WO2004033455A2 - Sels succiniques d'inhibiteurs heterocycliques de dpp-iv - Google Patents

Sels succiniques d'inhibiteurs heterocycliques de dpp-iv Download PDF

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Publication number
WO2004033455A2
WO2004033455A2 PCT/DK2003/000668 DK0300668W WO2004033455A2 WO 2004033455 A2 WO2004033455 A2 WO 2004033455A2 DK 0300668 W DK0300668 W DK 0300668W WO 2004033455 A2 WO2004033455 A2 WO 2004033455A2
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alkyl
aryl
salt according
heteroaryl
hemisuccinate salt
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WO2004033455A3 (fr
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Kaare Gyberg Rasmussen
Anette Frost Jensen
Lars Nygaard
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Novo Nordisk AS
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Definitions

  • the present invention relates to therapeutically active and selective hemisuccinate salts of inhibitors of the enzyme DPP-IV, pharmaceutical compositions comprising the salts and the use of such salts for and the manufacture of medicaments for treating diseases that are associated with proteins that are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity.
  • DPP-IV Dipeptidyl peptidase-IV
  • DPP-IV Dipeptidyl peptidase-IV
  • serine protease belonging to the group of post- proline/alanine cleaving amino-dipeptidases specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2.
  • DPP-IV Although the physiological role of DPP-IV has not been completely established, it is believed to play an important role in neuropeptide metabolism, T-cell activation, gastric ul- ceration, functional dyspepsia, obesity, appetite regulation, impaired fasting glucose (IFG) and diabetes.
  • DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones Glucagon like peptide-1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms, removal of their two N-terminal amino acids inactivates them. In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. Therefore, such inhibitors have been proposed for the treatment of patients with Type 2 diabetes, a disease characterised by decreased glucose tolerance. (Hoist, J. J., Deacon, C. F. Diabetes 47 (1998) 1663-70)
  • Diabetic dyslipidemia is characterized by multiple lipoprotein defects, including moderately high serum levels of cholesterol and triglycerides, small LDL particles, and low levels of HDL cholesterol.
  • the results of recent clinical trials reveal beneficial effects of cholesterol-lowering therapy in diabetic and non-diabetic patients, thus supporting increased emphasis on treatment of diabetic dyslipidemia.
  • the National Cholesterol Education Program's Adult Treatment Panel II advocated this need for intensive treatment of diabetic dyslipidemia.
  • Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world.
  • initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients eventually regain their weight.
  • An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.
  • physiologically acceptable salt with good stability, good solubility, non-hygroscopicity, good bioavailability, and good handling properties, like high melting point and a reproducible crystalline form.
  • the present invention consists of hemisuccinate salts of purine derivatives, attached at position 8 of the purine skeleton to a cyclic diamine, at either one or the other of the amino groups of the diamine.
  • These salts are potent and selective inhibitors of DPP-IV, and are effective in treating conditions that may be regulated or normalised via inhibition of DPP-IV.
  • the invention also concerns methods for preparing the salts, pharmaceutical compositions comprising the salts, a method of inhibiting DPP-IV comprising administering to a patient in need of such treatment a therapeutically effective amount of the salts of the invention, the salts for use as a pharmaceutical, and their use in a process for the preparation of a medicament for treating a condition which may be regulated or normalised via inhibition of DPP-IV.
  • DPP-IV Dipeptidyl peptidase IV
  • DPP-IV also known as CD26.
  • DPP-IV cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline or alanine residue in the penultimate position.
  • treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of hemisuccinate salt of a compound of the present invention to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • beta cell degeneration is intended to mean loss of beta cell function, beta cell dysfunction, and death of beta cells, such as necrosis or apoptosis of beta cells.
  • C C 10 alkyl refers to a straight or branched, saturated hydrocarbon chain having from 1-10 carbon atoms such as but not limited to e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. Butyl, isobutyl, tert.
  • C 2 -C 10 -alkenyl used herein, alone or in combination, refers to a straight or branched, unsaturated hydrocarbon chain having from 2-10 carbon atoms and at least one double bond such as but not limited to vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n- pentenyl and n-hexenyl and the like.
  • C 2 -C 10 alkynyl refers to an un- saturated hydrocarbon chain having from 2-10 carbon atoms and at least one triple bond such as but not limited to -C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CH, -CH 2 -CH 2 -C ⁇ CH, -CH(CH 3 )C ⁇ CH and the like.
  • C C 10 -alkoxy as used herein, alone or in combination is intended to include those C C 10 -alkyl groups of the designated length in either a linear or branched or cyclic con- figuration linked through an ether oxygen having its free valence bond from the ether oxygen.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy and iso- hexoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclo- hexyloxy.
  • C 3 -C 10 cycloalkyl refers to a radical of one or more saturated cyclic hydrocarbon having from 3-10 carbon atoms such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.
  • C 3 -C ⁇ 0 cycloalkane refers to a saturated cyclic hydrocar- bon having from 3-10 carbon atoms such as but not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane and the like.
  • C 5 -C ⁇ 0 cycloalkenyl refers to a radical of one or more cyclic hydrocarbon having at least one double bond having from 5-10 carbon atoms such as but not limited to cyclopentenyl, cyclohexenyl and the like
  • C 3 -C 7 cycloheteroalkyl refers to a radical of totally saturated heterocycle like a cyclic hydrocarbon containing one or more heteroatoms selected from nitrogen, oxygen and sulphur independently in the cycle such as pyrrolidine (1- pyr- rolidine, 2- pyrrolidine, 3- pyrrolidine, 4- pyrrolidine, 5- pyrrolidine), pyrazolidine (1- pyra- zolidine, 2- pyrazolidine, 3- pyrazolidine, 4-pyrazolidine, 5-pyrazolidine), imidazolidine (1- imidazolidine, 2- imidazolidine, 3- imidazolidine, 4- imidazolidine, 5-
  • aryl as used herein includes carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems.
