WO2002092556A1 - Sulfonamide derivatives - Google Patents
Sulfonamide derivatives Download PDFInfo
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- WO2002092556A1 WO2002092556A1 PCT/EP2002/005240 EP0205240W WO02092556A1 WO 2002092556 A1 WO2002092556 A1 WO 2002092556A1 EP 0205240 W EP0205240 W EP 0205240W WO 02092556 A1 WO02092556 A1 WO 02092556A1
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- triazol
- hydrogen
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- 0 CNS(c1c(*)cc(*)c(*)c1)(=O)=O Chemical compound CNS(c1c(*)cc(*)c(*)c1)(=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
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- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- the present invention relates to novel sulfonamide derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
- R 1 is phenyl, 1 ,2-dichlorophenyl, 3-methylphenyl, 3-bromophenyl, naphth-2-yl, indan-5-yl benzo[1 ,3]dioxol-5-yl or 1 ,2,3,4-tetrahydronaphth-6-yl;
- R 2 is hydrogen, halogen, unsubstituted d-C 4 alkyl or substituted C C 4 al yl;
- R 3 is hydrogen, halogen or CrC 4 alkyl;
- R 4 is hydrogen or C C alkyl;
- R 5 is hydrogen or C C 4 alkyl;
- R 6 is CH 2 OH; tetrazol-5-yl; 1 ,2,4-triazol-5-yl; 1 ,2,3-triazol-5-yl; C(O)OH, C(O)NH 2 ; or
- Z is -C(O)- or -CH 2 -, n is zero, 1 , 2, 3 or 4;
- R 7 is unsubstituted or substituted C C 4 alkyl, C(O)OH, C(O)OC C 4 alkyl;
- R 8 is hydrogen, unsubstituted or substituted CrC 4 alkyl, unsubstituted or substituted C 5 -
- C C alkyl, C 5 -C ⁇ 0 aryl or heteroC 5 -C ⁇ 0 aryl, when substituted may be one or more substituents selected from OH, C(O)OH, halogen, CrC 4 alkyl, C- ⁇ -C 6 alkoxy, benzyl, pyridinyl or pyrimidinyl.
- C C aIkyl may be substituted by OH, C(O)OH, CrC 4 alkoxy, C C alkyl, benzyl, pyridinyl or pyrimidinyl; phenyl may be substituted by one or more halogen, C ⁇ -C alkyl or C C 6 alkoxy; benzyl may be substituted by one or more halogen or C C 6 alkoxy.
- the compounds of the invention may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example trifluoroacetic acid or hydrochloride acid, or salts obtainable when they comprise a carboxy group, e.g. with a base, for example alkali salts such as sodium, potassium, or substituted or unsubstituted ammonium salts.
- Suitable pharmaceutically acceptable acid addition salts for pharmaceutical use in accordance with the invention include in particular the hydrochloride salt or sodium salt.
- R 1 is indan-5-yl
- R 2 is hydrogen, CI, Br, methyl or trifluoromethyl
- R 3 is CI or Br
- R 4 is hydrogen or methyl
- R 5 is hydrogen or methyl
- R 6 is CH 2 OH, C(O)NH 2 , tetrazol-5-yl, C(O)OH or ZNH(CH 2 ) n CHR 8 R 9 wherein Z is -C(O)- or -CH 2 -; (g) n is zero or 1 ; (h) R 7 is C(O)OH or CH 2 C(O)OH;
- R 8 is phenyl; benzyl; 4,5-dimethoxyphenyl; 2-chlorobenzyl; 2-methoxybenzyl; 3- methoxybenzyl; 4-methoxybenzyl; CH 2 -benzyI; CH 2 -pyridin-3-yl or CH 2 -pyrimidin-3-yl; and (g) m is 2.
