Patent Application
20080039458
The present invention relates to pyrazolopyrimidine derivatives, which can act as novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and their use as a medicament for the treatment of various diseases and/or prevention of disorders, e.g. neurological disorders, by administration of such substances.
Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron. L-glutamic acid is considered to be a major excitatory neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the other comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a subfamily of the G-protein-coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside the CNS e.g. in chronic pain states.
At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to low-molecular weight compounds, these eight receptors can be divided into three groups. MGluR1 and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions. MGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of which are negatively coupled to adenylyl cyclase, i.e., their activation causes a reduction in second messenger cAMP and thus a dampening of neuronal activity.
The mGluR5 modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms. Moreover, as these modulators can be both positive and/or negative mGluR5 modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
Of particular interest are those modulators which are negative mGluR5 modulators. Such modulators decrease the effects mediated through metabotropic glutamate receptors. Since a variety of patho-physiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and mGluR5 receptors are shown to be expressed in several areas of the CNS, modulators of these receptors could be therapeutically beneficial in the treatment of CNS diseases.
Therefore, mGluR5 positive or negative modulators may be administered to provide neuroprotection and/or disease modification in the following acute or chronic pathological conditions or to provide a symptomatological effect on the following conditions:
Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium.
The mGluR5 negative or positive modulators may also be administered to provide inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS. MGluR5 modulators may be administered to provide therapeutic intervention in neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, and other tumours.
Further indications for mGluR5 negative or positive modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement, learning impairment and/or neuroprotection.
Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment.
In the literature, several types of modulators of mGluR5 have already been described.
Furthermore, several types of pyrazolopyrimidine compounds have been disclosed in the prior art.
Various methods for preparing substituted pyrazolopyrimidine derivatives are known, e.g. from G. Hajos and Z. Riedl, Science of Synthesis 109, 613-678 (2002) and from Laura Bettinetti (Ph. D. Thesis, University of Erlangen, Germany, 2004).
In WO 2004/087153 various pyrazolopyrimidines of formula (XXII) are described, which can act as small molecule immune potentiators (SMIP) and which can be used e.g. for cancer treatment.
Furthermore, in WO 2004/089471, the use of substituted pyrazolo[1,5-a]pyrimidines or prodrugs or salts thereof are described for the preparation of a pharmaceutical composition for the treatment of disorders and diseases where it is desirable to modulate the activity of the enzyme 11βHSD1 or to inhibit 11βHSD1. In the document WO 2004/089471, pyrazolo(1,5-a)pyrimidine derivates of the following general formula (C) are disclosed:
In WO 2003/037900, further specific pyrazolopyrimidine compounds are described as inhibitors of ion-channels in human cells. In this document compounds having the following general formula (X) are described:
Several pyrazolopyrimidine compounds according to the present invention, however have been tested which are found to be not significantly active as inhibitors of ion-channels in human cells. In this document WO 2003/037900, compounds of the following two structures are mentioned as example compounds (B308) and (B310), which however have shown no particular activity as metabotropic glutamate receptor (mGluR5) modulators:
In WO 2003/101993 several types of pyrazolopyrimidine compounds and their use for the treatment of hepatitis infections are disclosed. WO 2003/101993 deals with compounds of the following general formula (Z)
In the document WO 2003/091256 particular pyrazolopyrimidine derivatives which have a NADPH-oxidase inhibitor activity are described. The compounds have the following general formula (Y)
A further pyrazolopyrimidine compound which has already been described in the literature as chemical substance (see ChemBridge Corporation; Registry Nr. 833441-66-0; of Feb. 18, 2005), has the following structure (M):
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-methanon. This compound, however has a more limited activity as metabotropic glutamate receptor (mGluR5) modulator and has a reduced selectivity. However, according to this invention, the compound can be used as a medicament. Typical medical indications are those mentioned above.
In WO 2006/015737 further heterocyclic compounds which can contain a carboxylic acid amid function are disclosed which have an activity at dopamine receptors and which can be used for the treatment of CNS-diseases. As one example structure, pyrazolopyrimidines are mentioned.
In WO 2002/088088 the synthesis of tetrahydro-isoquinolin compounds is disclosed which can serve as intermediates for the synthesis of pharmaceutically active compounds.
It now has been found that certain pyrazolopyrimidine derivatives which differ in structure from the known pyrazolopyrimidines, are potent mGluR5 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
These substances are preferably administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
It is an object of the present invention to provide novel pharmaceutical compounds which are mGluR5 modulators and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable CNS disorders which involve abnormal glutamate neurotransmission by employing a compound of the invention or a pharmaceutical composition containing the same.
An additional object of the invention is the provision of processes for producing the pyrazolopyrimidine derivatives.
The invention in general deals with: A compound selected from those of formula (Ig)
Furthermore, a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), wherein
Such compound of Formula (Ig), wherein
Such compound of Formula (Ig), wherein
Furthermore, a compound of Formula (Ig), wherein
Such compound of Formula (Ig), wherein
Furthermore, a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), wherein
Such a compound of Formula (Ig), which is selected from those of Formula (IgA),
Such a compound of Formula (IgA),
Such a compound of Formula (IgA),
Furthermore, a compound selected from those of Formula (Ig)
In the compounds of the invention R1 defined by Formula (Ig) and Formula (IgA) may represent bromo. Alternatively, R1 defined by Formula (Ig) and Formula (IgA) may represent chloro. It will be apparent to those skilled in the art that the invention also includes optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs of the described compounds.
Moreover the invention deals with a pharmaceutical composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, at least one compound of formula (Ig) or of formula (IgA), wherein the substituents are as defined above, or optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
Moreover, a method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating mGluR5 receptors to achieve therapeutic benefit, or a method for enhancing cognition, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound selected of those of formula (Ig) or formula (IgA).
Furthermore, the preparation of and the uses of a compound of formula (Ig) or formula (IgA) or optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof or the manufacturing or preparation of a medicament are part of the invention.
The present invention in particular relates to a compound selected from those of formula (I)
The invention also relates to a compound of formula (I) as described above, wherein R10 and R11 independently represent hydrogen, halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C6alkyl, C1-C6alkyloxy, cyclohexyl, phenyl, or a ring system from the group: thiophene, pyrrole, furan, pyrazole, tetrazole, oxazole, isoxazole, thiazole, pyridine, pyrimidine, morpholino.
The invention also relates to a compound of formula (I) as described above, wherein R10 and R11 together with the two carbon atoms carrying them represent a heteroaryl having 5 or 6 ring members from the group pyridine, pyrimidine, thiophene, pyrrole, furan, pyrazole, tetrazole, oxazole, isoxazole, thiazole or a heterocyclyl group having 5 or 6 ring members from the group morpholin, piperazin and piperidin, which can be substituted by methyl;
The invention also relates to a compound of formula (I) wherein R2, R3, R4 and R5 independently represent hydrogen, methyl, ethyl, isopropyl, cyclohexyl or trifluoromethyl.
The invention also relates to a compound of formula (I) wherein one of R2 and R3 represents methyl, ethyl or trifluoromethyl and the remaining of R2 and R3 represent hydrogen.
The invention also relates to a compound of formula (I) wherein R2, R3, R4 and R5 independently represent hydrogen, methyl, ethyl or trifluoromethyl; and R6 and R7 represent hydrogen or methyl.
The invention also relates to a compound of formula (I) wherein R2, R3, R4, R5, R6 and R7 independently represent hydrogen, methyl or ethyl.
The invention also relates to a compound of formula (I) wherein R2 and R3 independently represent hydrogen, methyl or ethyl.
The invention also relates to a compound of formula (I) wherein R2 represent methyl or ethyl and R3 represent hydrogen and which has at least one chiral carbon atom.
The invention also relates to a compound of formula (I) wherein R2 and represents methyl or ethyl and R3, R4, R5, R6, R7 represent hydrogen and which has at least one chiral carbon atom in the R-configuration.
The invention also relates to a compound of formula (I) wherein R2 and represents methyl or ethyl and R3, R4, R5, R6, R7 represent hydrogen and which has at least one chiral carbon atom in the S-configuration.
The invention also relates to a compound of formula (I), wherein Y1, Y2, Y3 and Y4 all represent a carbon atom. The invention also relates to a compound of formula (I), wherein three of Y1, Y2, Y3 and Y4 represent a carbon atom and one of Y1, Y2, Y3 and Y4 represents a nitrogen atom.
The invention also relates to a compound of formula (I) wherein R1 represents chloro.
The invention also relates to a compound of formula (I), wherein R1 represents bromo.
The invention also relates to a compound of formula (I) wherein R4, R5, R6 and R7 represent hydrogen.
The invention also relates to a compound of formula (I) wherein two of the groups Y1, Y2, Y3 and Y4 represent a carbon atom and two of the groups Y1, Y2, Y3 and Y4 represent a nitrogen atom.
The invention also relates to a compound of formula (I), wherein:
R10 and R11 independently represent the following groups: hydrogen, halogen, amino, hydroxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3-7cycloalkyloxy, C2-6alkenyloxy, C2-6alkynyloxy, heteroaryl, heterocyclyl, aryloxy, heteroaryloxy, heterocyclyloxy, C1-6alkylamino, di-C1-6alkylamino, C3-7cycloalkylamino, C1-6alkyl-C3-7cycloalkylamino, C2-6alkenylamino, C2-6alkynylamino, aryl-C1-6alkylamino, heteroarylamino, heteroaryl-C1-6alkylamino, heterocyclylamino, heterocyclyl-C1-6alkylamino, acyl, acyloxy, acylamino, C1-6alkoxycarbonyl, C3-7-cycloalkoxy-carbonyl, heterocyclyloxycarbonyl, aminocarbonyl, C1-6alkylamino-carbonyl, di-C1-6alkylaminocarbonyl, C3-7cycloalkylaminocarbonyl, arylamino-carbonyl, aryl-C1-6alkylaminocarbonyl, aryl-C2-6alkynylaminocarbonyl, heteroarylamino-carbonyl, heterocyclylaminocarbonyl, heterocyclyl-C1-6alkylaminocarbonyl, alkylsulfinyl, alkylsulfonyl, C1-6-alkylsulfonylamino and arylsulfonylamino.
The invention also relates to a compound of formula (I), wherein:
R10 and R11 independently represent the following groups: hydrogen, halogen, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, aryl, C1-6alkyl, C3-7cycloalkyl, C1-6alkoxy, acetyl, acyetyloxy, acetylamino, C1-6alkoxycarbonyl, heteroaryl (including furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl), heteroaryl (including furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl) which is substituted by one or two radicals from: halogen, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, hydroxy, nitro, cyano, C1-6alkoxycarbonyl, C1-6alkoxycarbonyloxy, C1-6alkylamino, di-C1-6alkylamino; heterocyclyl (including piperidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperazinyl) and heterocyclyl (including piperidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperazinyl) which is substituted by one or two radicals selected from the group: halogen, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, hydroxy, nitro, cyano, C1-6alkoxycarbonyl, C1-6alkoxycarbonyloxy, C1-6alkylamino, di-C1-6alkylamino.
The invention also relates to a compound of formula (I), wherein the radical R10 represents hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C1-C6alkyl, C1-C6alkyloxy phenyl or a thiophene, pyrrole, furan, pyridine, pyrimidine, or morpholine ring and the radical R11 represents hydrogen.
The invention also relates to a compound of formula (I), wherein both radicals R10 and R11 represent hydrogen.
The invention also relates to a compound of formula (I), wherein Y1, Y2, Y3 and Y4 all represent a carbon atom, R2 and R3 independently represent hydrogen or methyl, R4, R5, R6 and R7 represent hydrogen and R10 and R11 independently represent hydrogen or methyl.
The invention also relates to a compound according to formula (I) and having one of the following chemical names:
The invention also relates to a compound of formula (I) which has the structure (Q)
wherein the radicals R1 to R7, R10 and R11 are defined as above for the general formula (I).
The invention also relates to a compound wherein the radicals R2, R3, R4 and R5 independently represent hydrogen or methyl and R6 and R7 represent hydrogen.
The invention also relates to compounds of the formula (I) or of the formula (Ia) which are marked by radioactive atoms. Typical compounds include those where one or more hydrogens are substituted by tritium, where one or more C12 are substituted by C14, where one or more fluor atoms are substituted by F18 or other isotopes. These can be used for the treatment of diseases (e.g. cancer) but also for diagnostic purposes. The radioactive atoms exchanged in the molecule are often isotopes of carbon, hydrogen, halogen, sulphur or phosphor.
The invention in general relates to the use of a metabotropic glutamate receptor modulator (and in particular of a mGluR5 modulator) for the preparation of a medicament and for the treatment of various diseases as mentioned hereunder in a mammal, including humans.
Further, the invention relates to the use of a compound of formula (I) or of formula (Ia) as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the preparation of a medicament and for the treatment of a mammal, including humans.
Also the compound of formula (I) with the chemical name (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone or optical isomers, pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof can be used for the preparation of a medicament.
The invention also relates to the use of a compound for the preparation of a medicament for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission. Such a use includes the use of a compound for the preparation of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by the negative modulatory effect of mGluR5 modulators.
The invention is dealing with the use of a mGluR5 modulator and in particular a compound according to formula (I), for the preparation of a medicament, including for the conditions or diseases selected from those mentioned earlier in the description.