  • heteroaryl as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
  • aryl and “heteroaryl” as used herein refers to an aryl which can be optionally substituted or a heteroaryl which can be optionally substituted and includes phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluo- renyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrroly
  • aryl-C ⁇ -C 5 alkyl refers to an "aryl” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • heteroaryl-C C 5 alkyl refers to a “heteroaryl” group as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
  • C 3 -C 7 cycloa!kyl-C 1 -C 5 alkyl refers to a "cycloalkyl” group as defined above having the indicated number of carbon atoms attached through an "alkyl” group as defined above having the indicated number of carbon atoms.
  • C 3 -C 7 cycloheteroalkyl-C Cs alkyl refers to a "cyclohet- eroalkyl” group as defined above having the indicated number of carbon atoms attached through an "alkyl” group as defined above having the indicated number of carbon atoms.
  • the present invention provides hemisuccinate salts of the compounds of formula
  • A may be attached at either N 1 or at N 2 to the purine system and each n and m is one or two independently
  • R 1 is aryl optionally substituted with one or more R 2 independently or heteroaryl op- tionally substituted with one or more R 2 independently,
  • R 2 is H, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, -NHCOR 3 , -NHSO 2 R 3 , -SR 3 , -SOR 3 , -SO 2 R 3 , -OCOR 3 , -CO 2 R 4 , -CON(R 4 ) 2 , -CSN(R 4 ) 2 , -NHCON(R 4 ) 2 , -NHCSN(R 4 ) 2 , -NHCONNH 2 , -SO 2 N(R 4 ) 2 , -OR 4 , cyano, nitro, halo- gen, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is optionally substituted with one or more R 3
  • R 3 is Halogen, C C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, aryl, heteroaryl, -OR 11 , -N(R 11 ) 2 , -SR 11 , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and het- eroaryl is substituted with one or more R 11 independently,
  • R 4 is H, C Cio alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, aryl-CrC 5 alkyl, heteroaryl, heteroaryl-CrC- 5 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-CrC 5 alkyl, heteroaryl, and heteroaryl-d-Cs alkyl is substituted with one or more R 11 independently,
  • R 5 is H, C C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloal- kyl-d-C ⁇ alkyl, C 3 -C 7 cycloheteroalkyl, C 3 -C 7 cycloheteroalkyl-CrC 5 alkyl, aryl, heteroaryl, aryl-C r C 5 alkyl, heteroaryl-CrC 5 alkyl, -OR 7 , -[(CH 2 ) o -O] p -alkyl, wherein o and p are 1-3 independently, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyI-C ⁇ -C 5 alkyl, cycloheteroalkyl, C 3 -C 7 cycloheteroalkyl-Cr
  • R 6 is C 1 -C 10 alkyl, C 2 -C ⁇ 0 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, heteroaryl, aryl-C- ⁇ -C- 5 alkyl, heteroaryl-C C 5 alkyl, C 3 -C 7 cycloheteroalkyl-C ⁇ -C 5 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, C 3 -C 7 cycloheteroal- kyl-C C 5 alkyl, aryl, aryl-CrCs alkyl, heteroaryl, aryl-C C 5 alkyl, and heteroaryl-CrC 5 alkyl is optionally substituted with one or more R 11 independently,
  • R 8 is C ⁇ -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, aryl, heteroaryl, -OR 11 , -N(R 11 ) 2 , -SR 11 , wherein each alkyl, alkenyl, alkynyl, cycloal- kyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 11 independently,
  • R 9 and R 10 is independently H, C C 10 alkyl optionally substituted with one or more R 8 independently, or halogen,
  • R 11 is H, -CF 3 , -CCI3, -OCF3, -OMe, cyano, halogen, -OH, -COMe, -CONH 2 , - CONHMe, -CONMe 2 , -NO 2 , C C 10 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently,
  • R 12 is H, C 1 -C 1 0 alkyl, -CF 3 , -CCI 3 , -OCF 3 , -OMe, cyano, halogen, -OH, -COMe, - CONH 2 , -CONHMe, -CONMe 2 , -NH 2) -NO 2
  • R 9 and R 10 is C ⁇ -C 10 alkyl they may be connected to form a cyclopropyl ring, if two R 4 or two R 11 are attached to the same nitrogen they may be connected to form a 3- to 7-membered ring,
  • R 1 is aryl optionally substituted with one or more R 2 independently.
  • R 1 is phenyl substituted with one or more R 2 independently.
  • R 1 is aryl. In a further embodiment of the invention R 1 is phenyl.
  • R 2 is C C 7 alkyl, C 2 -C 7 alkynyl, cyano, or halogen, wherein each alkyl and alkynyl is optionally substituted with one or more R 3 independently.
  • R 2 is C C 7 alkyl, C 2 -C 7 alkynyl, cyano, or halogen.
  • R 2 is methyl. In a further embodiment of the invention R 2 is cyano or halogen.
  • R 3 is C- ⁇ -C 10 alkyl or aryl, wherein each alkyl or aryl is substituted with one or more R 11 independently.
  • R 3 is C C 10 alkyl or aryl. In a further embodiment of the invention R 3 is methyl or phenyl. In a further embodiment of the invention R 4 is H, C C ⁇ 0 alkyl or aryl, wherein each alkyl or aryl is substituted with one or more R 11 independently.
  • R 4 is H, d-Cio alkyl or aryl. In a further embodiment of the invention R 4 is H, methyl or phenyl. In a further embodiment of the invention R 5 is H, C 1 -C 10 alkyl, aryl-C-i-C 5 alkyl, or heteroaryl-CrC 5 alkyl, wherein each alkyl, aryl-d-Cs alkyl and heteroaryl-CrC 5 alkyl is optionally substituted with one or more R 7 independently.
  • R 5 is H or C ⁇ -C 10 alkyl optionally substituted with one or more R 7 independently.