- R 1 is indan-5-yl
- R 2 is CI
- R 3 is CI or Br
- R 4 is hydrogen
- R 5 is hydrogen
- R 6 is C(O)OH or C(O)NH(CH 2 ) n CHR 7 R 8 wherein n is zero or 1 , R 7 is C(O)OH or CH 2 C(O)OH
- R 8 is phenyl, benzyl, 4,5-dimethoxyphenyl, 2-chlorobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, CH 2 -benzyl or CH 2 -pyrimidin-3-yl; and m is 2.
- the present invention also provides a process for the production of a compound of formula I and its salts, comprising
- R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined above and R 9 is C C 4 alkyl; or
- R 5 is as defined above, R 6 is CH 2 OH, tetrazol-5-yl; 1,2,4-triazol-5-yl and 1 ,2,3- triazol-5-yl or ZNH(CH 2 ) n CHR 7 R 8 wherein Z is -CH 2 - and n, R 7 and R 8 are as defined above and Hal is halogen;
- a compound of formula (III), (V) or (VI) may be used in protected form in processes (b), (c), or (d) and the resulting compound deprotected after the reaction.
- R 5 and R 9 are as defined above and Hal is halogen.
- reaction may be carried out in accordance with standard procedures, for example as illustrated for processes (a) and (b) in example 1.
- derivatives where R 6 is a heterocyclic group, such as tetrazol-5-yl may be prepared from compounds of formula I where R 6 is C(O)OH, via appropriate amide intermediates, using known standard procedures, for example as illustrated in example 2.
- Work up of the reaction mixture can be effected by conventional procedures.
- the salt forms are made by standard procedures known to the skilled artisan.
- agents of invention have pharmacological activity and are useful as pharmaceuticals.
- the agents of invention exhibit bradykinin antagonist activity.
- the agents of invention e.g. the compound of examples 1 - 35 are active at the human Bi bradykinin receptor. Bradykinin receptor interaction of the agents of invention is demonstrated by their ability to displace desArg 10 kallidin at human bradykinin Bi receptor sites, e.g. as demonstrated in accordance with the following test method.
- Test I Bradykinin receptor binding assay
- WI-38 cells are grown in Dulbecco's Modified Eagle Medium s supplemented with 1% non- essential amino acids, 2 mM L-glutamine, 100 lU/ml penicillin, 100 g/ml streptomycin and 10 % foetal calf serum. The cells are grown in 175 cm 2 tissue culture flasks and split approximately 1-2 times a week at a ratio of 1 :2 using trypsin to detach the cells. WI-38 cells are plated onto 24 well plates at approximately 50,000 cells per well and grown overnight. To upregulate expression of the Bi receptor the cells are treated with 100 units/ml of IL-1 ⁇ for 3 hours prior to the assay.
- the binding buffer is 10 mM HEPES in Hank's Balanced Salt solution pH 7.4 plus 1 mM phenanthroline and 0.14 mg/ml bacitracin.
- the cells are incubated for 1 h at 4°C in binding buffer containing the radioligand [ 3 H]- desArg 10 kallidin in a volume of 500 ⁇ . Non-specific binding is determined with 3 /M desArg 10 kallidin.
- the cells are washed 3 times with 50 mM Tris- HCI pH 7.4 containing 300 mM sucrose.
- the cells are solubilised with 0.2 % SDS and the amount of radioactivity in the samples determined by liquid scintillation counting.
- the affinity constant (K d ) is obtained by incubating the cells with a range of [ 3 H]-desArg 10 kallidin concentrations. For displacement experiments the cells are incubated with approximately 1 nM [ 3 H]-desArg 10 kallidin and various concentrations of test compound. Compounds are made up in DMSO and diluted into binding buffer to give a final DMSO concentration of 0.5 %.
- Results are calculated by subtracting the value for non-specific binding from all values and calculating the amount of binding for each concentration of compound as a percentage of the specific binding with no compound.
- the IC 50 values are calculated in ORIGIN using a logistic fit.
- Activity specifically as anti-hyperalgesic agents may be demonstrated in accordance with standard test methods, e.g. as described in the following test.
