US20040248927A1 - Preventive agent/remedial agent for constipation predominant ibs - Google Patents

Preventive agent/remedial agent for constipation predominant ibs Download PDF

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Publication number
US20040248927A1
US20040248927A1 US10/487,491 US48749104A US2004248927A1 US 20040248927 A1 US20040248927 A1 US 20040248927A1 US 48749104 A US48749104 A US 48749104A US 2004248927 A1 US2004248927 A1 US 2004248927A1
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United States
Prior art keywords
azabicyclo
thieno
oct
oxo
dihydro
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.)
Abandoned
Application number
US10/487,491
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English (en)
Inventor
Satoshi Yamazaki
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.)
Mitsubishi Pharma Corp
Original Assignee
Mitsubishi Pharma Corp
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 Mitsubishi Pharma Corp filed Critical Mitsubishi Pharma Corp
Assigned to MITSUBISHI PHARMA CORPORATION reassignment MITSUBISHI PHARMA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YAMAZAKI, SATOSHI
Publication of US20040248927A1 publication Critical patent/US20040248927A1/en
Priority to US11/514,905 priority Critical patent/US7897614B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Definitions

  • IBS is a syndrome defined as a functional disorder in which abdominal symptoms consisting mainly of abdominal pain and irregular bowel movement continue but organic disorders as causes therefor cannot be identified (Clinical Gastroenterology, 2000, VOL. 15, No. 13, p. 1607). It is often associated with psychological manifestations such as anxiety and depression.
  • the present invention has firstly and experimentally revealed that the specific thieno[3,2-b]pyridinecarboxamide compounds are effective against the constipation predominant IBS by administering said compounds to human constipation predominant IBS patients.
  • the purpose of the present invention is to provide to a medicament for preventing and/or treating constipation predominant IBS containing the specific thieno[3,2-b]pyridinecarboxamide compounds as the active ingredients.
  • the gist of the present is as follows:
  • a preventive and/or therapeutic medicament for a constipation predominant IBS which comprises as an active ingredient a thieno[3,2-b]pyridinecarboxamide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof, or any solvate or hydrate thereof.
  • R 1 and R 2 each independently represents hydrogen atom or a lower alkyl group and A represents a substituent selected from the group consisting of 1-azabicyclo[3.2.2]nonyl group, 1-azabicyclo[2.2.2]octyl group, and an N-oxides thereof,.
  • A represents 1-azabicyclo[3.2.2]nonyl group or 1-azabicyclo[2.2.2]octyl group, preferably 1-azabicyclo[2.2.2]octyl group, or a substituent wherein the nitrogen atom of these groups forms an N-oxide.
  • a bond of the substituent A and the carboxamide group of the compound of the formula (I) is formed by any carbon atom of the substituent A and the nitrogen atom of the carboxamide group.
  • the substituent A can include 1-azabicyclo[2.2.2]oct-2-yl group, 1-azabicyclo[2.2.2]oct-3-yl group, 1-azabicyclo[2.2.2]oct-4-yl group, 1-azabicyclo[3.2.2]non-2-yl group, 1-azabicyclo[3.2.2]non-3-yl group, 1-azabicyclo[3.2.2]non-4-yl group, 1-azabicyclo[3.2.2]non-5-yl group, 1-azabicyclo[3.2.2]non-6-yl group, 1-azabicyclo[3.2.2]non-7-yl group, and the groups of N-oxide thereof.
  • the preferable example includes 1-azabicyclo[2.2.2]oct-3-yl group.
  • the particularly preferable compounds include racemates, or any optically active isomers, or N-oxides thereof such as N-(1 azabicyclo[2,2,2]oct-3-yl)-4, 7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide;
  • more preferable compound is R-( ⁇ )—N-(1-azabicyclo[2,2,2]oct-3-yl) -4, 7-dihydro-7-oxo-thieno[3,2-b]pyridine-6-carboxamide; [also referred to as (R)—N-(3-quinuclidinyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide] or N-oxide thereof
  • R 1 is hydrogen atom
  • 4,7-dihydro-7-oxo-thieno[3,2-b]pyridine ring as the heteroaromatic ring may also exist 7-hydroxythieno[3,2-b]pyridine ring as tautomer thereof.
  • Such tautomers also embrace the active ingredients of the therapeutic medicaments of the present invention.
  • the active ingredients of the therapeutic medicaments of the present invention may be used as pharmaceutically acceptable salts of the aforementioned compounds.
  • Such salts include acid addition salts, quaternary ammonium salts and the like.
  • Such pharmaceutically acceptable acid addition salts include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like and organic acid addition salts thereof such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and the like.
  • the quaternary ammonium salts include, for example, quarternary ammonium salts with lower alkyl halogenides such as methyl iodide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like; lower alkyl sulfonate such as methyl methanesulfonate, ethyl methanesulfonate and the like; and lower alkyl arylsulfonates such as methyl p-toluenesulfonate and the like.
  • lower alkyl halogenides such as methyl iodide such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like
  • lower alkyl sulfonate such as methyl methanesulfonate, ethyl methanesulfonate and the like
  • the compounds of the formula (I) and pharmaceutically acceptable salts thereof also exist as solvates or hydrates These solvates and hydrates may be used as the active ingredients of the therapeutic medicaments of the present invention.
  • compositions containing one or not less than two active ingredients are prepared and administered to patients.
