WO2012004900A1 - Composés thiénopyrimidines - Google Patents

Composés thiénopyrimidines Download PDF

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WO2012004900A1
WO2012004900A1 PCT/JP2010/062022 JP2010062022W WO2012004900A1 WO 2012004900 A1 WO2012004900 A1 WO 2012004900A1 JP 2010062022 W JP2010062022 W JP 2010062022W WO 2012004900 A1 WO2012004900 A1 WO 2012004900A1
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stands
alkyl
oxo
salts
group
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PCT/JP2010/062022
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Makoto Okada
Shuichiro Sato
Kenji Kawade
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Aska Pharmaceutical Co., Ltd.
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Priority to PCT/JP2010/062022 priority Critical patent/WO2012004900A1/fr
Publication of WO2012004900A1 publication Critical patent/WO2012004900A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • This invention relates to novel thienopyrimidine compounds and salts thereof, which exhibit type 9 phosphodiesterase
  • Dysuria can be largely divided into emptying disorder due to inability to urinate with sufficient force at the time of emptying the bladder, and bladder-filling disorder due to inability to retain urine during the filling time.
  • cci blocker is frequently used for treating the emptying disorder and anticholine agent, for treating bladder-filling disorder.
  • QOL quality of life
  • cGMP plays an important role in variegated cellular
  • PDE9 shows the least Km value (J. Biol. Chemistry, Vol. 273, No. 25, 15559 - 15564 (1998), has high affinity to cGMP and is considered to participate in degradation of cGMP with particular significance.
  • pyrazolopyrimidine compounds are known as the compounds exhibiting PDE9-inhibiting activity, and as patent literature relating to the compounds, for example, there are PCT International Publication WO 03/037432 Pamphlet disclosing their utility for treating insulin-resistant diseases, WO 03/037899
  • Pamphlet disclosing their utility for treating cardiovascular disorder and WO 2004/018474 Pamphlet disclosing their utility for improving perception, learning and memory functions.
  • the object of the present invention is to provide novel
  • thienopyrimidine compounds which have PDE9 _ inhibiting action and are useful as treating agent for disorders including dysuria.
  • R 1 stands for hydrogen, d-6 alkyl, d e alkoxyd-e alkyl or d-6 haloalkyl containing 1 - 6 halogen atoms,
  • R 2 stands for hydrogen, d-6 alkyl, phenyld-6 alkyl or amino
  • R 3 stands for d-6 alkyl, C2-6 alkenyl, carbamoyld-6 alkyl, aminoCi-6 alkyl, d-6 alkylaminoCi 6 alkyl, dr(d-6 alkyl)aminod 6 alkyl, d-6 alkylthio or ⁇ - ⁇ - group, or
  • R 2 and R 3 may together form tetr am ethylene
  • R 4 stands for carboxylic acid or its equivalent
  • heterocyclic group 4— 7-membered cycloalkyl group, 4— 7-membered cycloalkenyl group, 5 - 7-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms, or 5— 7-membered saturated heterocyclic group forming a condensed ring with 5 or 6-membered saturated cyclic group and containing 1 or 2 nitrogen atoms, all of these groups optionally containing 1— 3 substituents selected from halogen atom, d-6 alkyl, d-6 haloalkyl containing 1—6 halogen atoms, d-6 haloalkyloxy containing 1— 6 halogen atoms, d-6 haloalkylthio containing 1— 6 halogen atoms, d-6 alkoxy, d-e alkylthio, d-4
  • n is 0 or an integer of 1— 4, and
  • a 1 and A 2 stands for carbon atom and the other stands for sulfur atom
  • R 1 is attached to the carbon atom represented by either A 1 or
  • C2 - ⁇ indicate that the carbon numbers in the groups to which these expressions are attached are respectively within the range of given numbers.
  • Ci-6 alkyl may be linear or branched, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Of these, methyl, ethyl, n-propyl, isopropyl and n-butyl are preferred. Also “C2-6 alkyl” encompasses those groups defined as to above Ci- ⁇ alkyl except methyl, among which ethyl, n-propyl, isopropyl and n-butyl are preferred.
  • C2-6 alkenyl can have one or plural double bonds at optional position(s) and may be linear or branched, of which specific examples include vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 2-methylallyl, 1-pentenyl and 1-hexenyl, among which vinyl, allyl and isopropenyl are preferred.
