OA17911A - Quinazolin-THF-amines as PDE1 inhibitors. - Google Patents

Quinazolin-THF-amines as PDE1 inhibitors. Download PDF

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OA17911A
OA17911A OA1201600249 OA17911A OA 17911 A OA17911 A OA 17911A OA 1201600249 OA1201600249 OA 1201600249 OA 17911 A OA17911 A OA 17911A
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amine
quinazolin
dimethoxy
tetrahydrofuran
compound
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OA1201600249
Inventor
Jan Kehler
Lars Kyhn Rasmussen
Morten LANGGÅRD
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H. Lundbeck A/S
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Publication of OA17911A publication Critical patent/OA17911A/en

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Abstract

The present invention provides QuinazolinTHF-amines as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

Description

FIELD OF THE INVENTION
The présent invention provides compounds that are PDE1 enzyme inhibitors and their use as a médicament, in particular for the treatment of neurodegenerative disorders and psychiatrie disorders. The présent invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced in full. The disclosures of these publications are hereby incorporated by référencé into this application to describe more fully the state of the art to which this invention pertains.
The second messenger cyclic Nucléotides (cNs), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play a major rôle in intracellular signal transduction cascade, by regulating cN-dependent protein kinases (PKA and PKG), EPACs (Exchange Protein Activated by cAMP), phosphoprotein phosphatases, and/or cN-gated cation channels. In neurons, this includes the activation of cAMP- and cGMP-dependent kinases and subséquent phosphorylation of proteins involved in acute régulation of synaptic transmission as well as in neuronal différentiation and survival. Intracellular concentrations of cAMP and cGMP are strictly regulated by the rate of biosynthesis by cyclases and by the rate of dégradation by phosphodiesterases (PDEs, EC 3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP by catalytic hydrolysis of the 3’-ester bond, forming the inactive 5’monophosphate. Since PDEs provide the only means of degrading the cyclic nucléotides cAMP and cGMP in cells, PDEs play an essential rôle in cyclic nucléotide signalling. The catalytic activities of PDEs provide for breakdown of cNs over a spectrum of concentrations in ail cells, and their varied regulatory mechanisms provide for intégration and crosstalk with myriad signalling pathways. Particular PDEs are targeted to discrète compartiments within cells where they control cN level and sculpt microenvironments for a variety of cN signalosomes (Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91: 651-690).
On the basis of substrate specificity, the PDE families can be divided into three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7, and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) the dual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.
Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique in that it is Ca2+dependently regulated via calmodulin (CaM, a 16 kDa Ca2+-binding protein) complexed with four Ca2+ (for review, Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91: 651-690). Thus, this family represents an interesting regulatory link between cyclic nucléotides and intracellular Ca2+. The PDE1 family is encoded by three genes: PDE1A (mapped on human chromosome 2q32), PDE1B (human chromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They hâve alternative promoters and give rise to a multitude of proteins by alternative splicing which differ in their regulatory properties, substrate affinities, spécifie activities, activation constants for CaM, tissue distribution and molecular weights. More than 10 human isoforms are identified. Their molecular weights vary from 58 to 86 kDa per monomer. The N-terminal regulatory domain that contains two Ca2+/CaM binding domains and two phosphorylation sites differentiate their corresponding proteins and modulate their biochemical functions. PDE1 is a dual substrate PDE and the PDE1 C-subtype has equal activity towards cAMP and cGMP (Km « 1-3 μΜ), whereas the subtypes PDE1A and PDE1B has a preference for cGMP (Km for cGMP « 1-3 μΜ and for cAMP ~ 10-30 pM).
The PDE1 subtypes are highly enriched in the brain and located especially in the striatum (PDE1B), hippocampus (PDE1A) and cortex (PDE1A) and this localization is conserved across species (Amy Bernard et al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is présent mainly in deep cortical layers 5 and 6 (output layers), and used as a specificity marker for the deep cortical layers. PDE1 inhibitors enhance the levels of the second messenger cNs leading to enhanced neuronal excitability.
Thus, PDE1 is a therapeutic target for régulation of intracellular signalling pathways, preferably in the nervous System and PDE1 inhibitors can enhance the levels of the second messengers cAMP/cGMP leading to modulation of neuronal processes and to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molécules. These neuronal plasticity enhancement properties together with the modulation of synaptic transmission make PDE1 inhibitors good candidates as therapeutic agents in many neurological and psychiatrie conditions. The évaluation of PDE1 inhibitors in animal models (for reviews see e.g. Blokland et al. Expert Opinion on Therapeutic Patents (2012), 22(4), 349-354; and Médina, A. E. Frontiers in Neuropharmacology (2011), 5(Feb.), 21) hâve suggested the potential for the therapeutic use of PDE1 inhibitors in neurological disorders, like e.g. Alzheimer's, Parkinson's and Huntington's Diseases and in psychiatrie disorders like e.g. Attention Déficit hyperactivity Disorder (ADHD), restless leg syndrome, dépréssion, narcolepsy, cognitive impairment and cognitive impairment associated with schizophrenia (CIAS). There hâve also been patent applications claiming that
PDE1 inhibitors are useful in diseases that may be alleviated by the enhancement of progesterone-signalling such as female sexual dysfunction.
The compounds of the invention may offer alternatives to current marketed treatments for neurodegenerative and/or psychiatrie disorders, which are not efficacious in ail patients. Hence, there remains a need for alternative methods of treatment.
SUMMARY OF THE INVENTION
PDE1 enzymes are expressed in the Central Nervous System (CNS), making this gene family an attractive source of new targets for the treatment of psychiatrie and neurodegenerative disorders.
The objective of the présent invention is to provide compounds that are PDE1 inhibitors, and as such are useful to treat neurodegenerative disorders and psychiatrie disorders. In a preferred embodiment the compounds are sélective PDE1 inhibitors.
Accordingly, the présent invention relates to compounds of formula (I)
(I) wherein
R-i is selected from the group consisting of H and Cf to C3 alkyl;
R2 is selected from the group consisting of H and C1-C3 alkyl, wherein the CfC3 alkyl optionally is substituted one or more times with one or more substituents selected from the group consisting of phenyl and C3-C6 cycloalkyl,
R3 is selected from the group consisting of H, methyl and ethyl,
R4 is selected from the group consisting of H, hydroxy, methoxy and ethoxy,
R5, R6 and R7 are H,
R8 is selected from the group consisting of H, methyl, ethyl and cyclopropyl
Rg is selected from the group consisting of H, methyl and ethyl and pharmaceutically acceptable acid addition salts of Compound I, racemic mixtures of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphie forms of Compound I as well as tautomeric forms of Compound I.
DETAILED DESCRIPTION OF THE INVENTION
EMBODIMENTS OF THE INVENTION
In a first embodiment (E1) the présent invention relates to compounds of formula (I) (Compound I)
Compound (I) wherein Ri is selected from the group consisting of H and CrC3 alkyl;
R2 is selected from the group consisting of H and CrC3 alkyl wherein the CrC3 alkyl optionally is substituted with phenyl or C3-C6 cycloalkyl;
R3 is selected from the group consisting of H, methyl and ethyl
R4 is selected from the group consisting of H, hydroxyl, methoxy and ethoxy and;
R5, R6 and R7 are H
R8 is selected from the group consisting of H, methyl, ethyl and cyclopropyl
Rg is selected from the group consisting of H, methyl and ethyl and pharmaceutically acceptable acid addition salts of Compound I, racemic mixtures of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphie forms of Compound I as well as tautomeric forms of Compound I.In an embodiment (E2) of (E1 ) R2 is H.
In an embodiment (E3) of (E1 ) R2 is CH3.
In an embodiment (E4) of (E3) R2 is substituted with phenyl or cyclopropyl.
In an embodiment (E5) of (E1) Rt is methyl.
In an embodiment (E6) of any of any of (E1 ) to (E5) the compound is a PDE1 inhibitor.
In an embodiment (E7) of any of (E1 ) to (E6) the compound is seiected from the compounds of Table 1
In an embodiment (E8) of any of (E1 ) to (E7) the compound is for use as a médicament.
In an embodiment (E9) of any of (E1 ) to (E7) the compound is for use in treating ADHD, schizophrenia or cognitive impairment associated with schizophrenia.
Embodiment (E10) is the use of the compound of any of (E1 ) to (E7) for the manufacture of a médicament for the treatment of ADHD schizophrenia or cognitive impairment associated with schizophrenia.