The invention also relates to the use of a mGluR5 modulator, in particular a compound according to formula (I), wherein the condition associated with abnormal glutamate neurotransmission is selected from those mentioned earlier in the description.
Further, the invention relates to the use of a compound wherein the condition associated with abnormal glutamate neurotransmission is selected from: neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumatic arthritis, inflammatory pain, L-dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, reflux, migraine or for cognitive enhancement and/or neuroprotection.
Further, the invention in particular relates to a pharmaceutical composition comprising as active ingredient at least one compound of formula (I) as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with one or more pharmaceutically acceptable excipients.
The invention also relates to a process for the synthesis of a compound of formula (I)
The invention also relates to an amine compound of formula (VII)
The compounds of formula (VII) may have the definitions of the various radicals as defined above for formula (I).
The invention also relates to a process for the synthesis of a compound selected from those of formula (I)
The invention also relates to a process where the compound of formula (I) is prepared in an enantio-selective reaction.
Moreover, the mGluR modulators of formula (I) as described above are expected to have a high activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
The invention also relates to a pharmaceutical composition comprising at least two different active ingredients, containing at least one compound of formula (I) as defined above, and furthermore containing at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients. These compositions can be used for the treatment of CNS-related diseases, cognitive enhancement and for neuro-protection.
Simultaneous administration of Group I mGluR modulators and NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (see e.g. Zieminska et al. Neurochemistry International, 2006, 66, 301-309; Zieminska et al. Neurochemistry International, 2003, 43, 481-492; Zieminska et al. Neurochemistry International, 2006, 48, 491-497).
With respect to the specific compounds as described above, the combined therapy exhibits a greater neuroprotective effect than monotherapy with either an mGluR modulator or an NMDA receptor antagonist. As particularly active NMDA receptor antagonist, the compound Memantine can be named, which is also known as 1-amino-3,5-dimethyladamantane (see U.S. Pat. No. 4,122,193; U.S. Pat. No. 4,273,774; and U.S. Pat. No. 5,061,703).
Furthermore, the compound Neramexane, which also is known as 1-amino-1,3,3,5,5-pentamethylcyclohexane, is a further active NMDA receptor antagonist and is disclosed in detail in U.S. Pat. No. 6,034,134 and U.S. Pat. No. 6,071,966. Memantine and Neramexane are systemically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor.
They exhibit strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. Görtelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42:904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14:135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002, 8:835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555-565).
The combination of NMDA antagonists with mGluR5 modulators can be realized in a single pharmaceutical composition (as principally described in the prior art) comprising a mGluR5 modulator of the present invention and an NMDA receptor antagonist, in one pharmaceutical formulation, or in two separate pharmaceutical compositions or formulations, one comprising a mGluR5 modulator of the present invention and one comprising an NMDA receptor antagonist in a pharmaceutical formulation, to be administered conjointly (simultaneously or sequentially). For the sequential administration to be considered “conjoint”, however, the mGluR5 modulator of the present invention and the NMDA receptor antagonist must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal. For example, the mGluR5 modulator of the present invention and the NMDA receptor antagonist must be administered on the same day (e.g., each—once or twice daily), preferably within an hour of each other, and most preferably simultaneously.
This invention also relates to a pharmaceutical composition comprising a combination of a compound of formula (I) as described above and an NMDA receptor antagonist. Of particular interest is a composition, wherein the NMDA receptor antagonist is selected from Memantine and Neramexane (or a combination thereof) and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
The invention also relates to a pharmaceutical composition comprising at least two different active ingredient, containing at least one compound of formula (I) as defined above, and furthermore containing at least one of L-DOPA, another dopaminomimetics (in particular an antiparkinsonian dopaminomimetics e.g. bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and a neuroleptic (in particular a classical neuroleptic, e.g. haloperidol, perphenazin, chlorpromazine, metoclopramide).
These combination products can e.g. be used for the treatment of CNS-related disorders and diseases. Because of the antidyskinetic effect of the compounds of formula (I), drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias can be treated in addition to the conditions which are typically treated with L-Dopa, dopaminomimetics or neuroleptics.
The invention also relates to a method of providing neuroprotection to a living animal, including a human, comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a composition as described.
This invention is also dealing with the compounds of formula (I) for the use as a medicament. Furthermore, the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of the diseases and conditions mentioned above.
The invention also relates to a compound of formula (I) and the compound (6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone and all optical isomers, pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof for use as a medicament.
Furthermore, the invention relates to the use of a composition as described above for the manufacture of a medicament to provide neuroprotection in an animal, including a human.
Furthermore, the invention relates to the use of a compound of formula (I) in the manufacture of a medicament for treatment of a condition associated with abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit. The disorders which can be treated have already been described above. Such conditions and indications include:
a) For mGluR5 modulators: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumatic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection.
b) For negative modulation of mGluR5: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumatic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, migraine, irritable bowel syndrome (IBS), functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Huntington's chorea and/or epilepsy.
c) For positive modulation of mGluR5: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.
The mGluR5 negative modulators in general and in particular the compounds of formula (I) according to the invention can be used for the treatment of binge eating disorders.
For the purpose of the present invention, in the compounds of formula (I) the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive. Thus, for example, (C1-3)alkyl refers to alkyl of one to three carbon atoms (i.e. 1, 2 or 3 carbon atoms), inclusive, (methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof; (C1-6) for instance refers to a radical of one to six carbon atoms (i.e. 1, 2, 3, 4, 5 or 6 carbon atoms).
As used herein, the following definitions are applicable unless otherwise described, the term “C1-6alkyl” represents straight or branched chain alkyl groups which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C1-6alkoxy, amino, hydroxy, C1-6alkylamino, and di-(C1-6alkyl)amino. Examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, —CF3, —C2F5, —CBr3 and —CCl3.
The term “C2-6alkenyl” represents straight or branched chain alkenyl groups. The term “C1-6alkoxy” represents straight or branched chain —O—C1-6alkyl groups which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, amino, hydroxy, C1-6alkylamino and di-(C1-6alkyl)amino. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, —OCF3 and —OC2F5.
The term “cycloC3-12alkyl” represents monocyclic or bicyclic, or tricyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl, which may be optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C1-6alkoxycarbonyl, C1-6alkylamino, and di-(C1-6alkyl)amino, C1-6alkylcarbonylamino, and C1-6alkylenedioxy.
The term “aryl” represents in particular phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, C1-6alkyl, hydroxyC1-6alkyl C2-6alkenyl, C1-6alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C1-6alkoxycarbonyl, C1-6alkylcarbonyloxy, C1-6alkylamino, di-(C1-6alkyl)amino, C1-6alkyl-carbonylamino, aminocarbonyl, N—C1-6alkylaminocarbonyl, di-N,N—C1-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, cycloC3-12alkyl or optionally C1-6alkylenedioxy. Typical examples of aryl are phenyl and phenyl which is substituted by one or two of the above mentioned substituents.
The term “acyl” includes —(C═O)-alkyl; —(C═O)aryl; —(C═O)-aralkyl, —(C═O)-heterocyclyl, C1-6-alkylcarbonyl, C3-7cycloalkylcarbonyl, C2-6alkenylcarbonyl, C2-6alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein the terms alkyl, aryl and heterocyclyl are defied as above. Examples are acetyl, propionyl, benzoyl or pivaloyl.
The term “heteroaryl” represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more (e.g., one or two) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, C1-6alkyl, hydroxyC1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, hydroxy, nitro, cyano, C1-6alkoxycarbonyl, C1-6alkoxycarbonyloxy, C1-6alkylamino, and di-(C1-6alkyl)amino, C1-6alkylcarbonylamino, aminocarbonyl, N—C1-6alkylaminocarbonyl, di-N,N—C1-6alkyl-aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3-12alkyl, C1-6alkylenedioxy and aryl. Representative heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphtyridinyl, and isoquinolinyl. Examples are pyridyl, pyrimidyl, thienyl, furyl and others.
The term “heterocyclyl” represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system is optionally substituted by one or more substituents selected independently from a halogen, trifluoromethyl, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, amino, hydroxy, nitro, cyano, C1-6alkoxycarbonyl, C1-6alkylamino, di-C1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, and aryl; examples of such heterocyclyl groups include piperidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, or piperazinyl, wherein the heterocyclic ring or ring system is linked to the group to which it is attached optionally via nitrogen or a carbon atom.
The term “halogen” represents fluorine, chlorine, bromine and iodine.
The compounds of the present invention are usually named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. “Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours, and “rt” for room temperature).
The term “analog” or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, but has been modified in a targeted and controlled manner to replace one or more specific substituents of the referent molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs (e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
The phrase “pharmaceutically acceptable”, as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
Compounds of the present invention may be in the form of pharmaceutically acceptable salts. “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.
All patents, applications, publications, test methods, literature, and other materials cited in this application are hereby incorporated by reference.
The following Schemes 1-3 describe the preparation of compounds of Formula (I) of the present invention. All of the starting materials may be prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry, or may be obtained commercially. All of the final compounds of the present invention may be prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes are as defined below or as in the claims. The compounds containing one or more chiral centers can be prepared as racemates or mixtures of various stereoisomers and then separated. However, they also can be prepared by a special enantioselective synthesis. For several of the chiral compounds, the enantiomers differ in pharmacological activity.
Compounds of the present invention may be synthesized according to Scheme 1.
5-Nitro-1H-pyrazole-3-carboxylic acid 1 is reduced under standard conditions, such as treatment with hydrogen in the presence of palladium(0) on carbon in a solvent such as methanol, to yield 5-amino-1H-pyrazole-3-carboxylic acid 2. Compound 2 is reacted with di-aldehyde 3, carrying a bromo or chloro substituent at the R1 position, under acid conditions, such as acetic acid, at elevated temperatures to give 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4). A compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 in the presence of a condensation agent, including, for example, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (“TBTU”) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
General procedure towards compounds of Formula I.
The amines (5) are commercially available or may be prepared according to literature procedures (see, for example, Bull. Soc. Chim. Belg., v. 71, 1962; p. 592; US 2002/049223 A1 (2002/04/25); Chem. Ber., 84, 1951, p. 795-798; Bull. Soc. Chim. Fr. 5, 4, 1937, p. 1265-1269; Zh. Obshch. Khim., 7, 1937, p. 1999-2004; Chem. Pharm. Bull., EN, 31, 8, 1983, p. 2583-2592; Tetrahedron, 28, 1972, p. 5999-6004; J. Org. Chem., 34, 8, 1969, p. 2478; Pharm. Chem. J. (Engl. Tran.); 5; 5; 1971, p. 260; Khfzan; Khim. Farm. Zh., 5, 5, 1971, p. 13).
Compound 4 may also be prepared according to Scheme 2.
General procedure towards Compound 4.
5-Nitro-3-pyrazole carboxylic acid 1 is dissolved in an alcoholic solvent, e.g. methanol or ethanol, and reacted with thionyl chloride to give compound 1a bearing an alkyl ester group. The term “PG” denotes any C1-6 alkyl chain, including branched alkyl chains, for example, methyl and ethyl groups. 5-Nitro-3-pyrazole-carboxylic acid alkyl ester 1a is reduced under standard conditions, such as treatment with hydrogen in the presence of palladium(0) on carbon in a solvent such as methanol, to yield 5-amino-1H-pyrazole-3-carboxylic acid alkyl ester 2a. Compound 2a is reacted with di-aldehyde 3, carrying a bromo or chloro substituent at the R1 position, under acid conditions, such as acetic acid, at elevated temperatures to give 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid alkyl ester (4a). The ester 4a is hydrolyzed under acidic conditions such as sulphuric acid (30%) to yield 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4. A compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 as shown in Scheme 1.
Compound 4 may also be prepared according to Scheme 3.
Ethyl 3-cyano-2-oxopropionate sodium salt (“NaCOPE”) 6 is treated with methyl hydrazino formate to yield ethyl 5-aminopyrazole-3-carboxylate 7. Compound 7 is reacted with dialdehyde 3, carrying a bromo or chloro substituent at the R1 position, under acidic conditions, to yield ethyl 6-bromo- or 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate 8. The ester 8 is hydrolyzed under acidic conditions to yield 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4. A compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 as shown in Scheme 1.
General procedure towards Compound 4.
It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.
Hereinafter, “DMF” is defined as N,N-dimethylformamide, “HCl” as hydrochloric acid, “DMSO” as dimethylsulfoxide and “TBTU” as O-(benzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium tetrafluoroborate.
5-Nitro-3-pyrazol carboxylic acid (21.44 g, 136.5 mmol) is dissolved in dry methanol (200 mL). Then, thionyl chloride (9.9 mL, 136.5 mmol) is added slowly in a drop wise manner at RT. The reaction mixture is heated over night under reflux and under argon atmosphere. After cooling down, the solvent is evaporated under vacuum and the crude material is heated with boiling hexane (200 ml). After cooling down and removal of the hexane, the material is washed two times with 200 ml pentane. Then, the solvent is removed and the product is dried under vacuum to give 5-nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g, 95.7%).