- Test II Thermal antinociception in monkeys (warm water tail-withdrawal)
- Carrageenan at a dosage of 2 mg in 100 ⁇ l saline is injected subcutaneously into the terminal 1 to 4 cm of the tail of adult rhesus monkeys (Macaca mulatta) followed by administration of Pharmaceutical Compound in 100 ⁇ l vehicle (50 % PEG400 - saline) or vehicle to the animal.
- the animals are seated in restraint chairs and the lower part of the shaved tail (approximately 15 cm) immersed into warm water maintained at temperatures of 42, 46, and 50°C.
- Tail-withdrawal latencies are recorded manually by a computerized timer. A maximum cutoff latency (20 sec) is recorded if the subjects fail to remove their tails by this time. A single dosing procedure is used in all test sessions.
- Each experimental session begins with control determinations at each temperature. Subsequent tail withdrawal latencies are determined based on each experimental condition. The subjects are tested 1 to 2 times at three temperatures in a varying order, with approximately 1 to 2 min interval between tests. Experimental sessions are conducted once per week.
- the agents of invention are efficient in preventing or reversing carrageenan-induced hyperalgesia at a dosage in the range of from 0.01 ⁇ Mol/kg to 1 mMol/kg.
- the agents of the invention are thus in particular useful as bradykinin B ⁇ receptor antagonists, e.g. for the treatment of pain of various genesis or aetiology and as anti-inflammatory and/or anti-oedemic agents for the treatment of inflammatory reactions, diseases or conditions, as well as for the treatment of allergic responses.
- they are useful for the treatment of inflammatory pain, for the treatment of hyperalgesia and, in particular, for the treatment of severe chronic pain.
- They are, for example, useful for the treatment of pain, inflammation and/or oedema consequential to trauma, e.g. associated with bums, sprains, fracture or the like, subsequent to surgical intervention, e.g.
- analgesics as post-operative analgesics, as well as for the treatment of inflammatory pain of diverse genesis, e.g. for the treatment of bone and joint pain (osteoarthritis), rheumatoid arthritis, rheumatic disease, teno- synovitis, gout, cancer pain, myofascial pain (muscular injury, fibromyalgia), chronic neuropathic pain, e.g. diabetic neuropathy, phantom limb pain and perioperative pain (general surgery, gynecologic surgery). They are further suitable as analgesics for the treatment of pain associated with, e.g., angina, menstruation or cancer. As anti- inflammatory/anti-oedema agents, they are further useful, e.g., for the treatment of inflammatory skin disorders, for example psoriasis and eczema.
- the agents of the invention may also be useful in other pathophysiological conditions where bradykinin B n receptors are upregulated, for example in tissues during acute transplant rejection and in renal glomerular disease.
- the agents of the invention may also be useful to reduce angiogenesis associated with tumor growth for example in oesophageal, renal and gastric carcinomas.
- the contents of a review describing the involvement of bradykinin Bi receptors is incorporated herewith by reference (Bhoola et al 2001 , Biol Chem; 382:77-89).
- the agents of the invention are also useful as smooth muscle relaxants, e.g. for the treatment of spasm of the gastro-intestinal tract or uterus, e.g. in the treatment of glaucoma/intra-ocular pressure, e.g. in the therapy of Crohn's disease, ulcerative colitis or pancreatitis and for the treatment of muscle spasticity and tremor in e.g. multiple sclerosis.
- the appropriate dosage of the agents of the invention will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular agent of the invention employed.
- the amount of active agent required may be determined on the basis of known in vitro and in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
- satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 mg/kg p.o.
- an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g.
- Oral dosage forms accordingly suitably comprise from about 0.2 to about 700 mg of an agent of the invention admixed with an appropriate pharmaceutically acceptable diluent or carrier.
- the agents of the invention may alternatively be administered e.g. topically in the form of a cream, gel or the like for example for the treatment of conditions of the skin as hereinbefore described or by inhalation, e.g. in dry powder form, for example for the treatment of asthma.
- compositions comprising an agent of the invention include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of, e.g. a hydrochloride salt of a compound of formula I in the range of from 0.1 to 1 %, e.g.0.5 %.
