comparison. [ 13] Analgesic activity: The prolongation time of the pain threshold of a mouse tail was determined in accordance with the D'Amour-Smith Method (J. Pharmacol. Exp. Ther.,
72, 74(1941)). After 20 mg/kg of these prodrugs were administered transdermally, the tails of mice were exposed to heat and the prolongation time of pain threshold was determined. The results obtained are shown in Figure 3. The prodrugs of oxicams have shown analgesic activity nicely when they were administered transdermally. [14] The number of writhings that occurred when mice were administered an acetic acid solution intraperitoneally were counted, and the rate of inhibition based on the control group was calculated.
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl (50 mg/kg, B), N-
(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl (50 mg/kg, C),
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l
,2-thiazine-3-carboxamide 1,1-dioxide.HCl (50mg/kg, D),
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1 -dioxide .HCl (50 mg/kg, E),
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ ^-dithia-S-azabicycloK^OJnona-SJO-dien-S-one.HCl (50 mg/kg, F), 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl ( 50 mg/kg, G) , and 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-l,l-dioxide.HCl (50 mg/kg, H) were administered transdermally the mice 60 minutes before the acetic acid solution was administered. The group A is the control group. The results are shown in Table 1. Table 1. The Rate of Writhings Inhibition by Prodrugs of Oxicams.
[15]
Figure imgf000012_0001
The results show that the prodrugs demonstrate exceptional analgetic activity. Other compounds of the general 'Structure 1' show similar analgetic activity.
[16] Antipyretic activity: Rats received a sterilized E. coli suspension as a pyrogen. The control group is group A. 2 hours later,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl (25 mg/kg, B), N-
(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl (25 mg/kg, C),
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l ,2-thiazine-3-carboxamide 1,1-dioxide.HCl (25mg/kg, D),
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1-dioxide.HCl (25 mg/kg, E),
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ6'7-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (25 mg/kg, F), 4- N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl ( 25 mg/kg, G) , and 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-l,l-dioxide.HCl (25 mg/kg, H) were administered transdermally. The body temperature of the rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 2.
Table 2. Antipyretic Activity of Prodrugs of Oxicams.
[17]
Figure imgf000013_0001
The results shown that the prodrugs demonstrated strong antipyretic activity at 25 mg/ kg dose. Other compounds of the general 'Structure 1' show similar antipyretic activity.
[18] It is also known that a high oral dose of some of NSAIAs shows an anti- reactive-antiasthmatic activity by inhibition of the cyclooxygenase activity. Due to their very high membrane penetration rate, these prodrugs can be used in treating asthma by spraying into the mouth or nose of the host.
[19] These prodrugs can also be used to treat psoriasis, acne, sunburn or other skin disorders due to inhibition of the cyclooxygenase activity and very high skin penetration rate. They may useful for treating skin, lung, breast, and other cancers.
[20] The present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for administration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration. The new active compounds of the general 'Structure 1' can be combined with vitamins such as A, B, C or E or beta-carotene, or other pharmaceuticals, such as beta-carotene, Caffeine , pseudoephedrine, azapirone, folic acid, etc., for treating any oxicams- treatable conditions in humans or animals.
[21] Transdermal therapeutic application systems of compounds of the general
