WO1994000448A1 - Azacyclic and azabicyclic hydroxylamines as muscarinic receptor agonists - Google Patents

Azacyclic and azabicyclic hydroxylamines as muscarinic receptor agonists Download PDF

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Publication number
WO1994000448A1
WO1994000448A1 PCT/EP1993/001493 EP9301493W WO9400448A1 WO 1994000448 A1 WO1994000448 A1 WO 1994000448A1 EP 9301493 W EP9301493 W EP 9301493W WO 9400448 A1 WO9400448 A1 WO 9400448A1
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Prior art keywords
azabicyclo
oct
compounds
compound
hydroxylamine
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PCT/EP1993/001493
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English (en)
French (fr)
Inventor
Enzo Cereda
Carlomaria Pellegrini
Angelo Sagrada
Giovanni Battista Schiavi
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Boehringer Ingelheim Italia S.P.A.
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Application filed by Boehringer Ingelheim Italia S.P.A. filed Critical Boehringer Ingelheim Italia S.P.A.
Priority to AU43253/93A priority Critical patent/AU4325393A/en
Publication of WO1994000448A1 publication Critical patent/WO1994000448A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a class of phar ⁇ macologically active azacyclic and azabicyclic alkyli ⁇ den hydroxylamines, to the process for their produc ⁇ tion, to the pharmaceutical compositions containing them.
  • the new compounds stimulate cortical cholinergic neurotransmission and therefore they are useful in the treatment of neurological and mental diseases whose clinical manifestations are due to impaired cholinergic transmission.
  • Cognitive disorders are characterized by symptoms of forgetfulness, confusion, memory loss and affective disturbance. They may arise as a consequence of the normal aging process or, under pathological conditions, from an organic brain disease. The etiology and the pathogenesis of those mental diseases are still unk ⁇ nown.
  • Acetylcholinesterase inhibitors such as physostigmine or tacrine, which increase the available amount of acetylcholine in the synaptic cleft by blocking the inactivating enzyme, have been proposed [Drachnan D.A. et al.. Arch. Neurol. 3_7_, 674 (1980); Summers .K. et al., New Engl. J. Med. 315, 1241 (1986)]. Also compounds which promote acetylcholine synthesis or its release from the containing vesicles have been tested [Etienne P. "Treatment of Alzheimer's disease with lecithin" in Alzheimer's disease, Reisberg B. Editor, Free Press New York, 1983; Davis H. P.
  • musca ⁇ rinic agonists possess quaternary ammonium groups (for instance carbachol) and therefore are expected not to cross the blood brain barrier following peripheral ad- ministration.
  • quaternary ammonium groups for instance carbachol
  • the target of recent research in the cholinomimetic field is the selective activation of the M.. muscarinic receptor subtype which is postsynapti- cally placed in the cholinergic neurones and, as said before, is still present in the damaged cerebral areas.
  • the inability to activate M_ and M ⁇ subtypes is highly sought as these latter are responsible for unwanted effects resulting from peripheral cholinergic stimulation.
  • This aspect is particularly relevant con ⁇ sidering that a large amount of a drug penetrating into the CNS, is however present in the periphery.
  • the lack of agonistic activity at M_ subtypes could be favourably accompanied by a weak antagonistic effect at the same receptor subtypes.
  • Mohn and M 3 muscarinic receptor subtypes owing to a different intrinsic efficacy.
  • certain of the compounds, here provided possess a selective stimulant action at the M, receptor sites relative to the M_ and M_, .
  • the selective stimulant effect at the M. sub- type is even increased by an antagonistic effect at the M_ subtype.
  • These new compounds can be useful in the treatment or in the prevention of disorders related to a central cholinergic deficit.
  • their use may be be ⁇ neficial in the treatment of cognitive disorders, age associated memory impairment, in different forms of de ⁇ mentia, in Alzheimer's disease, in Huntington's chorea, in tardive dyskinesia, in hyperkinesia, in Tourrette syndrome.
  • the compounds included in the present invention can be also of use as analgesics in the treatment of pain.