- the composition may be buffered to a pH in the range of, e.g. from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer.
- the agents of the invention are also useful as research chemicals.
- the agents of the invention can be administered in vivo either alone or in combination with other pharmaceutical agents effective in the treatment of diseases and conditions in which bradykinin B t receptor activation plays a role or is implicated including cyclooxygenase-2 (COX-2) inhibitors, such as specific COX-2 inhibitors (e.g. celecoxib, COX189, and rofecoxib) or in general nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. acetylsalicylic acid, propionic acid derivatives), vanilloid receptor antagonists, tricyclic antidepressants (e.g.
- COX-2 cyclooxygenase-2
- specific COX-2 inhibitors e.g. celecoxib, COX189, and rofecoxib
- NSAIDs nonsteroidal anti-inflammatory drugs
- acetylsalicylic acid, propionic acid derivatives e.g. acetylsalicylic acid, propionic acid derivatives
- anticonvulsants e.g. gabapentin
- GABA B agonists e.g. L-baclofen
- compositions for separate administration of the combination partners and for the administration in a fixed combination i.e. a single galenical composition comprising at least two combination partners
- a single galenical composition comprising at least two combination partners can be prepared in a manner known per se and are thus suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
- Novel pharmaceutical compositions contain, for example, from about 0.1 % to about 99.9 %, preferably from about 20 % to about 60 %, of the active ingredients.
- Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar- coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
- a therapeutically effective amount of each of the combination partners may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
- the method of delay of progression or treatment of a proliferative disease according to the invention may comprise (i) administration of the combination partner (a) in free or pharmaceutically acceptable salt form and (ii) administration of a combination partner (b) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described herein.
- the individual combination partners can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
- administering also encompasses the use of a pro-drug of a combination partner that converts in vivo to the combination partner as such.
- the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
- each of the combination partners employed may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated.
- the dosage regimen is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
- a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition.
- Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites. In general, satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 mg/kg p.o.
- an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g. from about 50 to 200 mg, conveniently administered once or in divided doses up to 4 x per day or in sustained release form.
- Oral dosage forms accordingly suitably comprise from about 0.2 to about 700 mg.
- the present invention also provides:
- An agent of the invention for use as a pharmaceutical for example for use as a bradykinin B receptor antagonist in any of the particular indications hereinbefore set forth;
- a pharmaceutical composition comprising an agent of the invention as active ingredient together with a pharmaceutically acceptable diluent or carrier therefore, e.g. for the treatment or prevention of a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated;
- a method for treating or preventing a disease or condition in which bradykinin Bi receptor activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of an agent of the invention
- a combination comprising a therapeutically effective amount of an agent of the invention and a second drug substance, said second drug substance being for example for use in any of the particular indications hereinbefore set forth.
- Example 1 Preparation of (S)-3-(2- ⁇ (4-bromo-2-chloro-benzenesulfonyl)-[2-(indan-5- yloxy)-ethyl]-amino ⁇ -acetylamino)-4-phenyl-butyric acid
- reaction mixture is diluted with ethyl acetate (200 ml) and washed successively with sodium bicarbonate solution (2 x 50 ml), water (2 x 50 ml), and brine (50 ml). After drying over magnesium sulfate and filtration, the ethyl acetate is evaporated to give a oil, which is purified by column chromatography on silica gel (eluent: ethyl acetate - cyclohexane 1 :3) to give ⁇ (4-bromo-2-chloro-benzenesulfonyl)-[2-(indan-5-yloxy)-ethyl]-amino ⁇ -acetic acid methyl ester.
- the mixture is diluted with ethyl acetate (100 ml) and washed successively with water (2 x 200 ml), sodium bicarbonate solution, and brine. After drying over magnesium sulfate and filtration, the ethyl acetate is evaporated to dryness.