5-Nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g, 130.61 mmol) is dissolved in each 160 mL THF und glacial acetic acid. Then, Pd—C (10%, 4.36 g) are added and the reaction is stirred for 6 days under hydrogen atmosphere at RT. Then, the mixture is filtered over celite and the solvent is removed under vacuum. The crude material is dissolved in methylene chloride (800 mL) and sodium hydrogen carbonate (200 g) are added, filtered and the solvent is again removed under vacuum. This procedure is repeated until the acetic acid smell is lost. 5-Amino-3-pyrazole-carboxylic acid methyl ester is isolated in high yields (16.91 g, 91.7%)
5-Amino-3-pyrazolcarboxylic acid methyl ester (16.91 g, 119.8 mmol) is dissolved in ethanol (2.4 L) and hydrochloric acid (37%, 12.5 mL, 150 mmol) is added. Then, a solution of 2-bromo-malonealdehyde (18.9 g, 125.2 mmol) is dissolved in ethanol (1.4 L) and is quickly added in a drop wise manner at RT. After 30 min, a precipitation is observed; after 6 hours the precipitate is removed and washed with 50 ml ethanol and thereafter with 50 ml diethyl ether. Here, 4.19 g of the clean product are isolated. After evaporation of the filtrate and crystallisation, additional 1.43 g product are obtained to yield 6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid methyl ester (5.62 g, 18.3% d.Th.). In case of a smaller scale reaction with only 1 g of the starting amine 5-amino-3-pyrazolcarboxylic acid methyl ester, the yield is much better e.g. 68%.
6-Bromopyrazolo[1,5a]pyrimidin-2-carboxylic acid methyl ester (3.76 g, 14.68 mmol) is heated in 600 mL water, 190 mL sulphuric acid (30%) and 50 mL of the methanol/water mixture is removed from the reaction mixture via distillation. After cooling down, 50 mL water is added, the mixture is heated again and 50 mL of the alcohol-water mixture is removed. This cycle is repeated 6 times, the reaction mixture is cooled to RT and filtered over a glass filter. The crude material is washed with water (100 mL), acetone (20 mL) and ether (20 mL) and dried under vacuum to give 6-Bromo-pyrazolo[1,5a]pyrimidine-2-carboxylic acid (2.61 g, 10.78 mmol; 73.5%).
Physical characteristics are as follows: 1H NMR (DMSO): δ (ppm) 13.4, 9.7, 8.7, 7.2.
The hydrolysis of methyl 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate is performed under similar conditions as described above for methyl 6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate.
A 10 L three-necked flask is equipped with mechanical stirrer, reflux condenser and nitrogen inlet. To ethyl 3-cyano-2-oxopropionate sodium salt (“NaCOPE”) (653.18 g; 4.0 mol), 585 mL of water, 3.6 L of ethanol and 350 mL of hydrochloric acid (12N, 4.2 mol) are added. The resulting suspension is stirred at RT for 15 min. Then, methyl hydrazino formate (356.0 g; 3.95 mol) is added as a solid material. A slightly exothermic reaction occurs. After the mixture is stirred at RT for 6 h, another portion of methyl hydrazino formate (12.0 g; 133.7 mmol) is added and the orange suspension is stirred at RT over night. Then potassium carbonate (K2CO3, 300.0 g; 2.17 mol) is added, followed by 250 mL of water. The internal temperature rises to 60° C. and a vigorous evolution of gas starts. The mixture is heated at reflux for four hours. After cooling to RT, the alcohol is evaporated to yield a red paste, which is taken up in 1 L of water and 3 L of ethyl acetate. The aqueous phase is extracted with another 500 mL portion of ethyl acetate. The organic extracts are washed with brine and dried over sodium sulfate (Na2SO4). After filtration the solvent is evaporated to yield 330 g of a brown paste. This crude product is mixed with 1 L of ether to give a light brown solid, which is separated from an orange liquid phase by filtration. The solid is dried under vacuum to yield 229.12 g of the title compound. The liquid phase is evaporated; the residue is taken up in 250 mL of ether and cooled to −30° C. to yield another 15.09 g of the title compound. The total yield of the title compound is 244.21 g (1.57 mol; 39.3%). Physical characteristics are as follows: 1H-NMR (DMSO): δ (ppm) 1.26, 4.21, 5.0, 5.76, 12.12.
A 2 L round bottom flask is charged with ethyl 5-aminopyrazole-3-carboxylate (7) (44.92 g; 289.50 mmol), 1.2 L of ethanol and 27 mL of hydrochloric acid (12N, 324.0 mmol). 2-Bromomalonaldehyde (43.71 g; 289.54 mmol) is added as a solid to the resulting yellow solution. A light brown solution is formed, from which a tan solid started to precipitate after 15 min. The suspension is stirred at RT over night and thereafter, filtered with suction. The solid is washed with 200 mL of ether to yield 62.50 g of (8a) after drying at 40° C./1 Torr. Additional crystals are isolated from the filtrate by concentration and cooling to −30° C. A total yield of 74.12 g (274.4 mmol; 94.8%) of the title compound is obtained with a HPLC-purity>97%.
Physical characteristics are: 1H-NMR (DMSO): δ (ppm) 1.35, 4.39, 7.24, 8.74, 9.68.
A 2 L Schlenk flask equipped with a 500 mL addition funnel is charged with mucochloric acid (100.0 g; 592.0 mmol) dissolved in 400 mL of ethanol. Then, a solution of aniline (108 mL; 1.18 mmol) in 400 mL of ethanol is added over a period of 5 min. The reaction proceeds exothermic via the formation of large amounts of carbon dioxide. Thereafter, the orange solution is heated to reflux for 5 min and then cooled down to RT. Overnight, a yellow precipitate is formed. 500 mL of HCl (1N) are added and the suspension is filtered with suction. The residue is washed with 200 mL of ethanol and 500 mL of ether. It is dried at 40° C./1 Torr to yield the hydrochloride of the dianilide (107.8 g; 313.8 mmol; 53.7%) as a yellow solid which is used for the next step without further purification. In a 10 L three necked flask, 5 L of water are heated to reflux and the crude dianilide (81.2 g; 239.3 mmol) is added in 6 portions over 15 min. The foaming suspension is heated for a further 15 min. Then, the mixture is cooled to RT overnight. After filtration with suction, the residue is suspended in 150 mL of ethanol and treated in an ultrasonic bath for 2 min. The mixture is filtered again with suction and washed with 200 mL of ether. The pale yellow residue is dried at 40° C./1 Torr to yield 39.68 g of the monoanilide of chloromalonaldehyde (218.5 mmol; 91.2%) with a HPLC-purity>97%. A 1 L round bottom flask is charged with 39.68 g the monoanilide of chloromalonaldehyde (218.5 mmol) and 200 mL of NaOH (2N solution). It is heated to reflux for about 5 min until the solid is dissolved. At an internal temperature of 45° C., ethyl acetate (40 mL) is added. The alkaline aqueous layer is washed with a 40 mL portion of ethyl acetate and cooled to 5° C. After 12 hrs, the colorless needles are filtered off and washed with 50 mL of ethanol and 200 mL of ether. Concentration and cooling of the mother liquor yielded another crop of crystals. In total, 29.16 g (159.7 mmol; 73.1%) of the trihydrate of the sodium salt of chloromalonaldehyde are isolated after drying at 40° C./1 Torr.
A 100 ml round bottom flask is charged with ethyl 5-aminopyrazole-3-carboxylate (7) (2.0 g; 12.89 mmol) and 50 mL of ethanol. To this solution hydrogen chloride (12 N; 1.2 mL; 14.4 mmol) is added. Then, the sodium salt of chloromalonaldehyde (Preparation 7) (2.35 g; 12.89 mmol) is added as a solid in one portion. The resulting suspension is stirred at RT over night. Thereafter, it is filtered with suction and washed with 50 mL of ether. The residue is extracted with 120 mL of chloroform in a soxleth apparatus for 5 h. Then, the solvent is evaporated from the organic extract yielding 2.44 g of the title compound (10.8 mmol; 83.9%) with >97% by HPLC.
Physical characteristics are: 1H-NMR (DMSO): δ (ppm) 1.35, 4.39, 7.25, 8.72, 9.63.
The hydrolysis of the ethyl 6-halogeno-pyrazolo[1,5a]pyrimidine-2-carboxylates (8) with aqueous acids leads to the carboxylic acids (4) in good yields (>80%). Hydrochloric acid is used to hydrolyze the 6-chloro-ester. The 6-bromo-derivative is hydrolyzed using sulfuric acid. In a typical hydrolysis the compounds (8) are suspended in water and the acid is added. Then, small amounts of alcohol-water-azeotrope are distilled off until no more ester is detected by TLC (MeCN+H2O=10+2, plate type: Alugram□SIL G/UV254). The suspensions are cooled by means of an ice-water bath and filtered with suction. The residues are washed with water, acetone and ether. After drying at 40° C./1 Torr the 6-halogenopyrazolo[1,5a]pyrimidine-2-carboxylic acids (4) are examined by HPLC.
A 500 mL round bottom flask is charged with ethyl 6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate (2.0 g; 7.41 mmol) and 240 mL of water. After addition of diluted sulfuric acid (30 vol %; 62 mL) the suspension is heated to reflux and 20 mL of an ethanol-waterazeotrope is distilled off. 20 mL of water are added to the suspension and another 20 mL portion is distilled off. After eight of these cycles, no more ester is detected by TLC. The mixture is cooled to 10° C. by means of an ice-bath. It is filtered with suction and washed with 100 mL of water, followed by 20 mL of acetone and 100 mL of ether. The residue is dried at 40° C./1 Torr to yield 1.54 g of the title compound (6.36 mmol; 83.5) as a beige powder.
Physical characteristics are as follows: 1H-NMR (DMSO): (ppm) 7.21, 8.75, 9.70, 13.44.
The hydrolysis of ethyl 6-chloro-pyrazolo[1,5a]pyrimidine-2-carboxylate is performed under similar conditions as described above for ethyl 6-bromo-pyrazolo[1,5a]pyrimidine-2-carboxylate.
In order to prepare the amine component of the pyrazolopyrimidine compounds of formula (I) the following General Schemes can be used:
There are several routes for the synthesis of chiral pyrazolopyrimidines which are outlined in the following:
A) Enantiomer synthesis by reduction of amine building block with a chiral reducing agent:
Chiral 1-methyl-1,2,3,4-tetrahydroisoquinolines are prepared by reduction of 1-methyl-3,4-dihydroisoquinolines with amino acid-derived chiral reducing agents. Examples of such reducing agents are triacyloxy sodium borohydrides 9 and 10, prepared by mixing chiral N-isobutoxycarbonyl proline with sodium borohydride. Low temperature reduction of 1-methyl-3,4-dihydroisoquinoline 11 with these reducing agents affords 1-methyl-1,2,3,4-tetrahydroisoquinolines with 74% enantiomeric excess. The L-proline-derived reducing agent 10 provides S-isomer of 1-methyl-1,2,3,4-tetrahydroisoquinoline 13, whereas the agent derived from D-proline 9 gives R-isomer of the product 12. The enantiomeric purity is further increased by recrystallization at the stage of amine or after coupling of amine with the corresponding acid.
A solution of isobutyl chloroformate (4.4 mL, 34.04 mmol) in acetone is added dropwise to a solution of L- or D-proline (4.0 g, 34.74 mmol) and sodium bicarbonate (10 g, 125 mmol) in water (50 mL). The mixture is stirred overnight. After removal of acetone, the aqueous solution is acidified to pH 2 with hydrochloric acid while maintaining the temperature below 20° C., and then extracted with ethyl acetate (3×25 mL). The combined organic phase is dried over anhydrous magnesium sulfate and evaporated in vacuo to give (S)-N-isobutoxycarbonylproline (from L-proline) or (R)-N-isobutoxycarbonylproline (from D-proline) correspondingly, as colorless oil.
A solution of (R)-N-isobutoxycarbonylproline (502 mg, 2.33 mmol) in THF (1.5 mL) is added dropwise over 10 min to a stirred solution of sodium borohydride (29 mg, 0.77 mmol) in THF (1.5 mL) at 0° C. The mixture is stirred overnight and then concentrated in vacuo to give the reducing agent 9. Analogously, reducing agent 10 is prepared from (S)-N-isobutoxycarbonylproline.
To a cooled (−35° C.) solution of reducing agent 9 (526 mg, (0.78 mmol) in dichloromethane (3 mL) is added solution of 1-methyl-3,4-dihydroisoquinoline (32 mg, 0.22 mmol) in dichloromethane (3 mL) dropwise over 15 min. The mixture is allowed to warm to −10° C. over 1 h and then kept at 0° C. for 4 h. The solvent is removed in vacuo and the residue is dissolved in methanol (10 mL). After cooling to 0° C., Amberlyst 15 (1 g) is added and the mixture is shaken for 1 h at room temperature. The resin is filtered off and washed with dichloromethane and methanol, then solution of ammonia in methanol (2M, 3 mL) is added and the mixture is shaken overnight, then filtered. The filtrate is evaporated in vacuo to give (R)-1-Methyl-1,2,3,4-tetrahydroisoquinoline (26 mg, 82%, e.e.=74%, determined by chiral HPLC).
Analogously, (S)-1-Methyl-1,2,3,4-tetrahydroisoquinoline is prepared using the reducing agent 10, derived from L-proline.
B) Enantiomer Synthesis via Chiral Synthesis
Alternatively, chiral 1-Methyl-1,2,3,4-tetrahydroisoquinolines 12 and 13 are prepared using a 6-step synthesis starting from chiral α-phenethylamine 14, (developed by Shinohara et al. Chemical & Pharmaceutical Bulletin (1998), 46(3), 430-433). This sequence utilizes a Pummerer rearrangement of sulfoxide 15 as a key step. No racemization occurs during the sequence, and the commercially available R and S α-phenetylamines with 99.5% enantimeric purity yield chiral 1-Methyl-1,2,3,4-tetrahydroisoquinolines with the same enantiomeric purity.