  • Such pharmaceutical compositions include pharmaceutical preparations for oral administration such as tablets, capsules, fine granules, powders, pills, troches, sublingual tablets, and liquid preparations and the like and pharmaceutical preparations for parenteral administration such as injections, suppositories, ointments, patches and the like.
  • Tablets or capsules for oral administration are usually provided in a unit dosage form, and can be prepared by adding conventional pharmaceutical carriers such as binders, fillers, diluents, compressing agents, lubricants, disintegrators, coloring agents, flavoring agents, and moistening agents.
  • the tablets may be coated, for example, by using an enteric coating agent according to the well known methods in the art.
  • enteric coating agent for example, fillers such as cellulose, mannitol or lactose; disintegrating agents such as starch, polyvinylpyrrolidone, starch derivatives or sodium starchglycolate; lubricants such as magnesium stearate; and moistening agents such as sodium lauryl sulfate can be used.
  • Liquid preparations for oral administration can be provided in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs, as well as dried formulations that is re-dissolvable in water or an appropriate medium before use.
  • Such liquid formulations conventional additives such as, for example, precipitating preventing agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous media such as almond oil, refined coconut oil, oily esters(e.g.
  • glycerin esters examples include propylene glycol or ethyl alcohol (edible oil may be included); preservatives such as methyl ester, ethyl ester or propyl ester of p-hydroxybenzoic acid, or sorbic acid; and, if necessary, conventional flavoring agents or coloring agents.
  • the pharmaceutical preparations for oral administration can be prepared according to the well known methods in the art such as mixing, filling or compressing. In addition, it is possible to disperse the active ingredient in a preparation containing a large amount of filler by repetitive mixing operation.
  • the pharmaceutical preparations for parenteral administration are generally provided as liquid type unit dosage form preparations containing the compound as the active ingredient and a sterilized medium.
  • the pharmaceutical preparations for parenteral administration can be manufactured by dissolving the compound in the medium, subjecting the solution to filtration for sterilization, filling the resultant solution in suitable vials or ampoules, and then sealing the vials or ampoules. It is possible to freeze the composition, fill it in vials and then removing the moisture in vacuo to improve the stability.
  • Parenteral suspensions can be substantially prepared by the same methods as those applied the parenteral solution and preferably prepared by suspending the active ingredient in a medium, and subjecting the resultant suspension to sterilization by using ethylene oxide or the like. Further, surfactants, moistening agents and the like can also be added so that the uniform dispersion of the active ingredient can be achieved.
  • Dose of the aforementioned compound as the active ingredient may be decided depending on the purpose of the therapeutic or preventive treatment, sort of the diseases to be treated or prevented, conditions, body weight, age, sex and the like of the patient. In general, about 0.001 to about 10 mg may orally be administered, or about 0.001 to about 10 mg may intraveneously be administered to an adult daily. Such doses may be desirably administered once or several times a day as divided portions.
  • FIG. 1 shows the rate of improvement against each description of stool state, difficulty in defecation, feeling of residual stool after defecation, abdominal bloating, abdominal discomfort and abdominal pain by the administration of placebo and 0.2 mg of the medicament of the present invention.
  • P in the horizontal axis shows the placebo-administration group
  • 0.2 mg shows the 0.2 mg administration group of the medicament of the present invention.
  • the test conducted here was a double blind test by two groups.
  • One group was administered with placebo and the other one was administered with 0.2 g (twice a day) of the medicament of the present invention.
  • Administration period consisted of 2-week screening and 4 week treatment.
  • the total impression of the patients upon completion of the treatment was evaluated by 5-scale rating, that is, “highly effective”, “moderately effective”, “slightly effective”, “not effective” and “aggravated”.
  • the results are shown in Table 1.
  • an ameliorating ratio of each symptom that is, stool state, difficulty in defecation, feeling of residual stool after defecation, abdominal bloating, abdominal discomfort and abdominal pain is shown in FIG. 1 TABLE 1 Not Highly Moderately Slightly effec- Aggra- effective effective effective tive vated Total Placebo 1 2 6 1 0 10 Group 0.2 mg 0 5 2 2 0 9 Adminis- tration Group
  • the present invention has firstly proved that the medicaments of the present invention have about two fold effective rate than placebo and improved all of the characteristic diseases and symptoms of constipation predominant IBS, and it has made clear that the medicaments of the present invention are useful as the therapeutic medicaments for constipation predominant IBS.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pyridine Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
US10/487,491 2001-08-24 2002-03-14 Preventive agent/remedial agent for constipation predominant ibs Abandoned US20040248927A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/514,905 US7897614B2 (en) 2001-08-24 2006-09-05 Preventive agent/remedial agent for constipation predominant IBS