  • Ci-6 alkoxy is oxy (O) group substituted with Ci- ⁇ alkyl, of which specific examples include methoxy, ethoxy, n-propoxy,
  • methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy are preferred.
  • d-e alkylthio is thio (S) group substituted with d- ⁇ alkyl, of which specific examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, secbutylthio, tert-butylthio, n-pentylthio and n-hexylthio. Of those, methylthio, ethylthio, n-propylthio, isopropylthio and n-butylthio are preferred.
  • Ci 4 alkylenedioxy includes, for example, methylenedioxy, ethylenedioxy, propylenedioxy and tetramethylenedioxy. Of those, methylenedioxy and ethylenedioxy are preferred.
  • cycloalkyl includes cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Of those, cyclopentyl and cyclohexyl are preferred.
  • Halogen atom includes fluorine, chlorine, bromine and iodine, fluorine, chlorine and bromine being particularly preferred.
  • Ci-6 haloalkyl containing 1— 6 halogen atoms signifies Ci-e alkyl following the earlier given definition, which are substituted with same or different 1—6 halogen atoms, of which specific examples include fluoromethyl, trifluoromethyl, 1,2-dichloroethyl,
  • Ci-6 haloalkyloxy containing 1 - 6 halogen atoms signifies oxy (O) group substituted with above "Ci-6 haloalkyl containing 1— 6 halogen atoms”
  • Ci-6 haloalkylthio containing 1 — 6 halogen atoms signifies thio (S) group substituted with above "Ci-6 haloalkyl containing 1— 6 halogen atoms”.
  • Ci-6 alkoxyCi-6 alkyl in the definition of R 1 in the formula (I) signifies Ci- ⁇ alkyl substituted with d-e alkoxy following the earlier given definition, of which specific examples include methoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-n-butyl, methoxy-n-hexyl, ethoxymethyl, isopropoxymethyl, ethoxyethyl and n-butoxy-n-propyl. Of those, methoxymethyl, methoxyethyl, ethoxymethyl and
  • Phenyld-6 alkyl in the definition of R 2 in the formula (I) signifies d-6 alkyl following its definition as given earlier, which is substituted with phenyl; and "carbamoylCi ⁇ alkyl”, the Ci-6 alkyl following the earlier given definition, which is substituted with carbamoyl (-CONH2); and "aminod-6 alkyl", the d-e alkyl following the earlier given definition, which is substituted with amino (-NH2).
  • d-6 alkylaminod-6 alkyl in the definition of R 3 in the formula (I) signifies the above aminod-e alkyl whose amino group is further substituted with one of d-6 alkyl groups following the earlier given definition! and "di-(Ci-6 alkyl)aminod-6 alkyl” signifies the same as above except that the amino group is substituted with two of the d-6 alkyl groups following the earlier given definition.
  • the two d-6 alkyl substituting an amino group in di-( d-6 alkyl)aminoCi-6 alkyl may be the same or different.
  • Ci-6 alkylthio in the definition of R 3 signifies thio (S) group substituted with the Ci- ⁇ alkyl following the earlier given definition
  • d-6 alkoxycarbonyl in the definition of Y in the formula (I) signifies carbonyl (CO) substituted with the Ci-6 alkoxy group following the earlier given definition
  • alkylsulfonamide carboxylic acid hydroxyamide, carboxylic acid amide, carboxylic acid cyanoamide, sulfonic acid amide, sulfonic acid, sulfonic acid Ci- ⁇ alkylamide, phosphonic acid, phosphonic acid monoCi 6 alkyl ester, 5-(lH-tetrazol ), 5-(3"hydroxyisoxazol),
  • Ce-20 aromatic carbocyclic groups encompasses Ce-20 aromatic carbocyclic groups, of which specific examples include phenyl, 1-indenyl, 1-naphthyl, 2-naphthyl,
  • cycloalkenyl in the definition of Y, for example, 1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl,
  • 1-cycloheptenyl, 2-cyclobutenyl, 2-cyclopentenyl and 3-cyclohexenyl can be named. Of those, 1-cyclohexenyl and 2-cyclohexenyl are preferred.