C) Separation via Chiral Column Chromatography
In the following, specific compounds according to the invention are described in more detail:
Building Block Syntheses:
1 mmol of substituted isoquinoline is dissolved in acetic acid (5 mL) and 3.5 eq of NaBH4 is added portionwise. The reaction mixture is stirred for 1 h, then poured into ice and NH4OH is added to pH 9. The mixture is extracted with CH2Cl2 and the organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography to give the title compound.
In close analogy to the procedure described above, 5-Bromo-isoquinoline is reacted with sodium borohydride to provide the title compound.
LC/MS: m/z=212 (MH+)
1H NMR (CDCl3) δ: 2.73, 3.16, 3.98, 7.00, 7.37-7.42.
In close analogy to the procedure described above, 6-Bromo-isoquinoline is reacted with sodium borohydride to provide the title compound.
LC/MS: m/z=212 (MH+)
1H NMR (CDCl3) δ: 2.76, 3.11, 3.94, 6.86, 7.22, 7.55-7.99.
In close analogy to the procedure described above, 5-Nitro-isoquinoline is reacted with sodium borohydride to provide the title compound.
LC/MS: m/z=178 (MH+)
2-Chloro-nicotinic acid (10.0 g, 63.5 mmol, 1.0 equiv) is suspended in dichloromethane (400 mL) and THF (100 mL). N,O-Dimethyl-hydroxylamine hydrochloride (6.81 g, 69.8 mmol, 1.1 equiv) and triethylamine (9.70 mL, 69.8 mmol, 1.1 equiv) are added, resulting in a clear solution. The mixture is cooled in an ice bath and EDCI (13.4 g, 69.8 mmol, 1.1 equiv) and HOAt (0.86 g, 6.35 mmol, 0.1 equiv) are added. The resulting mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is redissolved in ethyl acetate (200 mL) and washed with 1N NaOH solution, twice with sat. NaHCO3 solution and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. This gives 7.53 g of the title compound as a white solid. Yield: 59%
LC/MS: m/z=142 (MH+)
1H NMR (CDCl3) δ: 3.08, 3.31, 3.46, 3.78, 7.53, 8.01, 8.49.
2-Chloro-N-methoxy-N-methyl-nicotinamide (3.90 g, 19.4 mmol, 1.0 equiv) is dissolved in THF (200 mL) under nitrogen and the mixture is cooled in an ice bath. Methylmagnesium chloride (17.0 ml, 48.6 mmol, 2.5 equiv) is added within 2 minutes. After 15 min a grey precipitate is formed. Stirring is continued for 2 h, the mixture is cooled in an ice bath and sat. NH4Cl (150 mL) is added. The solution is acidified with 1N HCl solution (60 mL) followed by addition of sat. NaHCO3 solution (30 mL). The organic layer is separated and concentrated in vacuo. The residue is combined with the remaining water layer and extracted with diethyl ether (200 mL). The combined etheral layers are washed twice with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. This provides 2.57 g of the title compound as a yellow oil.
Yield: 85%
1H NMR (CDCl3) δ: 2.71, 7.35, 7.92, 8.50.
1-(2-Chloro-pyridin-3-yl)-ethanone (2.21 g, 14.2 mmol, 1.0 equiv), ethylene glycol (4.41 g, 71.0 mmol, 5.0 equiv) and p-toluenesulfonic acid monohydrate (1.35 g, 7.1 mmol, 0.5 equiv) are dissolved in toluene (100 mL). The resulting mixture is heated overnight under Dean Stark conditions. After cooling to room temperature the mixture is washed twice with saturated NaHCO3 solution, brine, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash column chromatography (10% to 50% ethyl acetate in heptane) to yield 2.19 g of the title compound.
Yield: 77%
1H NMR (CDCl3) δ: 1.82, 3.79, 4.09, 7.24, 7.98, 8.35.
A solution of 2-chloro-3-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (2.19 g, 11.0 mmol, 1.0 equiv) and acetonitrile (577 μL, 11.0 mmol, 1.0 equiv) in THF (75 mL) is cooled to 5° C. under nitrogen atmosphere. 2M Sodium bis(trimethylsilyl)amide solution in THF (11.0 mL, 21.9 mmol, 2.0 equiv) is added within 1 minute. This results in a bright yellow solution which turns orange over time. Stirring at 0° C. is continued for exact 1 h. According to TLC there is complete conversion. Saturated NH4Cl solution (50 mL) is added. The organic layer is separated and concentrated in vacuo. The residue is combined with the water layer and extracted with ethyl acetate (75 mL). The organic layer is washed three times with sat. NH4Cl solution, dried over Na2SO4 and evaporated in vacuo. The residue is purified by flash column chromatography (10% to 50% ethyl acetate in heptane) and gave 540 mg of the title compound as an oil.
Yield: 24%
1H NMR (CDCl3) δ: 1.82, 3.79, 4.10, 7.24, 7.98, 8.35.
[3-(2-Methyl-1,3-dioxolan-2-yl)-2-pyridyl]methyl cyanide (540 mg, 2.64 mmol, 1.0 equiv) is dissolved in ethanol. A catalytic amount of Raney Nickel is added and the resulting mixture is placed under a hydrogen atmosphere. The mixture is stirred for 7 h using a hot water bath to warm the reaction mixture. After flushing with nitrogen, the mixture is filtered over kieselguhr and rinsed with ethyl acetate. The filtrate is concentrated in vacuo with replenishment of dichloromethane. This gave 490 mg of the title compound as a yellow oil.
Yield: 99%
1H NMR (CDCl3) δ: 1.71, 3.16, 3.75, 4.06, 7.11, 7.86, 8.48.
2-[3-(2-Methyl-[1,3]dioxolan-2-yl)-pyridin-2-yl]-ethylamine (490 mg, 2.35 mmol, 1.0 equiv) is dissolved in 1N HCl solution (47 mL, 47.0 mmol, 20.0 equiv) and heated at 100° C. for 2 hours. According to TLC analysis the reaction is completed. The mixture is cooled and 1N NaOH solution is added. The mixture is extracted twice with dichloromethane, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. This gave the title compound.
1H NMR (CDCl3) δ: 2.39, 2.93, 3.84, 7.26, 7.73, 8.53.
5-Methyl-7,8-dihydro-[1,6]naphthyridine (1.0 equiv) dissolved in ethanol (50 mL) and PtO2 (100 mg) is added. The mixture is placed under hydrogen atmosphere and stirred for 2 h. The catalyst is filtered off over kieselguhr and the filter is rinsed with ethyl acetate. The filtrate is evaporated in vacuo and purified by flash column chromatography (5 to 40% 10% 7N NH3 in methanol in CH2Cl2/CH2Cl2). This provided 178 mg of the title compound as a yellow oil.
Yield: 51% for two steps
1H NMR (CDCl3) δ: 1.46, 1.61, 2.93, 3.09-3.13, 3.36, 4.12, 7.10, 7.44, 8.40.
To a solution of aldehyde A (1 mol) in benzene (approx. 20 ml per 1 g of the starting compound) nitromethane (1.2 mol), piperidine (0.1 mol) and acetic acid (0.1 mol) are added. The reaction mixture is refluxed for 2.5 h with azeotrope removing of water. Then, the solvent is evaporated in vacuo. The residue is triturated with cold methanol, filtered, washed with cold methanol that resulted in product crystals in good to moderate yields.
In close analogy to the procedure described above, 4-Trifluoromethyl-benzaldehyde is reacted with nitromethane to provide the title compound.
Yield: 98%
LC/MS: m/z=218 (MH+) 1-(2-Nitro-vinyl)-2-trifluoromethyl-benzene
In close analogy to the procedure described above, 2-Trifluoromethyl-benzaldehyde is reacted with nitromethane to provide the title compound.
LC/MS: m/z=217 (MH+)
In close analogy to the procedure described above, 2,3-Dimethoxy-benzaldehyde is reacted with nitromethane to provide the title compound.
LC/MS: m/z=209 (MH+) 4-(2-Nitro-vinyl)-benzo[1,3]dioxole
In close analogy to the procedure described above, Benzo[1,3]dioxole-4-carbaldehyde is reacted with nitromethane to provide the title compound.
1H NMR (CDCl3) δ: 6.12, 6.91, 7.87.
In close analogy to the procedure described above, 2,3-Dihydro-benzo[1,4]dioxine-5-carbaldehyde is reacted with nitromethane to provide the title compound.
LC/MS: m/z=207 (MH+)
To a suspension of lithium aluminium hydride (2 mol) in diethyl ether (approx. 20 ml per 1 g of LAH) solution of the corresponding nitro derivative B (1 mol) in dry THF is added dropwise at stirring within 30 min. The reaction mixture is stirred at 35° C. for 2 h, and then, cooled with ice water. Then, 20% aqueous NaOH and water (n ml, n ml, 3n ml per n g LAH) are added step by step carefully. The resulting mixture is stirred for 30 min, filtered and concentrated on rotary evaporator. The residue is purified by flash column chromatography on silica gel (eluent: chloroform/methanol—0→20%) that gave products in good to moderate yields.
In close analogy to the procedure described above, 1-(2-Nitro-vinyl)-4-trifluoromethyl-benzene is reacted with lithium aluminium hydride to provide the title compound.
LC/MS: m/z=190 (MH+)
In close analogy to the procedure described above, 1-(2-Nitro-vinyl)-2-trifluoromethyl-benzene is reacted with lithium aluminium hydride to provide the title compound.
LC/MS: m/z=189 (MH+)
In close analogy to the procedure described above, 1,2-Dimethoxy-3-(2-nitro-vinyl)-benzene is reacted with lithium aluminium hydride to provide the title compound.
LC/MS: m/z=181 (MH+)
In close analogy to the procedure described above, 4-(2-Nitro-vinyl)-benzo[1,3]dioxole is reacted with lithium aluminium hydride to provide the title compound.
1H NMR (CDCl3) δ: 1.36, 2.71, 5.91, 6.68.
In close analogy to the procedure described above, 5-(2-Nitro-vinyl)-2,3-dihydro-benzo[1,4]dioxine is reacted with lithium aluminium hydride to provide the title compound.
LC/MS: m/z=180 (MH+)
To a solution of the amine C (1 mol) in CH2Cl2 (approx. 10 ml per 1 g of the starting compound) triethylamine (1.1 mol) and acetic anhydride (1.2 mol) are added. The reaction mixture is stirred at room temperature for 1 h and concentrated on rotary evaporator. The residue is triturated with hexane, filtered, washed with hexane to give a crystalline compound in good yields.
In close analogy to the procedure described above, 2-(4-trifluoromethyl-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Yield: 29% for two steps
LC/MS: m/z=232 (MH+)
In close analogy to the procedure described above, 2-o-tolyl-ethylamine is reacted with acetic anhydride to provide the title compound.
Yield: 88%
LC/MS: m/z=178 (MH+)
In close analogy to the procedure described above, 2-p-tolyl-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=178 (MH+)
In close analogy to the procedure described above, 2-(4-chloro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=198 (MH+)
In close analogy to the procedure described above, 2-(2-chloro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=198 (MH+)
In close analogy to the procedure described above, phenethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=164 (MH+)
In close analogy to the procedure described above, 2-(2-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=181 (MH+)
In close analogy to the procedure described above, 2-(3-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=181 (MH+)
In close analogy to the procedure described above, 2-(4-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=181 (MH+)
In close analogy to the procedure described above, 2-(2-Bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=184 (MH+)
1H NMR (CDCl3) δ: 1.94, 2.95, 3.49, 7.07, 7.22-7.53.
In close analogy to the procedure described above, 2-(3-bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=243 (MH+)
In close analogy to the procedure described above, 2-(4-bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=243 (MH+)
1H NMR (CDCl3) δ: 1.38, 2.76, 3.47, 5.41, 7.06, 7.42.
In close analogy to the procedure described above, 2-(2-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=193 (MH+)
In close analogy to the procedure described above, 2-(3-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=193 (MH+)
In close analogy to the procedure described above, 2-(4-methoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=193 (MH+)
In close analogy to the procedure described above, 2-(2-trifluoromethyl-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=223 (MH+)
In close analogy to the procedure described above, 2-(2,3-dimethoxy-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=231 (MH+)
In close analogy to the procedure described above, 2-benzo[1,3]dioxol-4-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
1H NMR (DMSO-d6) δ: 1.77, 2.65, 3.24, 5.98, 7.74, 7.93.
In close analogy to the procedure described above, 2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
LC/MS: m/z=221 (MH+)
To a solution of the amide D (1 mol) in toluene (approx. 10 ml per 1 g of the starting compound) phosphorus pentoxide (approx. 1.5 g per 1 g of the starting compound) and phosphorus oxychloride (2-3 mol) are added. The reaction mixture is refluxed for 3 h and cooled to 0° C. Some ice is carefully added to the reaction mixture, and it is stirred for 1 h. Then, the mixture is filtered. The organic layer is separated and washed with water. The combined aqueous layers are washed with benzene, then alkalified with 25% sodium hydroxide, extracted with benzene, dried over Na2SO4 and concentrated on rotary evaporator. Resulting oil is used in the next step without purification.