DEFINITIONS
PDE1 ENZYMES
The PDE1 isozyme family includes numerous splice variant PDE1 isoforms. It has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. In the context of the présent invention PDE1 and PDE1 enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes as well as their isoforms.
SUBSTITUENTS
As used in the context of the présent invention, the terms “halo” and “halogen” are used interchangeably and refer to fluorine, chlorine, bromine or iodine.
The terms ”CrC3 alkyl”, ”CrC4 alkyl”, C^Cs alkyl” and ”C-,-C6 alkyl” refer to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl.
The term “C3-C6 cycloalkyl” typically refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The expression “alkoxy” refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and nhexyloxy.
The term “aryl” refers to a phenyl ring, optionally substituted with halogen, C-|-C6 alkyl, alkoxy or halo(C1-C6)alkyl as defined above.
The term “heteroaryl” monocyclic- or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)triazolyl, (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furanyl, thiophenyl, isoxazolyl, thiazolyl, isoxazolyl, and oxazolyl.
A heteroaryl group can be unsubstituted or substituted with one or two suitable substituents. Preferably, the heteroaryl of this invention is a monocyclic 5 or 6 membered heteroaryl, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as “monocyclic 5 or 6 membered heteroaryl”
ISOMERIC FORMS
Where compounds ofthe présent invention contain one or more chiral centers reference to any ofthe compounds will, unless otherwise specified, coverthe enantiomerically or diastereomerically pure compound as well as mixtures ofthe enantiomers or diastereomers in any ratio.
For example reference to the compound 7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3yl)quinazolin-4-amine without any further spécification covers (R)-7,8-dimethoxy-N-methyl-N(tetrahydrofuran-3-yl)quinazolin-4-amine, (S)-7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3yl)quinazolin-4-amine as well as mixtures ofthe enantiomers in any ratio, including the racemic mixture (±)7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine.
Correspondingly, reference to the compound 7,8-dimethoxy-N-(-2-methyltetrahydrofuran-3yl)quinazolin-4-amine without any further spécification covers ail four covers ail four stereoisomeric variants as well as mixtures thereof in any ratio, including the racemic mixture.
The above also applies where compounds of the invention contain more than two chiral centers.
PDE1 INHIBITORS
In the context of the présent invention a compound is considered to be a PDE1 inhibitor if the amount required to reach the IC50 level of PDE1B is 5 micro molar or less, preferably less than 4 micro molar, such as 3 micro molar or less, more preferably 2 micro molar or less, such as 1 micro molar or less, in particular 500 nM or less. In preferred embodiments the required amount of PDE1 inhibitor required to to reach the IC50 level of PDE1B is 400nM or less, such as 300 nM or less, 200nM or less, 100 nM or less, or even 80 nM or less, such as 50 nM or less, for example 25 nM or less.
PHARMACEUTICALLY ACCEPTABLE SALTS
The présent invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.
Représentative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Représentative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, the contents of which are hereby incorporated by reference.
Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of this invention.
THERAPEUTICALLY EFFECTIVE AMOUNT
In the présent context, the term therapeutically effective amount of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adéquate to accomplish this is defined as therapeutically effective amount. Effective amounts for each purpose will dépend on the severity ofthe disease or injury as well as the weight and general state ofthe subject. Itwill be understood that determining an appropriate dosage may be achieved using routine expérimentation, by constructing a matrix of values and testing different points in the matrix, which is ail within the ordinary skills of a trained physician.
In the présent context, the term treatment and treating means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration ofthe active compound to alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prévention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (préventive) and therapeutic (curative) treatments are two separate aspects ofthe invention. The patientto be treated is preferably a mammal, in particular a human being.
PHARMACEUTICAL COMPOSITIONS
The présent invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The présent invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the spécifie compounds disclosed in the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.
The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parentéral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It wili be appreciated that the route wili dépend on the general condition and âge of the subject to be treated, the nature of the condition to be treated and the active ingrédient.
Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingrédient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, émulsions, suspensions, syrups and élixirs.
Pharmaceutical compositions for parentéral administration include stérile aqueous and nonaqueous injectable solutions, dispersions, suspensions or émulsions as well as stérile powders to be reconstituted in stérile injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage wili dépend upon the frequency and mode of administration, the sex, âge, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors évident to those skilled in the art.
The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
For parentéral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration.
The présent invention also provides a process for making a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of formula (I) and at least one pharmaceutically acceptable carrier or diluent. In an embodiment, of the présent invention, the compound utilized in the aforementioned process is one of the spécifie compounds disclosed in the Experimental Section herein.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable sait thereof. One example is an acid addition sait of a compound having the utility of a free base. When a compound of formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula (I) with a molar équivalent of a pharmaceutically acceptable acid. Représentative examples of suitable organic and inorganic acids are described above.
For parentéral administration, solutions of the compounds of formula (I) in stérile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonie with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subeutaneous and intraperitoneal administration. The compounds of formula (I) may be readily incorporated into known stérile aqueous media using standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, stérile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnésium stéarate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, 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 pharmaceutical compositions formed by combining the compounds of formula (I) and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules or tablets, each containing a predetermined amount of the active ingrédient, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid émulsion.
If a solid carrier is used for oral administration, the préparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the préparation may be in the form of a syrup, émulsion, soft gelatin capsule or stérile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingrédient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tableting machine préparé tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnésium stéarate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingrédients.
TREATMENT OF DISORDERS
As mentioned above, the compounds of formula (I) are PDE1 enzyme inhibitors and as such are useful to treat associated neurological and psychiatrie disorders.
The invention thus provides a compound of formula (I) or a pharmaceutically acceptable acid addition sait thereof, as well as a pharmaceutical composition containing such a compound, for use in the treatment of a neurodegenerative disorder, psychiatrie disorder or drug addiction in mammals including humans; wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drugrelated dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné; and wherein the psychiatrie disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and wherein the drug addiction is an alcohol, amphétamine, cocaïne, or opiate addiction.
The compounds of formula (I) or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the présent invention hâve utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the présent invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the présent invention. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the compounds of the présent invention. Accordingly, the pharmaceutical compositions of the présent invention include those that contain one or more other active ingrédients, in addition to the compounds of the présent invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
The présent invention provides a method of treating a mammal, including a human, suffering from a neurodegenerative disorder selected from a cognition disorder or movement disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).
This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) effective in inhibiting PDE1.
This invention also provides a method of treating a subject suffering from a psychiatrie disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of psychiatrie disorders that can be treated according to the présent invention include, but are not limited to, Attention Déficit Hyperactivity Disorder (ADHD) schizophrenia, for example ofthe paranoid, disorganized, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and the anxiety disorder is selected from panic disorder; agoraphobia; a spécifie phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
It has been found that the compounds of formula (I) or pharmaceutically acceptable salts thereof may advantageously be administered in combination with at least one neuroleptic agent (which may be a typical or an atypical antipsychotic agent) to provide improved treatment of psychiatrie disorders such as schizophrenia. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are résistant to other known treatments.
The présent invention thus provides a method of treating a mammal suffering from a psychiatrie disorder, such as schizophrenia, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I), either alone or as combination therapy together with at least one neuroleptic agent.
The term neuroleptic agent as used herein refers to drugs, which hâve the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenylbutylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., rispéridone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.
Particularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
The présent invention further provides a method of treating a subject suffering from a cognition disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of cognition disorders that can be treated according to the présent invention include, but are not limited to, Alzheimer's disease, multiinfarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné.
This invention also provides a method of treating a movement disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of movement disorders that can be treated according to the présent invention include, but are not limited to, Huntington's disease and dyskinesia associated with dopamine agonist therapy. This invention further provides a method of treating a movement disorder selected from Parkinson's disease and restless leg syndrome, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I).
This invention also provides a method of treating a mood disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula (I). Examples of mood disorders and mood épisodes that can be treated according to the présent invention include, but are not limited to, major dépressive épisode ofthe mild, moderate or severe type, a manie or mixed mood épisode, a hypomanie mood épisode; a dépressive épisode with a typical features; a dépressive épisode with melancholic features; a dépressive épisode with catatonie features; a mood épisode with postpartum onset; post-stroke dépréssion; major dépressive disorder; dysthymie disorder; minor dépressive disorder; premenstrual dysphorie disorder; post-psychotic dépressive disorder of schizophrenia; a major dépressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymie disorder. It is understood that a mood disorder is a psychiatrie disorder.