  • A represents the residue of a 4-8 membered azacyclo- alkane, or of a 7-9 membered azabicycloalkane, op ⁇ tionally N- substituted by a C, . alkyl; n represents 0 or 1; R, and R ⁇ represent independently hydrogen; linear or branched c ⁇ _ fi alkyl optionally substituted by alkoxy groups, alkylmercapto, CN or by halogen; C 2 _ 6 alkenyl; C__, alkynyl; halogen; aryl optio ⁇ nally substituted by halogen, C. ., alkyl, C, _, alkoxy; C ⁇ i ?
  • Non-limitative examples of azacycloalkane reside A are l-azacyclobut-3-yl, l-azacyclopent-3-yl, 1-azacy- clohex-3-yl, l-azacyclohex-4-yl and l-azacyclopent-3-yl groups, optionally N-substituted by C 1-3 alkyl.
  • Non-limitative examples of azabicycloalkane resi ⁇ due A are l-azabicyclo[2.2.l]-hept-3-yl, 1-azabicy- clo[2.2.2]-oct-3-yl, l-azabicyclo[3.2.l]-oct-3-yl, 1- azabicyclo[3.2.l]-oct-6-yl, l-azabicyclo[3.3.1]-non-3- yl, and 8-azabicyclo[3.2.l]-oct-3-yl groups optionally N-substituted by C, 3 alkyl.
  • R, and R 2 When in the compounds of formula (I) R, and R 2 re- present a linear or branched C, g alkyl group, it may, for example, be methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, 2-methylpentyl and the like.
  • R, and R- represent an alkyl groups optionally contai ⁇ ning a substituent, they may be, methoxyethyl, methyl- thioethyl, ethylthioethyl or cyanoethyl.
  • halo ⁇ gen means fluorine, chlorine, bromine and iodine.
  • Pre ⁇ ferred halogens are fluorine, chlorine and bromine, particularly fluorine and chlorine.
  • R, and R 2 re ⁇ present C 2 _ fi alkenyl group it may, for example, be al- lyl or 3-methyl-buten-2-yl.
  • R, and R 2 represent ⁇ 2 _ c alkynyl group it may, for example, be propargyl.
  • R, and R 2 represent an aryl group it may, for example, be phenyl, optionally substituted by one or more substituents selected from methyl, ethyl, methoxy, ethoxy, fluorine, chlorine or bromine.
  • R, and R_ represent a C fi _ 12 aralkyl group, it may, for example, be benzyl.
  • R, and R_ are heteroaryl, it may, for example, be a 5-6 membered ring containing 1-3 heteroa- toms, such as furan, pyridine, piridazine, oxadiazole.
  • R, and R ⁇ together with the carbon atom to which they are linked represent a 4 to 7 membered ring, it may, for example, be cyclobutane or cyclopentane.
  • Compounds according to the present invention which possess one or more asymmetric carbon atoms can exist as the optical active enantiomers with a defined configuration, or they can exist as a particular dia- stereoisomer or a diastereoisomeric mixture and also as a full racemic mixture.
  • some of the com ⁇ pounds of the present invention can exist as endo and exo isomers; the term endo is here referred to that possessing the hydroxylamine side chain on the opposite side of the methylene bridge -(CH 2 ) .
  • an additional isomerism of geometric type can be present.
  • a preferred group of compounds is the one formed by the compounds of general formula (I) wherein A is the residue of an azabicycloalkane, n is o, R, is hydrogen, lower C, ⁇ alkyl group or halogens and R_ is hydrogen or lower C,_, alkyl group optionally substituted by alkoxyl or halogen, 2 _ g alkynyl or halogen.
  • Particularly preferred compounds are the following: R(-)-0-(1-Azabicyclo[2.2.2]oct-3-yl)-N-ethylidenhydro- xylamine, hydrochloride (Compound 2)
  • the compounds of general formula (I) may, for example, be prepared by the following process which constitute a further feature of the present invention.
  • Compounds of formula (I) are obtained by reacting azacyclo or azabicyclo O-substituted hydroxylamine of formula (II) with a carbonyl derivative of formula ( III )
  • the reaction can be conveniently carried out in an hy- droxylic solvent selected from methanol, ethanol, iso- propanol, or in tetrahydrofuran or in toluene prefera- bly in methanol.
  • the reaction temperature is generally kept between 0°C and the boiling point of the solvent of choice, preferably at room temperature.
  • the interme ⁇ diates of formula (II) used as starting material may be used as free bases or, if desired, as salt addition de ⁇ rivatives.
  • the process is carried out by means of a suitable reducing agent such as hydrazine hydrate or ethanola- ine , preferably hydrazine hydrate in an alcoholic sol ⁇ vent such as methanol , ethanol and isopropanol , prefe- rably methanol .