In close analogy to the procedure described above, N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=214 (MH+)
In close analogy to the procedure described above, N-(2-o-tolyl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Yield: 59%
LC/MS: m/z=160 (MH+)
In close analogy to the procedure described above, N-(2-p-tolyl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=160 (MH+)
In close analogy to the procedure described above, N-[2-(4-chloro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=180 (MH+)
In close analogy to the procedure described above, N-[2-(2-chloro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=180 (MH+)
In close analogy to the procedure described above, N-phenethyl-acetamide is reacted with phosphorus pentoxide to provide the title compound.
1H NMR (CDCl3) δ: 2.38, 2.69, 3.65, 7.15-7.49.
In close analogy to the procedure described above, N-[2-(2-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=163 (MH+)
In close analogy to the procedure described above, N-[2-(4-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=163 (MH+)
In close analogy to the procedure described above, N-[2-(3-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=163 (MH+)
In close analogy to the procedure described above, N-[2-(3-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=163 (MH+)
In close analogy to the procedure described above, N-[2-(2-bromo-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=224 (MH+)
1H NMR (CDCl3) δ: 2.37, 2.79, 3.68, 7.17, 7.44, 7.52.
In close analogy to the procedure described above, N-[2-(4-bromo-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=224 (MH+)
1H NMR (CDCl3) δ: 2.25, 2.64, 3.66, 7.06, 7.47, 7.58.
In close analogy to the procedure described above, N-[2-(3-bromo-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=224 (MH+)
1H NMR (CDCl3) δ: 2.35, 2.67, 3.64, 7.32-7.44.
In close analogy to the procedure described above, N-[2-(2-methoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=175 (MH+)
In close analogy to the procedure described above, N-[2-(4-methoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=175 (MH+)
In close analogy to the procedure described above, N-[2-(2,3-dimethoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=205 (MH+)
In close analogy to the procedure described above, N-[2-(2-trifluormethyl-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=213 (MH+)
In close analogy to the procedure described above, N-[2-(3-methoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=175 (MH+)
In close analogy to the procedure described above, N-(2-Benzo[1,3]dioxol-4-yl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=189 (MH+)
1H NMR (CDCl3) δ: 2.34, 2.65, 3.65, 6.01, 6.72, 7.06.
In close analogy to the procedure described above, N-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
LC/MS: m/z=203 (MH+)
To a solution of compound E (1 mol) in CH2Cl2 (approx. 20 ml per 1 g of the starting compound) sodium borohydride (1.5 mol) is added. The reaction mixture is stirred for 12 h at room temperature. The reaction mixture is poured into saturated sodium bicarbonate solution and stirred for 30 min. The organic layer is separated, and aqueous layer is extracted with chloroform. The combined organic phases are dried over Na2SO4 and concentrated on rotary evaporator. The residue is purified by flash column chromatography on silica gel (eluent: chloroform/methanol—0→20%) to give yellowish oil. Then, 6 N isopropanolic HCl is added to the oil, stirred for 5 min, concentrated on rotary evaporator, triturated with diethyl ether, filtered off, washed with ether and dried in vacuo to give crystalline compound in acceptable yields on 2 steps.
In close analogy to the procedure described above, 1-methyl-7-trifluoromethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Yield: 44% for two steps
LC/MS: m/z=216 (MH+)
In close analogy to the procedure described above, 1,5-dimethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
Yield: 12%
LC/MS: m/z=162 (MH+)
In close analogy to the procedure described above, 1,7-dimethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=162 (MH+)
In close analogy to the procedure described above, 7-chloro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=182 (MH+)
In close analogy to the procedure described above, 5-chloro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=182 (MH+)
In close analogy to the procedure described above, 1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=147 (MH+)
1H NMR (CDCl3) δ: 1.45, 2.67-3.05, 3.21-3.29, 4.12, 7.09-7.14.
In close analogy to the procedure described above, 5-fluoro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=165 (MH+)
1H NMR (CDCl3) δ: 1.50, 2.79-3.35, 4.15, 6.82-7.14.
In close analogy to the procedure described above, 7-fluoro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=165 (MH+)
1H NMR (CDCl3) δ: 1.44, 2.58-2.83, 2.98, 3.25, 4.04, 6.79-7.06.
In close analogy to the procedure described above, 6-fluoro-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=165 (MH+)
1H NMR (CDCl3) δ: 1.44, 2.72-2.92, 3.04, 3.25, 4.05, 6.74, 6.83-6.88, 7.04-7.11.
In close analogy to the procedure described above, 8-fluoro-1-methyl-3,4-dihydro-isoquinolines is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=165 (MH+)
1H NMR (CDCl3) δ: 1.48, 2.75-3.35, 4.34, 6.79-6.89, 7.04-7.15.
In close analogy to the procedure described above, 5-bromo-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=226 (MH+)
1H NMR (CDCl3) δ: 1.44, 1.56, 2.72-2.78, 2.96-3.05, 3.23-3.33, 4.08, 7.01-7.11, 7.39.
In close analogy to the procedure described above, 6-bromo-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=226 (MH+)
1H NMR (CDCl3) δ: 1.42, 1.55, 2.62-2.83, 2.92-3.04, 3.18-3.29, 4.02, 6.99, 7.25, 7.22.
In close analogy to the procedure described above, 7-bromo-1-methyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=226 (MH+)
1H NMR (CDCl3) δ: 1.43, 2.66-2.75, 2.91-3.01, 3.19-3.27, 4.05, 6.92-7.25.
In close analogy to the procedure described above, 1-Methyl-5-methoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=177 (MH+)
1H NMR (CDCl3) δ: 1.45, 1.98, 2.67-2.69, 2.95-3.05, 3.21-3.32, 3.81, 4.03-4.13, 6.68, 6.76, 7.13.
In close analogy to the procedure described above, 1-Methyl-6-methoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=177 (MH+)
1H NMR (CDCl3) δ: 1.43, 2.62-3.28, 3.77, 4.04, 6.60, 6.69-6.74, 7.05.
In close analogy to the procedure described above, 1-Methyl-7-methoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=177 (MH+)
1H NMR (CDCl3) δ: 1.45, 1.6, 2.58-3.00, 3.19-3.30, 3.77, 4.01-4.11, 6.68, 6.70, 6.99.
In close analogy to the procedure described above, 1-Methyl-5,6-dimethoxy-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=207 (MH+)
1H NMR (CDCl3) δ: 1.42, 1.64, 2.73-3.02, 3.20-3.31, 3.79, 3.83, 4.02, 6.73-6.88.
In close analogy to the procedure described above, 1-Methyl-5-trifluoromethyl-3,4-dihydro-isoquinoline is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=215 (MH+)
1H NMR (CDCl3) δ: 1.46, 1.64, 2.96, 3.02-3.07, 3.22-3.32, 4.16, 7.18-7-34, 7.47.
In close analogy to the procedure described above, 6-Methyl-8,9-dihydro-1,3-dioxa-7-aza-cyclopenta[a]naphthalene is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=191 (MH+)
1H NMR (CDCl3) δ: 1.42, 1.62, 2.68, 2.98, 3.27, 4.02, 5.92, 6.64.
In close analogy to the procedure described above, 8-methyl-2,3,5,6-tetrahydro-1,4-dioxa-7-aza-phenanthrene is reacted with sodium triacetoxyborohydride to provide the title compound.
LC/MS: m/z=205 (MH+)
1H NMR (CDCl3) δ: 1.43, 2.49, 2.66, 2.99, 3.25, 4.05, 4.24, 6.63, 6.71.
1 mmol of either isomer of bromo-1,2,3,4-tetrahydro-isoquinoline, 2 eq. of corresponding boronic acid, and 12.5 mol % of Pd(PPh3)4 are placed in a microwave reactor vial (Personal Chemistry). 3 ml of THF and 2 eq of K2CO3 in 1 ml H2O are added via syringe and the vial is purged with argon. The vial is heated by microwaves at 120° C. for 40 minutes. After cooling the mixture is partitioned between CH2Cl2 and water (30 mL each). The organic layer is washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated at reduced pressure. The residue is dissolved in diethyl ether (2 mL) and treated with excess of ethereal solution of hydrogen chloride. The precipitate is collected by filtration, washed and dried to give sufficiently pure title compound as a hydrochloride salt.
In close analogy to the procedure described above, 5-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 6-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 7-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 5-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 6-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 7-Bromo-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=226 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=226 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=226 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=255 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=255 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=255 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=255 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=255 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=255 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=243 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=243 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z 243 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=243 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=243 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=243 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=285 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=285 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=285 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=286 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=286 (MH+)
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
LC/MS: m/z=286 (MH+)
1 mmol of either isomer of bromo-tetrahydroisoquinoline, 1.5 mmol of 2-trimethylstannyl-pyridine, 5 mol. % of Pd(PPh3)4 and 5 mol. % of AsPh3 in 7 ml of toluene are heated at 120° C. for 48 hrs. The reaction mixture is cooled and aqueous 2M K2CO3 solution (5 mL) is added. The mixture is partitioned between EtOAc and water. The organic layer is dried over Na2SO4, filtered through Celite and evaporated. The residue is dissolved in ether (2 mL) and treated with excess ethereal hydrogen chloride solution. The precipitate is filtered, washed with ether and dried to give sufficiently pure title compound as a hydrochloride salt.
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
LC/MS: m/z=225 (MH+)
In close analogy to the procedure described above, 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with 2-trimethylstannyl-pyridine to provide the title compound.
LC/MS: m/z=225 (MH+)
1 mmol of either isomer of bromo-isoquinoline, 1.5 mmol of 2-trimethylstannyl-pyridine, 5 mol. % of Pd(PPh3)4 and 5 mol. % of AsPh3 in 7 ml of toluene are heated at 120° C. for 48 hrs. The reaction mixture is cooled and aqueous 2M K2CO3 solution (5 mL) is added. The mixture is partitioned between EtOAc and water. The organic layer is dried over Na2SO4, filtered through Celite and evaporated. The residue is purified by flash chromatography (eluent hexane/EtOAc=1:1 to 1:3).
The purified product is dissolved in acetic acid and 3.5 eq of NaBH4 is added portionwise. The reaction mixture is stirred for 1 h, then poured into ice and NH4OH is added to pH 9. The mixture is extracted with CH2Cl2 and the organic layer is dried over Na2SO4, filtered and evaporated to give sufficiently pure title compound.
In close analogy to the procedure described above, 7-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 6-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
LC/MS: m/z=211 (MH+)
In close analogy to the procedure described above, 5-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
LC/MS: m/z=211 (MH+)
7-Bromotetrahydroisoquinoline (1 mmol) is dissolved in CH2Cl2 (5 mL) and treated with 1.2 eq. of Boc2O in the presence of 0.1 eq. of DMAP. The reaction mixture is left overnight stirring overnight. The solution is washed with 1M HCl, aq. NaHCO3, and brine. The organic layer is dried over Na2SO4, filtered and evaporated. The product is purified by flash chromatography (eluent hexane:EtOAc=5:1).
LC/MS: m/z=313 (MH+)
1H NMR (CDCl3) δ: 1.48, 2.77, 3.62, 4.53, 7.02, 7.25, 7.29.
The purified N-Boc protected 7-bromotetrahydroisoquinoline, 0.1 eq. Pd2(dba)3 0.15 eq. BINAP, 2.0 eq. Cs2CO3, 1.5 eq. of morpholine are dissolved in toluene (3 mL) and the mixture is heated at 120° C. for 48 hrs, cooled and evaporated at reduced pressure. The residue is dissolved in EtOAc and washed with water and brine. Organic layer is washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude product is purified by flash chromatography (eluent hexane:EtOAc=3:1).
LC/MS: m/z=319 (MH+)
1H NMR (CDCl3) δ: 1.48, 2.75, 3.11, 3.62, 3.85, 4.53, 6.64, 6.76, 7.04.
The obtained compound is dissolved in CH2Cl2 containing 20% TFA, and left stirring for 1 h. The reaction mixture is washed with aq. NaHCO3, water and brine, the organic layer is dried over Na2SO4, filtered and evaporated to give sufficiently pure title compound as colorless oil.
LC/MS: m/z=220 (MH+)
1H NMR (CDCl3) δ: 2.71, 3.10, 3.85, 3.97, 6.55, 6.74, 7.00.
General Scheme for Final Coupling:
Acid G (1 equiv., 0.4 mmol) is mixed with TBTU (1.1 equiv., 0.145 g, 0.45 mmol) in dry CH3CN. Then, Et3N (2.5 equiv., 0.14 mL, 1 mmol) is added. The corresponding amine (1 equiv., 0.4 mmol) is added. The reaction is stirred at 50° C. for 2 h to adjust full resolution of the acid. Then, the reaction is carried out at room temperature. The reaction is monitored with TLC. When the reaction is over, some water is added to the reaction mixture. If a precipitate formed it is filtered off, ished with 5% ammonia solution and ether. If an oil formed it is extracted with methylene chloride and separated on a column (different systems) providing the final compounds in good to moderate yields.
The following compounds according to the invention are prepared as examples, which are intended as an illustration of and not a limitation upon the scope of the invention:
To a solution of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.4 g, 5.8 mmol, 1.0 equiv) and TBTU (2.0 g, 6.2 mmol, 1.1 equiv) in dry acetonitrile (30 mL) triethylamine (2 mL, 14.5 mmol, 2.5 equiv) is added. 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol (1.4 g, 7.25 mmol, 1.25 equiv) is then added. The reaction mixture is stirred at 50° C. for 2 h, then at room temperature for 8 h, and concentrated. The residue is extracted with dichloromethane. The extract is washed with water (20 ml), dried over sodium disulfate, and concentrated. The residue is purified by column chromatography on silica gel (eluent: hexane/ethyl acetate—1/1, Rf 0.3) to provide 0.511 g of the title compound as an oil.