This invention further provides a method of treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) effective in treating said disorder.
Other disorders that can be treated according to the présent invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.
As used herein, and unless otherwise indicated, a neurodegenerative disorder or condition refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous System. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons. The term neurotrophic agent as used herein refers to a substance or agent that has some or ail of these properties.
Examples of neurodegenerative disorders and conditions that can be treated according to the présent invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cérébral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cérébral infarct;
hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
In one embodiment of the présent invention, the neurodegenerative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
In a further embodiment of the présent invention, the neurodegenerative disorder or condition is Huntington's disease.
Ail référencés, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety (to the maximum extent permitted by law).
Headings and sub-headings are used herein for convenience only, and should not be construed as limiting the invention in any way.
The use of any and ail examples, or exemplary language (including “for instance”, “for example”, “e.g.”, and “as such”) in the présent spécification is intended merely to better illuminate the invention, and does not pose a limitation on the scope of invention unless otherwise indicated.
The citation and incorporation of patent documents herein is done for convenience only, and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.
The présent invention includes ail modifications and équivalents of the subject-matter recited in the daims appended hereto, as permitted by applicable law.
COMPOUNDS OFTHE INVENTION
Compound number Compound PDE1C IC50 (nM) PDE1B IC50 (nM) PDE1A IC50 (nM)
1 7,8-Dimethoxy-N(tetrahydrofuran-3yl)quinazolin-4-amine 590 230 1200
1 Stereoisomer 1 7,8-Dimethoxy-N(tetrahydrofuran-3yl)quinazolin-4-amine 280 54 280
Compound number Compound PDE1C IC50 (nM) PDE1B IC50 (nM) PDE1A IC50 (nM)
1 Stereoisomer 2 7,8-Dimethoxy-N(tetrahydrofuran-3yl)quinazolin-4-amine 1200 600 1900
2 trans-N-(-2cyclopropyltetrahydrofuran-3yl)-7,8-dimethoxyquinazolin-4amine 1300 260 2400
3 Stereoisomer 1 7,8-dimethoxy-N-(-2m ethyltetrahyd rof u ra n-3yl)quinazolin-4-amine 3000 1200 2500
3 Stereoisomer 2 7,8-dimethoxy-N-(-2m ethyltetra hyd rof u ra n-3yl)quinazolin-4-amine 310 94 490
3 Stereoisomer 3 7,8-dimethoxy-N-(-2m ethyltetra hyd rofu ra n-3yl)quinazolin-4-amine 390 100 890
3 Stereoisomer 4 7,8-dimethoxy-N-(-2methyltetrahydrofuran-3yl)quinazolin-4-amine 270 120 580
4 (7,8-dimethoxy-N-methyl-N- (tetrahydrofuran-3- yl)quinazolin-4-amine 140 84 360
4 Stereoisomer 1 (R)-7,8-dimethoxy-N-methylN-(tetra hyd rofu ran-3yl)quinazolin-4-amine 140 80 370
4 Stereoisomer 2 (S)-7,8-dimethoxy-N-methyl- N-(tetrahydrofuran-3- yl)quinazolin-4-amine 140 80 1400
5 N-(2,3- dimethyltetrahydrofuran-3-yl)7,8-dimethoxyquinazolin-4amine 130 33 130
Compound number Compound PDE1C IC50 (nM) PDE1B IC50 (nM) PDE1A IC50 (nM)
5 Stereoisomer 1 N-(2,3- d i m ethyltetra hyd rof u ran-3-yl )- 7,8-dimethoxyquinazolin-4- amine 1100 300 590
5 Stereoisomer 2 N-(2,3- d i methyltetra hyd rof ura n-3-y I )- 7,8-dimethoxyquinazolin-4- amine 400 87 240
5 Stereoisomer 3 N-(2,3- d i m ethyltetra hyd rof u ra n-3-yl )- 7,8-dimethoxyquinazolin-4amine 67 6 33
5 Stereoisomer 4 N-(2,3dimethyltetrahydrofuran-3-yl)7,8-dimethoxyquinazolin-4amine 140 15 77
6 7,8-dimethoxy-N-(3methyltetra- hydrofuran-3yl)quinazolin-4-amine 160 62 150
6 stereoisomer 1 7,8-dimethoxy-N-(3methyltetra-hydrofuran-3yl)quinazolin-4-amine 400 110 290
6 Stereoisomer 2 7,8-dimethoxy-N-(3methyltetra- hydrofuran-3yl)quinazolin-4-amine 110 37 140
7 (S)-7,8-dimethoxy-N- (tetrahydrofuran-3- yl)quinazolin-4-amine n.d. n.d. n.d.
8 (S)-N-ethyl-7,8-dimethoxy-N(tetrahydrofuran-3yl)quinazolin-4-amine 510 250 480
Compound number Compound PDE1C IC50 (nM) PDE1B IC50 (nM) PDE1A IC50 (nM)
9 (S)-7,8-dimethoxy-N-propyl-N(tetrahydrofuran-3yl)quinazolin-4-amine 540 180 280
10 (S)-N-benzyl-7,8-dimethoxy- N-(tetrahydrofuran-3- yl)quinazolin-4-amine 1400 360 820
11 (S)-N-(cyclopropylmethyl )-7,8dimethoxy-N-(tetrahydrofuran3-yl)quinazolin-4-amine 1600 420 850
12 (R)-7,8-dimethoxy-N- (tetrahydrofuran-3- yl)quinazolin-4-amine n.d. n.d. n.d.
13 (R)-N-ethyl-7,8-dimethoxy-N- (tetrahydrofuran-3- yl)quinazolin-4-amine 1500 600 1200
14 (R)-7,8-dimethoxy-N-propylN-(tetra hyd rofu ra n-3yl)quinazolin-4-amine 360 180 270
15 (R)-N-(cyclopropylmethyl)-7,8dimethoxy-N-(tetrahydrofuran3-yl)quinazolin-4-amine 2100 820 2500
16 (R)-N-benzyl-7,8-dimethoxy- N-(tetrahydrofuran-3- yl)quinazolin-4-amine 1600 410 1200
17 trans-7,8-dimethoxy-N-4methoxytetrahydrofuran-3yl)quinazolin-4-amine 1300 520 2200
18 trans-4-((7,8dimethoxyquinazolin-4yl)amino)tetrahydrofuran-3-ol 2600 1300 2300
19 cis-4-((7,8dimethoxyquinazolin-4y I )am i no )tetra hyd rofu ra n-3-ol n.d. 840 4600
Compound number Compound PDE1C IC50 (nM) PDE1B IC50 (nM) PDE1A IC50 (nM)
20 Stereoisomer 1 N-(2,3- Dimethyltetrahydrofuran-3-yl)- 7,8-dimethoxy-N- methylquinazolin-4-amine 33 5 19
20 Stereoisomer 2 N-(2,3- Dimethyltetrahydrofuran-3-yl)- 7,8-dimethoxy-N- methylquinazolin-4-amine 27 4 26
20 Stereoisomer 3 N-(2,3- Di m ethyltetra hyd rof u ran-3-yl )7,8-dimethoxy-Nmethylquinazolin-4-amine 890 190 440
20 Stereoisomer 4 N-(2,3- D i m ethyltetra hyd rof u ra n-3-yl )7,8-dimethoxy-Nmethylquinazolin-4-amine 170 39 120
21 Stereoisomer 1 N-(2,2- d i m ethyltetra hyd rof u ra n-3-yl )7,8-dimethoxyquinazolin-4amine 2800 780 1500
21 Stereoisomer 2 N-(2,2- dimethyltetrahydrofuran-3-yl)- 7,8-dimethoxyquinazolin-4- amine 1600 260 1300
22 Stereoisomer 1 7,8-dimethoxy-N-methyl-N-(2m ethyltetra hyd rof u ra n-3yl)quinazolin-4-amine 79 28 110
22 Stereoisomer 2 7,8-dimethoxy-N-methyl-N-(2methyltetrahydrofuran-3yl)quinazolin-4-amine 55 35 210
22 Stereoisomer 3 7,8-dimethoxy-N-methyl-N-(2m ethyltetra hyd rof u ra n-3yl)quinazolin-4-amine 1500 430 1100
Compound number Compound PDE1C IC50 (nM) PDE1B IC50 (nM) PDE1A IC50 (nM)
22 Stereoisomer 4 7,8-dimethoxy-N-methyl-N-(2methyltetrahydrofuran-3yl)quinazolin-4-amine 780 1100 1500
23 Stereoisomer 1 7,8-dimethoxy-N-methyl-N-(3methyltetrahydrofuran-3yl)quinazolin-4-amine 500 70 240
23 Stereoisomer 2 7,8-dimethoxy-N-methyl-N-(3m ethyltetra hyd rof u ra n-3yl)quinazolin-4-amine 170 55 160
24 /V-(3-Ethyltetrahydrofuran-3yl)-7,8-dimethoxyquinazolin-4amine n.d. n.d. n.d.