- 3-Aminopropionitrile (0.190g, 2.71 mmol, 1.2eq.) in anhydrous dimethylformamide (1ml), benzotriazole (0.305g, 2.26mmol, 1eq), and 1 ,3-dicyclohexylcarbodiimide (0.466g, 2.26mmol, 1.Oeq) is added to a stirred solution of ⁇ (2,4-dichloro-benzenesulfonyl)-[2-(indan- 5-yloxy)ethyl]-amino ⁇ -acetic acid (1.0g, 2.26mmol, 1.0eq) in dimethylformamide (10 ml) at 0 ° C under nitrogen, and the mixture allowed to warm to room temperature overnight.
- reaction mixture is poured into saturated sodium bicarbonate solution (20ml), extracted with NaCO 3 solution, and then extracted with EtOAc (3x20ml). The combined organic extracts are washed with water (3x25ml) and then with brine (25ml), dried over MgSO 4 , filtered, and concentrated to give the crude product (1.18g).
- Triphenylphosphine (0.387g,1.47mmol,1.0eq.), diethyl azodicarboxylate (0.256g, 1.47mmol, 1.Oeq.), and trimethylsilyl azide are added to a stirred solution of N-(2-cyano-ethyl)-2- ⁇ (2,4- dichlorobenzenesuphonyl)-[2-(indan-5-yloxy)-ethyl]-amino ⁇ -acetamide (0.732g, 1.47mmol, 1.0eq.) in anhydrous THF (15ml) at room temperature and allowed to stir overnight. Another 1 eq.
- Triphenylphosphine, diethylazodicarboxylate, trimethylsilyl azide is added to the reaction mixture, which is heated at 40 ° C (oil-bath temperature) for 6 hours.
- the reaction mixture is cooled to 0 ° C and excess ammonium cerium (IV) nitrate solution (5.5%, 120ml, 12mmol) is added slowly.
- the reaction mixture is concentrated and stirred in EtOAc (300ml) at room temperature overnight.
- the preferred compound of formula I for use in accordance with the invention are compounds of Example 5. These compounds are potent bradykinin antagonists, in vitro with a Kj value of about 0.3 ⁇ M.
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002443721A CA2443721A1 (en) | 2001-05-14 | 2002-05-13 | Sulfonamide derivatives |
DE60235536T DE60235536D1 (en) | 2001-05-14 | 2002-05-13 | sulfonamide |
AT02742997T ATE459598T1 (en) | 2001-05-14 | 2002-05-13 | SULFONAMIDE DERIVATIVES |
JP2002589442A JP4150597B2 (en) | 2001-05-14 | 2002-05-13 | Sulfonamide derivatives |
EP02742997A EP1389183B1 (en) | 2001-05-14 | 2002-05-13 | Sulfonamide derivatives |
BR0209386-3A BR0209386A (en) | 2001-05-14 | 2002-05-13 | Sulfonamide Derivatives |
US10/475,420 US7109203B2 (en) | 2001-05-14 | 2002-05-13 | Sulfonamide derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29082701P | 2001-05-14 | 2001-05-14 | |
US60/290,827 | 2001-05-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002092556A1 true WO2002092556A1 (en) | 2002-11-21 |
Family
ID=23117717
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/005240 WO2002092556A1 (en) | 2001-05-14 | 2002-05-13 | Sulfonamide derivatives |
Country Status (13)
Country | Link |
---|---|
US (1) | US7109203B2 (en) |
EP (1) | EP1389183B1 (en) |
JP (1) | JP4150597B2 (en) |
CN (1) | CN1268610C (en) |
AR (1) | AR035891A1 (en) |
AT (1) | ATE459598T1 (en) |
BR (1) | BR0209386A (en) |
CA (1) | CA2443721A1 (en) |
DE (1) | DE60235536D1 (en) |
ES (1) | ES2340664T3 (en) |
PE (1) | PE20021158A1 (en) |
PT (1) | PT1389183E (en) |
WO (1) | WO2002092556A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1572678A2 (en) * | 2002-12-19 | 2005-09-14 | Elan Pharmaceuticals, Inc. | Substituted n-phenyl sulfonamide bradykinin antagonists |