Yield: 21%
LC/MS: m/z=417 (MH+)
1H NMR (CDCl3) δ: 1.62, 2.70, 3.02, 3.55, 3.90, 4.45, 5.73, 6.70, 7.08, 8.53, 8.85.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 64%
LC/MS: m/z 328 (MH+)
1H NMR (d6-DMSO) δ: 1.63, 1.69, 3.02, 3.30, 3.63, 4.71, 4.98, 5.69, 5.85, 7.12, 7.19, 7.32, 8.46, 8.51, 8.75.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=327 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=372 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=386 (MH+)
1H NMR (CDCl3) δ: 1.96, 2.94, 3.72, 6.98, 7.08-7.38, 8.52, 8.84.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=341 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=392 (MH+)
1H NMR (d6-DMSO) δ: 9.6, 8.7, 7.0-7.4, 4.9, 3.9, 2.9.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=387 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z 373 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
LC/MS: m/z=418 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
LC/MS: m/z=432 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1,2,3′,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a solid.
LC/MS: m/z=404 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a solid.
LC/MS: m/z=359 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a colorless solid.
LC/MS: m/z=373 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
LC/MS: m/z=432 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
LC/MS: m/z=387 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a colorless solid.
LC/MS: m/z=446 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
LC/MS: m/z=401 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=373 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-methyl-5,6,7,8-tetrahydro-[1,7]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=328 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=373 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=328 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound.
Yield: 54%
LC/MS: m/z=374 (MH+)
1H NMR (CDCl3) δ: 1.63, 1.68, 3.02, 3.19-3.39, 3.62, 4.71, 4.98, 5.69, 5.85, 7.11, 7.19, 7.33, 7.52, 8.46, 8.55, 8.85.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=328 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=373 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=328 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
A solution of 28 mg (0.12 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 19 mg (0.13 mmol) of 1-methyl-1,2,3,4-tetrahydro-isoquinoline, 23 mg (0.12 mmol) of EDC and 19 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo. Purification of the residue by flash column chromatography (chloroform:methanol 99:1) gives 26 mg (58%) of title compound as a crystalline solid.
Physical characteristics are as follows:
Mp 121-123° C., 1H NMR (CDCl3) δ: 1.65, 2.74-3.62, 4.47 and 4.82, 5.55 and 5.80, 6.97-7.23, 8.52, 8.82.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
LC/MS: m/z=358 (MH+)
A solution of 80 mg (0.33 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 66 mg (0.40 mmol) of 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline, 63 mg (0.33 mmol) of EDC and 50 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo.
Purification of the residue by flash column chromatography (methylene chloride:ether 92:8) gives 20 mg (16%) of title compound as a crystalline solid.
Physical characteristics are as follows:
Mp 174-176° C., 1H NMR (CDCl3) δ: 1.63, 2.58-3.59, 4.50 and 4.83, 5.58 and 5.78, 6.67-7.13, 8.53, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=390 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=390 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=390 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=345 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=345 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=345 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=345 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=404 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=404 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=404 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=404 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=359 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=359 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=359 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=359 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=444 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=444 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=444 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=444 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=399 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=399 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=399 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=399 (MH+)
The stereoisomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Ethyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=400 (MH+)
1H NMR (CDCl3) δ: 1.58; 1.72; 2.72; 3.13; 4.54; 4.91; 5.45; 5.70; 6.98; 7.01-7.22; 8.52; 8.82. The four diastereomers can be separated. They have different activities.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=372 (MH+)
1H NMR (CDCl3) δ: 1.18-1.25; 2.65; 3.24; 4.56; 4.97; 5.28; 7.05; 7.16-7.22; 8.53; 8.84.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=372 (MH+)
1H NMR (CDCl3) δ: 1.18-1.25; 2.65; 3.24; 4.56; 4.97; 5.28; 7.05; 7.16-7.22; 8.53; 8.84.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the titles-configurated compound in moderate yield.
LC/MS: m/z=327 (MH+).
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=392 (MH+)
In close analogy to the procedure described in. Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=437 (MH+)
1H NMR (CDCl3) δ: 2.93; 4.04; 4.91; 5.05; 7.04; 7.11; 7.32; 7.54; 8.83.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=445 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=341 (MH+)
1H NMR (CDCl3) δ: 1.34, 1.65, 2.91, 3.11-3.21, 4.41, 4.81, 5.54, 5.82, 6.95-7.36, 8.49, 8.73. The diasteromers of this compound are separated. The different configurated compounds (R,R), (R,S), (S,R) and (S,S) have different activities.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,4-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=386 (MH+)
1H NMR (CDCl3) δ: 1.29, 1.40, 1.64, 2.85-3.21, 4.37, 4.77, 5.50, 5.78, 6.95-7.37, 8.53, 8.84.
The diasteromers of this compound are separated. The different configurated compounds have different activities.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=402 (MH+)
1H NMR (CDCl3) δ: 1.60, 2.77, 2.88-3.61, 3.78, 4.45, 4.82, 5.47, 5.75, 6.66-7.09, 7.14, 8.67, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=357 (MH+)
1H NMR (CDCl3) δ: 1.60, 2.70-3.61, 3.78, 4.45, 4.80, 5.47, 5.75, 6.66-7.13, 8.48, 8.72.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=385 (MH+)
1H NMR (CDCl3) δ: 0.94; 1.09; 1.83-2.04; 2.82-3.67; 4.39-4.47-; 4.68-4.81; 5.47-5.55; 5.74; 7.04; 7.13-7.21; 8.53; 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Isopropyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=399 (MH+)
1H NMR (CDCl3) δ: 0.89; 1.00; 1.08-1.13; 2.04-2.25; 2.90-3.15; 3.49-3.87; 4.25-4.38; 4.56-4.69; 5.17; 5.50; 6.99; 7.11-7.23; 8.51; 8.81.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Isopropyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=355 (MH+)
1H NMR (CDCl3) δ: 0.89; 1.00; 1.08-1.13; 2.04-2.23; 2.90-3.14; 3.49-3.87; 4.25-4.37; 4.55-4.69; 5.17; 5.50; 6.99; 7.11-7.23; 8.51; 8.81.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=341 (MH+)
1H NMR (CDCl3) δ: 0.94; 1.09; 1.90-2.01; 2.60-3.68; 4.37-4.47-; 4.70-4.81; 5.47-5.55; 5.74; 7.06; 7.13-7.22; 8.48; 8.72.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=425 (MH+)
1H NMR (CDCl3) δ: 2.84-3.91; 4.72-4.98; 7.14; 7.22-7.47; 8.55; 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=381 (MH+)
1H NMR (CDCl3) δ: 2.83-3.91; 4.69-4.97; 7.15; 7.23-7.47; 8.50; 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.62, 2.685-3.425, 3.50, 5.61, 5.76, 6.98-7.33, 8.53, 8.82.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=406 (MH+)
1H NMR (CDCl3) δ: 1.63, 2.77, 2.95-3.33, 3.51, 4.53, 4.83, 5.77, 6.99-7.34, 8.49, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Cyclohexyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=439 (MH+)
1H NMR (CDCl3) δ: 0.91-1.26; 1.55-1.92; 2.85-3.14; 3.48-3.87; 4.23-4.36; 4.53-4.68; 5.15; 5.50; 6.99; 7.15-7.19; 8.51; 8.81.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Cyclohexyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=395 (MH+)
1H NMR (CDCl3) δ: 1.08-1.26; 1.51-1.93; 2.86-3.15; 3.48-3.87; 4.24-4.36; 4.54-4.64; 5.18; 5.50; 6.98; 7.01-7.20; 8.51; 8.82.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Propyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=400 (MH+)
1H NMR (CDCl3) δ: 0.85, 0.99, 1.21-2.04, 2.72-3.46, 3.62, 4.44, 5.75, 5.64, 5.81, 6.99-7.20, 8.52, 8.82.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(S)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=372 (MH+)
1H NMR (CDCl3) δ: 1.63; 2.74-89; 3.06-3.32; 3.55; 4.47; 4.83; 5.55; 5.81; 7.07; 7.15-7.22; 8.54; 8.84.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(R)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=372 (MH+)
1H NMR (CDCl3) δ: 1.63; 2.74-89; 3.06-3.32; 3.55; 4.47; 4.83; 5.55; 5.81; 7.07; 7.15-7.22; 8.54; 8.84.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=406 (MH+)
1H NMR (CDCl3) δ: 1.63, 2.98, 3.25-3.59, 4.61, 4.75, 5.63, 5.77, 6.97-7.16, 7.46, 8.49, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=402 (MH+)
1H NMR (CDCl3) δ: 1.63; 2.77-2.89; 3.15-3.55; 4.48; 4.89; 5.52; 5.59; 6.61-6.84; 7.05; 7.06-7.20; 8.53; 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.65, 2.96-3.03, 3.19-3.34, 3.44-3.59, 4.61, 4.91, 5.62, 5.8, 6.94-7.19, 7.45, 8.54, 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 3.05, 4.10, 5.02, 5.16, 7.12, 7.30, 7.48, 8.54, 8.66, 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=401 (MH+)
1H NMR (CDCl3) δ: 1.62, 1.65, 2.64-2.84, 2.94-3.16, 3.20-3.37, 3.45-3.61, 3.75, 3.81, 4.39-4.49, 4.75-4.87, 5.51, 5.77, 6.50, 6.73, 6.74-6.79, 7.01-7.10, 8.53, 8.82-8.85.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=357 (MH+)
1H NMR (CDCl3) δ: 1.62, 1.65, 2.65-2.85, 2.95-3.16, 3.21-3.37, 3.45-3.61, 3.75, 3.81, 4.39-4.49, 4.76-4.87, 5.51, 5.77, 6.51, 6.73, 6.75-6.79, 7.02-7.10, 8.49, 8.70-8.75.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.61, 2.77, 3.03-3.33, 3.52, 4.52, 4.81, 5.57, 5.72, 7.05-7.09, 7.29-7.37, 8.53, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,6-Dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=432 (MH+)
1H NMR (CDCl3) δ: 1.60, 2.93-3.01, 3.15-3.27, 3.39-3.54, 3.82, 4.47, 4.84, 5.48, 5.75, 6.68-6.99, 7.06, 8.53, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,8-Difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=408 (MH+)
1H NMR (CDCl3) δ: 1.59, 1.65, 2.93, 3.26, 3.49, 4.62, 4.91, 5.84, 5.99, 6.80-6.93, 7.09, 8.54, 8.85.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,8-Difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=363 (MH+)
1H NMR (CDCl3) δ: 1.60, 1.65, 2.87-2.98, 3.24, 3.50, 4.64, 4.91, 5.84, 6.00, 6.80-6.93, 7.10, 8.49, 8.74.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=439 (MH+)
1H NMR (CDCl3) δ: 1.58-1.71; 3.02-3.63; 4.58-4.65; 4.81-4.89; 5.66-5.88; 7.11; 7.20-7.56; 8.54; 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=395 (MH+)
1H NMR (CDCl3) δ: 1.57-1.71; 3.11-3.64; 4.57-4.65; 4.82-4.87; 5.66-5.88; 7.09; 7.21-7.56; 8.48; 8.73
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=328 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Bromo-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound.
Yield: 66%
LC/MS: m/z=394 (MH+)
1H NMR (d6-DMSO) δ: 2.97, 4.02, 4.89, 4.96, 7.07, 7.12, 7.79, 8.07, 8.53, 8.72, 9.65.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (DMSO-d6) δ: 1.60, 2.82-2.98, 4.29, 4.63, 5.34, 5.70, 7.05, 7.50-7.74, 7.98-8.05, 8.70-8.83, 9.19, 9.65.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(5-Bromo-pyridin-3-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=514 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.70, 2.88, 3.11-3.41, 3.59, 4.52, 5.37, 5.66, 5.90, 7.09, 7.20-7.39, 7.83, 8.54, 8.58, 8.77, 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-7-carbonitrile to provide the title compound in moderate yield.
LC/MS: m/z=383 (MH+)
1H NMR (CDCl3) δ: 3.05, 4.05, 4.13, 4.96, 5.15, 7.13, 7.32, 7.48, 8.55, 8.84.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.70, 2.81-2.96, 3.08-3.41, 3.59, 4.57, 4.88, 5.71, 5.91, 7.10, 7.29, 7.42-7.51, 8.54, 8.66, 8.85.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=402 (MH+)
1H NMR (CDCl3) δ: 3.29, 4.04, 4.15, 5.03, 5.22, 7.16, 7.29-7.53, 7.89, 8.55, 8.86.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=358 (MH+)
1H NMR (CDCl3) δ: 3.29, 4.04, 4.15, 5.03, 5.22, 7.16, 7.29-7.53, 7.89, 8.50, 8.75.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
1H NMR (CDCl3) δ: 1.70, 2.90, 2.97-3.41, 3.33, 4.59, 4.88, 5.73, 5.91, 7.10, 7.20-7.42, 8.54, 8.84-8.88, 8.94, 9.19
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
1H NMR (CDCl3) δ: 2.89, 3.11, 3.85, 4.02, 4.90, 4.97, 6.25, 6.77, 7.09, 8.53, 8.82.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=398 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=398 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=398 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=398 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
1H NMR (DMSO-d6) δ: 1.55, 2.81-3.59, 4.27, 4.62, 5.35, 5.69, 7.04, 7.23, 7.51, 7.64, 8.70, 9.13, 9.67.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
1H NMR (CDCl3) δ: 1.68, 2.57, 2.95-3.54, 4.53, 4.78, 5.72, 5.86, 7.086-7.15, 7.29-7.41, 8.52, 8.72, 8.85, 9.21.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
1H NMR (DMSO-d6) δ: 1.57, 2.92-3.47, 4.35, 4.49, 5.43, 5.72, 7.05, 7.27-7.54, 8.08-8.14, 8.63, 8.69, 8.97, 9.65.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Bromo-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound.