'Structure 1' or a composition comprising of at least one compound of the general 'Structure 1', as an active ingredient, can be used for treating any oxicams-treatable conditions in humans or animals. These systems can be a bandage or a patch comprising of one active substance-containing matrix layer and an impermeable backing layer. The most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of oxicams and related compounds. These systems can be worn on the wrist, ankle, arm, leg, or any part of body.
[22] The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from oxicams and related compounds, by reaction with compounds of the general formula (2) 'Structure 2' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O- (Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- (Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol- l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, et al.
Figure imgf000014_0001
Structure 2 Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2, 3, 4, 5,
6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues, and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ....
[23] The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from oxicams and related compounds, by reaction with compounds of the general formula (3) 'Structure 3'.
Figure imgf000015_0001
Structure 3 Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2, 3, 4, 5,
6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; X represents halogen, or p-toluenesulphonyl, A" represents Cl", Br", F", I", AcO", citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10....
Advantageous Effects
[24] These pro-drugs of oxicams and related compounds have a lipophilic portion and a hydrophilic portion (the amine groups that exist in the protonated form at physiological pH). The positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new prodrugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. Second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drugs into the cytosol, which is a semi-liquid concentrated aqueous solution or suspension. Experiment results show that more than 90% of the pro-drugs were changed back to the parent drugs in a few minutes. The pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than oxicams and related compounds at the same dosage. The experiment results suggest that the pro-drugs of oxicams diffuses through human skin -100 times faster than do oxicams. It takes 1-2 hours for oxicams and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about -50 minutes to reach the peak plasma level. The most exciting result is that the pro-drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of oxicams and related compounds, most notably GI disturbances such as dyspepsia, gas- troduodenal bleeding, gastric ulcerations, and gastritis. Another great benefit of the transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.
Description of Drawings [25] Figure 1 : Cumulative amounts of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl (A, 20% solution), N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl (B, 20% solution),
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l
,2-thiazine-3-carboxamide 1,1-dioxide.HCl (C, 20% solution),
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1-dioxide.HCl (D, 20% solution),
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ67-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (E, 20% solution), 4- N,N-dimethylaminobutyryloxy -2-methyl-N -
[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1 -dioxide] .HCl (F, 20% solution) , 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide- 1,1-dioxide.HCl (G, 20% solution) ,
Piroxicam (H, 20% suspension), sudoxiam (I, 20% suspension), lornoxicam (J, 20% suspension), tenoxicam (K, 20% suspension), lomoxicam (L, 20% suspension), isoxicam (M, 20% suspension), and meloxicam (N, 20% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M). [26] Figure 2: Total plasma levels of drugs after topical application of 1 ml of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl, N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl,