  • octahydroisoindolyl decahydroquinolyl, decahydroisoquinolyl, dodecahydrobenzo[b]azepinyl, octahydropyrrolo[2,3"d]pyridyl, octahydropyrrolo[l,2-a]pyrazyl, octahydropyrido[l,2-a]pyrimidinyl, decahydrophthalazinyl, decahydronaphthyridinyl and
  • decahydroquinazolinyl can be named. Of those, decahydroquinolyl, decahydroisoquinolyl and octahydropyrrolo[l,2-a]pyrazyl are preferred.
  • a 2 is sulfur atom and R 4 is hydroxyl has already been posted in PCT International Publication WO 2006/135080, and therefore it is excluded from the compounds represented by the formula (I) of the present invention.
  • the present invention also provides PDE9"inhibiting agents containing the compounds including thienopyrimidine compounds represented by the formula (I) or salts thereof; pharmaceutical compositions comprising compounds of the formula (I) or salts thereof and pharmaceutically acceptable carriers; and treating agents for overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria in benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis, urolithiasis, benign prostatic hyperplasia, erectile dysfunction, cognitive impairment, neuropathy, Alzheimer's disease, pulmonary hypertension, chronic obstructive pulmonary disease, ischemic heart disease, hypertension, angina, myocardial infarction, arteriosclerosis, thrombosis, embolism, type 1 diabetes, and type 2 diabetes, which are characterized by containing
  • a group of compounds which are preferred for the present invention are those of the formula (I) in which R 1 stands for hydrogen or Ci-6 alkyl, in particular, methyl.
  • Another preferred group of compounds for the present invention are those of the formula (I) in which R 2 stands for hydrogen.
  • Still another preferred group of compounds for the present invention are those of the formula (I) in which R 3 stands for ⁇ - ⁇ - group, in particular, the compounds of the formula (I) in which X stands for CH2, S, O or NH, inter alia, CH2.
  • R 3 stands for ⁇ - ⁇ - group
  • Still different group of compounds preferred for the present invention are those of the formula (I) in which R 4 stands for carboxylic acid or carbonyl Ci- ⁇ alkylsulfonamide.
  • Still another different group of compounds preferred for the present invention are those of the formula (I) in which n is 0.
  • Typical examples of the compounds of the formula (I) which are provided by the present invention include the following, besides those shown in the later appearing Examples-
  • the compounds of the formula (I) of this invention can also form salts, for example, alkali metal salts such as sodium salts, potassium salts, lithium salts and the like! alkaline earth metal salts such as calcium salts, magnesium salts and the like; salts with organobases such as trie thy lamine, dicyclohexylamine, pyrrolidine, morpholine, pyridine and the like; and ammonium salts. Depending on the kind(s) of substituent(s), they can also form salts with
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid,
  • the compounds of the formula (I) in which Z stands for O can be prepared, for example, by either one of the methods (a)— (c) as described in the following, depending on the kind of R 2 .
  • the compounds of the formula (I) in which Z stands for O and R 2 and R 3 together form tetramethylene group can be prepared, for example, by the method (d) as described in the following.
  • the compounds of the formula (I) in which Z stands for S can be prepared, for example, by the method (e) as described in the following.
  • R 1 , R 3 , R 4 , n, A 1 and A 2 have the previously defined
  • R 1 , n, A 1 and A 2 have the previously defined significations, and R' stands for Ci-6 alkyl, R 41 stands for carboxylic acid Ci-6 alkyl ester or carboxylic acid equivalent,
  • R 3 has the previously given signification
  • R 1 , R 3 , n, A 1 , A 2 and R 41 have the previously defined
  • R 41 stands for carboxylic acid Ci-e alkyl ester.
  • R 1 , R 3 , R 4 , n, A 1 and A 2 have the previously defined
  • R 21 stands for Ci-6 alkyl or phenylCi- ⁇ alkyl
  • R 1 , R 3 , R 4 , n, A 1 and A 2 have the previously defined
  • R 1 , R 3 , R 41 , n, A 1 , A 2 and R' have the previously defined significations
  • R 1 , R 4 , n, A 1 and A 2 have the previously defined significations, can be prepared, for example, by reacting a compound of the formula (II) with a compound of the formula, in the formula,
  • Hal stands for halogen
  • R 1 , R 41 , n, A 1 , A 2 and Hal have the previously defined
  • R 1 , R 41 , n, A 1 and A 2 have the previously defined significations, and in the case of R 41 standing for carboxylic acid Ci- ⁇ alkyl ester in a compound of formula (VIII), thereafter hydrolyzing the ester similarly to the method (a).