  • R 5 is H or C r C 10 alkyl. In a further embodiment of the invention R 5 is H. In a further embodiment of the invention R 5 is methyl.
  • R 6 is CrC 10 alkyl, aryl-C- ⁇ -C 5 alkyl, or het- eroaryl-d-Cs alkyl, wherein each alkyl, ary!-d-C 5 alkyl and heteroaryI-C ⁇ -C 5 alkyl is optionally substituted with one or more R 11 independently.
  • R 6 is C C ⁇ 0 alkyl, aryl-d-C 5 alkyl, or het- eroaryl-C C 5 alkyl.
  • R 6 is C C ⁇ 0 alkyl optionally substituted with one or more R 11 independently.
  • R 6 is d-C 10 alkyl. In a further embodiment of the invention R 6 is methyl.
  • R 8 is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more R 1 independently.
  • R 8 is aryl or heteroaryl. In a further embodiment of the invention R 8 is phenyl.
  • R 9 is H, d-C 10 alkyl, or halogen.
  • R 9 is H.
  • R 10 is H, d-C 10 alkyl, or halogen.
  • R 10 is H.
  • R 11 is H, -CF 3 , cyano, halogen, -OH, -NO 2 , d-C 10 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently
  • R 11 is H, halogen, -OH, C C 10 alkyl, aryl, heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 2 independently.
  • R 11 is H, halogen, -CH 3 , aryl, heteroaryl, C 3 - C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R 12 independently.
  • R 11 is H, halogen, -CH 3> heteroaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R 12 independently
  • R 11 is H, halogen, or -CH 3
  • R 11 is heteroaryl, C 3 -C cycloalkyl, C 3 -C 7 cycloheteroalkyl, wherein each cycloalkyl, cycloheteroalkyl.and heteroaryl is optionally substituted with one or more R 12 independently
  • R 11 is selected from the group consisting of pyridine, cyclopentane, cyclohexane, and pyrrolidine, wherein each cycloalkyl, cycloheteroal- kyl, and heteroaryl is optionally substituted with one or more R 12 independently
  • R 12 is H, C C 10 alkyl, -CF 3 , cyano, halogen, -OH, -COMe, -NH 2 , -NO 2
  • R 12 is H, -CF 3) cyano, halogen, -OH, -NH 2
  • R 12 is -OH or -NH 2
  • n is two.
  • n is one.
  • m is two or three.
  • hemisuccinate salts of the following compounds of Formula I are preferred: 2-(8-(3-Aminopiperidin-1-yl)-1 ,3-dimethyl-2,6-dioxo-1 ,2,3,6-tetrahydropurin-7- ylmethyl)benzonitrile.
  • the compounds of the present invention may be chiral, and it is intended that any hemisuccinate salts of enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention. Furthermore, when a double bond or a fully or partially saturated ring system or more than one centre of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any hemisuccinate salts of diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any hemisuccinate salts of tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.
  • Hemisuccinate salts of compounds of formula I may be used for the manufacture of a medicament for treating diseases associated with proteins that are subject to inactivation by DPP-IV.
  • a further aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for treating a condition that may be regu- lated or normalised via inhibition of DPP-IV.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for treatment of metabolic disorders.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for blood glucose lowering.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for treatment of Type 2 diabetes
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for the treatment of impaired glucose tolerance (IGT).
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for the treatment of impaired fasting glucose (IFG).
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for prevention of hyperglycemia.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for delaying the progression of impaired glucose tolerance (IGT) to Type 2 diabetes.
  • ITT impaired glucose tolerance
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for delaying the progression of non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for increasing the number and/or the size of beta cells in a mammalian subject.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for treatment of beta cell degeneration, in particular apoptosis of beta cells.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for the treatment of disorders of food in- take.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for the treatment of obesity.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for appetite regulation or induction of sati- ety.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for the treatment of dyslipidemia.
  • Another aspect of the invention is the use of a hemisuccinate salt of a compound of the invention for the manufacture of a medicament for treatment of functional dyspepsia, in particular irritable bowel syndrome.
  • a further aspect of the invention is a method for treating the conditions mentioned above by administering to a subject in need thereof an effective amount of a hemisuccinate salt of a compound of the invention.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one hemisuccinate salt of a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing a hemisuccinate salt of a compound of the invention of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy. 19 th Ed.. 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a hemisuccinate salt of a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the hemisuccinate salt of an active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the hemisuccinate salt of an active compound.
  • the hemisuccinate salt of an active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring sub- stances and the like, which do not deleteriously react with the hemisuccinate salt of an active compounds.
  • the route of administration may be any route, which effectively transports the active hemisuccinate salt of a compound of the invention which inhibits the enzymatic activity of DPP-IV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a hemisuccinate salt of a compound of the invention which inhibits the enzymatic activity of DPP-IV, dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • solubilizing agents e.g. propylene glycol
  • surfactants e.g. propylene glycol
  • absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the hemisuccinate salt of an active compound dissolved in polyhydroxylated castor oil
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • the hemisuccinate salts of compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used.
  • a most preferable dosage is about 0.5 mg to about 250 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the hemisuccinate salts of compounds of the present invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the hemisuccinate salts of compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • the invention also encompasses prodrugs of a hemisuccinate salt of a compound of the invention which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of hemisuccinate salts of a compound of the invention which are readily convertible in vivo into a compound of formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Pro- drugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention furthermore relates to the use of hemisuccinate salts of a compound according to the present invention for the preparation of a medicament for use in the treatment of diabetes in a regimen which additionally comprises treatment with another antidiabetic agent.
  • insulinidiabetic agent includes compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
  • the antidiabetic agent is insulin or GLP-1 or any analogue or derivative thereof.
  • the antidiabetic agent is a hypoglycaemic agent, preferably an oral hypoglycaemic agent.