Yield: 62%
LC/MS: m/z=440 (MH+)
1H NMR (CDCl3) δ: 3.12, 4.14, 4.23, 4.95, 5.15, 7.15, 7.51, 7.67, 8.52, 8.56, 8.84.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 16%
LC/MS: m/z=396 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 18%
LC/MS: m/z=440 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 60%
LC/MS: m/z=341 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 58%
LC/MS: m/z=341 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 55%
LC/MS: m/z=386 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 19%
LC/MS: m/z=385 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 54%
LC/MS: m/z=363 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 46%
LC/MS: m/z=407 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Yield: 61%
LC/MS: m/z=363 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
LC/MS: m/z=370 (MH+)
1H NMR (CDCl3) δ: 2.17-2.22, 2.83-2.88, 4.03-4.14, 4.96, 5.08, 6.83-6.93, 7.08-7.23, 7.43-7.61, 8.49, 8.73.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1,2,3,4-Tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
LC/MS: m/z=414 (MH+)
1H NMR (CDCl3) δ: 2.17-2.27, 2.82-2.92, 4.00-4.15, 4.95, 5.07, 6.83-6.99, 7.05-7.23, 7.44-7.64, 8.54, 8.83.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
LC/MS: m/z=384 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
LC/MS: m/z=429 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.
LC/MS: m/z=384 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide to provide the title compound in moderate yield.
LC/MS: m/z=398 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-2,3,5,6,7,8-hexahydro-1,4-dioxa-7-aza-phenanthrene to provide the title compound in moderate yield.
LC/MS: m/z=429 (MH+)
1H NMR (CDCl3) δ: 1.51-1.63, 2.80-2.85, 3.11-3.28, 3.36-3.55, 4.25-4.29, 4.40-4.53, 4.81-4.93, 5.38-5.52, 5.68-5.80, 6.47, 6.65-6.83, 7.04, 8.53, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-5-carbonitrile to provide the title compound in moderate yield.
LC/MS: m/z=383 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-7-carbonitrile to provide the title compound in moderate yield.
LC/MS: m/z=383 (MH+)
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 3.04-3.11, 4.03-4.16, 5.01, 5.12, 7.12, 7.30-7.36, 7.45-7.57, 8.54, 8.64, 8.84.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=390 (MH+)
1H NMR (CDCl3) δ: 3.04-3.12, 4.05-4.16, 5.01, 5.12, 7.13, 7.29-7.36, 7.44-7.53, 8.50, 8.64, 8.73.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=405 (MH+)
1H NMR (CDCl3) δ: 1.68, 2.91, 3.14-3.40, 3.59, 4.58, 4.89, 5.67, 5.87, 7.12, 7.31-7.49, 8.49, 8.65, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.67, 2.83-2.97, 3.13-3.40, 3.58, 4.57, 4.89, 5.66, 5.86, 7.09, 7.14, 7.26-7.52, 8.53, 8.64, 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-6,7,8,9-tetrahydro-1,3-dioxa-7-aza-cyclopenta[a]naphthalene to provide the title compound in moderate yield.
LC/MS: m/z=416 (MH+)
1H NMR (CDCl3) δ: 2.95, 3.98-4.09, 4.94, 6.88, 7.08, 7.35, 8.54, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.73, 2.59-2.71, 3.03-3.46, 3.53, 4.57, 4.77, 5.75, 5.93, 7.17-7.20, 7.36-7.78, 8.59, 8.73, 8.90.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=405 (MH+)
1H NMR (CDCl3) δ: 1.69, 2.53-2.65, 2.99-3.23, 3.64, 4.44, 4.72, 5.69, 5.87, 7.10-7.12, 7.30-7.71, 8.48, 8.67-8.76.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=437 (MH+)
1H NMR (CDCl3) δ: 1.54, 2.73-3.02, 3.21-3.35, 3.50, 4.49, 4.84, 5.52, 5.80, 5.96, 6.46, 6.63-6.77, 7.06, 8.53, 8.83.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=435 (MH+)
1H NMR (CDCl3) δ: 3.07, 4.08, 5.04, 7.10-7.33, 7.72-7.85, 8.54, 8.68, 8.84.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=449 (MH+)
1H NMR (CDCl3) δ: 1.67, 2.85-2.98, 3.12-3.35, 3.58, 4.75, 4.87, 5.64, 5.86, 7.10, 7.23-7.33, 7.67-7.83, 8.54, 8.69, 8.85.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=405 (MH+)
1H NMR (CDCl3) δ: 1.67, 2.85-2.99, 3.12-3.35, 3.58, 4.54, 4.87, 5.64, 5.87, 7.09, 7.19-7.33, 7.72-7.83, 8.49, 8.67-8.74.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=405 (MH+)
1H NMR (CDCl3) δ: 1.71, 2.88, 3.11-3.42, 3.62, 4.53, 4.85, 5.70, 5.91, 7.08, 7.23, 7.70-7.84, 8.49, 8.64-8.75.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=437 (MH+)
1H NMR (CDCl3) δ: 3.01, 4.08, 5.01, 6.94-7.19, 7.46, 8.54, 8.84.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=392 (MH+)
1H NMR (CDCl3) δ: 3.01, 4.08, 5.01, 6.94-7.19, 7.46, 8.49, 8.73.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=435 (MH+)
1H NMR (CDCl3) δ: 3.04, 3.96, 5.06, 7.06-7.10, 7.23-7.42 7.77, 8.52, 8.68, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=510 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.43-3.56, 3.96, 4.04-4.48, 4.71-4.76, 5.61-5.75, 5.80-5.90, 7.06-7.10, 7.20-7.35, 8.09, 8.51.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=465 (MH+)
1H NMR (CDCl3) δ: 1.63, 1.70, 2.42-3.54, 3.97, 4.04, 4.40-4.47, 4.71-4.76, 5.62-5.72, 5.81-5.92, 7.05-7.11, 7.23-7.32, 8.08, 8.47, 8.72.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=509 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.38-3.59, 3.91, 3.96, 4.35-4.40, 4.68-4.74, 5.62, 5.84, 6.37, 6.98-7.39, 8.50-8.53, 8.76-8.86.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=465 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.38-3.60, 3.91, 3.96, 4.35-4.40, 4.68-4.75, 5.62, 5.84, 6.37, 6.98-7.39, 8.45-8.49, 8.67-8.76.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.71, 2.50-3.54, 4.45-4.53, 4.69-4.77, 5.64-5.74, 5.81-5.91, 6.97-7.38, 7.70-7.79, 8.18; 8.52, 8.81-8.87.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=422 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.71, 2.50-3.54, 4.47-4.52, 4.69-4.78, 5.64-5.74, 5.81-5.91, 6.97-7.38, 7.70-7.79, 8.18, 8.47-8.50, 8.70-8.76.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=479 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.34-3.63, 3.92, 4.39, 4.70, 5.62-5.69, 5.82-5.89, 6.93-7.48, 8.19-8.21, 8.51-8.55, 8.77-8.87.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 1.67, 1.69, 2.33-3.55, 3.92, 4.32-4.46, 4.64-4.74, 5.62-5.69, 5.83-5.89, 6.93-7.48, 8.18-8.21, 8.46-8.50, 8.67-8.75.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 1.65, 1.70, 2.56-3.54, 3.98, 4.41-4.47, 4.69-4.76, 5.62-5.73, 5.81-5.91, 6.80, 7.03-7.14, 7.29-7.36, 7.53-7.57, 8.10-8.14, 8.47-8.50, 8.70-8.76.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=479 (MH+)
1H NMR (CDCl3) δ: 1.63, 1.70, 2.57-3.62, 3.98, 4.41-4.48, 4.69-4.75, 5.62-5.72, 5.80-5.90, 6.80, 7.03-7.14, 7.20-7.36, 7.50-7.57, 8.12, 8.50-8.55, 8.81-8.86.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=479 (MH+)
1H NMR (CDCl3) δ: 1.65, 1.69, 2.79-3.66, 3.96, 3.98, 4.47-4.55, 4.85-4.91, 5.55-5.65, 5.80-5.90, 6.94-7.07, 7.29-7.62, 7.55-7.62, 8.15, 8.53, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 1.65, 1.70, 2.79-3.66, 3.96, 3.97, 4.47-4.55, 4.82-4.92, 5.55-5.65, 5.80-5.90, 6.94-7.08, 7.29-7.45, 7.55-7.62, 8.14-8.18, 8.48, 8.74.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.82-3.66, 4.51-4.60, 4.84-4.91, 5.61-5.70, 5.85-5.91, 7.09-7.12, 7.29-7.45, 7.82-7.91, 8.19, 8.54, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=422 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.80-3.66, 4.51-4.61, 4.84-4.91, 5.61-5.70, 5.81-5.91, 7.10-7.12, 7.24-7.45, 7.80-7.91, 8.19, 8.48, 8.72.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.69, 2.83-3.66, 4.53-4.61, 4.86-4.91, 5.61-5.71, 5.82-5.91, 6.98-7.13, 7.32-7.43, 7.91-8.00, 8.40, 8.54, 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=422 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.70, 2.83-3.65, 4.53-4.60, 4.86-4.92, 5.61-5.71, 5.82-5.91, 6.98-7.13, 7.32-7.43, 7.90-8.00, 8.40-8.51, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=509 (MH+)
1H NMR (CDCl3) δ: 1.64, 1.68, 2.84-3.64, 3.95, 3.96, 4.47-4.53, 4.81-4.90, 5.51-5.61, 5.78-5.87, 6.99-7.06, 7.21-7.42, 7.51-7.57, 8.53; 8.82.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=464 (MH+)
1H NMR (CDCl3) δ: 1.64, 1.67, 2.77-3.65, 3.95, 3.96, 4.44-4.53, 4.81-4.90, 5.51-5.61, 5.78-5.90, 6.36-6.40, 7.00-7.07, 7.21-7.42, 7.51-7.57, 8.48, 8.72.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=509 (MH+)
1H NMR (CDCl3) δ: 1.69, 2.79-3.65, 4.01, 4.04, 4.51, 4.86, 5.56-5.66, 5.83-5.90, 7.08, 7.30-7.39, 8.23, 8.53, 8.28-8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=464 (MH+)
1H NMR (CDCl3) δ: 1.66, 2.78-3.64, 4.00, 4.03, 4.53, 4.85, 5.55-5.65, 5.78-5.88, 7.05, 7.26-7.38, 8.22, 8.47, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(6-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 1.69, 2.77-3.66, 3.95, 3.99, 4.48-4.57, 4.82-4.91, 5.61-5.71, 5.83-5.93, 6.75-6.85, 7.10-7.36, 7.68-7.80, 8.30-8.50, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=434 (MH+)
1H NMR (CDCl3) δ: 1.64, 1.70, 2.78-3.65, 3.93, 3.98, 4.47-4.55, 4.82-4.88, 4.82-4.88, 5.56-5.66, 5.82-5.92, 6.90-7.40, 7.55-7.61, 8.11, 8.50, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z==510 (MH+)
1H NMR (CDCl3) δ: 1.64, 1.70, 2.78-3.65, 3.99, 4.03, 4.47-4.61, 4.81-4.91, 5.57-5.67, 5.82-5.92, 7.08, 7.18-7.33, 8.22, 8.54, 8.84.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=465 (MH+)
1H NMR (CDCl3) δ: 1.62, 1.70, 2.78-3.65, 3.99, 4.03, 4.47-4.55, 4.81-4.91, 5.57-5.66, 5.82-5.92, 7.08, 7.18-7.33, 8.22, 8.49, 8.73.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
1H NMR (CDCl3) δ: 1.67, 1.71, 2.81-3.66, 4.51-4.60, 4.83-4.91, 5.62-5.72, 5.84-5.94, 7.09, 7.23-7.42, 7.78-7.91, 8.16-8.22, 8.53, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=422 (MH+)
1H NMR (CDCl3) δ: 1.66, 1.71, 2.08-3.67, 4.51-4.60, 4.83-4.91, 5.62-5.72, 5.84-5.94, 7.10, 7.23-7.39, 7.78-7.91, 8.15-8.22, 8.49, 8.74.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
1H NMR (CDCl3) δ: 1.69, 2.51-3.57, 4.47, 4.72, 5.64-5.74, 5.81-5.92, 7.09, 7.22-7.34, 7.72, 8.23, 8.51, 8.83.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=422 (MH+)
1H NMR (CDCl3) δ: 1.69, 2.45-3.58, 4.46, 4.73, 5.64-5.73, 5.81-5.91, 7.10, 7.15-7.34, 7.71, 8.25, 8.48, 8.70.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-furan-2-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(5-methyl-furan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-furan-3-yl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[8-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[7-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[6-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=467 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[5-(3,5-dimethyl-isoxazol-4-yl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=438 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=452 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(3-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=440 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-8-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=440 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=440 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-(2H-tetrazol-5-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=440 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(2H-tetrazol-5-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=373 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-methanone is synthesized in a similar way.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-[2,6]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=373 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-3,4-dihydro-1H-[2,6]naphthyridin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine to provide the title compound in moderate yield.
