WO1994012480A1 - 1,3-diazacycloalkyl oxime derivatives - Google Patents

1,3-diazacycloalkyl oxime derivatives Download PDF

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Publication number
WO1994012480A1
WO1994012480A1 PCT/EP1993/003324 EP9303324W WO9412480A1 WO 1994012480 A1 WO1994012480 A1 WO 1994012480A1 EP 9303324 W EP9303324 W EP 9303324W WO 9412480 A1 WO9412480 A1 WO 9412480A1
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Prior art keywords
diazacycloalkyl
oxime
lower alkyl
solution
hydrogen
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PCT/EP1993/003324
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French (fr)
Inventor
Ralf Plate
Original Assignee
Akzo Nobel N.V.
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Priority to AU56281/94A priority Critical patent/AU5628194A/en
Publication of WO1994012480A1 publication Critical patent/WO1994012480A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the invention relates to 1,3-diazacycloalkyl oxime derivatives, a process for the preparation thereof, a pharmaceutical composition containing the same, as well as to the use of these 1,3-diazacycloalkyl oxime deriv ⁇ atives for the preparation of a medicament.
  • 4-Hydroxy-l, ,5,6-tetrahydropyrimidine compounds are disclosed in JP 60185770 as useful antioxidants for, inter alia, vitamins.
  • Related tetrahydropyrimidines are disclosed in European Patent Application 0,309,425 as muscarinic receptor blocking agents, useful for the treatment of gastrointestinal disorders. The latter compounds are muscarinic antagonists rather than agonists.
  • O-Substituted tetrahydropyridine oximes are disclosed in European Patent Application 0,271,798 as cholinergic agents.
  • the muscarinic agonist potency of the compounds of the present invention is, however, very pronounced, especially with respect to the important Ml and M3 muscarinic subtypes.
  • the compounds of this invention bind to muscarinic agonist receptor sites with preference as compared to muscarinic antagonist receptor sites, as is exemplified in their ability to bind preferentially to the agonist site of muscarinic receptors in membrane preparations of rat cerebral cortex, or membrane from rat forebrain.
  • Preferred compounds show an agonist/antagonist binding ratio of between 10 and 400.
  • the 1,3-diazacycloalkyl oxime derivatives are suitable for the treatment of cognition disorders, like presenile and senile dementia, including Alzheimer's disease, learning and memory disturbances, and for the treatment
  • CONFIRMATION COW of other cholinergic anomalies like Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and Tourette syndrome or similar conditions characterized by a decrease in cerebral acetylcholine production or release.
  • the compounds of the invention are useful for the treatment of glaucoma and as analgetic agents for the treatment of pain in mammals, including man.
  • the invention relates to 1,3-diazacycloalkyl oxime derivative having the general formula I
  • R- ⁇ is hydrogen or lower alkyl
  • R 2 is hydrogen or lower alkyl
  • R 3 is hydrogen, halogen, CN, lower alkyl or halogen substituted lower alkyl
  • R 4 is lower alkyl, optionally substituted with halogen, or lower alkenyl or lower alkynyl
  • n is 1 or 2
  • the oxime group R 3 C NOR -*- s attached to one of the methylene groups of the 1,3-diazacycloalkyl ring; or a pharmaceutically acceptable salt thereof.
  • lower alkyl as used in the definition of formula I, means a branched or unbranched alkyl group having preferably 1-6 carbon atoms, like hexyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl, and, preferably, methyl.
  • halogen means F, Cl, Br or I. When halogen is a substituent at a lower alkyl group, Cl and F are preferred, F being most preferred.
  • lower alkenyl means a group having preferably 2-6 carbon atoms, like 2-propenyl, vinyl, 2-butenyl, 1,3-butadienyl, or 2-methyl-propenyl.
  • lower alkynyl means a lower alkyl group having preferably 2-6 carbon atoms, like ethynyl, 2-propynyl, 3-butynyl, or 2-hexynyl.
  • Preferred compounds according to the invention are the 1,3-diazacycloalkyl oxime derivatives of formula I, in which R-L and R 2 are hydrogen, and R 3 , R and n have the previously given meanings. More preferred are the compounds in which R- ⁇ and R 2 are hydrogen, R 3 is hydrogen or methyl, and wherein R 4 is 2-hexynyl, 2- propynyl, 2-butenyl, 2-propenyl, 2-propynyl, isopropyl, ethyl or methyl.
  • novel compounds of formula I may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HC1, HBr, HI, H 2 S0 , H 3 P0 4 , acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methane- sulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • an organic or inorganic acid such as HC1, HBr, HI, H 2 S0 , H 3 P0 4 , acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methane- sulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • the compounds of the invention may exist in either the Z or the E isomeric form. Both forms, as well as mixtures of the Z and E forms, are included in the present invention.
  • the compounds of this invention may possess a chiral carbon atom, and may therefore be obtained as a pure enantiomer, or as a mixture of enantio ers, among which the racemic mixture.
  • Methods for obtaining the pure enantiomers are well known in the art, e. ⁇ . crystal- lization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns.
  • 1,3-diazacycloalkyl oxime derivatives of the invention can be prepared by methods known for the preparation of analogous compounds.
  • a suitable method for the preparation of compounds of formula I is the condensation of an oxime having the formula II
  • a suitable method for the preparation of the aldoxime ⁇ according to formula I , wherein R , R 2 and R 3 are hydrogen, is the condensation of a diamino acid deriv- ative having formula III,
  • COOR 5 group is attached to one of the methylene groups, and R 5 is hydrogen or lower alkyl, preferably methyl, with trialkyl orthoformate, wherein
  • alkyl has the meaning as previously defined for lower 5 alkyl, pre erably methyl, after which the resulting
  • alkyl 1,3-diazacycloalkyl carboxylate is reduced to the corresponding carboxaldehyde, which is than condensed with a hydroxylamine derivative having the formula H 2 N- OR , wherein R has the previously defined meaning.
  • the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,001-10 mg per kg body weight.
  • Mixed with pharmaceutically suitable auxiliaries e.g. as
  • the compounds may be compressed into solid dosage units,
  • the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • dosage units e.g. tablets
  • conventional additives such as fillers, colorants, poly ⁇ meric binders and the like is contemplated.