25 Λ/-(2- Cyclopropyltetrahydrofuran-3yl)-7,8-dimethoxyquinazolin-4amine 1300 260 2400
Table 1: Compounds ofthe invention; n.d. means “not determined”
EXPERIMENTAL SECTION
PREPARATION OF THE COMPOUNDS OF THE INVENTION
General Methods
Analytical LC-MS data were obtained using one of the methods identified below.
Method 1: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7pm; 2.1x50mm; Column température: 60 °C; Solvent System: A = water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /water/trifluoroacetic acid (94.965:5:0.035); Method: Linear gradient elution with 10 A:B = 90:10 to 0:100 in 1.0 minutes and with a flow rate of 1.2 mL/min.
Method 2: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7pm; 2.1x50mm; Column température: 60 °C; Solvent System: A = water/formic acid (99.9:0.1) and B = acetonitrile /water/formic acid (94.9:5:0.1); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 1.0 minutes and with a flow rate of 1.2 mL/min.
Method 3: An Agitent 1200 LCMS System with ELS detector was used. Column: Agilent TC-C18 5 pm; 2.1x50mm; Column température: 50 °C; Solvent System: A = water/trifluoroacetic acid (99.9:0.1) and B = acetonitrile /trifluoroacetic acid (99.95:0.05); Method: Linear gradient elution with A:B = 99:1 to 0:100 in 4.0 minutes and with a flow rate of 0.8 mL/min.
Method 4: An Agilent 1200 LCMS System with ELS detector was used. Column: Agilent TC-C18 5 pm; 2.1x50mm; Column température: 50 °C; Solvent System: A = water/trifluoroacetic acid (99.9:0.1) and B = acetonitrile /trifluoroacetic acid (99.95:0.05); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 4.0 minutes and with a flow rate of 0.8 mL/min.
Method 5: An Agilent 1200 LCMS System with ELS detector was used. Column: XBridge ShieldRP18, 5 pm, 50x2.1mm; Column température: 40 °C; Solvent System: A = water/NH3*H2O (99.95:0.05) and B = acetonitrile; Method: Linear gradient elution with A:B = 95:5 to 0:100 in 3.4 minutes and with a flow rate of 0.8 mL/min.
Method 6: An Agilent 1200 LCMS System with ELS detector was used. Column: XBridge ShieldRP18, 5 pm, 50x2.1mm; Column température: 40 °C; Solvent System: A = water/NH3*H2O (99.95:0.05) and B = acetonitrile; Method: Linear gradient elution with A:B = 99:1 to 0:100 in 3.4 minutes and with a flow rate of 0.8 mL/min.
Préparative LC-MS-purification was performed on a PE Sciex API 150EX instrument with atmospheric pressure chemical ionization. Column: 50 X 20 mm YMC ODS-A with 5 pm particle size; Solvent System: A = water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /water/trifluoroacetic acid (94.965:5:0.035); Method: Linear gradient elution with A:B = 80:20 to 0:100 in 7 minutes and with a flow rate of 22.7 mL/minute. Fraction collection was performed by split-flow MS détection.
Préparative SFC was performed on a Thar 80 instrument. Exemplified conditions can be, but not limited to: Column AD 250 X 30mm with 20 pm particle size; Column température: 38 °C, Mobile phase: Supercritical CO2/ EtOH(0.2%NH3H2O) =45/55.
Example 1
7,8-Dimethoxy-N-(tetrahydrofuran-3-y!)quinazolin-4-amine:
To a solution of 4-chloro-7,8-dimethoxyquinazoline (1.5 g, 6.7 mmol) in DMF (30 mL) was added tetrahydrofuran-3-amine (698 mg, 8.01 mmol), DIPEA (2.3 mL, 13 mmol). Nitrogen was bubbled through the mixture for 5 min. The reaction was then heated at 100 °C for 2 h. The crude mixture was evaporated and the residue was dissolved in ethyl acetate (20 mL), and filtered. The solid was washed with ethyl acetate (10 mL) to give 7,8-dimethoxy-N(tetrahydrofuran-3-yl)quinazolin-4-amine 1.4 g (76%).
The racemate of 7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 1.4 g was purified by SFC séparation and numbered according to the order of elution:
Stereoisomer 1 (first eluting by SFC): 388 mg,
LC-MS (m/z) 276.1 (MH+) tR (minutes, method 3) = 1.82.
[a]20 D = -32 (c = 0.10 mg/mL, MeOH)
Stereoisomer 2 (second eluting by SFC): 413 mg
LC-MS (m/z) 276.1 (MH+) tR (minutes, method 3) = 1.81.
[a]2% = 23 (c = 0.10 mg/mL, MeOH)
Example 2
trans-N-(-2-cyclopropyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine: 4-Chloro-
7,8-dimethoxyquinazoline (200 mg, 0.890 mmol) and trans-2-cyclopropyl- tetrahydrofuran-3amine (170 mg, 1.34 mmol) were mixed in isopropanol (10 ml) and DIPEA (230 mg, 0.311 ml, 1.78 mmol). The reaction was heated in a microwave reactor for 40 min at 160 °C. After cooling to RT for a couple of hours a white precipitate was collected and dried overnight at 40 °C. Further purified by flash chromatography using a gradient of ethyl acetate and heptane to yield trans-N-(-2-cyclopropyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine 80 mg (29%).
LC-MS (m/z) 316.0 (MH+), tR (minutes, method 2) = 0.36.
Example 3
7,8-Dimethoxy-N-(-2-methyltetrahydrofuran-3-yl)quinazoIin-4-amine:
To a solution of 2-methyltetrahydrofuran-3-amine 2,2,2-trifluoroacetate (9.6 g, 45 mmol), 4chloro-7,8-dimethoxyquinazoline (5.0 g, 22 mmol) in DMF (200 mL) was added DIPEA(14.4 g, 111 mmol). The mixture was stirred at 120 °C overnight. The mixture was concentrated and the residue purified by prep-HPLC to afford 1.2 g (19%) of 7,8-dimethoxy-N-(-2methyltetrahydrofuran-3-yl)quinazolin-4-amine as a white solid.
A mixture of ail possible stereoisomers of 7,8-dimethoxy-N-(-2-methyltetrahydrofuran-3yl)quinazolin-4-amine (1.43 g, 4.90 mmol) was purified by SFC séparation and numbered according to their order of elution:
Stereoisomer 1 (first eluting by SFC): 213 mg,
LC-MS (m/z) 290.1 (MH+).
[o]20d = 21 (c = 0.1 mg/mL, MeOH)
Stereoisomer 2 (second eluting by SFC): 141 mg,
LC-MS (m/z) 290.1 (MH+).
[o]20d = -24 (c = 0.1 mg/mL, MeOH)
Stereoisomer 3 (third eluting by SFC): 58 mg,
LC-MS (m/z) 290.1 (MH+).
[α]2% = 65 (c = 0.1 mg/mL, MeOH)
Stereoisomer 4 (fourth eluting by SFC): 132 mg,
LC-MS (m/z) 290.1 (MH+).
[a]20 D = -54 (c = 0.1 mg/mL, MeOH)
7,8-Dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine: 4-Chloro-7,8dimethoxyquinazoline (200 mg, 0.890 mmol) and N-methyltetrahydrofuran-3-amine (180 mg,
1.78 mmol) were mixed in isopropanol (10 ml) and DIPEA (575 mg, 0.78 ml, 4.5 mmol). The mixture was heated in a microwave oven for 30 min at 150 °C. The reaction mixture was poured into H2O (20 mL), extracted with ethyl acetate (3x20 mL), the combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of ethyl acetate and ethyl acetate + 5% methanol to yield 7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 140 mg (54%).
