EP1959964A1 - Composes de sulfonamide heteroaromatiques - Google Patents

Composes de sulfonamide heteroaromatiques

Info

Publication number
EP1959964A1
EP1959964A1 EP06829355A EP06829355A EP1959964A1 EP 1959964 A1 EP1959964 A1 EP 1959964A1 EP 06829355 A EP06829355 A EP 06829355A EP 06829355 A EP06829355 A EP 06829355A EP 1959964 A1 EP1959964 A1 EP 1959964A1
Authority
EP
European Patent Office
Prior art keywords
quinine
carboxylate
sulfamoyl
triene
sulfamoylthiophene
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06829355A
Other languages
German (de)
English (en)
Inventor
Ralf Wyrwa
Reinhard Nubbemeyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Schering Pharma AG
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
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP1959964A1 publication Critical patent/EP1959964A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • the invention relates to sulfonamide prodrugs of the general formula (I)
  • X is a heteroaromatic, a process for the preparation of these prodrugs, pharmaceutical compositions containing these compounds and their use for the preparation of orally available drugs.
  • WO 01/91797 discloses steroidal compounds which are bound to erythrocytes via a group - SO 2 NR 1 R 2 and accumulate there.
  • concentration ratio of the compounds between erythrocytes and plasma is 10- 1000: 1, preferably 30-1000: 1, so that one can speak of a deposit formation in the erythrocytes. Strong binding of the compounds to the erythrocytes avoids metabolism during liver passage. Disadvantageously, despite a reduced metabolization with the indicated dosages no therapeutically relevant drug levels are given. Reasons for this are to be found in an excessive binding to erythrocytes, an enzyme-induced cleavage and in low solubilities.
  • heterocyclic sulfonamide prodrugs of the general formula (I) in which a sulfamoyl radical is bonded to the drug to be released via a heteroaromatic spacer X by means of a carboxylic ester bond, in which
  • X is an unsubstituted or substituted heteroaromatic radical or an alkyl radical
  • Drug a pharmaceutical agent which can form a carboxylic acid ester via an OH group, such as steroids, antimalarials, nucleosides, isoflavonoids, which may optionally be substituted.
  • the sulfonamide prodrugs according to the invention with heteroaromatic linker X bind to erythrocytes, are readily soluble in water and are hydrolytically cleaved without the involvement of enzymes.
  • a heteroaromatic radical means, for example, thiophene, pyridine, pyrrole, furan or else thiophene, pyridine, pyrrole or furan substituted by C 1-4 -alkyl or halogen.
  • Substituted heteroaromatics include 2-bromothiophene, 2-ethylthiophene, N-methylpyrrole and 2-bromopyridine.
  • Ci -4 alkyl is methyl, ethyl, propyl, butyl or isopropyl group.
  • halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine, bromine atom.
  • alkyl heteroaromatic means a heteroaromatic bonded to the ester function via a C 1 -C 4 alkyl radical.
  • Heteroaromatics means the groups named heteroaromatic radical.
  • D 3 -alkyl radical denotes a methylene, ethylene or propylene bridge.
  • Preferred heteroaromatics are pyridine and thiophene. Preferred compounds are listed below:
  • the therapeutically relevant drug compound is released by hydrolysis.
  • the sulfamoyl prodrugs of the general formula (I) according to the invention surprisingly inhibit the carbonic anhydrase II. From this an accumulation of the prodrugs according to the invention in the erythrocytes can be deduced.
  • the SO 2 -NH 2 group of the substances according to the invention can lead to an accumulation in erythrocytes by binding to carbonic anhydrases.
  • Freshly obtained, heparinized blood of a rat is mixed with a defined amount of active ingredient.
  • the active substance concentration in the plasma obtained therefrom is measured against a calibration curve from spiked (with known active ingredient concentration) plasma.
  • the blood-plasma ratio is calculated from the measured concentration and the theoretical concentration.
  • the concentration ratios of the compounds according to the invention between erythrocytes and plasma are not in a range of 10-1000: 1, but in the range ⁇ 10: 1. This has proven to be a major disadvantage for achieving therapy-relevant active ingredient levels.
  • suitable linkers it is possible to set the optimal blood / plasma ratio for a prodrug compound.
  • the compounds of the general formula (I) can be used in the case where "Drug "a steroid such as androgen or estrogen is used in hormone replacement therapy (HRT) in women and men or in the treatment of hormonal disorders in men (prostate, breast cancer, hypogonadism) and women (endometriosis, breast cancer) become.
  • HRT hormone replacement therapy
  • the compounds of the general formula (I) according to the invention in which "drug” is, for example, an androgen or estrogen, can be used for fertility control in men or women
  • drug is, for example, an androgen or estrogen
  • further drugs mentioned for “drugs” such as quinine, chinchonidine, hydroxychloroquine, Primaquine or mefloquine concerns the treatment of malaria.
  • drug is a cortisol derivative
  • drug is a nucleoside (zidovudine, brivudine, indinavir, nelfinavir) and can be used to treat viral diseases (herpes, HIV).
  • the invention also provides the pharmaceutical compositions comprising the compounds of the general formula (I) according to the invention and optionally other active compounds, for example progestagens (norethisterone, dienogest, drospirenone, levonorgestrel), antigestagens (mifepristone, onapristone) and / or progesterone receptor modulators (mesoprogestins such as asoprisnil).