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l
,2-thiazine-3-carboxamide 1 , 1 -dioxide.HCl,
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1-dioxide.HCl,
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ67-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl, 4-
N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide]
.HCl, 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide-l,l-dioxide.HCl , Piroxicam, and sudoxiam in isopropanol to the backs of hairless mice (n=5). [27] Figure 3: The prolongation time of the pain threshold of mice tails after 20mg/kg of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-carb oxamide 1,1-dioxide.HCl (B), N-
(2-thiazoyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l,2-benzothiazine-3-carbo xamide 1,1-dioxide.HCl (C),
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l
,2-thiazine-3-carboxamide 1,1-dioxide.HCl (D),
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazin e-3-carboxamide 1,1-dioxide.HCl (E),
8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridine-2-ylamino-methylidene)-3-methy l-2,2-dioxo-2λ67-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one.HCl (F), 4-
N,N-dimethylaminobutyryloxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide]
.HCl (G), and 4- N,N-dimethylaminobutyryloxy -2-methyl-N-(5-methyl-2- thiazolyl)-2H-l,2-benzothiazine-3-carboxamide- 1,1-dioxide.HCl (H) were administered transdermally. Group A is the control group. [28] Figure 4: Structure 1. Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, CH , C H , CF or C F ; R represents ary or heteroaryl system as indicated in the claim 1. Ar represents ary or heteroaryl rings as indicated in the claim 1. X represents halogen, or p- toluenesulphonyl, A" represents Cl", Br", F", I", AcO , citrate, or any negative ions; and n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10....
Best Mode Preparation of 4-N^V-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H,l,2-benzothiazine-3-ca rboxamide 1,1-dioxide.HCl. [29] 33.1 g (0.1 mol) of
4-hydroxy-2-methyl-N-2-pyridinyl-2H, 1 ,2-benzothiazine-3-carboxamide 1 , 1 -dioxide was dissolved in 200 ml of acetone and 250 ml of 10% NaHCO . 22.3 g (0.12 mol) of dimethylaminobutyryl chloride hydrochloride was added into the mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 500 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with 5% NaHCO (1 x 200 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 40 g of the hygroscopic desired product (83.2%). Solubility in water: 250 mg/ml; Elementary analysis: C2 H25ClN4O5S; MW: 480.96. Calculated % C: 52.44, H: 5.24, Cl: 7.37, N: 11.65, O: 16.63, S: 6.67; Found % C: 52.40, H: 5.27, Cl: 7.42, N: 11.60; O: 16.70, S: 6.61. 1H-NMR (400 MHz, D2O): δ: 2.00 (m, 2H), 2.23 (m, 2H), 2.46 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.60-6.70 (m, 2H), 7.20 (m, IH), 7.40-7.44 (m, 2H), 7.56 (m, IH), 7.80 (m, IH), 8.10 (m, IH).
Mode for Invention Preparation of N-
(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H,l^-benzothiazine-3-carb oxamide 1,1-dioxide.HCl
[30] 32.5g (0.1 mol) of N-
(2-thiazolyl)-4-hydroxy-2-methyl-2H, 1 ,2-benzothiazine-3-carboxamide 1 , 1 -dioxide and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethylene. The mixture is cooled to 0 °C with ice bath. 20.6 g (0.1 mol) of N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0 °C and 2 hours at RT. The solid is removed by filtration. The dichloromethylene solution was washed with 5% NaHCO (2 x 100 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 37 g of the hygroscopic desired product (76%). Solubility in water: 250 mg/ml; Elementary analysis: C H ClN4O5S2; MW: 486.99. Calculated % C: 46.86, H: 4.76, Cl: 7.28, N: 11.50, O: 16.43, S: 13.17; Found % C: 46.83, H: 4.78, Cl: 7.31, N: 11.52, O: 16.41, S: 13.15. 1H-NMR (400 MHz, D2O): δ: 2.01 (m, 2H), 2.22 (m, 2H), 2.44 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.50 (m, IH), 7.20 (m, IH), 7.40 (m, IH), 7.50 (m, IH), 7.58 (m, IH), 7.85 (m, IH).