LC-MS (m/z) 290.3 (MH+), tR (minutes, method 1) = 0.34.
(R)-7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:
To a solution of (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (390 mg, 1.42 mmol) in THF (20 mL) was added NaH (283 mg, 7.08 mmol, 60%) at 0 °C, and the mixture was stirred at 0 °C for 10 min. To the solution was added methyl iodide (1.0 g, 7.1 mmol) at 0°C. The reaction was allowed to warm 20°C and stirred for 2 hours. The solution was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine, dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (ethyl acetate/petroleum ether =1/10 to 2/1) to give (R)-7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 400 mg (97%) as a white solid
LC-MS (m/z) 290.1 (MH+), tR (minutes, method 6) = 1.753.
[a]2% = 19 (c = 0.1 mg/mL, CHCI3)
Stereoisomer 2 ^0 (S)-7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:
To a solution of (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (420 mg, 1.52 mmol) in THF (20 mL) was added NaH (305 mg, 7.63 mmol, 60%) at 0°C. The reaction was stirred at 0°C for 10 min. Methyl iodide (1.08 g, 7.63 mmol) was added at 0°C and the mixture allowed to warm to 20°C and stirred for 2 hours. The solution was quenched with sat.aq. NH4CI (0.3 mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine, dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted ethylacetate/petroleum ether=1/10 to 2/1) to give (S)-7,8dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 410 mg (93%) as a white solid. LC-MS (m/z) 290.1 (MH+), tR (minutes, method 6) = 1.767.
[a]20 D = -21 (c = 0.1 mg/mL, CHCI3)
Example 5
N-(2,3-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine: A mixture of 4chloro-7,8-dimethoxyquinazoline (8.4 g, 37 mmol), 2,3-dimethyltetrahydrofuran-3-amine (4.0 g, 35 mmol) and NaHCO3 (2.6 g, 31 mmol) in DMSO (120 mL) was stirred at 100 °C for 12 hours. The solution was poured into ice-water (200 mL), extracted with DCM (3x100 mL). The combined organic phases were washed with brine (3x10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and petroleum ether to give N-(2,3-dimethyltetrahydrofuran-3-yl)-7,8dimethoxyquinazolin-4-amine 4.0 g (43%) as a white solid.
A mixture of ail possible stereoisomers of N-(2,3-dimethyltetrahydrofuran-3-yl)-7,8dimethoxyquinazolin-4-amine 6.0 g was purified by SFC séparation and numbered according to their order of elution:
Stereoisomer 1 (first eluting by SFC): 536 mg,
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 1.98.
[a]2% = 25 (c = 0.10 mg/mL, MeOH)
Stereoisomer 2 (second eluting by SFC): 546 mg,
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 1.98.
[a]20o = -14 (c = 0.10 mg/mL, MeOH)
Stereoisomer 3 (third eluting by SFC): 920 mg,
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 2.00.
[a]20o = 22 (c = 0.10 mg/mL, MeOH)
Stereoisomer 4 (fourth eluting by SFC): 999 mg,
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 2.00.
[a]20 D = -20 (c = 0.1 mg/mL, MeOH)
Example 6
7.8- Dimethoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine: 4-Chloro-7,8dimethoxyquinazoline (200 mg, 0.890 mmol) and 3-methyltetrahydrofuran-3-amine (90 mg, 0.890 mmol) were mixed in isopropanol (10 mL) and DIPEA (345 mg, 466 pl, 2.67 mmol). The reaction was heated for 2 hours at 170 °C in a microwave oven. Conversion not complété as judged by LCMS. 3-Methyltetrahydrofuran-3-amine (90 mg, 0.89 mmol) was then added and mixture heated for 40 min at 170 °C in a microwave oven. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (3x20mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of ethyl acetate and heptane yielding 7,8dimethoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine 63 mg, (23%).
LC-MS (m/z) 290.2 (MH+), tR (minutes, method 2) = 0.33.
7.8- Dimethoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine (900 mg, 0.35 mmol) was purified by SFC séparation
The pure fractions were collected and solvent was evaporated under vacuum to afford
Stereoisomer 1 (first eluting by SFC): 400 mg (44%).
LC-MS (m/z) 290.1 (MH+), tR (minutes, method 3) = 1.945, ee% = 98.9%.
[a]2% = 11.67 (c = 0.1 mg/mL, MeOH)
Stereoisomer 2 (second eluting by SFC): 400 mg (44%).
LC-MS (m/z) 290.1 (MH+), tR (minutes, method 3) = 1.951, ee% = 97.7%.
[a]20 D = -12.00 (c = 0.1 mg/mL, MeOH)
Example 7
Ο (S)-7,8-Dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine: A solution of 4-chloro-7,8dimethoxyquinazoline (1.5 g, 6.7 mmol), (S)-tetrahydrofuran-3-amine hydrochloride (1.00 g, 8.00 mmol) and DIPEA (3.44 g, 26.7 mmol) in DMF (20 mL) was stirred at 100 °Cfor 3 hours. The solution was concentrated under vacuum. The residue was diluted with DCM (300 mL) and washed with brine (3x50 mL). The organic layer was evaporated and the residue was purified by prep-HPLC to afford (S)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 1.2 g (67%) as a white solid
Example 8 (S)-N-ethyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:
To a solution of (S)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (200 mg, 0.73 mmol) in THF (2 mL) was added NaH (60%, 58 mg, 2.4 mmol) at 0°C, then it was stirred at 0°C for 10 min. lodoethane (135 mg, 0.87 mmol) was added at 0°C and the reaction was warmed to 20°C and stirred 12 hours. The solution was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with ethylacetate (50 mL), washed with brine, dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted ethylacetate/petroleum ether=1/10 to 2/1) to give the (S)-N-ethyl-7,8dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 58 mg (26%) as a white solid.
LC-MS (m/z) 304.2 (MH+), tR (minutes, method 3) = 1.984.
Example 9
(S)-7,8-dimethoxy-N-propyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:
To a solution of (S)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (200 mg, 0.73 mmol) in THF (2 mL) was added NaH (60%, 58 mg, 2.4 mmol) at 0 °C, it was stirred at 0°C for 10 min. 1-lodopropane (148 mg, 0.87 mmol) was added to the reaction mixture at 0°C, then it was stirred at 20°C for 12 hours. The reaction was quenched with sat. aq. NH4CI (0.3 mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine, dried and concentrated under vacuum. The residue was purified by préparative LC-MS to give (S)-7,8-dimethoxy-N-propyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 40 mg (17%) as a white solid.
LC-MS (m/z) 318.2 (MH+), tR (minutes, method 3) = 2.176.
(S)-N-benzyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:
To a solution of (S)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (200 mg, 0.73 mmol) in THF (2 mL) was added NaH (58 mg, 2.4 mmol, 60%) at 0°C, then it was stirred at 0°C for 10 min. benzylbromide (150 mg, 0.87 mmol) was added at 0°C, then it was stirred at 20°C for 12 hours. The reaction was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with EA (50 mL), washed with brine, dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and heptane to give the (S)-N-benzyl-7,8-dimethoxy-N-(tetrahydrofuran-3yl)quinazolin-4-amine 60 mg (23%) as a white solid.
LC-MS (m/z) 366.2 (MH+), tR (minutes, method 4) = 1.640.
(S)-N-(cyclopropylmethyl)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:
To a solution of (S)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (100 mg, 0.36 mmol) in DMF (3 mL) was added NaH (100 mg, 2.5 mmol, 60%) at 0°C, then it was stirred at 0°C for 20 min. (bromomethyl)cyclopropane (58 mg, 0.44 mmol) was added at 0°C, then it was stirred at 20°C for 12 hours. The reaction was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine, dried and concentrated under vacuum. The residue was purified by préparative LC-MS to give the (S)-N-(cyclopropylmethyl)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 30 mg, (25%) as a white solid.
LC-MS (m/z) 330.0 (MH+), tR (minutes, method 3) = 1.834.