  • Oral hypoglycaemic agents are preferably selected from the group consisting of sulfonylureas, non-sulphonylurea insulin secretagogues, biguanides, thiazolidinediones, alpha glu- cosidase inhibitors, glucagon antagonists, GLP-1 agonists, potasium channel openers, insulin sensitizers, hepatic enzyme inhibitors, glucose uptake modulators, compounds modifying the lipid metabolism, compounds lowering food intake, and agents acting on the ATP-dependent potassium channel of the ⁇ -cells.
  • sulfonylureas tolbutamide, glibenclamide, glipizide and gliclazide are preferred.
  • non-sulphonylurea insulin secretagogues repaglinide and nateglinide are preferred.
  • metformin is preferred.
  • troglitazone Among the thiazolidinediones, troglitazone, rosiglitazone and ciglitazone are preferred.
  • glucosidase inhibitors acarbose is preferred.
  • agents acting on the ATP-dependent potassium channel of the ⁇ -cells the following are preferred: glibenclamide, glipizide, gliclazide, repaglinide.
  • 3-aminopiperidine was made from 3-aminopyridine by reduction with PtO 2 (Nienburg. Chem.
  • Aminopyrrolidine was made according to Moon, S-H and Lee, S. Synth. Commun.
  • CD26/DPP-IV is tested for their ability to inhibit the enzyme activity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IV is measured in vitro by its ability to cleave the synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro- pNA by DPP-IV liberates the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the enzyme activity. Inhibition of the enzyme activity by specific enzyme inhibitors slows down the generation of pNA. Stronger interaction between an inhibitor and the enzyme results in a slower rate of generation of pNA. Thus, the degree of inhibition of the rate of accumulation of pNA is a direct measure of the strength of enzyme inhibition. The accumulation of pNA is measured spectrophotometrically. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of enzyme with several different con- centrations of inhibitor and substrate. Materials:
  • the activity of purified CD26/DPP-IV is assayed in reactions containing: 70 ⁇ l assay buffer 10 ⁇ l inhibitor or buffer
  • Reactions containing identical amounts of enzyme, but varying concentrations of inhibitor and substrate, or buffer as control, are set up in parallel in individual wells of a 96-well ELISA plate.
  • the plate is incubated at 25 °C and absorbance is read at 405 nm after 60 min incubation.
  • the inhibitor constants are calculated by non-linear regression hyperbolic fit and the result is expressed as inhibition constant (Ki) in nM.
  • the Zucker Diabetic Fatty (ZDF) rat model can be used to investigate the effects of the hemisuccinate salt of compounds of the invention on both the treatment and prevention of diabetes as rats of this sub-strain are initially pre-diabetic although develop severe type 2 diabetes characterised by increased HbA1 c levels over a period of 6 weeks.
  • the same strain can be used to predict the clinical efficacy of other anti-diabetic drug types.
  • the model predicts the potency and limited clinical efficacy of thiazolidinedione insulin sensitizers compounds.
  • the LC system consists of a Gilson 321 pump, 235 injector and 215-fraction collector equipped with a Waters Xterra 7.8 mm * 100 mm column run with a gradient from 10 % aqueous acetonitril with 0.01% TFA to 100 % acetonitril with 0.01% TFA over 11 min. Flow rate 10 ml/min.
  • the effluent is split 1:1000 to an Agilent 1100 MSD by a LC Packings ACM 10-50 flow splitter.
  • the MS is equipped with an Agilent fraction collector kit, from which the analogue signal from extracted the target ion, is used for controlling fraction collection.
  • Method F Microwave assisted reactions
  • the reactants are mixed in an appropriate solvent in a closed teflon vessel (XP 1500).
  • the chiral analysis of 3-aminopiperidine consists of a derivatisation step prior to chiral analysis using capillary electrophoresis (CE). Derivatisation. 50 ⁇ l 40mM 3-aminopiperidine solution in water is added to 200 /I 40mM OPA solution (40mM OPA in 1 :15:185 mercaptaethanol:MeOH:water). The reaction in carried out in the dark within 2 minutes. 50 ⁇ l of this reaction mixture is diluted with 950 /I water and analysed directly on the CE instrument.
  • CE capillary electrophoresis
  • HP 3D CE instrumentation and conditions HP 3D CE instrument equipped with a 48.5/40.0cm bubble cell capillary and detection at 226nm UV. The injection was 50mbar in 4.0 seconds.. The applied voltage was +19kV which yielded +60//A and prior to each injection the capillary was washed with 0.1 N NaOH for 1 minute and electrolyte for 1.5 minutes. The electrolyte was 0.5% (w/v) carboxyethyl-jff-cyclodextrin (Cyclolab, Hungary) dissolved in 50mM fosphate buffer pH 7.0. The two enantiomers migrate within 5 minutes of electrophoresis and the identity of specific enantiomers is confirmed by spiking of the racemate.
  • Step B (R) 3-tert-Butoxycarbonylamino-piperidine-1 -carboxylic acid benzyl ester
  • Step C (R) Piperidin-3-yl-carbamic acid tert.-butyl ester (R) 3-tert-Butoxycarbonylamino-piperidine-1 -carboxylic acid benzyl ester (50 g, 150 mmol) was dissolved in abs. EtOH (500 ml), and hydrogenated (1 atm, 7 days, 10 % Pd/C
  • 3-Amino-azepan-2-one (24,0g, 0,188mol) was dissolved in THF and cooled on an ice bath in a nitrogen atmosphere. LiAIH 4 (35,6g, 0.938 mol) was added in small portions. After the last addition the re-action mixture was allowed to warm up to room temperature and stirred for 72 hours, then refluxed for 48 hours. Water was added very slowly until a white reaction mixture was obtained. K 2 CO 3 was added until a filterable slurry was obtained. Then the reaction mixture was filtered, and the precipitate was washed with THF (3 x 300 ml). The combined THF phase was evaporated in vacuo giving the title compound as a yellow oil. No further purification was performed.