Preparation of
6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]- l,2-thiazine-3-carboxamide 1,1-dioxide.HCl
[31] 36 g (0.1 mol) of 6-chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e] - l,2-thiazine-3-carboxamide 1,1-dioxide.HCl was dissolved in 200 ml of acetone and 200 ml of 10% NaHCO . 22.3 g (0.12 mol) of dimethylaminobutyryl chloride hy- drochloride was added into the mixture and the mixture was stirred for 3 hours at RT. The solvents were evaporated off. 500 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with 10 % NaHCO (I x 500 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 42 g of the hygroscopic desired product (80.5%). Solubility in water: 250 mg/ml; Elementary analysis: C H Cl2N4O5S 2; MW: 521.44. Calculated % C: 43.76, H: 4.25, Cl: 13.60, N: 10.74, O: 15.34, S: 12.30; Found % C: 43.72, H: 4.27, Cl: 13.67, N: 10.70; O: 15.37, S: 12.27. 1 H-NMR (400 MHz, D O): δ: 2.02 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 2.86 (s, 6H), 3.18 (m, 2H), 6.60-6.70 (m, 2H), 7.10 (s, IH), 7.44 (m, IH), 8.10 (m, IH).
Preparation of
4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazi ne-3-carboxamide 1,1-dioxide.HCl.
[32] 32.5 g (0.1 mol) of 4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e] - l,2-thiazine-3-carboxamide 1,1 -dioxide and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethylene. The mixture is cooled to 0 °C with ice bath. 20.6 g (0.1 mol) of N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0 °C and 2 hours at RT. The solid is removed by filtration. The dichloromethylene solution was washed with 5% NaHCO (2 x 100 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 39 g of the hygroscopic desired product (80.1 %). Solubility in water: 250 mg/ml; Elementary analysis: C 9H23ClN4O5S2; MW: 486.99. Calculated % C: 46.86, H: 4.76, Cl: 7.28, N: 11.50, O: 16.43, S: 13.17; Found % C: 46.82, H: 4.77, Cl: 7.30, N: 11.47; O: 16.47, S: 13.15. 1H-NMR (400 MHz, D2O): δ: 2.02 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 2.86 (s, 6H), 3.18 (m, 2H), 6.61-6.70 (m, 2H), 7.30 (d, IH), 7.45 (m, IH), 7.60 (d, IH), 8.11 (m, IH).
Preparation of 4-N,N-dimethylaminobutyryloxy-2-methyl-7V - [5-Methyl-3-isoxolyl-2H-l^-benzothiazine-3-carboxamide l,l-dioxide].HCl
[33] 32.5g (0.1 mol) of 4- hydroxy -
2-methyl-N-[5-Methyl-3-isoxolyl-2H-l,2-benzothiazine-3-carboxamide 1,1-dioxide] .HCl and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethylene. The mixture is cooled to 0 °C with ice bath. 20.6 g (0.1 mol) of N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0 °C and 2 hours at RT. The solid is removed by filtration. The dichloromethylene solution was washed with 5% NaHCO (2 x 100 ml) and water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. HCl gas (4 g) is bubbled into the solution. The solid product was collected by filtration. After drying, it yielded 37 g of the hygroscopic desired product (78.7%). Solubility in water: 250 mg/ml; Elementary analysis: C H ClN4O6S; MW: 470.93. Calculated % C: 48.46, H: 4.92, Cl: 7.53, N: 11.90, O: 20.38, S: 6.81; Found % C: 48.43, H: 4.94, Cl: 7.57, N: 11.86, O: 20.41, S: 6.79. 1H-NMR (400 MHz, D2O): δ: 2.01 (m, 2H), 2.22 (m, 2H), 2.44 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.40 (m, IH), 7.20 (m, IH), 7.40 (m, IH), 7.52 (m, IH), 7.58 (m, IH), 7.85 (m, IH).
Industrial Applicability
[34] The pro-drugs of the general formula (1) 'Structure 1' are superior to oxicams and related compounds. They can be used medicinally in treating any oxicams and related compounds-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by inhalation to a host. They can be used for treating breast cancer, colorestal cancer, pancreatic cancer, skin cancer, and any other cancers and for treating psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties.
Sequence List Text
[35]