EP2305652A2 (en) | 2005-12-08 | 2011-04-06 | Novartis AG | Trisubstituted quinazolinone derivatives as vanilloid antagonists |
WO2011051375A1 (en) | 2009-10-28 | 2011-05-05 | Dompé S.p.A. | 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them |
WO2012164473A1 (en) | 2011-05-27 | 2012-12-06 | Novartis Ag | 3-spirocyclic piperidine derivatives as ghrelin receptor agonists |
WO2013164790A1 (en) | 2012-05-03 | 2013-11-07 | Novartis Ag | L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists |
EP2813502A1 (en) * | 2013-06-14 | 2014-12-17 | Dompe' S.p.A. | Bradykinin receptor antagonists and pharmaceutical compositions containing them |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6214807B1 (en) * | 1999-06-22 | 2001-04-10 | Cv Therapeutics, Inc. | C-pyrazole 2A A receptor agonists |
US6403567B1 (en) * | 1999-06-22 | 2002-06-11 | Cv Therapeutics, Inc. | N-pyrazole A2A adenosine receptor agonists |
USRE47351E1 (en) | 1999-06-22 | 2019-04-16 | Gilead Sciences, Inc. | 2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists |
AU2001238665A1 (en) * | 2000-02-23 | 2001-09-03 | Cv Therapeutics, Inc. | Method of identifying partial agonists of the a2a receptor |
US8470801B2 (en) | 2002-07-29 | 2013-06-25 | Gilead Sciences, Inc. | Myocardial perfusion imaging methods and compositions |
NZ537975A (en) * | 2002-07-29 | 2007-08-31 | Cv Therapeutics Inc | Method of producing coronary vasodilation without peripheral vasodilation comprising administering at least 10 mcg of at least one A2A receptor agonist |
US20050020915A1 (en) * | 2002-07-29 | 2005-01-27 | Cv Therapeutics, Inc. | Myocardial perfusion imaging methods and compositions |
KR20070083714A (en) | 2004-10-20 | 2007-08-24 | 씨브이 쎄러퓨틱스, 인코포레이티드 | Use of a2a adenosine receptor agonists |
KR101494125B1 (en) * | 2006-02-03 | 2015-02-16 | 길리애드 사이언시즈, 인코포레이티드 | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
JP2009541354A (en) * | 2006-06-22 | 2009-11-26 | シーブイ・セラピューティクス・インコーポレイテッド | Use of A2A adenosine receptor agonists in the treatment of ischemia |
US20090081120A1 (en) * | 2006-09-01 | 2009-03-26 | Cv Therapeutics, Inc. | Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods |
BRPI0716174A2 (en) * | 2006-09-01 | 2013-09-24 | Cv Therapeutics Inc | Methods and compositions for increasing patient tolerability during myocardial imaging methods. |
EP2066232A1 (en) * | 2006-09-29 | 2009-06-10 | Cv Therapeutics, Inc. | Methods for myocardial imaging in patients having a history of pulmonary disease |
MX2009007071A (en) * | 2007-01-03 | 2009-10-13 | Cv Therapeutics Inc | Myocardial perfusion imaging. |
PT2268612E (en) * | 2008-03-24 | 2014-11-13 | Novartis Ag | Arylsulfonamide-based matrix metalloprotease inhibitors |
AU2009296235A1 (en) * | 2008-09-29 | 2010-04-01 | Gilead Sciences, Inc. | Combinations of a rate control agent and an A-2-alpha receptor antagonist for use in multidetector computed tomography methods |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6015812A (en) * | 1996-01-11 | 2000-01-18 | Sanofi-Synthelabo | N-(arylsulphonyl)amino acid derivatives having bradykinin receptor affinity |
WO2000075107A2 (en) * | 1999-06-04 | 2000-12-14 | Novartis Ag | Bradykinin receptor antagonists |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE120047C (en) * | ||||