  • R 1 , R 2 , R 3 , R 4 , n, A 1 and A 2 have the previously defined significations
  • R 1 , R 2 , R 3 , R 41 , n, A 1 and A 2 have the previously defined significations
  • R 1 , R 2 , R 3 , R 41 , n, A 1 and A 2 have the previously defined significations
  • reaction of a compound of the formula (II) with a nitrile compound of the formula (III) in the above method (a) can be performed generally in an inert solvent such as amides including ⁇ , ⁇ -dimethylformamide and N,N-dimethylacetamide> " alcohols including methanol, ethanol and isopropanoL ' or ethers including tetrahydrofuran and dioxane, in the presence of an acid catalyst such as hydrochloric acid, hydrobromic acid and p-toluenesulfonic acid, at -20°C to the refluxing temperature of the reaction mixture, preferably 0 - 80°C.
  • an inert solvent such as amides including ⁇ , ⁇ -dimethylformamide and N,N-dimethylacetamide> " alcohols including methanol, ethanol and isopropanoL ' or ethers including tetrahydrofuran and dioxane, in the presence of an acid catalyst such as hydroch
  • the use ratio of the nitrile compound of the formula (III) to the compound of the formula (II) is not particularly limited, while it is preferable to use generally at least 1 mol, in particular, within a range of 1.05 - 5 mols, inter alia, 1.2— 2 mols, of the nitrile compound of the formula (III), per mol of the compound of the formula (II).
  • the acid catalyst can be used within a range of about 0.2— about 50 mols, per mol of the compound of the formula (II).
  • N-alkylation reaction of the compound of the formula (IV) in the above method (b) can be performed, for example, by
  • nucleophilic substitution reaction using alkyl halide (R 21 -Hal, wherein R 21 and Hal have the previously defined significations).
  • the reaction is generally conducted in an inert organic solvent such as amides including ⁇ , ⁇ -dimethylformamide and N,N-dimethylacetamide;
  • alcohols including methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and dioxanel organic bases including pyridine;
  • alkali such as sodium hydride, sodium methoxide, potassium butoxide, potassium hydroxide, potassium carbonate or the like; or organic base such as triethylamine, 2,6-di-tert-butyl-4-methylpyridine or the like, at temperatures ranging 0°C to refluxing temperature of the reaction mixture, preferably room temperature to refluxing temperature of the reaction mixture.
  • the use ratio of alkyl halide used for N-alkylation of the compound of the formula (IV), to the same compound is not critical, while it is generally at least 1 mol, preferably 1.1-20 mols, inter alia, 1.2 - 10 mols, per mol of the compound of the formula (IV).
  • the alkali or organic base can be normally used within a range of 1.1— about 20 mols per mol of the compound of the formula (IV).
  • the ring closure reaction of the compound of the formula (V) with hydrazine in the method (c) can be generally performed in an inert organic solvent such as amides including
  • N,N-dimethylformamide and ⁇ , ⁇ -dimethylacetamide alcohols including methanol, ethanol and isopropanoll ethers including tetrahydrofuran and dioxane; at temperatures within a range of 0°C to the refluxing temperature of the reaction mixture, preferably room temperature to the refluxing temperature of the reaction mixture.
  • hydrazine to the compound of the formula (V) is not critical, while hydrazine can be used within a range of at least 1 mol, preferably 1.2— 10 mols, inter alia, 1.3— 5 mols, per mol of the compound of the formula (V).
  • halogenated nitrile compound of the formula (VI) in the method (d) can be performed by a method similar to the reaction of a compound of the formula (II) with a nitrile compound of the formula (III) in the method (a).
  • the ring closure reaction of the compound of the formula (VII) in the method (d) can be performed by a method similar to the
  • the treating reaction of the compound of the formula (IX) with Lawesson's reagent in the method (e) can be performed generally in an inert organic solvent, for example, ethers including
  • Lawesson's reagent to the compound of the formula (IX) is not particularly limited, while generally it can be at least 0.5 mol, preferably 0.5— 5 mols, inter alia, 0.6— 2 mols, per mol of the compound of the formula (IX).