  • the starting material (16 ⁇ mol) is dissolved in a mixture of DMF and DIEA (3% DIEA, 250 ⁇ l).
  • the alkylation reagent R 1 -CR 9 R 9 -X (16.8 ⁇ mol, 1.05 equiv) is dissolved in DMF (100 ⁇ l) and added. The mixture is heated to 65 °C for 2h.
  • Alkylation reagent R 5 -Br (32 ⁇ mol) is dissolved in DMF (100 ⁇ l) and added to the reaction mixture followed by a solution of TMG in DMF (1.16 ml TMG diluted to 5.8 ml, 48 ⁇ l). The mixture is kept at 65 °C for 4h.
  • the diamine (200 ⁇ mol) is dissolved in a mixture of DMF and DIEA (3% DIEA, 200 ⁇ l) and added to the reaction mixture.
  • the reaction is kept at 50 °C for 24h.
  • Samples are neutralized using HOAc (20 ⁇ l), stripped and purified by HPLC. Samples are dissolved in DMSO/H 2 O (4:1 , 500 ⁇ l).
  • the starting material (16 ⁇ mol) is dissolved in a mixture of DMF and DIEA (3% DIEA, 250 ⁇ l).
  • the alkylation reagent R 1 -CR 9 R 9 -X (16.8 ⁇ mol, 1.05 equiv) is dissolved in DMF (100 ⁇ l) and added. The mixture is heated to 65°C for 2h.
  • Diamine (200 ⁇ mol) is dissolved in a mixture of DMF and DIEA (3% DIEA, 200 ⁇ l) and added to the reaction mixture. The reaction is kept at 50°C for 24-48h, and then all vola- tiles are stripped. Samples are neutralized using HOAc (20 ⁇ l), stripped and purified by HPLC methods A1 , A2 or A3. Samples are dissolved in DMSO/H 2 O (4:1 , 500 ⁇ l).
  • 8-Chlorotheophylline (1 eq.) and K 2 CO 3 (2.2 eq) is slurried in DMF (app. 12 ml/g of 8-Chlorotheophylline).
  • the benzyl chloride (or bromide) is added (1.1 eq), and the slurry is stirred until the reaction is finished (1 - 7 days) at RT.
  • the reaction mixture is poured into water (app. 70 ml/g 8-Chlorotheophylline) and stirred until the precipitation of the product has completed.
  • the benzylated 8-Chlorotheophylline (1 eq.) is dissolved in DMSO (app. 35 ml/g), K 2 CO 3 (4 eq.) is added, and then (R) Piperidin-3-yl-carbamic acid tert-butyl ester (2 eq.) is added, and the reaction is stirred at either RT, 50 °C, or at 65 °C until finished (usually overnight).
  • the reaction mixture is poured into water (4 - 10 ml / ml DMSO) with stirring, and the precipitated product is isolated by filtration, and washed with water, and dried.
  • step B The product from step B (1 eq.) is dissolved in MeCN (app. 20 ml / g), and cone. HCI is added (10 eq.). The reaction is left with stirring overnight, and evaporated in vacuo.
  • the product is dissolved in EtOAc and water (1 + 1, app. 50 ml/g), separated, and the aqueous phase washed with EtOAc (2 x 25 ml/g).
  • the aqueous phase is added an equal amount of 2N K 2 CO 3 , and extracted with EtOAc (3 x 25 ml/g).
  • the combined EtOAc phase is washed with brine, dried (MgSO 4 ), and about half the solvent is removed by evaporation in vacuo.
  • Cone. HCI is added (1.1 eq.), and the solvent is evaporated in vacuo.
  • the product is dissolved in hot EtOH, precipitated with Et 2 O, collected by filtration, and dried in vacuo.
  • Step A The starting material (32 ⁇ mol) is dissolved in a mixture of DMF and DIEA (3%).
  • Step B Alkylation reagent R 5 -Br (64 ⁇ mol) is dissolved in DMF (250 ⁇ l) and added to the reaction mixture. The mixture is kept at 25 °C for 48h. Volatiles are stripped
  • the diamine (400 ⁇ mol) is dissolved in DMSO and added to the reaction mixture. If the dihydrochloride salt of the diamine is employed, four equivalents of DCHMA is added. The reaction is kept at 50 °C for 48h.
  • Step A The starting material (4.08 mmol) is dissolved in a mixture of DMF and DIEA (3%).
  • the starting material (32 ⁇ mol) is dissolved in a mixture of DMF and DIEA (3% DIEA, 500 ⁇ l).
  • the alkylation reagent R 1 -CR 9 R 9 -X (33.6 ⁇ mol, 1.05 equiv) is dissolved in DMF (200 ⁇ l) and added. The mixture is heated to 65°C for 2h.
  • Samples are neutralized using HOAc (30 ⁇ l) and purified by HPLC Method A2 or A3.
  • Step A The starting material (20.40 mmol) is dissolved in DMF (50 ml) and DIEA (10 ml).
  • the alkylation reagent R 1 -CR 9 R 9 -X (22.03 mmol, 1.08 equiv) is dissolved in DMF (10 ml) and added. Heating the mixture to 65 °C for 2h affords the products that are isolated by filtration upon adding the reaction mixture onto ice (300 ml).
  • the product from Step B (0.472 mmol) is dissolved in DMSO (5 ml) and the diamine (2.36 mmol) is added to the reaction mixture. If the dihydrochloride salt of the diamine is employed, K 2 CO 3 (2.36 mmol) is added. The reaction is kept at 50 °C for 24h and poured onto ice (20 ml). The product is isolated by filtration. The compounds may be purified by HPLC methods A1 , A2 or A3 or by treatment with hot acetonitrile.
  • Step A The starting material (20.40 mmol) is dissolved in DMF (50 ml) and DIEA (10 ml).