Claims

Claims
[1] The compounds of the general formula (1) 'Structure 1'
Figure imgf000021_0001
Structure 1 Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2,
3, 4, 5, 6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, CH , C H , CF or C F ; A represents Cl", Br", F, I", AcO", citrate, or any negative ions; R represents an ary or heteroaryl system, they include, but are not limited to:
Figure imgf000021_0002
Figure imgf000022_0001
Wherein, X 1 and X 2 represent H, F, Cl, Br, I, CF 3 , C2 F5 , SO2 CF3 , SO2 C :HH 33 , NO2 , alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms.
represents ary or heteroaryl system, they include, but are not limited to
Figure imgf000022_0002
Figure imgf000022_0003
Wherein, X 1 and X 2 represent H, F, Cl, Br, I, CF 3 , C2 F5 , SO2 CF3 , SO2 CH3 , NO2 , alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 8 carbon atoms. All R, - (CH 2 ) n -, groups are branched or straight chains and may include O, S, Cl, F, Br,
I, or N atoms and may have single, double, and triple bonds. Any CH groups may be replaced with O, S, or NH.
[2] Processes for the preparation of compounds of the general formula (1) 'Structure I' according to Claim 1, wherein the compounds can be prepared from oxicams and related compounds, by reaction with compounds of the general formula (2) 'Structure 2' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-
(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- (Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Ben- zotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate, et al.
Figure imgf000023_0001
Structure 2 Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2,
3, 4, 5, 6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues. [3] Processes for the preparation of compounds of the general formula (1) 'Structure
I' according to Claim 1, wherein the compounds can be prepared from metal salts, organic base salts, or immobilized base salts of oxicams and related compounds, by reaction with compounds of the general formula (3) 'Structure 3'.
Figure imgf000023_0002
Structure 3 Wherein, R represents a branched or straight chain, -(CH 2 ) n -, wherein n=0, 1, 2,
3,
4, 5, 6, 7, 8, 9, 10 ..., aryl residues or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, aryl or heteroaryl residues; X represents halogen, or p- toluenesulphonyl, A" represents Cl", Br", F", I", AcO", citrate, or any negative ions. [4] Compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, where they can be administered orally or transdermally, for treating any oxicams-treatable conditions in humans or animals. The oxicams-treatable conditions include, but are not limited to, pain from a toothache, headache, arthritis and other inflammatory pain, fever, cancer, dysmenorrhea, radiation-induced vomiting, diabetic neuropathy and acute migraine headache, hemophilic arthropathy, bone loss, and sunburn.
[5] Methods for treating any oxicams-treatable conditions in humans or animals by administering transdermally to any part of body (in the from of a solution, spray, lotion, ointment, emulsion or gel) to deliver therapeutically effective plasma levels of the compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1.
[6] Methods for topically treating pain such as a headache, toothache, and muscle pain, and arthritis and other inflammatory pain in humans or animals by administering to the inflamed area a therapeutically effective amount of the compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1.
[7] Compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, may be administered transdermally for treating psoriasis, acne, sunburn or other skin disorders in the from of a solution, spray, 1 otion, ointment, emulsion or gel.
[8] Compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, are administered by spraying to through the mouth or nose or other parts of body for treating asthma.
[9] Compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, for treating any eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/or painful conditions (otitis) in humans or animals.
[10] Compounds of the general formula (1) 'Structure 1' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, for treating breast cancer, colorestal cancer, pancreatic cancer, skin cancer, and any other cancers.
[11] Transdermal therapeutic application systems of compounds of the general formula (1) 'Structure l' or a composition comprising of at least one compound of the general formula (1) 'Structure 1', as an active ingredient, according to Claim 1, for treating any NSAIAs-treatable conditions in humans or animals. These systems can be a bandage or a patch comprising of one active substance- containing matrix layer and an impermeable backing layer. The most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables the oxicams to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of oxicams.
PCT/IB2006/053741 2006-07-09 2006-10-11 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate WO2008044095A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
JP2009531929A JP5378221B2 (en) 2006-10-11 2006-10-11 Positively charged water-soluble prodrugs of oxicam and related compounds with very high skin permeability
PCT/IB2006/053741 WO2008044095A1 (en) 2006-10-11 2006-10-11 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
CN200680056073A CN101522692A (en) 2006-10-11 2006-10-11 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
EP06809572.8A EP2084165B1 (en) 2006-10-11 2006-10-11 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
US12/351,804 US20090238763A1 (en) 2006-07-09 2009-01-09 High penetration compositions and uses thereof
US12/397,308 US20090221703A1 (en) 2006-07-09 2009-03-03 High penetration composition and uses thereof
US15/379,866 US11135153B2 (en) 2006-07-09 2016-12-15 High penetration composition and uses thereof
US15/402,618 US9872846B2 (en) 2006-07-09 2017-01-10 High penetration compositions and uses thereof
US15/402,575 US20170209585A1 (en) 2006-07-09 2017-01-10 High penetration compositions and uses thereof
US16/421,735 US20210353579A1 (en) 2006-07-09 2019-05-24 High penetration compositions and uses thereof
US17/493,321 US20220096370A1 (en) 2006-07-09 2021-10-04 High penetration composition and uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2006/053741 WO2008044095A1 (en) 2006-10-11 2006-10-11 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/053090 Continuation-In-Part WO2008029199A1 (en) 2006-07-09 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate

Related Child Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB2006/053090 Continuation-In-Part WO2008029199A1 (en) 2006-07-09 2006-09-03 Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
US12/351,804 Continuation-In-Part US20090238763A1 (en) 2006-07-09 2009-01-09 High penetration compositions and uses thereof