(R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazoIin-4-amine: A solution of 4-chloro-7,8dimethoxyquinazoline (1.5 g, 6.7 mmol), (R)-tetrahydrofuran-3-amine hydrochloride (1.00 g, 8.00 mmol) and DIPEA (3.44 g, 26.7mmol) in DMF (20 mL) was stirred at 100°C for 3 hours. The solution was concentrated under vacuum. The residue was diluted with DCM (300mL) washed with brine (3x50mL). The combined organic phases were evaporated and the residue was purified by prep-HPLC to afford (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4amine 1.2 g (67%) as a white solid
Example 13
(R)-N-ethyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine: To a solution of (R)-
7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (100 mg, 0.36 mmol) in THF (5 mL) was added NaH 60% (44 mg, 1.82 mmol) at 0°C, then stirred at 0°C for 10 min. To the solution was added iodoethane (283 mg, 1.82 mmol) at 0°C, then stirred at 20°C for 12 hours. The solution was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether=1/10 to 2/1) to give the (R)-N-ethyl-7,8-dimethoxy-N(tetrahydrofuran-3-yl)quinazolin-4-amine 36 mg (32%) as a white solid.
LC-MS (m/z) 304.1 (MH+), tR (minutes, method 5) = 1.720.
(R)-7,8-dimethoxy-N-propy]-N-(tetrahydrofuran-3-yl)quinazolin-4-amine: To a solution of (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (100 mg, 0.36 mmol) in THF (5 mL) was added NaH 60% (44 mg, 1.82 mmol) at 0°C, then stirred at 0°C for 10 min. Then 1iodopropane (309 mg, 1.82 mmol) was added to the solution at 0°C, the reaction was stirred at 20°C for 12 hours. The solution was quenched with sat. aq. NH4CI (0.3 mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50mL), washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent ethyl acetate/petroleum ether-=1/10 to 2/1) to give (R)-7,8-dimethoxy-N-propylN-(tetrahydrofuran-3-yl)quinazolin-4-amine 41 mg (35%) as a white solid.
LC-MS (m/z) 318.1 (MH+), tR (minutes, method 3) = 1.779.
Example 15
(R)-N-(cyclopropylmethyl)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine: Το a solution of (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (100 mg, 0.36 mmol) in DMF (5 mL) was added NaH 60% (44 mg, 1.82 mmol) at 0°C, then stirred at 0°C for 20 min. Then (bromomethyl)cyclopropane (246 mg, 1.82 mmol) was added to the solution at 0°C, then stirred at 20°C for 12 hours. The solution was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50mL), washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified prep-HPLC to give (R)-N-(cyclopropylmethyl)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 36 mg (32%) as a white solid.
LC-MS (m/z) 330.1 (MH+), tR (minutes, method 3) = 1.816.
(R)-N-benzyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine: To a solution of (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (100 mg, 0.36 mmol) in THF (5 mL) was added NaH 60% (73 mg, 1.82 mmol) at 0°C, then stirred at 0°C for 10 min. Then benzylbromide (311 mg, 1.82 mmol) was added to the solution at 0°C, then stirred at 20°C for 12 hours. The solution was quenched with sat. aq. NH4CI (0.3mL), and concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether=1/10 to 1/1) to give (R)-N-benzyl-7,8-dimethoxyN-(tetrahydrofuran-3-yl)quinazolin-4-amine 52 mg (45%) as a white solid.
LC-MS (m/z) 366.2 (MH+), tR (minutes, method 4) = 1.705.
Trans-7,8-dimethoxy-N-(4-methoxytetrahydrofuran-3-yl)quinazolin-4-amine:
4-Chloro-7,8-dimethoxyquinazoline (200 mg, 0.890 mmol) and trans-4-methoxytetrahydrofuran-
3-amine hydrochloride (164 mg, 1.07 mmol) were mixed in isopropanol (4 mL) and DIPEA (1270 pl, 7.27 mmol). The reaction was heated for 40 min at 160 °C under microwave irradiation. The reaction was poured into H2O (25 mL) and extracted with ethyl acetate (3x25 mL), the combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purified by flashchromatography using a gradient of heptane and ethyl acetate to yield trans-7,8dimethoxy-N-4-methoxytetrahydrofuran-3-yl)quinazolin-4-amine (220 mg, 0.721 mmol, 81 % yield).
LC-MS (m/z) 306.2 (MH+), tR (minutes, method 2) = 0.37.
trans-4-((7,8-dimethoxyquinazolin-4-yl)amino)tetrahydrofuran-3-ol:
4-Chloro-7,8-dimethoxyquinazoline (200 mg, 0.890 mmol) and 4-amino-tetrahydrofuran-3-ol hydrochloride (149 mg, 1.068 mmol) were mixed in isopropanol (3.6 mL) and DIPEA (1270 pl,
7.27 mmol). The mixture was heated in microwave oven for 40 min at 160 °C. The reaction was cooled to RT overnight, and the precipitate was isolated by filtration to yield trans-4-((7,8dimethoxyquinazolin-4-yl)amino)tetrahydrofuran-3-ol 214 mg (83 % yield)
LC-MS (m/z) 292.1 (MH+), tR (minutes, method 2) = 0.31.
Example 19
cis-4-((7,8-djmethoxyquinazolin-4-yl)amino)tetrahydrofuran-3-ol:
4-Chloro-7,8-dimethoxyquinazoline (200 mg, 0.890 mmol) and cis-4-amino-tetrahydrofuran-3-ol hydrochloride (149 mg, 1.07 mmol) were mixed in isopropanol (3.6 mL) and DIPEA (1270 pl,
7.27 mmol). The mixture was heated for 40 min at 160 °C in microwave oven. Cooled to RT and the solid precipitate was filtered of to yield cis-4-((7,8-dimethoxyquinazolin-4yl)amino)tetrahydrofuran-3-ol 224 mg (86%).
LC-MS (m/z) 292.1 (MH+), tR (minutes, method 2) = 0.31.
Example 20
N-(2,3-dimethyItetrahydrofuran-3-yl)-7,8-dimethoxy-N-methylquinazolin-4-amine:
To an ice-cold solution of N-(2,3-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxy- quinazolin-4amine (example 5) (800 mg, 2.64 mmol), in THF (50 mL) was added NaH (160 mg, 3.97mmol, 60% in minerai oil). The mixture was allowed to warm to 20 °C and stirred for 30 min. Mel (560 mg, 3.97mmol) was added and the reaction was stirred for a further 3 hrs. The solution was quenched with sat. NH4CI (aq. 2mL) at 0 °C, and concentrated under vacuum. The residue was diluted with DCM (50 mL), washed with brine (3x5mL), dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and petroleum ether to give the N-(2,3-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxy-Nmethylquinazolin-4-amine 580 mg (69%).
N-(2,3-Dimethyltetrahydrofuran-3-yl)-7,8-dimethoxy-N-methylquinazolin-4-amine 580 mg was purified by preparative-TLC (ethyl acetate/petroleum ether=2/1) to give racemic diastereomer 1
300 mg, (52%), and racemic diastereomer 2, 240 mg, (41%).
The racemate of diastereomer 1 (300 mg) was purified by SFC to afford:
Stereoisomer 1 (first eluting by SFC): 120 mg, (40%) 1H NMR (CDCI3 varian 400): δ 8.76 (s, 1 H), 7.71 (d, J =4.6 Hz, 1 H), 7.21 (d, J = 4.6 Hz, 1 H),
4.39- 4.36 (m, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 3.92-3.89 (m, 1H), 3.85-3.81 (m, 1H), 3.22 (s, 3H), 2.56-2.49 (m, 1 H), 2.31-2.23 (m, 1H), 1.60 (s, 3H), 1.37 (d, J =3.2 Hz, 3H).
LC-MS (m/z) 318.2 (MH+) tR (minutes, method 3) = 2.01.
[a]D 20 -35 (c = 0.10, MeOH).
Stereoisomer 2 (second eluting by SFC): 120 mg, (40%).
1H NMR (CDCI3 varian 400): δ 8.75 (s, 1 H), 7.71 (d, J =4.6 Hz, 1 H), 7.21 (d, J = 4.6 Hz, 1 H),
4.39- 4.35 (m, 1H), 4.08 (s, 3H), 4.03 (s, 3H), 3.92-3.89 (m, 1H), 3.85-3.81 (m, 1H), 3.19 (s, 3H), 2.55-2.49 (m, 1H), 2.31-2.23 (m, 1H), 1.61 (s, 3H), 1.37 (d, J =3.0 Hz, 3H).
LC-MS (m/z) 318.2 (MH+) tR (minutes, method 3) = 2.00.