  • any pharmaceutical acceptable additive which does not interfere with the function of the active compounds can be used.
  • Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
  • lactose lactose
  • starch starch
  • cellulose derivatives and the like or mixtures thereof, used in suitable amounts.
  • the invention is further illustrated by the following examples.
  • a solution of methyl chloroformate (49.5 g, 0.53 mol) and malononitril (33 g, 0.5 mol) in tetrahydrofuran (75 ml) was slowly added to a vigorously stirred solution of potassium hydroxide (56.1 g, 1 mol) in water (50 ml), while keeping the temperature below 40 °c. After stirring for 2 hours at room temperature, the reaction mixture was cooled to 0 °C. The precipitate was filtered off and successively washed with ice-cold water and ethanol and dried to give 68 g (84%) of the white crystalline potassium salt of methyl dicyanoacetate.
  • Diisobutylaluminum hydride 17.1 ml of a 1.2 N solution in toluene; 1.2 equivalents was added to a cooled (-70 ° C) solution of methyl N,N'-(dibenzyloxy- carbony1)-3-amino-2-methylaminopropionate (6.8 g, 17.1 mmol) in dry dichloromethane (50 ml).
  • the reaction mixture was stirred for 3 hours and then quenched with methanol (3 ml) .
  • the mixture was allowed to warm to room temperature, after which water (20 ml) was added.
  • the mixture was filtered and the organic phase was separated and subsequently dried over magnesium sulfate.
  • Methoxylamine hydrochloride (790 mg, 9.5 mmol) was added to a solution of crude N,N'-(dibenzyloxycarbonyl)- 3-amino-2-methylamino-propionaldehyde (3.7 g, crude) in dry methanol (125 ml). After stirring of the reaction mixture for 3.5 hours at 65 °C the solvent was evaporated in vacuo. Ethyl acetate was added to the residue. Residual methoxylamine hydrochloride was removed by filtration.
  • Example 7A 4-Phthalimido-3-phthalimidomethyl-butan-2-one (Example 7A) was condensed with O-ethylhydroxylamine hydrochloride using the etho ⁇ as described in Example 7B to give 4-phthalimido-3-phthalimidomethyl-butan-2-one O-ethyloxime in a yield of 65%.
  • 4-Phthalimido-3-phthalimidomethyl-butan-2-one O- ethyloxime was successively treated with sodium methanolate and methanolic hydrogen chloride using the method as described in Example 7C to a quantitative yield of 4-amino-3-aminomethyl-butan-2-one O-ethyloxime dihydrochloride.
  • Example 7A was condensed with O-propargyl hydroxyl- amine hydrochloride using the method as described in Example 7B to give 4-phthalimido-3-phthalimidomethyl- butan-2-one O-2-propynyloxime in a yield of 70 %.
  • A Agon st binding.
  • Agonist binding potency of the compounds of the invention was determined using an in vitro test whereby the ability of a compound to inhibit the binding of the muscarinic agonist oxotremerine-M (Oxo-M) to high affinity agonist sites of muscarinic cholinergic receptors in rat cerebral cortex membranes is esta ⁇ blished (Freedman, S.B., Harley, E.A. and Iversen, L.L. , Br. J. Pharmacol. 93, 437-455, 1988).
  • Oxo-M oxotremerine-M
  • the crude synaptosomal mitochondrial pellet was freshly used or stored at -70 ° C (and subsequently used within 2 weeks). Just before use the pellet was resuspended in ice-cold 0.020 M HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethylsulfonic acid) ) buffer, pH 7.4, to give a protein concentration of approximately 350 ⁇ g/ml.
  • HEPES N-(2-hydroxyethyl)piperazine-N'-(2-ethylsulfonic acid)
  • Binding assay A solution was prepared containing HEPES buffer (0.55 ml), 0.10 ml of a solution of the test compound in ultrapure water or 0.01 M hydrochloric acid (final concentration of test compounds ranged from 1 nM to 10 ⁇ M) and 0.05 ml of a solution of [methyl- 3 H]- oxotremorine-M acetate in' HEPES buffer (final concentration of approximately 0.5 nM) .
  • the mixture was incubated, with shaking, for 40 minutes at 30 °C
  • the incubation was terminated by rapid filtration of the whole volume through a glass fibre filter sheet (pre-soaked with a 0.05% (v/v) aqueous polyethyleneimine solution for 1 hour) using the Brandel cell harvester.
  • the residue was rapidly washed with 20 ml of ice-cold sodiumchloride (9 g/1) solution for 15 seconds.
  • the filter was transferred to a scintillation vial containing Picofluor 30 (5 ml), and the sample was counted for 4 min.
  • Non-specific Oxo-M binding was determined in assay mixtures containing 2 ⁇ M atropine. IC 50 values, the inhibitory concentration in mol/1 causing 50% displacement of specific binding, were determined from the inhibition data. Binding results for a number of compounds of the invention are presented in the Table as the pK ⁇ -value, the negative logaritm of K ⁇ .
  • Binding to antagonist binding sites of muscarinic cholinergic receptors was determined using an in vitro test whereby the ability of a compound to inhibit the binding of the muscarinic antagonist pirenzepine (Pz) to a subclass of muscarinic cholinergic receptors in rat brain membrane homogenates is determined (Yamamura,H. and Snijder, S . , Proc.Natl. Acad. Sci. U.S.A., 7_i, 1725- 1729, 1974; Luthin, G.R. and Wolfe, B.B. , J. Pharmacol. Exp.. Therap. , 228. 648-655, 1984). Preparation of rat brain homogenate.
  • a male rat was decapitated and the whole brain was removed and placed on ice.
  • the cerebellum was excised.
  • the brain was homogenized in 10 volumes (m/v) of ice- cold 0.32 M sucrose solution using the Potter-Elvehjem homogenizer (10 strokes up and down at 1000 rp .).
  • the homogenate was centrifuged at 10.000 N/kg for 10 minutes at 4 °C.