  • a suitable reducing agent such as hydrazine hydrate or ethanola- ine , preferably hydrazine hydrate in an alcoholic sol ⁇ vent such as methanol , ethanol and isopropanol , prefe- rably methanol .
  • the temperature of the reaction process is kept between 10 °C and 80 °C preferably at room tempe ⁇ rature .
  • the phthaloyl derivatives of general formula ( IV) are conveniently obtained from the suitable azacyclic or azabicyclic hydroxy derivative of formula (V) and hydroxyphthalimide ( VI ) , according to a procedure known as the Mitsunobu reaction [Mitsunobu 0. , Synthe ⁇ sis 1 ( 1981) ] (V) (VI ) wherein A and n are as hereinbefore defined.
  • the condensation-dehydratation process is carried out in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at room temperature or below in the presence of triphenyl phosphine as dehydrating agent and utilizing DEAD (diethylazodicarboxylate) as activating agent.
  • anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at room temperature or below in the presence of triphenyl phosphine as dehydrating agent and utilizing DEAD (diethylazodicarboxylate) as activating agent.
  • the compounds of general formula (I) can be prepared by reacting a com- pound of formula (VII) with an oxime of formula (VIII)
  • Oximes of formula (VIII) are obtained by reacting carbonyl com ⁇ pound of formula (III) previously described with hy- droxylamine hydrochloride in methanol at room tempera- ture, according to a well known procedure (Organic Fun ⁇ ctional Groups Preparation, Vol. Ill Sec. Edition by Sadler and Karo, Academic Press S. Diego, 1989).
  • the compounds of general formula (I) may be, if desired, converted into the corresponding salts of phy- siologically acceptable inorganic or organic acid by conventional methods, for example by reacting the com ⁇ pounds as bases with a solution of the corresponding acid in a suitable solvent.
  • salts of physiologically acceptable acids are those formed with hydrochloric, fumaric, ma- leic, succinic, citric, tartaric, phosphoric, sulphu ⁇ ric, salicylic, lactic, gluconic, aspartic or methane- sulphonic acid [see for example Berg S.M. et al. "Pharmaceutical "Salts" in J. Pharm. Sci. 6, 1 (1977)].
  • Particularly preferred acids include for example hydrochloric, tartaric and fumaric acid.
  • the new com ⁇ pounds of formula (I) have interesting pharmacological properties owing to their capacity to stimulate the different muscarinic receptor subtypes M.,, M 2 and M 3 with an intrinsic efficacy which is peculiar to each subtype. Therefore the new compounds are therapeuti ⁇ cally useful in the treatment or in the prevention of disorders related to a central cholinergic deficit. In particular their use may be beneficial in the treatment of cognitive disorders, age associated memory impair ⁇ ment, in different forms of dementia, in Alzheimer's disease, in Huntington's chorea, in tardive dyskinesia, in hyperkinesia, in Tourette syndrome. Moreover, as centrally acting muscarinic agents, the compounds in ⁇ cluded in the present invention can be also of use as analgesics in the treatment of pain.
  • the compounds of the present invention can be ad ⁇ ministered orally, parenterally or rectally at a daily dose of 0.01 to 100 mg/kg of body weight, preferably about 0.5 to 10 mg/kg, and may be administered on a re ⁇ gimen of 1 to 4 times a day.
  • the pharmaceutical formulations which constitute a further feature of the present invention comprise ta- blets, pills, capsules, powders, granules, sterile pa ⁇ renteral solutions or suppositories.
  • a suitable pharmaceu- tic carrier such as corn starch, lactose, sorbitol, ma- gnesium stearate, etc.
  • the liquid forms in which the novel compounds may be incorporated for orally admini ⁇ stration or injection include aqueous solutions, fla ⁇ voured syrup and emulsions with oils or other vehicles. Also dispersing or suspending agents are of use. It may be advantageous, in order to prevent pe ⁇ ripheral side effects, to include in the pharmaceutical composition a peripherally acting cholinergic antago ⁇ nist such as N-methylscopolamine, or glycopyrrolate or propantheline.
  • the affinity of the compounds (I) for the M. , Mlois and M- muscarinic receptor subtypes was assessed "in vitro" by receptor binding studies in three tissues en ⁇ dowed with M. , M 2 and M 3 receptor subtypes (rat cere ⁇ bral cortex, heart and submandibular glands, respecti- vely) .