  • the alkylation reagent R 1 -CR 9 R 9 -X (22.03 mmol, 1.08 equiv) is dissolved in DMF (10 ml) and added. Heating the mixture to 65 °C for 2h affords the products that are isolated by filtration upon adding the reaction mixture onto ice (300 ml).
  • Step B The product from step A is dissolved in DMSO (app. 40 ml/g), DIEA (2 eq.) is added, and then (R) Piperidin-3-yl-carbamic acid tert-butyl ester (2 eq.) is added, and the reaction is stirred at either RT, 50 °C, or at 65 °C until finished (usually overnight).
  • the reaction mixture is poured into ice/water (4 - 10 ml / ml DMSO) with stirring, and the precipitated product is isolated by filtration, and washed with water, and dried.
  • Step C Step C:
  • step B The product from step B is dissolved in DMF (1 eq. app. 10 ml/g). Ethyl 2- bromoacetate is added (2 eq.) is added, K 2 CO 3 (3.5 eq) is further added, and the reaction is left with stirring at RT until completed. The reaction is poured onto ice/water (app. 100 ml), and the precipitated product is isolated by filtration, and washed with water, and dried.
  • step C The product from step C is dissolved in EtOH (25 ml) with stirring, added 1 N NaOH (6 ml), and left with stirring overnight. HOAc (6 ml) is added, and the solvent is evaporated. The residue is poured onto ice/water (app. 100 ml), and the precipitated product is isolated by filtration, and washed with water, and dried.
  • step D (1 eq. 20 ⁇ mol) is dissolved in a solution of Carbonyldiimi- dazole (1.5 eq. 30 ⁇ M) in DMF (250 ⁇ l), and left for 2 hours.
  • the amine NRR' (2 eq. 40 ⁇ M), dissolved in DMF (50 ⁇ l), was added and the reaction left with stirring overnight at RT. An- other portion of the amine was added as before, and the reaction left with stirring overnight
  • the product was isolated by evaporation of the solvent.
  • step E The product from step E was added TFA in DCM (200 ⁇ l 1:1), and the reaction was left for 2 hours. Evaporation of the solvent overnight gave the product, which may be further purified by prep. HPLC methods A1 , A2 or A3.
  • the following compounds are examples of compounds of Formula I that are subsequently converted to hemisuccinate salts.
  • NNC 0072-0000-1085-Step B 2-(8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-2.6-dioxo-1.2.3.6- tetrahvdropurin-7-ylmethyl)benzonitrile.
  • Step A 7-Benzyl-8-chloro-1.3-dimethyl-3,7-dihvdropurine-2.6-dione (2A)
  • Step B 8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1.3-dimethyl-3.7-dihvdropurine-2.6-dione.
  • Step A (S) (1-(7-Benzyl-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8-yl)pyrrolidin-3- vDcarbamic acid tert-butyl ester (3A)
  • Step B (S) 8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1.3-dimethyl-3.7-dihvdropurine-2,6-dione. HCI (3)
  • 8-Chlorotheophylline (8.5 g, 39.6 mmol) was dissolved in 400 ml of DMF and 2- iodobenzyl chloride (10.0 g, 39.6 mmol), potassium carbonate (5.47 g, 39.6 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 7 days. Water (2500 ml) and EtOAc (800 ml) were added and the layers were separated.
  • Step A N-(2-Oxoazepan-3-yl)-4-methylbenzenesulfonamide (6A) DL-3-Amino-E-caprolactam (3 g, 23.4 mmol) was dissolved in 140 ml of dry DCM and dry triethylamine (4.5 ml) and 4-toluenesulfonyl chloride (4.5 g, 23.6 mmol) were added. The reaction was stirred for 3 days at room temperature and then filtered through celite. The filtrate was extracted with 50 ml of 1M aqueous potassium hydrogen sulphate, 50 ml of saturated sodium hydrogen carbonate, 50 ml of water, and 50 ml of brine, and dried over sodium sulphate.
  • N-(2-Oxoazepan-3-yl)-4-methylbenzenesulfonamide (6A) (4.24 g, 15 mmol) was dissolved in 250 ml of dry THF under a nitrogen atmosphere, and lithium aluminium hydride (1.11 g, 30 mmol) was added slowly. The reaction was heated to reflux for 20 hours and then quenched with water until the effervescence ceased. Solid potassium carbonate was added until a white suspension appeared, and the mixture was allowed to stir for half an hour. The suspension was filtered through celite, which was washed with 3 x 50 ml of EtOAc. The solvents were evaporated and the residue was dissolved in 100 ml of EtOAc and 100 ml of water.
  • Step C N-(1-(7-Benzyl-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8-yl)azepan-3-yl)-4- methylbenzenesulfonamide (6C)
  • Step D 8-(3-Aminoazepan-1-yl)-7-benzyl-1.3-dimethyl-3.7-dihvdropurine-2.6-dione.
  • TFA (6) N-(1-(7-Benzyl-1 ,3-dimethyl-2,6-dioxo-1 ,2,3,6-tetrahydropurin-8-yl)azepan-3-yI)-4- methylbenzenesulfonamide (6C) (100 mg, 0.19 mmol) was dissolved in hydrobromic acid (48%, 5 ml) and benzene (0.07 ml), and phenol (61.4 mg, 0.65 mmol) was added.
  • Step A (S) (1-(7-(2-lodobenzyl)-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8- yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (7A)
  • Step B (S) 8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1.3-dimethyl-3.7-dihvdropurine-2.6- dione.
  • Step A (S) (1-(7-(2-Cvanobenzyl)-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8- yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (8A)
  • Step B (S) 2-(8-(3-Aminopyrrolidin-1-yl)-1.3-dimethyl-2.6-dioxo-1 ,2,3.6-tetrahvdropurin-7- ylmethvDbenzonitrile.
  • Step A 7-(2-Bromobenzyl)-8-chloro-1.3-dimethyl-3,7-dihvdropurine-2,6-dione (10A)
  • Step B 8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1 ,3-dimethyl-3 -dihvdropurine-2,6- dione.