WO2001024786A1 (en) * | 1999-05-13 | 2001-04-12 | Shionogi & Co., Ltd. | Preventive or therapeutic drugs for diabetes |
-
2002
- 2002-05-13 CA CA002443721A patent/CA2443721A1/en not_active Abandoned
- 2002-05-13 JP JP2002589442A patent/JP4150597B2/en not_active Expired - Fee Related
- 2002-05-13 PT PT02742997T patent/PT1389183E/en unknown
- 2002-05-13 BR BR0209386-3A patent/BR0209386A/en not_active IP Right Cessation
- 2002-05-13 US US10/475,420 patent/US7109203B2/en not_active Expired - Fee Related
- 2002-05-13 EP EP02742997A patent/EP1389183B1/en not_active Expired - Lifetime
- 2002-05-13 AT AT02742997T patent/ATE459598T1/en not_active IP Right Cessation
- 2002-05-13 DE DE60235536T patent/DE60235536D1/en not_active Expired - Fee Related
- 2002-05-13 AR ARP020101737A patent/AR035891A1/en unknown
- 2002-05-13 CN CNB028098900A patent/CN1268610C/en not_active Expired - Fee Related
- 2002-05-13 WO PCT/EP2002/005240 patent/WO2002092556A1/en active Application Filing
- 2002-05-13 ES ES02742997T patent/ES2340664T3/en not_active Expired - Lifetime
- 2002-05-14 PE PE2002000401A patent/PE20021158A1/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6015812A (en) * | 1996-01-11 | 2000-01-18 | Sanofi-Synthelabo | N-(arylsulphonyl)amino acid derivatives having bradykinin receptor affinity |
WO2000075107A2 (en) * | 1999-06-04 | 2000-12-14 | Novartis Ag | Bradykinin receptor antagonists |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1572678A2 (en) * | 2002-12-19 | 2005-09-14 | Elan Pharmaceuticals, Inc. | Substituted n-phenyl sulfonamide bradykinin antagonists |
EP1572678A4 (en) * | 2002-12-19 | 2008-05-07 | Elan Pharm Inc | Substituted n-phenyl sulfonamide bradykinin antagonists |
EP2305652A2 (en) | 2005-12-08 | 2011-04-06 | Novartis AG | Trisubstituted quinazolinone derivatives as vanilloid antagonists |
WO2011051375A1 (en) | 2009-10-28 | 2011-05-05 | Dompé S.p.A. | 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them |
WO2012164473A1 (en) | 2011-05-27 | 2012-12-06 | Novartis Ag | 3-spirocyclic piperidine derivatives as ghrelin receptor agonists |
WO2013164790A1 (en) | 2012-05-03 | 2013-11-07 | Novartis Ag | L-malate salt of 2, 7 - diaza - spiro [4.5 ] dec- 7 - yle derivatives and crystalline forms thereof as ghrelin receptor agonists |
EP2813502A1 (en) * | 2013-06-14 | 2014-12-17 | Dompe' S.p.A. | Bradykinin receptor antagonists and pharmaceutical compositions containing them |
US9409876B2 (en) | 2013-06-14 | 2016-08-09 | Dompe' Farmaceutici S.P.A. | Bradykinin receptor antagonists and pharmaceutical compositions containing them |
Also Published As
Publication number | Publication date |
---|---|
PT1389183E (en) | 2010-04-26 |
US7109203B2 (en) | 2006-09-19 |
CA2443721A1 (en) | 2002-11-21 |
JP2004528385A (en) | 2004-09-16 |
JP4150597B2 (en) | 2008-09-17 |
BR0209386A (en) | 2004-07-06 |
US20040127533A1 (en) | 2004-07-01 |
EP1389183A1 (en) | 2004-02-18 |
DE60235536D1 (en) | 2010-04-15 |
CN1268610C (en) | 2006-08-09 |
CN1509269A (en) | 2004-06-30 |
ES2340664T3 (en) | 2010-06-08 |
AR035891A1 (en) | 2004-07-21 |
ATE459598T1 (en) | 2010-03-15 |
EP1389183B1 (en) | 2010-03-03 |
PE20021158A1 (en) | 2003-03-03 |
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