LC/MS: m/z=374 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine to provide the title compound in moderate yield.
LC/MS: m/z=374 (MH+).
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=417 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=417 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=417 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=417 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-8-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-nitro-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
LC/MS: m/z=418 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(1-methyl-5-nitro-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrile to provide the title compound in moderate yield.
LC/MS: m/z=397 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrile is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester to provide the title compound in moderate yield.
LC/MS: m/z=430 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid methyl ester is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-6,7,8,9-tetrahydro-3-oxa-1,7-diaza-cyclopenta[a]naphthalene to provide the title compound in moderate yield.
LC/MS: m/z=427 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2,6-dimethyl-8,9-dihydro-6H-3-oxa-1,7-diaza-cyclopenta[a]naphthalen-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-1,2,3,4-tetrahydro-[3,7]phenanthroline to provide the title compound in moderate yield.
LC/MS: m/z=423 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2,6-dimethyl-8,9-dihydro-6H-thiazolo[4,5-f]isoquinolin-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-6,7,8,9-tetrahydro-thiazolo[4,5-f]isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(2,6-dimethyl-8,9-dihydro-6H-thiazolo[4,5-f]isoquinolin-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=450 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methanesulfonyl-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,7-Dimethyl-1,2,3,4,7,8,9,10-octahydro-[3,7]phenanthroline to provide the title compound in moderate yield.
LC/MS: m/z=441 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4,7-dimethyl-1,4,7,8,9,10-hexahydro-2H-[3,7]phenanthrolin-3-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-ethanone to provide the title compound in moderate yield.
LC/MS: m/z=414 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
1-[2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl]-ethanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-ethanone to provide the title compound in moderate yield.
LC/MS: m/z=414 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid methyl ester is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-ethanone to provide the title compound in moderate yield.
LC/MS: m/z=414 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
2-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid methyl ester is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
LC/MS: m/z=485 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
((6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-5-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
LC/MS: m/z=485 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-7-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
LC/MS: m/z=485 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-[1-methyl-6-(morpholine-4-carbonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-6,7,8,9-tetrahydro-furo[3,2-f]isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=412 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-methyl-8,9-dihydro-6H-furo[3,2-f]isoquinolin-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,6-Dimethyl-6,7,8,9-tetrahydro-3H-pyrrolo[3,2-f]isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=425 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(3,6-dimethyl-3,6,8,9-tetrahydro-pyrrolo[3,2-f]isoquinolin-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=412 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-methyl-5,8-dihydro-6H-furo[3,2-g]isoquinolin-7-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-1,2,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-3-one to provide the title compound in moderate yield.
LC/MS: m/z=441 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
7-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-2,6-dimethyl-1,2,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-3-one is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-2,3,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-1-one to provide the title compound in moderate yield.
LC/MS: m/z=441 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
7-(6-Chloro-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-2,6-dimethyl-2,3,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-1-one is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(6-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-amine to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(5-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-amine to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(8-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amine to provide the title compound in moderate yield.
LC/MS: m/z=443 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-diethylamino-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-methanone is synthesized in a similar way.
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=408 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=363 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dichloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=441 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dichloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=395 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dibromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=530 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dibromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=485 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=457 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=412 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=457 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=412 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=457 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=412 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=457 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=412 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-piperidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z 456 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-piperidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=410 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=441 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-pyrrolidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
LC/MS: m/z=396 (MH+)
The stereo-isomers of this compound are separated. The S-configurated compound has a different activity than the R-configurated compound.
The pure stereoisomeric forms (including optical isomers) of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers (optically active isomers) may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselectively. Stereoisomeric forms of Formula (I) are included within the scope of this invention.
For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form.
Pharmaceutical Compositions
The active ingredients of formula (I) of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use.
Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
The term “carrier” applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A.R. Gennaro, 20th Edition, describes suitable pharmaceutical carriers in “Remington: The Science and Practice of Pharmacy”.
Method of Treating and Pharmaceutical Formulations
Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of formula (I) of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1-1000 milligrams daily, preferably 10-500 milligrams daily, and especially 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
The active agents of formula (I) of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20th Edition). The orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
For oral administration in the form of a tablet or capsule, the active drug component of formula (I) may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the drug components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
The tablets containing as active compound a compound of formula (I) may be coated by methods well known in the art. The compositions of the invention containing as active compound a compound of formula (I) may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
The active drugs of formula (I) may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
Drugs of the invention containing as active compound a compound of formula (I) may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drugs may also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
For administration by inhalation, the therapeutics according to the present invention containing as active compound a compound of formula (I) may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The formulations of the invention containing a compound of formula (I) may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
Compositions of the present invention containing a compound of formula (I) may also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
The compositions containing a compound of formula (I) may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio ED50/LD50. Compositions that exhibit large therapeutic indices are preferred.
Examples of Representative Pharmaceutical Compositions
With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions containing a compound of formula (I) according to the present invention follow:
(a) Tablets suitable for oral administration which contain the active ingredient, may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
The following examples are given by way of illustration. As active ingredient, the compound according to example 1 can be used as active ingredient.
A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
Another suitable formulation for a tablet containing 100 mg is as follows:
A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
This formulation is filled in a gelatin capsule.
A suitable formulation for an injectable solution is as follows:
A suitable formulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
180 g of the aerosol solution contain:
15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.
100 g of the solution contain:
1.8 ml of the solution is placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use.
10 g of polybutylcyanoacrylate nanoparticles contain:
Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCl/ethanol mixture as polymerization medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
1.0 g of the suspension contains the following:
Hypromellose is dispersed in water homogeneously with a high speed mixer/blender. After about one hour of hydration time of the hypromellose, the active ingredient is blended homogeneously into the hypromellose solution. The viscosity of the suspension can be adjusted by the amount of hypromellose, resulting in a very stable suspension with a very slow tendency of particle sedimentation and particle agglomeration.
1.0 ml of solution contain:
The active ingredient is dissolved in DMSO by stirring and heating (solution 1). The mannitol is dissolved in WFI (solution 2). After cooling down to room temperature solution 1 is mixed with solution 2 by continuous stirring. The solution is sterilized by filtration of by autoclaving.
Pharmacology
The active principles of the present invention, and pharmaceutical compositions containing them and method of treating therewith, are characterized by unique and advantageous properties. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics
Methods
Binding Assays for the Characterization of mGluR5 Antagonists [3H]-MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes.
Preparation of Rat Cortical Membranes:
Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000×g for 10 minutes. The pellet is discarded and the supernatant centrifuged at 20,000×g for 20 minutes. The resulting pellet is re-suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000×g. Then the supernatant and the buffy coat are centrifuged at 48,000×g for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. The pellet is then re-suspended and centrifuged two to three more times at 48,000×g for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. All centrifugation steps are carried out at 4° C. After resuspension in 5 volumes of 50 mM Tris-HCl, pH 8.0 the membrane suspension is frozen rapidly at −80° C.
On the day of assay the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCl, pH 8.0 and centrifugation at 48,000×g for 20 minutes and finally re-suspended in 50 mM Tris-HCl, pH 7.4. The amount of protein in the final membrane preparation (500-700 μg/ml) is determined according to the method of Lowry (Lowry O. H. et al. 1951. J. Biol. Chem. 193, 256-275).
[3H]-MPEP Assay
Incubations are started by adding [3H]-MPEP (50.2 Ci/mmol, 5 nM, Tocris, GB) to vials with 125-250 μg protein (total volume 0.25 ml) and various concentrations of the agents. Alternatively, assays are performed with [3H]-MMPEP (2-(3-methoxyphenylethynyl)-6-methylpyridine hydrochloride) as radioligand. The incubations are continued at room temperature for 60 minutes (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 μM). Incubations are terminated using a Millipore filter system. The samples are rinsed twice with 4 ml of ice-cold assay buffer over glass fibre filters (Schleicher & Schuell, Germany) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Canberra Packard, Germany).
Characterization:
Specific binding is extremely high i.e. normally>85% and essentially independent of buffer (Tris or HEPES both 50 mM) and pH (6.8-8.9). There is a clear saturable protein dependence and the chosen protein concentration used for subsequent assays (500-700 μg/ml) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC50 of 11.2±0.64 nM. The Kd of [3H]-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC50 Of cold MPEP equates to a Ki of 8.2 nM). Bmax is 0.56 pm/mg protein.
Functional Assays of mGluR5 Receptors
Cytosolic Calcium Studies with Stably Transfected Cells:
Chinese hamster ovary cells (CHO-K1 cells), stably transfected for inducible expression of a human metabotropic glutamate receptor mGluR5, are seeded into black clear bottom 96 well plates at a density of 35.000 cells per well. The standard growth medium used (Dulbecco's modified Eagle Medium, DMEM plus L-proline) contains the appropriate inducer isopropyl-β-D-thiogalactopyranosid (IPTG) to achieve optimal receptor expression. One day after seeding the growth medium is exchanged for reconstituted Ca-Kit (Molecular Devices, USA) and incubated for one hour. Ca-Kit is reconstituted in an assay buffer containing 20 mM HEPES pH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS). Agonistic compounds to the receptor elicit increases in cytosolic calcium which can be measured as increases in fluorescence signals by use of a fluorescence imaging plate reader (Molecular Devices). To analyze their potency to modulate the Ca-response test compounds, dissolved in a final DMSO concentration of 0.5%, are added on-line 5 minutes before the agonist to the receptor (L-quisqualic acid at a concentration giving ˜80% of the maximal signal).
Astrocyte Culture:
Primary astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3):97-105). Briefly, Sprague-Dawley rat pups (2-4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (pore size 80 μm) and carefully triturated. The cell suspension is plated on poly-D-lysine pre-coated flasks (Costar, Netherlands) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) supplemented with 10% foetal calf serum (FCS, Sigma, Germany), 4 mM glutamine and 50 μg/ml gentamycin (both Biochrom, Germany) at 37° C. in a humidified atmosphere of 5% CO2/95% air for 7 d with exchanging the medium at day 2 and 6.
After 7 days in vitro (DIV), cells are shaken overnight at 250 rpm to remove oligodendrocytes and microglia. The next day, astrocytes are rinsed twice with CMF-PBS (calcium- and magnesium-free phosphate buffered saline, Biochrom, Germany), trypsinized and subplated on poly-D-lysine pre-coated 96-well plates (Greiner, Germany) at a density of 40,000 cells/well. 24 h after establishing the secondary culture the astrocytes are rinsed with PBS++ (phosphate buffered saline, Biochrom, Germany), and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1×G5-supplement (Invitrogen, Germany), 0.5 μg/ml heparan sulfate, and 1.5 μg/ml fibronectin (both Sigma, Germany) (Miller et al., (1993) Brain Res. 618(1):175-8). 3 d later the medium is exchanged and the cells incubated for another 2-3 d, so that at the time of experiments astrocytes are 14-15 DIV.
Immunocytochemistry
Immunostaining is performed to confirm the presence of astrocytic markers such as the glial fibrillary acidic protein (GFAP) as well as to monitor the expression of mGluR5 receptors.
Cytosolic Calcium Studies with Astrocytes:
The increase of cytosolic calcium after stimulation with the mGluR5 agonist L-quisqualate is measured using a fluorometric imaging plate reader (FLIPR) and the Ca-Kit (both Molecular Devices). Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 μl of loading buffer consisting of Ca-sensitive dye reconstituted in sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, plates are transferred to FLIPR to detect calcium increase with the addition of L-quisqualate (100 nM) measured as relative fluorescence units (RFU). If antagonists are tested, these compounds are pre-incubated for 10 minutes at RT before addition of the respective agonist.
For positive modulators, concentration-response curves for quisqualate are performed in the presence and absence of 10 μM modulator to determine the extent of potentiation/agonist potency increase. Thereafter, concentration-response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM).
Data Analysis
The fluorescence signal increase after addition of agonist reflects the increase of cytosolic calcium. Inconsistencies in the amount of cells per well are normalised by using the spatial uniformity correction of the FLIPR software. The mean of replicated temporal data (n=3-5) is calculated and used for graphical representation. For the evaluation of the pharmacology, the calcium changes in response to different concentrations of agonist or antagonist are determined using a maximum minus minimum (MaxMin) calculation.
All responses (RFU-values) are determined as percentage of control (=maximum response). EC50 and IC50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0 (GraphPad Software, USA). The compounds of the present invention have a potency (IC50) within a range of about 0.5 nM to about 100 μM.
Results for representative compounds of the invention are shown in Tables A1-A3.
In conclusion, from the foregoing, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions.
The instant compounds of formula (I) represent a novel class of mGluR5 modulators. In view of their potency, they will be useful therapeutics in a wide range of disorders, in particular CNS disorders, which involve excessive glutamate induced excitation.
These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement.
Neuroprotection as well as cognitive enhancement can also be achieved by combining application of these compounds with NMDA receptor antagonists like Memantine and Neramexane.
The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
| Number | Date | Country | |
|---|---|---|---|
| 60835820 | Aug 2006 | US | |
| 60877544 | Dec 2006 | US |