  • TFA dO 8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1 ,3-dimethyl-3 -dihvdropurine-2,6- dione.
  • Step A (R) (1-(7-(2-Bromobenzyl)-1.3-dimethyl-2,6-dioxo-1.2,3.6-tetrahvdropurin-8- yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (11 A)
  • Step B (R) 8-(3-Aminopyrrolidin-1-yl)-7-(2-bromobenzyl)-1.3-dimethyl-3.7-dihvdropurine-2.6- dione.
  • Step A 2-(8-Chloro-1 ,3-dimethyl-2,6-dioxo-1.2.3.6-tetrahvdropurin-7-ylmethyl)benzonitrile (16A)
  • Step B (R) 1-r7-(2-Cvanobenzyl)-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8-yll- piperidin-3-yl)carbamic acid tert-butyl ester (16B) From (16A) (4g, 12.1 mmol) Yield: 4.8 g (80%)
  • Step C (R) 2-r8-(3-Aminopiperidin-1-yl)-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-7- ylmethvnbenzonitrile.
  • Step A 7-Benzyl-8-chloro-1.3-dimethyl-3.7-dihydropurine-2.6-dione (17A)
  • Step B (R) ri-(7-Benzyl-1 ,3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8-yl)piperidin-3- yllcarbamic acid tert-butyl ester (17B) From (17A) (4 g, 13.1 mmol) Yield: 5.1 g (84%)
  • Step C (R) 8-(3-Aminopiperidin-1-yl)-7-benzyl-1.3-dimethyl-3,7-dihydropurine-2.6-dione. HCI (17)
  • Step A 8-Chloro-1.3-dimethyl-7-(2-methylbenzyl)-3.7-dihvdropurine-2.6-dione (18A)
  • Step B (R) (1-n ,3-Dimethyl-7-(2-methylbenzyl)-2.6-dioxo-1.2.3.6-tetrahvdropurin-8- yllpiperidin-3-yl)carbamic acid tert-butyl ester (18B) From (18A) (4 g, 12.5 mmol) Yield: 4.9 g (82%).
  • Step C (R) 8-(3-Aminopiperidin-1-yl)-1.3-dimethyl-7-(2-methylbenzyl)-3.7-dihvdropurine-2.6- dione. HCI (18)
  • Step A 8-Chloro-7-(2-chlorobenzyl)-1.3-dimethyl-3.7-dihvdropurine-2.6-dione (19A)
  • Step B (R) (1-r7-(2-Chlorobenzyl)-1.3-dimethyl-2,6-dioxo-1.2.3.6-tetrahvdropurin-8- yllpiperidin-3-yl)carbamic acid tert-butyl ester (19B)
  • Step C (R) 8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-1.3-dimethyl-3.7-dihvdropurine-2.6- dione.
  • Step A 7-(2-Bromobenzyl)-8-chloro-1 ,3-dimethyl-3,7-dihvdropurine-2,6-dione (20A) From 8-Chorotheophylline (10 g, 46.6 mol) and 2-bromobenzyl bromide (12.2 g, 48.93 mol). Yield: 17.2 g (96%).
  • Step B (R) (1-r7-(2-Bromobenzyl)-1.3-dimethyl-2.6-dioxo-1.2.3.6-tetrahvdropurin-8- yllpiperidin-3-yl)carbamic acid tert-butyl ester (20B)
  • Step C (R) 8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1.3-dimethyl-3.7-dihvdropurine-2,6- dione. HCI (20)
  • Step A 8-Bromo-7-(2-chlorobenzyl)-3-methyl-3.7-dihvdropurine-2.6-dione.
  • Step B 2-(8-Bromo-7-(2-chlorobenzyl)-3-methyl-2.6-dioxo-1 ,2.3,6-tetrahvdropurin-1- ylmethvDbenzonitrile (75B)
  • Step C 2-(8-(3-Aminoazepan-1-yl)-7-(2-chlorobenzyl)-3-methyl-2.6-dioxo-1 ,2,3,6- tetrahvdropurin-1-ylmethyl)benzonitrile.
  • Step A 7-Benzyl-8-bromo-3-methyl-3,7-dihvdropurine-2,6-dione (77A)
  • Step B 7-Benzyl-8-bromo-3-methyl-1 -(2-oxo-2-phenylethyl)-3.7-dihvdropurine-2,6-dione
  • Step C 8-(3-Aminoazepan-1 -yl)-7-benzyl-3-methyl-1 -(2-oxo-2-phenylethyl)-3,7- dihvdropurine-2.6-dione.
  • Step A 2-(8-Bromo-3-methyl-2,6-dioxo-1 ,2,3,6-tetrahvdropurin-7-ylmethyl)benzonitrile.
  • (79A) 8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and alpha-bromo-o-tolunitrile were reacted and purified as described in the General procedure G, step A, to afford 79A as white crystals in 91% yield.
  • Step B 2-(8-(3-Aminoazepan-1-yl)-3-methyl-2.6-dioxo-1 ,2.3.6-tetrahvdropurin-7- ylmethvDbenzonitrile.
  • Step A 8-Bromo-7-(2-bromobenzyl)-3-methyl-3,7-dihvdropurine-2,6-dione (80A)
  • Step B 8-(3-Aminoazepan-1 -yl)-7-(2-bromobenzyl)-3-methyl-3,7-dihvdropurine-2.6-dione.
  • Step A 8-Bromo-3-methyl-7-(2-trifluoromethylbenzyl)-3.7-dihvdropurine-2,6-dione (81A)
  • Step B 8-(3-Aminoazepan-1 -yl)-3-methyl-7-(2-trifluoromethylbenzyl)-3,7-dihvdropurine-2,6- dione TFA (81) 8-Bromo-3-methyl-7-(2-trifluoromethyIbenzyl)-3,7-dihydropurine-2,6-dione (81 A)
  • Step A 8-Bromo-3-methyl-7-(2-methylbenzyl)-3.7-dihvdropurine-2.6-dione
  • 82A 8-Bromo-3-methyI-3,7-dihydropurine-2,6-dione and 2-methylbenzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 82A as white crystals in 79%.