Publications (1)

Publication Number Publication Date
WO2008044095A1 true WO2008044095A1 (en) 2008-04-17

Family

ID=39282470

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/053741 WO2008044095A1 (en) 2006-07-09 2006-10-11 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate

Country Status (4)

Country Link
EP (1) EP2084165B1 (en)
JP (1) JP5378221B2 (en)
CN (1) CN101522692A (en)
WO (1) WO2008044095A1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2170826A4 (en) * 2007-06-04 2012-11-07 Techfields Inc Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses
US9193672B2 (en) 2007-01-15 2015-11-24 Chongxi Yu High penetration prodrug compositions of retinoids and retinoid-related compounds
US9248109B2 (en) 2009-05-08 2016-02-02 Chongxi Yu High penetration prodrug compositions of peptides and peptide-related compounds
US9376381B2 (en) 2006-11-08 2016-06-28 Techfields Pharma Co., Ltd. High penetration prodrug compositions of peptides and peptide-related compounds
US9567329B2 (en) 2007-01-31 2017-02-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions of 1H-imidazo[4,5-c]quinolin-4-amines and 1H-imidazo[4,5-c]quinolin-4-amine-related compounds and uses thereof
CN107320732A (en) * 2008-12-04 2017-11-07 于崇曦 High-penetration composition and its application
US9862698B2 (en) 2014-12-16 2018-01-09 Adt Pharmaceuticals, Inc. Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US9931315B2 (en) 2014-12-16 2018-04-03 Adt Pharmaceuticals, Inc. Method of selectively inhibiting Ras-mediated tumor growth in humans
US9969751B2 (en) 2009-06-10 2018-05-15 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US10233197B2 (en) 2006-12-10 2019-03-19 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US11186596B2 (en) 2018-04-26 2021-11-30 Adt Pharmaceuticals, Llc Anticancer indenes, indanes, azaindenes, azaindanes, pharmaceutical compositions and uses
US11555014B2 (en) 2006-10-02 2023-01-17 Techfields Pharma Co., Ltd. High penetration prodrug compositions of prostaglandins and related compounds
US11813256B2 (en) 2012-01-18 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2015012559A (en) 2013-03-15 2016-07-18 Techfields Pharma Co Ltd Novel high penetration drugs and their compositions thereof for treatment of parkinson diseases.
CN106632403B (en) * 2017-01-23 2018-09-11 牡丹江医学院 A kind of operation analgesic antiphlogistic medicine and preparation method thereof

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3787324A (en) 1971-03-01 1974-01-22 Warner Lambert Co 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production
US4180662A (en) 1977-09-06 1979-12-25 Hoffmann-La Roche Inc. Thiazine derivatives
US4376768A (en) 1980-06-27 1983-03-15 Mitsui Toatsu Chemicals, Inc. Benzothiazine derivative
US4551452A (en) * 1983-12-21 1985-11-05 Pfizer Inc. Anti-inflammatory 2-methyl-2H-1,2-benzo-(or -thieno-)thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor
EP0208404A2 (en) 1985-05-29 1987-01-14 Pfizer Inc. Benzothiazine dioxide derivatives
WO1990002141A1 (en) * 1988-08-31 1990-03-08 Australian Commercial Research & Development Limited Compositions and methods for drug delivery and chromatography
US5081118A (en) * 1987-10-26 1992-01-14 Pfizer Inc. Benzothiazine dioxide derivatives
US5607691A (en) 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
US5654337A (en) 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent
US5885597A (en) 1997-10-01 1999-03-23 Medical Research Industries,Inc. Topical composition for the relief of pain
US6190690B1 (en) 1996-07-03 2001-02-20 Stc Corporation Sustained/immediate acting ketoprofen patch and process for manufacturing the same
US6346278B1 (en) 1995-09-11 2002-02-12 Pharmalink International Limited Lipid extract having anti-inflammatory activity
US6416772B1 (en) 2001-01-12 2002-07-09 H. Wayne Van Engelen Topical dermal anaesthetic
US6444234B1 (en) 1998-07-07 2002-09-03 Kenneth B Kirby Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof
US7052715B2 (en) 2003-04-11 2006-05-30 All Natural Fmg, Inc. Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3704298A (en) * 1971-06-22 1972-11-28 Warner Lambert Co 4-acyloxy-3-(2-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides
IN162323B (en) * 1983-12-21 1988-04-30 Pfizer
JPS60184077A (en) * 1984-02-23 1985-09-19 フアイザー・インコーポレーテツド Antiinflammatory oxime precursor drug
WO1993025197A1 (en) * 1992-06-12 1993-12-23 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
IL150929A0 (en) * 2000-01-28 2003-06-24 Rohm & Haas Pharmaceutical compounds comprising a pharmaceutically active moiety and a moiety comprising a substituent that enhances its properties