  • the supernatant was separated and subsequently homogenized for 5 seconds using the Polytron homo ⁇ genizer. Just before use the supernatant was diluted with ice-cold 0.32 M sucrose solution to give a homo ⁇ genate containing 25 mg wet tissue/ml.
  • a solution was prepared containing 0.05 M phosphate buffer pH 7.4 (0.75 ml), 0.10 ml of a solution of the test compound in ultrapure water or in 0.1 M hydrochlo ⁇ ric acid followed by neutralization to pH 7-8 (final concentration of test compounds ranged from 10 nM to 0.1 mM) and 0.05 ml of a solution of [N-methyl- 3 H]-piren- zapine in phosphate buffer (final concentration in reaction mixture of approximately 1 nM) .
  • 0.1 ml rat brain membrane homogenate the mixture was incubated, with occasional shaking, for 60 minutes at 25 "c.
  • the incubation was terminated by rapid filtering of 0.80 ml of the incubated homogenate through a pre-wetted glass fibre filter. The residue was rapidly washed three times with 5 ml of ice-cold phosphate buffer. The filter was transferred to a scintillation vial containing Picofluor 30 (5 ml), and the sample was counted for 4 min. Non-specific pirenzepine (Pz) binding was determined in assay mixtures containing 1 ⁇ M atropine. Binding results for a number of compounds of the invention are presented in the Table as the pK ⁇ -value.

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Abstract

The invention relates to 1,3-diazacycloalkyl oxime derivatives having general formula (I), wherein R1 is hydrogen or lower alkyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, halogen, CN, lower alkyl or halogen substituted lower alkyl; R4 is lower alkyl, optionally substituted with halogen, or lower alkenyl or lower alkynyl; n is 1 or 2; and wherein the oxime group R3C = NOR4 is attached to one of the methylene groups of the 1,3-diazacycloalkyl ring; or a pharmaceutically acceptable salt thereof. The compounds of the invention have muscarinic properties and can be used for the treatment of cognition disorders, and for the treatment of cholinergic anomalies.

Description

1,3-DIAZACYC OA KYL OXIME DERIVATIVES
The invention relates to 1,3-diazacycloalkyl oxime derivatives, a process for the preparation thereof, a pharmaceutical composition containing the same, as well as to the use of these 1,3-diazacycloalkyl oxime deriv¬ atives for the preparation of a medicament.
4-Hydroxy-l, ,5,6-tetrahydropyrimidine compounds are disclosed in JP 60185770 as useful antioxidants for, inter alia, vitamins. Related tetrahydropyrimidines are disclosed in European Patent Application 0,309,425 as muscarinic receptor blocking agents, useful for the treatment of gastrointestinal disorders. The latter compounds are muscarinic antagonists rather than agonists. O-Substituted tetrahydropyridine oximes are disclosed in European Patent Application 0,271,798 as cholinergic agents.
The muscarinic agonist potency of the compounds of the present invention is, however, very pronounced, especially with respect to the important Ml and M3 muscarinic subtypes. The compounds of this invention bind to muscarinic agonist receptor sites with preference as compared to muscarinic antagonist receptor sites, as is exemplified in their ability to bind preferentially to the agonist site of muscarinic receptors in membrane preparations of rat cerebral cortex, or membrane from rat forebrain. Preferred compounds show an agonist/antagonist binding ratio of between 10 and 400.
The 1,3-diazacycloalkyl oxime derivatives are suitable for the treatment of cognition disorders, like presenile and senile dementia, including Alzheimer's disease, learning and memory disturbances, and for the treatment
CONFIRMATION COW of other cholinergic anomalies, like Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and Tourette syndrome or similar conditions characterized by a decrease in cerebral acetylcholine production or release. The compounds of the invention are useful for the treatment of glaucoma and as analgetic agents for the treatment of pain in mammals, including man.
The invention relates to 1,3-diazacycloalkyl oxime derivative having the general formula I
Figure imgf000004_0001
wherein R-^ is hydrogen or lower alkyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, halogen, CN, lower alkyl or halogen substituted lower alkyl; R4 is lower alkyl, optionally substituted with halogen, or lower alkenyl or lower alkynyl; n is 1 or 2; and wherein the oxime group R3C=NOR -*-s attached to one of the methylene groups of the 1,3-diazacycloalkyl ring; or a pharmaceutically acceptable salt thereof.
The term lower alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having preferably 1-6 carbon atoms, like hexyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl, and, preferably, methyl.
The term halogen means F, Cl, Br or I. When halogen is a substituent at a lower alkyl group, Cl and F are preferred, F being most preferred. The term lower alkenyl means a group having preferably 2-6 carbon atoms, like 2-propenyl, vinyl, 2-butenyl, 1,3-butadienyl, or 2-methyl-propenyl.
The term lower alkynyl means a lower alkyl group having preferably 2-6 carbon atoms, like ethynyl, 2-propynyl, 3-butynyl, or 2-hexynyl.
Preferred compounds according to the invention are the 1,3-diazacycloalkyl oxime derivatives of formula I, in which R-L and R2 are hydrogen, and R3, R and n have the previously given meanings. More preferred are the compounds in which R-^ and R2 are hydrogen, R3 is hydrogen or methyl, and wherein R4 is 2-hexynyl, 2- propynyl, 2-butenyl, 2-propenyl, 2-propynyl, isopropyl, ethyl or methyl.
The novel compounds of formula I may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HC1, HBr, HI, H2S0 , H3P04, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methane- sulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
The compounds of the invention may exist in either the Z or the E isomeric form. Both forms, as well as mixtures of the Z and E forms, are included in the present invention.
The compounds of this invention may possess a chiral carbon atom, and may therefore be obtained as a pure enantiomer, or as a mixture of enantio ers, among which the racemic mixture. Methods for obtaining the pure enantiomers are well known in the art, e.σ. crystal- lization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns.
The 1,3-diazacycloalkyl oxime derivatives of the invention can be prepared by methods known for the preparation of analogous compounds.