  • the potency and the intrinsic activity of the compounds of formula (I) at M.,, M 2 and M., receptor sub ⁇ types was checked in three functional models: the rat superior cervical ganglion (M.), the guinea pig atrium (M 2 ) and the guinea pig ileum ( 3 ).
  • Receptor binding studies were checked "in vitro" by receptor binding studies in three tissues en ⁇ dowed with M. , M 2 and M 3 receptor subtypes (rat cere ⁇ bral cortex, heart and submandibular glands, respecti- vely) .
  • Rat tissues were removed, cle ⁇ aned, homogenized (w/v: cerebral cortex, 1:100; whole heart, 1:200; submandibular salivary glands, 1:200) with an Ultra- urrax at maximal speed for 30 s, fol- lowed by use of a Potter-Elvehjem homogenizer (30 strokes), in Na + -Mg 2+ -HEPES buffer, pH 7.4 (nM: NaCl, 100; MgCl 2 , 10; HEPES, 20), and filtered through two layers of cheesecloth.
  • Binding Experiments. Binding curves for the different compounds were derived indirectly from competition ex-
  • Radioactivity was then counted after addition of 4 ml of liquid scin- tillation solution (Lipoluma, Lumac). Assays were car ⁇ ried out in triplicate and the nonspecific binding was defined as the radioactivity bound or entrapped in the pellet when the incubation medium contained 1 ⁇ M 3-qui- nuclidinyl benzylate racemic mixture (QNB) . Nonspecific binding averaged less than 30% and 10%, respectively.
  • the inhibition constants (Ki) were calculated after correction for the radioligand occupancy shift with the equation of Cheng and Prusoff (see Cheng Y. et al., Biochem. Pharmacol. 22 ⁇ , 3099, 1973). The results are reported in Table I.
  • Superior cervical ganglia were excised from male Sprague-Dawley rats, weighing 150-200 g, which had been anaesthetized with urethan (1.2 g/kg i.p.). Each gan ⁇ glion was desheathed under a microscope and then sub ⁇ merged in a three compartments bath. The ganglion body was situated in the central compartment and the pregan- glionic (cervical sympathetic) and postganglionic (internal carotid) trunks protruded through greased slots into two outer chambers. The central compartment (volume approx.
  • the me ⁇ dium was an aqueous solution containing (mM) : NaCl 124.1, KC1 4.8, NaHC0 3 24.8, CaCl 2 2.5, MgS0 4 1.2, KH 2 P0 4 1.2, glucose 10.
  • one agonist was superfused for 75 sec periods in increasing semi-logarithmic molar concentra- tion units (e.g. 1, 3, 10 ⁇ M) until the maximum re ⁇ sponse was evoked. These applications were usually made at 10-15 min intervals, but longer intervals were used in case of a slower return to the base-line.
  • pirenzepine was superfu ⁇ sed at 0.1 ⁇ M for 60 min, followed by re-determination of the agonist concentration-response curve in the pre ⁇ sence of pirenzepine in the superfusion medium.
  • the concentration of agonist producing 50%, of its maximal response was calculated by the least squares li ⁇ near regression analysis applied to the first concen ⁇ tration-response curve.
  • the relative maximum was obtained by comparing the agonist maximum response to the standard maximum response to 1 ⁇ M muscarine taken as 1.
  • the dose-ratio was calculated at the EC 50 level from the rightward displacement by pirenze ⁇ pine of the concentration-response curve to the ago ⁇ nist, after checking for parallelism of the curves.
  • RM Relative maximum, in comparison with the ef ⁇ fect of 1 ⁇ M muscarine taken as 1
  • Example 3 a) N-methyl-N-(ethoxy carbonylmethyl)-5-aminopenta- noic acid, ethyl ester 5-bromopentanoic acid ethyl ester (30 g) was added portionwise to a well stirred suspension of sarcosine hydrochloride (22 g) and triethylamine (29 g) in to ⁇ luene (220 ml). The reaction mixture was refluxed 20 hours, then cooled at 5°C. A solution of 5% aqueous hy ⁇ drochloric acid (200 ml) was added, the organic layer separated and discharged.
  • Method of preparation the active ingredient, lac- tose and a portion of corn starch were mixed and granu ⁇ lated to a 10% corn starch paste. The resulting granu ⁇ lation is sieved, dried and blended with the remainder of the corn starch and magnesium stearate. The resul ⁇ ting granulation was then compressed into tablets con ⁇ taining 50 mg and 100 mg of the active ingredient per tablet.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/EP1993/001493 1992-06-26 1993-06-14 Azacyclic and azabicyclic hydroxylamines as muscarinic receptor agonists WO1994000448A1 (en)