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3787324A (en) 1971-03-01 1974-01-22 Warner Lambert Co 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production
US3822258A (en) 1971-03-01 1974-07-02 Warner Lambert Co 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US4180662A (en) 1977-09-06 1979-12-25 Hoffmann-La Roche Inc. Thiazine derivatives
US4376768A (en) 1980-06-27 1983-03-15 Mitsui Toatsu Chemicals, Inc. Benzothiazine derivative
US4551452A (en) * 1983-12-21 1985-11-05 Pfizer Inc. Anti-inflammatory 2-methyl-2H-1,2-benzo-(or -thieno-)thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor
EP0208404A2 (en) 1985-05-29 1987-01-14 Pfizer Inc. Benzothiazine dioxide derivatives
US5081118A (en) * 1987-10-26 1992-01-14 Pfizer Inc. Benzothiazine dioxide derivatives
WO1990002141A1 (en) * 1988-08-31 1990-03-08 Australian Commercial Research & Development Limited Compositions and methods for drug delivery and chromatography
US5607691A (en) 1992-06-12 1997-03-04 Affymax Technologies N.V. Compositions and methods for enhanced drug delivery
US5654337A (en) 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent
US6346278B1 (en) 1995-09-11 2002-02-12 Pharmalink International Limited Lipid extract having anti-inflammatory activity
US6190690B1 (en) 1996-07-03 2001-02-20 Stc Corporation Sustained/immediate acting ketoprofen patch and process for manufacturing the same
US5885597A (en) 1997-10-01 1999-03-23 Medical Research Industries,Inc. Topical composition for the relief of pain
US6444234B1 (en) 1998-07-07 2002-09-03 Kenneth B Kirby Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof
US6416772B1 (en) 2001-01-12 2002-07-09 H. Wayne Van Engelen Topical dermal anaesthetic
US7052715B2 (en) 2003-04-11 2006-05-30 All Natural Fmg, Inc. Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP2084165A4 *
SUSAN MILOSOVICH ET AL., J. PHARIN. SCI., vol. 82, 1993, pages 227