A suitable method for the preparation of compounds of formula I is the condensation of an oxime having the formula II
Figure imgf000006_0001
wherein n, R2 , R3 and R4 have the previously given meanings and the oxime group R3C=NOR4 is attached to one of the methylene groups, with an orthoformate derivative having the formula (alky1-0) -jC-Rj^, wherein -^ has the previously defined meaning and alkyl has the meaning as previously defined for lower alkyl, and is preferably methyl.
A suitable method for the preparation of the aldoximeε according to formula I , wherein R , R2 and R3 are hydrogen, is the condensation of a diamino acid deriv- ative having formule III,
Figure imgf000006_0002
wherein the COOR5 group is attached to one of the methylene groups, and R5 is hydrogen or lower alkyl, preferably methyl, with trialkyl orthoformate, wherein
* alkyl has the meaning as previously defined for lower 5 alkyl, pre erably methyl, after which the resulting
* alkyl 1,3-diazacycloalkyl carboxylate is reduced to the corresponding carboxaldehyde, which is than condensed with a hydroxylamine derivative having the formula H2N- OR , wherein R has the previously defined meaning.
10
The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,001-10 mg per kg body weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as
15 described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences (18th ed.. Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture) the compounds may be compressed into solid dosage units,
20 such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liguids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
25 For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, poly¬ meric binders and the like is contemplated. In general any pharmaceutical acceptable additive which does not interfere with the function of the active compounds can
30 be used.
Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. The invention is further illustrated by the following examples.
Example 1.
1.4.5.6-tetrahvdro-5-pyrimidinecarboxaldehyde O-methyl- oxime
A: Potassium salt of methvl dicvanoacetate. A solution of methyl chloroformate (49.5 g, 0.53 mol) and malononitril (33 g, 0.5 mol) in tetrahydrofuran (75 ml) was slowly added to a vigorously stirred solution of potassium hydroxide (56.1 g, 1 mol) in water (50 ml), while keeping the temperature below 40 °c. After stirring for 2 hours at room temperature, the reaction mixture was cooled to 0 °C. The precipitate was filtered off and successively washed with ice-cold water and ethanol and dried to give 68 g (84%) of the white crystalline potassium salt of methyl dicyanoacetate.
B: Methvl 3-amino-2-methvlaminopropionate dihvdrochloride.
Potassium salt of methyl dicyanoacetate (12.8 g, 80 mmol) was suspended in methanol (4 1) containing 3 egui- valents of hydrochloric acid. Palladium (10% w/w) on activated carbon (26 g) was added, after which hydrogen was passed through the suspension. After 24 hours the catalyst was removed by filtration. The filtrate was evaporated in vacuo. Recrystallisation of the crude product from methanol/ethyl acetate afforded methyl 3- amino-2-methylaminopropionate dihydrochloride in 58 % yield. Mp. 178 °C (dec).
C; Methyl N.N'-fdibenzyloxycarbonyl -3-amino-2-methyl- aminopropionate
A solution of methyl 3-amino-2-methylaminopropionate dihydrochloride (9.1 g, 44.6 mmol) and triethylamine (12.5 ml, 89.2 mmol) in dry dimethylformamide (250 ml) was stirred for 20 minutes. Triethylamine (12.5 ml, 89.2 mmol) was added followed by N-(benzyloxy-carbon- yloxy)succinimide (22.2 g, 89.2 mmol) while keeping the temperature at 20-25 °C. After stirring of the reaction mixture at room temperature for 5 hours, the precipitate was removed by filtration. The filtrate was evaporated in vacuo to give a residue that was subsequently partitioned between water and ethyl acetate. The organic layer was washed twice with small portions of water. The dried (magnesium sulfate) organic phase was evaporated in vacuo. The residue was purified by column chromato- graphy on neutral aluminum oxide using toluene/ethyl acetate as the eluent. Methyl N,N'-(dibenzyl- oxycarbonyl)-3-amino-2-methyl--aminopropionate was obtained as a syrup (11 g, 62%).
D: N.N'- (dibenzvloxvcarbonvl )-3-amino-2-methvlamino- propionaldehvde.
Diisobutylaluminum hydride ( 17.1 ml of a 1.2 N solution in toluene; 1.2 equivalents) was added to a cooled (-70 ° C) solution of methyl N,N'-(dibenzyloxy- carbony1)-3-amino-2-methylaminopropionate (6.8 g, 17.1 mmol) in dry dichloromethane (50 ml). The reaction mixture was stirred for 3 hours and then quenched with methanol (3 ml) . The mixture was allowed to warm to room temperature, after which water (20 ml) was added. The mixture was filtered and the organic phase was separated and subsequently dried over magnesium sulfate. The solvents were evaporated in vacuo to leave a residue (7.45 g) containing a mixture of the aldehyde and the starting material (approximately 30%). The crude aldehyde derivative was used in the next step without further purification. E: N.N'-fdibenzyloxycarbonyl)- -amino-2-methylamino- propionaldehvde O-methyloxime.
Methoxylamine hydrochloride (790 mg, 9.5 mmol) was added to a solution of crude N,N'-(dibenzyloxycarbonyl)- 3-amino-2-methylamino-propionaldehyde (3.7 g, crude) in dry methanol (125 ml). After stirring of the reaction mixture for 3.5 hours at 65 °C the solvent was evaporated in vacuo. Ethyl acetate was added to the residue. Residual methoxylamine hydrochloride was removed by filtration. The filtrate was evaporated in vacuo to give a residue (2 g), which was chromatographed on silica in the solvent system toluene/ethyl acetate (8:2, v/v) to give three fractions of 390 mg (Z/E isomer ratio of 1:4), 740 mg (mixture) and 190 mg (Z-isomer), respectively.
F: 3-amino-2-methvlamino-propionaldehvde O-methvloxime dihydrochloride. Hydrogen was passed through a solution of N,N'- (dibenzyloxycarbonyl)-3-amino-2-methy1-amino-propion- aldehyde O-methyloxime (350 mg, 0.88 mmol; Z/E ratio of 1:4 ) in dry methanol (15 ml) also containing 2 equi¬ valents of hydrochloric acid and palladium (10% w/w) on activated carbon (35 mg). After 4 hours nitrogen was passed through the solution for 0.5 hour. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 3-amino-2-methylamino-propionaldehyde o- methyloxime dihydrochloride in quantitative yield.