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ITMI921571A IT1255179B (it) 1992-06-26 1992-06-26 Azaciclo e azabiciclo alchiliden idrossilamine
ITMI92A001571 1992-06-26

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AU (1) AU4325393A (enrdf_load_stackoverflow)
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MX (1) MX9303443A (enrdf_load_stackoverflow)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0805153A1 (en) * 1996-04-30 1997-11-05 Pfizer Inc. Novel muscarinic receptor agonists
WO2009125434A3 (en) * 2008-04-07 2010-04-15 Cadila Healthcare Limited Oxime derivatives, process for their preparation, pharmaceutical composition containing the same and medicinal use thereof
US10428056B2 (en) 2015-06-26 2019-10-01 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10548899B2 (en) 2015-10-20 2020-02-04 Takeda Pharmaceutical Company Limited Quinazolinone and benzotriazinone compounds with cholinergic muscarinin M1 receptor positive allosteric modulator activity

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19547759A1 (de) * 1995-12-20 1997-06-26 Basf Ag Stabilisierte Hydroxylaminlösungen

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0338723A1 (en) * 1988-04-15 1989-10-25 Beecham Group Plc Novel compounds
EP0458214A1 (de) * 1990-05-19 1991-11-27 Boehringer Ingelheim Kg Bicyclische 1-Aza-cycloalkane

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0338723A1 (en) * 1988-04-15 1989-10-25 Beecham Group Plc Novel compounds
EP0458214A1 (de) * 1990-05-19 1991-11-27 Boehringer Ingelheim Kg Bicyclische 1-Aza-cycloalkane

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0805153A1 (en) * 1996-04-30 1997-11-05 Pfizer Inc. Novel muscarinic receptor agonists
WO2009125434A3 (en) * 2008-04-07 2010-04-15 Cadila Healthcare Limited Oxime derivatives, process for their preparation, pharmaceutical composition containing the same and medicinal use thereof
US10428056B2 (en) 2015-06-26 2019-10-01 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10899752B2 (en) 2015-06-26 2021-01-26 Takeda Pharmaceutical Company Limited 2,3-dihydro-4H-1,3-benzoxazin-4-one derivatives as modulators of cholinergic muscarinic M1 receptor
US10548899B2 (en) 2015-10-20 2020-02-04 Takeda Pharmaceutical Company Limited Quinazolinone and benzotriazinone compounds with cholinergic muscarinin M1 receptor positive allosteric modulator activity

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TW225523B (enrdf_load_stackoverflow) 1994-06-21
MX9303443A (es) 1994-01-31
CN1084516A (zh) 1994-03-30
ITMI921571A0 (it) 1992-06-26
IT1255179B (it) 1995-10-20
AU4325393A (en) 1994-01-24
SI9300331A (sl) 1993-12-31

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