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US11555014B2 (en) 2006-10-02 2023-01-17 Techfields Pharma Co., Ltd. High penetration prodrug compositions of prostaglandins and related compounds
US9376381B2 (en) 2006-11-08 2016-06-28 Techfields Pharma Co., Ltd. High penetration prodrug compositions of peptides and peptide-related compounds
US10233197B2 (en) 2006-12-10 2019-03-19 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US9193672B2 (en) 2007-01-15 2015-11-24 Chongxi Yu High penetration prodrug compositions of retinoids and retinoid-related compounds
US11786497B2 (en) 2007-01-15 2023-10-17 Techfields Pharma Co., Ltd. High penetration prodrug compositions of retinoids and retinoids-related compounds
US9567329B2 (en) 2007-01-31 2017-02-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions of 1H-imidazo[4,5-c]quinolin-4-amines and 1H-imidazo[4,5-c]quinolin-4-amine-related compounds and uses thereof
AU2016228230B2 (en) * 2007-06-04 2018-04-05 Techfields Inc Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
EP2170826A4 (en) * 2007-06-04 2012-11-07 Techfields Inc Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses
AU2016228230C1 (en) * 2007-06-04 2018-08-30 Techfields Inc Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
US10233198B2 (en) 2007-06-04 2019-03-19 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAs with very high skin and membranes penetration rates and their new medicinal uses
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
CN107320732A (en) * 2008-12-04 2017-11-07 于崇曦 High-penetration composition and its application
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications
US9248109B2 (en) 2009-05-08 2016-02-02 Chongxi Yu High penetration prodrug compositions of peptides and peptide-related compounds
US9969751B2 (en) 2009-06-10 2018-05-15 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US11485744B2 (en) 2009-06-10 2022-11-01 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US11857545B2 (en) 2012-01-18 2024-01-02 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
US11813256B2 (en) 2012-01-18 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions
US9862698B2 (en) 2014-12-16 2018-01-09 Adt Pharmaceuticals, Inc. Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US11198679B2 (en) 2014-12-16 2021-12-14 Adt Pharmaceuticals, Llc Method of treating or preventing Ras-mediated diseases
US11407727B2 (en) 2014-12-16 2022-08-09 Adt Pharmaceuticals, Llc Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US11130744B2 (en) 2014-12-16 2021-09-28 Adt Pharmaceuticals, Llc Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US11104658B2 (en) 2014-12-16 2021-08-31 Adt Pharmaceuticals, Llc Method of treating or preventing Ras-mediated diseases
US10981886B2 (en) 2014-12-16 2021-04-20 Adt Pharmaceuticals, Llc Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US10975054B2 (en) 2014-12-16 2021-04-13 Adt Pharmaceuticals, Llc Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US10526307B2 (en) 2014-12-16 2020-01-07 Adt Pharmaceuticals, Llc Indenyl compounds, pharmaceutical compositions, and medical uses thereof
US9931315B2 (en) 2014-12-16 2018-04-03 Adt Pharmaceuticals, Inc. Method of selectively inhibiting Ras-mediated tumor growth in humans
US11186596B2 (en) 2018-04-26 2021-11-30 Adt Pharmaceuticals, Llc Anticancer indenes, indanes, azaindenes, azaindanes, pharmaceutical compositions and uses
US11680073B2 (en) 2018-04-26 2023-06-20 Adt Pharmaceuticals, Llc Anticancer indenes, indanes, azaindenes, azaindanes, pharmaceutical compositions and uses

Also Published As

Publication number Publication date
JP2010505936A (en) 2010-02-25
EP2084165A4 (en) 2011-01-05
EP2084165B1 (en) 2013-06-12
CN101522692A (en) 2009-09-02
EP2084165A1 (en) 2009-08-05
JP5378221B2 (en) 2013-12-25

Similar Documents

Publication Publication Date Title
EP2084165B1 (en) Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
EP2046727B1 (en) Positively charged water-soluble prodrugs of diclofenac with very fast skin penetration rate
CA2661649C (en) Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate
EP2623495B1 (en) Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
DK2041068T3 (en) POSITIVELY CHARGED, WATER SOLUBLE PRODRUGS OF IBUPROFEN WITH VERY FAST SKIN PENETRATION SPEED
EP2049482B1 (en) Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate
WO2008012603A1 (en) Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate
AU2006347391A1 (en) Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate
WO2008012605A1 (en) Positively charged water-soluble prodrugs of ketoprofen and related compounds with very fast skin penetration rate
AU2014201024B2 (en) Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate
CN103980228B (en) Positively charged water-soluble prodrugs of oxicams and related compounds with fast skin penetration rates
AU2006347925B2 (en) Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate
AU2018202140A1 (en) Positively charged water-soluble pro-drugs of ibuprofen
CN104140422A (en) Positively charged water-soluble oxicam with fast skin penetration speed and prodrug of related compound of oxicam

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680056073.6

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06809572

Country of ref document: EP

Kind code of ref document: A1

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: 2009531929

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2006809572

Country of ref document: EP

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)