G: 1.4.5.6-tetrahvdro- -pyrimidine carboxaldehvde
O-methvloxime.
A solution of 3-amino-2-methylamino-propionaldehyde
O-methyl oxime dihydrochloride (170 mg, 0.84 mmol) and tri ethyl orthofor ate (10 ml) in dry methanol (25 ml) was refluxed for 24 hours. The mixture was evaporated in vacuo to afford a syrup (120 m , 77%), which solidified on standing. The Z/E ratio was 1:4.
Example 2 fEl-1. .5.6-tetrahvdro-5-pyrimidinecarboxaldehyde o-ethyloxime hydrochloride
A: methvl 1.4.5. -tetrahvdro-5-Pvrimidine carboxvlate A solution of methyl 3-amino-2-methylaminopropionate dihydrochloride (8.68 g, 42.3 mmol), prepared as des¬ cribed in Example IB, and trimethyl orthoformate (50 ml) in dry methanol (250 ml) was refluxed for 18 hours, after which the mixture was evaporated to drynesε. Crystallization of the residue from methanol/ethyl acetate gave methyl 1,4,.5,6-tetrahydro-5-pyrimidine carboxylate (5.5 g, 73%) as a yellow solid.
B:1.4.5.6-tetrahvdro-5-pvrimidine-carboxaldehvde
To a cooled (-78°C) suspension of methyl 1,4,5,6- tetrahydro-5-pyrimidine carboxylate (1.5 g, 8.40 mmol) in dry dichloromethane (100 ml) 2.5 equivalents of cold (-78°C) diisobutylaluminum hydride (21 ml of a 1M solution in dichloromethane) was added dropwise. The reaction mixture was stirred for 3 hours and then quenched with cold (-78°C) methanol (5 ml). Then water (3 ml) was added, followed by methanol (20 ml), upon which the reaction mixture was allowed to warm to -20"C to give a solution of 1,4,5,6-tetrahydro-5-pyrimidine- carboxaldehyde. The in situ generated aldehyde was imme- diately used for the preparation of an oxime.
C: (E1-1.4.5.6-tetrahydro-5-pyrimidinecarboxaldehvde
O-ethvloxime hydrochloride
O-Ethyl hydroxylamine (819 mg, 8.40 mmol) was added to a solution of in situ generated 1,4,5,6-tetrahydro-5- pyrimidinecarboxaldehyde (Example 2B; 8.40 mmole) at -20 C. The reaction mixture was stirred for 20 hours at room temperature. Then the aluminum salts were filtered off and the filtrate was evaporated. The crude mixture contained a small amount of methyl 1,4 ,5,6-tetrahydro-5- pyrimidine carboxylate, which was removed by treatment with sodium hydroxide in water. Subsequent extraction with dichloromethane and treatment with methanolic hydrogen chloride gave 500 mg of 1,4,5,6-tetrahydro-5- pyrimidinecarboxaldehyde O-ethyloxime hydrochloride (27%) as the E-isomer. M.p.: 139 °C
Example 3
(E■-1.4.5.6-tetrahvdro-5-pvrimidinecarboxaldehvde
O- (1-methvlethvl )oxime hydrochloride
0-(l-Methylethyl)-hydroxylamine was reacted with in situ generated 1,4,5,6-tetrahydro-5-pyrimidinecarboxaldehyde using the method as described in Example 2C to give (E)- 1,4,5,6-tetrahydro-5-pyrimidinecarboxaldehyde O-(l-methylethyl)oxime hydrochloride. M.p.: 133 °C.
Example 4
1.4.5.6-tetrahvdro-4-pvrimidine carboxaldehvde O- methyloxime
A: m thyl. 1.4.5.6-tetrahvdro-4-pvrimidine carbφxylate hydrochloride
A solution of DL-2,4-diaminobutyric acid dihydro¬ chloride (49.7 g, 0.26 mol) and trimethyl orthofor ate (114 ml, 1.04 mol) in dry methanol (500 ml) was refluxed for 18 hours and subsequently evaporated to dryness. The residue was dissolved in dry methanol (500 ml) and cooled to 0°C. Thionylchloride (37.1 g, 0.31 mol) was added dropwise, then the solution was refluxed for 3 hours and subsequently evaporated to dryness. Toluene was added and the suspension was evaporated to dryness to leave methyl 1,4,5,6-tetrahydro-4-pyrimidine carbox¬ ylate hydrochloride (46.4 g, 100%) as a white solid.
B: 1.4.5.6-tetrahvdro-4-pyrimidine carboxaldehyde
To a cooled (-78°C) suspension of methyl 1,4,5,6- tetrahydro-4-pyrimidine carboxylate hydrochloride (2.0 g, 11.2 mmol) in dry dichloromethane (125 ml) 2.5 equi- valents of cold (-78°C) diisobutylaluminum hydride (28 ml of a 1M solution in dichloromethane) was added drop¬ wise. The reaction mixture was stirred for 3 hours and then quenched with cold (-78°C) methanol (5 ml). Then water (3 ml) was added, followed by methanol (20 ml), upon which the reaction mixture was allowed to warm to
-20°C to give a solution of crude 1,4,5,6-tetrahydro-4- pyrimidinecarboxaldehyde. The in situ generated aldehyde was immediately used for the preparation of an oxime.
C: 1.4.5.6-tetrahvdro-4-pvrimidine carboxaldehvde O m$thyJLς>χime
A solution of O-methyl hydroxyla ine hydrochloride (940 mg, 11.2 mmol) in methanol (25 ml) was added to a solution of in situ generated 1,4,5,6-tetrahydro- 4-pyrimidinecarboxaldehyde (Example 4B; 11.2 mmol) at
-20°C. The reaction mixture was stirred for 20 hours at room temperature. Then the aluminum salts were filtered off and the filtrate was evaporated to dryness to give 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde O-methyl- oxime (2.0 g, 100%) as a 1/1 Z/E-mixture. A solution of this product in ethanol was heated to reflux for 20 hours and then evaporated to dryness. Crystallization of the residue from methanol/ethyl acetate gave the E- isomer of 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde O-methyloxime hydrochloride (1.22 g, 61%). M.p.: 149 °C. Example 5
The following compounds were prepared using the methods as described in Example 4:
(E,Z) 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde O-ethyloxime monohydrochloride; 2:5 Z/E mixture; M.p. : 96°C.