[a]D 20 +40 (c = 0.10, MeOH).
The racemate of diastereomer 2 (240 mg) was purified by SFC to afford:
Stereoisomer 3 (first eluting by SFC): 100 mg (42%), 1H NMR (CDCI3 varian 400): 5 8.67 (s, 1H), 7.71 (d, J =4.8 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 4.80-4.79 (m, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 4.05-4.02 (m, 1H), 3.94-3.87 (m, 1H), 3.28 (s, 3H),
2.46- 2.38 (m, 1H), 2.18-2.14(m, 1H), 1.72 (s, 3H), 0.95 (d, J=3.2 Hz, 3H).
LC-MS (m/z) 318.2 (MH+) tR (minutes, method 3) = 1.99.
[a]D 20+10 (c = 0.10, MeOH).
Stereoisomer 4 (second eluting by SFC): 100 mg, (42%), 1H NMR (CDCI3 varian 400): 5 8.70 (s, 1H), 7.71 (d, J =4.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 4.83-4.78 (m, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 4.06-4.02 (m, 1H), 3.94-3.87 (m, 1H), 3.30 (s, 3H),
2.47- 2.39 (m, 1 H), 2.18-2.14 (m, 1 H), 1.71 (s, 3H), 0.95 (d, J =3 Hz, 3H).
LC-MS (m/z) 318.2 (MH+) tR (minutes, method 3) = 1.99.
[a]D 20-10 (c = 0.10, MeOH).
N-(2,2-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine:
Step 1: To a solution of methyl 2-hydroxy-2-methylpropanoate (10 g, 185 mmol) in THF (120 mL) was added NaH 60% in minerai oil (3.4 g, 84.7 mmol) at 0°C. The mixture was allowed to warm to 20 °C and stirred for 30 minutes. The solvent was removed under vacuum. A solution of methyl acrylate (8.0 g, 93 mmol) in DMSO (100 mL) was added. The mixture was stirred at 20 °C for 30 minutes. A 6 M solution HCl (80 mL) was added. The mixture was extracted with MTBE (3x50 mL). The organic layer was washed with sat. aqueous NaHCO3 (40 mL), then brine (40 mL), dried over Na2SO4 and evaporated under vacuum. The crude product of methyl
5,5-dimethyl-4-oxotetrahydrofuran-3-carboxylate (12 g) was used directly for step 2 without further purification.
Step 2: Methyl 5,5-dimethyl-4-oxotetrahydrofuran-3-carboxylate (5.0 g, 29 mmol) was dissolved in 12N HCl (30 mL). The mixture was stirred at 100 °C for 2 hours. Then allowed to cool to rt and pH was adjusted to pH 8 with sat. aqueous NaHCO3 and extracted with MTBE (3x30 mL). The combined organic phases were washed with water (2x30 mL), dried over Na2SO4 and evaporated under vacuum. The crude product of 2,2-dimethyldihydrofuran-3(2H)-one (1.1 g) was used in the next step.
Step 3: 2,2-Dimethyldihydrofuran-3(2H)-one (1.0 g, 8.8 mmol) and 2-methylpropane-2sulfinamide (1.1 g, 8.8 mmol) were dissolved in THF (30 mL). Ti(i-PrO)4 (2.9 g, 10 mmol) was added. The mixture was stirred at 60 °C for 8 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with water (2*50 mL). The organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel chromatography using a gradient of petroleum ether and ethyl acetate to give N-(2,2-dimethyldihydrofuran-3(2H)ylidene)-2-methylpropane-2-sulfinamide 900 mg (47%).
Step 4: N-(2,2-dimethyldihydrofuran-3(2H)-ylidene)-2-methylpropane-2-sulfinamide (900 mg,
4.1 mmol) was dissolved in THF (30 mL). NaBH4 (310 mg, 8.2 mmol) was added at 0°C. The reaction was then stirred at 20°C for 1 hr. The mixture was quenched with aqueous sat. NH4CI (0.5 mL) and diluted with ethyl acetate (100 mL) and washed with water (30 mL). The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product (700 mg) was used directly in the next step.
Step 5: N-(2,2-dimethyltetrahydrofuran-3-yl)-2-methylpropane-2-sulfinamide (400 mg, 1.80 mmol) was dissolved in 12 M HCl (80 mL). The mixture was stirred at 50 °C for 2 hrs. The reaction mixture was basified with sat. aqueous NaHCO3 to pH=8 and extracted with DCM (3x10 mL). The combined organic phases were washed with water (2x10 mL), dried over Na2SO4 and evaporated under vacuum. The crude product of 2,2-dimethyltetrahydrofuran-3amine (209 mg) was used directly in the next step.
Step 6: A mixture of 2,2-dimethyltetrahydrofuran-3-amine (209 mg, 1.80 mmol), 4-chloro-7,8dimethoxyquinazoline (500 mg, 1.80 mmol) and DIPEA (470 mg, 3.60 mmol) in DMF (15 mL) was stirred at 100°C for 1 hr. The solvent was removed under vacuum. And the residue was dissolved in DCM (50 mL) and washed with water (3x15 mL). The organic phase was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel chromatography using a gradient of DCM and MeOH to give N-(2,2-dimethyltetrahydrofuran-3-yl)-7,8dimethoxyquinazolin-4-amine 75 mg (13%).
The racemate of N-(2,2-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine 75 mg was purified by SFC séparation and numbered according to their order of elution:
Stereoisomer 1 (first eluting by SFC): 30 mg (40%)
LC-MS (m/z) 304.2 (MH+) tR (minutes, method 3) = 1.95.
[a]D 20 -74 (c = 0.10, MeOH).
Stereoisomer 2 (second eluting by SFC) : 30 mg (40%)
LC-MS (m/z) 304.2 (MH+) tR (minutes, method 3) = 1.95. [a]D 20 +67 (c = 0.10, MeOH).
Example 22
7,8-dimethoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yI)quinazolin-4-amine:
Step 1: To a solution of 2-methyltetrahydrofuran-3-amine hydrochloride (mixture of ail four possible stereoisomers) (600 mg, 4.34 mmol) in DMF (10 mL) was added 4-chloro-7,8dimethoxyquinazoline (650 mg, 2.89 mmol) and DIPEA (1.2 g, 9.3 mmol). The reaction was stirred ovemight at 100°C. The reaction mixture was concentrated in vacuo and the residue was diluted with DCM (100 mL), washed with sat. NaHCO3(aq), then brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=10:1) to afford 700 mg of 7,8-dimethoxy- N-(2-methyltetrahydrofuran-3yl)quinazolin-4-amine (84%).
Step 2: A solution of 7,8-dimethoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine (750 mg, 2.59 mmol) in DMF/THF (2 mL/10mL) was cooled to 0°C. NaH (207 mg, 5.18 mmol, 60% in minerai oil) was added. The mixture was stirred at 0°C for 10 min. Then Mel (736 mg, 5.18 mmol) was added. After the addition, the mixture was allowed to warm to rt and stirred for 1h. The mixture was quenched with sat. NH4CI (aq), extracted with DCM (2x50mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The residue purified by preparative-HPLC to afford 250 mg of 7,8-dimethoxy-N-methyl-N-(2methyltetrahydrofuran-3-yl)quinazolin-4-amine (32%).
The mixture of ail possible stereoisomers of 7,8-dimethoxy-N-methyl-N-(2methyltetrahydrofuran-3-yl)quinazolin-4-amine 280 mg was purified by SFC séparation twice. The first run separated the two racemic diastereomers. Each of these racemates were then subjected to another SFC-purification and separated into enantiomers.
Stereoisomers 1: 55 mg 1H NMR (CDCI3 400 MHz): δ 8.64 (s, 1H), 7.76 (d, J=9.2 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 5.42 (brs, 1H), 4.20-4.14 (m, 1H), 4.07-4.01 (m, 7H), 3.74-3.71 (m, 1H), 3.36 (s, 3H), 2.44-2.39 (m, 1 H), 2.30-2.28 (m, 1 H), 1.28 (d, J=6.4 Hz, 3H).
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 1.57.
[a]D 20 -47 (c = 0.10, MeOH).
Stereoisomer 2:17 mg 1H NMR (CDCI3 400 MHz): δ 8.67 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 4.87 (brs, 1H), 4.15-4.08 (m, 1H), 4.03-3.96 (m, 8H), 3.29 (s, 3H), 2.50-2.43 (m, 1H), 2.10-2.03 (m, 1H), 1.23 (d, J=6.4 Hz, 3H).