  • the compounds of the formula (V) which are used as the starting materials in the method (c) can be synthesized, for example, by amidation of the compounds of the formula (II) with carboxylic acid compounds of the formula,
  • thienopyrimidine compounds represented by the formula (I) or salts thereof provided by the present invention exhibit potent PDE9-inhibiting activity, and are useful for curative and treating agents of diseases associated with degradation of cGMP by PDE9, for example, overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria in benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis, urolithiasis, benign prostatic hyperplasia, erectile dysfunction, cognitive impairment, neuropathy, Alzheimer's disease, pulmonary hypertension, chronic obstructive pulmonary disease, ischemic heart disease, hypertension, angina, myocardial infarction, arteriosclerosis, thrombosis, embolism, type 1 diabetes, and type 2 diabetes.
  • diseases associated with degradation of cGMP by PDE9 for example, overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria in benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis,
  • hsPDE9Al fragment was amplified by polymerase chain reaction under the following conditions, using the following sequence (Amasham Pharmacia
  • hPDE9-5A primer CTAGCTAGCCACCATGGGATCCGGCTCCTCC
  • hPDE9-3A primer TTTTCCTTTTGCGGCCGCTTATTAGGCACAGTCTCCTTCACTG PCR condition : [95°C, 5 min] xl cycle, [(95°C, 1 min), (58°C, 2 min), (72°C, 3 min)] x 25 cycle, [72°C, 10 min] x 1 cycle
  • hsPDE9Al fragment was given a restricted enzymatic treatment with Nhel and NotI, and thereafter inserted into pcDNA 3.l(+) expression vector (Invitrogen) to let it serve as a human PDE9 expression vector.
  • Pep statin A 1 ⁇ g/mL Leupeptin, 5 mmol/L EDTA
  • the supernatant was isolated to provide human recombinant PDE9 protein solution.
  • buffer B 70 mmol/L Tris-HCl, pH7.5; 16.7 mmol/L MgCl 2 , 33.3 nmol L [ 3 H]-cGMP
  • PDE9 inhibition of the tested compound can be calculated by the following formula-
  • GenBank database accession No.: NM_001083
  • hsPDE5Al fragment was amplified by polymerase chain reaction under the following conditions, using the following sequence (SIGMA GENOSYS) as the primer and Human Prostate MATCHMAKER cDNA library
  • hPDE5-5' E primer CGGAATTCCAACCATGGAGCGGGC
  • hPDE5-3' primer GCTCTAGATCAGTTCCGCTTGGCCTGG
  • hsPDE5Al fragment was given a restricted enzymatic treatment with XBal and EcoRI, and thereafter inserted into pcDNA 3.l(+) expression vector (Invitrogen) to let it serve as a human PDE5 expression vector.
  • thienopyrimidine compounds represented by the formula (I) or their salts of the present invention can be administered as PDE9 inhibitor or PDE9 inhibitor concurrently exhibiting slight PDE5 inhibitory activity, for therapy or treatment of PDE9-associated diseases of human and other mammals, orally or parenterally (e.g., intramuscular injection, intravenous injection, rectal administration, percutaneous administration and the like).
  • the drugs of the present invention can be formulated, together with non-toxic excipients, any preparation forms such as solid (e.g., tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche and the like); semi-solid (e.g., suppository, ointment and the like); or liquid (e.g., injection, emulsion, suspension, lotion, spray and the like).
  • non-toxic excipients useful for such formulation for example, starch, gelatin, glucose, lactose, fructose, maltose,
  • magnesium carbonate talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or salts thereof, gum Arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, vaseline, Carbowax, glycerine, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like can be named. These formulations may also contain other therapeutically useful drugs.
  • Content of a compound of the formula (I) in these formulations differs depending on the preparation form and administration route, while generally it can be present at a concentration of 0.1 - 50 wt% in solid and semi-solid forms, and of 0.05 - 10 wt%, in liquid form.
  • Dosage of a compound of the formula (I) is variable over a broad range according to the kind of warm-blooded animals including human to be treated, kind of involved disease, administration route, seriousness of symptoms, doctor's diagnosis and the like. Whereas, generally it can be within a range of 0.01 - 5 mg/kg per day, preferably 0.02 - 2 mg/kg per day, it being obviously possible to administer doses less than the above lower limit or more than the above upper limit, for example, according to individual patient's symptom and doctor's diagnosis.
  • the dosage can be administered once a day or dividedly plural times per day. Examples
  • the title compound was synthesized in the manner similar to Production Example 1 except that 3,4-dichlorobenzylcyanide was replaced with benzylcyanide.