(E,Z) 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde
O-2-propynyloxime monohydrochloride; 3:7 Z/E mixture; M.p.: 127 "C.
(E) 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde 0-(l-methylethyl)oxime monohydrochloride; M.p.: 110 °C.
(E,Z) 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde 0-(2-butenyl)oxime monohydrochloride; M.p.: Ill °C.
(E,Z) 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde O-(1,1-dimethylethyl)oxime (Z)-2-butenedioate; 1:5 Z/E mixture; M.p.: 122 "C.
(E,Z) 1,4,5,6-tetrahydro-4-pyrimidinecarboxaldehyde θ-(2-hexynyl)oxime monohydrochloride. 1:5 Z/E mixture.
Example 6
4.5.6.7-tetrahydro-lH-l .3-diazepine-4-carboxaldehvde O- ethyloxime
A: methyl 4.5.6,7-tetrahvdro-lH-l.3-diazepine-4- carbox¬ ylate hydrochloride
A solution of DL-ornithine dihydrochloride (30.4 g, 0.18 mol) and trimethyl orthoformate (59 ml, 0.54 mol) in dry methanol (600 ml) was refluxed for 18 hours and subsequently evaporated to dryness. The residue was dissolved in dry methanol (400 ml) and cooled to 0"C. Thionylchloride (53.7 g, 0.45 mol) was added dropwise, then the solution was refluxed for 3 hours and subsequently evaporated to dryness. Toluene was added and the suspension was evaporated to dryness to leave methyl 4,5,6,7-tetrahydro-lH-l,3-diazepine-4-carboxylate hydrochloride (27.5 g, 79%) as a white solid.
B: 4.5.6.7-tetrahvdro-lH- .3-diazepine-4-carboxaldehvde To a cooled (-78*C) suspension of methyl 4,5,6,7- tetrahydro-lH-1,3-diazepine-4-carboxylate hydrochloride
(2.0 g, 10.4 mmol) in dry dichloromethane (125 ml) 2.5 equivalents of cold (-78°C.) diisobutylaluminum hydride
(26 ml of a 1M solution in dichloromethane) was added dropwise. The reaction mixture was stirred for 3 hours and then quenched with cold (-78°C) methanol (5 ml).
Then water (3 ml) was added, followed by methanol (20 ml), upon which the reaction mixture was allowed to warm to -20°C to give a solution of crude 4,5,6,7-tetrahydro- lH-l,3-diazepine-4-carboxaldehyde. The in situ generated aldehyde was immediately used for the preparation of an oxime.
C: 4.5.6.7-tetrahvdro-lH-l.3-diazepine-4-carboxaldehvde O-methvloxime
A solution of O-methyl hydroxylamine hydrochloride (870 mg, 10.4 mmol) in methanol (25 ml) was added to a solution of in situ generated l,4,5,6-tetrahydro-lH-l,3- pyrimidine-4-carboxaldehyde (Example 5B; 10.4 mmol) at -20°C. The reaction mixture was stirred for 20 hours at room temperature. Then the aluminum salts were filtered off and the filtrate was evaporated to dryness to give 4,5,6,7-tetrahydro-lH-l,3-diazepine-4-carboxaldehyde O- methyloxime (85%) as a 1/1 Z/E-mixture. A solution of this product in ethanol was heated to reflux for 20 hours and then evaporated to dryness. Crystallization of the residue from methanol/ethyl acetate gave 4,5,6,7- tetrahydro-lH-1.3-diazepine-4-carboxaldehyde O-methyl- oxime hydrochloride (35%) as a 1/14 Z/E-mixture. M.p. : 126 °C.
Example 7
1- ( 1 .4 .5 . 6-tetrahvdro-5-pvrimidine ) ethanone O-methvl- oxjjiie
A: 4-phthalimido-3-phthalimidomethvl-butan-2-one
Ethylacetoacetate 1 (14.7 g, 113 mmol) was added to cooled (0°C) concentrated sulfuric acid (240 ml), then N-(hydroxymethyl)phtaliraide 2 (40 g, 226 mmol) was added. The reaction mixture was stirred for 24 hours at room temperature. The dark-red solution was poured on ice-water, the yellow solid was filtered and washed with water. The crude solid was stirred in hot acetone and after cooling collected by filtration to give 4-phthal- imido-3-phthalimidomethyl-butan-2-one (32 g, 75%; yellow solid) .
B: 4-Phthalimido-3-phthalimidomethvl-butan-2-one O-methvloxime To a solution of 4-phthalimido-3-phthalimidomethyl- butan-2-one (8.0 g, 21.3, mmol) in dichloromethane (120 ml), methoxylamine.HC1 (1.78 g, 21.3 mmol) and methanol (80 ml) were added. The reaction mixture was stirred for 60 hours at room temperature and then evaporated to dryness. The crude solid was stirred in hot acetone and after cooling collected by filtration to give 4- phthalimido-3-phthalimidomethyl-butan-2-one O-methyl- oxime (5.7 g, 66%) as a yellow solid.
C: 4-amino-3-aminomethyl-butan-2-one O-methyloxime Sodium (1.38 g, 60 mmol) was added to dry methanol (100 ml), whereupon hydroxylamine hydrochloride (1.95 g, 28 mmol) was added. After stirring for 15 minutes, 4- phthalimido-3-phthalimidomethyl-butan-2-one O-methyl- oxime (5.67 g, 14 mmol), dissolved in dry dichloro¬ methane (150 ml), was added. The dark-red solution was stirred for 3 hours at room temperature. A methanolic hydrogen chloride solution (60 mmol, 32 ml of a 1.9 M solution of hydrogen chloride in methanol) was added to the reaction mixture. Sodium chloride was filtered from the reaction mixture and the filtrate was evaporated to dryness. Crystallization from methanol/ ethyl acetate gave 4-amino-3-aminomethyl-butan-2-one O-methyloxime (2.2 g, 68%) as a yellow solid.