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 1.56.
[a]D 20 +17 (c = 0.10, MeOH).
Stereoisomer 3: 45 mg 1H NMR (CDCI3 400 MHz): δ 8.70 (s, 1H), 7.75 (d, J=9.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 4.83 (brs, 1H), 4.20-4.14 (m, 1H), 4.08-4.01 (m, 8H), 3.30 (s, 3H), 2.55-2.47 (m, 1H), 2.16-2.07 (m, 1H), 1.28 (d, J=6.0 Hz, 3H).
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 1.57.
[a]D 20 -17 (c = 0.10, MeOH).
Stereoisomer 4: 25 mg 1H NMR (CDCI3 400 MHz): 5 8.58 (s, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 5.34-
5.33 (m, 1H), 4.13-4.09 (m, 1H), 4.01-3.95 (m, 7H), 3.68-3.65 (m, 1H), 3.30 (s, 3H), 2.38-2.34 (m, 1 H), 2.25-2.22 (m, 1 H), 1.23 (d, J=6.4 Hz, 3H).
LC-MS (m/z) 304.1 (MH+) tR (minutes, method 3) = 1.57.
[a]D 20 +56 (c = 0.10, MeOH).
Example 23
7,8-Dimethoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine:
To an ice-cold solution of 7,8-dimethoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine (300 mg, 1.03 mmol) in THF (15mL) was added NaH (60% in minerai oil) (60 mg, 1.5 mmol) at 0 °C and it was then allowed to RT. After stirring at rt for for 30 min. Mel (211 mg, 1.5 mmol) was added. Stirring was continued for 3 hrs. The solution was quenched by addition of sat. NH4CI (aq. 1mL), and subsequently concentrated under vacuum. The residue was diluted with DCM (60mL).The organic layer was washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography silica gel using a gradient of ethyl acetate and petroleum ether to give 7,8-dimethoxy-N-methyl-N-(3-methyltetrahydrofuran-
3-yl)quinazolin-4-amine 260 mg (86%).
The racemate of 7,8-dimethoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine 260 mg was purified by SFC séparation and numbered according to the order of elution:
Stereoisomer 1 (first eluting by SFC): 80 mg
LC-MS (m/z) 304.2 (MH+) tR (minutes, method 3) = 1.81.
[a]D 20 +15 (c = 0.10, MeOH).
Stereoisomer 2 (second eluting by SFC): 74 mg
LC-MS (m/z) 304.2 (MH+) tR (minutes, method 3) = 1.82.
[a]D 20-17 (c = 0.10, MeOH).
Example 24
/V-(3-Ethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine:
To a mixture of 4-chloro-7,8-dimethoxyquinazoline (100 mg, 0.445 mmol) and 3ethyltetrahydrofuran-3-amine hydrochloride (68 mg, 0.45 mmol) in isopropanol (1.5 mL) was added DIPEA (144 mg, 1.1 mmol). The mixture was heated under microwave irradiation at 170 °C for 80 min. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3x50mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The mixture was purified by flash chromatography using a gradient of ethyl acetate and heptane to yield 54 mg /V-(3-ethyltetrahydrofuran-3-yl)-7,8dimethoxyquinazolin-4-amine (48%).
LC-MS (m/z) 304.2 (MH+) tR (minutes, method 2) = 0.39.
Example 25
/V-(2-Cyclopropyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine:
To a mixture of 4-chloro-7,8-dimethoxyquinazoline (200 mg, 0.890 mmol) and 2cyclopropyltetrahydrofuran-3-amine (170 mg, 1.34 mmol) in isopropanol (10 mL) was added DIPEA (0.311 ml, 1.78 mmol) and the reaction was heated under microwave irradiation at 160 °C for 40 min. After cooling to room température for 4 hours a white precipitate was collected and dried in vacuo at 40°C overnight to yield 80 mg of trans-N-(2-Cyclopropyltetrahydrofuran-3yl)-7,8-dimethoxyquinazolin-4-amine (29%).
LC-MS (m/z) 316.0 (MH+) tR (minutes, method 2) = 0.36.
PDE1 INHIBITION ASSAY
PDE1A, PDE1B and PDE1C assays were performed as follows: the assays was performed in 60 pL samples containing a fixed amount ofthe PDE1 enzyml (sufficientto convert 20-25% of the cyclic nucléotide substrate), a buffer (50 mM HEPES pH 7.6; 10 mM MgCI2; 0.02% Tween20), 0.1 mg/ml BSA, 15 nM tritium labelled cAMP and varying amounts of inhibitors.
Reactions were initiated by addition ofthe cyclic nucléotide substrate, and reactions were allowed to proceed for 1 h at room température before being terminated through mixing with 20 pL (0.2 mg) yttrium silicate SPA beads (PerkinElmer). The beads were allowed to settle for 1 h in the dark before the plates were counted in a Wallac 1450 Microbeta counter. The measured signais were converted to activity relative to an uninhibited control (100%) and IC50 values were calculated using XIFit (model 205, IDBS).

Claims (8)

  1. Claims
    1. A compound having the structure
    Compound (I) wherein
    R-i is selected from the group consisting of H and Ci-C3 alkyl;
    R2 is selected from the group consisting of H and CpCs alkyl wherein the C-|-C3 alkyl optionally is substituted with phenyl or C3-C6 cycloalkyl;
    R3 is selected from the group consisting of H, methyl and ethyl
    R4 is selected from the group consisting of H,, hydroxyl, methoxy and ethoxy and;
    R5, R6 and R7 are H
    R8 is selected from the group consisting of H, methyl, ethyl and cyclopropyl
    Rg is selected from the group consisting of H, methyl and ethyl and pharmaceutically acceptable acid addition salts of Compound I, racemic mixtures of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphie forms of Compound I as well as tautomeric forms of Compound I.
  2. 2. The compound according to claim 1, wherein R2 is H.
  3. 3. The compound according to claim 1, wherein R2 is methyl.
  4. 4. The compound according to claim 3, wherein R2 is substituted with phenyl or cyclopropyl.
  5. 5. The compound according to claim 1 selected from the group consisting of
    7,8-Dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine trans-N-(-2-cyclopropyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine
    7.8- dimethoxy-N-(-2-methyltetrahydrofuran-3-yl)quinazolin-4-amine (7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (R) -7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (S) -7,8-dimethoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine
    N-(2,3-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine
    7.8- dimethoxy-N-(3-methyltetra- hydrofuran-3-yl)quinazolin-4-amine (S)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (S)-N-ethyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (S)-7,8-dimethoxy-N-propyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (S)-N-benzyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (S)-N-(cyclopropylmethyl)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (R)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (R)-N-ethyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (R)-7,8-dimethoxy-N-propyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (R)-N-(cyclopropylmethyl)-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (R)-N-benzyl-7,8-dimethoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine trans-7,8-dimethoxy-N-4-methoxytetrahydrofuran-3-yl)quinazolin-4-amine trans-4-((7,8-dimethoxyquinazolin-4-yl)amino)tetrahydrofuran-3-ol cis-4-((7,8-dimethoxyquinazolin-4-y))amino)tetrahydrofuran-3-ol
    N-(2,3-Dimethyltetrahydrofuran-3-yl)-7,8-dimethoxy-N-methylquinazolin-4-amine
    N-(2,2-dimethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine
    7.8- dimethoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine
    7.8- dimethoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine /V-(3-Ethyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine /V-(2-Cyclopropyltetrahydrofuran-3-yl)-7,8-dimethoxyquinazolin-4-amine
  6. 6. The compound of any of daims 1 to 5, wherein the compound is for use as a médicament.
    5
  7. 7. The compound of any of daims 1 to 5, wherein the compound is for use in treating
    ADHD, schizophrenia or cognitive impairment associated with schizophrenia
  8. 8. The compound of any of claim 1 to 5 for the manufacture of a médicament for the treatment of ADHD, schizophrenia or cognitive impairment associated with schizophrenia.
OA1201600249 2013-12-19 2014-12-18 Quinazolin-THF-amines as PDE1 inhibitors. OA17911A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA201300707 2013-12-19
DKPA201400249 2014-05-06

Publications (1)

Publication Number Publication Date
OA17911A true OA17911A (en) 2018-02-27

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