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2001-254662 2001-08-24
JP2001254662 2001-08-24
PCT/JP2002/002402 WO2003018012A1 (fr) 2001-08-24 2002-03-14 Agent pour la prevention/le traitement du syndrome du colon irritable (sci) avec predominance de constipation

Related Child Applications (1)

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US11/514,905 Continuation US7897614B2 (en) 2001-08-24 2006-09-05 Preventive agent/remedial agent for constipation predominant IBS

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US11/514,905 Expired - Fee Related US7897614B2 (en) 2001-08-24 2006-09-05 Preventive agent/remedial agent for constipation predominant IBS

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US (2) US20040248927A1 (zh)
EP (2) EP1419772B1 (zh)
JP (1) JPWO2003018012A1 (zh)
KR (1) KR100869759B1 (zh)
CN (1) CN1545412A (zh)
AT (2) ATE367813T1 (zh)
CA (1) CA2457053C (zh)
CY (1) CY1106913T1 (zh)
DE (2) DE60221402T2 (zh)
DK (1) DK1419772T3 (zh)
ES (1) ES2289086T3 (zh)
PT (1) PT1419772E (zh)
WO (1) WO2003018012A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050059704A1 (en) * 2003-08-29 2005-03-17 Dynogen Pharmaceuticals, Inc. Compositions useful for treating gastrointestinal motility disorders
US20080269276A1 (en) * 2007-02-12 2008-10-30 Dynogen Pharmaceuticals, Inc. Compositions useful for treating irritable bowel syndrome

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0401578D0 (sv) 2004-06-18 2004-06-18 Active Biotech Ab Novel compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352685A (en) * 1992-03-12 1994-10-04 Mitsubishi Kasei Corporation Thieno[3,2-b]pyridine derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3250921B2 (ja) * 1994-11-21 2002-01-28 三菱化学株式会社 腸管運動機能不全性疾患の治療剤
JPH08286450A (ja) 1995-04-19 1996-11-01 Matsushita Electric Ind Co Ltd 画像読取り等複合装置
JP2003514853A (ja) * 1999-11-23 2003-04-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ 底を弛緩させるための５ｈｔ３アゴニストの使用
TWI256314B (en) * 2000-02-09 2006-06-11 Mitsubishi Pharma Corp Preventive-therapeutical medicament for gastroesophageal reflux disease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352685A (en) * 1992-03-12 1994-10-04 Mitsubishi Kasei Corporation Thieno[3,2-b]pyridine derivatives

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050059704A1 (en) * 2003-08-29 2005-03-17 Dynogen Pharmaceuticals, Inc. Compositions useful for treating gastrointestinal motility disorders
US20060189648A1 (en) * 2003-08-29 2006-08-24 Landau Steven B Compositions useful for increasing lower esophageal sphincter pressure
US20080269276A1 (en) * 2007-02-12 2008-10-30 Dynogen Pharmaceuticals, Inc. Compositions useful for treating irritable bowel syndrome
US20100152231A1 (en) * 2007-02-12 2010-06-17 Edusa Pharmaceuticals, Inc. Compositions Useful For Treating Irritable Bowel Syndrome
US20110269792A1 (en) * 2007-02-12 2011-11-03 Edusa Pharmaceuticals, Inc. Compositions useful for treating irritable bowel syndrome

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ATE367813T1 (de) 2007-08-15
CN1545412A (zh) 2004-11-10
KR20040047774A (ko) 2004-06-05
WO2003018012A1 (fr) 2003-03-06
EP1419772A1 (en) 2004-05-19
ES2289086T3 (es) 2008-02-01
CY1106913T1 (el) 2012-09-26
PT1419772E (pt) 2007-09-05
EP1829543B1 (en) 2009-01-21
DE60221402D1 (de) 2007-09-06
DE60221402T2 (de) 2008-04-03
DK1419772T3 (da) 2007-11-12
ATE421323T1 (de) 2009-02-15
DE60231017D1 (de) 2009-03-12
EP1419772B1 (en) 2007-07-25
JPWO2003018012A1 (ja) 2004-12-09
CA2457053A1 (en) 2003-03-06
EP1829543A1 (en) 2007-09-05
EP1419772A4 (en) 2004-11-24
US20070004770A1 (en) 2007-01-04
KR100869759B1 (ko) 2008-11-21
CA2457053C (en) 2010-10-26
US7897614B2 (en) 2011-03-01

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Owner name: MITSUBISHI PHARMA CORPORATION, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:YAMAZAKI, SATOSHI;REEL/FRAME:015601/0556

Effective date: 20040203

STCB Information on status: application discontinuation

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