D: l-f1.4.5.6-tetrahvdro-5-pyrimidine)ethanone O-methyl¬ oxime (Zl-2-butenedioate. A solution of 4-amino-3-aminomethyl-butan-2-one O- methyloxime (2.2 g, 9.5 mmol) and trimethyl ortho ormate (15 ml) in dry methanol (60 ml) was refluxed for 20 hours and concentrated to dryness. The residue was partitioned between a solution of sodium hydroxide in brine (5 ml) and dichloromethane (100 ml), and then the organic layer was concentrated to leave crude 1- (1,4,5,6-tetrahydro-5-pyrimidine)ethanone O-methyloxime. To a solution of l-(l,4,5,6-tetrahydro-5-pyrimidine)- ethanone O-methyloxime (960 mg, 6.2 mmol) in methanol maleic acid (719 mg, 6.2 mmol) was added. Crystal¬ lization from methanol/ether gave l-(1,4 ,5,6-tetrahydro- 5-pyrimidine)ethanone O-methyloxime (Z)-2-butenedioate (910 mg, 36%) as a solid. M.p.: 138 °C.
Example 8. l-fl . .5.6-tetrahvdro-5-pyrimidine)ethanone O-ethyloxime
A: 4-phthalimido-3-phthalimidomethyl-butan-2-one O-ethyloxime
4-Phthalimido-3-phthalimidomethyl-butan-2-one (Example 7A) was condensed with O-ethylhydroxylamine hydrochloride using the ethoα as described in Example 7B to give 4-phthalimido-3-phthalimidomethyl-butan-2-one O-ethyloxime in a yield of 65%.
B: 4-amino-3-aminomethyl-butan-2-one O-ethyloxime
4-Phthalimido-3-phthalimidomethyl-butan-2-one O- ethyloxime was successively treated with sodium methanolate and methanolic hydrogen chloride using the method as described in Example 7C to a quantitative yield of 4-amino-3-aminomethyl-butan-2-one O-ethyloxime dihydrochloride.
C: l-fl .4.5.6-tetrahvdro-5-py imidine ,ethanone O-ethvl¬ oxime (Z)-2-butenedioate. Treatment of 4-amino-3-aminomethyl-butan-2-one o- ethyloxime dihydrochloride with trimethyl orthoformate using the method as described in Example 7D and subsequent treatment with maleic acid gave, following crystallisation from methanol/ether, l-(1,4 ,5,6-tetra- hydro-5-pyrimidine)ethanone O-ethyloxime (Z)-2-butene- dioate in 11% yield. M.p.: 137 °C.
Example 9 l-fl .4.5.6-tetrahydro-5-pyrimidine)ethanone O-2-propyn- yloxjme
A: 4-Phthalimido-3-phthalimidomethyl-butan-2-one o-propynyloxime 4-Phthalimido-3-phthalimidomethyl-butan-2-one
(Example 7A) was condensed with O-propargyl hydroxyl- amine hydrochloride using the method as described in Example 7B to give 4-phthalimido-3-phthalimidomethyl- butan-2-one O-2-propynyloxime in a yield of 70 %.
B: 4-amino-3-aminomethyl-butan-2-one O-2-propynyloxime 4-Phthalimido-3-phthalimidomethyl-butan-2-one 0-2- propynyloxime was successively treated with sodium methanolate and methanolic hydrogen chloride using the method as described in Example 7C to a quantitative yield of 4-amino-3-aminomethyl-butan-2-one O-2-prop- ynyloxime dihydrochloride.
C: 1- (1.4.5.6-tetrahvdro-5-pvrimidine )ethanone 0-2- propvnvloxi e ( ~ -2-butenedioate.
Treatment of 4-amino-3-aminomethyl-butan-2-one 0-2- propynyloxime dihydrochloride with trimethyl ortho¬ formate using the method as described in Example 7D and subsequent treatment with maleic acid gave, following crystallization from methanol/ether, 1-(1,4,5,6-tetra- hydro-5-pyrimidine)ethanone 0-2-propynyloxime (Z)-2- butenedioate. M.p.: 131 °C.
Example 10
Binding to muscarinic receptors.
A: Agon st binding.
Agonist binding potency of the compounds of the invention was determined using an in vitro test whereby the ability of a compound to inhibit the binding of the muscarinic agonist oxotremerine-M (Oxo-M) to high affinity agonist sites of muscarinic cholinergic receptors in rat cerebral cortex membranes is esta¬ blished (Freedman, S.B., Harley, E.A. and Iversen, L.L. , Br. J. Pharmacol. 93, 437-455, 1988).
Preparation of cerebral cortex membrane homoαenate: Male rats were decapitated and their cerebral cortices were dissected free and immediately placed into an ice-cold 0.32 M sucrose solution. At 4 °C the cortex was homogenized in 10 volumes (m/v) of ice-cold 0.32 M sucrose solution using the Potter-Elvehjem homogeniser (10 strokes up and down at 1000 rpm with the smooth Teflon pestle, with a clearance of 0.25 mm). The homogenate was centrifuged at 10.000 N/kg for 12 minutes. The supernatant was subsequently centrifuged at 400.000 N/kg for 10 minutes. The crude synaptosomal mitochondrial pellet was freshly used or stored at -70 °C (and subsequently used within 2 weeks). Just before use the pellet was resuspended in ice-cold 0.020 M HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethylsulfonic acid) ) buffer, pH 7.4, to give a protein concentration of approximately 350 μg/ml. Binding assay: A solution was prepared containing HEPES buffer (0.55 ml), 0.10 ml of a solution of the test compound in ultrapure water or 0.01 M hydrochloric acid (final concentration of test compounds ranged from 1 nM to 10 μM) and 0.05 ml of a solution of [methyl-3H]- oxotremorine-M acetate in' HEPES buffer (final concentration of approximately 0.5 nM) . Immediately af er the addition of 0.3 ml cerebral cortex membrane homogenate, the mixture was incubated, with shaking, for 40 minutes at 30 °C The incubation was terminated by rapid filtration of the whole volume through a glass fibre filter sheet (pre-soaked with a 0.05% (v/v) aqueous polyethyleneimine solution for 1 hour) using the Brandel cell harvester. The residue was rapidly washed with 20 ml of ice-cold sodiumchloride (9 g/1) solution for 15 seconds. The filter was transferred to a scintillation vial containing Picofluor 30 (5 ml), and the sample was counted for 4 min.