  • the title compound was synthesized in the manner similar to Production Example 1 except that 3,4-dichlorobenzylcyanide was replaced with 4-chlorobenzylcyanide.
  • the title compound was synthesized in the manner similar to Production Example 1 except that 3,4-dichlorobenzylcyanide was replaced with 3-chloro-4-fluorobenzylcyanide.
  • the title compound was synthesized in the manner similar to Production Example 1 except that 3,4-dichlorobenzylcyanide was replaced with 3-trifluoromethylbenzylcyanide.
  • the title compound was synthesized in the manner similar to Production Example 1 except that 3,4-dichlorobenzylcyanide was replaced with 4-fluorobenzylcyanide.
  • the title compound was synthesized in the manner similar to Production Example 1 except that 3,4-dichlorobenzylcyanide was replaced with thiophene-3-acetonitrile.
  • Step 1-B Synthesis of 2-(3-chlorobenzyl)-4-oxo-3,4- dihydroquinazoline- 7-carboxylic acid
  • Step 1-C Synthesis of N-[2-(3-chlorobenzyl)-4-oxo-3.4- dihydroq uinazoline - 7 - carbon yl] methane sulfonamide
  • the active ingredient was pulverized to grain sizes not greater than 70 ⁇ , to which starch, lactose and carboxymethyl cellulose calcium were added and thoroughly mixed. Then 10% starch paste was added to the powdery mixture and mixed by stirring to provide granules. After drying them, their grain sizes were dressed to around 1,000 ⁇ , with which talc and magnesium stearate were mixed. The mixture was tabletted

Abstract

La présente invention porte sur des composés thiénopyrimidines de la formule (I), dans laquelle R1 est un atome d'hydrogène, un groupe alkyle ou autre, et R1 est fixé à A1 ou A2; R2 représente un atome d'hydrogène, un groupe alkyle ou amino ou autre, R3 représente un groupe alkyle, alcényle ou alkylthio ou autre, ou un groupe Y-X-; ou R2 et R3 peuvent ensemble former un groupe tétraméthylène; R4 représente un groupe acide carboxylique, un groupe alkylsulfonylaminocarbonyle, ou autre; X représentant une liaison directe ou un groupe de liaison tel que CH2, CH(OH), S, O, NH; Y représentant un groupe carbocyclique aromatique, hétérocyclique aromatique, cycloalkyle ou hétérocyclique saturé, substitué ou non substitué, ou autre; Z représente S ou O, et n vaut 0 ou est un entier de 1 à 4; l'un des radicaux A1 et A2 représente un atome de carbone et l'autre représente un atome de soufre, ou les sels de ces composés, qui présentent un effet inhibiteur du PDE9 et qui sont donc utiles pour la prévention ou le traitement du syndrome de la vessie hyperactive, de la pollakiurie, de l'incontinence urinaire, de la dysurie associée à une hyperplasie prostatique, de l'urolithiase, de la maladie d'Alzheimer, de la bronchopneumopathie chronique obstructive, de l'infarctus du myocarde, de la thrombose, du diabète et autres.
PCT/JP2010/062022 2010-07-09 2010-07-09 Composés thiénopyrimidines WO2012004900A1 (fr)

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US9744176B2 (en) 2012-04-03 2017-08-29 Sanofi Therapeutic uses of novel thienopyrimidine derivatives
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
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US10220044B2 (en) 2012-04-03 2019-03-05 Sanofi Thienopyrimidine derivatives, processes for the preparation thereof and therapeutic uses thereof
US10500212B2 (en) 2012-04-03 2019-12-10 Sanofi Thienopyrimidine derivatives, processes for the preparation thereof and therapeutic uses thereof
US10736904B2 (en) 2012-04-03 2020-08-11 Sanofi Thienopyrimidine derivatives, processes for the preparation thereof and therapeutic uses thereof
US9744176B2 (en) 2012-04-03 2017-08-29 Sanofi Therapeutic uses of novel thienopyrimidine derivatives
US9617269B2 (en) 2012-08-08 2017-04-11 Sun Yat-Sen University N-substituted pyrazolo [3,4-D] pyrimidine ketone compound, and preparation process and use thereof
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11026930B1 (en) 2017-06-21 2021-06-08 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

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