  • active compounds for example progestagens (norethisterone, dienogest, drospirenone, levonorgestrel), antigestagens (mifepristone, onapristone) and / or progesterone receptor modulators (mesoprogestins such as asoprisnil).
  • compositions and medicaments are preferably administered orally.
  • pharmaceutical compositions and medicaments are preferably administered orally.
  • conventional carriers and / or diluents they contain at least one compound of the general formula I.
  • the prodrugs according to the invention can be administered orally.
  • compositions of the invention are prepared in a known manner with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical excipients according to the desired mode of administration with a suitable dosage.
  • the preferred preparations consist in one Dosage form suitable for oral administration.
  • dosage forms are, for example, tablets, coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
  • Corresponding tablets for example, by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve Depot effect such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate, are obtained.
  • excipients for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents to achieve Depot effect such as carboxyl polymethylene, carb
  • Coated tablets can accordingly be prepared by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions with the compounds of general formula I according to the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • the capsules containing the compounds of the general formula I can be prepared, for example, by mixing the compound (s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatine capsules.
  • an inert carrier such as lactose or sorbitol
  • prodrugs according to the invention can be synthesized according to the following examples, these serving for the more detailed explanation, without restricting the invention.
  • beta-picoline-5-sulfonic acid 3.5 g are under protective gas, with 6.5 g PCl 5 and 2.5 ml POCI 3 combined and heated 3 h at 120 0 C.
  • the POCl 3 is distilled off in vacuo and 3 ml of ice water are added with cooling.
  • the mixture is dissolved in 150 ml of NH 3 solution. stirred in and the solution concentrated to dryness.
  • the mixture is extracted with MeOH and the product obtained after concentration is purified by column chromatography on silica gel. 5-sulfamoyl-.beta.-picoline is obtained.
  • 5-sulfamoyl nicotinic acid 8.0 g of 5-sulfamoyl-ß-picoline are placed in 250 ml of water. After addition of 12.5 g KMnO 4 is heated to 70 0 C. After decolorization 12.5 g of KMnO 4 are added again and heated to 70 0 C for 12 h. It is filtered hot and concentrated to about 20 ml. It is acidified with 10% HCl (pH ⁇ 2). The crystallized in the cold substance is filtered off with suction, washed with water and dried. 5-sulfamoylnicotinic acid is obtained.
  • 3-tert-butyldimethylsilyloxyestra-1, 3.5 (1 OH-17 ⁇ -yl) 5'-sulfamoyl nicotinate 0.55 g of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -triene-17 ⁇ -ol and 0.55 g of 5 Sulfamoylnicotinic acid is dissolved in 7 ml of pyridine under argon, 0.12 g of p-Tos-OH and finally 0.55 g of DCC are added at 0 ° C.
  • Example 8 3-Hydroxypropyl-1, 3,5 (10) -triene-17 ⁇ -yl 2'-bromo-5'-sulfamoylthiophene-3'-carboxylate (4) 330 mg of 3-tert-butyldimethylsilyloxyestra-1, 3.5 ( 10) -trien-17ß-yl 2'-bromo-5'-sulfo-amoylthiophene-3'-carboxylate are dissolved in 30 ml of THF. While stirring, 300 mg of TBAF are added at RT. After 1 hour, 30 ml of water are stirred.
  • DCC dicyclohexyl-carbodiimide
  • DCC dicyclohexyl-carbodiimide
  • Example 11 3-tert-butyldimethylsilyloxyestra-1.3.5 (10) -trien-17 ⁇ -yl N-methyl-5'-sulfamoyl-1H-pyrrole-2'-carboxylate 0.50 g of 3-tert-butyldimethylsilyloxyestra-1, 3,5 (10) -triene-17 ⁇ -ol and 0.50 g of N-methyl-5'-sulfamoyl-1H-pyrrole-2'-carboxylic acid are dissolved in 7 ml of pyridine under argon. Subsequently, 0.12 g p-Tos-OH and finally at 0 0 C 0.5 g DCC are added. The reaction mixture is stirred for 48 h at RT.
  • 3-Hydroxypropyl-1, 3,5 (10) -triene-17 ⁇ -yl N-methyl-5'-sulfamoyl-1H-pyrrole-2'-carboxylate 300 mg 3-tert-butyldimethylsilyloxyestra-1, 3.5 (10 ) -trien-17 ⁇ -yl N-methyl-5'-sulfamoyl-1H-pyrrole-2'-carboxylate are dissolved in 20 ml of THF. With stirring, 250 mg of TBAF are added at RT. After 1 hour, 20 ml of water are stirred. The reaction mixture is concentrated and the precipitated substance is filtered off with suction, washed with water and chromatographed on silica gel.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Epidemiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Pregnancy & Childbirth (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des promédicaments de sulfonamide de formule générale (I), comprenant un lieur hétéroaromatique, un procédé pour produire ceux-ci, des compositions pharmaceutiques contenant ces composés, ainsi que leur utilisation pour produire des médicaments qui peuvent être administrés par voie orale. Les composés selon cette invention se lient à des carboanhydrases et inhibent ces enzymes.
EP06829355A 2005-11-30 2006-11-27 Composes de sulfonamide heteroaromatiques Withdrawn EP1959964A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005057421A DE102005057421A1 (de) 2005-11-30 2005-11-30 Heteroaromatische Sulfonamid-Prodrugs
PCT/EP2006/011727 WO2007062875A1 (fr) 2005-11-30 2006-11-27 Composes de sulfonamide heteroaromatiques