Non-specific Oxo-M binding was determined in assay mixtures containing 2 μM atropine. IC 50 values, the inhibitory concentration in mol/1 causing 50% displacement of specific binding, were determined from the inhibition data. Binding results for a number of compounds of the invention are presented in the Table as the pK^-value, the negative logaritm of K^. The affinity constant K^ for the binding of the test compound to the receptor was calculated from the formula K =IC50/(l+c/Kα) , wherein c is the concentration of labelled Oxo-M and Kd is the dissociation constant for the binding of Oxo-M to the receptor (calculated using the scatchard analysis).
B: Antagonist binding.
Binding to antagonist binding sites of muscarinic cholinergic receptors was determined using an in vitro test whereby the ability of a compound to inhibit the binding of the muscarinic antagonist pirenzepine (Pz) to a subclass of muscarinic cholinergic receptors in rat brain membrane homogenates is determined (Yamamura,H. and Snijder, S . , Proc.Natl. Acad. Sci. U.S.A., 7_i, 1725- 1729, 1974; Luthin, G.R. and Wolfe, B.B. , J. Pharmacol. Exp.. Therap. , 228. 648-655, 1984). Preparation of rat brain homogenate.
A male rat was decapitated and the whole brain was removed and placed on ice. The cerebellum was excised. The brain was homogenized in 10 volumes (m/v) of ice- cold 0.32 M sucrose solution using the Potter-Elvehjem homogenizer (10 strokes up and down at 1000 rp .). The homogenate was centrifuged at 10.000 N/kg for 10 minutes at 4 °C. The supernatant was separated and subsequently homogenized for 5 seconds using the Polytron homo¬ genizer. Just before use the supernatant was diluted with ice-cold 0.32 M sucrose solution to give a homo¬ genate containing 25 mg wet tissue/ml.
Pinflinq assay:
A solution was prepared containing 0.05 M phosphate buffer pH 7.4 (0.75 ml), 0.10 ml of a solution of the test compound in ultrapure water or in 0.1 M hydrochlo¬ ric acid followed by neutralization to pH 7-8 (final concentration of test compounds ranged from 10 nM to 0.1 mM) and 0.05 ml of a solution of [N-methyl-3H]-piren- zapine in phosphate buffer (final concentration in reaction mixture of approximately 1 nM) . Immediately after the addition of 0.1 ml rat brain membrane homogenate, the mixture was incubated, with occasional shaking, for 60 minutes at 25 "c. The incubation was terminated by rapid filtering of 0.80 ml of the incubated homogenate through a pre-wetted glass fibre filter. The residue was rapidly washed three times with 5 ml of ice-cold phosphate buffer. The filter was transferred to a scintillation vial containing Picofluor 30 (5 ml), and the sample was counted for 4 min. Non-specific pirenzepine (Pz) binding was determined in assay mixtures containing 1 μM atropine. Binding results for a number of compounds of the invention are presented in the Table as the pK^-value.
Table ,
Binding to muscarinic receptors,
Figure imgf000023_0001
Ratio = Ki(Pz)/Ki(Oxo-M)

Claims

Claims :
1. A 1,3-diazacycloalkyl oxime derivative having the general formula I
Figure imgf000024_0001
wherein R is hydrogen or lower alkyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, halogen, CN, lower alkyl or halogen substituted lower alkyl; R is lower alkyl, optionally substituted with halogen, or lower alkenyl or lower alkynyl; n is 1 or 2; and wherein the oxime group R3C=NOR4 is attached to one of the methylene groups of the 1,3-diazacycloalkyl ring; or a pharmaceutically acceptable salt thereof.
2. The 1,3-diazacycloalkyl oxime derivative of claim 1 wherein R and R are hydrogen, and R3, R4 and n have the previously given meanings, or a pharmaceutically acceptable salt thereof.
3. The 1,3-diazacycloalkyl oxime derivative of claim 1 or 2 for use in therapy.
4. The 1,3-diazacycloalkyl oxime derivative of claim 1 or 2 for use in treatment of Alzheimer's disease or other cognitive disorders.
5. A process for the preparation of the 1,3- diazacycloalkyl oxime derivative of claim 1 , characterized in that an oxime having formula II
, 5
wherein, R2, R3 , R4 and n have the meanings as given in claim l and the oxime group R3C=NOR4 is attached to one of the methylene groups, is condensed with an 15 orthoformate derivative having the formula
(alkyl-0)3C-R1, wherein R1 has the meaning given in claim 1 and alkyl is lower alkyl, after which the compound obtained is optionally converted into its pharmaceutically acceptable salt.
20
6. A pharmaceutical composition comprising the 1,3- diazacycloalkyl oxime derivative of claim 1 or 2 in admixture with pharmaceutically acceptable auxilliaries.
25
7. A use of the 1 ,3-diazacycloalkyl oxime derivative of claim 1 or 2 for the manufacture of a medicament which can be used for the treatment of cognition disorders, or for the treatment of cholinergic 30 anomalies.
PCT/EP1993/003324 1992-11-27 1993-11-25 1,3-diazacycloalkyl oxime derivatives WO1994012480A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010000396A1 (en) * 2008-07-03 2010-01-07 Merck Patent Gmbh Salts comprising a pyrimidinecarboxylic acid derivative for cosmetic use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0271798A2 (en) * 1986-12-08 1988-06-22 Warner-Lambert Company O-Substituted tetrahydropyridine oxime cholinergic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0271798A2 (en) * 1986-12-08 1988-06-22 Warner-Lambert Company O-Substituted tetrahydropyridine oxime cholinergic agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010000396A1 (en) * 2008-07-03 2010-01-07 Merck Patent Gmbh Salts comprising a pyrimidinecarboxylic acid derivative for cosmetic use

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