  • Step B 8-(3-Aminoazepan-1 -yl)-3-methyl-7-(2-methylbenzv0-3.7-dihvdropurine-2,6-dione.
  • TFA (82)
  • Step A 7-(2-Bromobenzyl)-8-chloro-1.3-dimethyl-3.7-dihvdropurine-2,6-dione (83A)
  • Step B 8-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-1 ,3-dimethyl-3,7-dihvdropurine-2,6-dione TFA (83)
  • Step A 7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3.7-dihvdropurine-2,6-dione (84A)
  • Step A 8-Chloro-1 ,3-dimethyl-7-(2-methylbenzyl)-3,7-dihvdropurine-2,6-dione (85A)
  • Step B 8-(3-Aminoazepan-1-yl)-1 ⁇ 3-dimethyl-7-(2-methylbenzyl)-3,7-dihvdropurine-2,6- dione.
  • TFA (85)
  • General Prodedure I for preparation of succinate and hemisuccinate salts A compound of the general formula I is suspended or dissolved in an appropriate solvent or a mixture of solvents. The mixture is eventually heated to 40-120°C depending on the boiling point of the appropriate solvent or solvent mixture so that the solution becomes clear. The solution can be filtered before one (if the succinate is desired) or half (if the hemisuccinate is desired) an equivalent of succinic acid is added, as a solid or dissolved in an appropriate solvent or a mixture of solvents. The succinic acid can also be added before a clear solution of the compound is obtained.
  • Crystallisation can be achieved by distilling off solvent, or slowly cooling the solution, or adding the solution to a third solvent or mixture of solvents, or adding solvent or a mixture of solvents to the solution or combinations thereof.
  • the succinate or hemisuccinate salt is isolated by filtration or centrifugation?, washed with the appropriate solvent or mixture of solvents and drying to constant weight.
  • solvents include but are not limited to: water, hydrocarbons (aromatic, aliphatic, unsaturated, aromatic) such as pentane, heptane, cumene or toluene; alcohols (monohydric or polyhydric aliphatic, unsaturated, aromatic) such as methanol, ethanol, 1- propanol, 2-propanol, 2-methyl-1 -propanol, 1-butanol, 2-butanol, 1-pentanol; ethers (open chain or cyclic) such as ethyl ether, tert-butyl methyl ether, anisole, 1 ,4-dioxane or tetrahydro- furane; carbonyls (aldehydes, ketones) such as acetone, methyl ethyl ketone, methyl isobutyl ketone; carbonic acids such as formic acid, acetic acid,.
  • hydrocarbons aromatic, aliphatic, uns
  • esters mono or poly saturated aliphatic, unsaturated or aromatic
  • esters such as ethyl formiate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert butyl acetate
  • carbonates such as dimethylcarbonate; halogenated hydrocarbons such as dichloromethane; solvents containing nitrogen (nitriles, amines, nitro, amides ureas), oxosulfor compounds such as acetonitril, N,N- dimethylformamide, ⁇ /-methyl-2-pyrrolidinone, sulfolane, dimethylsulfoxide, 1 ,3-dimethyl-3,4,5,6-tetrahydroxy-2(1 H)-pyrimidinone or combinations thereof.
  • the process for the preparation of the various succinate and hemisuccinate salts of the present invention comprises: a) suspending or dissolving compound of the general formula I in an appropriate solvent or a mixtures of solvents, b) optionally heating the mixture to 40-120°C depending on the boiling point of the appropriate solvent or solvent mixture so that the solution becomes clear, and filtering the clear solution, c) addition of one (if the succinate salt is desired)or a half equivalent succinic acids (if the hemisuccinate is desired) as a solid or dissolved in an appropriate solvent or a mixtures of solvents, d) optionally the succinic acid is added before a clear solution of the compound of the general formula....
  • solvents include but are not limited to: water, hydrocarbons (aromatic, aliphatic, unsaturated, aromatic) such as pentane, heptane, cumene or toluene; alcohols (monohydric or polyhydric aliphatic, unsaturated, aromatic) such as methanol, ethanol, 1- propanol, 2-propanol, 2-methyl-1 -propanol, 1-butanol, 2-butanol, 1-pentanol; ethers (open chain or cyclic) such as ethyl ether, tert-butyl methyl ether, anisole, 1 ,4-dioxane or tetrahydro- furane; carbonyls (aldehydes, ketones) such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters (mono or poly saturated aliphatic, unsaturated or aromatic) such as ethyl for

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des sels hémisucciniques sélectifs et actifs sur le plan thérapeutique d'inhibiteurs de l'enzyme DPP-IV représentés par la formule (I), des compositions pharmaceutiques contenant ces sels et l'utilisation de ces derniers afin de préparer des médicaments servant à traiter des maladies associées à des protéines susceptibles d'être inactivées par DPP-IV, telles que le diabète de type 2 et l'obésité.
PCT/DK2003/000668 2002-10-08 2003-10-08 Sels succiniques d'inhibiteurs heterocycliques de dpp-iv Ceased WO2004033455A2 (fr)

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AU2003269850A AU2003269850A1 (en) 2002-10-08 2003-10-08 Hemisuccinate salts of heterocyclic dpp-iv inhibitors

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DKPA200201507 2002-10-08
DKPA200201507 2002-10-08
US41867702P 2002-10-15 2002-10-15
US60/418,677 2002-10-15

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WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
US20150166481A1 (en) * 2007-02-19 2015-06-18 Kaneka Corporation Method for producing optically active 3-aminopiperidine or salt thereof
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