Publications (1)

Publication Number Publication Date
EP1959964A1 true EP1959964A1 (fr) 2008-08-27

Family

ID=37875507

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06829355A Withdrawn EP1959964A1 (fr) 2005-11-30 2006-11-27 Composes de sulfonamide heteroaromatiques

Country Status (14)

Country Link
EP (1) EP1959964A1 (fr)
JP (1) JP2009517425A (fr)
KR (1) KR20080074197A (fr)
CN (1) CN101321535A (fr)
AU (1) AU2006319381A1 (fr)
BR (1) BRPI0619214A2 (fr)
CA (1) CA2632279A1 (fr)
DE (1) DE102005057421A1 (fr)
EA (1) EA200801209A1 (fr)
EC (1) ECSP088488A (fr)
IL (1) IL191563A0 (fr)
NO (1) NO20082916L (fr)
WO (1) WO2007062875A1 (fr)
ZA (1) ZA200805660B (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101987104A (zh) * 2009-08-05 2011-03-23 天津金耀集团有限公司 一种杂芳香基氨磺酰基羧酸酯碳酸酐酶抑制剂的眼用组合物
CN101987102A (zh) * 2009-08-05 2011-03-23 天津金耀集团有限公司 一种糖皮质激素杂芳香基氨磺酰基羧酸酯的眼用抗炎组合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1593609A (en) * 1978-01-31 1981-07-22 Christiaens Sa A Pyridine sulfonamides
DE10027887A1 (de) * 2000-05-31 2001-12-13 Jenapharm Gmbh Verbindungen mit einer Sulfonamidgruppe und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen
US6355666B1 (en) * 2000-06-23 2002-03-12 Medinox, Inc. Protected forms of pharmacologically active agents and uses therefor
AR053845A1 (es) * 2005-04-15 2007-05-23 Tibotec Pharm Ltd 5-tiazolilmetil[(1s,2r)-3-[[(2-amino-6-benzoxazolil)sulfonil)](2-metilpropil)amino]-2-hidroxi-1-(fenilmetil)propil]carbamato como mejorador de farmacos metabolizados por el citocromo p450

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007062875A1 *

Also Published As

Publication number Publication date
WO2007062875A1 (fr) 2007-06-07
WO2007062875B1 (fr) 2007-08-09
ZA200805660B (en) 2009-11-25
IL191563A0 (en) 2009-08-03
JP2009517425A (ja) 2009-04-30
DE102005057421A1 (de) 2007-05-31
EA200801209A1 (ru) 2008-12-30
BRPI0619214A2 (pt) 2011-09-20
NO20082916L (no) 2008-06-27
CN101321535A (zh) 2008-12-10
KR20080074197A (ko) 2008-08-12
AU2006319381A1 (en) 2007-06-07
CA2632279A1 (fr) 2007-06-07
ECSP088488A (es) 2008-06-30

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